Radiation Therapy as Primary and Adjuvant Treatment for Local and Regional Melanoma

Lawrence B. Berk, MD, PhD

Disclosures

Cancer Control. 2008;15(3):233-238. 

In This Article

Definitive Radiation Therapy for Melanoma

Clinical studies suggest that larger fractions are needed for the local control of primary cutaneous and nodal melanoma. Danish authors reported on 618 tumors from their own database, combined with reports from the literature.[9,10] They examined factors such as total dose, dose per fraction, treatment time, and tumor volume. They determined the alpha:beta ratio of melanoma to be 2.5 Gy and an isoeffect formula for dose and fraction size of ETDvol = D × ([d + 2.5]/2.5) × M–0.33, where ETD is the extrapolated total dose (an isoeffect dose corrected for fraction size), D is the total given dose, d is the fraction size, and M is the mean diameter of the lesion. The ETD for 50% control was estimated at 83 Gy for a tumor 1 cm in diameter. There was a strong association between local control and survival; the 3-year survival rate was 56% for patients with local control and 0% for patients without local control.

The same group then further analyzed their own data using stricter analytic methods on 239 lesions.[11] These data suggested an alpha:beta ratio of 0.57, lower than many tumors, which have ratios of around 10. They hypothesized that melanomas respond to radiation similarly to normal late-responding tissues, and therefore larger daily fractions, up to 6 Gy, may be more effective than standard 2-Gy fractions. Control was also related to the size of the tumor, and correcting for size eliminated much of the apparent variability of the sensitivity of melanomas.

Several retrospective trials show a dependence of control on fraction size. Investigators at Ellis Fischel State Cancer Hospital[12] analyzed 41 lesions from 27 patients. They reported a 37% overall response rate but when regimens using at least 4 Gy were used, the response rate was 67%. Dvorak et al[13] analyzed the response pattern of 36 patients and also concluded that a larger fraction size (8 Gy) was more successful than standard fractionation or 4-Gy fractionation. A study from the Mallinckrodt Center at Washington University[14] on 67 lesions from 35 patients found no correlation with response and total dose but did find a strong correlation with fraction size. Four complete responses (9%) were seen in 43 lesions treated with fractions less than or equal to 5 Gy compared with 12 complete responses (50%) in 24 lesions treated with fractions greater than 5 Gy. The correlation was seen for cutaneous lesions but not for nodal lesions. Olivier et al[15] reported their experience with 114 lesions on 84 patients. The median dose was 30 Gy (39 Gy biologically equivalent dose, BED). They found that a higher dose correlated with improved freedom from progression and survival. In a report by Strauss et al[16] on radiation used for 83 sites from 48 patients, fractions of 6 Gy to 8 Gy produced the highest response rates (80%). In a study of 31 patients with bulky nodal disease treated with primary radiation therapy, Burmeister et al[17] reported an 84% response rate. They observed a better local control rate with fractions of at least 4 Gy compared with fractions of less than 4 Gy.

Overgaard et al,[18] however, reported a randomized trial of 35 tumors in 14 patients with metastatic or recurrent malignant melanoma. The patients were randomized to high dose-per-fraction radiotherapy: either 9 Gy × 3 or 5 Gy × 8, twice weekly. Among 35 patients,complete and persistent regression was found in 24 (69%) and partial response in 10 (29%) of the tumors. No difference in response was observed between the two treatment regimens. Also, a randomized trial was conducted by the Radiation Therapy Oncology Group (RTOG 83-05) for the primary treatment of measurable metastatic melanoma lesions of either 32 Gy in 4 fractions of 8 Gy or 50 Gy in 20 fractions of 2.5 Gy for the primary treatment of melanoma.[19] Of 131 treated patients, 126 were evaluable, and there was no difference in local control between the two arms. The overall complete remission rate was 24% and the partial remission rate was 35%. An increased rate of grade IV toxicities occurred in the 8-Gy arm (3 vs 0), the majority being skin toxicities. A grade IV skin toxicity was ulceration.

Thus, the preponderance of retrospective data suggests that use of larger doses per fraction results in improved local control rates. However, the only randomized trial using smaller fractions, comparing 8-Gy fractions and 2.5-Gy fractions, showed no difference in response rate.[19] The best conclusion that can be drawn is that for the treatment of gross melanoma at least 2.5- Gy fractions should be used.

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