Cancer Radiation Therapy-1

Along with surgery and chemotherapy, radiation therapy (radiotherapy) is one of the most important methods of cancer treatment. At least 50 percent of all cancer patients will receive radiotherapy at some stage during the course of their illness. It is currently used to treat localized solid tumors, such as cancers of the skin, brain, breast, or cervix, and can also be used to treat leukemia and lymphoma (Tobias JS 1992).

Most types of radiation do not attack cancer cells specifically, and therefore cause injury to normal tissues surrounding the tumor. The adverse effects are a major factor limiting the success of radiation treatment. However, proton therapy and CyberKnife® therapy are technologically advanced forms of radiotherapy that cause little damage to normal tissue because they focus intensely on the tumor.

The effectiveness of radiation therapy can be enhanced by both radiosensitizers, such as genistein, curcumin, green tea, and hyperthermia, and radioprotectors, such as ginseng, glutathione, whey protein, and shark liver oil. Overall, the use of specific nutritional supplements, drugs, and other strategies may prevent and help to alleviate and treat the side effects caused by radiation, and thereby improve the effectiveness of radiotherapy.

Principles of Radiation Therapy (Radiotherapy)
Radiation therapy is the treatment of cancer with ionizing radiation. Radiation works by damaging the DNA (genetic material) within the tumor cells, making them unable to divide and grow. Radiation is often given with the intent of destroying the tumor and curing the disease (curative treatment). However, although radiation is directed at the tumor, it is inevitable that the normal, non-cancerous tissues surrounding the tumor will also be affected by the radiation and therefore damaged (Burnet NG et al. 1996). The goal of radiation therapy is to maximize the dose to tumor cells while minimizing exposure to normal, healthy cells (Emami B et al. 1991).

Because no single therapy can provide complete treatment for a patient with a solid tumor, radiotherapy is often used in combination with surgery or chemotherapy to improve the chances of a successful treatment outcome. Sometimes radiation is used to relieve symptoms, such as pain or seizures; this is called palliative treatment (Hoskin PJ et al. 1992).

What Is Ionizing Radiation?

Radiation used for cancer treatment is called ionizing radiation because it forms ions as it passes through a tissue. Ions are atoms that have acquired an electric charge through the gain or loss of an electron (Dunne-Daly CF 1999). Ions can cause cell death or genetic change either directly or indirectly. The direct effect causes a change in the molecular structure of biologically important molecules, most likely DNA. The indirect action of radiation occurs when it interacts with water molecules in the cells, resulting in the production of highly reactive and unstable free radicals or reactive oxygen species, which immediately react with any biomolecules in the surrounding area, producing cellular damage (Fang YZ et al. 2002).

This damage can lead to cell death by two mechanisms (Ross GM 1999). The first process, known as apoptosis, results in cell death within a few hours of radiation (Kerr JF et al. 1994). The second mechanism is radiation-induced failure of cell division and the inhibition of cellular proliferation, which in turn leads to cell death. Several enzymatic and nonenzymatic antioxidant defense mechanisms exist in cells and prevent excessive damage through the scavenging and inactivation of these reactive oxygen species (Mates JM et al. 2000).

Types of Radiation Therapy

External beam radiation therapy (EBRT). EBRT creates a radiation beam and aims it at the tumor. The radiation adequately covers the tumor but minimizes the dose to the non-tumor normal tissues. Radiation is given in fractions rather than as a single dose, and the use of this fractionated radiotherapy allows normal cells time to repair between each radiation session, protecting them from injury.

Conventional fractionation in the United States is 1.8 to 2 Gray (Gy) per day, administered five days a week for five to seven weeks, depending on the particular clinical situation. (Gray is a unit of measure of absorbed radiation dose.) While this schedule is strictly for the convenience of physicians trying to maintain a normal workweek, the relatively long intervals between doses of radiation may allow cancer cells (as well as normal cells) to recover and regrow.

A number of different radiotherapy schedules have been suggested to overcome this problem (Shah N et al. 2000). These include hyperfractionation, in which the time between fractions is reduced from 24 hours to 6 to 8 hours to enhance the toxic effects on tumor cells (Fu KK et al. 2000) while still preserving an adequate time interval for the recovery of normal cells. Continuous hyperfractionated accelerated radiation therapy (CHART) is an intense schedule of treatment, in which multiple daily fractions are administered within a short period of time. Clinical studies have shown benefits of altered fractionation over conventional treatment for several cancers, including head and neck cancer (Goodchild K et al. 1999) and non-operable lung cancer (Ghosh S et al. 2003).

Proton beam radiation therapy. This is one of the most precise and sophisticated forms of external beam radiation therapy available. The advantage of proton radiation therapy over x-rays is its ability to deliver higher doses of shaped beams of radiation directly into the tumor while minimizing the dose to normal tissues. This leads to reduced side effects and improved survival rates (Suit HD 2003). As of 2002, more than 32,000 patients around the world had received part or all of their radiation treatment by proton beams.

There are approximately 19 proton treatment centers worldwide. Two major hospital-based facilities in the United States that regularly treat patients with proton beams (often fractionated) are Loma Linda University Medical Center in southern California (LLUMC Proton Treatment Center) and the Northeast Proton Treatment Center at Massachusetts General Hospital in Boston. The Midwest Proton Radiotherapy Institute in Bloomington, Indiana (http://www.mpri.org/) treats children and adults with certain brain tumors, as well as those with tumors that are close to vital organs and therefore cannot be treated successfully using traditional methods.

The efficacy of proton beam radiation therapy has been clinically proven (Shipley WU et al. 1995) in prostate (Slater JD et al. 1999; Zietman AL et al. 2005), lung (Bush DA et al. 1999), hepatocellular (Matsuzaki Y et al. 1995), and uveal melanoma (Courdi A et al. 1999; Munzenrider JE 1999; Spatola C et al. 2003), sarcomas of the skull base and cervical spine (Munzenrider JE et al. 1999), optic pathway gliomas (Fuss M et al. 1999), astrocytomas (Habrand JL et al. 1999), benign meningioma (Gudjonsson O et al. 1999), non-resectable rectal, esophageal (Koyama S et al. 2003), and liver cancers (Ask A et al. 2005b), head and neck cancers, including thyroid cancer (Ask A et al. 2005a; Sugahara S et al. 2005), and more.

Intensity modulated radiation therapy (IMRT). IMRT creates a shaped radiation beam, delivering high doses of radiation to the tumor and significantly smaller doses of radiation to the surrounding normal tissues (Hurkmans CW et al. 2002; Nutting C et al. 2000). This may result in a higher cancer-control rate and a lower rate of side effects (Garden AS et al. 2004; Welsh JS et al. 2005).

IMRT has been used successfully in the treatment of several types of cancer, including prostate (De Meerleer G et al. 2004), cervical (Ahmed RS et al. 2004), nasopharyngeal (Kwong DL et al. 2004), and pediatric cancers (Penagaricano JA et al. 2004).

Brachytherapy. Brachytherapy can be used for many types of cancers, but it is most commonly used to treat prostate cancer (Woolsey J et al. 2003) and gynecologic cancers, such as cervical or uterine cancer (Nakano T et al. 2005). Brachytherapy usually involves the insertion of devices around or within the tumor to hold radioactive sources or seeds. Radioactive isotopes, such as cesium, are then inserted into the delivery device, either temporarily or permanently, allowing for the slow delivery of a high dose of radiation to the interior of the tumor (Fieler VK 1997).

Radioimmunotherapy (RIT). Radioimmunotherapy, one of the newest developments in the treatment of non-Hodgkin's lymphoma (Harris M 2004), has achieved a high tumor response rate (up to 80 percent) in several clinical trials (Witzig TE et al. 2002). Radioimmunotherapy uses drugs called monoclonal antibodies, which have a radioactive isotope attached to them. This is targeted to the surface of a cancer cell, destroying it. Radioimmunotherapy can be used (in a targeted fashion) to treat single cells that have spread around the body (Riley MB et al. 2004). Because the radiation does not concentrate in any one area of the body, radioimmunotherapy does not cause side effects commonly seen with external beam radiation therapy. The most significant side effect associated with radioimmunotherapy may be a temporary drop in white blood cell or platelet count (Witzig TE et al. 2003).

Stereotactic body radiation therapy (SBRT). SBRT is a standard form of treatment for primary and metastatic brain cancer (Phillips MH et al. 1994). It is delivered using a machine called a gamma knife, which uses converging beams of gamma radiation that meet at a central point within the tumor, where they add up to a very high, precisely focused dose of radiation in a single fraction. Due to this precision, the cancer can be located in an area of the brain or spinal cord that might normally be considered inoperable (Song DY et al. 2004).

CyberKnife®. CyberKnife® is a non-invasive, precise radiation technique that can deliver concentrated and accurate beams of radiation to any site in the body. This system combines robotics and advanced image guidance cameras to locate the tumor’s position in the body and deliver highly focused beams of radiation that converge at the tumor, avoiding normal tissue. It is a successful method used to treat spinal tumors (Gerszten PC et al. 2004b) or tumors at other critical locations that are not amenable to open surgery or radiation, as well as to treat medically inoperable patients (Gerszten PC et al. 2004a). It can also be used to treat benign tumors and lesions in a previously irradiated site, or to boost standard radiotherapy (Bhatnagar AK et al. 2005; Degen JW et al. 2005).

Three-dimensional conformal radiation therapy (3D-CRT). 3D-CRT is a technique that uses imaging computers to precisely map the location of a tumor (Symonds RP 2001). The patient is fitted with a plastic mold or cast to keep the body part still so that the radiation can be aimed more accurately from several directions. By aiming the radiation more precisely at the tumor, it is possible to reduce radiation damage to normal tissues surrounding the tumor by up to 50 percent (Perez CA et al. 2002).

Radiation Therapy versus Medical X-rays (Diagnostic Imaging)

Although diagnostic x-rays provide great benefits, including the earlier detection of cancers and the possibility of early treatment, their use is associated with small increases in cancer risk (Ron E 2003). One study estimated that cancer risk due to diagnostic x-rays varied from 0.6 percent to 3 percent in the 15 developed countries studied (Berrington de Gonzalez A et al. 2004).

Therefore, it is prudent to avoid unnecessary x-ray procedures. Up to 30 percent of chest x-rays may not be necessary (McCreath GT et al. 1999). Unnecessary computed tomography (CT) examinations may result in increased radiation exposure (Fleszler F et al. 2003; Frush DP 2004). The cumulative risk of cancer mortality from CT examinations in the United States is about 800 radiation-induced cancer deaths per 1 million examinations in children under the age of 15 (Brenner D et al. 2001).

Mammography (chest x-ray) uses low-dose x-rays to create a detailed image of the breasts. Although there is some controversy regarding mammography’s effectiveness in reducing breast cancer mortality, successful treatment is linked to early diagnosis, as mammography can often show changes in the breast before they can be detected by manual examination (Olsen O et al. 2001).

The effective radiation dose from a mammogram is about the same as the average person receives from background radiation over a three-month period (Sabel M et al. 2001).

At present, the consensus view is that the benefits of screening women over 50 years of age with yearly or twice-yearly mammograms substantially outweighs the associated risks due to radiation exposure (Beckett JR et al. 2003). However, there appears to be no significant benefit for women under the age of 40, and there may be harm for women under 30 due to the danger of cancer developing after exposure to radiation (Brenner DJ et al. 2002). Therefore, the main area of controversy concerns women between the ages of 40 and 49

Radiation: A Cause of Cancer?

The link between radiation and cancer was first recognized by studying atomic bomb survivors in Japan (Wakeford R 2004). Some cases of leukemia are related to radiation exposure and usually develop within a few years of exposure, peaking at five to nine years after exposure, then slowly declining (Ron E 2003; Wakeford R 2004). The development of other types of cancer after radiation exposure can take much longer to occur. Most cancers do not occur until 10 years after radiation exposure and some are diagnosed 15 or more years later (Hall EJ et al. 2003).

What You Have Learned So Far

1)Radiation therapy is one of the primary methods currently used to treat cancer.

2)It involves targeting the tumor with a beam of ionizing radiation, leading to the death of tumor cells through either the production of reactive oxygen species or from direct DNA damage.

3)Radiation cannot selectively target the tumor; therefore, normal cells within the radiation field suffer damage, leading to potentially serious side effects (Porock D 2002).

4)Ionizing radiation is used in many diagnostic techniques, such as mammography and computed tomography (CT) scans.

5)Radiation is a potent carcinogen that can give rise to a second radiation-induced cancer.

6)Exposure to diagnostic x-rays should be kept to a minimum, and women under the age of 49 should not undergo yearly mammograms.


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).