Cancer Radiation Therapy

Cancer Radiation Therapy

1 Introduction

Summary and Quick Facts

  • Along with surgery and chemotherapy, radiation therapy is one of the most important methods of cancer treatment. About half of all cancer patients receive radiotherapy during the course of their treatment.
  • The aim of this protocol is to empower cancer patients and their families with knowledge about basic principles of radiation therapy and strategies to optimize radiation therapy response. Readers will also learn strategies to protect healthy cells from the damaging effects of radiation therapy without interfering with the cancer-killing efficacy of radiotherapy.
  • New methods of delivering radiotherapy aim to increase precision and minimize damage to healthy tissue. Radiotherapy techniques continue to improve quality of life and survival in many cancer patients.

Cancer radiation therapy, or radiotherapy, involves precisely delivering high-energy radiation to kill cancer cells and shrink tumors. Along with surgery and chemotherapy, radiation therapy is one of the most important methods of cancer treatment. About half of all cancer patients receive radiotherapy during the course of their treatment (NCI 2010; Orth 2014; NCI 2015).

One of the central challenges with radiotherapy is that it is difficult to administer radiation only to cancer cells. Radiation can also damage healthy cells near the tumor. Damage to normal cells causes side effects and limits the amount of radiation a patient can tolerate.

New methods of delivering radiotherapy aim to increase precision and minimize damage to healthy tissue. Promising emerging techniques include intensity-modulated radiation therapy, proton therapy, and CyberKnife therapy. These technologically advanced forms of radiotherapy cause less damage to normal tissue because the radiation can be focused more accurately on the tumor (Baskar 2012; Bucci 2005; NCI 2010; Bast 2000). Researchers are also developing methods, such as therapeutic hyperthermia, to make cancer cells more sensitive to radiation (Rycaj 2014; Ogawa, Yoshioka 2013; Peeken 2017).

Despite potentially serious side effects, radiation is a fundamental aspect of cancer treatment (Kaliberov 2012; Baskar 2014; Kaur 2011). Fortunately, several natural interventions have been shown to offset some of these side effects when used in conjunction with radiotherapy. For instance, probiotics may ease radiation-induced diarrhea (Delia 2007; Liu, Li 2017), Boswellia serrata may help brain swelling (Kirste 2011), cranberry may alleviate bladder inflammation (Hamilton 2015; Bonetta 2012), and Calendula officinalis may ease skin burns caused by radiation (Pommier 2004). Also, some natural products such as genistein found in soy, curcumin from the culinary herb turmeric, and resveratrol found in grapes and Japanese knotweed (Sebastia 2014) may help sensitize cancer cells to radiation.

The aim of this protocol is to empower cancer patients and their families with knowledge about basic principles of radiation therapy and strategies to optimize radiation therapy response. Readers will also learn strategies to protect healthy cells from the damaging effects of radiation therapy without interfering with the cancer-killing efficacy of radiotherapy.

2 Background

Radiotherapy can be used with several aims in cancer therapy. These include shrinking early-stage tumors, preventing cancer recurrence in specific locations, and minimizing symptoms. Although radiation is directed at the tumor, non-cancerous tissues surrounding the tumor will inevitably be affected as well. A key goal of radiotherapy is maximizing the dose of radiation to tumor cells while minimizing the dose to healthy cells, thus limiting unwanted side effects. Radiation therapy is often combined with surgery, chemotherapy, or immunotherapy to treat cancer (Baskar 2012; Trikalinos 2009b; NCI 2010; ACS 2014a).

How Radiation Kills Cancer Cells

Radiotherapy uses high-energy radiation, usually x-rays, to destroy cancer cells. The radiation damages tumor cell DNA and disrupts cellular division. Radiation can also produce highly reactive molecules called free radicals that further damage the DNA of tumor cells. Cancer cells are usually more susceptible to the effects of radiation because they divide more rapidly than healthy cells. Healthy cells can usually repair radiation-induced damage faster than cancer cells (ACS 2014b; Baskar 2014).

Radiation therapy does not kill cancer cells right away. It takes hours, days, or even weeks of treatment before cancer cells begin to die. Cancer cells continue dying for weeks to months after radiation therapy ends. This delayed effect applies to healthy cells too, which can explain why some side effects take time to manifest. Rapidly dividing cells, such as those of the skin, bone marrow, and intestinal lining, are often the first to show signs of damage. Slower-dividing cells, such as those from the brain and spinal cord, are more susceptible to later effects (ACS 2014a; Baskar 2012; Chapel 2013; Akita 2014; Prasanna 2012).

Radiation Therapy Dose Fractioning

Radiation therapy is often administered as several treatments over time. Treatment sessions are called “fractions.” This dosing strategy is necessary to maximize effectiveness and minimize damage to normal tissues. Fractionated radiotherapy gives normal cells time to recover from radiation-induced damage between each radiation session (Baskar 2012; Schreiber 2013; Trikalinos 2009b). Another benefit is that fractionation increases the likelihood that cancer cells will be exposed to radiation at the points in the cell cycle when they are most susceptible to DNA damage (Schreiber 2013). Also, tumor tissue that may have been oxygen-depleted (hypoxic) can re-oxygenate between fractions. This can increase the likelihood that radiation will kill tumor cells during the next treatment session because the presence of oxygen increases production of cell-killing free radicals (Joiner 2009).

In most patients, fractionation typically entails therapy five days a week for five to eight weeks, but the regimen depends on the unique situation of each patient (ACS 2017a). Different radiotherapy schedules may be used when five to eight weeks of treatment are inconvenient or an altered schedule may work better.

The Five R’s of Radiobiology

Many factors influence how tumors respond to radiation therapy. Knowledge of these factors can be helpful when planning cancer radiotherapy. A concept in radiation oncology, the five R’s of radiobiology, is a framework to better understand cellular characteristics that influence tumor response (Steel 1989; Pajonk 2010; Good 2013; Olbryt 2014; De Meerleer 2014; Blanco 2011; Stinauer 2011; Witkowska 2015; Cognetti 2008):

  1. Repair. Healthy and cancerous cells can repair the damage caused by radiation. This helps healthy cells, but contributes to treatment failure in cancer cells. Cancer cells in which DNA repair mechanisms have been disrupted may be more susceptible to the effects of radiation. This is the basis for therapeutic DNA repair inhibitors used in cancer treatment in some cases.
  2. Redistribution. Most cells, including cancer cells, go through a replication process called the cell cycle. Cells are least sensitive to radiation when they are replicating their DNA for the new cell (S-phase) and most sensitive when they are actively dividing into two cells (mitosis). Since cells progress through all phases of the cell cycle, giving radiation in fractionated doses increases the likelihood that cancer cells in the radio-resistant S-phase during one radiotherapy session will be in the sensitive phase during a subsequent session.
  3. Repopulation. Between radiotherapy doses, viable cells—healthy and malignant—divide and repopulate. Healthy cell repopulation is desirable, but cancer cell repopulation can lead to treatment failure. Long breaks between radiation treatments can cause cancer cell repopulation. This is one reason why adhering to a planned radiotherapy fractionation schedule is so important.
  4. Reoxygenation. The presence of oxygen in tumor cells increases their sensitivity to radiation. The oxygen reacts with radiation to produce cell-killing free radicals. Lack of oxygen, or hypoxia, in tumor cells has been associated with poor treatment prognosis. Radiotherapy, especially large doses, causes a tumor to become hypoxic. Tumors must be allowed to re-oxygenate between radiation fractions to avoid irradiating radio-resistant hypoxic cells. Reoxygenation can take from hours to several days.
  5. Radiosensitivity. Some cancers are naturally more susceptible to the effects of radiation than others. Renal cell carcinomas and melanomas, for example, are often more radioresistant than other cancers. Hodgkin’s lymphoma and head and neck carcinomas tend to be highly radiosensitive.

The five R’s provide a basis for understanding the success or failure of radiation therapy and for developing strategies to target cancer cells (Pajonk 2010; Joiner 2009). These concepts are discussed throughout this protocol, and there are many natural and pharmaceutical agents that can help overcome one or more of these biological challenges when combined with radiotherapy.

3 Methods Of Radiation Administration

Radiation therapy can be administered via several methods including external beam radiation, brachytherapy or internal radiation, and radiopharmaceuticals or systemic radiotherapy (ACS 2014a).

External Beam Radiation Therapy

External beam radiation therapy (EBRT) is the most widely used method of radiation therapy. A machine called a linear accelerator (LINAC) is used to deliver the radiation beam to the tumor (ACS 2014a). Techniques to specifically target the tumor and spare healthy tissue have improved over time; however, healthy tissue damage continues to be a problematic side effect of EBRT. Strategies for managing these side effects are discussed at length in the “Preventing Damage to Healthy Tissue” section.

EBRT can be delivered in various ways:

  • Three-dimensional conformal radiation therapy (3D-CRT) uses imaging computers to precisely map the location of a tumor in three dimensions (ACS 2014a; Gupta 2012) and is the main form of EBRT used in clinics around the world (Purdy 2008). By targeting the radiation precisely to the tumor, doctors reduce radiation damage to normal tissues (ACS 2014a).
  • Intensity-modulated radiation therapy (IMRT) is similar to 3D-CRT. However, IMRT changes the strength of the radiation beam in some areas, increasing it over certain regions of the tumor. This reduces the risk of damage to nearby healthy tissue (ACS 2014a; Purdy 2008; Schild 2017).
  • Image-guided radiation therapy (IGRT) combines radiation with an imaging scanner, allowing the doctor to see if minor adjustments are necessary just prior to administering radiation (ACS 2014a; Purdy 2008; Mahase 2015).
  • Intraoperative radiation therapy (IORT) is external radiation that is delivered to the tumor during a surgical procedure and is especially applicable to cancers deep inside the body (ACS 2014a; Dutta 2017).
  • Stereotactic radiosurgery (SRS) delivers a large dose of radiation to a small tumor, usually in the brain or within the skull, and no surgery is involved (ACS 2014a). Stereotactic body radiation therapy (SBRT) uses this technique in other parts of the body including the spine, liver, and lung (ACS 2014a; Baliga 2017). SRS and SBRT use a machine called a Gamma Knife, which delivers multiple beams from many different angles. Other machines, including CyberKnife or X-Knife, combine advanced cameras to locate the tumor’s position in the body and robotics to deliver highly focused beams of radiation at the tumor. All these technologies aim at avoiding normal tissue (ACS 2014a).

Proton Beam Radiation Therapy

Proton beam radiation therapy, or “proton therapy,” is one of the most precise and sophisticated forms of external beam radiation therapy available (Thariat 2013; Foote 2012; DeLaney 2011; Wang 2015). Protons are subatomic particles that interact with the body’s tissues in unique ways due to their physical characteristics. The physical properties of proton beams allow the technician to better target and deliver high-intensity radiation selectively to tumor tissue compared with standard radiation therapy. Proton beam therapy can minimize damage to healthy tissue outside the tumor (DeLaney 2011; Foote 2012).

Standard external beam radiation therapy penetrates through the body, including healthy tissues. A high dose enters the body and then dissipates as it passes through and exits the body. In contrast, when a beam of protons enters the body, the protons deliver their energy as they approach their target, and then they stop moving. Thus, the radiation dose to healthy tissue is minimized, and side effects are decreased (Foote 2012; DeLaney 2011; Liu, Chang 2011; NAPT 2015; MDACC 2015). Proton therapy, due to its targeted delivery, allows for about 60% lower total radiation dose than other forms of external beam photon radiation (DeLaney 2011).

Proton therapy is appropriate for patients with solid tumors that have defined borders, as it is delivered as a precise beam to a specific area (MDACC 2015; ASCO 2015). According to the American Society of Clinical Oncology, cancers currently treated with proton therapy include (ASCO 2015):

  • Certain brain cancers
  • Melanoma of the eye
  • Head and neck cancers
  • Lung cancer
  • Liver cancer
  • Prostate cancer
  • Spinal and pelvic sarcomas

As of 2017, there are over 50 operating proton treatment centers worldwide, with more than 50 additional facilities in building or planning stages (Wikipedia 2017; Trikalinos 2009a).

Brachytherapy or Internal Radiation

Brachytherapy involves the insertion of radioactive materials into the body around or within the tumor. Devices such as small pellets, wires, capsules, or tubes that emit radiation are inserted either temporarily or permanently. Radiation is delivered to the interior of the tumor (ACS 2014a; Tanderup 2017). In some cases, imaging techniques are used to guide placement of a brachytherapy device (Wang, Tang 2017; Tanderup 2017; Yoshida 2017).

Brachytherapy is increasingly used to treat prostate cancer (Heysek 2007), but is also used for cervical, uterine, breast, head and neck, and skin cancers, and several other cancers (Lukens 2014; Lloyd 2017; Wang, Tang 2017; Tanderup 2017; Yoshida 2017). Radioembolization is a technique used for liver cancer in which radioactive beads called microspheres are injected into the artery feeding the tumor (ACS 2014a; Kishore 2017).

Brachytherapy implants may stay in place for minutes to days, or in some cases, permanently. The intensity of the radiation emitted by the implanted device can also vary according to the needs of each patient (ACS 2017b).

Systemic Radiotherapy

Radiopharmaceuticals are drugs that contain radioactive isotopes. They are administered orally or intravenously. Radiopharmaceuticals can be used therapeutically to treat cancer and as tracers for imaging tests to determine the location of a tumor. Strontium 89 (Metastron), samarium 153 (Quadramet), and radium 223 (Xofigo) are used to treat bone metastases, including those from breast and prostate cancers (Heianna 2014; Thapa 2015; Nilsson 2015; Body 2015; Humm 2015; Jong 2016; Florimonte 2016; Choudhury 2012). Iodine 131 is used to treat thyroid cancer (Fard-Esfahani 2014).

Radioimmunotherapy uses drugs called monoclonal antibodies attached to a radioactive isotope. These antibodies target molecules on cancer cell surfaces, delivering their radioactive payload to the malignant cells (Kawashima 2014). Radioimmunotherapy showed promise in treating non-Hodgkin B-cell lymphoma, but has not proven to be as effective for solid tumors (Kawashima 2014; Kraeber-Bodere 2014; Rizzieri 2016). One important side effect observed with some radioimmunotherapy products included a temporary drop in white blood cell and platelet count (Ghobrial 2004).

Approved Radioprotective Medications

Two drugs are approved for protection against radiation damage and minimization of side effects of radiotherapy (Hall 2016; Panjwani 2013).

Amifostine (Ethyol) is a synthetic antioxidant initially developed to protect against radiation in the event of nuclear warfare (Gu, Zhu 2014; Okunieff 2008). This FDA-approved drug reduces the incidence of moderate-to-severe xerostomia (dry mouth) in people with head and neck cancer who are undergoing radiation treatment (MedImmune 2007). Amifostine also reduces the incidence of mouth sores and difficulty swallowing (Gu, Zhu 2014). Amifostine reduces side effects such as dermatitis, lower gastrointestinal mucositis, esophagitis, and pneumonitis in patients treated with radiation therapy (Kouvaris 2007). Importantly, amifostine does not protect the tumor against the toxic effects of radiotherapy and does not reduce survival. Amifostine may cause nausea, vomiting, transient hypotension, or allergic reactions, which limit its use (Gu, Zhu 2014; Kamran 2016).

Palifermin (Kepivance) is an injectable recombinant human growth factor (Lauritano 2014). Palifermin was approved by the FDA in 2004 for certain cancer patients who develop severe oral mucositis as a result of radiation or chemotherapy treatment (Blijlevens 2007; Lucchese 2016; Nooka 2014; Peterson 2010). In clinical trials, the most important adverse effects from palifermin included rashes, itching, and skin-related swelling (NCI 2013; Gold Standard 2016).

4 Novel And Emerging Strategies To Optimize Radiotherapy Response

Radiotherapy techniques continue to improve quality of life and survival in many cancer patients (Baskar 2012). Moreover, scientists are trying to further improve response rates by combining radiation therapy with chemotherapy, molecular-targeted agents, immunotherapy, and surgery (Thariat 2013; Weichselbaum 2017; Kma 2013; Espenel 2017). There are a number of active research avenues in this area.

Personalized Medicine

Personalized medicine is a rapidly emerging field. The goal of personalized medicine is to treat patients based on their own unique genetic makeup and tumor characteristics, rather than use a standard “one-size-fits-all” approach (Streeter 2017; Coyle 2017). An emerging trend in personalized radiation oncology is to emphasize the patient’s satisfaction with outcomes rather than solely objective clinical criteria. Also, empowering the cancer patient to be actively involved in his or her treatment decisions is being recognized as an important part of successful treatment. Radiotherapy is an involved and arduous journey for patients, and objectifying treatment success based solely on clinical outcomes may not fully reflect the patient’s experience. Some researchers in this area suggest that even contemporary clinical trial design may benefit by focusing on patient-reported outcomes as primary outcomes rather than clinical criteria. This burgeoning trend in radiation oncology may translate into improved patient experiences and ultimately better quality of life for those undergoing treatment (Berman 2016).

Genetic Analysis

Ongoing research is evaluating genetic characteristics that may make a person’s cancer more or less susceptible to the tumor-killing effects or side effects of radiation therapy. This information may someday help doctors design a treatment strategy customized for each patient (Guo 2015; Kerns 2014; Proud 2014; West 2011; Orth 2014; Danielsson 2014; Weichselbaum 2008).

One intriguing development in personalized medicine, in the context of radiotherapy, is a ten-gene signature index called the genomic-adjusted radiation dose (GARD). This index successfully predicts radiosensitivity and prognosis in multiple cancer types, including head and neck, rectal, esophageal, breast, and colon cancers (Eschrich 2009; Eschrich 2012; Ahmed, Fulp 2015; Ahmed, Chinnaiyan 2015; Scott 2017). Also, the GARD radiosensitivity index was found to correlate with overall survival in glioblastoma (Ahmed, Chinnaiyan 2015). In a 2017 study, the index was measured in over 8,000 tumor samples from patients treated with radiation. The index independently predicted patient outcome in breast cancer, pancreatic cancer, glioblastoma, and lung cancer (Scott 2017). One surprising finding using this technology is that radiosensitivity differs by metastatic site in colon cancer. Metastases in ovaries were the most radioresistant, and lymph node metastases were the most radiosensitive (Ahmed, Fulp 2015). Future research will attempt to confirm the value of this index in clinical trials and examine how the index correlates with cellular and molecular aspects of the tumor.

Hypoxia-Modifying Treatments

Low oxygen levels (hypoxia) in tumor tissue have been associated with increased risk of metastasis and recurrence in several types of cancer. Radiation cannot kill cancer cells as effectively when oxygen levels are low because free radical production depends on oxygen (Harrison 2004). Decreased blood oxygen levels can increase the acquisition of mutations, resistance to cell death, and growth of new blood vessels that provide nutrition to the tumor (Gaspar 2015). Tumor oxygen levels can be measured by oxygen electrode measurements, tissue and blood markers, imaging techniques, and gene expression profiling (Peters 2012).

A number of chemical agents have been designed to sensitize hypoxic cells to radiation by mimicking oxygen. Preclinical results have been promising, but high toxicity and low effectiveness in patients have limited use of these agents (Kaanders 2004). However, one agent, nimorazole (Naxogin), has been shown to improve outcomes in studies of radiation for head and neck cancers (Peters 2012; Bentzen 2015; Joiner 2009). Another compound that has attracted considerable interest is tirapazamine. It shows limited toxicity towards oxygen-replete cells, but under low oxygen conditions increases radiation damage in cancers. Researchers proposed that selecting patients with hypoxic tumors using positron emission tomography (PET) imaging prior to treatment may help identify those who would be most responsive to tirapazamine (Joiner 2009). Other researchers have established gene signatures that can predict the response of patients to hypoxia-modifying treatment (Yang, Taylor 2017).

A hypoxia-modifying therapy intended to both reduce hypoxia and prevent tumor cell repopulation has been the subject of several preclinical and clinical studies (Kaanders 2002). This therapy, which uses a mixture of oxygen and carbon dioxide (known as carbogen gas) in combination with nicotinamide (a form of the B vitamin niacin), provided benefits in early clinical trials for bladder and head and neck cancers (Kaanders 2002; Hoskin 2010). In 2015, a randomized clinical trial in laryngeal cancer, comparing radiotherapy with and without this combination, showed that this therapy decreased the risk of metastases (Rademakers 2015; Eustace 2013).

A meta-analysis confirmed that hypoxia-modifying treatments improved survival of patients with squamous cell carcinoma of the head and neck. The treatments included normobaric oxygen (oxygen given at normal pressure), carbogen gas breathing, hyperbaric oxygen, and hypoxic radiosensitizing medications (Overgaard 2011).

Hyperbaric Oxygen Therapy (HBOT)

Hyperbaric oxygen is a therapy in which the patient, while in a sealed pressurized chamber, breathes pure oxygen. This saturates hemoglobin, the oxygen-carrying molecule in red blood cells, with oxygen (ACS 2014a; Latham 2014). Hyperbaric oxygen has been studied in clinical trials for radiosensitization of tumor cells, and it was proposed to help the healing of tissues and prevent problems that may occur after surgery (Bennett 2016; Bennett 2012; Hampson 2012). HBOT for normal tissue healing will be discussed further in the “Preventing Damage to Healthy Tissue” section.

A systematic review concluded that there is some evidence that HBOT can improve local tumor control, decrease local recurrences, and increase survival for patients with head and neck cancers. Patients with uterine cancer may also benefit. Potential adverse effects included radiation tissue injury and oxygen toxicity seizures (Bennett 2012). Some studies have found HBOT given immediately before radiotherapy, rather than at the same time, to be safe and effective for high-grade gliomas. This approach may also protect normal tissues from radiation injury (Ogawa, Kohshi 2013; Stepien 2016).

Immunotherapy

Early in tumor development, a patient’s immune system can effectively recognize tumor cells and destroy them. However, later on, tumors develop ways to avoid detection by the immune system (Mittal 2014). Immunotherapy is a rapidly developing and exciting approach to cancer treatment. Immunotherapies are designed to tip the balance in favor of the patient’s immune system, so even well-established tumors can be shrunk or destroyed (D'Errico 2017).

Combining immunotherapy with radiation therapy is an emerging approach in cancer management (Weichselbaum 2017). Immune activation is believed to contribute to the effectiveness of radiation therapy. In some patients, radiation to a very localized region has resulted in regression of tumors in other regions of the body. Researchers have hypothesized that this observation, called the abscopal effect, occurs when radiotherapy triggers an immune response to the tumor. Radiation therapy is thought to act as an immune modulator, and cause the release of molecules that, together with molecules released from dead cells, stimulate the immune system (Hu, McArthur 2017).

One of the most promising types of immunotherapy is a group of drugs called checkpoint inhibitors. These drugs remove the “brakes” from immune system cells to allow them to fight the tumor (Menon 2016). In mice, checkpoint inhibitors and radiation therapy synergistically increased the number and activity of tumor cell-killing immune cells (Deng 2014) while in another study the combination prolonged survival (Zeng 2013).

As of mid-2017, almost 100 clinical trials in humans have been registered to test combinations of radiotherapy and checkpoint inhibitors, and laboratory studies have been critical in helping understand the promises of this approach (Schaue 2017). The abscopal effect has been noted in several patients being treated with a checkpoint inhibitor called ipilimumab (Yervoy) at the time of radiotherapy (Postow 2012; Chandra 2015). In one trial of the checkpoint inhibitor pembrolizumab (Keytruda) in non-small cell lung cancer, patients treated with radiation therapy before pembrolizumab survived approximately twice as long on average as those who had not received radiation therapy (Shaverdian 2017). Several success stories in individual patients have recently been published (Nagasaka 2016; Haymaker 2017). More information about immunotherapy is available in the Cancer Immunotherapy protocol.

Hyperthermia

Hyperthermia treatment involves heating the tumor as high as 113°F to activate cellular destruction mechanisms (Lutgens 2010; Rao 2010). The effectiveness of hyperthermia treatment greatly depends on how hot the tumor becomes and for how long (ACS 2016a). Conventional techniques for induction of hyperthermia are ultrasound, microwaves, and infrared radiation. Hyperthermia can be induced locally, by external or internal energy sources; regionally, by perfusion of organs or limbs or by irrigation of body cavities; and systemically, with whole-body hyperthermia (Ahmed 2013). However, each of these methods suffers from limitations. The heat might not penetrate the tumor or the healthy tissue might get too hot.

Randomized trials have demonstrated benefit, including improved survival, with the addition of hyperthermia to radiation therapy in the treatment of many different cancers. Hyperthermia sensitizes tumors to radiation by increasing blood flow and tumor oxygenation and activating tumor cell death pathways (Hurwitz 2014). Utilizing hyperthermia as a radiosensitizer reduces the dose of radiation required to fight the tumor (Zagar 2010).

In a 2017 meta-analysis of 19 randomized controlled trials evaluating the addition of hyperthermia to chemoradiation to treat esophageal cancer, 5-year survival was significantly higher in patients treated with hyperthermia (Hu, Li 2017). In a group of patients with superficial breast cancer and chest wall recurrence, the addition of hyperthermia to radiotherapy increased the eradication of the local tumor, and participants experienced a modest increase in toxicity that was self-limited (Zagar 2010). Intracavity hyperthermia increased the 5-year overall survival of patients with nasopharyngeal cancer treated with radiation therapy from 70.3% to 78.2% (Hua 2011). Hyperthermia may prolong life expectancies of patients with pancreatic cancer while maintaining quality of life (Roesch 2015).

Aspirin, Statins, and Metformin as Radiotherapy Adjuncts

The repurposing of existing drugs as radiotherapy adjuvants is an exciting area in radiation oncology research. Drugs under investigation in this way include statins (cholesterol-lowering drugs), aspirin, and metformin (an antidiabetic glucose-lowering drug). It is thought that these drugs have the potential to sensitize tumor cells to radiation therapy (Gash 2017).

Statins. There is increasing evidence that statin use is associated with protection against colorectal cancer and increased survival in cancer patients. Through their inhibitory effects on the cholesterol synthesis pathway, statins appear to reduce proliferation, increase apoptosis (programmed cell death), and prevent invasion and metastasis of colorectal cancer cells. In addition, simvastatin (Zocor) was found to enhance the effect of radiation on cultured colorectal cancer cells in a laboratory study (Gash 2017).

One study examined data from 349 rectal cancer patients, 33 of whom were taking statins. Statin use was associated with a four-fold increased rate of pathologic complete response to neoadjuvant chemo-radiotherapy, which was defined as no microscopic evidence of the cancer. Interestingly, this beneficial effect appeared to be blunted by regular use of non-steroidal anti-inflammatory medication. Another study examined data from 407 rectal cancer patients, 99 of whom were taking statins. Patients receiving statin therapies had a significantly lower median tumor grade than patients not using statins (Mace 2013). A third study evaluated data from 885 rectal cancer patients, of whom 18% had a pathologic complete response to neoadjuvant chemo-radiotherapy, and found statin use at the time of the initial consult was a significant predictor of pathologic complete response (Armstrong 2015).

Aspirin. A number of studies have demonstrated a correlation between long-term low-dose aspirin use and reduced colorectal cancer risk and morality (Garcia-Albeniz 2011; Coyle 2016). Preclinical evidence suggests the anti-inflammatory and antiplatelet actions of aspirin may block cancer growth through several mechanisms, such as interfering with cancer stem cell activities, inhibiting inflammation in the tumor microenvironment, and modulating pathways linked to cancer cell survival, proliferation, and migration. Aspirin’s potential role as a radiation therapy adjunct has only begun to be explored (Gash 2017).

One study analyzed data from 241 rectal cancer patients, of whom 37 were taking aspirin. All aspirin users were taking 100 mg of aspirin daily as a cardiovascular disease prevention strategy. More aspirin users (67.6%) than non-users (43.6%) had a response to neoadjuvant chemo-radiotherapy that resulted in downgrading of their cancer stage. Also, more aspirin users than non-users (46% vs. 19%) had a good pathological response to treatment, resulting in cancer being detectable only in the rectal wall and without having spread to the lymph nodes. Aspirin use was further correlated with significantly better five-year progression-free survival (87% vs. 67%) and overall survival (91% vs. 73%) (Restivo 2015).

Three ongoing trials will help clarify the role of aspirin in the prevention and treatment of cancer more generally. These trials are the CAPP3 trial, testing aspirin in people with Lynch syndrome; the ASPREE trial, testing whether low-dose aspirin can reduce the risk of cancer, heart attack, stroke, or dementia in people 65 and older; and the Add-Aspirin trial, which will test different doses of aspirin in people who have undergone surgery for early-stage breast, colorectal, prostate, or esophageal cancer.

Metformin. Epidemiological research suggests metformin reduces the risk of several types of cancer. The anticancer properties may be related to regulation of tumor cell pathways linked to growth inhibition and induction of apoptosis. Laboratory studies in colorectal cancer cells also indicate metformin’s potential role as a radio-sensitizing agent (Gash 2017).

One study included 422 non-diabetics, 40 diabetics not taking metformin, and 20 diabetics taking metformin. Pathologic complete response rates were highest in diabetic patients taking metformin (35%), followed by non-diabetics (16.6%), and lowest in diabetics not taking metformin (7.5%). Metformin use, compared with non-use, in diabetics was associated with higher disease-free and overall survival rates at both five and 10 years. However, non-metformin-treated diabetics had a slightly larger average tumor size prior to chemo-radiotherapy than the other two groups, which may have influenced the findings (Skinner 2013). A second study, on patients with rectal cancer, evaluated 472 non-diabetics, 29 diabetics not taking metformin, and 42 diabetics taking metformin. Although survival rates were not significantly different between groups, metformin-treated diabetics had higher response rates to neoadjuvant chemo-radiotherapy, as indicated by greater improvement in lymph node status and tumor regression (Oh 2016).

5 Natural Interventions For Improving Radiation Sensitivity

This section summarizes data identifying radioprotective properties of a variety of natural compounds. Table 1, later in this section, summarizes human data on specific natural interventions shown to improve outcomes when used along with radiotherapy.

Curcumin is extracted from the spice turmeric (Curcuma longa) and has been extensively studied for its radiosensitizing properties (Verma 2016). In laboratory studies, curcumin sensitized multiple types of cancer cells to radiation (Qiao 2013). In prostate cancer cell lines, curcumin was a potent radiosensitizer that overcame the effects of radiation-induced pro-survival gene expression (Chendil 2004). In head and neck squamous cell cancer cell lines, curcumin arrested cells in the mitosis phase of cell division, which is the phase where cells are most susceptible to the effects of radiation (Wilken 2011). In colorectal cancer cell lines, curcumin led to an improved antitumor effect by blocking the pro-survival protein complex nuclear factor kappa B (NF-κB) that may be responsible for radioresistance (Sandur 2009). Similarly, in breast cancer cell lines, curcumin blocked NF-κB and was able to overcome hypoxia, thus sensitizing breast cancer cells to the antitumor effect of radiation (Aravindan 2013).

Resveratrol, found in grapes, blueberries, red wine and Japanese knotweed, among other plant sources, is a polyphenol with anti-inflammatory properties. Resveratrol has been shown to control cell proliferation, angiogenesis, and cancer cell death (Borriello 2014; Kma 2013; Dobrzynska 2013). In a cell-line study in radioresistant melanoma cells, resveratrol enhanced radiosensitivity, reduced proliferation, and increased cell death (Fang 2013). A similar effect was observed in a study of a radioresistant prostate cancer cell line treated with resveratrol and radiation (Fang 2012). Other similar cell-line studies have confirmed favorable radiosensitizing effects with the addition of resveratrol (Dobrzynska 2013; Kma 2013; Luo 2013; Tan 2017).

A study was performed in which mice were injected with glioblastoma multiforme cells. This type of brain cancer is inherently resistant to radiation. Results showed the glioblastoma cells pretreated with resveratrol were more sensitive to radiation. The tumors that formed were smaller than those formed from cells that were not pretreated. The mice receiving the cells pretreated with resveratrol survived longer (Yang 2012; Kma 2013). This result was confirmed in a more recent study (Wang, Long 2015).

The marker CD133 has been used extensively to identify cancer stem cells, which are very resistant to treatment with radiation therapy (Wu 2009). A study in which mice were injected with resveratrol-treated CD133-positive atypical teratoid/rhabdoid cells (a rare type of tumor) in combination with radiation showed enhanced survival in mice. Researchers concluded that resveratrol was an effective radiosensitizer in this radioresistant form of cancer (Kao 2009). In a separate study, researchers found decreased CD133 expression in radioresistant glioblastoma cells treated with resveratrol (Wang, Long 2015).

Quercetin is a flavonoid from plants with radiosensitizing effects in medulloblastoma, breast, cervical, and colorectal cancer cell lines (Lagerweij 2016; Malik 2016). In a mouse study on colorectal cancer, tumor growth was significantly slowed in mice treated with quercetin, and the DNA repair mechanism was compromised in tumor cells (Lin 2012).

Genistein is an isoflavone from soy that enhanced the effects of radiation in prostate, cervical, and estrogen receptor-positive and estrogen receptor-negative breast cancer cell line studies (Mahmoud 2014; Liu 2013; Zhang 2006; Malik 2016). Genistein inhibited growth of colon cancer cells when combined with radiation by decreasing epidermal growth factor receptor (EGFR) activation. EGFR activation results in multiple signaling cascades related to cancer cell growth and metastasis, and overactive EGFR is associated with a worse prognosis (Gruca 2014).

A constituent from the plant Panax ginseng sensitized non-small cell lung cancer cells to radiation (Wang, Li 2015), while a Panax ginseng extract protected against radiation-induced liver injury (Kim 2017). Zerumbone, a constituent of ginger (Zingiber officinale), sensitized colorectal cancer cells to radiation (Deorukhkar 2015).

Ashwagandha (Withania somnifera) is a plant with anti-inflammatory, immune-modulating, anti-stress, and antitumor effects (Winters 2006; Marlow 2017; Lee 2016; Wadhwa 2016). Ashwagandha acted as a radiosensitizer in studies in renal cancer, melanoma, and lymphoma cell lines (Yang 2011b; Kalthur 2010; Yang 2011a; Abdallah 2016). In a study of mice bearing melanoma tumors, there was an at least 50% decrease in tumor size in 62.5% of the animals after treatment with radiation therapy, ashwagandha (15 mg/kg injected five days/week for three weeks), and local hyperthermia (Kalthur 2010). In another rodent study, radioresistant mouse melanoma cells or radiosensitive fibrosarcoma cells were implanted into mice. The mice were then treated with a combination of radiation, hyperthermia, and ashwagandha (40 mg/kg) one hour before radiation. A complete response was seen in 37% of mice with melanoma and 64% with fibrosarcoma. A complete response was defined as tumor regression with no regrowth at the site of the primary tumor for 120 days (Uma Devi 2003). These results are particularly encouraging because of the high rate of radioresistance in melanomas (Kalthur 2010).

An increasing number of studies have investigated the relationship between vitamin D3 levels and vitamin D receptor gene abnormalities and certain cancers, including colorectal, breast, and other cancers (Ordonez Mena 2014). Vitamin D3 has also been studied for its radiosensitizing properties. Vitamin D3 radiosensitized breast cancer cells intrinsically resistant to radiation (Bristol 2012; Wilson 2011), non-small cell lung cancer cells (Sharma 2014), and colorectal cancer cells (Sharma 2014; Findlay 2014). One proposed mechanism for this effect is a process called autophagy, in which the cell degrades its own contents to generate energy and metabolic precursors in response to stress (Bristol 2012; Sharma 2014; Gewirtz 2007). In an aggressive breast (Mineva 2009) and prostate tumor cell line (Xu 2007), vitamin D3 improved radiosensitivity by decreasing gene expression of RELB, a gene that promotes survival in tumor cells by protecting them from radiation.

Epigallocatechin gallate (EGCG) is a component of green tea. A study was conducted on the effects of EGCG during radiation in 10 patients with locally advanced breast cancer. Five patients received 400 mg EGCG three times daily plus radiotherapy, and five received radiotherapy alone. Patients taking EGCG had lower serum levels of VEGF, hepatocyte growth factor (HGF), and metalloproteinases 2 and 9 (MMP-2/MMP-9), all factors associated with tumor progression and metastasis. Serum from patients taking EGCG was applied to cells from a highly metastatic breast cancer cell line. The serum decreased the proliferation of the cancer cells, increased apoptosis, and reduced activation of proteins involved in resistance to radiation (Zhang 2012). Another study examined the effects of EGCG on radiosensitization of human brain microvascular endothelial cells. Vascular endothelial cells are important in the formation of blood vessels by the tumor. In cells treated with EGCG and radiation, cell death was 5-fold higher than in cells treated with radiation alone (McLaughlin 2006).

Sulforaphane is a plant chemical found in broccoli (Brassica oleracea) and other cruciferous vegetables (eg, Brussels sprouts, cabbage, and cauliflower) (Kotowski 2011; Higdon 2016). When head and neck cancer cells were treated with sulforaphane and then irradiated, researchers observed that the combined therapy resulted in a stronger inhibition of cell proliferation than either treatment alone (Kotowski 2011). Additionally, sulforaphane enhanced the radiosensitivity of mouse osteosarcoma cells (Sawai 2013).

Cell line studies have found that eicosapentaenoic acid (EPA), an omega-3 fatty acid from fish and fish oil, sensitizes colorectal cancer and glioblastoma cells to radiation (Manda 2011; Benais-Pont 2006). Omega-3 fatty acids, particularly EPA and docosahexaenoic acid (DHA), have been shown to benefit people undergoing radiotherapy or chemotherapy, primarily by preserving body composition (de Aguiar Pastore Silva 2015).

A randomized controlled trial of Boswellia serrata extract in 44 patients receiving radiation for brain tumors found, on MRI examination, that the largest tumor of those in the Boswelliagroup was reduced in size by 88% after radiotherapy, while the largest tumor shrank by only 19% in the placebo group (Kirste 2011). Polysaccharide K (PSK), derived from the mushroom Coriolus versicolor, has been used in traditional Chinese medicine for hundreds of years (Standish 2008). A review of scientific research showed PSK in combination with standard radiation and chemotherapy for lung cancer prolonged survival, reduced tumor-related symptoms, and improved immune function (Fritz 2015). In a study of 187 patients with esophageal squamous cell carcinoma, 5-year survival was assessed for different treatment regimens: radiation therapy (40% survival), radiation therapy with PSK (42%), radiation therapy with chemotherapy (29%), or radiation therapy with chemotherapy and PSK (37%) (Ogoshi 1995). In another study, 90 patients with cervical cancer were treated with either radiation and 3 grams PSK or radiation alone. Sixty percent of patients in the PSK group had a response rated as “good,” but only 32% of the control group had a good response. Additionally, the PSK group had better immune system response throughout treatment (Kazuta 1985; Fritz 2015).

Radiation depletes nutrients such as pyridoxine (vitamin B6), and administration of pyridoxine can reverse the deficiency without side effects. A study in 210 women with stage II endometrial cancer randomized to receive 300 mg pyridoxine daily or no pyridoxine during radiation therapy showed 15% improved 5-year survival and improved tolerance to radiation in those taking pyridoxine. Improvements in nausea, vomiting, and diarrhea were also noted (Ladner 1988).


Table 1: Natural Agents Shown to Improve Radiotherapy Outcomes

Cancer Type

Natural Agent

Human Data

Lung

 

 

Astragalus (Astragalus membranaceus)

He 2013 – A meta-analysis including 29 randomized controlled trials on astragalus-based Chinese herbal medicine preparations in combination with radiotherapy for non-small cell lung cancer. Several of these studies showed reduced risk of death at up to three years. Twenty-six studies revealed enhanced tumor response. Multiple studies showed improved quality of life and amelioration of some radiotherapy side effects.

Alpha tocopherol (a form of vitamin E) plus pentoxifylline (a drug)

Misirlioglu 2006 – Sixty-six patients were randomized to receive either radiation alone (one group) or radiation together with 400 mg pentoxifylline three times daily and 300 mg alpha-tocopherol twice daily (the second group). One-year overall survival was 55% in the study group and 40% in the control group. Two-year survival was 30% in the study group and 14% in the control group. Progression-free survival rates also improved in the study group. Smokers should not take alpha-tocopherol during radiation therapy, as it can lead to worse outcomes (Meyer 2008).

Polysaccharide K (PSK)

Fritz 2015 – A review of the scientific literature on PSK combined with radiotherapy and chemotherapy showed improved 1-, 2-, and 5-year survival rates; improved immune function and blood cell function; and decreased fatigue, loss of appetite, and body weight.

Cervical

 

Polysaccharide K (PSK)

Kazuta 1985 – Ninety patients treated for cervical cancer received either 3 grams PSK with radiation therapy or radiation alone. Sixty percent of patients in the PSK group had a response rated as “good,” but only 32% of the control group had a good response.

Vitamin A

Basu 2016 – Several studies that examined interferon-alpha and retinoic acid (vitamin A) in combination with radiotherapy for the treatment of cervical cancer have found a better response to radiation in combination with interferon-alpha and retinoic acid than to radiation alone.

Esophageal

Polysaccharide K (PSK)

Ogoshi 1995 – Patients were randomly assigned to receive different therapies for esophageal squamous cell carcinoma and 5-year survival was assessed: radiation therapy (40% survival), radiation therapy plus PSK (42%), radiation therapy plus chemotherapy (29%), or radiation therapy plus chemotherapy and PSK (37%).

Glioblastoma

Melatonin

Lissoni 1996 – Melatonin (20 mg daily) was given to 30 patients during radiotherapy, until disease progression. One-year survival was significantly higher in the melatonin plus radiotherapy group (six of 14 patients) than the radiation alone group (one of 16 patients). Quality of life also improved in the melatonin group.

Endometrial

Pyridoxine (vitamin B6)

Ladner 1988 – Patients receiving radiation therapy were randomized to either receive vitamin B6 or not. There was a 15% improvement in the 5-year survival rate in those taking B6.

Bladder

Nicotinamide (a form of vitamin B3)

Hoskin 2010 – Patients receiving radiation for locally advanced bladder carcinoma who also received carbogen (2% CO2 and 98% O2) and nicotinamide had improvement in overall survival, decreased risk of death, and a reduced risk of local relapse compared with those receiving radiation alone.

Eustace 2013 – Patients with bladder cancer received either carbogen and nicotinamide during radiotherapy or radiotherapy alone. Those taking carbogen and nicotinamide with radiation, and showing tumor necrosis, had a 5-year overall survival of 56%. Only 34% of those receiving radiotherapy alone survived five years. Overall survival was not significantly improved in patients who did not have tissue necrosis (tissue death) at baseline.

Head and Neck

Zinc

Lin 2009 – In a double-blind study, patients with advanced (stages III and IV) nasopharyngeal carcinoma were randomized to receive chemoradiotherapy with either 75 mg zinc or placebo daily for two months. The zinc group experienced higher 5-year overall survival and less local recurrence.

Breast

Multivitamins and/or Nutrient Combinations

Lockwood 1994 – In patients undergoing standard treatment for high-risk breast cancer and receiving a combination of antioxidants, quality of life improved and some participants showed partial remission. No deaths occurred in the 24-month study period (statistically deaths were expected among high-risk populations). There was no sign of metastasis in the group receiving antioxidants.

Greenlee 2012 – Decreased risk of breast cancer recurrence was observed in patients taking vitamins C and E during radiotherapy compared with those not taking supplements. Decreased risk of all-cause mortality was observed in vitamin E users.

Kwan 2011 – Patients taking a multivitamin prior to diagnosis and throughout treatment with radiation had reduced recurrence of breast cancer and reduced total mortality.

Multiple Cancers (head and neck, cervical, esophageal, skin, Ewing’s sarcoma)

Ascorbic acid

Hanck 1988 – Patients taking 5 grams ascorbic acid five times daily throughout the entire course of radiotherapy experienced improved response to treatment. Disease-free survival after 6-month follow-up was 67% in the study group and 45% in the control group. The ascorbic acid group also had fewer side effects of radiation therapy.

Brain Metastasis

Omega-3 fatty acids

Gramaglia 1999 – Patients taking supplemental omega-3 fatty acids while being treated with stereotactic radiotherapy had improved survival time and decreased radionecrosis.

6 Antioxidants And Radiation Therapy

Antioxidants and Radiation Therapy: Ongoing Controversy

The use of nutrients with the capacity to neutralize free radicals (ie, antioxidants) during radiation therapy is controversial (Moss 2007). The main concern raised by radiation oncology researchers and practitioners is that antioxidants could protect cancer cells from the damaging effects of reactive oxygen species or oxidants, which are formed by radiation and are integral to the cancer-killing effect of radiation therapy (Yun 2017). This could result from the antioxidants directly scavenging reactive oxygen species or repairing cellular damage in tumor cells (Lawenda 2008; Nakayama 2011; Ozben 2014; D'Andrea 2005). While this may be true in theory, the biochemistry is much more complex. Vitamins and natural compounds classified as antioxidants also have additional biochemical and pharmacologic effects that may be beneficial for use with radiotherapy, as shown in multiple studies (Sagar 2005). Some authors take a conservative approach and recommend that high-dose antioxidants be avoided for patients undergoing treatment for cancer (Lawenda 2008; Simone 2007a) and that more human clinical trials be conducted to determine safety and efficacy of doses of individual and combination antioxidants (Simone 2008; Bhutani 2008). However, literature reviews have found, in the vast majority of studies examined, no evidence of reduced survival or treatment response with the use of dietary antioxidants in patients being treated for cancer. On the contrary, these same reviews identified substantial evidence for reduced treatment-related side effects with radiation therapy and chemotherapy (Block 2007; Block 2008; Block 2009; Simone 2007a; Simone 2007b; Moss 2007; Lamson 2000).

Synthetic prescription antioxidants such as amifostine, mesna (eg, Mesnex), and dexrazoxane (Zinecard) have been used with various chemotherapy and radiotherapy regimens with beneficial effects and no evidence of tumor protection in clinical studies (Moss 2007; Gu, Zhu 2014; Koukourakis 2003; Koukourakis 2013; Jiang 2015). Multiple commonly prescribed conventional medications possess antioxidant capability, yet large-scale studies on the risk of interfering with treatment are lacking. Some of these medications, including corticosteroids, are prescribed alongside chemotherapy to counteract the side effects of treatment (Lemmo 2014; Barbour 2012).

Natural Compounds with Antioxidant Properties

The use of supplemental antioxidants may help protect normal cells from the increased damage and side effects caused by radiation therapy (Lamson 2000; Yun 2017). Moreover, levels of antioxidants decline in response to cancer therapy (Simone 2007a; Ladas 2004). Supplementation with dietary antioxidants such as vitamins C and E may improve the efficacy of radiation therapy by increasing tumor response and decreasing radiation toxicity to normal cells (Prasad 2002). Dietary antioxidants including vitamins C and E, selenium (a component of antioxidant selenoproteins), as well as antioxidant enzymes found within cells, such as superoxide dismutase and glutathione peroxidase, can help maintain an appropriate balance between desirable and undesirable effects of reactive oxygen species (Seifried 2003).

Although concern surrounds the use of supplemental antioxidants during radiation therapy, studies show antioxidants can be used safely in combination with radiotherapy. For example, various antioxidants did not interfere with radiation treatment in a retrospective study of 134 men with early-stage prostate cancer. Evidence that higher dose antioxidants do not interfere with radiation was based on five or more years of follow-up measurements of prostate specific antigen (PSA). PSA levels were similar in both the antioxidant group and the group that did not receive antioxidants (Braun 2013). Beta-carotene did not interfere with treatment in a trial in 383 men receiving radiation therapy for prostate cancer. Long-term follow-up did not show increased risk of death from prostate cancer or metastasis with the use of beta-carotene (Margalit 2012).

Beta-Carotene, Alpha-Tocopherol, and Smoking

Beta-carotene and alpha-tocopherol should be avoided in smokers undergoing radiation therapy due to decreased radiation effectiveness and worse outcomes (Meyer 2008; Block 2009). A study was conducted on 540 patients with head and neck cancer receiving radiation therapy while taking 400 IU per day dl-alpha-tocopherol (one form of vitamin E) and 30 mg per day beta-carotene. Results showed reduced side effects and decreased effectiveness of radiation in the group receiving antioxidants (Bairati 2005). A re-evaluation of the same data revealed that the decreased radiation effectiveness was seen only in participants who smoked during radiation therapy, and the final conclusion was that smokers should not take antioxidants while undergoing radiation therapy (Meyer 2008; Block 2009).

Zinc may improve five-year overall survival and reduce local recurrences for patients with nasopharyngeal cancer treated with concomitant chemotherapy and radiotherapy. Thirty-four patients with stages III or IV cancer received chemoradiotherapy and 75 mg zinc or placebo daily for two months. The zinc group had a better disease-free five-year survival rate than the placebo group. However, the five-year metastasis-free survival rate was not significantly different between the two groups, possibly due to the advanced nature of the disease (Lin 2009).

Selenium has been studied for its radiosensitizing and radioprotective properties (Schueller 2004). A review of literature analyzing clinical studies on selenium and radiotherapy showed that blood selenium levels decreased following radiotherapy and could be increased with supplementation. The range of doses used for supplementation in the studies included 200 to 500 mcg daily of oral sodium selenite or 1000 mcg daily of intravenous sodium selenite. Most of the supplementation studies reported improved quality of life while taken during radiotherapy, and none showed decreased radiation effectiveness or toxicity from supplementation (Puspitasari 2014). Authors of one study advocated for measuring serum selenium levels before and during radiation therapy for gynecologic cancers. Patients deficient in selenium can be safely supplemented during radiotherapy (Muecke, Micke, Schomburg, Kisters 2014; Muecke, Micke, Schomburg, Glatzel 2014). A 10-year follow-up study on patients with cervical or uterine cancer who had taken selenium during radiation demonstrated that selenium did not negatively impact the effectiveness of radiation therapy or long-term survival. Furthermore, selenium supplementation reduced radiation therapy-induced diarrhea in selenium-deficient patients (Muecke, Micke, Schomburg, Glatzel 2014).

Supplementation with 200 mcg daily of sodium selenite for eight weeks, beginning on the first day of standard treatment (surgery and/or radiation) for squamous cell carcinoma of the head and neck, resulted in a significantly enhanced cell-mediated immune response during and after therapy (Kiremidjian-Schumacher 2000).

Lycopene, a carotenoid that gives fruits and vegetables their red color, is one of the most potent free radical scavengers among the carotenoids. In general, consumption is associated with decreased risk of multiple cancers (Gajowik 2014; Farzaei 2016). Lycopene has been shown in multiple preclinical studies to have radioprotective effects in gastrointestinal cells (Saada 2010; Andic 2009), white blood cells (Srinivasan 2009), and liver cells (Meydan 2011).

Black cumin (Nigella sativa) is a flowering plant native to southwest Asia where it has been used historically as a food and a medicine (Ahmad 2013). Oil extracted from black cumin seeds, sometimes called black seed oil, and its active constituent thymoquinone, have been shown in laboratory animals to protect healthy tissues from the side effects of radiation (Cikman 2014; Ustun 2014; Taysi 2015; Assayed 2010; Cemek 2006; Velho-Pereira 2012). In addition, black cumin has been shown to have anticancer properties itself, so may complement other treatment modalities (Majdalawieh 2017).

Supplementation with coenzyme Q10 (CoQ10), a co-enzyme involved in cellular energy production, has been shown to provide benefits in the context of cancer radiotherapy (Kumar 2009; Awa 2017; Liu, Cheng 2017). A study of 32 breast cancer patients given different standard treatments, some including radiation therapy, and a packet of nutrients containing 90 mg CoQ10, 2850 mg vitamin C, 2500 IU vitamin E, 32.5 IU beta-carotene, 387 mcg selenium, 1.2 grams gamma linolenic acid, 3.5 grams omega-3 fatty acids, and other vitamins and minerals found a decrease in distant metastases and increase in long-term survival. In addition, participants’ quality of life improved. Four deaths were expected based on statistical modeling, but there were no deaths during the 18-month follow-up period (Lockwood 1994; Lockwood 1995). In a more recent study in rats, relatively low-dose CoQ10 significantly reduced markers of kidney damage after radiation (Ki 2017).

Melatonin is a hormone secreted from the pineal gland in response to a dark environment. Melatonin reaches maximal levels at night and plays a role in the circadian rhythm guided by the light/dark phases in a 24-hour cycle (Sanchez-Barcelo 2012; Malhotra 2004; Shirazi 2007). Commonly used as a treatment for insomnia, melatonin improves quality of sleep and reduces fatigue related to sleep disorders (Malhotra 2004). Night-shift workers may have perturbations in melatonin secretion, which have been associated with increased risk of breast and other cancers (Seely 2012).

Melatonin reduces oxidative damage directly, by scavenging free radicals, and indirectly, by stimulating antioxidant enzymes and suppressing pro-oxidative enzymes (Mihandoost 2014; Shirazi 2007). Studies have shown melatonin to be a more potent and efficient antioxidant than vitamin E in rats exposed to radiation (Mihandoost 2014). Several studies indicate that melatonin functions as a radioprotector (Karbownik 2000; El-Missiry 2007; Shirazi 2007; Reiter 2017; Fernandez-Gil 2017; Zetner 2016), reducing the toxic effects of radiation on mammalian cells (Vijayalaxmi 2004). In cell culture and animal models, administration of melatonin alone inhibited the growth and division of several types of cancer cells, including breast, colon, and prostate cancer cells (Shirazi 2007; Seely 2012; Sainz 2005; Moretti 2000). In addition to radioprotective and anti-cancer effects, melatonin has also been shown to sensitize breast cancer cells to radiation (Alonso-Gonzalez 2015).

Melatonin may alleviate symptoms caused by radiation-induced organ injuries, including damage to the spleen, liver, lung, colon, small intestine, lens of the eye, spinal cord, brain (Mihandoost 2014), and kidneys (Kucuktulu 2012). Although an optimal dose for use with radiation has not yet been established, higher doses of melatonin are generally well tolerated (Mihandoost 2014; Shirazi 2007; Seely 2012; Wang, Jin 2012). Literature reviews of clinical studies have shown that melatonin increases the rate of tumor remission, prolongs survival, and reduces side effects including fatigue, neurotoxicity, and low platelet count. The most common dose used among the studies was 20 mg (Wang, Jin 2012; Seely 2012).

Patients with glioblastoma generally have a poor prognosis. A small study of patients with untreatable glioblastoma showed that the likelihood of survival at one year was significantly greater in those who received melatonin orally (20 mg daily) with radiotherapy compared with those who received radiotherapy alone. A reduction in radiation-induced toxicity including hair loss and infection was also observed in the melatonin-treated group. Most patients receiving melatonin experienced decreased anxiety, improved sleep, and better dreams (Lissoni 1996).

7 Strategies For Minimizing Radiation Therapy Side Effects

The goal of radiation therapy is to deliver a precisely measured dose of radiation to a defined tumor area, with as little damage as possible to surrounding healthy tissue. However, a common side effect of radiotherapy is damage to healthy tissues, which may limit how much radiation a patient can tolerate.

Radiation’s effects on normal tissues are commonly divided into two categories: “early” and “late” reactions. Early, or acute, effects develop within 90 days of radiation therapy and persist for 2‒3 weeks after treatment has been completed. Late effects appear after a period of months or years, typically after 90 days, and may persist for life. Early effects mostly occur in high turnover tissues, such as the skin, gastrointestinal tract, urinary tract, and bone marrow. Late effects mostly occur in slowly growing tissues such as the lungs, heart, liver, and nervous system. These effects are influenced by several factors, including total radiation dose, irradiation field, fraction size, time between fractions, concurrent administration of chemotherapy, age at diagnosis, ability of tissues to heal, and genetics (Giotopoulos 2007; Walker 2014; Tolentino Ede 2011; Joiner 2009; Wong 2014).

This section discusses strategies for minimizing radiation therapy side effects.

Head and Neck Radiation Side Effects

Cerebral edema. Cerebral edema, or swelling of the brain, can result from brain tumors or radiation to the brain. Associated symptoms typically include headache, nausea, and vomiting (Giglio 2010). Refer to the section titled “Skin, Systemic, and Other Radiation Side Effects” for strategies to treat nausea and vomiting. The typical treatment for cerebral edema includes corticosteroids such as dexamethasone (Kostaras 2014; Giglio 2010). The side effects of corticosteroids may limit their use and other therapies have been suggested including bevacizumab (Avastin), an antiangiogenic agent used in the treatment of multiple cancers. However, bevacizumab has a high rate of potentially serious complications (Dietrich 2011; Lubelski 2013).

  • Boswellia serrata is an Indian frankincense plant extract from which a number of compounds with anti-inflammatory properties have been isolated and studied. A randomized placebo-controlled trial in 44 patients receiving radiation therapy for brain cancer or metastasis to the brain showed a reduction in cerebral edema in the group taking Boswellia extract. In the treatment group, patients received 4,200 mg of a Boswellia extract daily in divided doses starting on the first day of radiation and ending on the final day. Sixty percent of patients in the Boswellia group were found, on MRI examination, to have just 25% of the baseline edema volume or even no detectable edema. Only 26% achieved this optimal outcome in the placebo group. Authors commented that the reduction of edema may have resulted not only from Boswellia’s anti-inflammatory properties, but also from antitumor and radiosensitizing effects. The authors suggested additional research should be conducted into these possible properties of Boswellia. There were no serious side effects associated with Boswellia extract;the course of radiotherapy and dexamethasone treatment doses were not statistically different, and the authors stated that the Boswellia extract treatment posed no risk to the patients (Kirste 2011).

Radiation-induced brain injury. Acute and early-delayed symptoms in the brain occur within the first three months after initiation of radiotherapy and typically resolve spontaneously. Associated symptoms may include headache, nausea, and drowsiness due to dilation of blood vessels and edema. Late-delayed effects occur three months to years following radiation, and may include radiation necrosis, or tissue death, vascular abnormalities, and cognitive decline (Verma 2013; Hunter 2003; Clavo 2011; Lee 2012; Greene-Schloesser 2012; Chapman 2012). The type of damage includes vascular abnormalities, damage to white matter of the brain, and damage to the myelin sheath surrounding nerves (Warrington 2013). The incidence of radiation necrosis is 3% to 24% and is dependent on radiation dose, duration, and volume of area treated (Verma 2013). Cognitive decline occurs in 40% to 50% of long-term brain tumor survivors (Warrington 2013).

  • Melatonin prevented some aspects of brain damage caused by gamma radiation in rats (Erol 2004). Other studies demonstrated that melatonin protects against radiation-induced decreases in nerve growth and cognition (Manda 2010).
  • Omega-3 fatty acids such as eicosapentaenoic acid (EPA) from fish oil are anti-inflammatory and neuroprotective and have been shown to decrease inflammatory interleukin-1 beta (IL-1β) and increase anti-inflammatory interleukin-10 (IL-10) in rat brains (Lynch 2003). In one clinical study, over 400 patients treated with stereotactic radiotherapy for brain metastasis were supplemented with omega-3 fatty acids and flavonoids. Patient survival time increased and rate of radionecrosis decreased (Gramaglia 1999).
  • In a case study of a patient who underwent stereotactic radiosurgery for meningioma, along with acetylsalicylic acid and corticosteroids, brain imaging showed tissue death and decreased tissue metabolism. The patient received ozone therapy, which improved cerebral blood flow and brain tissue metabolism. Ozone was administered via auto-hemotransfusion, which is intravenous administration of the patient’s own blood sample that had been exposed to ozone. More studies are needed to support the use of ozone in radiation-induced brain injury and stroke (Clavo 2011; Clavo 2004). This method has been studied in a number of smaller clinical trials related to other vascular diseases and results are mixed (Coppola 2007; Giunta 2001; Clavo 2015).
  • A study in rats receiving L-carnitine daily, vitamin E, or both, in combination with radiation, showed decreased brain and eye damage in the rats that received vitamin E or L-carnitine (Sezen 2008). L-carnitine reduced cochlear (inner ear) damage induced by radiation to the brain in guinea pigs (Altas 2006).
  • A study in rats receiving electroacupuncture immediately following brain irradiation showed prevention of cognitive impairments by protecting against molecular changes induced by radiation (Fan 2015).
  • Other helpful nutrients for radiation-induced brain changes may include vitamin E (Erol 2004; Sezen 2008) and Ginkgo biloba extract (Lamproglou 2000; Ertekin 2004; Ismail 2016). In a trial of 34 patients with brain tumors treated with radiation, Ginkgo biloba was associated with improvement in cognitive function, attention, concentration, memory, and mood (Attia 2012).

Refer to the protocols on Amnesia, Alzheimer’s Disease, and Age-Related Cognitive Decline for more information on protecting neurological tissues and preventing cognitive decline.

Osteoradionecrosis. Osteoradionecrosis (bone loss) of the jaw is a late adverse effect experienced by 5% to 7% of head and neck cancer patients treated with radiation therapy. Possible treatments include surgery, hyperbaric oxygen therapy (HBOT), and prophylactic antibiotics (Lee 2014; Karagozoglu 2014). Symptoms vary depending on severity and may include pain, ulceration, difficulty chewing, loss of sensation in the jaw, or fracture (CCS 2015). Predictors of severity of necrosis include diabetes, active smoking, excessive alcohol consumption, and dental treatment or local pathological conditions of the mouth (Chronopoulos 2015).

  • A randomized controlled trial in 54 patients who received radiotherapy for cancers of the head and neck showed benefit with a combination treatment for refractory osteoradionecrosis. All patients received a combination of anti-radiation fibrosis medications known as PENTOCLO, which includes pentoxifylline (800 mg), tocopherol (vitamin E, 1,000 IU), and clodronate (Bonefos, 1,600 mg). PENTOCLO was given five days per week. Additionally, 20 mg prednisone and 1,000 mg ciprofloxacin were given two days per week. Treatment lasted 16 months on average and was safe and well tolerated. All patients experienced complete recovery in nine months on average, with marked symptom improvement and healing (Delanian 2011). A 2015 case report described success with the PENTOCLO protocol in a 52-year-old woman who underwent radiotherapy for a salivary gland tumor (Glicksman 2015).
  • Hyperbaric oxygen therapy (HBOT) has been discussed for its use as a radiosensitizer, but it is also beneficial for healing radiation-induced injury. Reviews of scientific literature established that HBOT after radiation therapy is generally safe with rare adverse effects such as reversible ear and eye trauma from the oxygen under pressure, dental complications, oxygen toxic seizures, and heart attack (Tahir 2015; Hoggan 2014; Bennett 2012).

    Radiation can cause scarring and narrowing of the blood vessels and fibrosis within the area treated, decreasing blood supply to the tissues. Healing of normal tissues is dependent on oxygen delivery to the injured tissues. HBOT provides a better healing environment, leads to growth of new blood vessels (Hampson 2012), and helps eliminate bacteria that may cause infection (Signoretto 2007).

    In a study of 411 patients, hyperbaric oxygen was effective for many radiation-induced injuries (Hampson 2012). HBOT is effective for head, neck, anal, and rectal soft tissue damage and for osteoradionecrosis of the jaw (Hoggan 2014; Bennett 2012). At one treatment center, 18 of 21 patients with osteoradionecrosis were successfully treated with hyperbaric oxygen over a 16-year period (Gavriel 2017). Patients with stage I and II osteoradionecrosis may be the best candidates for HBOT (Dieleman 2017). However, use of HBOT is not widespread, partly because it is cumbersome and difficult in practice (Ogawa, Kohshi 2013), and partly because many studies to date have involved relatively few patients (Sultan 2017). Larger, well-designed clinical trials are needed to investigate the efficacy of HBOT and determine which patients can benefit most (Hoggan 2014).

Head and Neck Radiation Therapy May Increase Stroke Risk

Radiation therapy is an important part of treating many different head and neck tumors. A side effect of radiation therapy to the head and neck is increased risk of a transient ischemic attack (TIA), also referred to as a “mini stroke” (Abayomi 2004; Campen 2012; Arthurs 2016). Studies of head and neck cancer patients who received radiation therapy found that stroke rates were 2.1 to 8.5 times greater than expected. An analysis of patients with head and neck tumors treated with radiation therapy revealed that the average time between radiation treatment and stroke was 10.9 years, but the increased risk of stroke persisted for several years after radiation therapy (Chu 2011; Dorresteijn 2002). Patients receiving radiation therapy to the neck for Hodgkin’s lymphoma also experienced an increase in stroke or TIA, with an average of 17.4 years between radiation treatment and the first stroke or TIA event (De Bruin 2009). Another study on pediatric patients with brain tumors showed a 100-fold increased risk of stroke or TIA (Campen 2012). Other cancers associated with increased stroke risk include urogenital, breast, lung, gastrointestinal, and hematological cancers (Chu 2011).

Radiation to the head and neck can cause carotid artery stenosis or narrowing, impeding blood flow to the head. Through several mechanisms that are the topic of intensive research studies, this can increase the risk of stroke and TIA (Xu 2014; Abayomi 2004). Some common approaches for managing stenosis include endarterectomy, or surgical removal of plaque from an artery, and stenting, or placement of a device to open up the vessel allowing for better blood flow (Abayomi 2004). Radiation can damage vessels leading to plaque buildup, hardening of the arteries, and vascular insufficiency, which may result in decreased blood supply to brain tissues (Campen 2012; Stewart 2006). The vascular damage may be caused by oxidative stress and inflammation. Inflammatory markers may be useful for monitoring carotid stenosis, but more research in this area is needed (Xu 2014; Gujral 2014).

Techniques to reduce damage to surrounding healthy tissues may help decrease the risk of stroke. Such techniques, described earlier, include conformal radiation therapy, proton therapy, image-guided radiation therapy, hyperfractionated radiation, stereotactic radiation, brachytherapy, and radioprotective agents (Xu 2014). As of the time of this writing, clinical studies have not been conducted on nutritional or botanical protective agents specifically to reduce or prevent stroke associated with radiation therapy.

Long-term surveillance with carotid ultrasound techniques can be helpful in identifying changes in carotid arteries in the years following treatment with radiation therapy (Xu 2014; Thalhammer 2015; Gujral 2016). Additionally, other imaging techniques may be appropriate for follow-up after radiation to the brain, including magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA), which assesses larger vessels in the brain (Campen 2012).

Traditional risk factors for stroke should be addressed including diabetes, obesity, hypertension, hyperlipidemia, and smoking (Xu 2014; Goldstein 2011). For additional prevention and treatment suggestions related to these and other risk factors, refer to the protocols on stroke, high blood pressure, diabetes and glucose control, weight loss, cholesterol management, and atherosclerosis and cardiovascular disease. Healthy diet, physical activity, minimal alcohol consumption, and maintaining a healthy weight are among the important lifestyle interventions that can help prevent stroke (Goldstein 2011) and are outlined in the protocols. Methods for reducing oxidative stress and inflammation, which underlie many chronic diseases, are also outlined in the protocols.

Oral mucositis. Depending on the treatment regimen, 60% to 100% of patients receiving radiation for head and neck cancer will develop mucositis, or inflammation of the lining of the mouth. Symptoms include ulceration, redness, oral pain, and pain on swallowing (Lalla 2014; Epstein 2012). Mucositis usually appears after the second week of radiation therapy and may continue for a few weeks after treatment has ended (Noe 2009; Epstein 2012).

Oral mucositis can lead to secondary complications, including infection, poor nutritional intake, and xerostomia, or dry mouth. Several treatment interventions have been suggested for preventing and treating oral mucositis, such as low-level laser therapy, palifermin, benzydamine mouthwash, oral cryotherapy (ice chips), and pain medications (Lalla 2014; Worthington 2011). Maintaining good oral hygiene, which includes a combination of tooth brushing, flossing, and mouth rinses, is important in preventing oral mucositis (Lalla 2014).

  • Glutamine is a conditionally essential amino acid and serves as a major source of energy for intestinal cells (Noe 2009). Glutamine is necessary for proper immune function, and many heavily treated cancer patients are glutamine deficient (Morris 2017; Gaurav 2012). A trial of patients with head and neck cancer found that oral glutamine (16 grams in 240 mL of normal saline, swished four times daily during radiation) reduced the duration and severity of oral mucositis during radiotherapy (Huang 2000). Another study of patients being treated with chemotherapy and radiotherapy found that, while mucositis developed in all patients, those taking 10 grams glutamine three times daily had significantly less severe symptoms (Tsujimoto 2015). A 2016 study of head and neck cancer patients being treated with radiation tested a solution of glutamine and arginine used twice daily. The group using the solution had significant improvements in symptoms of oral mucositis, including dry mouth, appetite, pain, and swallowing problems (Yuce Sari 2016).
  • Zinc is a trace element and component of many enzymes that play an important role in antioxidant defense, tissue repair, and gene expression (NAS 2001). In a randomized placebo-controlled trial in 35 patients receiving radiation for head and neck cancers, 50 mg zinc sulfate three times daily at the beginning of radiotherapy, with or without chemotherapy, and continuing for a month afterwards was shown to improve taste (Najafizade 2013). A double-blind randomized study reported in patients receiving radiation therapy, zinc was beneficial for delaying oral mucositis and alleviating its severity (Lalla 2014; Lin 2006). Another study showed zinc was more beneficial in preventing mucositis in patients with oral cancer than those receiving radiation for nasopharyngeal cancer (Lin 2010). Zinc L-carnosine was studied as an oral rinse, and patients taking the zinc solution experienced less mucositis, pain, dry mouth, and taste disturbance than the group not taking zinc (Watanabe 2010). Another form of zinc was prepared in a lozenge for patients being treated with high-dose chemotherapy. Grade 2 or more severe oral mucositis affected 74% of patients who did not use the lozenge versus only 13% who did (Hayashi 2016).
  • Honey reduces symptoms of mucositis. Forty patients diagnosed with head and neck cancer were divided into two groups. One group was advised to rinse their mouths with 20 mL pure honey 15 minutes before, 15 minutes after, and six hours after radiotherapy. The subjects were instructed to rinse with the honey then slowly swallow it to coat the mucosal surfaces of their throats. In the honey-treated group, symptomatic grade 3/4 mucositis was reduced significantly, with no change in weight or a positive weight gain compared with the control group (Biswal 2003). A review of multiple studies showed an 80% risk reduction of oral mucositis with the use of honey (Song 2012).
  • In a clinical study on patients with head and neck cancer, 53 patients were given proteolytic enzyme tablets three times daily starting three days before radiation therapy and continuing until five days after completion of treatment. The severity of mucositis, dysphagia, and skin reactions were significantly reduced in the enzyme-treated group compared with controls (Gujral 2001).
  • A study on the Indian spice turmeric (Curcuma longa) showed benefit when swished as a mouthwash for oral mucositis. In this randomized controlled trial, 80 patients with head and neck cancer undergoing seven weeks of chemoradiotherapy received either a turmeric or povidone-iodine gargle. The level of oral mucositis in the turmeric group was significantly reduced compared with the povidone-iodine group. There was also decreased incidence of treatment breaks in the turmeric group and better maintenance of body weight (Rao 2013).
  • Green tea (Camelia sinensis) leaf extract was the active ingredient in a mouthwash tested in leukemia, lymphoma, and multiple myeloma patients. Oral mucositis occurred in 82% of the group that did not use the mouthwash versus only 50% of the group that did (Carulli 2013).

Xerostomia (dry mouth). Damage to the salivary glands is another common adverse effect of radiotherapy to the head and neck. Reduced saliva production can cause chronic dry mouth. Xerostomia can promote tooth decay and greatly impair a patient's ability to speak, chew, swallow, taste, and fight oral infections. Therefore, xerostomia is often accompanied by a loss of appetite and weight, leading to adverse effects on quality of life (Pinna 2015). In a large study of elderly patients receiving treatment for head and neck cancer, patients were over nine times more likely to develop xerostomia if they received concurrent chemotherapy and radiotherapy and over six times more likely if they received radiotherapy alone (Liu, Xia 2011).

Amifostine, a prescription antioxidant, reduces the incidence of xerostomia and mucositis in patients receiving head and neck irradiation. Amifostine is associated with side effects, including nausea, vomiting, transient hypotension, and allergic reaction, which limit its use (Gu, Zhu 2014; Simone 2007a). Pilocarpine (Salagen) and similar medications are used to stimulate salivation but also have side effects, including sweating, urinary frequency, tearing of the eyes, and runny nose (Kaluzny 2014).

Stimulation of the salivary glands with sugar-free lemon drops during and after radiation therapy can potentially preserve salivary function. Saliva substitutes in the form of gels, lozenges, sprays, or mouthwashes may provide temporary relief from dryness. Ice chips or frequent sips of water throughout the day may help. Foods that are sugary, acidic, dry, spicy, astringent, or excessively hot or cold should be avoided.

  • Acupuncture may have benefit for promoting recovery from xerostomia (Zhuang 2013; O'Sullivan 2010). A study on acupuncture for the prevention of xerostomia in 24 patients showed improved salivary flow and decreased symptoms associated with xerostomia in the group receiving acupuncture before and during radiation therapy. Symptoms were not completely absent, but severity was significantly minimized (Braga 2011). In two literature reviews, authors concluded that available data support further testing of acupuncture in patients with cancer and undergoing radiation therapy (Hanchanale 2015; Jensen 2010).
  • A study of 30 patients with radiation-induced xerostomia evaluated the effectiveness of transcutaneous electrical nerve stimulation (TENS) for relieving xerostomia (Vijayan 2014). A TENS unit delivers a pulsed electrical current via electrode pads to stimulate superficial nerves and is widely used in pain management (Kasat 2014). The TENS electrode pads were placed on the skin over the parotid glands and saliva was collected in tubes for five minutes before and five minutes during the TENS treatment. Twenty-nine out of 30 patients experienced increased salivary flow (Vijayan 2014). These results were supported by a follow-up study in postmenopausal women with oral dryness (Konidena 2016).
  • Zinc L-carnosine (see the section on oral mucositis) is beneficial for relieving xerostomia (Watanabe 2010).
  • A small study of patients who underwent radiation therapy for head and neck tumors showed increased salivary secretion rate with hyperbaric oxygen (Cankar 2011).

Chest Radiation Side Effects

Esophagitis. Acute radiation esophagitis can persist for one to three weeks following the completion of radiotherapy and can result in difficulty swallowing, painful swallowing, and chest pain. Mucositis, or inflammation of the mucosa, and ulcerations can cause significant symptoms. Esophageal stricture is a late complication that can occur three to eight months after radiotherapy. Concurrent chemotherapy is likely to increase the risk of acute esophagitis. Severe esophagitis can lead to hospitalization, tube feeding, and treatment interruptions (Bar-Ad 2012; Baker 2016).

  • In three separate studies, patients diagnosed with lung cancer were treated with 10 grams of the amino acid glutamine powder every eight hours or no glutamine in combination with radiation. The groups receiving glutamine had significantly fewer cases of esophagitis (Gul 2015; Topkan 2009; Tutanc 2013; Hall 2016).
  • Epigallocatechin-3 gallate (EGCG), an extract from green tea, was given orally as a liquid (440 mmol/L) to 37 patients with lung cancer at the appearance of acute radiation esophagitis during radiotherapy and continuing for two weeks following radiotherapy. EGCG decreased the pain associated with esophagitis (Zhao 2015; Zhao 2014). Another study noted dramatic reductions in esophagitis severity in 22 of 24 patients treated with EGCG (440 mmol/L) (Zhao 2014).

Heart Damage. With three-dimensional conformal radiation therapy (3DCRT), deep inspiration breath holding, and different patient positioning techniques, clinicians can reduce the dose and volume of radiation exposure to the heart. However, significant risks remain, and cardiovascular abnormalities may result following radiation therapy. Fibrosis, characterized by scar tissue formation in and around the heart, is a significant concern (Taunk 2015). Hodgkin's disease survivors treated with chest radiation therapy are at increased risk of death from cardiovascular disease (Daniels 2014). Patients with breast cancer treated with radiation therapy have an increased risk of ischemic heart disease. The risk of coronary events increases within a few years of radiotherapy and can continue for at least 20 years (Darby 2013). Patients receiving radiotherapy for cancers of the esophagus or lung are also at risk of heart damage (Wang, Eblan 2017; Mukherjee 2003).

Targeting a tumor that moves as a patient breathes is a challenge in radiation therapy and may require a larger treatment field to ensure that the tumor is targeted. This approach inadvertently may also target healthy tissues. A device called the Active Breathing Coordinator (ABC) monitors the patient’s breathing and, under the patient’s control, during a very brief pause in breathing, helps increase the distance between the tumor and critical organs such as the heart or lungs before the radiation dose is delivered, thus minimizing damage to these organs. Breath holding also immobilizes organs that shift with each breath, making it easier to target the correct tissues and obtain better images for proper positioning. The deep breath hold procedure is usually repeated on average four to six times during a treatment session (Elekta 2017; Cleveland Clinic 2015; SCI 2015; Estoesta 2017). A study using the ABC device was conducted on 112 patients with non-metastatic cancer in their left breast. In this study, significant reductions in the average dose to the heart (>20%) and left lung were observed in most patients in the ABC group compared with the free breathing group. Target coverage was not compromised (Eldredge-Hindy 2015). A 2017 study that examined 45 patients with left-sided breast cancer found that the ABC device led to a nearly 50% reduction in mean radiation dose to the heart (Kunheri 2017). Benefits have also been observed during treatment for lymphoma (Charpentier 2014).

  • In a study of rats receiving total body irradiation, black grape juice protected heart tissue. The grape juice had high levels of resveratrol and quercetin. Rats received grape juice for one week before and four days after radiation and had lower levels of metabolites of lipid peroxidation (from free radical damage) in heart tissue compared with rats not receiving grape juice (de Freitas 2013). Another rat study on the effects of grape seed extract also showed protection against radiation-induced heart damage. Hearts from rats given grape seed extract daily for 14 days before total body irradiation were less damaged than those of rats not receiving grape seed extract (Saada 2009).
  • Compounds studied to treat cardiac fibrosis may reduce cardiovascular complications.
    • Hesperidin, a citrus flavanoglycone, was given to rats for seven days after total body irradiation. Minimal damage to the heart, liver, and kidneys was observed in rats treated with hesperidin. Other parameters including serum enzymes and free radical damage also improved in the treated groups in a dose-dependent manner (Pradeep 2012).
    • The effect of astragalus was studied on irradiated cardiac fibroblast cells. Astragalus reversed some molecular changes associated with fibrosis caused by radiation (Gu, Liu 2014).

The protocols on Atherosclerosis and Cardiovascular Disease and Heart Failure contain additional information that may be beneficial in treating cardiovascular issues.

Lung (pulmonary) toxicity. The lung is among the most radiosensitive organs, and associated side effects seriously compromise treatment outcomes (Mahmood 2013). Radiation pneumonitis, or inflammation of the lung, is a common acute side effect during the first six months after radiotherapy and occurs in 13–37% of patients (Giridhar 2015; Shi 2012). Radiation therapy-induced fibrosis typically occurs more than six month after radiotherapy, and is associated with scarring of the lung. Corticosteroids and antibiotics are the main treatments used for mitigating these late side effects (Giridhar 2015).

The drug pentoxifylline reduces the production of proinflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-α), and therefore may protect against radiation-induced, cytokine-mediated damage (Rube 2002). In a clinical trial, 64 patients with non-small cell lung cancer were randomized to receive either pentoxifylline (400 mg, three times daily) plus radiotherapy or radiotherapy alone. After treatment, patients in the pentoxifylline plus radiotherapy group had a longer one-year survival rate (60%) than the radiation therapy alone group (35%). The median time to relapse was 11 months in the pentoxifylline group and nine months in the radiation alone group (Kwon 2000). In another clinical trial, 66 patients with stage IIIB non-small cell lung cancer were randomized to receive pentoxifylline (400 mg, three times daily) and alpha-tocopherol (300 mg twice daily) plus radiation or radiation alone. The study group continued to receive 400 mg pentoxifylline and 300 mg alpha-tocopherol daily for three months after completion of radiotherapy. The one-year survival rate was 55% in the study group and 40% in the control group (Misirlioglu 2006). In a randomized trial of 91 lung cancer patients that utilized the same regimen of pentoxifylline and alpha-tocopherol, acute and late-phase radiation-induced lung toxicity was more frequent in the control group (Misirlioglu 2007). Rats that were administered 20 mg/kg/day vitamin E plus pentoxifylline after radiation had significantly less fibrosis than rats receiving radiation alone or pentoxifylline and radiation (Kaya 2014; Bese 2007).

  • Mouse studies have shown that flaxseed meal can help protect against radiation-induced lung injury (Lee 2009) and radiation-related death (Pietrofesa 2013). Flaxseed contains beneficial omega-3 fatty acids and lignans. Flaxseed decreased oxidative damage and reduced the number of inflammatory cells in the lungs, thus reducing fibrosis in lung tissues. Flaxseed did not reduce radiation effectiveness in mice (Lee 2009). Fourteen patients with stage III and IV non-small cell lung cancer had less pneumonitis when eating a flaxseed muffin daily during radiotherapy (Berman 2013).
  • Curcumin reduces inflammatory cytokines and scavenges free radicals (Shi 2012). In rats, curcumin was given before radiation (five days per week) and for eight weeks after radiation. Rats treated with curcumin had reduced lung inflammation and fibrosis (Cho 2013). In mice, curcumin given daily as part of the diet before and after radiotherapy also decreased fibrosis (Lee 2010).
  • In rat and mouse studies, genistein was shown to decrease radiation-induced lung fibrosis (Mahmood 2013; Calveley 2010; Para 2009). Genistein is an isoflavone component of soy. Rats were fed a diet containing genistein for 28 weeks. An improved breathing rate and decreases in inflammatory cytokines and fibrosis were observed (Calveley 2010). In general, soy isoflavones (including genistein and other isoflavones) have been found to mitigate lung injuries and sensitize tumor tissues to radiation (Hillman 2011).
  • Melatonin has shown a wide range of benefits for use with radiotherapy. In animal studies, melatonin mitigated early and late radiation-induced lung damage (Tahamtan 2015; Jang 2013; Serin 2007). Human studies on melatonin have shown that doses up to 20 mg daily can be beneficial during cancer treatment (Seely 2012; Wang, Jin 2012).
  • A study in mice found that grape seed proanthocyanidins given one hour before and for four weeks after radiation mitigated radiation-induced lung injury (Huang 2014). Grape seed proanthocyanidins can reduce radiation-induced breaks in DNA, protect white blood cells, and increase body weight (Huang 2016; Yang, Liu 2017).
  • The amino acids taurine and L-arginine may protect against radiation-induced lung fibrosis by reducing production of collagen, a protein involved in the fibrotic process (Song 1998). Taurine decreased levels of the fibrosis-inducing inflammatory cytokine TGF-beta1 in mice that received radiotherapy to the chest (Robb 2010).
  • In a review of scientific literature, the herb astragalus was found to enhance therapeutic effectiveness and decrease toxicity of radiotherapy for non-small cell lung cancer. Studies have shown reduced risk of death at one, two, and three years. In patients taking astragalus, the rate of radiation pneumonia, an early side effect of radiation for lung cancer, was lower, and white blood cell counts were higher (He 2013). When flavonoids were extracted from astragalus and given to mice, radiation-induced lung injury was reduced (Wang, Xu 2012).

Preventing Anemia

Anemia is a condition in which there are insufficient red blood cells or hemoglobin to adequately deliver oxygen to the tissues. Studies show 40–64% of cancer patients who receive treatment have anemia (Gaspar 2015). Anemia is assessed by measuring red blood cells and hemoglobin, the protein component of red blood cells that delivers oxygen to tissues. Cancer patients with low hemoglobin levels do not respond as well to radiotherapy as non-anemic patients because the tumor cells do not receive enough oxygen (Hoff 2012). Low tumor oxygen and low blood oxygen enhance tumor growth and create resistance to treatment as described in the section “The Five R’s of Radiobiology” (Gaspar 2015). Hemoglobin values measured during treatment can predict how well a patient will respond to treatment. Smoking leads to a decrease in hemoglobin and poorer treatment outcome and should be avoided in order to improve the efficacy of radiotherapy (Hoff 2012).

Severe cases of anemia can be treated with blood transfusions or the drug erythropoietin (Procrit), which is a growth factor that produces a steady, sustained increase in hemoglobin levels. However, while these methods may improve anemia, studies have not shown that they improve outcomes related to tumor control (Hoff 2012).

A study of 103 patients with cervical cancer showed that supplementation with antioxidants during treatment with cisplatin and radiation decreased oxidative stress and improved hemoglobin levels and quality of life. The dose of antioxidants used included 4.8 mg beta-carotene, 10 mg vitamin C, 200 IU vitamin E, and 15 mcg selenium daily (Fuchs-Tarlovsky 2013).

Nutritional supplements that may help correct anemia, depending on the cause, include melatonin, iron, folate, and vitamin B12. For more information, refer to the Blood Disorders protocol.

Astragalus is an herb used in Chinese medicine that has been shown to promote bone marrow function and formation of blood cells in mice (Lv 2005; Zhu 2007). Mice that were injected with astragalus before radiation therapy and/or chemotherapy had higher levels of red blood cells, hemoglobin, platelets, and bone marrow cells than animals from a control group (Lv 2005).

Abdominal Radiation and Gastrointestinal Side Effects

Gastrointestinal mucositis (inflammation of the gut lining). Radiation to the abdomen or pelvis for gastrointestinal, urological, and gynecological cancers can result in acute or chronic gastrointestinal side effects. Acute enteritis (inflammation of the intestine) is characterized by diarrhea, abdominal pain, bloating, loss of appetite, nausea, and fecal urgency that occurs during or very soon after a course of radiotherapy. These symptoms usually start during the second week of radiation therapy and resolve within three months of completing treatment. Approximately 15–20% of patients require a change to the treatment protocol to decrease the severity of symptoms. Chronic small intestine radiation disease can develop 18 months to six years after radiation therapy and encompasses symptoms such as pain after eating, acute or intermittent small bowel obstruction, nausea, weight loss, loss of appetite, bloating, diarrhea, fatty stools, and nutrient malabsorption. Bile salt malabsorption, small intestinal bacterial overgrowth (SIBO), and lactose intolerance may also occur (Stacey 2014).

  • Glutamine is an amino acid that helps maintain mucosal growth and function. Glutamine is widely used in patients receiving various chemotherapy regimens to ameliorate side effects of the treatment, including mucositis and diarrhea (Kuhn 2010; Savarese 2003). Several human studies have shown benefits from glutamine for radiation-induced esophageal mucositis and oral mucositis (Gul 2015; Huang 2000; Savarese 2003). However, several human studies have failed to identify a clear benefit of glutamine in the lower intestinal tract of people undergoing radiation therapy (Vidal-Casariego 2014; Membrive Conejo 2011; Rotovnik Kozjek 2011; Savarese 2003; Kozelsky 2003; Cao 2017).

    Glutamine may be particularly helpful in preventing severe diarrhea. In a trial of patients receiving radiotherapy, 15 grams of oral glutamine or placebo was given three times daily. There was no difference in incidence in diarrhea between the two groups, but severe diarrhea was seen in 69% of the placebo group versus no patients in the glutamine group. Additionally, unlike the placebo group, the patients taking glutamine did not have to stop treatment because of side effects (Kucuktulu 2013).

  • Probiotics, beneficial bacteria that contribute to the health of the gastrointestinal tract, have a positive effect on gastrointestinal toxicity. Probiotics maintain the balance between pro- and anti-inflammatory molecules, modulate immune activity, favor the healing of damaged mucosal tissue, and reduce harmful bacteria (Delia 2007; Visich 2010; Fuccio 2009). A review of scientific literature showed patients undergoing radiotherapy and chemotherapy had marked changes in the bacteria residing in their intestines. This shift in bacteria can be problematic and is thought to lead to treatment-related symptoms such as diarrhea. The authors of the review stated that, “The gut microbiota may play a major role in the pathogenesis of mucositis through the modification of intestinal barrier function, innate immunity and intestinal repair mechanisms” (Touchefeu 2014).In a clinical trial on 490 patients receiving postoperative radiation therapy for cervical, sigmoid colon, or rectal cancers, patients were treated with either probiotics or placebo throughout the entire course of radiotherapy. The prescription probiotic formula VSL#3 was given as a sachet three times daily with each sachet containing 450 billion bacteria, including multiple strains of Lactobacillus and Bifidobacterium and one strain of Streptococcus thermophilus. Fewer patients had radiation-induced diarrhea in the probiotic group (31.6%) than the placebo group (51.8%). In the probiotic group, only 1.4% had severe (grade 3 or 4) diarrhea. In the placebo group, 55.4% of participants experienced severe diarrhea. The number of bowel movements decreased in the probiotic group, and anti-diarrheal agents were generally needed sooner in the placebo group. Treatment with this high-dose probiotic formula was safe, with no toxicity observed (Delia 2007).

    A randomized, double-blind, placebo-controlled study in 206 patients receiving radiotherapy for cancers in the abdomen and pelvis showed that those taking 1.5 billion colony forming units (CFUs) Lactobacillus rhamnosus three times daily had decreased diarrhea and required less and later anti-diarrheal medication than those taking placebo (Urbancsek 2001).

    A 2017 meta-analysis of six trials confirmed the benefits of probiotics for patients with cancers in the abdominal or pelvic area (Liu, Li 2017). In general, guidelines recommend probiotics containing Lactobacillus species for the prevention of radiation-induced diarrhea for pelvic cancers (Lalla 2014).

  • Prebiotics can stimulate the growth of beneficial bacteria in the gut. A randomized trial of 38 women being treated with abdominal radiation therapy for gynecological cancers found that the prebiotics inulin and fructooligosaccharide improved the consistency of stools (Garcia-Peris 2016).
  • Selenium can decrease the severity of diarrhea caused by radiotherapy for cervical or uterine cancer. In a study of patients with cervical or uterine cancer, 81 patients with low blood selenium levels were randomized to receive either selenium plus radiation or radiation alone. Patients receiving selenium were given 500 mcg sodium selenite on days of radiation and 300 mcg on days without treatment. Severe diarrhea occurred in 20.5% of the selenium group and 44.5% of the control group. Blood selenium levels were significantly higher in the supplemented group by the end of radiation therapy (Muecke 2010; Muecke, Micke, Schomburg, Glatzel 2014). A 10-year follow-up study demonstrated that selenium did not reduce the effectiveness of radiation therapy or long-term survival, making selenium a beneficial treatment for diarrhea in selenium-deficient patients with cervical or uterine cancer (Muecke, Micke, Schomburg, Glatzel 2014; Grober 2016).
  • Psyllium fiber administered daily significantly decreased the incidence and severity of radiation-induced diarrhea in 60 patients with cancer undergoing four weeks of radiation treatment to the pelvis. There was also a reduction in the use of anti-diarrheal medication (Murphy 2000). Practice guidelines conclude that soluble fiber likely reduces chemotherapy- and radiotherapy-induced diarrhea; however, dose and best type of fiber have not been established (Muehlbauer 2009). A gradual increase in fiber intake can minimize the effects of bloating, abdominal distension, and gas seen with rapid fiber introduction (Stubbe 2013).
  • Eighty patients enrolled in a study, and receiving radiotherapy for various cancers including colon, rectum, liver, kidney, stomach, and lung cancer, were observed while being treated with tablets containing 100 mg curcuminoids with 200 mg soy lecithin plus radiation or radiation alone. Patients started taking curcumin the day after the first day of radiation and continued for four months. In the curcumin group there was less nausea, vomiting, diarrhea, constipation, fatigue, malnutrition, weight loss, memory, cognitive impairment, and local pain and swelling (Belcaro 2014).

Some treatment regimens may require dietary changes. For more information about diet change recommendations, refer to the “Dietary and Lifestyle Considerations” section.

Liver damage. Primary liver cancer, also known as hepatocellular carcinoma, may be treated with radiation therapy. However, one of the most frequently encountered complications following treatment is radiation-induced liver disease. One study reported that this complication occurred in approximately 19% of patients treated with radiotherapy for liver cancer (Cheng, Wu, Huang, Liu 2002). The liver disease typically includes enlargement of the liver, accumulated fluid in the abdominal cavity, and elevated liver enzymes (especially alkaline phosphatase) two weeks to four months after treatment (Ursino 2012). In one study, one-half of radiation-induced liver disease patients died from this complication (Cheng, Wu, Huang, Huang 2002).

Stereotactic body radiation therapy is a relatively new radiation technology that provides highly potent radiation doses to tumors outside of the brain (Ursino 2012). When robotic stereotactic body radiation therapy was used to treat certain unresectable (cannot be completely removed by surgery) liver tumors, the incidence of radiation-induced liver disease was low and the symptoms regressed on their own (Janoray 2014; Bae 2015).

  • Silymarin, a flavonoid complex found in the seeds, leaves, and fruit of the milk thistle (Silybum marianum) plant, is becoming popular among patients with liver disease (Levy 2004; Saller 2001). Silymarin reduces inflammation, scavenges free radicals (Feher 2012; Mohammadkhani 2013), maintains cellular glutathione content (Soto 2003), and may prevent or treat liver dysfunction in patients undergoing anticancer therapy (Ladas 2003). A study in rats found that an intravenous injection of silymarin protected against radiation-induced liver disease (Ramadan 2002). Silymarin is well tolerated and led to a small increase in glutathione and a decrease in lipid peroxidation in peripheral blood cells in certain patients (Lucena 2002).

Kidney toxicity (nephrotoxicity). The kidney is one of the most radiosensitive organs in the abdominal cavity and is at risk of being damaged during abdominal irradiation (Ki 2017; Williams 2010). Radiation nephropathy can include azotemia (dangerously high levels of nitrogen waste products in the bloodstream), hypertension, and anemia, starting several months to years after treatment. If left untreated, these conditions can lead to renal failure (Cohen 2003).

  • Dietary changes may help patients with nephrotoxicity. Too much protein can burden the kidneys, and a dietary protein restriction of 0.6‒0.8 g/kg/day is recommended for some patients with chronic kidney disease (Ko 2017).

Pelvic Radiation Side Effects

Pelvic radiation disease, also known as gastrointestinal radiation-induced toxicity, can cause transient or long-term problems. Even with radiation techniques to spare healthy tissue, such as intensity-modulated radiation therapy (IMRT), damage may still occur; additionally, damage can develop after several decades (Fuccio 2015). Refer to recommendations in the section on “Gastrointestinal mucositis” for preventive strategies.

Radiation proctopathy. Radiation proctopathy refers to a complication that presents with damage of the mucosa, scarring, and tissue death in the rectum, and occurs in 5–20% of patients receiving pelvic radiotherapy for cancers of the prostate, rectum, urinary bladder, testes, cervix, and uterus. While it may heal spontaneously, chronic radiation proctopathy can also lead to chronic problems such as tenesmus (fecal urgency with cramp-like rectal pain), diarrhea, and rectal bleeding (Rustagi 2011). This complication is sometimes referred to as radiation proctitis (Bansal 2016; Lenz 2016). Conventional treatments include enemas containing sucralfate (Carafate), 5-aminosalicylic acid, or corticosteroids to decrease inflammation and pain, but these treatments have not been shown to be very effective. For excessive bleeding, thermal therapy using a heat probe, electric current, or laser may be used. Argon plasma coagulation is the most common thermal therapy method used to control bleeding (Cleveland Clinic 2011).

  • Men undergoing radiotherapy for prostate cancer and taking either a powder containing 100 million CFUs Lactobacillus reuteri with 4.3 grams soluble fiber or placebo had reduced proctopathy symptoms and improved quality of life (Nascimento 2014).
  • Butyrate, a short-chain fatty acid normally produced by probiotic bacteria in the colon, serves as an energy source for colon cells, induces tissue regeneration, and improves the integrity of the mucosal lining. Research suggests early treatment with butyrate enemas can reduce severity and frequency of proctitis (Stojcev 2013). In a study of 31 patients with prostate cancer, sodium butyrate enemas were given for acute radiation proctopathy. Within an average of eight days, symptoms decreased in 74% of patients (Hille 2008). While some studies show mixed results with respect to the effectiveness of butyrate enemas for proctopathy, the majority show benefits (Maggio 2014; Vernia 2000; Stojcev 2013).
  • In a randomized double-blind trial comparing retinol palmitate (vitamin A, 10,000 IU orally for 90 days) to placebo, oral retinol palmitate significantly reduced rectal side effects of radiation in participants six months after pelvic radiotherapy (Ehrenpreis 2005).
  • In a pilot study, 20 patients with chronic radiation proctitis from previous pelvic irradiation took vitamin E (400 IU, three times daily) and vitamin C (500 mg, three times daily). Significant improvements were reported in bleeding and diarrhea, but not for rectal pain (Kennedy 2001).
  • In a 2016 analysis of 14 trials examining the effect of hyperbaric oxygen therapy on radiation-induced tissue damage, authors concluded that hyperbaric oxygen therapy can improve outcome for patients with late-stage tissue injuries such as proctitis (Bennett 2016). For instance, in a study in 226 patients with radiation-induced proctitis, hyperbaric oxygen therapy significantly improved healing and led to better quality of life (Clarke 2008).

Erectile dysfunction occurs in 6–84% of prostate cancer patients treated with external beam radiation and up to 51% treated with brachytherapy (Incrocci 2002). In a review of scientific research, phosphodiesterase-5 inhibitors such as sildenafil citrate (Viagra) were safe and effective in men with erectile dysfunction after radiotherapy for prostate cancer (Yang, Qian 2013).

  • Forty-two patients with prostate cancer were randomized to receive 200 mg soy isoflavone or placebo daily for six months beginning on the first day of radiation therapy. The soy-treated group had a higher overall ability to achieve erections (77% vs. 57.1%) and less urinary leakage, rectal cramping, diarrhea, and pain with bowel movements than the placebo group (Ahmad 2010).

Female-specific side effects. Women treated with radiation for cervical cancer experience more pain during intercourse (Noronha 2013).

  • In a randomized open-label trial of 120 patients with cervical cancer, oral enzymes including trypsin, chymotrypsin, and papain given during radiation therapy improved symptoms related to radiation-induced tissue damage. There were fewer skin, vaginal mucosa, urinary, and gastrointestinal symptoms in the group taking enzymes (Dale 2001).

Urinary symptoms. Radiation cystitis, or inflammation of the bladder, may cause pain, urinary frequency and urgency, and blood in the urine (hemorrhagic cystitis) (Rigaud 2004). Pelvic floor muscle exercises prescribed by a physical therapist may be beneficial for urinary incontinence following radiotherapy to the pelvis (Bernardo-Filho 2014).

  • Curcumin was studied in a pilot study of 40 patients with prostate cancer. Patients randomly assigned to the curcumin group took 3 grams of BCM-95 (Bio-curcumin) daily beginning one week prior and through completion of eight weeks of external beam radiation therapy. This form of curcumin is a more bioavailable form. Patients were asked to complete a quality of life questionnaire related to urinary, sexual, and bowel symptoms. Urinary symptoms were milder in the curcumin group than the placebo group after 20 weeks of treatment, suggesting a radioprotective effect of curcumin on healthy tissues (Hejazi 2013).
  • In a randomized, double-blind, placebo-controlled trial, prostate cancer patients with acute radiation cystitis (inflammation of the bladder) were given either cranberry capsules (containing 72 mg proanthocyanidins) or a placebo. Men took one capsule daily throughout radiation treatment and for two weeks after the end of treatment. Cystitis occurred in 65% of men taking cranberry capsules versus 90% in those taking placebo. The incidence of pain and burning was significantly lower in those taking cranberry (Hamilton 2015). Another study in 370 men treated with IMRT for six to seven weeks found a decreased rate of lower urinary tract infections (UTIs) in patients taking 200 mg cranberry tablets (30% proanthocyanidins). In the group taking the cranberry tablets, only 16 of 184 participants (8.7%) developed lower UTIs throughout treatment; in the group treated with radiation only, 45 of 186 participants (24.2%) developed lower UTIs. Additionally, painful urination, nighttime urination, and urinary frequency and urgency were all reduced (Bonetta 2012). Finally, in a large study of 924 men with prostate cancer treated with radiotherapy, taking cranberry extract for six to seven weeks during radiation reduced the number of lower UTIs by approximately 50% (Bonetta 2017).

Radiation-induced hemorrhagic cystitis can be treated successfully with hyperbaric oxygen therapy, which was shown in several studies to be safe, effective, and well tolerated (Dellis 2014; Payne 2013; Dellis 2017).

Skin, Systemic, and Other Radiation Side Effects

Acute radiation dermatitis (inflammation of the skin). Dermatitis is a common side effect of radiotherapy, and skin reactions can be more severe depending on many factors, including a larger treatment field, larger total dose of radiation, and a longer duration of treatment. Dermatitis includes redness (erythema), pain, and peeling skin (desquamation). Skin changes can occur in up to 95% of patients receiving radiotherapy and may limit treatment for some patients (McQuestion 2011; Chan 2014).

Several dressings and films used to treat radiation dermatitis can provide a moist healing environment that helps cells migrate across the wound, thereby shortening healing time. Topical agents, such as the topical antibiotic silver sulfadiazine (Silvadene) and the anti-inflammatory cream trolamine (Biafine), are commonly prescribed at the onset of radiation dermatitis or at the beginning of radiotherapy. Trolamine is a water-based emulsion used in France since 1973 to alleviate symptoms of radiation dermatitis (McQuestion 2011; Chan 2014; Pommier 2004).

  • A topical cream containing Boswellia serrata extract was studied as a preventive treatment against radiation dermatitis in a randomized controlled trial in 114 women undergoing radiation treatment after surgery for breast cancer. The cream was applied immediately after radiation and before bedtime on days that radiotherapy was received. Skin redness was significantly less severe in those in the Boswellia group. Only 25% of women in the Boswellia group, versus 63% in the placebo group, had to use cortisone cream for skin reactions. Adverse superficial skin reactions caused by radiation therapy occurred more frequently in the placebo group than the Boswellia group (Togni 2015).
  • Calendula officinalis, a variety of marigold flower, has anti-inflammatory properties and can aid in wound healing (Preethi 2009; Parente 2012). A randomized trial compared a cream containing calendula extract to the prescription medication trolamine for prevention of acute radiation dermatitis in breast cancer patients. Patients applied the preparation to the irradiated skin at least twice daily starting the first day of radiotherapy and continued until completion of their treatment. Calendula-treated patients had a significantly lower rate of acute dermatitis of grade 2 or higher (Pommier 2004).
  • In clinical trials, aloe vera gel added to soap had a protective effect against radiation-induced dermatitis for patients who received higher cumulative radiation doses, prolonging the time to detectable skin damage from three to five weeks (Olsen 2001).
  • A silymarin-based cream reduced radiation-induced dermatitis in a study of patients with breast cancer. Only 76.5% of patients treated with the silymarin-based cream experienced skin reactions versus 98% in the control group (Becker-Schiebe 2011).
  • Curcumin was studied in a randomized, double-blind, placebo-controlled trial of 30 patients with breast cancer undergoing radiation therapy. Patients took 2 grams oral curcumin capsules or placebo three times daily beginning on the first day of treatment and throughout four to seven weeks of radiation. Curcumin significantly reduced the severity of radiation dermatitis and moist desquamation (Ryan 2013).
  • A study in 71 patients receiving radiation for breast cancer showed that a product containing resveratrol, lycopene, vitamin C, and anthocyanins taken orally during treatment was associated with reduced skin toxicity compared with the group not taking this product. Both groups received a prophylactic topical therapy containing hyaluronic acid and steroids. The treatment began 10 days before the start of radiation therapy and continued until 10 days following the end of radiotherapy (Di Franco 2012; Kma 2013).
  • A review of two trials totaling 219 patients with head and neck cancers or cervical cancer showed that a proteolytic enzyme preparation called Wobe-Mugos E (100 mg papain, 40 mg trypsin, and 40 mg chymotrypsin) decreased the odds of developing radiation-induced skin reaction by 87% (Chan 2014).
  • In a phase 1 trial of patients with breast cancer receiving radiotherapy after surgery, grade 2 dermatitis developed in eight women, but severity decreased after topical treatment with EGCG (Zhao 2016). A second trial published the same year confirmed that EGCG reduced pain, burning, and itching in a similar group of patients (Bonucci 2017; Zhu 2016; Zhao 2016).
  • In a phase 2 randomized trial of patients with breast cancer treated with radiation therapy after surgery, a melatonin cream significantly reduced the incidence of dermatitis (Ben-David 2016).
  • Forty breast cancer patients undergoing radiation therapy were randomized to a group treated with oral glutamine (15 grams) or a control group. In the glutamine group, 11.1% of patients developed grade 2 skin reactions compared with 80% in the control group, a statistically significant difference (Eda 2016).

Radiation-induced fibrosis. Fibrosis, or thickening of connective tissue, is a serious late effect of radiotherapy that can affect the skin (Bray 2016). Twenty-two patients who developed radiation-induced fibrosis following radiotherapy for breast cancer were treated orally with 800 mg pentoxifylline and 1000 IU vitamin E daily. The area of radiation-induced fibrosis was significantly reduced after six months, with no adverse effects noted (Delanian 2003). For more information on fibrosis, see the section titled “Lung (pulmonary) toxicity.”

  • Quercetin, a plant-derived flavonol, decreased radiation-induced skin fibrosis in mice. Quercetin reduced TNF-α and TGF-β, increased MMP-1 activity, and reduced oxidative stress—all factors involved in the development of fibrosis. Mice ate food that contained quercetin for one week prior to radiation and throughout radiation and follow-up (Horton 2013).

Lymphedema. Lymphedema is an accumulation of protein-rich lymph fluid that results in swelling of the underlying skin (Cormier 2010; Rockson 2001; Ueda-Iuchi 2015). For instance, after radiotherapy for breast cancer, swelling may occur in the arm if the lymphatic drainage is unintentionally blocked or cut off. Lymphedema results in pain, increased risk of infection, and increased volume of the affected limb (Rebegea 2015). Obesity prior to initiating treatment can increase the chance of developing lymphedema (Ridner 2011).

Several non-pharmacological options are available for managing lymphedema, including graded compression garments, skin care, a gentle massage called manual lymphatic drainage, and physical therapy (Rebegea 2015; Smith 2015; Greene 2010). A literature review showed that low-level laser therapy may reduce pain and swelling for patients that have received radiotherapy for breast cancer (Smoot 2014).

  • Several studies have shown benefit of selenium as sodium selenite for reducing lymphedema at multiple sites at doses ranging from 300–500 mcg daily, administered for 4‒6 weeks after radiotherapy (Bruns 2003). In an exploratory study, 48 patients with upper limb edema or head and neck edema were evaluated after completing radiotherapy. Patients received 500 mcg sodium selenite daily over four to six weeks. The majority of patients showed a reduction in edema characteristics and were able to avoid major surgical interventions (Bruns 2003; Micke 2003).

Fatigue. Radiation therapy is associated with fatigue in up to 80% of patients while they undergo the treatment. Fatigue can persist after the completion of radiation therapy and is reported in 30% of patients during follow-up visits. The mechanism of radiation-induced fatigue is poorly understood (Jereczek-Fossa 2002). Fatigue during radiation is described as feeling tired, weak, and worn out. In some cases, fatigue may be a downstream effect of anemia, anxiety or depression, lack of activity, medication side effect, or infection (ACS 2007).

  • American ginseng (Panax quinquefolius) is an herb containing ginsenosides with anti-inflammatory properties (Wang 2009; Barton 2013). In an eight-week, randomized, double-blind, placebo-controlled study, 2,000 mg American ginseng reduced fatigue in 364 patients with cancer treated with radiotherapy and/or chemotherapy. At eight weeks, fatigue scores were significantly improved in the ginseng group compared with placebo. Participants in the ginseng group undergoing active cancer treatment showed more improvement than those who already completed cancer treatment. No adverse side effects were reported (Barton 2013).
  • Twelve patients with advanced cancer undergoing radiation and/or chemotherapy received 6 grams L-carnitine daily for four weeks. Fatigue decreased significantly, and lean body mass and appetite increased significantly after L- carnitine supplementation (Gramignano 2006).
  • Melatonin has been described previously in the antioxidant section of this protocol for beneficial effects against radiation-induced fatigue (Seely 2012; Wang, Jin 2012).
  • A number of studies have examined the therapeutic value of exercise for fatigue during cancer treatment, with group exercise programs being beneficial for increased motivation (Kuchinski 2009; Reif 2012). A study in 408 elderly patients receiving treatment for cancer with radiation, chemotherapy, or both showed that exercise during and after treatment decreased the severity of multiple symptoms including fatigue (Sprod 2012).

    A review of scientific literature found that patients with breast cancer who exercised while undergoing treatment experienced an improvement in fatigue, depression, and overall quality of life. Moderate physical activity for 90–120 minutes weekly was most effective for improving fatigue (Carayol 2013).

    In a study of men with prostate cancer receiving radiotherapy randomized to aerobic exercise three times per week for eight weeks or to radiotherapy alone, the exercise group experienced reduced fatigue, better quality of life, improved cardiovascular fitness, and increased flexibility and muscle strength (Monga 2007). Another trial was performed to determine whether aerobic exercise would reduce the incidence of fatigue and prevent deteriorating physical function during radiotherapy for localized prostate carcinoma. Men who followed advice to rest if they became fatigued experienced a slight deterioration in physical function and a significant increase in fatigue at the time of radiotherapy. By contrast, a home-based, moderate-intensity walking program produced significantly improved physical function among participants, with no significant increase in fatigue (Windsor 2004). Home-based, moderate-intensity walking programs also reduced fatigue in patients with breast cancer undergoing radiation and chemotherapy (Mock 2005; Juvet 2017; Lipsett 2017).

Other helpful modalities may include relaxation therapy, group psychotherapy, and sleep (Jereczek-Fossa 2002).

Nausea and vomiting. Radiation-induced nausea and vomiting occurs typically with radiation to the upper abdomen, liver, and brain, although it can occur with radiation to other parts of the body. Radiation-induced nausea and vomiting worsens for patients treated with chemotherapy at the same time (Maranzano 2010; ACS 2013; ACS 2016b). If untreated, nausea and vomiting can cause physiological changes, including dehydration, electrolyte imbalance, malnutrition, and cachexia. The use of a 5‐hydroxytryptamine-receptor antagonist, such as granisetron (Kytril), is the most common approach for treating radiation-induced nausea and vomiting. Steroids are also commonly prescribed (ACS 2013).

  • Zingiber officinale, or ginger, is often used to alleviate nausea and vomiting. However, ginger has not been widely studied in combination with radiation therapy and has had mixed efficacy in studies on chemotherapy-induced nausea and vomiting (Palatty 2013).
  • The effect of vitamin B6 on radiation sickness was tested in 104 patients undergoing radiotherapy. Fifty-two patients received 100 mg vitamin B6 one hour before radiation therapy daily for seven days, and the control group received radiation alone. The vitamin B6 group experienced reduced radiation sickness (32.6%) compared with the control group (48.1%), with less nausea and vomiting and improved appetite (Mahajan 1998).
  • Other strategies for minimizing nausea and vomiting described in the previous sections on gastrointestinal mucositis and esophagitis include green tea and zinc.
  • The use of acupressure bands has proven successful for both chemotherapy- and radiotherapy-induced nausea and vomiting. These over-the-counter bands are cost-effective and safe. In particular, they stimulate the “P6” acupuncture point on the wrist that is known to correlate with nausea. In a randomized study on 88 patients with nausea receiving radiation for different cancers, acupressure bands plus standard care decreased average nausea by 23.8%. Standard care alone reduced nausea by 4.8% (Roscoe 2009).

Cachexia and Poor Appetite

Cachexia, which refers to a rapid loss of fat and muscle tissue, may negatively impact patients’ quality of life and response to therapy (Topkan 2007). Cachexia is caused by an inflammatory reaction that involves the molecules TNF-α and IL-6, which play a role in radiation resistance. Therefore, treatment that inhibits cachexia could also increase the tumor’s radiosensitivity, leading to improved survival outcomes (Laine 2013).

Patients with inoperable head and neck and esophageal cancers who undergo chemoradiotherapy are prone to weight loss and cachexia, which sometimes appear before the start of therapy (Fietkau 2013). Radiation-induced side effects such as nausea, vomiting, esophagitis, mucositis, and diarrhea can limit the patient’s ability to eat or absorb nutrients, thereby worsening cachexia (Topkan 2007). Strategies for addressing these side effects can be found in the “Preventing Damage to Healthy Tissue” section. Medications used to stimulate appetite include megestrol acetate (Megace), which is a synthetic progesterone derivative, and dronabinol (Marinol), which is a synthetic form of tetrahydrocannabinol (THC), the main psychoactive substance found in the Cannabis sativa plant. Other medications may increase body mass, including anabolic steroids, growth hormone, non-steroidal anti-inflammatory drugs (NSAIDs), TNF-α inhibitors, and ghrelin, a hormone secreted by the stomach and pancreas during fasting (Gullett 2011).

  • Omega-3 fatty acids such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) from fish oil modulate inflammatory pathways (Calder 2013). A randomized controlled trial found that 111 patients undergoing chemoradiotherapy with the addition of EPA and DHA for head and neck and esophageal cancer had improved measures of nutritional and functional status compared with patients receiving only standard nutrition. The fatty acid content of the nutritional formula included 2 grams EPA and 0.85 grams DHA. The formula was administered daily over 14 weeks of treatment. There was a trend towards a smaller decrease in body mass. The experimental group lost an average of 0.82 kg and the control group lost 2.82 kg. The inflammatory cytokine IL-6 was increased in both groups, but much less in the fatty acid group, supporting the anti-inflammatory effect of EPA and DHA (Fietkau 2013).
  • L-carnitine, as described in the fatigue section, may increase lean body mass and appetite (Gramignano 2006).

For more information regarding cachexia and interventions, refer to the protocol on Catabolic Wasting.

Low Blood Cell Count

Low blood cell count is not generally associated with radiation unless there is excessive bleeding or radiation to the blood cell-producing bone marrow. Anemia is discussed previously in the section “Strategies to Optimize Radiotherapy Response.”

  • A literature review, including 1427 patients in 14 different studies, found that astragalus improved white blood cell count during radiotherapy (He 2013).
  • As described in the antioxidant supplement section, melatonin has been shown in multiple studies to improve platelet and white blood cell counts (Seely 2012; Wang, Jin 2012). Many white blood cells have receptors for melatonin on their surface. Melatonin can bind these cells and protect them from the effects of radiation (Najafi 2017).

Secondary Cancers

Although long-term survival after treatment for primary cancer has increased significantly in recent years, one of the most serious side effects of cancer treatment is development of a new tumor (Ng 2015). Second cancers account for up to 18% of all incident cancers in the United States, with 8% of them resulting from radiotherapy. The others are thought to arise as a result of genetic factors, aging, and lifestyle (Travis 2013; Oeffinger 2013).

The increased risk of second malignancy can occur either directly in the radiation field or elsewhere in the body (Hall 2003). The risk is dose-dependent and appears to be higher when radiation exposure occurs at a younger age (Wakeford 2004). The latency period is long; for example, the risk to develop leukemia is usually highest five to nine years after radiotherapy, and an interval of more than 10 years and often decades is common for solid tumors (Travis 2006).

A large number of studies have evaluated the risk of second cancers following radiotherapy for Hodgkin's lymphoma. In a study of patients treated for Hodgkin’s lymphoma between 1965 and 2000, the risk of second malignancy was 4.6-fold higher than the risk in the general population (van Eggermond 2014; Schaapveld 2015). A 2015 study showed that patients treated for Hodgkin’s lymphoma before the year 2000 had a slightly higher risk of developing a second cancer than those treated after 2000, which is thought to be attributed to improvement in treatment techniques (LeMieux 2015). An emerging technique for radiation therapy in Hodgkin’s lymphoma, called involved-site radiation therapy, appears to reduce the radiation dose to healthy tissue and may reduce the lifetime risk of second cancers (Mazonakis 2017).

Overall, the risk of second cancers is generally low, and the benefit of radiation therapy for patients outweighs the risk of developing a second tumor (Travis 2006). Because some research studies have identified the common sites of second cancers for certain types of primary cancers, this offers physicians the opportunity, in some instances, to increase surveillance and try to catch second cancers at an early stage (Rigter 2017; Koo 2015).

In general, smoking cessation, weight control, and physical activity can help prevent development of second cancers (Travis 2013). In fact, smoking was shown in a large study on head and neck cancer patients to significantly increase risk of second cancers and death (Khuri 2006). General strategies for cancer prevention as well as therapeutic recommendations are covered in the protocol on Cancer Adjuvant Therapy. Refer to recommendations in the section of this protocol on antioxidants for strategies that can potentially prevent the DNA changes that could lead to second cancers.

  • A study on cancer-free mice receiving resveratrol during whole body radiation found fewer chromosome abnormalities in bone marrow compared with mice not receiving resveratrol, suggesting a radioprotective effect on the bone marrow. Resveratrol was given for two days before and the day of whole body irradiation (3 Gy). Resveratrol was added to the drinking water for 30 days after (Carsten 2008).

8 Dietary And Lifestyle Considerations

Importance of Nutrition During Treatment

Radiation therapy can change nutritional needs and alter the body's digestion, absorption, and use of food. Common cancer symptoms and toxic effects of radiation treatment associated with nutritional status include anorexia, weight change, nausea, vomiting, and changes in taste and bowel habits. A study on counseling on the intake of nutrient-dense foods and high-protein liquid formulations showed improved maintenance of body weight and quality of life and reduced anorexia (poor appetite) and diarrhea (Rock 2005).

Specific Nutritional Interventions During Radiotherapy

Low-residue diet. Fiber slows gastrointestinal transit time and thus may not be appropriate for patients at risk for intestinal blockage or patients who have been advised to eat a low-residue (low-fiber) diet (Stubbe 2013). Patients who have had abdominal surgery or abdominal or pelvic irradiation are at increased risk of developing bowel obstruction (NCI 2015; Baxter 2007).

Calorie restriction. Certain dietary strategies, including calorie restriction, the ketogenic diet, or intermittent fasting may enhance chemotherapy or radiation therapy and reduce side effects (O'Flanagan 2017). On a cellular level, the pathways involved in cancer cell metabolism can be targeted with biological agents; those same pathways can also be influenced by calorie restriction. In mice, calorie restriction combined with radiation therapy targeted these pathways and slowed cancer growth, decreased metastases, and prolonged survival (Simone 2016). In humans, the same effect was seen with restriction of carbohydrates rather than full calorie restriction. This type of diet is a ketogenic diet, or a low-carbohydrate, high-fat diet. In a small study of 10 patients with advanced cancer, carbohydrates were restricted to 5% of total calorie intake for 26–28 days. In those patients with higher ketosis (burning fat instead of carbohydrates for energy), partial reversal of several indicators of poor prognosis was observed and insulin was decreased. Patients did lose some weight, although authors indicated the diet is safe (Fine 2012). For patients unable to tolerate a high-fat diet, intermittent fasting may be appropriate, and in those where weight change is not an issue, calorie restriction may be beneficial (Klement 2014).

Multivitamins and antioxidants. In one study of 2264 women, 81% took different antioxidants throughout treatment after a diagnosis of breast cancer. There was a decreased risk of breast cancer recurrence in those taking vitamins C and E and decreased risk of death from any cause in those taking vitamin E. In contrast, there was an increased risk of death from any cause and death from breast cancer in those taking combination carotenoids (Greenlee 2012). That same cohort of breast cancer patients was also assessed for multivitamin use. Those taking a multivitamin before diagnosis and throughout treatment had a reduced risk of breast cancer recurrence and total mortality. Women who took multivitamins before and after diagnosis, ate more fruits and vegetables, and were more physically active had better overall survival (Kwan 2011). The Shanghai breast cancer survivor study, another large trial, did not show the same beneficial effects of vitamins C or E or multivitamin use with radiotherapy, but this may be because fewer patients took a supplement after radiation (Nechuta 2011; Kwan 2011).

Avoid Smoking

Smoking decreases the oxygen-carrying capacity of the blood and leads to poorer treatment outcomes, and it should be avoided in order to improve the efficacy of radiotherapy (Hoff 2012). Smoking also leads to more severe osteoradionecrosis of the jaw in patients with head and neck cancer (Chronopoulos 2015). A 2017 meta-analysis of data from over 40,000 women treated for breast cancer found that the risks of radiation therapy may outweigh the benefits for long-term smokers (Taylor 2017). Women in this situation should consult their healthcare provider about the best treatment course.

Physical Activity

Extensive research shows that exercise is safe during radiotherapy and improves physical functioning, fatigue, and overall quality of life. Patients already on an exercise program prior to receiving radiotherapy may need to decrease the intensity and/or duration of exercise during treatment, but the goal is to maintain exercise as much as possible. For patients who did not exercise prior to radiation, exercises such as stretching and slow walks should be initiated gradually. In some cases, an exercise professional or physical therapist may be helpful (Rock 2012). The section on “fatigue” provides more information on the benefits of physical activity.

For More Information

The complications related to radiation can be acute (such as low blood cell counts) and chronic (gastrointestinal, pulmonary, neuropathic, and cardiac conditions). For more information on some of the topics outlined in this protocol, please consult the following protocols:

Proton Therapy Centers in North America

For a current list of centers visit: http://www.proton-therapy.org/map.htm

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

Abayomi OK. Neck irradiation, carotid injury and its consequences. Oral oncology. Oct 2004;40(9):872-878.

Abdallah NM, Noaman E, Eltahawy NA, Badawi AM, Kandil E, Mansour NA, Mohamed HE. Anticancer and Radiosensitization Efficacy of Nanocomposite Withania somnifera Extract in Mice Bearing Tumor Cells. Asian Pacific journal of cancer prevention: APJCP. 2016;17(9):4367-4375.

ACS. American Cancer Society. Nausea and Vomiting. www.cancer.org. Last updated 3/27/2013. Accessed 11/16/2017.

ACS. American Cancer Society. External Beam Radiation Therapy. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/radiation/external-beam-radiation-therapy.html. Last updated 2/10/2017a. Accessed 10/13/2017.

ACS. American Cancer Society. Hyperthermia to Treat Cancer. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/hyperthermia.html. Last updated 5/3/2016a. Accessed 10/13/2017.

ACS. American Cancer Society. The Science Behind Radiation Therapy. http://www.cancer.org/acs/groups/cid/documents/webcontent/003019-pdf.pdf. Last updated 10/27/2014a. Accessed 6/3/2015.

ACS. American Cancer Society. Understanding Nausea and Vomiting. https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/nausea-and-vomiting/what-is-it.html. Last updated 6/9/2016b. Accessed 10/13/2017.

ACS. American Cancer Society. Internal Radiation Therapy (Brachytherapy). https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/radiation/internal-radiation-therapy-brachytherapy.html. Last updated 2/10/2017b. Accessed 11/16/2017.

ACS. American Cancer Society. Radiation Therapy and You. http://www.cancer.gov/publications/patient-education/radiationttherapy.pdf. Last updated: 5/2007. Accessed 5/10/15.

ACS. American Cancer Society. Understanding Radiation Therapy: A Guide for Patients and Families. http://www.cancer.org/acs/groups/cid/documents/webcontent/003028-pdf.pdf. Last updated 5/2/14b. Accessed 2/28/15.

Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, Siddique NA, . . . Anwar F. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac J Trop Biomed. May 2013;3(5):337-352.

Ahmad IU, Forman JD, Sarkar FH, Hillman GG, Heath E, Vaishampayan U, . . . Kucuk O. Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer. Nutr Cancer. 2010;62(7):996-1000.

Ahmed K, Zaidi SF. Treating cancer with heat: hyperthermia as promising strategy to enhance apoptosis. J Pak Med Assoc. Apr 2013;63(4):504-508.

Ahmed KA, Chinnaiyan P, Fulp WJ, Eschrich S, Torres-Roca JF, Caudell JJ. The radiosensitivity index predicts for overall survival in glioblastoma. Oncotarget. Oct 27 2015;6(33):34414-34422.

Ahmed KA, Fulp WJ, Berglund AE, Hoffe SE, Dilling TJ, Eschrich SA, . . . Torres-Roca JF. Differences Between Colon Cancer Primaries and Metastases Using a Molecular Assay for Tumor Radiation Sensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection. International journal of radiation oncology, biology, physics. Jul 15 2015;92(4):837-842.

Akita S. Treatment of Radiation Injury. Advances in wound care. Jan 1 2014;3(1):1-11.

Alonso-Gonzalez C, Gonzalez A, Martinez-Campa C, Gomez-Arozamena J, Cos S. Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double-strand DNA break repair. Journal of pineal research. Mar 2015;58(2):189-197.

Altas E, Ertekin MV, Gundogdu C, Demirci E. L-carnitine reduces cochlear damage induced by gamma irradiation in Guinea pigs. Annals of clinical and laboratory science. Summer 2006;36(3):312-318.

Andic F, Garipagaoglu M, Yurdakonar E, Tuncel N, Kucuk O. Lycopene in the prevention of gastrointestinal toxicity of radiotherapy. Nutrition and cancer. 2009;61(6):784-788.

Aravindan S, Natarajan M, Herman TS, Awasthi V, Aravindan N. Molecular basis of 'hypoxic' breast cancer cell radio-sensitization: phytochemicals converge on radiation induced Rel signaling. Radiation oncology (London, England). 2013;8:46.

Armstrong D, Raissouni S, Price Hiller J, Mercer J, Powell E, MacLean A, . . . Vickers MM. Predictors of Pathologic Complete Response After Neoadjuvant Treatment for Rectal Cancer: A Multicenter Study. Clinical colorectal cancer. Dec 2015;14(4):291-295.

Arthurs E, Hanna TP, Zaza K, Peng Y, Hall SF. Stroke After Radiation Therapy for Head and Neck Cancer: What Is the Risk? Int J Radiat Oncol Biol Phys. Nov 01 2016;96(3):589-596.

ASCO. American Society of Clinical Oncology. Proton Therapy. http://www.cancer.net/navigating-cancer-care/how-cancer-treated/radiation-therapy/proton-therapy. Last updated 2015. Accessed 5/18/15.

Assayed ME. Radioprotective effects of black seed (Nigella sativa) oil against hemopoietic damage and immunosuppression in gamma-irradiated rats. Immunopharmacology and immunotoxicology. Jun 2010;32(2):284-296.

Attia A, Rapp SR, Case LD, D'Agostino R, Lesser G, Naughton M, . . . Shaw EG. Phase II study of Ginkgo biloba in irradiated brain tumor patients: effect on cognitive function, quality of life, and mood. Journal of neuro-oncology. Sep 2012;109(2):357-363.

Awa H, Futamura A, Higashiguchi T, Ito A, Mori N, Murai M, . . . Kaneko T. Effects of Combined Treatment with Branched-Chain Amino Acids, Citric Acid, L-Carnitine, Coenzyme Q10, Zinc, and Various Vitamins in Tumor-Bearing Mice. Biological & pharmaceutical bulletin. Mar 01 2017;40(3):266-271.

Bae SH, Kim MS, Jang WI, Cho CK, Yoo HJ, Kim KB, . . . Lee DH. Low Hepatic Toxicity in Primary and Metastatic Liver Cancers after Stereotactic Ablative Radiotherapy Using 3 Fractions. Journal of Korean medical science. Aug 2015;30(8):1055-1061.

Bairati I, Meyer F, Gelinas M, Fortin A, Nabid A, Brochet F, . . . Roy J. Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Aug 20 2005;23(24):5805-5813.

Baker S, Fairchild A. Radiation-induced esophagitis in lung cancer. Lung Cancer (Auckland, N.Z.). 2016;7:119-127.

Baliga S, Kabarriti R, Ohri N, Haynes-Lewis H, Yaparpalvi R, Kalnicki S, Garg MK. Stereotactic body radiotherapy for recurrent head and neck cancer: A critical review. Head & neck. Mar 2017;39(3):595-601.

Bansal N, Soni A, Kaur P, Chauhan AK, Kaushal V. Exploring the Management of Radiation Proctitis in Current Clinical Practice. Journal of clinical and diagnostic research : JCDR. Jun 2016;10(6):Xe01-xe06.

Bar-Ad V, Ohri N, Werner-Wasik M. Esophagitis, treatment-related toxicity in non-small cell lung cancer. Reviews on recent clinical trials. Feb 2012;7(1):31-35.

Barbour SY. Corticosteroids in the treatment of chemotherapy-induced nausea and vomiting. Journal of the National Comprehensive Cancer Network: JNCCN. Apr 2012;10(4):493-499.

Barton DL, Liu H, Dakhil SR, Linquist B, Sloan JA, Nichols CR, . . . Loprinzi CL. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. Journal of the National Cancer Institute. Aug 21 2013;105(16):1230-1238.

Baskar R, Dai J, Wenlong N, Yeo R, Yeoh KW. Biological response of cancer cells to radiation treatment. Frontiers in molecular biosciences. 2014;1:24.

Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193-199.

Bast, Jr, MD, Donald W Kufe, MD, Raphael E Pollock, MD, PhD, Ralph R Weichselbaum, MD, James F Holland, MD, ScD (hc), and Emil Frei, III, MD. Holland-Frei Cancer Medicine, 5th edition. Chapter 14: Ionizing Radiation. 2000.

Basu, Partha. A Pilot Phase II Two-Arm, Randomized Clinical Trial of Concomitant Immunotherapy (With Interferon-Alpha and Retinoic Acid) and Radiation Therapy for the Treatment of Advanced Cervical Cancer in India. ClinicalTrials.gov [Internet]. Bethesda (MD). Identifier NCT01276730. https://clinicaltrials.gov/ct2/show/study/NCT01276730. Last updated 11/23/2016. Accessed 11/20/2017.

Baxter NN, Hartman LK, Tepper JE, Ricciardi R, Durham SB, Virnig BA. Postoperative irradiation for rectal cancer increases the risk of small bowel obstruction after surgery. Ann Surg. Apr 2007;245(4):553-559.

Becker-Schiebe M, Mengs U, Schaefer M, Bulitta M, Hoffmann W. Topical use of a silymarin-based preparation to prevent radiodermatitis : results of a prospective study in breast cancer patients. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]. Aug 2011;187(8):485-491.

Belcaro G, Hosoi M, Pellegrini L, Appendino G, Ippolito E, Ricci A, . . . Togni S. A controlled study of a lecithinized delivery system of curcumin (Meriva(R)) to alleviate the adverse effects of cancer treatment. Phytotherapy research: PTR. Mar 2014;28(3):444-450.

Ben-David MA, Elkayam R, Gelernter I, Pfeffer RM. Melatonin for Prevention of Breast Radiation Dermatitis: A Phase II, Prospective, Double-Blind Randomized Trial. The Israel Medical Association journal: IMAJ. Mar-Apr 2016;18(3-4):188-192.

Benais-Pont G, Dupertuis YM, Kossovsky MP, Nouet P, Allal AS, Buchegger F, Pichard C. Omega-3 polyunsaturated fatty acids and ionizing radiation: combined cytotoxicity on human colorectal adenocarcinoma cells. Nutrition (Burbank, Los Angeles County, Calif.). Sep 2006;22(9):931-939.

Bennett MH, Feldmeier J, Hampson NB, Smee R, Milross C. Hyperbaric oxygen therapy for late radiation tissue injury. The Cochrane database of systematic reviews. Apr 28 2016;4:Cd005005.

Bennett MH, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour sensitisation to radiotherapy. The Cochrane database of systematic reviews. 2012;4:Cd005007.

Bentzen J, Toustrup K, Eriksen JG, Primdahl H, Andersen LJ, Overgaard J. Locally advanced head and neck cancer treated with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. Results from the DAHANCA 18 phase II study. Acta oncologica (Stockholm, Sweden). Jan 28 2015:1-7.

Berman AT, Rosenthal SA, Moghanaki D, Woodhouse KD, Movsas B, Vapiwala N. Focusing on the "Person" in Personalized Medicine: The Future of Patient-Centered Care in Radiation Oncology. Journal of the American College of Radiology: JACR. Dec 2016;13(12 Pt B):1571-1578.

Berman AT, Turowski J, Mick R, Cengel K, Farnese N, Basel-Brown L, . . . Rengan R. Dietary Flaxseed in Non-Small Cell Lung Cancer Patients Receiving Chemoradiation. Journal of pulmonary & respiratory medicine. Aug 30 2013;3(4):154.

Bernardo-Filho M, Barbosa Junior ML, da Cunha Sa-Caputo D, de Aguiar Ede O, de Lima RP, Santos-Filho SD, . . . Tavares A. The relevance of the procedures related to the physiotherapy in the interventions in patients with prostate cancer: short review with practice approach. International journal of biomedical science: IJBS. Jun 2014;10(2):73-84.

Bese NS, Munzuroglu F, Uslu B, Arbak S, Yesiladali G, Sut N, . . . Ober A. Vitamin E protects against the development of radiation-induced pulmonary fibrosis in rats. Clinical oncology (Royal College of Radiologists (Great Britain)). May 2007;19(4):260-264.

Bhutani M, Pathak AK. Re: Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? Journal of the National Cancer Institute. Sep 17 2008;100(18):1334; author reply 1334-1335.

Biswal BM, Zakaria A, Ahmad NM. Topical application of honey in the management of radiation mucositis: a preliminary study. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. Apr 2003;11(4):242-248.

Blanco AI, Teh BS, Amato RJ. Role of radiation therapy in the management of renal cell cancer. Cancers. Oct 26 2011;3(4):4010-4023.

Blijlevens N, Sonis S. Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic growth factor with multiple biological activities in preventing chemotherapy- and radiotherapy-induced mucositis. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. May 2007;18(5):817-826.

Block K, Koch A, Mead M, Newman RA, Gyllenhaal C. Re: Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? Journal of the National Cancer Institute. Jan 21 2009;101(2):124-125; author reply 125-126.

Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C. Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials. Cancer treatment reviews. Aug 2007;33(5):407-418.

Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C. Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials. International journal of cancer. Journal international du cancer. Sep 15 2008;123(6):1227-1239.

Body JJ, Casimiro S, Costa L. Targeting bone metastases in prostate cancer: improving clinical outcome. Nature reviews. Urology. Jun 2015;12(6):340-356.

Bonetta A, Di Pierro F. Enteric-coated, highly standardized cranberry extract reduces risk of UTIs and urinary symptoms during radiotherapy for prostate carcinoma. Cancer management and research. 2012;4:281-286.

Bonetta A, Roviello G, Generali D, Zanotti L, Cappelletti MR, Pacifico C, Di Pierro F. Enteric-coated and highly standardized cranberry extract reduces antibiotic and nonsteroidal anti-inflammatory drug use for urinary tract infections during radiotherapy for prostate carcinoma. Research and reports in urology. 2017;9:65-69.

Bonucci M, Fioranelli M, Roccia MG, Lotti T. Possible use of epigallocatechin-3-gallate (EGCG) as prevention of radio dermatitis in radiotherapy treated breast cancer patients. Dermatologic therapy. Apr 10 2017.

Borriello A, Bencivenga D, Caldarelli I, Tramontano A, Borgia A, Zappia V, Della Ragione F. Resveratrol: from basic studies to bedside. Cancer Treat Res. 2014;159:167-184.

Braga FP, Lemos Junior CA, Alves FA, Migliari DA. Acupuncture for the prevention of radiation-induced xerostomia in patients with head and neck cancer. Brazilian oral research. Mar-Apr 2011;25(2):180-185.

Braun DP, Gupta D, Birdsall TC, Sumner M, Staren ED. Effect of naturopathic and nutritional supplement treatment on tumor response, control, and recurrence in patients with prostate cancer treated with radiation therapy. Journal of alternative and complementary medicine. Mar 2013;19(3):198-203.

Bray FN, Simmons BJ, Wolfson AH, Nouri K. Acute and Chronic Cutaneous Reactions to Ionizing Radiation Therapy. Dermatology and therapy. Jun 2016;6(2):185-206.

Bristol ML, Di X, Beckman MJ, Wilson EN, Henderson SC, Maiti A, . . . Gewirtz DA. Dual functions of autophagy in the response of breast tumor cells to radiation: cytoprotective autophagy with radiation alone and cytotoxic autophagy in radiosensitization by vitamin D 3. Autophagy. May 1 2012;8(5):739-753.

Bruns F, Micke O, Bremer M. Current status of selenium and other treatments for secondary lymphedema. The journal of supportive oncology. Jul-Aug 2003;1(2):121-130.

Bucci MK, Bevan A, Roach M, 3rd. Advances in radiation therapy: conventional to 3D, to IMRT, to 4D, and beyond. CA: a cancer journal for clinicians. Mar-Apr 2005;55(2):117-134.

Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? British journal of clinical pharmacology. Mar 2013;75(3):645-662.

Calveley VL, Jelveh S, Langan A, Mahmood J, Yeung IW, Van Dyk J, Hill RP. Genistein can mitigate the effect of radiation on rat lung tissue. Radiation research. May 2010;173(5):602-611.

Campen CJ, Kranick SM, Kasner SE, Kessler SK, Zimmerman RA, Lustig R, . . . Fisher MJ. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke. Nov 2012;43(11):3035-3040.

Cankar K, Finderle Z, Jan J. The effect of hyperbaric oxygenation on postradiation xerostomia and saliva in patients with head and neck tumours. Caries research. 2011;45(2):136-141.

Cao DD, Xu HL, Xu M, Qian XY, Yin ZC, Ge W. Therapeutic role of glutamine in management of radiation enteritis: a meta-analysis of 13 randomized controlled trials. Oncotarget. May 02 2017;8(18):30595-30605.

Carayol M, Bernard P, Boiche J, Riou F, Mercier B, Cousson-Gelie F, . . . Ninot G. Psychological effect of exercise in women with breast cancer receiving adjuvant therapy: what is the optimal dose needed? Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. Feb 2013;24(2):291-300.

Carsten RE, Bachand AM, Bailey SM, Ullrich RL. Resveratrol reduces radiation-induced chromosome aberration frequencies in mouse bone marrow cells. Radiation research. Jun 2008;169(6):633-638.

Carulli G, Rocco M, Panichi A, Chios CF, Ciurli E, Mannucci C, . . . Petrini M. Treatment of oral mucositis in hematologic patients undergoing autologous or allogeneic transplantation of peripheral blood stem cells: a prospective, randomized study with a mouthwash containing camelia sinensis leaf extract. Hematology reports. Jan 25 2013;5(1):21-25.

CCS. Canadian Cancer Society. Osteoradionecrosis. http://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/managing-side-effects/osteoradionecrosis/?region=bc. 2015. Accessed 5/24/15.

Cemek M, Enginar H, Karaca T, Unak P. In vivo radioprotective effects of Nigella sativa L oil and reduced glutathione against irradiation-induced oxidative injury and number of peripheral blood lymphocytes in rats. Photochemistry and photobiology. Nov-Dec 2006;82(6):1691-1696.

Chan RJ, Webster J, Chung B, Marquart L, Ahmed M, Garantziotis S. Prevention and treatment of acute radiation-induced skin reactions: a systematic review and meta-analysis of randomized controlled trials. BMC cancer. 2014;14:53.

Chandra RA, Wilhite TJ, Balboni TA, Alexander BM, Spektor A, Ott PA, . . . Schoenfeld JD. A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology. Nov 2015;4(11):e1046028.

Chapel A, Francois S, Douay L, Benderitter M, Voswinkel J. New insights for pelvic radiation disease treatment: Multipotent stromal cell is a promise mainstay treatment for the restoration of abdominopelvic severe chronic damages induced by radiotherapy. World journal of stem cells. Oct 26 2013;5(4):106-111.

Chapman CH, Nagesh V, Sundgren PC, Buchtel H, Chenevert TL, Junck L, . . . Cao Y. Diffusion tensor imaging of normal-appearing white matter as biomarker for radiation-induced late delayed cognitive decline. International journal of radiation oncology, biology, physics. Apr 01 2012;82(5):2033-2040.

Charpentier AM, Conrad T, Sykes J, Ng A, Zhou R, Parent A, . . . Hodgson DC. Active breathing control for patients receiving mediastinal radiation therapy for lymphoma: Impact on normal tissue dose. Practical radiation oncology. May-Jun 2014;4(3):174-180.

Chendil D, Ranga RS, Meigooni D, Sathishkumar S, Ahmed MM. Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene. Feb 26 2004;23(8):1599-1607.

Cheng JC, Wu JK, Huang CM, Huang DY, Cheng SH, Lin YM, . . . Huang AT. Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description. Radiother Oncol. Apr 2002;63(1):41-45.

Cheng JC, Wu JK, Huang CM, Liu HS, Huang DY, Cheng SH, . . . Huang AT. Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: dosimetric analysis and implication. International journal of radiation oncology, biology, physics. Sep 1 2002;54(1):156-162.

Cho YJ, Yi CO, Jeon BT, Jeong YY, Kang GM, Lee JE, . . . Lee JD. Curcumin attenuates radiation-induced inflammation and fibrosis in rat lungs. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology. Aug 2013;17(4):267-274.

Choudhury PS, Savio E, Solanki KK, Alonso O, Gupta A, Gambini JP, . . . Dondi M. (99m)Tc glucarate as a potential radiopharmaceutical agent for assessment of tumor viability: from bench to the bed side. World journal of nuclear medicine. May 2012;11(2):47-56.

Chronopoulos A, Zarra T, Troltzsch M, Mahaini S, Ehrenfeld M, Otto S. Osteoradionecrosis of the mandible: A ten year single-center retrospective study. Journal of cranio-maxillo-facial surgery: official publication of the European Association for Cranio-Maxillo-Facial Surgery. Apr 1 2015.

Chu CN, Chen SW, Bai LY, Mou CH, Hsu CY, Sung FC. Increase in stroke risk in patients with head and neck cancer: a retrospective cohort study. British journal of cancer. Oct 25 2011;105(9):1419-1423.

Cikman O, Ozkan A, Aras AB, Soylemez O, Alkis H, Taysi S, Karaayvaz M. Radioprotective effects of Nigella sativa oil against oxidative stress in liver tissue of rats exposed to total head irradiation. Journal of investigative surgery : the official journal of the Academy of Surgical Research. Oct 2014;27(5):262-266.

Clarke RE, Tenorio LM, Hussey JR, Toklu AS, Cone DL, Hinojosa JG, . . . Walker MB. Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and controlled double-blind crossover trial with long-term follow-up. Int J Radiat Oncol Biol Phys. Sep 01 2008;72(1):134-143.

Clavo B, Perez JL, Lopez L, Suarez G, Lloret M, Rodriguez V, . . . Robaina F. Ozone Therapy for Tumor Oxygenation: a Pilot Study. Evidence-based complementary and alternative medicine : eCAM. Jun 01 2004;1(1):93-98.

Clavo B, Santana-Rodriguez N, Llontop P, Gutierrez D, Ceballos D, Mendez C, . . . Fiuza D. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients. Evidence-based complementary and alternative medicine : eCAM. 2015;2015:480369.

Clavo B, Suarez G, Aguilar Y, Gutierrez D, Ponce P, Cubero A, . . . Carreras JL. Brain ischemia and hypometabolism treated by ozone therapy. Forschende Komplementarmedizin (2006). 2011;18(5):283-287.

Cleveland Clinic. Active Breathing Coordinator. http://my.clevelandclinic.org/services/cancer/treatments-procedures/radiation-therapy/active-breathing-coordinator. 2015. Accessed 3/12/15.

Cleveland Clinic. Diseases and Conditions. Proctitis. http://my.clevelandclinic.org/health/diseases_conditions/hic_Proctitis. Last reviewed 10/2/11. Accessed 5/17/15.

Cognetti DM, Weber RS, Lai SY. Head and neck cancer: an evolving treatment paradigm. Cancer. Oct 01 2008;113(7 Suppl):1911-1932.

Cohen EP, Robbins ME. Radiation nephropathy. Seminars in nephrology. Sep 2003;23(5):486-499.

Coppola A, Coppola L, Luongo C, Arciello A, Cacciapuoti F, Lama D, . . . Gombos G. Ozonized autohemotransfusion does not affect arterial vasodilation in patients with peripheral arterial disease. The International journal of angiology : official publication of the International College of Angiology, Inc. Spring 2007;16(1):7-11.

Cormier JN, Askew RL, Mungovan KS, Xing Y, Ross MI, Armer JM. Lymphedema beyond breast cancer: a systematic review and meta-analysis of cancer-related secondary lymphedema. Cancer. Nov 15 2010;116(22):5138-5149.

Coyle C, Cafferty FH, Langley RE. Aspirin and Colorectal Cancer Prevention and Treatment: Is It for Everyone? Current colorectal cancer reports. 2016;12:27-34.

Coyle KM, Boudreau JE, Marcato P. Genetic Mutations and Epigenetic Modifications: Driving Cancer and Informing Precision Medicine. BioMed research international. 2017;2017:9620870.

D'Andrea GM. Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA: a cancer journal for clinicians. Sep-Oct 2005;55(5):319-321.

D'Errico G, Machado HL, Sainz B, Jr. A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet. Clinical and translational medicine. Dec 2017;6(1):3.

Dale PS, Tamhankar CP, George D, Daftary GV. Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: evidence of the reduction of acute side effects. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S29-34.

Daniels LA, Krol SD, de Graaf MA, Scholte AJ, van 't Veer MB, Putter H, . . . Creutzberg CL. Impact of cardiovascular counseling and screening in Hodgkin lymphoma survivors. International journal of radiation oncology, biology, physics. Sep 1 2014;90(1):164-171.

Danielsson D, Brehwens K, Halle M, Marczyk M, Sollazzo A, Polanska J, . . . Haghdoost S. Influence of genetic background and stress response on risk of mandibular osteoradionecrosis after radiotherapy of head and neck cancer. Head & neck. Oct 28 2014.

Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, . . . Hall P. Risk of ischemic heart disease in women after radiotherapy for breast cancer. The New England journal of medicine. Mar 14 2013;368(11):987-998.

de Aguiar Pastore Silva J, Emilia de Souza Fabre M, Waitzberg DL. Omega-3 supplements for patients in chemotherapy and/or radiotherapy: A systematic review. Clinical nutrition (Edinburgh, Scotland). Jun 2015;34(3):359-366.

De Bruin ML, Dorresteijn LD, van't Veer MB, Krol AD, van der Pal HJ, Kappelle AC, . . . van Leeuwen FE. Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. Journal of the National Cancer Institute. Jul 1 2009;101(13):928-937.

de Freitas RB, Boligon AA, Rovani BT, Piana M, de Brum TF, da Silva Jesus R, . . . de Freitas Bauerman L. Effect of black grape juice against heart damage from acute gamma TBI in rats. Molecules. 2013;18(10):12154-12167.

De Meerleer G, Khoo V, Escudier B, Joniau S, Bossi A, Ost P, . . . Mareel M. Radiotherapy for renal-cell carcinoma. The Lancet. Oncology. Apr 2014;15(4):e170-177.

DeLaney TF. Proton therapy in the clinic. Frontiers of radiation therapy and oncology. 2011;43:465-485.

Delanian S, Chatel C, Porcher R, Depondt J, Lefaix JL. Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial. International journal of radiation oncology, biology, physics. Jul 1 2011;80(3):832-839.

Delanian S, Porcher R, Balla-Mekias S, Lefaix JL. Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jul 1 2003;21(13):2545-2550.

Delia P, Sansotta G, Donato V, Frosina P, Messina G, De Renzis C, Famularo G. Use of probiotics for prevention of radiation-induced diarrhea. World journal of gastroenterology: WJG. Feb 14 2007;13(6):912-915.

Dellis A, Deliveliotis C, Kalentzos V, Vavasis P, Skolarikos A. Is there a role for hyberbaric oxygen as primary treatment for grade IV radiation-induced haemorrhagic cystitis? A prospective pilot-feasibility study and review of literature. International braz j urol: official journal of the Brazilian Society of Urology. May-Jun 2014;40(3):296-305.

Dellis A, Papatsoris A, Kalentzos V, Deliveliotis C, Skolarikos A. Hyberbaric oxygen as sole treatment for severe radiation - induced haemorrhagic cystitis. International braz j urol : official journal of the Brazilian Society of Urology. May-Jun 2017;43(3):489-495.

Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. The Journal of clinical investigation. Feb 2014;124(2):687-695.

Deorukhkar A, Ahuja N, Mercado AL, Diagaradjane P, Raju U, Patel N, . . . Krishnan S. Zerumbone increases oxidative stress in a thiol-dependent ROS-independent manner to increase DNA damage and sensitize colorectal cancer cells to radiation. Cancer medicine. Feb 2015;4(2):278-292.

Di Franco R, Calvanese M, Murino P, Manzo R, Guida C, Di Gennaro D, . . . Ravo V. Skin toxicity from external beam radiation therapy in breast cancer patients: protective effects of Resveratrol, Lycopene, Vitamin C and anthocianin (Ixor(R)). Radiation oncology (London, England). 2012;7:12.

Dieleman FJ, Phan TT, van den Hoogen FJ, Kaanders JH, Merkx MA. The efficacy of hyperbaric oxygen therapy related to the clinical stage of osteoradionecrosis of the mandible. International journal of oral and maxillofacial surgery. Apr 2017;46(4):428-433.

Dietrich J, Rao K, Pastorino S, Kesari S. Corticosteroids in brain cancer patients: benefits and pitfalls. Expert Rev Clin Pharmacol. Mar 2011;4(2):233-242.

Dobrzynska MM. Resveratrol as promising natural radioprotector. A review. Roczniki Panstwowego Zakladu Higieny. 2013;64(4):255-262.

Dorresteijn LD, Kappelle AC, Boogerd W, Klokman WJ, Balm AJ, Keus RB, . . . Bartelink H. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jan 1 2002;20(1):282-288.

Dutta SW, Showalter SL, Showalter TN, Libby B, Trifiletti DM. Intraoperative radiation therapy for breast cancer patients: current perspectives. Breast cancer (Dove Medical Press). 2017;9:257-263.

Eda K, Uzer K, Murat T, Cenk U. The effects of enteral glutamine on radiotherapy induced dermatitis in breast cancer. Clinical nutrition (Edinburgh, Scotland). Apr 2016;35(2):436-439.

Ehrenpreis ED, Jani A, Levitsky J, Ahn J, Hong J. A prospective, randomized, double-blind, placebo-controlled trial of retinol palmitate (vitamin A) for symptomatic chronic radiation proctopathy. Diseases of the colon and rectum. Jan 2005;48(1):1-8.

El-Missiry MA, Fayed TA, El-Sawy MR, El-Sayed AA. Ameliorative effect of melatonin against gamma-irradiation-induced oxidative stress and tissue injury. Ecotoxicology and environmental safety. Feb 2007;66(2):278-286.

Eldredge-Hindy H, Lockamy V, Crawford A, Nettleton V, Werner-Wasik M, Siglin J, . . . Anne PR. Active Breathing Coordinator reduces radiation dose to the heart and preserves local control in patients with left breast cancer: report of a prospective trial. Practical radiation oncology. Jan-Feb 2015;5(1):4-10.

Elekta. Active Breathing Coordinator™. https://www.elekta.com/radiotherapy/treatment-solutions/motion-management/active-breathing-coordinator.html. Copyright 2017. Accessed 10/19/17.

Epstein JB, Thariat J, Bensadoun RJ, Barasch A, Murphy BA, Kolnick L, . . . Maghami E. Oral complications of cancer and cancer therapy: from cancer treatment to survivorship. CA: a cancer journal for clinicians. Nov-Dec 2012;62(6):400-422.

Erol FS, Topsakal C, Ozveren MF, Kaplan M, Ilhan N, Ozercan IH, Yildiz OG. Protective effects of melatonin and vitamin E in brain damage due to gamma radiation: an experimental study. Neurosurg Rev. Jan 2004;27(1):65-69.

Ertekin MV, Kocer I, Karslioglu I, Taysi S, Gepdiremen A, Sezen O, . . . Bakan N. Effects of oral Ginkgo biloba supplementation on cataract formation and oxidative stress occurring in lenses of rats exposed to total cranium radiotherapy. Japanese journal of ophthalmology. Sep-Oct 2004;48(5):499-502.

Eschrich SA, Fulp WJ, Pawitan Y, Foekens JA, Smid M, Martens JW, . . . Torres-Roca JF. Validation of a radiosensitivity molecular signature in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. Sep 15 2012;18(18):5134-5143.

Eschrich SA, Pramana J, Zhang H, Zhao H, Boulware D, Lee JH, . . . Torres-Roca JF. A gene expression model of intrinsic tumor radiosensitivity: prediction of response and prognosis after chemoradiation. International journal of radiation oncology, biology, physics. Oct 01 2009;75(2):489-496.

Espenel S, Vallard A, Rancoule C, Garcia MA, Guy JB, Chargari C, . . . Magne N. Melanoma: Last call for radiotherapy. Critical reviews in oncology/hematology. Feb 2017;110:13-19.

Estoesta RP, Attwood L, Naehrig D, Claridge-Mackonis E, Odgers D, Martin D, . . . Carroll S. Assessment of voluntary deep inspiration breath-hold with CINE imaging for breast radiotherapy. Journal of medical imaging and radiation oncology. Apr 22 2017.

Eustace A, Irlam JJ, Taylor J, Denley H, Agrawal S, Choudhury A, . . . West CM. Necrosis predicts benefit from hypoxia-modifying therapy in patients with high risk bladder cancer enrolled in a phase III randomised trial. Radiother Oncol. Jul 2013;108(1):40-47.

Fan XW, Chen F, Chen Y, Chen GH, Liu HH, Guan SK, . . . Wu KL. Electroacupuncture prevents cognitive impairments by regulating the early changes after brain irradiation in rats. PloS one. 2015;10(4):e0122087.

Fang Y, Bradley MJ, Cook KM, Herrick EJ, Nicholl MB. A potential role for resveratrol as a radiation sensitizer for melanoma treatment. The Journal of surgical research. Aug 2013;183(2):645-653.

Fang Y, DeMarco VG, Nicholl MB. Resveratrol enhances radiation sensitivity in prostate cancer by inhibiting cell proliferation and promoting cell senescence and apoptosis. Cancer science. Jun 2012;103(6):1090-1098.

Fard-Esfahani A, Emami-Ardekani A, Fallahi B, Fard-Esfahani P, Beiki D, Hassanzadeh-Rad A, Eftekhari M. Adverse effects of radioactive iodine-131 treatment for differentiated thyroid carcinoma. Nuclear medicine communications. Aug 2014;35(8):808-817.

Farzaei MH, Bahramsoltani R, Rahimi R. Phytochemicals as Adjunctive with Conventional Anticancer Therapies. Current pharmaceutical design. 2016;22(27):4201-4218.

Feher J, Lengyel G. Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Current pharmaceutical biotechnology. Jan 2012;13(1):210-217.

Fernandez-Gil B, Moneim AE, Ortiz F, Shen YQ, Soto-Mercado V, Mendivil-Perez M, . . . Escames G. Melatonin protects rats from radiotherapy-induced small intestine toxicity. PLoS One. 2017;12(4):e0174474.

Fietkau R, Lewitzki V, Kuhnt T, Holscher T, Hess CF, Berger B, . . . Lubgan D. A disease-specific enteral nutrition formula improves nutritional status and functional performance in patients with head and neck and esophageal cancer undergoing chemoradiotherapy: results of a randomized, controlled, multicenter trial. Cancer. Sep 15 2013;119(18):3343-3353.

Findlay VJ, Moretz RE, Wang C, Vaena SG, Bandurraga SG, Ashenafi M, . . . Camp ER. Slug expression inhibits calcitriol-mediated sensitivity to radiation in colorectal cancer. Molecular carcinogenesis. Feb 2014;53 Suppl 1:E130-139.

Fine EJ, Segal-Isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, . . . Sparano JA. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition (Burbank, Los Angeles County, Calif.). Oct 2012;28(10):1028-1035.

Florimonte L, Dellavedova L, Maffioli LS. Radium-223 dichloride in clinical practice: a review. European journal of nuclear medicine and molecular imaging. Sep 2016;43(10):1896-1909.

Foote RL, Stafford SL, Petersen IA, Pulido JS, Clarke MJ, Schild SE, . . . Diasio RB. The clinical case for proton beam therapy. Radiation oncology (London, England). 2012;7:174.

Fritz H, Kennedy DA, Ishii M, Fergusson D, Fernandes R, Cooley K, Seely D. Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review. Integrative cancer therapies. May 2015;14(3):201-211.

Fuccio L, Frazzoni L, Guido A. Prevention of pelvic radiation disease. World J Gastrointest Pharmacol Ther. Feb 6 2015;6(1):1-9.

Fuccio L, Guido A, Eusebi LH, Laterza L, Grilli D, Cennamo V, . . . Bazzoli F. Effects of probiotics for the prevention and treatment of radiation-induced diarrhea. Journal of clinical gastroenterology. Jul 2009;43(6):506-513.

Fuchs-Tarlovsky V, Rivera MA, Altamirano KA, Lopez-Alvarenga JC, Ceballos-Reyes GM. Antioxidant supplementation has a positive effect on oxidative stress and hematological toxicity during oncology treatment in cervical cancer patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. May 2013;21(5):1359-1363.

Gajowik A, Dobrzynska MM. Lycopene - antioxidant with radioprotective and anticancer properties. A review. Roczniki Panstwowego Zakladu Higieny. 2014;65(4):263-271.

Garcia-Albeniz X, Chan AT. Aspirin for the prevention of colorectal cancer. Best Pract Res Clin Gastroenterol. Aug 2011;25(4-5):461-472.

Garcia-Peris P, Velasco C, Hernandez M, Lozano MA, Paron L, de la Cuerda C, . . . Guarner F. Effect of inulin and fructo-oligosaccharide on the prevention of acute radiation enteritis in patients with gynecological cancer and impact on quality-of-life: a randomized, double-blind, placebo-controlled trial. European journal of clinical nutrition. Feb 2016;70(2):170-174.

Gash KJ, Chambers AC, Cotton DE, Williams AC, Thomas MG. Potentiating the effects of radiotherapy in rectal cancer: the role of aspirin, statins and metformin as adjuncts to therapy. British journal of cancer. Jun 22 2017.

Gaspar BL, Sharma P, Das R. Anemia in malignancies: pathogenetic and diagnostic considerations. Hematology (Amsterdam, Netherlands). Jan 2015;20(1):18-25.

Gaurav K, Goel RK, Shukla M, Pandey M. Glutamine: A novel approach to chemotherapy-induced toxicity. Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology. Jan 2012;33(1):13-20.

Gavriel H, Eviatar E, Abu Eta R. Hyperbaric oxygen therapy for maxillary bone radiation-induced injury: A 15-year single-center experience. Head & neck. Feb 2017;39(2):275-278.

Gewirtz DA. Autophagy as a mechanism of radiation sensitization in breast tumor cells. Autophagy. May-Jun 2007;3(3):249-250.

Ghobrial I, Witzig T. Radioimmunotherapy: a new treatment modality for B-cell non-Hodgkin's lymphoma. Oncology (Williston Park, N.Y.). May 2004;18(5):623-630; discussion 633-624, 637-628, 640.

Giglio P, Gilbert MR. Neurologic complications of cancer and its treatment. Curr Oncol Rep. Jan 2010;12(1):50-59.

Giotopoulos G, Symonds RP, Foweraker K, Griffin M, Peat I, Osman A, Plumb M. The late radiotherapy normal tissue injury phenotypes of telangiectasia, fibrosis and atrophy in breast cancer patients have distinct genotype-dependent causes. British journal of cancer. Mar 26 2007;96(6):1001-1007.

Giridhar P, Mallick S, Rath GK, Julka PK. Radiation induced lung injury: prediction, assessment and management. Asian Pacific journal of cancer prevention: APJCP. 2015;16(7):2613-2617.

Giunta R, Coppola A, Luongo C, Sammartino A, Guastafierro S, Grassia A, . . . Coppola L. Ozonized autohemotransfusion improves hemorheological parameters and oxygen delivery to tissues in patients with peripheral occlusive arterial disease. Annals of hematology. Dec 2001;80(12):745-748.

Glicksman JT, Khalili S, Fung K, Parnes LS, Agrawal SK. Pentoxifylline-tocopherol-clodronate combination: A novel treatment for osteoradionecrosis of the temporal bone. Head & neck. Dec 2015;37(12):E191-193.

Gold Standard. Drug Monograph. Palifermin. www.clinicalkey.com. Last updated 7/8/2016. Accessed 12/20/2016.

Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, . . . Pearson TA. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. Feb 2011;42(2):517-584.

Good J, Harrington K. The hallmarks of cancer and the radiation oncologist: updating the 5Rs of radiobiology. Clinical Oncology. 2013;25(10):569-577.

Gramaglia A, Loi GF, Mongioj V, Baronzio GF. Increased survival in brain metastatic patients treated with stereotactic radiotherapy, omega three fatty acids and bioflavonoids. Anticancer research. Nov-Dec 1999;19(6c):5583-5586.

Gramignano G, Lusso MR, Madeddu C, Massa E, Serpe R, Deiana L, . . . Mantovani G. Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition (Burbank, Los Angeles County, Calif.). Feb 2006;22(2):136-145.

Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD. Radiation-induced brain injury: A review. Frontiers in oncology. 2012;2:73.

Greene R, Fowler R. Physical therapy management of primary lymphedema in the lower extremities: A case report. Physiotherapy theory and practice. Jan 2010;26(1):62-68.

Greenlee H, Kwan ML, Kushi LH, Song J, Castillo A, Weltzien E, . . . Caan BJ. Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort. Cancer. Apr 15 2012;118(8):2048-2058.

Grober U, Holzhauer P, Kisters K, Holick MF, Adamietz IA. Micronutrients in Oncological Intervention. Nutrients. Mar 12 2016;8(3):163.

Gruca A, Krawczyk Z, Szeja W, Grynkiewicz G, Rusin A. Synthetic genistein glycosides inhibiting EGFR phosphorylation enhance the effect of radiation in HCT 116 colon cancer cells. Molecules (Basel, Switzerland). 2014;19(11):18558-18573.

Gu J, Liu K, Li H, Wang X, Yang K. Astragalus saponin attenuates the expression of fibrosis-related molecules in irradiated cardiac fibroblasts. Acta biochimica et biophysica Sinica. Jun 2014;46(6):492-501.

Gu J, Zhu S, Li X, Wu H, Li Y, Hua F. Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials. PloS one. 2014;9(5):e95968.

Gujral DM, Cheung WK, Shah BN, Chahal NS, Bhattacharyya S, Hooper J, . . . Nutting CM. Contrast enhancement of carotid adventitial vasa vasorum as a biomarker of radiation-induced atherosclerosis. Radiother Oncol. Jul 2016;120(1):63-68.

Gujral DM, Shah BN, Chahal NS, Senior R, Harrington KJ, Nutting CM. Clinical features of radiation-induced carotid atherosclerosis. Clinical oncology (Royal College of Radiologists (Great Britain)). Feb 2014;26(2):94-102.

Gujral MS, Patnaik PM, Kaul R, Parikh HK, Conradt C, Tamhankar CP, Daftary GV. Efficacy of hydrolytic enzymes in preventing radiation therapy-induced side effects in patients with head and neck cancers. Cancer chemotherapy and pharmacology. Jul 2001;47 Suppl:S23-28.

Gul K, Muge A, Taner A, Sehri E. Oral glutamine supplementation reduces radiotherapy- induced esophagitis in lung cancer patients. Asian Pacific journal of cancer prevention : APJCP. 2015;16(1):53-58.

Gullett NP, Mazurak VC, Hebbar G, Ziegler TR. Nutritional interventions for cancer-induced cachexia. Current problems in cancer. Mar-Apr 2011;35(2):58-90.

Guo Z, Shu Y, Zhou H, Zhang W, Wang H. Radiogenomics helps to achieve personalized therapy by evaluating patient responses to radiation treatment. Carcinogenesis. Mar 2015;36(3):307-317.

Gupta T, Narayan CA. Image-guided radiation therapy: Physician's perspectives. Journal of medical physics. Oct 2012;37(4):174-182.

Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. International journal of radiation oncology, biology, physics. May 1 2003;56(1):83-88.

Hall S, Rudrawar S, Zunk M, Bernaitis N, Arora D, McDermott CM, Anoopkumar-Dukie S. Protection against Radiotherapy-Induced Toxicity. Antioxidants (Basel, Switzerland). Jul 05 2016;5(3).

Hamilton K, Bennett NC, Purdie G, Herst PM. Standardized cranberry capsules for radiation cystitis in prostate cancer patients in New Zealand: a randomized double blinded, placebo controlled pilot study. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. Jan 2015;23(1):95-102.

Hampson NB, Holm JR, Wreford-Brown CE, Feldmeier J. Prospective assessment of outcomes in 411 patients treated with hyperbaric oxygen for chronic radiation tissue injury. Cancer. Aug 01 2012;118(15):3860-3868.

Hanchanale S, Adkinson L, Daniel S, Fleming M, Oxberry SG. Systematic literature review: xerostomia in advanced cancer patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. Mar 2015;23(3):881-888.

Hanck AB. Vitamin C and cancer. Prog Clin Biol Res. 1988;259:307-320.

Harrison L, Blackwell K. Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? Oncologist. 2004;9 Suppl 5:31-40.

Hayashi H, Kobayashi R, Suzuki A, Yamada Y, Ishida M, Shakui T, . . . Itoh Y. Preparation and clinical evaluation of a novel lozenge containing polaprezinc, a zinc-L-carnosine, for prevention of oral mucositis in patients with hematological cancer who received high-dose chemotherapy. Medical oncology (Northwood, London, England). Aug 2016;33(8):91.

Haymaker CL, Kim D, Uemura M, Vence LM, Phillip A, McQuail N, . . . Diab A. Metastatic Melanoma Patient Had a Complete Response with Clonal Expansion after Whole Brain Radiation and PD-1 Blockade. Cancer immunology research. Feb 2017;5(2):100-105.

He H, Zhou X, Wang Q, Zhao Y. Does the couse of astragalus-containing chinese herbal prescriptions and radiotherapy benefit to non-small-cell lung cancer treatment: a meta-analysis of randomized trials. Evidence-based complementary and alternative medicine : eCAM. 2013;2013:426207.

Heianna J, Miyauchi T, Endo W, Miura N, Terui K, Kamata S, Hashimoto M. Tumor regression of multiple bone metastases from breast cancer after administration of strontium-89 chloride (Metastron). Acta Radiologica Short Reports. May 1, 2014 2014;3(4).

Hejazi J, Rastmanesh R, Taleban FA, Molana SH, Ehtejab G. A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer. Journal of Cancer Science and Therapy. 2013;5(10):320-324.

Heysek RV. Modern brachytherapy for treatment of prostate cancer. Cancer control : journal of the Moffitt Cancer Center. Jul 2007;14(3):238-243.

Higdon J. Linus Pauling Institute. Oregon State University. Micronutrient Information Center. Cruciferous Vegetables. http://lpi.oregonstate.edu/mic/food-beverages/cruciferous-vegetables. Last updated 12/2016. Accessed 11/20/17.

Hille A, Herrmann MK, Kertesz T, Christiansen H, Hermann RM, Pradier O, . . . Hess CF. Sodium butyrate enemas in the treatment of acute radiation-induced proctitis in patients with prostate cancer and the impact on late proctitis. A prospective evaluation. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]. Dec 2008;184(12):686-692.

Hillman GG, Singh-Gupta V, Runyan L, Yunker CK, Rakowski JT, Sarkar FH, . . . Konski AA. Soy isoflavones radiosensitize lung cancer while mitigating normal tissue injury. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. Nov 2011;101(2):329-336.

Hoff CM. Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy. Acta oncologica (Stockholm, Sweden). Apr 2012;51(4):419-432.

Hoggan BL, Cameron AL. Systematic review of hyperbaric oxygen therapy for the treatment of non-neurological soft tissue radiation-related injuries. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. Jun 2014;22(6):1715-1726.

Horton JA, Li F, Chung EJ, Hudak K, White A, Krausz K, . . . Citrin D. Quercetin inhibits radiation-induced skin fibrosis. Radiation research. Aug 2013;180(2):205-215.

Hoskin PJ, Rojas AM, Bentzen SM, Saunders MI. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Nov 20 2010;28(33):4912-4918.

Hu Y, Li Z, Mi DH, Cao N, Zu SW, Wen ZZ, . . . Qu Y. Chemoradiation combined with regional hyperthermia for advanced oesophageal cancer: a systematic review and meta-analysis. Journal of clinical pharmacy and therapeutics. Apr 2017;42(2):155-164.

Hu ZI, McArthur HL, Ho AY. The Abscopal Effect of Radiation Therapy: What Is It and How Can We Use It in Breast Cancer? Current breast cancer reports. 2017;9(1):45-51.

Hua Y, Ma S, Fu Z, Hu Q, Wang L, Piao Y. Intracavity hyperthermia in nasopharyngeal cancer: a phase III clinical study. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 2011;27(2):180-186.

Huang EY, Leung SW, Wang CJ, Chen HC, Sun LM, Fang FM, . . . Hsiung CY. Oral glutamine to alleviate radiation-induced oral mucositis: a pilot randomized trial. International journal of radiation oncology, biology, physics. Feb 1 2000;46(3):535-539.

Huang Y, Liu W, Liu H, Yang Y, Cui J, Zhang P, . . . Gao F. Grape seed pro-anthocyanidins ameliorates radiation-induced lung injury. Journal of cellular and molecular medicine. Jul 2014;18(7):1267-1277.

Huang Y, Zhao H, Cao K, Sun D, Yang Y, Liu C, . . . Gao F. Radioprotective Effect of Grape Seed Proanthocyanidins In Vitro and In Vivo. Oxid Med Cell Longev. 2016;2016:5706751.

Humm JL, Sartor O, Parker C, Bruland OS, Macklis R. Radium-223 in the treatment of osteoblastic metastases: a critical clinical review. International journal of radiation oncology, biology, physics. Apr 01 2015;91(5):898-906.

Hunter SE, Scher RL. Clinical implications of radionecrosis to the head and neck surgeon. Current opinion in otolaryngology & head and neck surgery. Apr 2003;11(2):103-106.

Hurwitz M, Stauffer P. Hyperthermia, radiation and chemotherapy: the role of heat in multidisciplinary cancer care. Seminars in oncology. Dec 2014;41(6):714-729.

Incrocci L, Slob AK, Levendag PC. Sexual (dys)function after radiotherapy for prostate cancer: a review. International journal of radiation oncology, biology, physics. Mar 1 2002;52(3):681-693.

Ismail AF, El-Sonbaty SM. Fermentation enhances Ginkgo biloba protective role on gamma-irradiation induced neuroinflammatory gene expression and stress hormones in rat brain. Journal of photochemistry and photobiology. B, Biology. May 2016;158:154-163.

Jang SS, Kim HG, Lee JS, Han JM, Park HJ, Huh GJ, Son CG. Melatonin reduces X-ray radiation-induced lung injury in mice by modulating oxidative stress and cytokine expression. International journal of radiation biology. Feb 2013;89(2):97-105.

Janoray G, Chapet S, Ruffier-Loubiere A, Bernadou G, Pointreau Y, Calais G. Robotic stereotactic body radiation therapy for tumors of the liver: radiation-induced liver disease, incidence and predictive factors. Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique. Jun 2014;18(3):191-197.

Jensen SB, Pedersen AM, Vissink A, Andersen E, Brown CG, Davies AN, . . . Brennan MT. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. Aug 2010;18(8):1061-1079.

Jereczek-Fossa BA, Marsiglia HR, Orecchia R. Radiotherapy-related fatigue. Critical reviews in oncology/hematology. Mar 2002;41(3):317-325.

Jiang Q, Huang H, Liu Q, Sun J, Zhou H, Fan Z, . . . Meng F. Continuous IV infusion of MESNA can prevent hemorrhagic cystitis in HSCT and retain MESNA concentration in urine. Bone marrow transplantation. Nov 2015;50(11):1490-1492.

Joiner M, Kogel Avd. Basic Clinical Radiobiology, 4th Ed. Hodder Arnold. 2009.

Jong JM, Oprea-Lager DE, Hooft L, de Klerk JM, Bloemendal HJ, Verheul HM, . . . van den Eertwegh AJ. Radiopharmaceuticals for Palliation of Bone Pain in Patients with Castration-resistant Prostate Cancer Metastatic to Bone: A Systematic Review. European urology. Sep 2016;70(3):416-426.

Juvet LK, Thune I, Elvsaas IKO, Fors EA, Lundgren S, Bertheussen G, . . . Oldervoll LM. The effect of exercise on fatigue and physical functioning in breast cancer patients during and after treatment and at 6 months follow-up: A meta-analysis. Breast (Edinburgh, Scotland). Jun 2017;33:166-177.

Kaanders JH, Bussink J, van der Kogel AJ. ARCON: a novel biology-based approach in radiotherapy. The Lancet. Oncology. Dec 2002;3(12):728-737.

Kaanders JH, Bussink J, van der Kogel AJ. Clinical studies of hypoxia modification in radiotherapy. Seminars in radiation oncology. Jul 2004;14(3):233-240.

Kaliberov SA, Buchsbaum DJ. Chapter seven--Cancer treatment with gene therapy and radiation therapy. Adv Cancer Res. 2012;115:221-263.

Kalthur G, Pathirissery UD. Enhancement of the response of B16F1 melanoma to fractionated radiotherapy and prolongation of survival by withaferin A and/or hyperthermia. Integrative cancer therapies. Dec 2010;9(4):370-377.

Kaluzny J, Wierzbicka M, Nogala H, Milecki P, Kopec T. Radiotherapy induced xerostomia: mechanisms, diagnostics, prevention and treatment--evidence based up to 2013. Otolaryngologia polska. The Polish otolaryngology. Jan-Feb 2014;68(1):1-14.

Kamran MZ, Ranjan A, Kaur N, Sur S, Tandon V. Radioprotective Agents: Strategies and Translational Advances. Medicinal research reviews. May 2016;36(3):461-493.

Kao CL, Huang PI, Tsai PH, Tsai ML, Lo JF, Lee YY, . . . Chiou SH. Resveratrol-induced apoptosis and increased radiosensitivity in CD133-positive cells derived from atypical teratoid/rhabdoid tumor. International journal of radiation oncology, biology, physics. May 1 2009;74(1):219-228.

Karagozoglu KH, Dekker HA, Rietveld D, de Bree R, Schulten EA, Kantola S, . . . van der Waal I. Proposal for a new staging system for osteoradionecrosis of the mandible. Medicina oral, patologia oral y cirugia bucal. Sep 2014;19(5):e433-437.

Karbownik M, Reiter RJ. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc Soc Exp Biol Med. Oct 2000;225(1):9-22.

Kasat V, Gupta A, Ladda R, Kathariya M, Saluja H, Farooqui AA. Transcutaneous electric nerve stimulation (TENS) in dentistry- A review. Journal of clinical and experimental dentistry. Dec 2014;6(5):e562-568.

Kaur P, Hurwitz MD, Krishnan S, Asea A. Combined hyperthermia and radiotherapy for the treatment of cancer. Cancers. Sep 30 2011;3(4):3799-3823.

Kawashima H. Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies. TheScientificWorldJournal. 2014;2014:492061.

Kaya V, Yazkan R, Yildirim M, Doguc DK, Suren D, Bozkurt KK, . . . Yalcin AY. The relation of radiation-induced pulmonary fibrosis with stress and the efficiency of antioxidant treatment: an experimental study. Medical science monitor : international medical journal of experimental and clinical research. 2014;20:290-296.

Kazuta M. [Enhancement of irradiation effect in carcinoma of the uterine cervix with the administration of protein-bound polysaccharide kureha (PS-K)]. Nihon Sanka Fujinka Gakkai zasshi. Sep 1985;37(9):1908-1914.

Kennedy M, Bruninga K, Mutlu EA, Losurdo J, Choudhary S, Keshavarzian A. Successful and sustained treatment of chronic radiation proctitis with antioxidant vitamins E and C. The American journal of gastroenterology. Apr 2001;96(4):1080-1084.

Kerns SL, West CM, Andreassen CN, Barnett GC, Bentzen SM, Burnet NG, . . . Rosenstein BS. Radiogenomics: the search for genetic predictors of radiotherapy response. Future oncology (London, England). Dec 2014;10(15):2391-2406.

Khuri FR, Lee JJ, Lippman SM, Kim ES, Cooper JS, Benner SE, . . . Hong WK. Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. Journal of the National Cancer Institute. Apr 5 2006;98(7):441-450.

Ki Y, Kim W, Kim YH, Kim D, Bae JS, Park D, . . . Nam J. Effect of Coenzyme Q10 on Radiation Nephropathy in Rats. J Korean Med Sci. May 2017;32(5):757-763.

Kim HG, Jang SS, Lee JS, Kim HS, Son CG. Panax ginseng Meyer prevents radiation-induced liver injury via modulation of oxidative stress and apoptosis. Journal of ginseng research. Apr 2017;41(2):159-168.

Kiremidjian-Schumacher L, Roy M, Glickman R, Schneider K, Rothstein S, Cooper J, . . . Newman R. Selenium and immunocompetence in patients with head and neck cancer. Biological trace element research. Feb 2000;73(2):97-111.

Kirste S, Treier M, Wehrle SJ, Becker G, Abdel-Tawab M, Gerbeth K, . . . Momm F. Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: a prospective, randomized, placebo-controlled, double-blind pilot trial. Cancer. Aug 15 2011;117(16):3788-3795.

Kishore S, Friedman T, Madoff DC. Update on Embolization Therapies for Hepatocellular Carcinoma. Current oncology reports. Jun 2017;19(6):40.

Klement RJ, Champ CE. Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R's through dietary manipulation. Cancer metastasis reviews. Mar 2014;33(1):217-229.

Kma L. Synergistic effect of resveratrol and radiotherapy in control of cancers. Asian Pacific journal of cancer prevention : APJCP. 2013;14(11):6197-6208.

Ko GJ, Obi Y, Tortorici AR, Kalantar-Zadeh K. Dietary protein intake and chronic kidney disease. Current opinion in clinical nutrition and metabolic care. Jan 2017;20(1):77-85.

Konidena A, Sharma D, Puri G, Dixit A, Jatti D, Gupta R. Effect of TENS on stimulation of saliva in postmenopausal women with or without oral dryness - An interventional study. Journal of oral biology and craniofacial research. Nov 2016;6(Suppl 1):S44-s50.

Koo E, Henderson MA, Dwyer M, Skandarajah AR. Management and Prevention of Breast Cancer After Radiation to the Chest for Childhood, Adolescent, and Young Adulthood Malignancy. Annals of surgical oncology. Dec 2015;22 Suppl 3:S545-551.

Kostaras X, Cusano F, Kline GA, Roa W, Easaw J. Use of dexamethasone in patients with high-grade glioma: a clinical practice guideline. Current oncology (Toronto, Ont.). Jun 2014;21(3):e493-503.

Kotowski U, Heiduschka G, Brunner M, Czembirek C, Eder-Czembirek C, Schmidt R, . . . Thurnher D. Radiosensitization of head and neck cancer cells by the phytochemical agent sulforaphane. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]. Sep 2011;187(9):575-580.

Koukourakis MI. Amifostine: is there evidence of tumor protection? Seminars in oncology. Dec 2003;30(6 Suppl 18):18-30.

Koukourakis MI, Kyrgias G, Panteliadou M, Papadopoulou A, Tsiarkatsi M, Papachristou E, Bebeli M. Dose escalation of amifostine for radioprotection during pelvic accelerated radiotherapy. American journal of clinical oncology. Aug 2013;36(4):338-343.

Kouvaris JR, Kouloulias VE, Vlahos LJ. Amifostine: the first selective-target and broad-spectrum radioprotector. Oncologist. Jun 2007;12(6):738-747.

Kozelsky TF, Meyers GE, Sloan JA, Shanahan TG, Dick SJ, Moore RL, . . . Martenson JA. Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. May 1 2003;21(9):1669-1674.

Kraeber-Bodere F, Bodet-Milin C, Rousseau C, Eugene T, Pallardy A, Frampas E, . . . Cherel M. Radioimmunoconjugates for the treatment of cancer. Seminars in oncology. Oct 2014;41(5):613-622.

Kuchinski AM, Reading M, Lash AA. Treatment-related fatigue and exercise in patients with cancer: a systematic review. Medsurg nursing : official journal of the Academy of Medical-Surgical Nurses. May-Jun 2009;18(3):174-180.

Kucuktulu E. Protective effect of melatonin against radiation induced nephrotoxicity in rats. Asian Pacific journal of cancer prevention: APJCP. 2012;13(8):4101-4105.

Kucuktulu E, Guner A, Kahraman I, Topbas M, Kucuktulu U. The protective effects of glutamine on radiation-induced diarrhea. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. Apr 2013;21(4):1071-1075.

Kuhn KS, Muscaritoli M, Wischmeyer P, Stehle P. Glutamine as indispensable nutrient in oncology: experimental and clinical evidence Eur J Nutr. Jun 2010;49(4):197-210.

Kumar A, Kaur H, Devi P, Mohan V. Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. Pharmacology & therapeutics. Dec 2009;124(3):259-268.

Kunheri B, Kotne S, Nair SS, Makuny D. A dosimetric analysis of cardiac dose with or without active breath coordinator moderate deep inspiratory breath hold in left sided breast cancer radiotherapy. Journal of cancer research and therapeutics. Jan-Mar 2017;13(1):56-61.

Kwan ML, Greenlee H, Lee VS, Castillo A, Gunderson EP, Habel LA, . . . Caan BJ. Multivitamin use and breast cancer outcomes in women with early-stage breast cancer: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. Nov 2011;130(1):195-205.

Kwon HC, Kim SK, Chung WK, Cho MJ, Kim JS, Kim JS, . . . Na BS. Effect of pentoxifylline on radiation response of non-small cell lung cancer: a phase III randomized multicenter trial. Radiotherapy and oncology : j Aug 2000;56(2):175-179.

Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM. Antioxidants and cancer therapy: a systematic review. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Feb 1 2004;22(3):517-528.

Ladas EJ, Kelly KM. Milk thistle: is there a role for its use as an adjunct therapy in patients with cancer? Journal of alternative and complementary medicine. Jun 2003;9(3):411-416.

Ladner HA, Salkeld RM. Vitamin B6 status in cancer patients: effect of tumor site, irradiation, hormones and chemotherapy Progress in clinical and biological research. 1988;259:273-281.

Lagerweij T, Hiddingh L, Biesmans D, Crommentuijn MH, Cloos J, Li XN, . . . Hulleman E. A chemical screen for medulloblastoma identifies quercetin as a putative radiosensitizer. Oncotarget. Jun 14 2016;7(24):35776-35788.

Laine A, Iyengar P, Pandita TK. The role of inflammatory pathways in cancer-associated cachexia and radiation resistance. Molecular cancer research: MCR. Sep 2013;11(9):967-972.

Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, . . . Elad S. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. May 15 2014;120(10):1453-1461.

Lamproglou I, Boisserie G, Mazeron JJ, Bok B, Baillet F, Drieu K. [Effect of Ginkgo biloba extract (EGb 761) on rats in an experimental model of acute encephalopathy after total body irradiation]. Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique. May-Jun 2000;4(3):202-206.

Lamson DW, Brignall MS. Antioxidants and cancer therapy II: quick reference guide. Alternative medicine review : a journal of clinical therapeutic. Apr 2000;5(2):152-163.

Latham E. Medscape. Hyperbaric Oxygen Therapy. http://emedicine.medscape.com/article/1464149-overview. Last updated 12/19/14. Accessed 4/20/15.

Lauritano D, Petruzzi M, Di Stasio D, Lucchese A. Clinical effectiveness of palifermin in prevention and treatment of oral mucositis in children with acute lymphoblastic leukaemia: a case-control study. International journal of oral science. Mar 2014;6(1):27-30.

Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? Journal of the National Cancer Institute. Jun 4 2008;100(11):773-783.

Lee A, Forner L, Jansen EC. Patient'S perspective on hyperbaric oxygen treatment of osteoradionecrosis. International journal of technology assessment in health care. Apr 2014;30(2):188-193.

Lee IC, Choi BY. Withaferin-A--A Natural Anticancer Agent with Pleitropic Mechanisms of Action. International journal of molecular sciences. Mar 04 2016;17(3):290.

Lee JC, Kinniry PA, Arguiri E, Serota M, Kanterakis S, Chatterjee S, . . . Christofidou-Solomidou M. Dietary curcumin increases antioxidant defenses in lung, ameliorates radiation-induced pulmonary fibrosis, and improves survival in mice. Radiation research. May 2010;173(5):590-601.

Lee JC, Krochak R, Blouin A, Kanterakis S, Chatterjee S, Arguiri E, . . . Christofidou-Solomidou M. Dietary flaxseed prevents radiation-induced oxidative lung damage, inflammation and fibrosis in a mouse model of thoracic radiation injury. Cancer biology & therapy. Jan 2009;8(1):47-53.

Lee YW, Cho HJ, Lee WH, Sonntag WE. Whole brain radiation-induced cognitive impairment: pathophysiological mechanisms and therapeutic targets. Biomol Ther (Seoul). Jul 2012;20(4):357-370.

LeMieux MH, Solanki AA, Mahmood U, Chmura SJ, Koshy M. Risk of second malignancies in patients with early-stage classical Hodgkin's lymphoma treated in a modern era. Cancer Med. Jan 26 2015.

Lemmo W. Potential interactions of prescription and over-the-counter medications having antioxidant capabilities with radiation and chemotherapy. International journal of cancer. Journal international du cancer. Sep 13 2014.

Lenz L, Rohr R, Nakao F, Libera E, Ferrari A. Chronic radiation proctopathy: A practical review of endoscopic treatment. World J Gastrointest Surg. Feb 27 2016;8(2):151-160.

Levy C, Seeff LD, Lindor KD. Use of herbal supplements for chronic liver disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. Nov 2004;2(11):947-956.

Lin C, Yu Y, Zhao HG, Yang A, Yan H, Cui Y. Combination of quercetin with radiotherapy enhances tumor radiosensitivity in vitro and in vivo. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. Sep 2012;104(3):395-400.

Lin LC, Que J, Lin LK, Lin FC. Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study. International journal of radiation oncology, biology, physics. Jul 01 2006;65(3):745-750.

Lin YS, Lin LC, Lin SW. Effects of zinc supplementation on the survival of patients who received concomitant chemotherapy and radiotherapy for advanced nasopharyngeal carcinoma: follow-up of a double-blind randomized study with subgroup analysis. The Laryngoscope. Jul 2009;119(7):1348-1352.

Lin YS, Lin LC, Lin SW, Chang CP. Discrepancy of the effects of zinc supplementation on the prevention of radiotherapy-induced mucositis between patients with nasopharyngeal carcinoma and those with oral cancers: subgroup analysis of a double-blind, randomized study. Nutr Cancer. 2010;62(5):682-691.

Lipsett A, Barrett S, Haruna F, Mustian K, O'Donovan A. The impact of exercise during adjuvant radiotherapy for breast cancer on fatigue and quality of life: A systematic review and meta-analysis. Breast (Edinburgh, Scotland). Apr 2017;32:144-155.

Lissoni P, Meregalli S, Nosetto L, Barni S, Tancini G, Fossati V, Maestroni G. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology. Jan-Feb 1996;53(1):43-46.

Liu CC, Xia R, Guadagnolo A, Cormier JN, Du XL. Risk of xerostomia in association with the receipt of radiation therapy in older patients with head and neck cancer. American journal of therapeutics. May 2011;18(3):206-215.

Liu H, Chang JY. Proton therapy in clinical practice. Chinese journal of cancer. May 2011;30(5):315-326.

Liu HT, Cheng SB, Huang YC, Huang YT, Lin PT. Coenzyme Q10 and Oxidative Stress: Inflammation Status in Hepatocellular Carcinoma Patients after Surgery. Nutrients. Jan 04 2017;9(1).

Liu MM, Li ST, Shu Y, Zhan HQ. Probiotics for prevention of radiation-induced diarrhea: A meta-analysis of randomized controlled trials. PLoS One. 2017;12(6):e0178870.

Liu X, Sun C, Jin X, Li P, Ye F, Zhao T, . . . Li Q. Genistein enhances the radiosensitivity of breast cancer cells via G(2)/M cell cycle arrest and apoptosis. Molecules (Basel, Switzerland). 2013;18(11):13200-13217.

Lloyd S, Alektiar KM, Nag S, Huang YJ, Deufel CL, Mourtada F, Gaffney DK. Intraoperative high-dose-rate brachytherapy: An American Brachytherapy Society consensus report. Brachytherapy. May - Jun 2017;16(3):446-465.

Lockwood K, Moesgaard S, Hanioka T, Folkers K. Apparent partial remission of breast cancer in 'high risk' patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Molecular aspects of medicine. 1994;15 Suppl:s231-240.

Lockwood K, Moesgaard S, Yamamoto T, Folkers K. Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases. Biochemical and biophysical research communications. Jul 06 1995;212(1):172-177.

Lubelski D, Abdullah KG, Weil RJ, Marko NF. Bevacizumab for radiation necrosis following treatment of high grade glioma: a systematic review of the literature. Journal of neuro-oncology. Dec 2013;115(3):317-322.

Lucchese A, Matarese G, Ghislanzoni LH, Gastaldi G, Manuelli M, Gherlone E. Efficacy and effects of palifermin for the treatment of oral mucositis in patients affected by acute lymphoblastic leukemia. Leukemia & lymphoma. 2016;57(4):820-827.

Lucena MI, Andrade RJ, de la Cruz JP, Rodriguez-Mendizabal M, Blanco E, Sanchez de la Cuesta F. Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study. International journal of clinical pharmacology and therapeutics. Jan 2002;40(1):2-8.

Lukens JN, Gamez M, Hu K, Harrison LB. Modern brachytherapy. Seminars in oncology. Dec 2014;41(6):831-847.

Luo H, Wang L, Schulte BA, Yang A, Tang S, Wang GY. Resveratrol enhances ionizing radiation-induced premature senescence in lung cancer cells. International journal of oncology. Dec 2013;43(6):1999-2006.

Lutgens L, van der Zee J, Pijls-Johannesma M, De Haas-Kock DF, Buijsen J, Mastrigt GA, . . . Lambin P. Combined use of hyperthermia and radiation therapy for treating locally advanced cervix carcinoma. The Cochrane database of systematic reviews. 2010(3):Cd006377.

Lv Y, Feng X, Zhu B. [Study on effect of Astragalus membranaceus injection on hematopoiesis in anemic mice with myelosuppression]. Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials. Sep 2005;28(9):791-793.

Lynch AM, Moore M, Craig S, Lonergan PE, Martin DS, Lynch MA. Analysis of interleukin-1 beta-induced cell signaling activation in rat hippocampus following exposure to gamma irradiation. Protective effect of eicosapentaenoic acid. The Journal of biological chemistry. Dec 19 2003;278(51):51075-51084.

Mace AG, Gantt GA, Skacel M, Pai R, Hammel JP, Kalady MF. Statin therapy is associated with improved pathologic response to neoadjuvant chemoradiation in rectal cancer. Diseases of the colon and rectum. Nov 2013;56(11):1217-1227.

Maggio A, Magli A, Rancati T, Fiorino C, Valvo F, Fellin G, . . . Vavassori V. Daily sodium butyrate enema for the prevention of radiation proctitis in prostate cancer patients undergoing radical radiation therapy: results of a multicenter randomized placebo-controlled dose-finding phase 2 study. International journal of radiation oncology, biology, physics. Jul 1 2014;89(3):518-524.

Mahajan MK, Singh V. Assessment of efficacy of pyridoxine in control of radiation induced sickness. Journal of the Indian Medical Association. Mar 1998;96(3):82-83.

Mahase SS, Wernicke AG, Nori D, Parashar B. Current and emerging roles of functional imaging in radiation therapy. Discovery medicine. Mar 2015;19(104):203-211.

Mahmood J, Jelveh S, Zaidi A, Doctrow SR, Hill RP. Mitigation of radiation-induced lung injury with EUK-207 and genistein: effects in adolescent rats. Radiation research. Feb 2013;179(2):125-134.

Mahmoud AM, Yang W, Bosland MC. Soy isoflavones and prostate cancer: a review of molecular mechanisms. The Journal of steroid biochemistry and molecular biology. Mar 2014;140:116-132.

Majdalawieh AF, Fayyad MW, Nasrallah GK. Anti-cancer properties and mechanisms of action of thymoquinone, the major active ingredient of Nigella sativa. Critical reviews in food science and nutrition. Dec 12 2017;57(18):3911-3928.

Malhotra S, Sawhney G, Pandhi P. The therapeutic potential of melatonin: a review of the science. MedGenMed : Medscape general medicine. 2004;6(2):46.

Malik A, Sultana M, Qazi A, Qazi MH, Parveen G, Waquar S, . . . Rasool M. Role of Natural Radiosensitizers and Cancer Cell Radioresistance: An Update. Analytical cellular pathology (Amsterdam). 2016;2016:6146595.

Manda K, Kriesen S, Hildebrandt G, Fietkau R, Klautke G. Omega-3 fatty acid supplementation in cancer therapy : does eicosapentanoic acid influence the radiosensitivity of tumor cells? Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]. Feb 2011;187(2):127-134.

Manda K, Reiter RJ. Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation. Progress in neurobiology. Jan 11 2010;90(1):60-68.

Maranzano E, De Angelis V, Pergolizzi S, Lupattelli M, Frata P, Spagnesi S, . . . Di Gennaro D. A prospective observational trial on emesis in radiotherapy: analysis of 1020 patients recruited in 45 Italian radiation oncology centres. Radiother Oncol. Jan 2010;94(1):36-41.

Margalit DN, Kasperzyk JL, Martin NE, Sesso HD, Gaziano JM, Ma J, . . . Mucci LA. Beta-carotene antioxidant use during radiation therapy and prostate cancer outcome in the Physicians' Health Study. International journal of radiation oncology, biology, physics. May 1 2012;83(1):28-32.

Marlow MM, Shah SS, Veliz EA, Ivan ME, Graham RM. Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives. Journal of natural medicines. Jan 2017;71(1):16-26.

Mazonakis M, Lyraraki E, Damilakis J. Second cancer risk assessments after involved-site radiotherapy for mediastinal Hodgkin lymphoma. Medical physics. May 11 2017.

McLaughlin N, Annabi B, Lachambre MP, Kim KS, Bahary JP, Moumdjian R, Beliveau R. Combined low dose ionizing radiation and green tea-derived epigallocatechin-3-gallate treatment induces human brain endothelial cells death. Journal of neuro-oncology. Nov 2006;80(2):111-121.

McQuestion M. Evidence-based skin care management in radiation therapy: clinical update. Seminars in oncology nursing. May 2011;27(2):e1-17.

DACC. MD Anderson Cancer Center. What is Proton Therapy? http://www.mdanderson.org/patient-and-cancer-information/proton-therapy-center/what-is-proton-therapy/index.html. Last updated 2015. Accessed 5/18/15.

MedImmune. MedImmune Pharma B. V. U.S. Food and Drug Administration. Ethyol® (amifostine) for Injection. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020221s024lbl.pdf. Last updated 5/2007. Accessed 3/15/15.

Membrive Conejo I, Reig Castillejo A, Rodriguez de Dios N, Foro Arnalot P, Sanz Latiesas J, Lozano Galan J, . . . Algara Lopez M. Prevention of acute radiation enteritis: efficacy and tolerance of glutamine. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. Oct 2011;13(10):760-763.

Menon S, Shin S, Dy G. Advances in Cancer Immunotherapy in Solid Tumors. Cancers. Nov 24 2016;8(12).

Meydan D, Gursel B, Bilgici B, Can B, Ozbek N. Protective effect of lycopene against radiation-induced hepatic toxicity in rats. The Journal of international medical research. 2011;39(4):1239-1252.

Meyer F, Bairati I, Fortin A, Gelinas M, Nabid A, Brochet F, Tetu B. Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients. International journal of cancer. Journal international du cancer. Apr 1 2008;122(7):1679-1683.

Micke O, Bruns F, Mucke R, Schafer U, Glatzel M, DeVries AF, . . . Buntzel J. Selenium in the treatment of radiation-associated secondary lymphedema. International journal of radiation oncology, biology, physics. May 1 2003;56(1):40-49.

Mihandoost E, Shirazi A. Can melatonin help us in radiation oncology treatments? 2014;2014:578137.

Mineva ND, Wang X, Yang S, Ying H, Xiao ZX, Holick MF, Sonenshein GE. Inhibition of RelB by 1,25-dihydroxyvitamin D3 promotes sensitivity of breast cancer cells to radiation. Journal of cellular physiology. Sep 2009;220(3):593-599.

Misirlioglu CH, Demirkasimoglu T, Kucukplakci B, Sanri E, Altundag K. Pentoxifylline and alpha-tocopherol in prevention of radiation-induced lung toxicity in patients with lung cancer. Medical oncology (Northwood, London, England). 2007;24(3):308-311.

Misirlioglu CH, Erkal H, Elgin Y, Ugur I, Altundag K. Effect of concomitant use of pentoxifylline and alpha-tocopherol with radiotherapy on the clinical outcome of patients with stage IIIB non-small cell lung cancer: a randomized prospective clinical trial. Medical oncology (Northwood, London, England). 2006;23(2):185-189.

Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. Curr Opin Immunol. Apr 2014;27:16-25.

Mock V, Frangakis C, Davidson NE, Ropka ME, Pickett M, Poniatowski B, . . . McCorkle R. Exercise manages fatigue during breast cancer treatment: a randomized controlled trial. Psycho-oncology. Jun 2005;14(6):464-477.

Mohammadkhani G, Pourbakht A, Khanavi M, Faghihzadeh S. Protective effect of silymarin on noise-induced hearing loss in Guinea pigs. Iran Red Crescent Med J. Nov 2013;15(11):e8890.

Monga U, Garber SL, Thornby J, Vallbona C, Kerrigan AJ, Monga TN, Zimmermann KP. Exercise prevents fatigue and improves quality of life in prostate cancer patients undergoing radiotherapy. Archives of physical medicine and rehabilitation. Nov 2007;88(11):1416-1422.

Moretti RM, Marelli MM, Maggi R, Dondi D, Motta M, Limonta P. Antiproliferative action of melatonin on human prostate cancer LNCaP cells. Oncology reports. Mar-Apr 2000;7(2):347-351.

Morris CR, Hamilton-Reeves J, Martindale RG, Sarav M, Ochoa Gautier JB.Acquired Amino Acid Deficiencies: A Focus on Arginine and Glutamine. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. Apr 2017;32(1_suppl):30s-47s.

Moss RW. Do antioxidants interfere with radiation therapy for cancer? Integrative cancer therapies. Sep 2007;6(3):281-292.

Muecke R, Micke O, Schomburg L, Glatzel M, Reichl B, Kisters K, . . .Buentzel J. Multicenter, phase III trial comparing seleniumsupplementation with observation in gynecologic radiation oncology:follow-up analysis of the survival data 6 years after cessation ofrandomization. Integrative cancer therapies. Nov2014;13(6):463-467.

Muecke R, Micke O, Schomburg L, Kisters K, Buentzel J, Huebner J, KrizJ. Selenium supplementation in radiotherapy patients: do we need to measure selenium levels in serum or blood regularly prior radiotherapy? Radiation oncology (London, England). Dec 16 2014;9(1):289.

Muecke R, Schomburg L, Glatzel M, Berndt-Skorka R, Baaske D, Reichl B,. . . Micke O. Multicenter, phase 3 trial comparing seleniumsupplementation with observation in gynecologic radiation oncology. International journal of radiation oncology, biology, physics.Nov 1 2010;78(3):828-835.

Muehlbauer PM, Thorpe D, Davis A, Drabot R, Rawlings BL, Kiker E.Putting evidence into practice: evidence-based interventions toprevent, manage, and treat chemotherapy- and radiotherapy-induceddiarrhea. Clinical journal of oncology nursing. Jun2009;13(3):336-341.

Mukherjee S, Aston D, Minett M, Brewster AE, Crosby TD. Thesignificance of cardiac doses received during chemoradiation ofoesophageal and gastro-oesophageal junctional cancers. Clinical oncology (Royal College of Radiologists (Great Britain)).May 2003;15(3):115-120.

Murphy J, Stacey D, Crook J, Thompson B, Panetta D. Testing control ofradiation-induced diarrhea with a psyllium bulking agent: a pilotstudy. Canadian oncology nursing journal = Revue canadienne de nursing oncologique.Summer 2000;10(3):96-100.

Nagasaka M, Zaki M, Kim H, Raza SN, Yoo G, Lin HS, Sukari A. PD1/PD-L1inhibition as a potential radiosensitizer in head and neck squamouscell carcinoma: a case report. Journal for immunotherapy of cancer. 2016;4:83.

Najafi M, Shirazi A, Motevaseli E, Geraily G, Norouzi F, Heidari M,Rezapoor S. The melatonin immunomodulatory actions in radiotherapy. Biophysical reviews. Apr 2017;9(2):139-148.

Najafizade N, Hemati S, Gookizade A, Berjis N, Hashemi M, Vejdani S, .. . Arbab N. Preventive effects of zinc sulfate on taste alterations inpatients under irradiation for head and neck cancers: A randomizedplacebo-controlled trial. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences.Feb 2013;18(2):123-126.

Nakayama A, Alladin KP, Igbokwe O, White JD. Systematic review:generating evidence-based guidelines on the concurrent use of dietaryantioxidants and chemotherapy or radiotherapy. Cancer investigation. Dec 2011;29(10):655-667.

NAPT. National Association for Proton Therapy. How It Works. http://www.proton-therapy.org/howit.htm. Last updated 2015. Accessed 5/18/15.

NAS. National Academy of Sciences. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Ch. 12: Zinc. 2001. https://www.nap.edu/read/10026/chapter/14. Accessed 11/8/2017.

Nascimento M, Aguilar-Nascimento JE, Caporossi C, Castro-Barcellos HM,Motta RT. Efficacy of synbiotics to reduce acute radiation proctitissymptoms and improve quality of life: a randomized, double-blind,placebo-controlled pilot trial. International journal of radiation oncology, biology, physics.Oct 1 2014;90(2):289-295.

NCI. National Cancer Institute. FDA Approval for Palifermin.https://www.cancer.gov/about-cancer/treatment/drugs/fda-palifermin.Last updated 7/3/2013. Accessed 12/20/2016.

NCI. National Cancer Institute. Radiation Therapy for Cancer.http://www.cancer.gov/about-cancer/treatment/types/radiation-therapy/radiation-fact-sheet.6/30/2010. Accessed 6/1/2015.

NCI. National Cancer Institute. Gastrointestinal Complications- forhealth professionals. http://www.cancer.gov/about-cancer/treatment/side-effects/constipation/gi-complications-hp-pdq#section/all. Last updated: 3/25/15. Accessed 5/10/15.

Nechuta S, Lu W, Chen Z, Zheng Y, Gu K, Cai H, . . . Shu XO. Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention : a publication of theAmerican Association for Cancer Research, cosponsored by the AmericanSociety of Preventive Oncology. Feb 2011;20(2):262-271.

Ng J, Shuryak I. Minimizing second cancer risk following radiotherapy:current perspectives. Cancer management and research. 2015;7:1-11.

Nilsson S. Radium-223 dichloride for the treatment of bone metastaticcastration-resistant prostate cancer: an evaluation of its safety. Expert opinion on drug safety. Jul 2015;14(7):1127-1136.

Noe JE. L-glutamine use in the treatment and prevention of mucositisand cachexia: a naturopathic perspective. Integrative cancer therapies. Dec 2009;8(4):409-415.

Nooka AK, Johnson HR, Kaufman JL, Flowers CR, Langston A, Steuer C, . .. Waller EK. Pharmacoeconomic analysis of palifermin to preventmucositis among patients undergoing autologous hematopoietic stem celltransplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.Jun 2014;20(6):852-857.

Noronha AF, Mello de Figueiredo E, Rossi de Figueiredo Franco TM,Candido EB, Silva-Filho AL. Treatments for invasive carcinoma of thecervix: what are their impacts on the pelvic floor functions? International braz j urol : official journal of the Brazilian Society of Urology.Jan-Feb 2013;39(1):46-54.

O'Flanagan CH, Smith LA, McDonell SB, Hursting SD. When less may bemore: calorie restriction and response to cancer therapy. BMC medicine. May 24 2017;15(1):106.

O'Sullivan EM, Higginson IJ. Clinical effectiveness and safety ofacupuncture in the treatment of irradiation-induced xerostomia inpatients with head and neck cancer: a systematic review. Acupuncture in medicine : journal of the British Medical Acupuncture Society.Dec 2010;28(4):191-199.

Oeffinger KC, Baxi SS, Novetsky Friedman D, Moskowitz CS. Solid tumorsecond primary neoplasms: who is at risk, what can we do? Seminars in oncology. Dec 2013;40(6):676-689.

Ogawa K, Kohshi K, Ishiuchi S, Matsushita M, Yoshimi N, Murayama S. Oldbut new methods in radiation oncology: hyperbaric oxygen therapy. International journal of clinical oncology. Jun2013;18(3):364-370.

Ogawa K, Yoshioka Y, Isohashi F, Seo Y, Yoshida K, Yamazaki H.Radiotherapy targeting cancer stem cells: current views and futureperspectives. Anticancer research. Mar 2013;33(3):747-754.

Ogoshi K, Satou H, Isono K, Mitomi T, Endoh M, Sugita M. Immunotherapyfor esophageal cancer. A randomized trial in combination withradiotherapy and radiochemotherapy. Cooperative Study Group forEsophageal Cancer in Japan. American journal of clinical oncology. Jun 1995;18(3):216-222.

Oh BY, Park YA, Huh JW, Cho YB, Yun SH, Lee WY, . . . Kim HC. Metforminenhances the response to radiotherapy in diabetic patients with rectalcancer. Journal of cancer research and clinical oncology. Jun2016;142(6):1377-1385.

Okunieff P, Swarts S, Keng P, Sun W, Wang W, Kim J, . . . Zhang L.Antioxidants reduce consequences of radiation exposure. Advances in experimental medicine and biology. 2008;614:165-178.

Olbryt M, Habryka A, Student S, Jarzab M, Tyszkiewicz T, Lisowska KM.Global gene expression profiling in three tumor cell lines subjected toexperimental cycling and chronic hypoxia. PloS one. 2014;9(8):e105104.

Olsen DL, Raub W, Jr., Bradley C, Johnson M, Macias JL, Love V, MarkoeA. The effect of aloe vera gel/mild soap versus mild soap alone inpreventing skin reactions in patients undergoing radiation therapy. Oncology nursing forum. Apr 2001;28(3):543-547.

Ordonez Mena JM, Brenner H. Vitamin D and cancer: an overview onepidemiological studies. Advances in experimental medicine and biology. 2014;810:17-32.

Orth M, Lauber K, Niyazi M, Friedl AA, Li M, Maihofer C, . . . Belka C.Current concepts in clinical radiation oncology. Radiation and environmental biophysics. Mar 2014;53(1):1-29.

Overgaard J. Hypoxic modification of radiotherapy in squamous cellcarcinoma of the head and neck--a systematic review and meta-analysis. Radiother Oncol. Jul 2011;100(1):22-32.

Ozben T. Antioxidant Supplementation on Cancer Risk and Concurrent Useof Antioxidants during Cancer Therapy: An Update. Current topics in medicinal chemistry. Dec 29 2014.

Pajonk F, Vlashi E, McBride WH. Radiation resistance of cancer stemcells: the 4 R's of radiobiology revisited. Stem cells (Dayton, Ohio). Apr 2010;28(4):639-648.

Palatty PL, Haniadka R, Valder B, Arora R, Baliga MS. Ginger in theprevention of nausea and vomiting: a review. Critical reviews in food science and nutrition. 2013;53(7):659-669.

Panjwani M. Efficacy of palifermin in the hematopoietic stem celltransplant setting. Journal of the advanced practitioner in oncology. Mar2013;4(2):89-100.

Para AE, Bezjak A, Yeung IW, Van Dyk J, Hill RP. Effects of genisteinfollowing fractionated lung irradiation in mice. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.Sep 2009;92(3):500-510.

Parente LM, Lino Junior Rde S, Tresvenzol LM, Vinaud MC, de Paula JR,Paulo NM. Wound Healing and Anti-Inflammatory Effect in Animal Modelsof Calendula officinalis L. Growing in Brazil. Evidence-based complementary and alternative medicine : eCAM. 2012;2012:375671.

Payne H, Adamson A, Bahl A, Borwell J, Dodds D, Heath C, . . . ThompsonA. Chemical- and radiation-induced haemorrhagic cystitis: currenttreatments and challenges. BJU international. Nov 2013;112(7):885-897.

Peeken JC, Vaupel P, Combs SE. Integrating Hyperthermia into ModernRadiation Oncology: What Evidence Is Necessary? Frontiers in oncology. 2017;7:132.

Peters L, Rischin D. Elusive goal of targeting tumor hypoxia fortherapeutic gain. Journal of clinical oncology: official journal of the American Society of Clinical Oncology.May 20 2012;30(15):1741-1743.

Peterson DE, Lalla RV. Oral mucositis: the new paradigms. Current opinion in oncology. Jul 2010;22(4):318-322.

Pietrofesa R, Turowski J, Tyagi S, Dukes F, Arguiri E, Busch TM, . . .Christofidou-Solomidou M. Radiation mitigating properties of the lignancomponent in flaxseed. BMC cancer. 2013;13:179.

Pinna R, Campus G, Cumbo E, Mura I, Milia E. Xerostomia induced byradiotherapy: an overview of the physiopathology, clinical evidence,and management of the oral damage. Therapeutics and clinical risk management. 2015;11:171-188.

Pommier P, Gomez F, Sunyach MP, D'Hombres A, Carrie C, Montbarbon X.Phase III randomized trial of Calendula officinalis compared withtrolamine for the prevention of acute dermatitis during irradiation forbreast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology.Apr 15 2004;22(8):1447-1453.

Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, . . .Wolchok JD. Immunologic correlates of the abscopal effect in a patientwith melanoma. The New England journal of medicine. Mar 082012;366(10):925-931.

Pradeep K, Ko KC, Choi MH, Kang JA, Chung YJ, Park SH. Protectiveeffect of hesperidin, a citrus flavanoglycone, againstgamma-radiation-induced tissue damage in Sprague-Dawley rats. Journal of medicinal food. May 2012;15(5):419-427.

Prasad KN, Cole WC, Kumar B, Che Prasad K. Pros and cons of antioxidantuse during radiation therapy. Cancer treatment reviews. Apr2002;28(2):79-91.

Prasanna PG, Stone HB, Wong RS, Capala J, Bernhard EJ, Vikram B,Coleman CN. Normal tissue protection for improving radiotherapy: Whereare the Gaps? Transl Cancer Res. Jun 2012;1(1):35-48.

Preethi KC, Kuttan G, Kuttan R. Anti-inflammatory activity of flowerextract of Calendula officinalis Linn. and its possible mechanism ofaction. Indian journal of experimental biology. Feb2009;47(2):113-120.

Proud C. Radiogenomics: the promise of personalized treatment inradiation oncology? Clinical journal of oncology nursing. Apr2014;18(2):185-189.

Purdy JA. Dose to normal tissues outside the radiation therapypatient's treated volume: a review of different radiation therapytechniques. Health physics. Nov 2008;95(5):666-676.

Puspitasari IM, Abdulah R, Yamazaki C, Kameo S, Nakano T, Koyama H.Updates on clinical studies of selenium supplementation inradiotherapy. Radiation oncology (London, England). 2014;9:125.

Qiao Q, Jiang Y, Li G. Curcumin enhances the response of non-Hodgkin'slymphoma cells to ionizing radiation through further induction of cellcycle arrest at the G2/M phase and inhibition of mTOR phosphorylation. Oncology reports. Jan 2013;29(1):380-386.

Rademakers SE, Hoogsteen IJ, Rijken PF, Terhaard CH, Doornaert PA,Langendijk JA, . . . Kaanders JH. Prognostic value of the proliferationmarker Ki-67 in laryngeal carcinoma: results of the acceleratedradiotherapy with carbogen breathing and nicotinamide phase IIIrandomized trial. Head & neck. Feb 2015;37(2):171-176.

Ramadan LA, Roushdy HM, Abu Senna GM, Amin NE, El-Deshw OA.Radioprotective effect of silymarin against radiation inducedhepatotoxicity. Pharmacological research : the official journal of the Italian Pharmacological Society.Jun 2002;45(6):447-454.

Rao S, Dinkar C, Vaishnav LK, Rao P, Rai MP, Fayad R, Baliga MS. TheIndian Spice Turmeric Delays and Mitigates Radiation-Induced OralMucositis in Patients Undergoing Treatment for Head and Neck Cancer: AnInvestigational Study. Integrative cancer therapies. Oct 282013;13(3):201-210.

Rao W, Deng ZS, Liu J. A review of hyperthermia combined withradiotherapy/chemotherapy on malignant tumors. Critical reviews in biomedical engineering. 2010;38(1):101-116.

Rebegea L, Firescu D, Dumitru M, Anghel R. The incidence and riskfactors for occurrence of arm lymphedema after treatment of breastcancer. Chirurgia (Bucharest, Romania : 1990). Jan-Feb2015;110(1):33-37.

Reif K, de Vries U, Petermann F. [What does really help againstcancer-related fatigue? An overview of systematic reviews]. Pflege. Dec 2012;25(6):439-457.

Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, YangSF, Xu K. Melatonin, a Full Service Anti-Cancer Agent: Inhibition ofInitiation, Progression and Metastasis. International journal of molecular sciences. Apr 172017;18(4).

Restivo A, Cocco IM, Casula G, Scintu F, Cabras F, Scartozzi M, ZorcoloL. Aspirin as a neoadjuvant agent during preoperative chemoradiationfor rectal cancer. British journal of cancer. Oct 202015;113(8):1133-1139.

Ridner SH, Dietrich MS, Stewart BR, Armer JM. Body mass index andbreast cancer treatment-related lymphedema. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer.Jun 2011;19(6):853-857.

Rigaud J, Hetet JF, Bouchot O. [Management of radiation cystitis]. Prog Urol. Sep 2004;14(4):568-572.

Rigter LS, Spaander MC, Moons LM, Bisseling TM, Aleman BM, de Boer JP,. . . van Leerdam ME. Colorectal cancer surveillance in Hodgkinlymphoma survivors at increased risk of therapy-related colorectalcancer: study design. BMC cancer. Feb 07 2017;17(1):112.

Rizzieri D. Zevalin((R)) (ibritumomab tiuxetan): After more than adecade of treatment experience, what have we learned? Critical reviews in oncology/hematology. Sep 2016;105:5-17.

Robb WB, Condron C, Moriarty M, Walsh TN, Bouchier-Hayes DJ. Taurineattenuates radiation-induced lung fibrosis in C57/Bl6 fibrosis pronemice. Irish journal of medical science. Mar2010;179(1):99-105.

Rock CL. Dietary counseling is beneficial for the patient with cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology.Mar 1 2005;23(7):1348-1349.

Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS,Schwartz AL, . . . Gansler T. Nutrition and physical activityguidelines for cancer survivors. CA: a cancer journal for clinicians. Jul-Aug2012;62(4):243-274.

Rockson SG. Lymphedema. The American journal of medicine. Mar2001;110(4):288-295.

Roesch M, Mueller-Huebenthal B. Review: the role of hyperthermia intreating pancreatic tumors. Indian journal of surgical oncology. Mar 2015;6(1):75-81.

Roscoe JA, Bushunow P, Jean-Pierre P, Heckler CE, Purnell JQ, PepponeLJ, . . . Morrow GR. Acupressure bands are effective in reducingradiation therapy-related nausea. Journal of pain and symptom management. Sep2009;38(3):381-389.

Rotovnik Kozjek N, Kompan L, Soeters P, Oblak I, Mlakar Mastnak D,Mozina B, . . . Velenik V. Oral glutamine supplementation duringpreoperative radiochemotherapy in patients with rectal cancer: arandomised double blinded, placebo controlled pilot study. Clinical nutrition (Edinburgh, Scotland). Oct2011;30(5):567-570.

Rube CE, Wilfert F, Uthe D, Schmid KW, Knoop R, Willich N, . . . RubeC. Modulation of radiation-induced tumour necrosis factor alpha(TNF-alpha) expression in the lung tissue by pentoxifylline. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.Aug 2002;64(2):177-187.

Rustagi T, Mashimo H. Endoscopic management of chronic radiationproctitis. World journal of gastroenterology : WJG. Nov 72011;17(41):4554-4562.

Ryan JL, Heckler CE, Ling M, Katz A, Williams JP, Pentland AP, MorrowGR. Curcumin for radiation dermatitis: a randomized, double-blind,placebo-controlled clinical trial of thirty breast cancer patients. Radiation research. Jul 2013;180(1):34-43.

Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat Biol. Aug 2014;90(8):615-621.

Saada HN, Rezk RG, Eltahawy NA. Lycopene protects the structure of thesmall intestine against gamma-radiation-induced oxidative stress. Phytotherapy research : PTR. Jun 2010;24 Suppl 2:S204-208.

Saada HN, Said UZ, Meky NH, Abd El Azime AS. Grape seed extract Vitisvinifera protects against radiation-induced oxidative damage andmetabolic disorders in rats. Phytotherapy research: PTR. Mar2009;23(3):434-438.

Sagar SM. Review Article: Should patients take or avoid antioxidantsupplements during anticancer therapy? An evidence-based review.Current Oncology. 2005;12(2):44-54.

Sainz RM, Mayo JC, Tan DX, Leon J, Manchester L, Reiter RJ. Melatonin reduces prostate cancer cell growth leading to neuroendocrinedifferentiation via a receptor and PKA independent mechanism. Prostate. Apr 01 2005;63(1):29-43.

Saller R, Meier R, Brignoli R. The use of silymarin in the treatment ofliver diseases. Drugs. 2001;61(14):2035-2063.

Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Reiter RJ.Melatonin uses in oncology: breast cancer prevention and reduction ofthe side effects of chemotherapy and radiation. Expert opinion on investigational drugs. Jun2012;21(6):819-831.

Sandur SK, Deorukhkar A, Pandey MK, Pabon AM, Shentu S, Guha S, . . .Krishnan S. Curcumin modulates the radiosensitivity of colorectalcancer cells by suppressing constitutive and inducible NF-kappaBactivity. International journal of radiation oncology, biology, physics.Oct 1 2009;75(2):534-542.

Savarese DM, Savy G, Vahdat L, Wischmeyer PE, Corey B. Prevention ofchemotherapy and radiation toxicity with glutamine. Cancer treatment reviews. Dec 2003;29(6):501-513.

Sawai Y, Murata H, Horii M, Koto K, Matsui T, Horie N, . . . Fushiki S.Effectiveness of sulforaphane as a radiosensitizer for murineosteosarcoma cells. Oncology reports. Mar 2013;29(3):941-945.

Schaapveld M, Aleman BM, van Eggermond AM, Janus CP, Krol AD, van derMaazen RW, . . . van Leeuwen FE. Second Cancer Risk Up to 40 Yearsafter Treatment for Hodgkin's Lymphoma. The New England journal of medicine. Dec 242015;373(26):2499-2511.

Schaue D. A Century of Radiation Therapy and Adaptive Immunity. Frontiers in immunology. 2017;8:431.

Schild MH, Schild SE, Wong WW, Vora SA, Keole SR, Vargas CE, . . .Roarke MC. A Prospective Trial of Intensity Modulated Radiation Therapy(IMRT) Incorporating a Simultaneous Integrated Boost for ProstateCancer: Long-term Outcomes Compared With Standard Image Guided IMRT. Int J Radiat Oncol Biol Phys. Apr 01 2017;97(5):1021-1025.

Schreiber GJ. Medscape. Drugs & Diseases. General Principles ofRadiation Therapy. Overview.http://emedicine.medscape.com/article/846797-overview#a1. Last updated9/18/2013. Accessed 6/3/2015.

Schueller P, Puettmann S, Micke O, Senner V, Schaefer U, Willich N.Selenium influences the radiation sensitivity of C6 rat glioma cells. Anticancer research. Sep-Oct 2004;24(5a):2913-2917.

SCI. Swedish Cancer Institute. Active Breathing Coordinator.http://www.swedish.org/services/cancer-institute/services/radiation-therapy/types-of-radiation-therapy/active-breathing-coordinator.2015. Accessed 3/12/15.

Scott JG, Berglund A, Schell MJ, Mihaylov I, Fulp WJ, Yue B, . . . Torres-Roca JF. A genome-based model for adjusting radiotherapy dose(GARD): a retrospective, cohort-based study. The Lancet. Oncology. Feb 2017;18(2):202-211.

Sebastia N, Montoro A, Hervas D, Pantelias G, Hatzi VI, Soriano JM, . .. Terzoudi GI. Curcumin and trans-resveratrol exert cellcycle-dependent radioprotective or radiosensitizing effects aselucidated by the PCC and G2-assay. Mutation research. Aug-Sep2014;766-767:49-55.

Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, Mills E.Melatonin as adjuvant cancer care with and without chemotherapy: asystematic review and meta-analysis of randomized trials. Integrative cancer therapies. Dec 2012;11(4):293-303.

Seifried HE, McDonald SS, Anderson DE, Greenwald P, Milner JA. Theantioxidant conundrum in cancer. Cancer research. Aug 12003;63(15):4295-4298.

Serin M, Gulbas H, Gurses I, Erkal HS, Yucel N. The histopathologicalevaluation of the effectiveness of melatonin as a protectant againstacute lung injury induced by radiation therapy in a rat model. International journal of radiation biology. Mar2007;83(3):187-193.

Sezen O, Ertekin MV, Demircan B, Karslioglu I, Erdogan F, Kocer I, . .. Gepdiremen A. Vitamin E and L-carnitine, separately or incombination, in the prevention of radiation-induced brain and retinaldamages. Neurosurg Rev. Apr 2008;31(2):205-213; discussion213.

Sharma K, Goehe RW, Di X, Hicks MA, 2nd, Torti SV, Torti FM, . . .Gewirtz DA. A novel cytostatic form of autophagy in sensitization ofnon-small cell lung cancer cells to radiation by vitamin D and thevitamin D analog, EB 1089. Autophagy. 2014;10(12):2346-2361.

Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW,Formenti SC, . . . Lee P. Previous radiotherapy and the clinicalactivity and toxicity of pembrolizumab in the treatment ofnon-small-cell lung cancer: a secondary analysis of the KEYNOTE-001phase 1 trial. The Lancet. Oncology. May 24 2017.

Shi HS, Gao X, Li D, Zhang QW, Wang YS, Zheng Y, . . . Chen LJ. Asystemic administration of liposomal curcumin inhibits radiationpneumonitis and sensitizes lung carcinoma to radiation. International journal of nanomedicine. 2012;7:2601-2611.

Shirazi A, Ghobadi G, Ghazi-Khansari M. A radiobiological review onmelatonin: a novel radioprotector. Journal of radiation research. Jul 2007;48(4):263-272.

Signoretto C, Bianchi F, Burlacchini G, Canepari P. Microbiologicalevaluation of the effects of hyperbaric oxygen on periodontal disease. The new microbiologica. Oct 2007;30(4):431-437.

Simone BA, Dan T, Palagani A, Jin L, Han SY, Wright C, . . . Simone NL.Caloric restriction coupled with radiation decreases metastatic burdenin triple negative breast cancer. Cell cycle (Georgetown, Tex.). Sep 2016;15(17):2265-2274.

Simone CB, 2nd, Simone NL, Simone V, Simone CB. Antioxidants and othernutrients do not interfere with chemotherapy or radiation therapy andcan increase kill and increase survival, part 1. Altern Ther Health Med. Jan-Feb 2007a;13(1):22-28.

Simone CB, 2nd, Simone NL, Simone V, Simone CB. Antioxidants and othernutrients do not interfere with chemotherapy or radiation therapy andcan increase kill and increase survival, Part 2. Altern Ther Health Med. Mar-Apr 2007b;13(2):40-47.

Simone CB, Simone CB, 2nd. Re: Should supplemental antioxidantadministration be avoided during chemotherapy and radiation therapy? Journal of the National Cancer Institute. Nov 52008;100(21):1558-1559; author reply 1559-1560.

Skinner HD, Crane CH, Garrett CR, Eng C, Chang GJ, Skibber JM, . . .Das P. Metformin use and improved response to therapy in rectal cancer. Cancer Med. Feb 2013;2(1):99-107.

Smith BG, Hutcheson KA, Little LG, Skoracki RJ, Rosenthal DI, Lai SY,Lewin JS. Lymphedema outcomes in patients with head and neck cancer. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.Feb 2015;152(2):284-291.

Smoot B, Chiavola-Larson L, Lee J, Manibusan H, Allen DD. Effect oflow-level laser therapy on pain and swelling in women with breastcancer-related lymphedema: a systematic review and meta-analysis. Journal of cancer survivorship : research and practice. Nov 292014.

Song JJ, Twumasi-Ankrah P, Salcido R. Systematic review andmeta-analysis on the use of honey to protect from the effects ofradiation-induced oral mucositis. Advances in skin & wound care. Jan 2012;25(1):23-28.

Song L, Wang D, Cui X, Hu W. The protective action of taurine andL-arginine in radiation pulmonary fibrosis. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer.1998;17(2):151-157.

Soto C, Recoba R, Barron H, Alvarez C, Favari L. Silymarin increasesantioxidant enzymes in alloxan-induced diabetes in rat pancreas. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP.Nov 2003;136(3):205-212.

Sprod LK, Mohile SG, Demark-Wahnefried W, Janelsins MC, Peppone LJ,Morrow GR, . . . Mustian KM. Exercise and Cancer Treatment Symptoms in408 Newly Diagnosed Older Cancer Patients. Journal of geriatric oncology. Apr 1 2012;3(2):90-97.

Srinivasan M, Devipriya N, Kalpana KB, Menon VP. Lycopene: Anantioxidant and radioprotector against gamma-radiation-induced cellulardamages in cultured human lymphocytes. Toxicology. Jul 282009;262(1):43-49.

Stacey R, Green JT. Radiation-induced small bowel disease: latestdevelopments and clinical guidance. Therapeutic advances in chronic disease. Jan 2014;5(1):15-29.

Standish LJ, Wenner CA, Sweet ES, Bridge C, Nelson A, Martzen M, . . .Torkelson C. Trametes versicolor mushroom immune therapy in breastcancer. Journal of the Society for Integrative Oncology. Summer 2008;6(3):122-128.

Steel GG, McMillan TJ, Peacock J. The 5Rs of radiobiology. International journal of radiation biology. 1989;56(6):1045-1048.

Stepien K, Ostrowski RP, Matyja E. Hyperbaric oxygen as an adjunctivetherapy in treatment of malignancies, including brain tumours. Medical oncology (Northwood, London, England). Sep2016;33(9):101.

Stewart FA, Heeneman S, Te Poele J, Kruse J, Russell NS, Gijbels M,Daemen M. Ionizing radiation accelerates the development ofatherosclerotic lesions in ApoE-/- mice and predisposes to aninflammatory plaque phenotype prone to hemorrhage. Am J Pathol. Feb 2006;168(2):649-658.

Stinauer MA, Kavanagh BD, Schefter TE, Gonzalez R, Flaig T, Lewis K, .. . Raben D. Stereotactic body radiation therapy for melanoma and renalcell carcinoma: impact of single fraction equivalent dose on localcontrol. Radiation oncology (London, England). Apr 082011;6:34.

Stojcev Z, Krokowicz L, Krokowicz P, Szczepkowski M, Borycka-Kiciak K,Kiciak A, . . . Banasiewicz T. Early treatment and prevention of theradiation proctitis--composite enemas containing sodium butyrate. International journal of colorectal disease. Dec2013;28(12):1731-1732.

Streeter OE, Jr., Beron PJ, Iyer PN. Precision Medicine: GenomicProfiles to Individualize Therapy. Otolaryngologic clinics of North America. May 17 2017.

Stubbe CE, Valero M. Complementary strategies for the management ofradiation therapy side effects. Journal of the advanced practitioner in oncology. Jul2013;4(4):219-231.

Sultan A, Hanna GJ, Margalit DN, Chau N, Goguen LA, Marty FM, . . .Mawardi H. The Use of Hyperbaric Oxygen for the Prevention andManagement of Osteoradionecrosis of the Jaw: A Dana-Farber/Brigham andWomen's Cancer Center Multidisciplinary Guideline. The oncologist. Mar 2017;22(3):343-350.

Tahamtan R, Shabestani Monfared A, Tahamtani Y, Tavassoli A, Akmali M,Mosleh-Shirazi MA, . . . Haddadi GH. Radioprotective effect ofmelatonin on radiation-induced lung injury and lipid peroxidation inrats. Cell journal. Spring 2015;17(1):111-120.

Tahir AR, Westhuyzen J, Dass J, Collins MK, Webb R, Hewitt S, . . .McKay M. Hyperbaric oxygen therapy for chronic radiation-induced tissueinjuries: Australasia's largest study. Asia Pac J Clin Oncol. Mar 2015;11(1):68-77.

Tan Y, Wei X, Zhang W, Wang X, Wang K, Du B, Xiao J. Resveratrolenhances the radiosensitivity of nasopharyngeal carcinoma cells bydownregulating E2F1. Oncology reports. Mar2017;37(3):1833-1841.

Tanderup K, Menard C, Polgar C, Lindegaard JC, Kirisits C, Potter R.Advancements in brachytherapy. Advanced drug delivery reviews. Jan 15 2017;109:15-25.

Taunk NK, Haffty BG, Kostis JB, Goyal S. Radiation-induced heartdisease: pathologic abnormalities and putative mechanisms. Frontiers in oncology. 2015;5:39.

Taylor C, Correa C, Duane FK, Aznar MC, Anderson SJ, Bergh J, . . .McGale P. Estimating the Risks of Breast Cancer Radiotherapy: EvidenceFrom Modern Radiation Doses to the Lungs and Heart and From PreviousRandomized Trials. J Clin Oncol. May 20 2017;35(15):1641-1649.

Taysi S, Abdulrahman ZK, Okumus S, Demir E, Demir T, Akan M, . . .Tarakcioglu M. The radioprotective effect of Nigella sativa onnitrosative stress in lens tissue in radiation-induced cataract in rat. Cutaneous and ocular toxicology. Jun 2015;34(2):101-106.

Thalhammer C, Husmann M, Glanzmann C, Studer G, Amann-Vesti BR. Carotidartery disease after head and neck radiotherapy. VASA. Zeitschrift fur Gefasskrankheiten. Jan 2015;44(1):23-30.

Thapa P, Nikam D, Das T, Sonawane G, Agarwal JP, Basu S. ClinicalEfficacy and Safety Comparison of 177Lu-EDTMP with 153Sm-EDTMP on anEquidose Basis in Patients with Painful Skeletal Metastases. Journal of nuclear medicine : official publication, Society of Nuclear Medicine.Oct 2015;56(10):1513-1519.

Thariat J, Hannoun-Levi JM, Sun Myint A, Vuong T, Gerard JP. Past,present, and future of radiotherapy for the benefit of patients. Nature reviews. Clinical oncology. Jan 2013;10(1):52-60.

Togni S, Maramaldi G, Bonetta A, Giacomelli L, Di Pierro F. Clinicalevaluation of safety and efficacy of Boswellia-based cream forprevention of adjuvant radiotherapy skin damage in mammary carcinoma: arandomized placebo controlled trial. European review for medical and pharmacological sciences. Apr2015;19(8):1338-1344.

Tolentino Ede S, Centurion BS, Ferreira LH, Souza AP, Damante JH,Rubira-Bullen IR. Oral adverse effects of head and neck radiotherapy:literature review and suggestion of a clinical oral care guideline forirradiated patients. Journal of applied oral science : revista FOB. Oct2011;19(5):448-454.

Topkan E, Yavuz AA, Ozyilkan O. Cancer cachexia: pathophysiologicaspects and treatment options. Asian Pacific journal of cancer prevention: APJCP. Jul-Sep2007;8(3):445-451.

Topkan E, Yavuz MN, Onal C, Yavuz AA. Prevention of acuteradiation-induced esophagitis with glutamine in non-small cell lungcancer patients treated with radiotherapy: evaluation of clinical anddosimetric parameters. Lung cancer (Amsterdam, Netherlands). Mar 2009;63(3):393-399.

Touchefeu Y, Montassier E, Nieman K, Gastinne T, Potel G, Bruley desVarannes S, . . . de La Cochetiere MF. Systematic review: the role ofthe gut microbiota in chemotherapy- or radiation-inducedgastrointestinal mucositis - current evidence and potential clinicalapplications. Alimentary pharmacology & therapeutics. Sep2014;40(5):409-421.

Travis LB. The epidemiology of second primary cancers. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.Nov 2006;15(11):2020-2026.

Travis LB, Demark Wahnefried W, Allan JM, Wood ME, Ng AK. Aetiology,genetics and prevention of secondary neoplasms in adult cancersurvivors. Nature reviews. Clinical oncology. May2013;10(5):289-301.

Trikalinos TA, Terasawa T, Ip S, Raman G, Lau J. Particle BeamRadiation Therapies for Cancer. Appendix F: Centers That PerformParticle Beam Treatment (Worldwide). Rockville, MD: Agency forHealthcare Research and Quality.https://www.ncbi.nlm.nih.gov/books/NBK44536/. Last updated 11/2009a.Accessed 12/20/2016.

Trikalinos TA, Terasawa T, Ip S, Raman G, Lau J. Particle BeamRadiation Therapies for Cancer. Technical Brief No. 1. (Prepared byTufts Medical Center Evidence-based Practice Center under Contract No.HHSA-290-07-10055.) Rockville, MD: Agency for Healthcare Research andQuality. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Lastupdated 11/2009b. Accessed 12/6/2016.

Tsujimoto T, Yamamoto Y, Wasa M, Takenaka Y, Nakahara S, Takagi T, . .. Ito T. L-glutamine decreases the severity of mucositis induced bychemoradiotherapy in patients with locally advanced head and neckcancer: a double-blind, randomized, placebo-controlled trial. Oncology reports. Jan 2015;33(1):33-39.

Tutanc OD, Aydogan A, Akkucuk S, Sunbul AT, Zincircioglu SB, Alpagat G,Erden ES. The efficacy of oral glutamine in prevention of acuteradiotherapy-induced esophagitis in patients with lung cancer. Contemp Oncol (Pozn). 2013;17(6):520-524.

Ueda-Iuchi T, Ohno N, Miyati T, Dai M, Okuwa M, Nakatani T, . . .Sugama J. Assessment of the interstitial fluid in the subcutaneoustissue of healthy adults using ultrasonography. SAGE open medicine. 2015;3:2050312115613351.

Uma Devi P, Kamath R. Radiosensitizing effect of withaferin A combinedwith hyperthermia on mouse fibrosarcoma and melanoma. Journal of radiation research. Mar 2003;44(1):1-6.

Urbancsek H, Kazar T, Mezes I, Neumann K. Results of a double-blind,randomized study to evaluate the efficacy and safety of Antibiophilusin patients with radiation-induced diarrhoea. European journal of gastroenterology & hepatology. Apr2001;13(4):391-396.

Ursino S, Greco C, Cartei F, Colosimo C, Stefanelli A, Cacopardo B, . .. Fiorica F. Radiotherapy and hepatocellular carcinoma: update andreview of the literature. European review for medical and pharmacological sciences. Oct2012;16(11):1599-1604.

Ustun K, Taysi S, Sezer U, Demir E, Baysal E, Demir T, . . . Aksoy N.Radio-protective effects of Nigella sativa oil on oxidative stress intongue tissue of rats. Oral diseases. Jan 2014;20(1):109-113.

van Eggermond AM, Schaapveld M, Lugtenburg PJ, Krol AD, de Boer JP,Zijlstra JM, . . . van Leeuwen FE. Risk of multiple primarymalignancies following treatment of Hodgkin lymphoma. Blood. Jul 17 2014;124(3):319-327; quiz 466.

Velho-Pereira R, Kumar A, Pandey BN, Mishra KP, Jagtap AG.Radioprotection by Macerated Extract of Nigella sativa in NormalTissues of Fibrosarcoma Bearing Mice. Indian journal of pharmaceutical sciences. Sep2012;74(5):403-414.

Verma N, Cowperthwaite MC, Burnett MG, Markey MK. Differentiating tumorrecurrence from treatment necrosis: a review of neuro-oncologic imagingstrategies. Neuro Oncol. May 2013;15(5):515-534.

Verma V. Relationship and interactions of curcumin with radiationtherapy. World journal of clinical oncology. Jun 102016;7(3):275-283.

Vernia P, Fracasso PL, Casale V, Villotti G, Marcheggiano A, StiglianoV, . . . Caprilli R. Topical butyrate for acute radiation proctitis:randomised, crossover trial. Lancet. Oct 72000;356(9237):1232-1235.

Vidal-Casariego A, Calleja-Fernandez A, de Urbina-Gonzalez JJ,Cano-Rodriguez I, Cordido F, Ballesteros-Pomar MD. Efficacy ofglutamine in the prevention of acute radiation enteritis: a randomizedcontrolled trial. JPEN. Journal of parenteral and enteral nutrition. Feb2014;38(2):205-213.

Vijayalaxmi, Reiter RJ, Tan DX, Herman TS, Thomas CR, Jr. Melatonin asa radioprotective agent: a review. International journal of radiation oncology, biology, physics.Jul 1 2004;59(3):639-653.

Vijayan A, Asha ML, Babu S, Chakraborty S. Prospective phase II studyof the efficacy of transcutaneous electrical nerve stimulation inpost-radiation patients. Clinical oncology (Royal College of Radiologists (Great Britain)).Dec 2014;26(12):743-747.

Visich KL, Yeo TP. The prophylactic use of probiotics in the preventionof radiation therapy-induced diarrhea. Clinical journal of oncology nursing. Aug 2010;14(4):467-473.

Wadhwa R, Konar A, Kaul SC. Nootropic potential of Ashwagandha leaves:Beyond traditional root extracts. Neurochemistry international. May 2016;95:109-118.

Wakeford R. The cancer epidemiology of radiation. Oncogene. Aug 23 2004;23(38):6404-6428.

Walker AJ, Ruzevick J, Malayeri AA, Rigamonti D, Lim M, Redmond KJ,Kleinberg L. Postradiation imaging changes in the CNS: how can wedifferentiate between treatment effect and disease progression? Future oncology (London, England). May 2014;10(7):1277-1297.

Wang D. A critical appraisal of the clinical utility of proton therapyin oncology. Medical devices (Auckland, N.Z.). 2015;8:439-446.

Wang F, Tang Q, Lv G, Zhao F, Jiang X, Zhu X, . . . Yan S. Comparisonof computed tomography and magnetic resonance imaging in cervicalcancer brachytherapy: A systematic review. Brachytherapy. Mar- Apr 2017;16(2):353-365.

Wang H, Peng D, Xie J. Ginseng leaf-stem: bioactive constituents andpharmacological functions. Chinese medicine. 2009;4:20.

Wang J, Xu HW, Li BS, Zhang J, Cheng J. Preliminary study of protectiveeffects of flavonoids against radiation-induced lung injury in mice. Asian Pacific journal of cancer prevention : APJCP. 2012;13(12):6441-6446.

Wang K, Eblan MJ, Deal AM, Lipner M, Zagar TM, Wang Y, . . . Marks LB.Cardiac Toxicity After Radiotherapy for Stage III Non-Small-Cell LungCancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90Gy. J Clin Oncol. May 01 2017;35(13):1387-1394.

Wang L, Li X, Song YM, Wang B, Zhang FR, Yang R, . . . Zhang GJ.Ginsenoside Rg3 sensitizes human nonsmall cell lung cancer cells togamma-radiation by targeting the nuclear factor-kappaB pathway. Molecular medicine reports. Jul 2015;12(1):609-614.

Wang L, Long L, Wang W, Liang Z. Resveratrol, a potential radiationsensitizer for glioma stem cells both in vitro and in vivo. Journal of pharmacological sciences. Dec 2015;129(4):216-225.

Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL. The efficacy andsafety of melatonin in concurrent chemotherapy or radiotherapy forsolid tumors: a meta-analysis of randomized controlled trials. Cancer chemotherapy and pharmacology. May2012;69(5):1213-1220.

Warrington JP, Ashpole N, Csiszar A, Lee YW, Ungvari Z, Sonntag WE.Whole brain radiation-induced vascular cognitive impairment: mechanismsand implications. Journal of vascular research. 2013;50(6):445-457.

Watanabe T, Ishihara M, Matsuura K, Mizuta K, Itoh Y. Polaprezincprevents oral mucositis associated with radiochemotherapy in patientswith head and neck cancer. International journal of cancer. Journal international du cancer.Oct 15 2010;127(8):1984-1990.

Weichselbaum RR, Ishwaran H, Yoon T, Nuyten DS, Baker SW, Khodarev N, .. . Minn AJ. An interferon-related gene signature for DNA damageresistance is a predictive marker for chemotherapy and radiation forbreast cancer. Proceedings of the National Academy of Sciences of the United States of America.Nov 25 2008;105(47):18490-18495.

Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy andimmunotherapy: a beneficial liaison? Nature reviews. Clinical oncology. Jun 2017;14(6):365-379.

West CM, Barnett GC. Genetics and genomics of radiotherapy toxicity:towards prediction. Genome medicine. Aug 23 2011;3(8):52.

Wikipedia contributors. Proton therapy. Wikipedia, The FreeEncyclopedia. Last updated 11/9/2017.https://en.wikipedia.org/wiki/Proton_therapy#United_States. Accessed11/20/2017.

Wilken R, Veena MS, Wang MB, Srivatsan ES. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Molecular cancer. 2011;10:12.

Williams JP, Brown SL, Georges GE, Hauer-Jensen M, Hill RP, Huser AK, .. . McBride WH. Animal models for medical countermeasures to radiationexposure. Radiation research. Apr 2010;173(4):557-578.

Wilson EN, Bristol ML, Di X, Maltese WA, Koterba K, Beckman MJ, GewirtzDA. A switch between cytoprotective and cytotoxic autophagy in theradiosensitization of breast tumor cells by chloroquine and vitamin D. Hormones & cancer. Oct 2011;2(5):272-285.

Windsor PM, Nicol KF, Potter J. A randomized, controlled trial ofaerobic exercise for treatment-related fatigue in men receiving radicalexternal beam radiotherapy for localized prostate carcinoma. Cancer. Aug 1 2004;101(3):550-557.

Winters M. Ancient medicine, modern use: Withania somnifera and itspotential role in integrative oncology. Alternative medicine review : a journal of clinical therapeutic.Dec 2006;11(4):269-277.

Witkowska M, Majchrzak A, Smolewski P. The role of radiotherapy inHodgkin's lymphoma: what has been achieved during the last 50 years? BioMed research international. 2015;2015:485071.

Wong HM. Oral complications and management strategies for patientsundergoing cancer therapy. TheScientificWorldJournal. 2014;2014:581795.

Worthington HV, Clarkson JE, Bryan G, Furness S, Glenny AM, LittlewoodA, . . . Khalid T. Interventions for preventing oral mucositis forpatients with cancer receiving treatment. The Cochrane database of systematic reviews. 2011(4):Cd000978.

Wu Y, Wu PY. CD133 as a marker for cancer stem cells: progresses andconcerns. Stem cells and development. Oct2009;18(8):1127-1134.

Xu J, Cao Y. Radiation-induced carotid artery stenosis: a comprehensivereview of the literature. Interventional neurology. Aug2014;2(4):183-192.

Xu Y, Fang F, St Clair DK, Josson S, Sompol P, Spasojevic I, St ClairWH. Suppression of RelB-mediated manganese superoxide dismutaseexpression reveals a primary mechanism for radiosensitization effect of1alpha,25-dihydroxyvitamin D(3) in prostate cancer cells. Molecular cancer therapeutics. Jul 2007;6(7):2048-2056.

Yang ES, Choi MJ, Kim JH, Choi KS, Kwon TK. Combination of withaferin Aand X-ray irradiation enhances apoptosis in U937 cells. Toxicol In Vitro. Dec 2011a;25(8):1803-1810.

Yang ES, Choi MJ, Kim JH, Choi KS, Kwon TK. Withaferin A enhancesradiation-induced apoptosis in Caki cells through induction of reactiveoxygen species, Bcl-2 downregulation and Akt inhibition. Chem Biol Interact. Mar 15 2011b;190(1):9-15.

Yang L, Qian S, Liu L, Pu C, Yuan H, Han P, Wei Q. Phosphodiesterase-5inhibitors could be efficacious in the treatment of erectiledysfunction after radiotherapy for prostate cancer: a systematic reviewand meta-analysis. Urologia internationalis. 2013;90(3):339-347.

Yang L, Taylor J, Eustace A, Irlam J, Denley H, Hoskin PJ, . . . WestCM. A Gene Signature for Selecting Benefit from Hypoxia Modification ofRadiotherapy for High Risk Bladder Cancer Patients. Clinical cancer research : an official journal of the American Association for Cancer Research.Apr 11 2017.

Yang X, Liu T, Chen B, Wang F, Yang Q, Chen X. Grape seedproanthocyanidins prevent irradiation-induced differentiation of humanlung fibroblasts by ameliorating mitochondrial dysfunction. Sci Rep. Dec 2017;7(1):62.

Yang YP, Chang YL, Huang PI, Chiou GY, Tseng LM, Chiou SH, . . . ChangCJ. Resveratrol suppresses tumorigenicity and enhances radiosensitivityin primary glioblastoma tumor initiating cells by inhibiting the STAT3axis. Journal of cellular physiology. Mar 2012;227(3):976-993.

Yoshida K, Miyawaki D, Ebina Y, Sasaki R. Image-Guided AdaptiveBrachytherapy for Cervical Cancer Using Magnetic Resonance Imaging:Overview and Experience. In: Onal C, ed. Radiotherapy: InTech;2017.

Yuce Sari S, Yazici G, Yuce D, Karabulut E, Cengiz M, Ozyigit G. Theeffect of glutamine and arginine-enriched nutritional support onquality of life in head and neck cancer patients treated with IMRT. Clinical nutrition ESPEN. Dec 2016;16:30-35.

Yun KL, Wang ZY. Target/signalling pathways of natural plant-derivedradioprotective agents from treatment to potential candidates: Areverse thought on anti-tumour drugs. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.May 17 2017;91:1122-1151.

Zagar TM, Oleson JR, Vujaskovic Z, Dewhirst MW, Craciunescu OI,Blackwell KL, . . . Jones EL. Hyperthermia combined with radiationtherapy for superficial breast cancer and chest wall recurrence: areview of the randomised data. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.2010;26(7):612-617.

Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, . . . LimM. Anti-PD-1 blockade and stereotactic radiation produce long-termsurvival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. Jun 01 2013;86(2):343-349.

Zetner D, Andersen LP, Rosenberg J. Melatonin as Protection AgainstRadiation Injury: A Systematic Review. Drug research. Jun2016;66(6):281-296.

Zhang B, Liu JY, Pan JS, Han SP, Yin XX, Wang B, Hu G. Combinedtreatment of ionizing radiation with genistein on cervical cancer HeLacells. Journal of pharmacological sciences. Sep2006;102(1):129-135.

Zhang G, Wang Y, Zhang Y, Wan X, Li J, Liu K, . . . Wu E. Anti-canceractivities of tea epigallocatechin-3-gallate in breast cancer patientsunder radiotherapy. Current molecular medicine. Feb2012;12(2):163-176.

Zhao H, Xie P, Li X, Zhu W, Sun X, Sun X, . . . Yu J. A prospectivephase II trial of EGCG in treatment of acute radiation-inducedesophagitis for stage III lung cancer. Radiother Oncol. Mar 102015.

Zhao H, Zhu W, Jia L, Sun X, Chen G, Zhao X, . . . Yu J. Phase I studyof topical epigallocatechin-3-gallate (EGCG) in patients with breastcancer receiving adjuvant radiotherapy. The British journal of radiology. 2016;89(1058):20150665.

Zhao H, Zhu W, Xie P, Li H, Zhang X, Sun X, . . . Xing L. A phase Istudy of concurrent chemotherapy and thoracic radiotherapy with oralepigallocatechin-3-gallate protection in patients with locally advancedstage III non-small-cell lung cancer. Radiother Oncol. Jan2014;110(1):132-136.

Zhu W, Jia L, Chen G, Zhao H, Sun X, Meng X, . . . Zheng M.Epigallocatechin-3-gallate ameliorates radiation-induced acute skindamage in breast cancer patients undergoing adjuvant radiotherapy. Oncotarget. Jul 26 2016;7(30):48607-48613.

Zhu XL, Zhu BD. Mechanisms by which Astragalus membranaceus injectionregulates hematopoiesis in myelosuppressed mice. Phytotherapy research: PTR. Jul 2007;21(7):663-667.

Zhuang L, Yang Z, Zeng X, Zhua X, Chen Z, Liu L, Meng Z. The preventiveand therapeutic effect of acupuncture for radiation-induced xerostomiain patients with head and neck cancer: a systematic review. Integrative cancer therapies. May 2013;12(3):197-205.