Role Of Ebrt In Second Malignancies

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There is general agreement that radiotherapy increases the incidence of SMNs in patients with Rb.24,61-64 The only large study reporting that the SMN incidence was independent of radiation therapy was that of DeSut-ter and coworkers.40 Radiation-induced tumors of the eye are classified as those that arise within the "field of radiation" (i.e., eyelids, orbit, periorbital sinuses, skin, and subcutaneous tissues overlying the periorbital area). In the study of Roarty and coworkers, the 30-year incidence of SMN following radiation therapy for Rb was reported to be 35.1%; in the same series, only 5.8% of Rb patients who did not receive radio therapy developed SMNs; 29.3% of these malignancies developed within the field of radiation, 8.1% were outside the radiation field (i.e., elsewhere in the body).38 Similarly, Draper and Abramson and their colleagues report an increased risk in radiation-treated patients, primarily within the field of radiation.24,26

If one considers conceptual and technological advances in radiation therapy over the past 50 years, the risk today may very well be less than what has been stated in the above-mentioned series. The case cited by Roarty et al., for example, dates back to 1922.38 Similarly, Abramson's series included patients from 60 years ago who received 3500 to 26,000 cGy of radiation with orthovoltage equipment. Others received up to 12,000 cGy of radiation on a betatron, probably in multiple courses. Draper's series dates back to the 1950s, and patients were reported to have received radiation of 1200 to 7500 cGy, although the majority were within the range of 3500 to 4000 cGy, comparable to today's treatments.26 Modern supervoltage radiation therapy equipment has less effect on normal bone than older orthovoltage equipment, is much more precise, and delivers a lower dose to a smaller area than older methods. It is not yet known, however, whether the use of this modified equipment will reduce the incidence of SMNs in the future.

Whatever improvements have been taking place, the fact remains that radiation treatment in Rb increases the risk of SMNs within the radiation field by a factor of 5 to 6; there is not enough evidence to indicate that it has the same effect on the incidence of SMNs elsewhere in the body. Attempts to determine a dose-response effect have been unsuccessful because radiation doses have decreased over the years and patients who received the highest doses have the longest follow-up periods. Since there is no determined "tumor-forming radiation dose," the only way to minimize the risk of SMNs due to EBRT is to use carefully fractionated treatment with shielding of normal tissues as much as possible. For example, brachyther-apy applications with 125I or 106Ru plaques are ideal in that they deliver curative doses to the tumor but minimize radiation toxicity to adjacent tissues. Individuals with hereditary Rb also have been reported to be prone to develop benign tumors such as lipomas and dysplastic nevi that may progress into cutaneous melanoma.65 Thirty percent of patients with hereditary Rb who had lipomas also developed an SMN, suggesting that certain Rb-I mutations may increase the risk of both benign and malignant tumors.

Another issue is the contribution of chemotherapy to SMN development. It is known that treatment with cytotoxic agents may lead to development of subsequent malignancies. This is best documented with cy-clophosphamide, which is probably the most widely used alkylating agent.66 Although there are anecdotal reports of SMNs developing in Rb patients following cyclophosphamide treatment, most of these patients have also received radiotherapy. The real risk of chemotherapy is difficult to determine. Hawkins and coworkers estimate a 26-fold risk of SMN development in Rb patients treated with radiation but no chemotherapy, and a 78-fold risk in patients who receive both radiation and chemotherapy.47 For bone sarcomas, the relative risks are significantly higher: 174 times for Rb patients who receive no chemotherapy or radiotherapy, and 340 times and 771 times, respectively, in patients who receive radiation but no chemotherapy, and radiation with chemotherapy. The alkylating cytotoxic agents and ionizing radiation are known carcinogens. It is quite conceivable that these agents alone, or in combination, increase the frequency of somatic mutations needed to produce SMNs in Rb patients.50,67

The high frequency of SMNs, radiation retinopa-thy, and orbital growth retardation in Rb patients who are treated with EBRT forced many investigators to look into alternative treatments.68,69 Neutralization of chemotherapy as a primary treatment for intraocular Rb seems particularly promising. Historically, combination chemotherapy has been utilized only when Rb is accompanied by extraocular extension and metastasis. The preliminary results of the new approach suggest that combination chemotherapy can markedly reduce the tumor bulk so that more conservative, local modalities (cryotherapy, photocoagulation, etc.) can be employed to eradicate the tumor. This approach is particularly useful as a means of avoiding enucleation or EBRT.70-72 Most chemore-duction regimens consist of vincristine sulfate, etopo-side, and carboplatin and achieve tumor shrinkage approximately 70% of the time. Gallie et al. reported better response when cyclosporin was added to the regimen, which may reverse the chemoresistance of the tumor that is due to the expression of phospho-glycoproteins.70,73

Although the promising results of the primary application of the chemotherapy in treating intraocular Rb should be celebrated, it should not be forgotten that the possibility of SMN development deterred widespread use of chemotherapy in Rb in the first place. There is evidence that alkylating agents increase the risk of leukemia when used in patients with childhood cancers and that cyclophosphamide may induce SMNs in patients with Rb.26,66 Therefore, enough follow-up time should be allowed before the use of primary chemotherapy is fully endorsed; after all, it took more than three decades to unveil the role of radiation in the induction of SMNs in Rb patients. It should also be kept in mind that the rapid improvement of the overall survival rate of Rb within the last century is primarily due to timely decision on enucleation. There is no doubt that efforts should be made to maximize the benefits of new chemicals and technologies; however, it is also important to be conscious of the potential danger of tumor dissemination when trying to preserve vision.

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