Correspondence
Late Effects of Treatment for Childhood Hodgkin's Disease
N Engl J Med 1996; 335:352-355August 1, 1996
- Article
To the Editor:
Bhatia et al. (March 21 issue)1 make the unwarranted statement that radiation, but not chemotherapy, increases the risk of solid tumors, especially breast tumors, in patients treated for childhood Hodgkin's disease.
In the study cohort, only 8 percent of the patients received chemotherapy alone; 23 percent received radiation alone. The remainder received both, but to compare the risks of treatments, only the patients receiving one or the other are appropriate for the analysis. Only one patient in the group receiving chemotherapy alone had a solid tumor, but since the expected number of cases was less than one, the risk was five times higher than expected. The confidence interval overlapped the excess risk (11 times higher than expected) among the patients receiving radiation alone and the excess risk (13 times higher) among those receiving both treatments. The confidence intervals for the cumulative probabilities of solid tumors in all groups also overlapped. The small size of the group receiving chemotherapy alone renders the analysis inadequate to assess the risk of solid tumors but does not support the conclusion of a lower risk or none in association with chemotherapy alone. In contrast, chemotherapy alone clearly posed a risk of leukemia, and radiation did not appear to increase this risk.
Studies of second tumors among patients receiving chemotherapy contribute to an understanding of the exposure–response relation for chemical carcinogens in people, as well as the contrast between relative and absolute risk. In this study, the observed risk ratio of 18 in the study group corresponded to a 7 percent incidence — a consequence of the low rate in the general population for such a young cohort. Chemotherapy represents treatment equivalent to the much maligned “maximal tolerated dose” in animal bioassays. The literature on second tumors should be compiled, and the collection of further data encouraged.
1 ReferencesFranklin E. Mirer, Ph.D.
International Union, United Automobile Workers, Detroit, MI 482141
Bhatia S ,Robison LL ,Oberlin O , et al. Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 1996;334:745-751
Full Text | Web of Science | Medline
To the Editor:
In their editorial on the report by Bhatia et al., Donaldson and Hancock make interesting statistical observations but miss the point.1 The high incidence of breast cancer in survivors of childhood Hodgkin's disease is due to the effect of irradiation on breast tissue. For a disease with a 90 percent cure rate but for which therapy carries a high risk of breast cancer, the pertinent question is whether radiotherapy has any role in the treatment of childhood Hodgkin's disease. In Australia, irradiation for childhood Hodgkin's disease was discontinued as early as 1973 in some pediatric oncology centers and by the 1980s in most centers. Using a regimen of mechlorethamine, vincristine, procarbazine, and prednisone or chlorambucil, vinblastine, procarbazine, and prednisone, my colleagues and I reported event-free survival of approximately 90 percent,2 and with an alternative, potentially less toxic regimen, the event-free survival was 80 percent.3 A review of the treatment of 33 children with massive mediastinal disease who received chemotherapy alone showed an event-free survival of 0.62±0.09 at 66 months and an overall survival of 0.82±0.08 (unpublished data). In addition, we have shown that salvage with irradiation or other chemotherapeutic regimens is achievable in the few patients who have only a partial remission or a relapse. To minimize the high risk of breast cancer in patients with childhood Hodgkin's disease, the strategy that is required is to eliminate unnecessary irradiation from the therapeutic regimens rather than, as Donaldson and Hancock state, “to improve the accuracy of our information, and to deal with the psychosocial consequences of surviving in the face of special risks.”
3 ReferencesHenry Ekert, M.D.
Royal Children's Hospital, Parkville, Victoria, 3052, Australia1
Donaldson SS ,Hancock SL . Second cancers after Hodgkin's disease in childhood. N Engl J Med 1996;334:792-794
Full Text | Web of Science | Medline2
Ekert H ,Waters KD . Results of treatment of 18 children with Hodgkin disease with MOPP chemotherapy as the only treatment modality. Med Pediatr Oncol 1983;11:322-326
CrossRef | Medline3
Ekert H ,Waters KD ,Smith PJ ,Toogood I ,Mauger D . Treatment with MOPP or ChlVPP chemotherapy only for all stages of childhood Hodgkin's disease. J Clin Oncol 1988;6:1845-1850
Web of Science | Medline
To the Editor:
Bhatia et al. found that 17 of 483 girls in whom Hodgkin's disease was diagnosed before the age of 16 years subsequently had breast cancer (ratio of observed to expected cases, 75.3; 95 percent confidence interval, 44.9 to 118.4). Radiotherapy was implicated in the development of many of the cases of breast cancer. Another recent study, involving 1641 patients treated for Hodgkin's disease as children in five Nordic countries, reported a relative risk that was 17 times higher than that in the general population, on the basis of 16 cases of breast cancer.1
We evaluated data on 3869 women in population-based registries participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program (for the period from 1973 to 1992) or in the Connecticut Tumor Registry (CTR) (for the period from 1935 to 1972). These registries account for approximately 10 percent of the U.S. population. All the women had received a diagnosis of Hodgkin's disease as a first primary cancer, had survived for two or more months, and had received radiotherapy as the initial treatment. The SEER and CTR files were examined to identify all invasive second primary breast cancers among these patients, and standard methods were used to quantify risk. Cases reported to the SEER Program between 1973 and 1985 and those reported to the CTR (1935 to 1972) were included in an earlier survey.2 We have extended the follow-up through 1992 for the current analysis.
Breast cancer developed in a total of 55 patients (ratio of observed to expected cases, 2.24), and the risk increased with the time since the diagnosis of Hodgkin's disease (P for trend <0.01) (Table 1Table 1
Cases of Breast Cancer after Radiotherapy for Hodgkin's Disease, According to Age at Treatment and Time since Diagnosis.). The risk of breast cancer was 60.57 (95 percent confidence interval, 22.1 to 132) among the women in whom Hodgkin's disease was diagnosed before the age of 16 years, with most tumors occurring 10 or more years after treatment. The risk of breast cancer decreased with increasing age at the time of therapy and was only slightly elevated among the women who were 30 years old or older when treated (ratio of observed to expected cases, 1.43). The excess risk of breast cancer among girls less than 16 years of age at the time of treatment (23.3 excess cases of cancer per 10,000 patients per year) was approximately two to three times that among the older women.Our results indicate that in the general population of the United States, substantial numbers of excess cases of breast cancer can be identified after radiotherapy for Hodgkin's disease during childhood. Prior studies3 have shown that in the young, the breast is especially sensitive to the carcinogenic effects of ionizing radiation, with excess cancers typically developing after a latent period of 10 or more years. Since the increased risk of cancer may persist for decades after irradiation,3 survivors of Hodgkin's disease should be monitored carefully throughout their lives. The influences of well-established risk factors for breast cancer (e.g., a family history of breast cancer and a younger age at menarche) and possibly others4 on the development of radiation-associated tumors should be considered in future studies.
4 ReferencesLois B. Travis, M.D., Sc.D.
Rochelle E. Curtis, M.S.
John D. Boice, Jr., Sc.D.
National Cancer Institute, Bethesda, MD 208921
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. J Clin Oncol 1996;14:1442-1446
Web of Science | Medline2
Curtis RE ,Boice JD Jr . Second cancers after radiotherapy for Hodgkin's disease. N Engl J Med 1988;319:244-245
Full Text | Web of Science | Medline3
United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and effects of ionizing radiation: UNSCEAR 1994 report to the General Assembly, with scientific annexes. New York: United Nations, 1994. (E.94.IX11.)
4
Hancock SL ,Tucker MA ,Hoppe RT . Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst 1993;85:25-31
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We based our conclusions about radiation as a risk factor for breast cancer on the following findings: of the 17 cases of breast cancer, 16 developed within or at the margin of the radiation field, and a multivariate analysis showed that a higher dose of radiation was independently associated with an increased risk of breast cancer. An increased risk of breast cancer has been reported among women exposed to radiation from atomic-bomb explosions, repeated chest fluoroscopy, or treatment of postpartum mastitis.1-3 Therefore, we feel confident in concluding that radiation played a part in the development of breast cancer in the patients we studied. It is true, however, that when all solid tumors were considered, the multivariate analysis showed that none of the treatments were significantly associated with an increased risk of cancer. Perhaps increasing the number of patients in the cohort and the period of follow-up will enable us to clarify the effect of treatment on the risk of second cancers.
We concur with Drs. Donaldson and Hancock and with Dr. Mirer that high standardized incidence ratios in cohorts of young patients must be viewed in the context of the low incidence of the cancers in question among persons of a similar age in the general population. In addition, actuarial analyses can overestimate the risk, especially if the cancers occur late in the course of follow-up and long-term follow-up of the entire cohort has not been possible. Several measures of risk are useful in considering the outcome of second cancers.4 One such measure is the absolute risk, or annual excess risk, which is calculated with the following equation:
Table 1Table 1
Estimated Absolute Risk of Second Cancers in the Study Cohort after the Diagnosis of Hodgkin's Disease, According to the Type or Site of Cancer. shows the absolute risk, or annual excess risk, of all cancers, leukemia, solid tumors, and breast cancer in our cohort.In the Appendix, Roswell Park Memorial Institute, Buffalo, New York (investigator, Dr. Daniel Green), was inadvertently omitted from the list of institutions that participated in the Late Effects Study Group. We would like to acknowledge the invaluable contribution of this institution to the study.
5 ReferencesSmita Bhatia, M.D., M.P.H.
Leslie L. Robison, Ph.D.
University of Minnesota, Minneapolis, MN 55455Anna T. Meadows, M.D.
Children's Hospital of Philadelphia, Philadelphia, PA 191041
Miller AB ,Howe GR ,Sherman GJ , et al. Mortality from breast cancer after irradiation during fluoroscopic examinations in patients being treated for tuberculosis. N Engl J Med 1989;321:1285-1289
Full Text | Web of Science | Medline2
Shore RE ,Hildreth N ,Woodard E ,Dvoretsky P ,Hempelmann L ,Pasternack B . Breast cancer among women given X-ray therapy for acute postpartum mastitis. J Natl Cancer Inst 1986;77:689-696
Web of Science | Medline3
Tokunaga M ,Land CE ,Yamamoto T , et al. Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1980. Radiat Res 1987;112:243-272
CrossRef | Web of Science | Medline4
Robison LL . Second primary cancers after childhood cancer. BMJ 1996;312:861-862
CrossRef | Web of Science | Medline5
Miller BA, Reis LAG, Hankey BF, et al. SEER cancer statistics review: 1973–1990. Bethesda, Md.: National Cancer Institute, 1993. (NIH publication no. 93-2789.)
Author/Editor Response
We appreciate Dr. Ekert's comments on the issues regarding the optimal treatment of childhood Hodgkin's disease implicit in the article by Bhatia et al. However, we believe the article illustrates well the tradeoffs between the toxic effects of the various treatments commonly used for childhood Hodgkin's disease between 1955 and 1986. Chemotherapeutic regimens like those advocated by Ekert et al.1 were associated with 26 early cases of leukemia, 25 of which were fatal; irradiation was implicated in 46 late cases of solid tumors (including 17 cases of breast cancer), 10 of which were fatal. Actuarial curves showed that the cumulative risk was 2.8 percent for leukemia, as compared with 24 percent for solid tumors. How data are reported remains important. Because of extensive censoring of data, actuarial methods tend to emphasize late events in a potentially alarming way while underemphasizing extremely serious consequences in the shorter term, including early leukemia or deaths due to acute toxicity of the treatment. The latter consequences may be completely excluded in actuarial analyses confined to “complete responders.”1
We agree that “unnecessary irradiation” should be avoided, and we recommend not using the wide-field, large-fraction, high-dose irradiation that was commonly used during the first decade of treatment included in our study. We prefer combined therapy. In a study of 57 children treated at Stanford, a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine or mechlorethamine, vincristine, procarbazine, and prednisone and low-dose irradiation of the involved field resulted in a mean (±SE) event-free survival of 93±3.5 percent, an overall survival of 96±2.5 percent, and no relapses among 13 children with massive mediastinal disease at stage I, II, or III.2 More recently, therapy has been tailored according to the extent of the risk from Hodgkin's disease on the basis of recognized clinical prognostic factors. Limited cycles of chemotherapy without alkylating agents are consolidated with low-dose irradiation of the involved field in early-stage disease with a favorable prognosis,3 and aggressive chemotherapeutic regimens are reserved for advanced-stage disease with an unfavorable prognosis. Consolidative low-dose irradiation of the involved field has contributed to higher cure rates than those reported for chemotherapy alone and may reduce the risks of secondary leukemia, non-Hodgkin's lymphoma, and sterility associated with conventional chemotherapeutic regimens. Many more years of careful follow-up will be required to determine the ultimate effects of all treatment approaches. All oncologists share the goal of effecting a cure without toxic effects, but how best to achieve this goal remains controversial.
3 ReferencesSarah S. Donaldson, M.D.
Steven L. Hancock, M.D.
Stanford University School of Medicine, Stanford, CA 943051
Ekert H ,Waters KD ,Smith PJ ,Toogood I ,Mauger D . Treatment with MOPP or ChlVPP chemotherapy only for all stages of childhood Hodgkin's disease. J Clin Oncol 1988;6:1845-1850
Web of Science | Medline2
Hunger SP ,Link MP ,Donaldson SS . ABVD/MOPP and low-dose involved-field radiotherapy in pediatric Hodgkin's disease: the Stanford experience. J Clin Oncol 1994;12:2160-2166
Web of Science | Medline3
Donaldson SS ,Hudson M ,Link MP , et al. Treatment of children with early stage and favorable Hodgkin's disease -- a model of success. Prog Proc Am Soc Clin Oncol 1995;14:408-408 abstract.
- Citing Articles (22)
Citing Articles
1
V. Brillaud, C. Tunon de Lara, P. Richaud, C. Breton-Callu, V. Brouste, E. Bussières. (2011) Maladie de Hodgkin et cancer du sein : une association pour quelles patientes ? À propos d’une série de l’institut Bergonié. Gynécologie Obstétrique & Fertilité
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S. M. Castellino, A. M. Geiger, A. C. Mertens, W. M. Leisenring, J. A. Tooze, P. Goodman, M. Stovall, L. L. Robison, M. M. Hudson. (2011) Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 117:6, 1806-1816
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Ebru Yilmaz Keskin, Turkiz Gursel, Omer Uluoglu, Meryem Albayrak, Zuhre Kaya, Ugur Coskun, Ulker Kocak. (2010) Parathyroid Adenoma and Chondrosarcoma After Treatment of Pediatric Hodgkin Disease. Journal of Pediatric Hematology/Oncology 32:7, e294-e296
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Icro Meattini, Lorenzo Livi, Calogero Saieva, Livia Marrazzo, Andrea Rampini, Carmine Iermano, Maria Grazia Papi, Beatrice Detti, Silvia Scoccianti, Giampaolo Biti. (2010) Breast Cancer Following Hodgkin’s Disease: The Experience of the University of Florence. The Breast Journal 16:3, 290-296
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(2010) References. Journal of the ICRU 10:1, 93-106
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Mohamed A. Alm El-Din, Kevin S. Hughes, Dianne M. Finkelstein, Keith A. Betts, Torunn I. Yock, Nancy J. Tarbell, Alan C. Aisenberg, Alphonse G. Taghian. (2009) Breast Cancer After Treatment of Hodgkin's Lymphoma: Risk Factors That Really Matter. International Journal of Radiation Oncology*Biology*Physics 73:1, 69-74
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Mohamed A. Alm El-Din, Samy A. El-Badawy, Alphonse G. Taghian. (2008) Breast Cancer After Treatment of Hodgkin's Lymphoma: General Review. International Journal of Radiation Oncology*Biology*Physics 72:5, 1291-1297
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James M. Allan. (2008) GENETIC SUSCEPTIBILITY TO RADIOGENIC CANCER IN HUMANS. Health Physics 95:5, 677-686
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Aliki J. Taylor, David L. Winter, Charles A. Stiller, Mike Murphy, Mike M. Hawkins. (2007) Risk of breast cancer in female survivors of childhood Hodgkin's disease in Britain: A population-based study. International Journal of Cancer 120:2, 384-391
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L. B. Travis, D. Hill, G. M. Dores, M. Gospodarowicz, F. E. van Leeuwen, E. Holowaty, B. Glimelius, M. Andersson, E. Pukkala, C. F. Lynch, D. Pee, S. A. Smith, M. B. Van't Veer, T. Joensuu, H. Storm, M. Stovall, J. D. Boice, E. Gilbert, M. H. Gail. (2005) Cumulative Absolute Breast Cancer Risk for Young Women Treated for Hodgkin Lymphoma. JNCI Journal of the National Cancer Institute 97:19, 1428-1437
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Merideth M. M. Wendland, Alexander Tsodikov, Martha J. Glenn, David K. Gaffney. (2004) Time interval to the development of breast carcinoma after treatment for Hodgkin disease. Cancer 101:6, 1275-1282
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F. E. van Leeuwen, W. J. Klokman, M. Stovall, E. C. Dahler, M. B. van't Veer, E. M. Noordijk, M. A. Crommelin, B. M. P. Aleman, A. Broeks, M. Gospodarowicz, L. B. Travis, N. S. Russell. (2003) Roles of Radiation Dose, Chemotherapy, and Hormonal Factors in Breast Cancer Following Hodgkin's Disease. JNCI Journal of the National Cancer Institute 95:13, 971-980
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D. L. Wahner-Roedler, D. F. Nelson, I. T. Croghan, S. J. Achenbach, C. S. Crowson, L. C. Hartmann, W. M. O'Fallon. (2003) Risk of Breast Cancer and Breast Cancer Characteristics in Women Treated With Supradiaphragmatic Radiation for Hodgkin Lymphoma: Mayo Clinic Experience. Mayo Clinic Proceedings 78:6, 708-715
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Daniel M. Green. (2003) Late effects of treatment for cancer during childhood and adolescence. Current Problems in Cancer 27:3, 127-142
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Gareth J. Morgan, Martyn T. Smith. (2002) Metabolic Enzyme Polymorphisms and Susceptibility to Acute Leukemia in Adults. American Journal of PharmacoGenomics 2:2, 79-92
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Jenny Huang, Willian J. Mackillop. (2001) Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma. Cancer 92:1, 172-180
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Jenny Huang, Willian J. Mackillop. (2001) Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma. Cancer 92:1, 172-180
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