Strategies to Optimize Radiotherapy Response
Tumor gene analysis. An examination of the genetic material of tumor cells often reveals differences between the cells that can be manipulated therapeutically. For example, the tumor suppressor gene p53 is the most frequently mutated gene in human tumors (Cuddihy AR et al. 2004), and tumors containing wild type p53 (p53 that is not mutated) are associated with a significantly better prognosis when treated with radiation (Alsner J et al. 2001; Ma L et al. 1998). However, this is not a universal finding (Saunders M et al. 1999).
Results of the largest known biomarker study of prostate cancer patients treated with radiation therapy indicate that the presence of a protein biomarker called Ki-67 is a significant predictor of outcome in men treated with both radiation and hormones (Li R et al. 2004). When a tumor cell tests positive for Ki-67, the tumor is actively growing, and the greater the proportion of prostate tumor cells with Ki-67, the more aggressive the cancer (Wilson GD et al. 1996). Ki-67 can be measured by a test offered by Genzyme Genetics (www.GenzymeGenetics.com).
Guarding against anemia. Anemia is one of the most common blood abnormalities of cancer. In patients with solid tumors, the incidence of anemia has been reported to vary between 45 percent in those with colon cancer up to 90 percent in patients with small-cell lung cancer (Knight K et al. 2004). An association between hemoglobin level and controlling tumor growth and survival has been identified for a large number of cancers, including breast (Henke M et al. 2004), cervical (Winter WE3 et al. 2004), and head and neck cancers (Daly T et al. 2003).
Cancer patients with low hemoglobin levels do not respond as well to radiotherapy as non-anemic patients (Ludwig H et al. 2001), due to impairment of oxygen transport to tumor cells (Dunst J 2004). Hemoglobin values measured during treatment are believed to be predictive of outcome (Tarnawski R et al. 1997).
Treatment outcome might be improved by correcting anemia (low hemoglobin levels) (Grogan M et al. 1999). Nutritional supplements that may help correct anemia include melatonin, folic acid, and vitamin B12; for more information, refer to the Blood Disorders chapter. The use of erythropoietin (sold under the drug brand name Procrit®) with minimal iron supplementation (Olijhoek G et al. 2001) or blood transfusions (Bokemeyer C et al. 2004) may be required in some cases. Erythropoietin is a growth factor that produces a steady, sustained increase in hemoglobin levels (Cheer SM et al. 2004; Stuben G et al. 2003).
Measurement of tumor oxygen levels. Low tumor oxygen levels (hypoxia) and anemia in the patient are associated with increased risk of spread (metastasis) and recurrence (Harrison L et al. 2004; Vaupel P 2004), especially for cervical cancers, head and neck cancers, and soft tissue sarcomas (Brizel DM et al. 1996; Nordsmark M et al. 2004). Hypoxia presents a problem for radiotherapy because radiation’s ability to kill cancer cells (i.e., radiosensitivity) rapidly decreases in areas of oxygen depletion, as free radicals cannot be produced due to limited oxygen supply (Fridovich I 1999).
Tumor oxygen levels are usually measured by the use of electrodes inserted directly into the tumor (Coleman CN 2003; Vaupel P et al. 2001). If a tumor is found to be hypoxic, strategies to improve oxygen levels could be employed to improve radiotherapy (Overgaard J et al. 2005) or, alternatively, radiotherapy may be reconsidered.
Tumor hypoxia has been exploited in cancer treatment (Brown JM 2000). A number of chemical agents, such as misonidazole, that preferentially sensitize hypoxic cells to radiation have been developed and tested in the clinic, particularly for the treatment of head and neck cancers (Brown JM et al. 2004). However, some have poor clinical effectiveness (Brown JM 1995). A number of approaches (e.g., carbogen and nicotinamide (ARCON)) have been introduced and are now in clinical trials (Kaanders JH et al. 2004).
Hypoxia is also implicated in the activation of angiogenic cytokines—especially vascular endothelial growth factor (VEGF)—that are necessary for the growth of new tumor blood vessels (Shweiki D et al. 1992; Vaupel P 2004) and thus tumor growth. Angiogenic inhibitors seek to interrupt the process of angiogenesis (the creation of new blood vessels) to prevent new tumor blood vessel formation, whereas vascular (blood vessel)-disrupting agents aim to cause direct damage to the existing tumor blood supply (Tozer GM et al. 2004). Lead agents of both categories (e.g., Combretastatin A-4) have now advanced into clinical trials (Thorpe PE 2004).
Silymarin/silibinin inhibits VEGF secretion in a range of human cancer cell lines, in concentrations that should be clinically feasible (Yang SH et al. 2003). Other naturally derived agents that impede cancer-induced angiogenesis include green tea polyphenols, fish oil, selenium, copper restriction, and curcumin (Gururaj AE et al. 2002).
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:
- 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.
- 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. 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. 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. 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. 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. 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).
Sulforaphane. Sulforaphane, which is an isothiocyanate, is most highly concentrated in broccoli as well as in other cruciferous vegetables (eg, brussels sprouts, cabbage and cauliflower). When head and neck cancer cells were treated with sulforaphane and subsequently irradiated, researchers observed that the combination therapy resulted in a stronger inhibition of cell proliferation than each treatment method alone (Kotowski 2011).
. 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).