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Originally published as JCO Early Release 10.1200/JCO.2009.22.9120 on August 10 2009 © 2009 American Society of Clinical Oncology.
Secondary Breast Cancer in Hodgkin's Lymphoma SurvivorsDivision of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Canada
Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Canada For the growing number of survivors of Hodgkin's lymphoma (HL), secondary cancer is a leading cause of death.1 For female HL survivors, breast cancer is the most common second malignancy, and several studies have defined the incidence and relative risk of second breast cancer in women treated for HL.2–5 The cumulative incidence increases with young age at initial treatment, radiation dose, radiation therapy (RT) field size, and time from treatment, and approaches 25% to 30% in a woman age 55 years who was treated for HL at age 25. This increased risk of breast cancer emerges approximately 10 years after primary therapy and persists beyond 25 years of follow-up.3,6 Since the initial reports of an increased incidence of breast cancer among female HL survivors,7 significant advances have occurred in the treatment of HL that have improved survival rates and reduced treatment-related toxicity. The regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has replaced alkylator-based regimens such as mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or MOPP/ABV, and is currently the standard chemotherapy regimen for limited stage HL.8–9 Combined-modality therapy including, MOPP/ABV or ABVD and RT has been shown to be superior to treatment without chemotherapy.9–11 After chemotherapy, RT limited to radiologically involved nodal regions (involved field radiation [IFRT]) has been shown to give equivalent disease control and less short-term toxicity compared with extended RT fields (for example, mantle with or without upper abdominal RT).12,13 Little is known about how much these changes in HL treatment will affect the risk of second solid cancers in general, and breast cancer in particular. In this issue of Journal of Clinical Oncology, De Bruin et al14 assessed breast cancer risk in women with HL treated at six hospitals in the Netherlands, who survived 5 years after initial HL therapy, and were observed for a median of 17.8 years. They collected information on radiation field size, as well as additional breast cancer risk factors in a subset of this cohort (height, weight, smoking history, menarche and menopause, oral contraceptive and hormone replacement therapy [HRT] use). RT doses during this time period were fairly homogenous, typically 40 Gy (36 to 44 Gy). They reported a standardized incidence ratio of 5.6 for breast cancer compared with the general population and a cumulative risk of breast cancer in women treated before age 41 of 25% (19% when death was considered a competing risk), figures similar to those reported previously from this group and others.3,15,16 Risk of breast cancer increased with decreasing age at first treatment and was highest in the youngest cohort (age < 21 years): 31% for women who attained an age of 51 years after 30 years of follow-up. A key observation in this study was that the exclusion of the axillae from supradiaphragmatic RT fields—the upper outer quadrant is the most common site of secondary breast cancer—was associated with a relative risk of breast cancer less than half of that seen with mantle fields, which include bilateral axillae. Remarkably, this translated into an almost 20% absolute reduction in the 30-year cumulative incidence of breast cancer, which was less than 10% among those receiving mediastinal RT without pelvic RT. However, long-term risks among patients receiving limited-field RT were based on very few patients, and longer follow-up will be required to reliably confirm these findings. Their reported reduction in the relative risk of breast cancer is almost identical to that observed in the meta-analysis recently published by Franklin et al17, which reported a three-fold reduction in secondary breast cancer among women receiving IFRT compared with extended-field RT. Both studies are consistent with a detailed dosimetric comparison of normal tissue dose associated with different HL RT fields, which found a 65% reduction in the mean breast dose with the transition from mantle irradiation to IFRT, due to the smaller volume of the breast radiated when axillary fields are omitted.18,19 A notable limitation of the study is the absence of individual patient-level radiation dosimetry. The usual RT dose delivered to patients in the study was 40 Gy, whereas the standard contemporary IFRT doses for adult HL patients is typically 30 Gy, and interim analysis of the German Hodgkin Study Group HD10 trial suggests that 20 Gy IFRT may be equally effective.20 The average breast tissue dose associated with these latter treatments would be expected to be approximately 20% to 25% of that produced by the mantle RT described in the study by De Bruin et al.18,19 Insofar as the risk of secondary breast cancer has been shown to be dose-related,4 the 30-year risk associated with contemporary mediastinal RT could reasonably be expected to be lower than that reported among patients receiving 40 Gy mediastinal RT in this study. De Bruin et al14 also reported that women with a longer period of intact ovarian function after combined-modality therapy for HL are at higher risk of developing breast cancer; conversely, those with premature ovarian failure experienced a lower relative risk, observations previously reported by the group from the Netherlands.4 This finding provides insight into one potential mechanism underlying the observation that younger age at treatment is associated with increased risks of subsequent breast cancer: adolescent females have a longer fertile life span after exposure to RT than older patients, and consequently a greater exposure to the breast cancer–promoting effects of estrogen. It also suggests that modern chemotherapy, with its limited gonadotoxicity,21 may not have the same "protective" effect on breast cancer risk as historic alkylator-based regimens. How this will affect the incidence of breast cancer following modern therapy remains to be determined. It does not appear that the use of HRT or oral contraceptives had an effect on subsequent breast cancer risk, although data on specific dose and duration of therapy were not obtained. The question of whether HRT in women with premature ovarian failure from chemotherapy and radiation for HL is harmful or protective remains unanswered. The authors demonstrate the importance of appropriate consideration of competing risks of death in the estimation of the cumulative incidence of second cancers. The Kaplan-Meier method overestimates the risk of late effects if patients are censored at the time of death: in this case, the 30-year incidence of breast cancer was 6% lower after accounting for competing causes of death. For a similar reason, readers should be aware that the magnitude of the risks reported in this study apply to 5-year survivors, and cannot be directly applied to discussions with newly diagnosed patients, whose greater risk of death from HL would decrease the cumulative incidence of breast cancer compared to women who have already survived 5 years after treatment. What are the implications of these data for women treated with modern chemotherapy, which generally preserves ovarian function, and IFRT? It is tempting, as some have argued, to discard RT as simply too toxic in the setting of effective combination chemotherapy.22 However, it is clear that second cancer risk estimates based on outdated treatments (gonadotoxic chemotherapy, mantle radiation) are an inadequate basis on which to make sophisticated judgments about the late effects of modern therapy. In this regard, the study by De Bruin et al14 provides some of the clearest evidence yet that that contemporary IFRT is likely to produce a significantly lower risk of RT-related breast cancer than historic mantle RT. Given the median time to development of breast cancer in most reports is 15 to 20 years, the true breast cancer risk in women treated with short courses of ABVD and 20 to 30Gy IFRT is currently unknown. Further, most available evidence suggests that for patients with limited-stage HL, treatment with chemotherapy alone produces a higher risk of relapse than combined modality treatment that includes RT.23 Consequently, the routine omission of IFRT among patients with early stage disease subjects them to a greater risk of relapse with almost no quantitative estimates of how much their second cancer risk is likely to be reduced. Moreover, women relapsing after ABVD will generally require high-dose therapy and autologous stem cell transplantation, which itself carries significant risks of infertility and second malignancy.24 It is also clear, however, that the majority of favorable risk HL patients can be cured without RT, and the challenge is to identify these patients and treat them accordingly. There are multiple studies that suggest that the normalization of positron emission tomography (PET) imaging after chemotherapy is associated with a low risk of subsequent relapse, and may identify a group of patients in whom RT can be omitted, although follow-up in many of these is short, and results do not unanimously confirm the safety of omitting RT based on PET results.25,26 There are several ongoing international phase III trials sponsored by the US Children's Oncology Group, European Organisation for Research and Treatment of Cancer, and the German Hodgkin Study Group that further reduce RT field size to involved nodes or withhold RT or chemotherapy agents in selected patients in an attempt to reduce treatment-related late toxicity.27 Commitment to long-term follow-up of patients treated with modern chemotherapy and IFRT, and to rigorous testing of new treatment approaches such as therapy modification based on imaging modalities such as PET,28 is required to maintain the high cure rate of early-stage HL and reduce late mortality. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Michael Crump, David Hodgson Manuscript writing: Michael Crump, David Hodgson Final approval of manuscript: Michael Crump, David Hodgson REFERENCES
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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