Affiliations of authors: Department of Radiotherapy (BMPA, NSR, HB), Department of Epidemiology (FEVL), The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Correspondence to: Berthe M. P. Aleman, MD, Department of Radiotherapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (e-mail: b.aleman{at}nki.nl)
Learn what is true in order to do what is right.
Thomas H. Huxley (18251895)
In his recent editorial (1) regarding our paper (2), Longo suggests that there is no foundation for radiation therapy in combination with chemotherapy for patients with Hodgkins lymphoma. We agree that one should always aim at minimal treatment intensity; however, this should not endanger individual patients cure rates.
Hence, the challenge is to properly select patients requiring radiation therapy. The rationale for radiation therapy is the observation that relapses usually involve initially involved sites and that radiation therapy reduces recurrence rates (3). In a randomized trial carried out by the European Organization for Research and Treatment of Cancer (EORTC) Lymphoma Group, radiation therapy did not improve outcomes in the 57% of advanced Hodgkins lymphoma patients who were in complete remission after chemotherapy with six to eight cycles of mechlorethamine, vincristine, procarbazine, prednisonedoxorubicin, bleomycin, and vinblastin (MOPPABV hybrid) (4). However, the 34% of patients who were in partial remission after chemotherapy and then received field radiation experienced cure rates as high as those experienced by patients in complete remission after chemotherapy. Radiation therapy also appears to be needed for patients with early-stage disease with favorable characteristics who are treated with mild chemotherapy. Indeed, the EORTC Lymphoma Group had to close the arm of an ongoing trial, H9F, in which patients did not receive radiation therapy after achieving a complete remission with epirubicin, bleomycin, vinblastin, and prednisone (EBVP) chemotherapy because of the high number of relapses in that arm (Noordijk EM, Thomas J: personal communication).
Longos suggestion that 80%85% of Hodgkins lymphoma patients can be cured without radiation therapy is not supported by present evidence for patients with early or advanced Hodgkins disease. For example, Duggan et al. (5) reported 5-year failure-free survival rates of only 63% (95% confidence interval [CI] = 59% to 68%) for patients with advanced Hodgkins disease. Despite successful salvage treatment in a substantial number of patients, the 5-year overall survival was only 82% (95% CI = 79% to 86%). Importantly, salvage treatment has been shown to be related to excess late morbidity and mortality (6,7).
Longo also worries about the interpretation of the risk of breast cancer after a relatively low dose of radiation. Our conclusion, that the risk of breast cancer increases with increasing radiation dose up to at least 40 Gy, has the important implication that the lower radiation doses used presently (2030 Gy in fractions of 2 Gy) may reduce the increased breast cancer risk compared with the radiation schedules used in the past (equivalent to 40 Gy in fractions of 2 Gy). The relative risk of developing breast cancer was not statistically significantly increased in patients who received doses of 423.2 Gy (median 15 Gy) to the area of the breast where the tumor developed as compared with patients who received less than 4 Gy, but we made no suggestions as to "safe" levels of radiation. Indeed, we cautioned readers about the elevated risks of late morbidity after treatment with new modalities (2).
Finally, Longo notes that the ABVD (doxorubicin, bleomycin, vinblastin, dacarbazine) regimen has replaced most alkylating agentbased regimens, and he notes that it has low toxicity. However, doxorubicin-associated cardiovascular damage and bleomycin-induced pulmonary toxicity are important side effects. Moreover, fatal toxicity has been reported in 2%3% of patients treated with ABVD alone (5).
In conclusion, it is important to restrict the intensity of treatment for young patients with Hodgkins lymphoma to the greatest extent possible. ABVD is an effective regimen, but unfortunately it cannot, as sole treatment modality, cure 80%85% of patients. Our primary concern is to cure patients of their Hodgkins lymphoma. Unfortunately, new trials have to be designed before long-term toxicity results of the previous trials are available. Balancing the risks of primary or secondary treatment failure against the risk of late morbidity is extremely difficult and should be done on the basis of the results of both retrospective and prospective studies.
REFERENCES
1 Longo DL. Radiation therapy in the treatment of Hodgkins diseasedo you see what I see? J Natl Cancer Inst 2003;95:9289.
2 van Leeuwen FE, Klokman WJ, Stovall M, Dahler EC, vant Veer MB, Noordijk EM, et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkins disease. J Natl Cancer Inst 2003;95:97180.
3 Specht L, Gray RG, Clarke MJ, Peto R. Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkins disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkins Disease Collaborative Group. J Clin Oncol 1998;16:83043.[Abstract]
4 Aleman BM, Raemaekers JM, Tirelli U, Bortolus R, vant Veer MB, Lybeert ML, et al. Involved-field radiotherapy for advanced Hodgkins lymphoma. N Engl J Med 2003;348:2396406.
5 Duggan DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkins disease: report of an intergroup trial. J Clin Oncol 2003;21:60714.
6 van Leeuwen FE, Klokman WJ, Veer MB, Hagenbeek A, Krol AD, Vetter UA, et al. Long-term risk of second malignancy in survivors of Hodgkins disease treated during adolescence or young adulthood. J Clin Oncol 2000;18:48797.
7 Aleman BM, van den Belt-Dusebout AW, Klokman WJ, Vant Veer MB, Bartelink H, van Leeuwen FE. Long-term cause-specific mortality of patients treated for Hodgkins disease. J Clin Oncol 2003;21:34319.
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