Cancer Radiation Therapy
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).