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Cancer Radiation Therapy

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).