Cancer Radiation Therapy-2

Hyperbaric oxygen treatment (HBOT). Following the identification of hypoxia as a possible source of radiation resistance, a major effort was made to solve the problem through the use of hyperbaric oxygen. Hyperbaric oxygen is a mode of therapy in which the patient breathes pure, 100-percent oxygen at pressures two to three times greater than normal atmospheric pressure (Feldmeier JJ 2004). The concentration of oxygen normally dissolved in the bloodstream is thus raised many times above normal (up to 2000 percent).

This hyperoxygenation provides immediate support to poorly perfused tumor tissue in areas of compromised blood flow (Plafki C et al. 1998). These include radiation-damaged tissue that has lost blood supply and is oxygen deprived due to scarring and narrowing of the blood vessels within the area treated (Anderson DW 2003). Healing is dependent on oxygen delivery to the injured tissues, and hyperbaric oxygen therapy provides a better healing environment, leads to the growth of new blood vessels, and also helps to eradicate anaerobic bacteria that may cause infection via toxin inhibition and inactivation (Anderson DW 2003; Marx RE et al. 1990).

Hyperbaric oxygen has been used to treat normal tissue injury caused by radiation therapy in several sites, including the head and neck (Feldmeier JJ et al. 2002), pelvis (Corman JM et al. 2003), breast (Carl UM et al. 2001), prostate (Mayer R et al. 2001), and brain (Kohshi K et al. 2003), with few serious side effects.

In a study of 45 patients with radiation-induced late side effects, the majority showed improvement in their condition after either hyperbaric oxygen therapy alone or hyperbaric oxygen therapy followed by other surgical or medical procedures (Bui QC et al. 2004). In particular, osteoradionecrosis (necrosis, or death of the bone following radiotherapy) appeared to be highly responsive to hyperbaric oxygen therapy (Mounsey RA et al. 1993). This condition usually involves the lower jaw in a minority (8 percent) of head and neck cancer patients treated with radiation therapy, is difficult to treat, leads to intense pain and fracture, and makes oral feeding impossible (Reuther T et al. 2003).

However, the use of hyperbaric oxygen therapy is not widespread, partly because it is cumbersome and difficult in practice and partly because many of the studies to date have involved small numbers of patients (Gothard L et al. 2004; Haffty BG et al. 1999). Larger trials are needed to investigate the true efficacy of hyperbaric oxygen therapy.

Breathing oxygen during radiotherapy. The inhalation of oxygen during radiotherapy may increase the radiation kill effect on the tumor by counteracting areas of hypoxia-based radioresistance, and thus improve overall survival. Stage II cervical cancer patients, with squamous cell carcinoma, who received oxygen (normobaric) during all radiotherapy sessions had significantly improved loco-regional cancer control (Sundfor K et al. 1999).

Patients with Stage III (7 percent) and Stage IV (93 percent) advanced squamous cell carcinomas of the head and neck who breathed pure, normobaric oxygen for 15 to 20 minutes during irradiation had improved mean survival time (15.8 versus 11.8 months) and three-year survival (19 percent versus 2 percent), respectively (p < 0.05). Thus, breathing normobaric oxygen before and during radiation therapy could increase the effectiveness of conventional radiotherapy for advanced squamous cell carcinomas of the head and neck (Zajusz A et al. 1995).

Radioprotectors/radiosensitizers. Researchers are investigating two types of drugs that may increase the effectiveness of radiation therapy (Yuhas JM et al. 1977). Radiosensitizers make tumor cells more susceptible to radiation damage, while radioprotectors protect normal tissues from the damaging effects of radiation, allowing a higher dose of radiation to be directed at the tumor.

Radiosensitizers are chemicals that increase the damaging effects of radiation if administered simultaneously. Two types of radiosensitizers have been used in conjunction with radiation therapy:

1)Halogenated pyrimidines, such as bromodeoxyuridine, which depend on the amount of drug incorporated in the cell (Jackson D et al. 1987). As tumor cells divide more rapidly than the surrounding normal cells, they take up more of the radiosensitizer.

2) Hypoxic cell sensitizers, which increase the radiosensitivity of only those cells located in areas of low oxygen (Brown JM 1989). As many tumors contain large regions of hypoxic cells compared to normal tissues, these drugs are able to produce a differential effect, that is, they are toxic to hypoxic cells only.

Amifostine (Ethyol®) has been approved by the FDA specifically for use as a radioprotector. It is approved for the prevention of xerostomia (dry mouth) in head and neck cancer patients treated with radiation therapy (Hensley ML et al. 1999). Adequate hydration is critical before amifostine administration (given intravenously once daily as a 3-minute infusion starting 15 to 30 minutes before standard fraction radiation therapy).

The two major side effects of amifostine that cause treatment discontinuation are vomiting and transient low blood pressure (hypotension) (Capizzi RL et al. 2000), and these adverse effects limit its wide acceptance.

Ginseng. Ginseng has several beneficial effects on blood vessels (Yun TK 2001). In experimental studies, ginseng was shown to be a promising radioprotector (Kim SR et al. 2003), that is, it may protect normal healthy tissue from damage during radiation therapy (Kim TH et al. 1996; Lee TK et al. 2004). In a clinical study, ginseng polysaccharide injection improved immune function in nasopharyngeal carcinoma patients during radiotherapy (Xie FY et al. 2001).

Glutathione is a natural antioxidant synthesized from the amino acids glutamine, cysteine, and glycine (Walzem RL et al. 2002). A severe reduction in glutathione content can predispose cells to oxidative damage. When tumor cells are irradiated, either lethal damage can occur and the cells die, or the damage can be modified via DNA repair and not lead to permanent cell death.

Cancer cells have higher glutathione levels than the surrounding normal healthy cells. Therefore, selective tumor depletion of glutathione presents a promising strategy in cancer management. Dietary glutamine supplementation lowers glutathione levels in tumor cells (Kennedy RS et al. 1995; Todorova VK et al. 2004), but increases production in normal tissues. Furthermore, glutamine supplementation decreases the toxicity of radiation therapy (Klimberg VS et al. 1992; Rouse K et al. 1995).

Whey protein is an effective and safe cysteine donor for glutathione replenishment (Kennedy RS et al. 1995; See D et al. 2002). Radiation therapy is known to cause immunosuppression (Wara WM et al. 1979). Cysteine is the critical limiting amino acid for intracellular glutathione synthesis (Bounous G 2000). The amino acid precursors to glutathione present in whey might increase glutathione concentration in relevant tissues, stimulate immunity, and detoxify potential carcinogens (Bounous G 2000). Glutathione stimulation is thought to be whey’s primary immune-modulating mechanism (Marshall K 2004).

Alkylglycerols are active ingredients of shark liver oil. They have been widely used for the treatment of cancer in Scandinavian countries (Krotkiewski M et al. 2003), and research suggests their use may result in a lower incidence of normal tissue radiation damage (Hasle H et al. 1991). Although their protective mechanism is not fully understood (Hichami A et al. 1997), they cause increased tumor cell death (apoptosis) and have many beneficial effects on the immune system, including the stimulation of neutrophils and macrophages (Tchorzewski H et al. 2002). Doses of shark liver oil up to 100 mg three times a day can be taken with no unfavorable side effects (Pugliese PT et al. 1998).

Hyperthermia with radiotherapy. Hyperthermia is the artificial elevation of the temperature of a tissue. Tumor cells can be selectively killed by temperatures between 40° and 44° centigrade (C) as compared with normal cells (van der Zee J 2002) because of improved tissue oxygenation and a consequent temporary increase in radiosensitivity (Song CW et al. 1997).

Numerous studies have shown that the combination of hyperthermia and radiation therapy improves clinical outcomes, particularly in breast cancer, melanoma, head and neck tumors, cervical cancer, and glioblastoma (van der Zee J et al. 2003).

Normal tissue toxicity with hyperthermia only results if the tissue temperature exceeds 44° C for more than one hour (Fajardo LF 1984). The toxicity from superficial hyperthermia is usually a skin burn; for deep-seated tumors, a subcutaneous fat or muscle burn may occur, which heals spontaneously (van der Zee J 2002).

Phytochemicals. Phytochemicals such as epigallocatechin-3 gallate (EGCG) found in green tea, curcumin, and genistein have been shown to enhance the radiation-induced death of cancer cells in addition to restraining tumor growth in animal models (Dorai T et al. 2004; Sarkar FH et al. 2004). They also have antioxidant properties and can therefore neutralize the detrimental effects of reactive oxygen species on normal cells (Katiyar SK et al. 2001).

EGCG (mainly derived from green tea) may increase the efficacy of radiation therapy by decreasing the activity of vascular endothelial growth factor (VEGF) (Lee YK et al. 2004). VEGF acts as a crucial survival factor for tumor cells (Ferrara N 2005).

Soy isoflavones, including genistein, daidzein, and glycitin (mainly derived from soybean), have been found to slow cancer growth in experimental animal studies (Sarkar FH et al. 2004). Genistein significantly enhances the radiation effect (that is, acts as a radiosensitizer) for cervical cancer cells (Yashar CM et al. 2005).

Curcumin, a natural anti-proliferative compound for many types of tumor, is extracted from the spice turmeric (Sikora E et al. 1997). Curcumin blocks the nuclear factor-kappa beta (NF-?B) activation process (Singh S et al. 1995). The maintenance of appropriate levels of NF-?B activity is crucial for normal cell division, and NF-?B activation is involved in the enhanced growth properties observed in several cancers (Bharti AC et al. 2002). Curcumin can sensitize squamous cell carcinoma cells to the ionizing effects of radiation (Khafif A et al. 2005). In prostate cancer cell lines, curcumin is a potent radiosensitizer and acts by overcoming the effects of radiation-induced prosurvival gene (bcl-2) expression (Chendil D et al. 2004).

Preventing and Counteracting Adverse Effects of Radiotherapy

Antioxidant use and radiation therapy

A survey of cancer patients found that 63 percent use vitamins and herbs (including antioxidants), and the majority combine them with conventional therapies (Richardson MA et al. 2000). Critics argue that excessive nutrient-derived antioxidant use during radiation therapy could, in theory, protect cancer cells against the damaging effects of reactive oxygen species or oxidants, which are formed by radiation. This could occur by the antioxidants directly scavenging reactive oxygen species or repairing cellular damage in tumor cells (Salganik RI 2001). However, this theory has never been confirmed by clinical studies, and antioxidants can have protective effects that have nothing to do with oxidation (Block KI 2004).

Furthermore, there is no controversy surrounding physician-prescribed antioxidants such as amifostine (Ethyol®), an FDA-approved orphan drug for the prevention of xerostomia (dry mouth) in head and neck cancer patients undergoing radiation treatment. Amifostine has been clearly shown to reduce the incidence of side effects (xerostomia and mucositis) in patients receiving head and neck irradiation (Schuchter LM et al. 2002). It has also been used in combination with radiation therapy in the treatment of lung, prostate, breast, cervical, and esophageal cancer patients, with much success. The problem with amifostine is that it causes intolerable nausea, vomiting, diarrhea, and abdominal cramping, which limits its use.

The use of supplemental antioxidants is further supported in that they may help protect normal cells from the increased damage and side effects caused by radiation therapy (Lamson DW et al. 1999). Moreover, it has been shown that levels of antioxidants are decreased in cancer patients in response to radiation therapy (Sabitha KE et al. 1999). Thus, supplementation with dietary antioxidants (such as vitamins C and E) may improve the efficacy of radiation therapy by increasing tumor response and decreasing some of its toxicity on normal cells (Prasad KN et al. 2002).

Dietary antioxidants (including vitamin E, vitamin C, and selenium) as well as antioxidant enzymes found within cells (e.g., superoxide dismutase and glutathione peroxidase) can help maintain an appropriate balance between the desirable and undesirable effects of reactive oxygen species formed by radiation therapy (Seifried HE et al. 2003).

In several clinical radiotherapy studies, supplementation with the antioxidants vitamin E, selenium, and melatonin during treatment was shown to improve the efficacy of radiation therapy by decreasing radiation toxicity in normal cells and enhancing the immune response (Kiremidjian-Schumacher L et al. 2000; Malmberg KJ et al. 2002; Prasad KN et al. 2002).

Many clinical studies (detailed herein) have shown that antioxidant supplementation (with vitamins C and E, N-acetylcysteine, glutamine, and glutathione) both before and during radiotherapy prevents normal tissue complications (De Maria D et al. 1992; Ersin S et al. 2000; Huang EY et al. 2000; Kaya E et al. 1999; Kim JA et al. 1983; Klimberg VS et al. 1990; Mills EE 1988; Wagdi P et al. 1996), thus improving radiotherapy outcomes.

Overall, the data suggest that careful, sensible use of the antioxidants outlined herein may be helpful in improving the outcome of radiation therapy. Natural antioxidants (such as tocopherols, ascorbic acid, squalene, and lecithin) are present in most plant-based foods (Foley DJ et al. 2002) and in fruit, fish, herbs, and cereals (Shahidi F 2000).

Vitamin A. Radiation therapy effectiveness is increased when combined with vitamin A, which is thought to be due to an increased immune response against the tumor (Tannock IF et al. 1972). Vitamin A (8000 IU taken orally twice daily for seven weeks) appeared to be very effective in the treatment of radiation-induced anorectal damage in a patient with human immunodeficiency virus (HIV) infection (Levitsky J et al. 2003).

In a randomized, double-blind trial comparing retinol palmitate (vitamin A, 10,000 IU taken orally for 90 days) to placebo, oral retinol palmitate significantly reduced the rectal symptoms of radiation proctopathy in 19 patients six months after pelvic radiotherapy (Ehrenpreis ED et al. 2005).

Vitamin C. Experimental studies show that radiation treatment reduces the level of vitamin C in the body (Beliaev IK 1991). Conversely, studies of mice have shown that supplementing vitamin C at high doses preferentially radiosensitizes tumors while offering some protection to normal tissues (Tewfik FA et al. 1982).

Vitamin E. Vitamin E has been recognized as one of the most important antioxidants. Tocopheryl succinate (dry powder vitamin E) enhanced radiation damage to ovarian and cervical cancer cells in culture, while protecting healthy cells (Kumar B et al. 2002).

Vitamin E and selenium have been reported to have an increased beneficial effect when used in combination (Weiss JF et al. 2000). A study of rats showed that pre-treatment with both selenium and vitamin E for four weeks before radiation gave some protection against radiation-induced intestinal injury.

Selenium. A large number of selenium derivatives have been studied for their radioprotective effects (Weiss JF et al. 2003). Selenium is a very efficient scavenger of reactive oxygen species and a radiosensitizer, with a very low toxicity profile (Schueller P et al. 2004).

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 immune response during and after therapy (Kiremidjian-Schumacher L et al. 2000).

Coenzyme Q10. Coenzyme Q10 (CoQ10), a mitochondrial enzyme, has been shown to have a therapeutic benefit in cancer patients at doses of 90 to 390 mg daily. A decrease in distant metastasis (Lockwood K et al. 1994) and increase in long-term survival (Lockwood K et al. 1995) have been noted in breast cancer patients. However, a study of mice indicated that CoQ10 reduced the effect of radiation therapy when used at a dose equivalent to 700 mg in humans; therefore, as a precaution, a dose of 100 to 400 mg a day should not be exceeded (Lund EL et al. 1998).

Melatonin.Melatonin is the chief secretory hormone of the pineal gland. Melatonin reduces oxidative damage from the production of free radicals (Reiter RJ 2004). Several studies indicate that melatonin functions as a radioprotector (Karbownik M et al. 2000), reducing the toxic effects of radiation on mammalian cells (Vijayalaxmi et al. 2004). In experiments and animal models, administration of melatonin has inhibited the growth and division of several types of cancer cells, particularly breast cancer and melanoma cells (Blask DE et al. 1986; Subramanian A et al. 1991).

Several reports indicate that melatonin administration improves quality of life for many cancer patients (Conti A et al. 1995). Patients with glioblastoma generally experience a poor survival rate, which is typically less than six months. A radio-neuroendocrine approach utilizing radiotherapy with melatonin supplementation (20 mg daily) in patients with untreatable glioblastoma showed that the likelihood of survival at one year was significantly higher in those who received melatonin with radiotherapy (6 of 14 patients alive) versus radiotherapy alone (1 of 16 patients alive) (Lissoni P et al. 1996a). A reduction in radiation-induced toxicity was also observed in the melatonin-treated group.

Melatonin reduces gamma radiation-induced primary DNA damage in human white blood cells (lymphocytes) (Vijayalaxmi 1998). It has been suggested that supplementing with an adjuvant therapy of melatonin may benefit cancer patients who are suffering from toxic therapeutic regimens such as radiotherapy and/or chemotherapy, and may alleviate symptoms caused by radiation-induced organ injuries (Karslioglu I et al. 2005).

Preventing Normal Tissue Complications

The goal of radiation therapy is to deliver a precisely measured dose of ionizing radiation to a defined tumor area, with as little damage as possible to surrounding healthy, non-cancerous tissue (Burnet NG et al. 1996). However, a number of patients undergoing radiation therapy will experience a range of side effects, which may lead to an interruption of treatment or limiting the dose of radiation (Fowler JF et al. 1992).

Radiation’s effects on normal tissues are commonly divided into two categories: “early” and “late” reactions. Early, or acute, effects occur within a few days or weeks of irradiation (Herskind C et al. 1998). Late effects appear after a period of months or years and occur predominantly in slowly growing tissues such as the lungs, kidneys, heart, liver, and central nervous system.

The size of the radiation treatment field, the dose per fraction, and the total dose of radiation received are important factors associated with these effects (Emami B et al. 1991).

Heart damage.
The use of 3D-CRT reduces the dose and volume of radiation exposure to the heart (Hurkmans CW et al. 2002). However, significant risks remain, and cardiovascular abnormalities may result following radiation therapy (Lipshultz SE et al. 1993). Hodgkin's disease survivors treated with chest radiation therapy are at increased risk of death as a result of cardiovascular disease (Lee CK et al. 2000). Women treated with radiation therapy following mastectomy for left-sided breast cancer, which involves exposure of the heart, have been shown to have an increased frequency of cardiovascular disease (Gyenes G et al. 1998).

In a small trial of a mixture of antioxidants—including vitamin E (600 mg), vitamin C (1 gram), and N-acetylcysteine (200 mg)—taken during treatment, researchers sought to determine the mixture’s ability to prevent heart damage during chemotherapy and radiation therapy. No patient taking the antioxidant mixture had a decrease in ejection fraction (the amount of blood pumped out of the heart during each heartbeat) of greater than 10 percent. By contrast, in the control group, in which four of six patients were treated with radiation therapy and two of seven patients underwent chemotherapy, the ejection fraction reduction was greater than 10 percent, indicative of a weakened heart (Wagdi P et al. 1996).

Gastrointestinal mucositis (inflammation of the gut lining).
More than 70 percent of patients treated for cancer of the prostate, bladder, and other malignancies in the pelvic region develop acute inflammatory small intestinal changes (Resbeut M et al. 1997). Acute enteritis or proctitis (inflammation of the intestine or rectum, respectively) is characterized by diarrhea, abdominal pain, and tenesmus (fecal urgency with cramp-like rectal pain) that usually starts during the second week of radiation therapy and resolves within two weeks of completing treatment (Ajlouni M 1999). In 5 percent to 10 percent of patients, serious gastrointestinal problems may occur, including bowel obstructions and bleeding (Denton AS et al. 2000).

Both glutamine (Hall JC et al. 1996) and arginine (Gurbuz AT et al. 1998) are amino acids that have an important role in maintaining mucosal growth and function. Supplementation with these amino acids before or after abdominal irradiation appears to decrease the likelihood of both acute and chronic effects on the lower intestine (Ersin S et al. 2000; Kaya E et al. 1999; Klimberg VS et al. 1990), but not all studies have shown benefits (Hwang JM et al. 2003; Kozelsky TF et al. 2003). Oral glutamine supplementation may enhance radiation therapy by protecting normal tissues from (and sensitizing tumor cells to) radiation damage (Savarese DM et al. 2003). In one study, oral glutamine supplementation (30 grams per day) reduced gut permeability and protected lymphocytes in patients with esophageal cancer during radiochemotherapy (Yoshida S et al. 1998).

Patients receiving 1200 mg of intravenous glutathione (diluted in normal saline solution) 15 minutes before pelvic irradiation suffered less post-therapy diarrhea (28 percent, compared to 52 percent for controls) and were more likely to complete their treatment without interruption than a control group (71 percent, compared to 52 percent) (De Maria D et al. 1992).

Several studies have reported a positive effect of hyperbaric oxygen therapy in patients with chronic radiation cystitis or proctitis (inflammation of the bladder or rectum, respectively) (Ennis RD 2002). Radiation-induced hemorrhagic cystitis can be treated successfully with hyperbaric oxygen therapy; it is well tolerated even in patients debilitated by advanced cancer and blood loss. Long-term remission is possible in most patients, and re-treatment effectively manages recurrent bleeding (Chong KT et al. 2005; Neheman A et al. 2005).

Short-chain fatty acids and butyrate are derived from the bacterial fermentation of unabsorbed carbohydrates within the colon (Cook SI et al. 1998). They are readily absorbed in the large bowel and are beneficial in treating colitis (inflammation of the bowel) (Kim YI 1998). A small study of seven patients who had received previous radiation therapy (for an average of 23 months before the study) examined the use of short-chain fatty acid enemas (administered twice daily for four weeks) for the treatment of proctitis (inflammation of the rectum) and found a significant decrease in rectal bleeding (al-Sabbagh R et al. 1996). This was confirmed in another study of 20 patients who presented with proctitis within three weeks of completing radiation therapy. Half were treated daily with one 80-ml sodium butyrate enema (80 mmol/L) and half with a sodium chloride placebo over a three-week period (Vernia P et al. 2000). All patients treated with butyrate reported a significant improvement in their symptoms compared to only three patients in the placebo group who reported a slight improvement.