Cancer Radiation Therapy
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 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).
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.
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).
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 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).