There are several methods being utilized for the prevention of radiation therapy side effects. These mainly include altering the manner in which radiation is delivered and administering drugs that protect normal cells from radiation damage.
Radiation Delivery Methods
Two delivery methods that were originally used to reduce radiation side effects include dose fractionation, or splitting the total dose of radiation therapy into multiple doses and physical shielding with lead blocks to reduce the area of exposure.
Fractionation and hyperfractionation: Radiation therapy was originally given in one large dose. More than a half-century ago it was found that it was less toxic and more effective to administer radiation on a daily basis, a method called dose fractionation. Fractionation allows the delivery of a larger total dose of radiation to the cancer than would have been possible as a single dose. Currently, most radiation treatments are administered daily, 5 days a week. The 5 days per week is strictly for the convenience of maintaining a normal work week. The 24-hour interval and the two-day interval between doses allows for recovery of normal tissues between doses while cancer cells, in general, have less capability for recovery. There is no doubt that using fractionation has reduced side effects compared to single-dose delivery.
While cancer cells tend to be less resilient than normal tissues, there is a chance that the intervals between fractionated doses of radiation may allow cancer cells to recover. Recent findings indicate that some cancers are best treated by reducing the 24-hour interval between doses to 6-8 hours, in order to enhance the toxic effects on cancer cells, while still preserving an adequate time interval for the recovery of normal cells. This technique, called hyperfractionation, is being widely used to treat a variety of cancers. Hyperfractionation requires sophisticated equipment and therefore it is important for patients to be treated at specialty medical centers that have experience and staff trained in this technique.
Intensity modulated radiation therapy (IMRT): IMRT delivers varying intensity of radiation with a rotating device. The intensity is varied by the placement of “leaves,” which either block or allow the passage of radiation. The rotating component of this technique allows for more specific targeting of the cancer, sparing normal tissues from damage due to radiation exposure. In conventional radiation therapy, the beam is usually delivered from several different directions, possibly 5-10. The greater the number of beam directions, the more the dose will be confined to the target cancer cells, sparing normal cells from exposure. IMRT delivers radiation from every point on a helix, or spiral, in contrast to only a few points.
IMRT is similar to CT scanning. In CT, a beam rotates around the patient, creating a sequence of cross-sectional images. IMRT also uses a rotating beam, except the beam delivers radiation. IMRT also delivers treatment one cross-section at a time.
Three-dimensional conformal radiation: Three-dimensional conformal radiation therapy is a promising approach for the treatment of some cancers with decreased toxicity to normal tissues. Using computerized tomography (CT) scans and other scans, radiation oncologists have developed methods for determining the tumor size and shape in 3 dimensions. This allows high-dose external beam radiation therapy to be delivered primarily to the cancer with less damage to normal cells. For example, three-dimensional conformal radiation has allowed radiation oncologists to reduce the amount of radiation to the breast by 50%, which should decrease the risk of secondary breast cancer. It is important for conformal radiation to be administered at special cancer centers with sophisticated equipment and trained staff.
While preventing radiation side effects from occurring is the ideal approach to management, sometimes side effects are inevitable. In these situations, several types of drugs can be used to decrease the side effects of radiation. Drug therapies for radiation-induced side effects fall into two categories:
- Those that protect the non-cancerous tissue from radiation damage through systemic administration.
- Those that are applied topically to mucus membranes to decrease or treat radiation damage.
Radiation protectors: Radioprotectants are drugs that selectively protect normal cells, but not cancer cells, from the effects of radiation. Over the past 50 years, many radiation protectors have been tested in laboratories to determine their efficacy in preventing radiation damage to normal cells and tissues.
Ethyol®: Ethyol® is a radiation protector and the only drug that has been approved by the FDA for xerostomia (dry mouth) in patients receiving radiation therapy for cancers of the head and neck. Xerostomia is a chronic dry-mouth condition, which is caused by damage from radiation therapy to the salivary glands. Xerostomia can greatly impair a patient’s ability to speak, chew, swallow and taste and therefore, can have a negative effect on a patient’s quality of life. Results from a clinical trial indicated that the incidence of severe xerostomia for patients receiving Ethyol® was 51%, compared to 78% for patients receiving radiation therapy alone. One year following completion of radiation therapy, only 35% of patients who had received Ethyol® were still experiencing symptoms of xerostomia, whereas 57% of patients who had received radiation therapy alone were still experiencing symptoms.1
Steroids: Steroids are naturally occurring hormones produced by the adrenal glands. As part of your radiation therapy treatment, your physician may prescribe steroids such as Prednisone® or Decadron® (generic name is dexamethasone). These drugs help decrease swelling in body tissues. Dexamethasone has also been shown to prevent radiation-induced vomiting, especially in treatment of cancers of the abdomen.
Topical agents: Some drugs can be applied topically to mucus membranes to decrease or treat radiation damage. The topical agent sucralfate may protect mucus membranes by several mechanisms and is often used during and after radiation therapy for the prevention and treatment of mucositis (mouth sores).2,3
Topical antiseptics, such as chlorhexidine or benzydamine, have been used for the prevention of mucositis, but recent research indicates that these are not effective. In a Mayo Clinic study involving 52 patients with head and neck cancers who received radiation therapy, chlorhexidine was found to be more toxic, and no more effective than placebo in the prevention of mucositis. German researchers reported that chlorhexidine mouthwashes were not effective in treating mucositis in patients with a low white blood cell count. Despite a significant decrease in the aerobic and anaerobic bacterial flora on the oral mucous membranes, the risk of mucositis seemed to be enhanced. The patients treated with chlorhexidine seemed to have more problems with inflammation, resulting in mucositis.
Strategies to Improve Prevention and Management of Radiation Side Effects
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the prevention and management of radiation side effects will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the prevention and management of radiation side effects include the following:
- Keratinocyte growth factor (KGF, palifermin)
- Interleukin 11
Keratinocyte growth factor (KGF, palifermin): This is a growth factor that has been shown to stimulate growth of epithelial cells, which make up the mucus membrane and line the mouth and throat. Keratinocyte growth factor is currently being tested in patients to prevent chemotherapy damage to the mucus membranes of the gastrointestinal tract.4
Antioxidants: The antioxidant agent Cu/Zn superoxide dismutase (SOD) has shown promise in reducing early and late radiation-induced tissue injury. In one clinical trial, 448 patients with bladder cancer were randomly allocated to receive either SOD or placebo after each radiation treatment. The patients who received SOD experienced fewer rectal problems and less bladder inflammation and skin toxicity than those who received placebo.5
Interleukin 11: Interleukin 11 is a growth factor that is similar but not identical to what the body normally produces. Interleukin 11 has been approved by the FDA to stimulate platelet recovery in patients with low platelet counts due to chemotherapy. Clinical trials are currently underway to determine if Interleukin 11 will prevent side effects, especially to the mucus membranes and gastrointestinal tract, associated with chemotherapy and radiation therapy.
Prostaglandins: Prostoglandins are a group of compounds that affect the healing of inflammation and wounds. Misoprostol is a prostaglandin that is effective in treating complications that arise in patients with prostate cancer who receive radiation treatment. Inflammation of the rectum (radiation proctitis) is a known complication of radiation therapy in the treatment of prostate cancer. Available medical treatment is usually ineffective and has focused on relieving symptoms after damage has occurred. One clinical study evaluated the effects of misoprostol in patients undergoing radiation therapy treatment for prostate cancer. In the study, nine patients received misoprostol rectal suppositories and seven patients received placebo. The results indicated that misoprostol rectal suppositories significantly reduced acute and chronic radiation proctitis symptoms in patients receiving radiation therapy for prostate cancer.6
1 Brizel DM, Wasserman TH, Henke M, et al. Phase III Randomized Trial of Amifostine as a Radioprotector in Head and Neck Cancer. J Clin Oncol 2000;18:3339-3345.
2 Foote RL, Loprinzi CL, Frank AR, et al. Randomized Trial of Chlorhexidine Mouthwash for Alleviation of Radiation Induced-Mucositis. J Clin Oncol 1994;12:2630-2633.
3 Pitten FA, Kiefer T, Buth C, et al. Do cancer patients with chemotherapy-induced leukopenia benefit from an antiseptic chlorhexidine-based oral rinse? A double-blind, block-randomized, controlled study. J Hosp Infect 2003;53:283-91.
6 Khan AM, Birk JW, Anderson JC, Georgsson M, et al. A prospective randomized placebo-controlled double-blinded pilot study of misoprostol rectal suppositories in the prevention of acute and chronic radiation proctitis symptoms in prostate cancer patients. Am J Gastroenterol 2000;95(8):1961-6.