Cancer Radiation Therapy-3

Hair loss. Radiation therapy can cause hair loss (alopecia), but only in the area being treated (Irvine L et al. 1999). Hair loss is usually temporary and re-growth is evident within a few weeks after completion of therapy.

Melatonin has been reported to have a beneficial effect on hair growth in animals (Oxenkrug G et al. 2001). Furthermore, a study of 40 women suffering from alopecia sought to determine whether topically applied melatonin influences hair growth. A melatonin solution (0.1 percent) or placebo was applied to the scalp daily for six months. Positive results were obtained in the melatonin-treated group (Fischer TW et al. 2004).

Liver damage. Hepatocellular carcinoma is a common malignancy, and 3D-conformal radiation therapy is increasingly used in treatment as part of multimodal therapy (Cheng JC et al. 2000). However, one of the most frequently encountered complications following such treatment is radiation-induced liver disease, occurring in approximately 18 percent of patients (Cheng JC et al. 2002b). Patients present with fatigue, rapid weight gain, and, in rare cases, jaundice, approximately four to eight weeks after treatment (Lawrence TS et al. 1995). Radiation-induced liver disease leads to the deterioration of liver function, and up to half of radiation-induced liver disease patients may die from this complication (Cheng JC et al. 2002a).

Silymarin, a flavonoid complex found in the herb milk thistle, is frequently used in the treatment of liver disease (Levy C et al. 2004; Saller R et al. 2001). It functions as an antioxidant (Feher J et al. 1987), maintains cellular glutathione content (Soto C et al. 2003), and has a low toxicity profile (Ladas EJ et al. 2003). A study of rats found that an intravenous injection of silymarin (50 mg/kg) 30 minutes before a single dose of radiation protected against radiation-induced liver disease (Ramadan LA et al. 2002). Silymarin is well tolerated and produces a small increase in glutathione and a decrease in lipid peroxidation in peripheral blood cells in certain patients (Lucena MI et al. 2002).Treatment with silymarin (600 mg/day) was found to reduce the lipoperoxidation of cell membranes and insulin resistance (Velussi M et al. 1997).

Hypersensitivity reactions: skin/fibrosis. Acute radiation dermatitis (inflammation of the skin) is a common side effect of radiotherapy. Dermatitis includes redness (erythema) and dry or moist peeling skin (desquamation). It has been estimated that 87 percent of all women undergoing radiation therapy for breast cancer will develop some degree of radiation dermatitis (Fisher J et al. 2000). Severe radiation dermatitis can be painful, may lead to infections, and can cause permanent scarring.

No standard treatment has been recommended for the prevention of radiation-induced dermatitis, though several therapies have been suggested (Westbury C et al. 2000; Wickline MM 2004). Several dressing types used to treat radiation dermatitis can provide a moist healing environment that is optimal for cell migration across the wound, thereby shortening healing time (Margolin SG et al. 1990).

Topical agents such as corticosteroid creams and other products, including aloe vera gel or trolamine (Biafine®), are commonly prescribed at the onset of radiation dermatitis or at the beginning of radiotherapy (Bostrom A et al. 2001; Schmuth M et al. 2002). Biafine® is a water-based emulsion that has been used in France since 1973 to alleviate symptoms of radiation dermatitis (Fenig E et al. 2001; Fisher J et al. 2000).

Calendula, derived from the marigold flower, has purported anti-inflammatory properties and is often used for wound healing. A recent trial found that calendula was significantly better than Biafine® in preventing mild-to-severe acute radiation dermatitis in breast cancer patients, as well as in providing pain relief (Pommier P et al. 2004). Patients applied the preparation to the irradiated skin at least twice a day at the onset of radiation therapy and continued this until completion of treatment.

In clinical trials, the application of aloe vera gel was no better than placebo or aqueous cream in reducing radiation-induced dermatitis (Heggie S et al. 2002; Williams MS et al. 1996). However, aloe vera gel added to soap has a protective effect for patients who received higher cumulative radiation doses, prolonging the time to detectable skin damage from three to five weeks (Olsen DL et al. 2001).

Dexpanthenol (vitamin B5) creams have been shown to improve acute radiotherapy skin reactions in some (Roper B et al. 2004) but not all studies (Lokkevik E et al. 1996).

N-acetylcysteine is capable of stimulating radio-protective cytokines (Baier JE et al. 1996). The application of gauze soaked in 10 percent N-acetylcysteine for 15 minutes before radiation therapy was associated with more rapid healing of skin reactions and less use of pain relievers compared to an untreated control group (Kim JA et al. 1983).

Unsaturated essential fatty acids (EFAs) are necessary for the production of prostaglandins (PGEs) (inflammatory modulators) and play an important role in maintaining cell membrane structure by regulating membrane fluidity (Horrobin DF 1992). The ability of EFAs containing both gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA) to modify radiation-induced skin reactions was studied in pigs (Hopewell JW et al. 1994). Oral administration of 3 ml of oil daily for four weeks before and up to 16 weeks after irradiation significantly reduced both acute and late radiation skin damage. Prospective studies suggest that prostaglandins have great potential in minimizing the adverse effects of radiotherapy on normal tissue. The potential use of misoprostol, a PGE(1) analogue, before irradiation may be considered in the prevention of radiation-induced side effects (Lee TK et al. 2002).

Radiation-induced fibrosis, a serious late effect of radiotherapy, is mainly characterized by changes in the connective tissue involving excessive extracellular matrix deposition and hyperactive fibroblasts (Burger A et al. 1998). A combination of pentoxifylline (Trental®), a methylxanthine derivative structurally related to theophylline and caffeine, and vitamin E (alpha tocopherol) may be effective in treating radiation-induced fibrosis (Delanian S et al. 1999). Pentoxifylline promotes healing and relieves pain following radiation damage (Futran ND et al. 1997), and vitamin E was used for its ability to scavenge reactive oxygen species (Rudolph R et al. 1988). Twenty-two patients who developed radiation-induced fibrosis following radiotherapy for breast cancer were treated with 800 mg/day of pentoxifylline and 1000 IU/day of vitamin E. The area of radiation-induced fibrosis was significantly reduced when these patients were examined after six months, with no adverse effects reported (Delanian S et al. 2003). For more information, see the later section of this chapter on Pulmonary Toxicity.

Lymphedema. Lymphedema is an accumulation of protein-rich fluid that results in swelling of the underlying skin. It may occur in the arm following radiotherapy for breast cancer, due to interruption of axillary (armpit) lymphatic drainage or because of axillary lymph node dissection or axillary radiation, or both. It results in pain, decreased stretching ability of tissue around the joints, and increased weight of the extremity (Allegra C et al. 2002). The reported incidence of lymphedema varies, with rates of 2 percent to 24 percent reported in a review of breast cancer patients (Petrek JA et al. 1998), and of 22 percent to 56 percent for the head and neck region (Dietz A et al. 1998).

Several non-pharmacological options are available for managing lymphedema (Harris SR et al. 2001), including the use of graded compression garments (Collins CD et al. 1995) and pneumatic compression pumps (Dini D et al. 1998).

Arm exercises may also help to control the symptoms caused by lymphedema, by strengthening the muscle-pumping action and consequently increasing lymph flow. Many clinicians encourage patients to continue exercising two or three times a day for six months, then daily for life (Granda C 1994). Scrupulous skin care should be followed and maintenance of an ideal body weight should be encouraged, as obesity is a contributing factor for the development of lymphedema (Johansson K et al. 2002).

Clinical studies have shown a beneficial effect of selenium in treating lymphedema at different locations (Bruns F et al. 2004; Kasseroller RG et al. 2000). Forty-eight patients were evaluated either 10 months (upper-limb) or 4 months (head and neck) after the end of radiotherapy. Patients received 500 mcg of sodium selenite per day over four to six weeks. Approximately 80 percent of patients showed a significant improvement in their lymphedema and quality of life (Micke O et al. 2003).

Other investigators concluded that sodium selenite represents a suitable adjuvant treatment of secondary lymphedema. Treatment with sodium selenite (1000 mcg daily for three weeks) can be instituted immediately after treatment and before wound healing when manual lymphatic decongestion therapy cannot be applied (Zimmermann T et al. 2005).

The Importance of Exercise
Fatigue is a major determinant of quality of life and is present in as many as 50 percent to 70 percent of patients with cancer at diagnosis (Irvine D et al. 1994). Several studies have investigated fatigue during radiation therapy for both breast (Geinitz H et al. 2001) and prostate cancer (Janda M et al. 2000). The initiation of radiation therapy is accompanied by significant increases in fatigue (Kurzrock R 2001). However, levels of fatigue tend to return to pre-treatment levels within several weeks of completing treatment (Jacobsen PB et al. 2003).

A number of studies have examined the therapeutic value of exercise during cancer treatment (Brown JK et al. 2003; Courneya KS 2003). A 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 (Windsor PM et al. 2004). Those men who followed advice to rest if they became fatigued demonstrated 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 a significant improvement in physical function, with no significant increase in fatigue.

An exercise program of walking (self-paced walks of 20 to 30 minutes, 4 to 5 days per week) was evaluated in participants who were to receive radiation therapy after surgery for breast cancer (Mock V et al. 1997). Before radiation therapy, patients were assigned to either the exercise intervention group or a control group. Those who underwent the walking program experienced significantly less fatigue on the completion of radiation therapy than those in the control group.


Kidney toxicity (nephrotoxicity). The kidney is one of the most radiosensitive organs at risk of developing damage after abdominal irradiation. Radiation nephropathy takes various forms, the most common of which, acute radiation nephritis, presents as azotemia (dangerously high levels of nitrogen waste products in the bloodstream), hypertension, and anemia, starting at 6 to12 months following treatment (Cohen EP et al. 2003). If left untreated, this can lead to renal failure, and survival on chronic dialysis is poor (Cohen EP et al. 1998).

Dietary protein restriction is effective in treating various chronic kidney diseases (Levey AS et al. 1999) though care must be taken to maintain adequate nutrition (Youngman LD 1993).

All-trans retinoic acid (a vitamin A-like drug) exacerbates radiation nephropathy, possibly by inhibiting renal nitric oxide production, and its use should be restricted during renal irradiation (Moulder JE et al. 2002).

Nerve toxicity (neurotoxicity). The nervous system is particularly sensitive to radiation therapy, and radiation-induced neurotoxicity can involve the central nervous system and peripheral nervous system (Liang BC 1999).

Radiation therapy for skull-base, orbital, and sinus tumors invariably involves the irradiation of brain tissue (Chong VF et al. 2002). Following brain irradiation, acute toxicity may cause headaches, dizziness, fatigue, and problems with speech (Young DF et al. 1974). Corticosteroids are useful in relieving a number of these acute complications, but should be used only as long as medically necessary, as they may have side effects. Early physical therapy can prevent lymphedema, frozen shoulder, and atrophy (muscle wasting). For more information, see the Peripheral Neuropathy chapter.

Radiation necrosis. Radiation necrosis (tissue ulceration) and cognitive dysfunction are the main late complications of brain irradiation. Radiation necrosis may occur from six months to two years following treatment (Keime-Guibert F et al. 1998), and is caused primarily by blood vessel damage (Lyubimova N et al. 2004). Up to 20 percent of patients receiving stereotactic radiosurgery and 80 percent undergoing interstitial brachytherapy will develop symptoms of radiation necrosis (Wen PY et al. 1994).

This is a serious condition with symptoms that vary from fatigue to dementia, and may require surgical intervention (Strohl RA 1998). Non-surgical treatments that have been clinically investigated include steroids, heparin, low-iron diets with iron chelators, pentoxifylline, and hyperbaric oxygen therapy (Chuba PJ et al. 1997; Hornsey S et al. 1990). Hyperbaric oxygen therapy is important in the treatment and healing of soft tissue radiation necrosis, particularly of the brain (Dion MW et al. 1990; Hart GB et al. 1976; Kohshi K et al. 2003).

The use of pentoxifylline is deemed safe and effective in preventing radiation necrosis, particularly in the prevention of radiation-induced lung toxicity (Ozturk B et al. 2004). At an oral dose of 400 mg three times daily, pentoxifylline has a protective effect against radiation necrosis complications, possibly by reducing platelet aggregation and preventing tumor necrosis factor-mediated inflammation (Aygenc E et al. 2004; Hong JH et al. 1995).

Osteoradionecrosis (see the earlier section of this chapter on Hyperbaric Oxygen Treatment) is a late adverse effect of radiation therapy that does not resolve spontaneously. In a preliminary study, a combination of pentoxifylline (800 mg daily), tocopherol (vitamin E, 1000 IU daily), and clodronate (1600 mg daily, Bonefos®) was of clinical benefit, with more than 50 percent regression of progressive osteoradionecrosis observed at six months in 12 patients (Delanian S et al. 2002b; Futran ND et al. 1997). In another study, this same regimen completely reversed severe progressive osteoradionecrosis when administered daily for three years (Delanian S et al. 2002a).

Oral complications. Between 60 percent and 90 percent of head and neck cancer patients receiving standard radiation therapy will develop inflammation of the lining of the mouth (mucositis) (Sutherland SE et al. 2001), which usually improves within a few weeks after completing treatment (Sonis ST et al. 2001).

One of the most important factors that predisposes someone to oral mucositis is preexisting oral or dental disease (Dodd MJ et al. 1996). Oral mucositis can lead to secondary complications, including infection, poor nutritional intake, and xerostomia (dry mouth). Several treatment interventions have been suggested for preventing and treating oral mucositis, though no effective treatment currently exists (Clarkson JE et al. 2003; Worthington HV et al. 2004).

Maintaining good oral hygiene is important in preventing mucositis, and it is particularly important to instigate this at least a week before starting radiation therapy (Shieh SH et al. 1997). Patients should brush twice daily with a soft-bristled tooth brush, floss daily, and rinse the mouth once daily with normal saline (1/2 teaspoon of salt in eight ounces of water) or sodium bicarbonate (baking soda or Alka-Seltzer®) (Dodd MJ et al. 2000).

A trial of head and neck cancer patients indicated that oral glutamine (16 grams in 240 ml of normal saline, four times daily during radiation) may significantly reduce the duration and severity of oral mucositis during radiotherapy (Huang EY et al. 2000).

Honey reduces the symptoms of mucositis. Forty patients diagnosed with head and neck cancer were divided into two groups. One group was advised to take 20 ml of pure honey 15 minutes before, 15 minutes after, and 6 hours after radiotherapy. In the honey-treated group, symptomatic mucositis was reduced significantly, and there was either no change in weight or positive weight gain compared to the control group (Biswal BM et al. 2003).

Antibiotics supplied either as a topical pastille or paste may be beneficial in preventing mucositis (Donnelly JP et al. 2003; Okuno SH et al. 1997). The overgrowth of certain yeast and bacteria, which occurs following radiation therapy, may be important in the progression of this condition (Spijkervet FK et al. 1991). Head and neck cancer patients who were given a pastille containing amphotericin, polymixin, and tobramycin to suck four times daily were significantly less likely to develop the most serious form of mucositis than those who received a placebo (Symonds RP et al. 1996). However, this beneficial finding has not been seen in all studies using antibiotics (Stokman MA et al. 2003; Wijers OB et al. 2001).

Alternatively, the flower Matricharia camomile may be beneficial in reducing mucositis during radiotherapy (Henriksson R et al. 1999), due to its antibacterial properties (Carl W et al. 1991). In a study in which Kamillosan® (a camomile preparation) oral rinse was given to patients receiving radiation therapy and chemotherapy, mucositis was less severe than expected (Carl W et al. 1991).

Hydrolytic enzymes have anti-inflammatory properties and are effective in reducing normal tissue reactions such as oral (Kaul R et al. 1999) and gastrointestinal mucositis (Dale PS et al. 2001). They function by reducing cytokine levels (Lehmann PV 1996). In one clinical study, 53 patients were given three tablets, three times a day, containing papain (100 mg), trypsin (40 mg), and chymotrypsin (40 mg). The treatment was started three days before radiation therapy and continued until five days after completion of treatment (Gujral MS et al. 2001). Both mucositis and skin reactions were significantly reduced in the enzyme-treated group compared to controls.

Beta-carotene (75 mg daily) during radiation therapy for advanced squamous cell carcinoma of the mouth markedly reduced the incidence of severe mucositis without causing noticeable side effects (Mills EE 1988).

Damage to the salivary glands is another common adverse effect of radiotherapy. Reduced saliva production can cause chronic dry mouth. This is a significant problem for cancer patients, with a reported prevalence of between 29 percent and 77 percent (Maltoni M et al. 1995). Xerostomia can greatly impair a patient's ability to speak, chew, swallow, and taste, and therefore is often accompanied by a loss of appetite and weight, leading to adverse effects on quality of life (Brown CG et al. 2004).

To manage this condition, some patients use artificial saliva substitutes, but most patients find them inadequate (van der Reijden WA et al. 1996). Salivary gland dysfunction after therapeutic radiation is a difficult, if not impossible, condition to reverse, though some evidence suggests that patients with this condition should be considered for hyperbaric oxygen therapy (Bui QC et al. 2004). The use of non-cinnamon or mint-based sugar-free drops, chewing gum, fresh pineapple chunks, or frequent sips of water to maintain adequate hydration has been suggested to stimulate salivary flow (Krishnasamy M 1995).

Poor appetite and cachexia. Patients undergoing radiotherapy for cancer of the head and neck or gastrointestinal tract are at higher risk of developing malnutrition (van Bokhorst-de van der S et al. 1999). Malnutrition increases the risk of infections and treatment toxicities, and decreases the response to treatment (Nitenberg G et al. 2000).

Cachexia is treated by attempting to increase nutritional intake and inhibit muscle and fat wasting. This is done by manipulating the metabolism with various pharmacological agents and by treating the causes of reduced food intake, such as nausea and vomiting (Davis MP et al. 2004) (for more information, see the chapter on Catabolic Wasting). Diets that include the omega-3 fatty acids EPA and DHA (Wigmore SJ et al. 2000), melatonin (Lissoni P et al. 1996b), and vitamin supplements (alpha-lipoic acid, 300 mg/day; carbocysteine lysine salt, 2.7 grams/day; vitamin E, 400 mg/day; vitamin A, 30,000 IU/day; vitamin C, 500 mg/day) (Mantovani G et al. 2004) have shown promise in some, but not all (Bruera E et al. 2003), studies undertaken.

Pulmonary toxicity. The lung is among the most radiosensitive organs, and therefore the risk of severe side effects seriously compromises treatment outcome. Radiation pneumonitis (inflammation of the lung) is a common acute side effect occurring in 5 percent to 30 percent of patients treated for lung cancer between one month and six months after radiotherapy (Tsujino K et al. 2003). Radiation therapy-induced fibrosis is associated with scarring of the lung and typically occurs months to years after radiotherapy.

The amino acids taurine and L-arginine may protect against radiation-induced lung fibrosis by reducing production of collagen, a protein implicated in the fibrotic process (Song L et al. 1998).

The drug pentoxifylline down-regulates the production of proinflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-alpha), and may therefore protect against radiation-induced, cytokine-mediated damage (Rube CE et al. 2002). In a clinical trial, 64 patients with non-small cell lung cancer were randomly divided into a pentoxifylline (400 mg, three times a day) plus radiotherapy group or a radiotherapy-only group (Kwon HC et al. 2000). Following treatment, patients in the pentoxifylline plus radiotherapy group had significantly longer survival and time to relapse.

A potentially important determinant of lung toxicity risk may be vitamin A nutritional status. Human studies have linked low vitamin A intake and/or reduced serum retinol levels with an increased risk of lung dysfunction (Chytil F 1992). Low levels of vitamin A have been found in human lung tissues obtained from patients undergoing lung resection (Redlich CA et al. 1996). Retinoids may exert their effects by modulating inflammatory cytokines and growth factors (Zitnik RJ et al. 1994). Experimental animal studies suggest that supplemental vitamin A may reduce lung inflammation after thoracic radiation and may be an important radioprotective agent in the lung (Redlich CA et al. 1998).

Radiation-induced nausea and vomiting typically occur within 24 hours of treatment, and over 80 percent of patients undergoing radiation of the upper body will develop symptoms of nausea and vomiting (Anonymous 1999; Goldsmith B 2004). If untreated, nausea and vomiting can cause physiological changes, including dehydration, electrolyte imbalance, malnutrition, and cachexia (Henriksson R et al. 1992).

The use of 5-hydroxytryptamine (5-HT3)-receptor antagonists, such as granisetron (Kytril®), is the current “gold standard” in treating nausea and vomiting resulting from radiation therapy (Goldsmith B 2004).

Hypnosis effectively treated anticipatory nausea in pediatric (Zeltzer LK et al. 1991) and adult cancer patients (Morrow GR et al. 1982). Clinical research found acupuncture to be effective for nausea in cancer patients, whether it be postoperative nausea or chemotherapy-induced nausea (Dundee JW et al. 1989a; Dundee JW et al. 1989b; Mayer DJ 2000). Acupuncture may also reduce radiation-induced symptoms (Johnstone PA et al. 2002; Lu W 2005; Samuels N 2003).