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© 2000 American Society for Clinical Oncology
Second Malignancies in Hodgkin’s DiseaseMassachusetts General Hospital Boston, MA To the Editor:We have long admired1,2 the work of van Leeuwan et al at the Netherlands Cancer Institute but take issue with some implications of their otherwise excellent recent article.3 A 2% per year risk of second solid cancers 20 years after Hodgkin’s disease treatment in a cohort with attained median age in the mid-forties (van Leeuwan et al,3 Tables 1 and 4) is a cause for great concern. The authors do not sufficiently emphasize the importance of high absolute excess risk over high relative risk in determining clinical hazard. The high second tumor risk is illustrated in our single institution study of breast cancer in treated Hodgkin’s disease.2 Building on earlier work, particularly that of Hancock et al,4 we analyzed 111 consecutive women with localized Hodgkin’s disease above the diaphragm with at least 5 years of follow-up after mantle irradiation. In 1997, we reported that the 25-year Kaplan-Meier risk of breast cancer was already 34% in the 33 women who were younger than 20 years when irradiated. In the summer of 1998, an inquiry received from the treating physician apprised us of breast cancer 34 years after radiation in the earliest-treated young Hodgkin’s disease patient in the series; this patient was only 53 years old when breast cancer supervened. This letter is a call for additional help from statisticians and others in addressing the issue of second malignancies, the central unsolved problem in Hodgkin’s disease management. Because most patients with favorable Hodgkin’s disease are readily cured today, there is now an increasing use of novel combined treatment programs1 that have not been thoroughly evaluated in controlled clinical trials. Statisticians can help us avoid reliving the mistakes of the past by careful design and analysis of these data. To increase sensitivity and minimize the statistical noise and confounding contingent variables that bedevil the field, study criteria must be refined using the known facts of radiation- and chemotherapy-induced carcinogenesis. In view of the complexity of carcinogenesis, separate analysis of each major second neoplasm with careful segregation of patients by treatment history is essential. Because the major risks of second solid malignancies and cardiac disease are a consequence of radiation therapy, we urgently need more information about risks after doxorubicin, bleomycin, vinblastine, and dacarbazine used as a single modality, which looks increasingly attractive in the primary treatment of favorable Hodgkin’s disease. REFERENCES
1.
Aisenberg AC: Problems in Hodgkin’s disease management. Blood 93:761-779, 1999 2. Aisenberg AC, Finkelstein DM, Dopke KP, et al: High risk of breast carcinoma in young women with Hodgkin’s disease. Cancer 79:1203-1210, 1997[Medline]
3.
van Leeuwen FE, Klokman WJ, Mars B, et al: Long-term risk of second malignancy in survivors of Hodgkin’s disease treated during adolescence or young adulthood. J Clin Oncol 18:487-497, 2000
4.
Hancock SL, Tucker MA, Hoppe RT: Breast cancer after treatment of Hodgkin’s disease. J Natl Cancer Inst 85:25-31, 1993
ResponseNetherlands Cancer Institute Amsterdam, the Netherlands In Reply:We fully agree with Drs Aisenberg and Finkelstein that absolute excess risk is the most appropriate risk measure by which to judge the second cancer burden in a cohort of patients. In fact, we stated this almost literally on page 490 of our recent article.1 A high relative risk may translate into a low absolute excess risk if the second tumor concerned occurs rarely in the general population (eg, leukemia after Hodgkin’s disease [HD]). Conversely, a slightly or moderately increased relative risk may result in a high absolute excess risk if the second tumor concerned has a high incidence (eg, lung cancer after HD). Because absolute excess risks were included in our Tables 2 through 4 and were extensively discussed in our Results and Discussion sections (including the estimate of two excess cases per 100 20-year survivors per year on pages 492 and 493),1 we feel that the importance of absolute excess risk was sufficiently addressed in our article. Although treatment-related second malignancies present a major problem for long-term survivors of HD, we consider it important that the risk is not overestimated. Overestimation of second cancer risk may occur in several ways. First, incomplete follow-up may lead to overestimation of second malignancy risk if patients who remain well lose contact with clinical follow-up, whereas those with second cancer come to attention because of this. Generally, surveys with more complete follow-up have found lower relative risks of breast cancer1-3 than those in which completeness of follow-up was less satisfactory or not addressed.4,5 Second, in the 1990s, many treatment centers have introduced breast cancer screening in female survivors of HD. Because screening is expected to advance the diagnosis by at least 5 years, it is likely that this has resulted in a (transient) overestimation of breast cancer risk in these centers. Furthermore, the very high actuarial risks reported by Aisenberg et al (34% at 25 years after first treatment for women treated at ages younger than 20 years; 95% confidence interval [CI], 14% to 54%)6 and by Bhatia et al (35% at 40 years of age for those treated at ages younger than 16 years; 95% CI, 17% to 53%)5 are likely to overestimate the true risk. This may be due to losses to follow-up but also to the fact that the actuarial method is less appropriate when including events that occur at follow-up intervals later than those at which data for most of the patients were censored.7 The latter phenomenon only comes to light when actuarial curves are accompanied by the number of patients still at risk at different follow-up intervals. In our study, with (nearly) complete follow-up and 27 female patients who were diagnosed before age 20 years and were still at risk at 25 years from first treatment, the 25-year actuarial risk of breast cancer amounted to 15% (95% CI, 7% to 27%).1 Although this is still a disturbingly high risk for 40-year-old women, we think that the implications of one in six versus one in three breast cancers among long-term female HD survivors may be different. Both the survivors and their treating clinicians need to be provided with valid risk estimates. We therefore feel that, for those evaluating the treatment of HD, there is an obligation to continue reporting on second cancer risk in large series of HD patients, with long-term and complete follow-up and with the use of appropriate statistical techniques. REFERENCES 1. van Leeuwen FE, Klokman WJ, van’t Veer MB, et al: Long-term risk of second malignancy in survivors of Hodgkin’s disease treated during adolescence or young adulthood. J Clin Oncol 18:487-497, 2000
2.
Sankila R, Garwicz S, Olsen JH, et al: Risk of subsequent malignant neoplasms among 1,641 Hodgkin’s disease patients diagnosed in childhood and adolescence: A population-based cohort study in the five Nordic countries—Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology. J Clin Oncol 14:1442-1446, 1996
3.
Swerdlow AJ, Barber JA, Vaughan Hudson GV, et al: Risk of second malignancy after Hodgkin’s disease in a collaborative British cohort: The relation to age at treatment. J Clin Oncol 18:498-509, 2000
4.
Mauch PM, Kalish LA, Marcus KC, et al: Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin’s disease: Long-term analysis of risk factors and outcome. Blood 87:3625-3632, 1996
5.
Bhatia S, Robison LL, Oberlin O, et al: Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med 334:745-751, 1996 6. Aisenberg AC, Finkelstein DM, Doppke KP, et al: High risk of breast carcinoma after irradiation of young women with Hodgkin’s disease. Cancer 79:1203-1210, 1997
7.
Donaldson SS, Hancock SL: Second cancers after Hodgkin’s disease in childhood. N Engl J Med 334:792-794, 1996 (editorial)
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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