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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 544-548 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.4396
Don't Throw Out the Baby With the Bathwater: On Optimizing Cure and Reducing Toxicity in Hodgkin's LymphomaMemorial Sloan-Kettering Cancer Center, New York, NY The metaphorical phrase —don't throw out the baby with the bathwater—is actually of German origin and first appeared in writing in a satirical book published in 1512 describing fools who by trying to rid themselves of a bad thing succeed in destroying whatever good there was as well.1 This metaphor is worthy of consideration in the light of a salvo of recent editorials that called for elimination of radiotherapy from treatment programs of Hodgkin's lymphoma (HL) regardless of stage.2-6 These recent editorials assert that chemotherapy alone provides equivalent outcome to that attained by using a combined modality program and also imply that by avoiding radiotherapy, one could keep the high cure rate of HL and avoid the late risks of developing second tumors and coronary heart disease. It is important to recognize that the increased risk for solid second cancers and particularly for breast cancer appears late (median, 15 years) and thus it has been detected mostly in patients cured of HL by treatments administered 20 to 40 years ago. This is the era when radical radiation alone or radiotherapy followed by consolidation or salvage chemotherapy (mostly mechlorethamine, vincristine, procarbazine, and prednisone [MOPP]) were the primary treatments for this disease. The alarm of excessive long-term risks draws from series of patients treated with the obsolete radical treatments of the past without accounting for the fact that the current practice of combined modality is dramatically different from antiquated treatment approaches. Current standards combine short chemotherapy with only mini radiotherapy. Emerging data from recent randomized trials and retrospective analyses such as the report in this issue of the Journal of Clinical Oncology by Koontz et al7 from Duke University (Durham, NC) support the notion that the long-term survival of currently treated patients is unlikely to be affected by long-term treatment-related complications. At the same time, several recent randomized studies that attempted to eliminate radiotherapy in early-stage HL, either had excessive relapse rate in the no-radiation arm and had to close early, or showed inferior disease control when chemotherapy alone was used; as will be detailed in this editorial. Unfortunately, although the National Cancer Comprehensive Network guidelines advocate combined-modality as the preferred treatment for early-stage disease,8 some practices in the United States have already adopted the chemotherapy alone approach. Clearly, clinicians and patients are hearing conflicting recommendations on the appropriate management of HL today. Are we compromising disease control by eliminating radiation and merely substituting one set of risks with another? Are there other ways to reduce the risks of radiotherapy and of chemotherapy while still maintaining excellent outcome? Is more of one modality better than less of two? In a disease for which we have treatment programs that have achieved a remarkable cure rate of 80 to more than 90% (stage-dependent), this is not a trivial issue. Recently reported randomized trials, case-control studies, and retrospective long-term data analysis, including the Duke University study reported in this issue7 are helpful in examining the real risk of modern treatments in comparison to the outdated radical radiation alone approach. The controversial issue of optimal and balanced choices for HL is worthy of further examination, this time from a different perspective. From a Single Radical Approach to a Combination of Mini Treatments Hodgkin's lymphoma remained incurable for almost 130 years after its description by Thomas Hodgkin's in 1832. This changed during the 1960s, when new technologies and new concepts of radiotherapy dose and field design merged into a curative approach for HL. This approach using the only modality available at that time at its maximal tolerated strength was termed radical radiotherapy by its creator—Henry Kaplan of Stanford University (Stanford, CA).9 Radical radiotherapy soon cured an increasing number of patients with HL. Slightly later, but during the same decade, Vincent DeVita and his colleagues at the National Cancer Institute (Bethesda, MD) pioneered new combinations of effective chemotherapy agents.10 Each group documented unprecedented cure rates by either radical radiotherapy in patients with HL in stages I through III, or with MOPP chemotherapy in advanced-stage HL patients. Each group pushed the envelope of its available modality close to the threshold of toxicity, radiotherapists used the newly available linear accelerators to treat enormous fields (total lymphoid irradiation) that spared little other than brain, limbs, and some of the lungs, liver, and kidneys. At the same period, chemotherapists used dose-intensive and/or long MOPP chemotherapy or similar combinations to the edge of tolerance. It should not be a surprise that simply combining both radical approaches often resulted in much toxicity and a relatively small additional benefit. Indeed, during the 1960s, 1970s, and 1980s, most preferred to treat the disease in its early stages with radical radiotherapy alone, and advanced stages with chemotherapy alone. Patients with bulky disease, early or advanced, commonly received combined modality treatments. This has also been the era of pathologic staging, using the now obsolete staging laparotomy. While the above approaches are not used anymore, it should be appreciated that, thanks to those pioneering efforts, tens of thousands of young patients who were treated during the 1960s, 1970s, and 1980s survive today, free of HL. Indeed, some succumbed to the early and to the then unknown, late treatment-related toxicities, such as leukemia and lung cancer related to MOPP and other chemotherapy regimens,11 or developed breast, lung, other solid tumors and coronary heart disease related to radiation.12,13 Through series of randomized trials, the following treatment principles have been established: doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is better than MOPP and is less toxic14; combined-modality is more effective and less toxic than radical radiation alone,15 when combined with chemotherapy, the radiation field could be minimized to include only the involved site (involved-field radiotherapy [IFRT])16 and the radiation dose can be reduced from over 40 Gy to 30 Gy and possibly even lower,17 and only four cycles of ABVD are sufficient in early-stage (and probably only two cycles in favorable disease) when used with mini-radiotherapy (Table 1). 18
Based on these data, it is safe to state that with a combination of relatively short chemotherapy and IFRT to only 30 Gy, over 90% of favorable and unfavorable early-stage disease can be cured. With this reduction of therapy and in particular, the radiotherapy component, the toxicity profile is expected to be very low and will be further discussed. New regimens will have to match those results, or offer better overall outcome. The road to the reduction of effective treatments for early-stage HL is best exemplified by the successive randomized trials of the German Hodgkin's Study Group (GHSG). Their HD7 study showed that adding ABVD x 2 to extended-field RT is better than extended-field RT alone, HD8 demonstrated that when combined with chemotherapy, the involved-field is as effective, and is even safer than the extended RT field.19 HD10, the most recent study, was designed to test how far the treatment may be reduced.18 The recent 4-year interim analysis is highly encouraging. In HD10, 1,370 patients with favorable early-stage HL were randomly assigned into four arms: ABVD x 4 or ABVD x 2, and each group was followed by IFRT of 30 Gy or 20 Gy. At 4 years of treatment, freedom from treatment failure (FFTF) was similar in all groups—94%, and overall survival was 97%. Reducing chemotherapy appeared safe, and at this point, there was no difference between the different RT doses. The HD10 twin study HD11 targeted patients with unfavorable early-stage disease and randomly assigned them to either ABVD x 4 or bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine (BEACOPP) x 4, either program was followed by either 20 Gy or 30 Gy to the involved field. The interim analysis at 2 years has not shown a difference between the arms with FFTF of 90%.18 The current GHSG study for favorable patients (HD13) is testing the exclusion of bleomycin (pulmonary toxicity) and/or dacarbazine (questionable efficacy) from the shorter chemotherapy regimen, while maintaining IFRT at 30 Gy. It is unlikely that the reduction of chemotherapy accomplished in H10 and HD11 and tested in HD13 could be possible without maintaining the mini-radiotherapy component, and vice versa. Combined-Modality Versus Chemotherapy Alone: The Data Are Out Several groups tested the hypothesis that chemotherapy alone could provide equivalent disease control to that achieved with combined-modality therapy. The studies from Europe,21 Asia,22 and North America23-25 targeted mostly early-stage favorable and unfavorable patients and were conducted in adults, children and adolescents, or in both. In some, the randomization was upfront,23,24 in others, it was limited to patients that achieved a clear complete response (CR) with chemotherapy.21,22,25 The results are summarized in Table 2.
All studies (with the exception of the small Memorial Sloan Kettering Cancer Center [New York, NY] study) showed a significantly superior event-free survival or freedom from progression when radiation was added to chemotherapy. Only in the study with the longest follow-up (8 years), superior initial disease control has translated into a significantly better overall survival.22 In HL, most randomized studies have not been able to document a significant survival advantage for the superior disease control arm, even when one arm was clearly more effective (eg, Cancer and Leukemia Group B MOPP v ABVD v MOPP/ABVD or the stem cell salvage trials) and thus was accepted as the standard treatment. There are many reasons for this phenomenon: good salvage for failures, long survival with disease, and (but not only) possibly more toxic events in the more effective arm. To make a conclusion based on survival in HL, follow-up that is longer and more complete than most study groups currently provide, is necessary. In the absence of adequate follow-up, dismissing a significantly superior disease control in HL because there is no significant survival advantage may be misleading. In addition, while salvage with high dose therapy is often effective, it is associated with a high risk of acute and late toxicity and is physically and psychological difficult for the patient. With regard to inferior survival attributed to adding radiation to chemotherapy, it is worthwhile to re-examine the European Organisation for Research and Treatment of Cancer trial for advanced-stage patients.26 This study clearly demonstrated that for those patients treated with six to eight courses of MOPP/ABV hybrid and carefully determined to be in CR, the addition of 24 Gy of IFRT will not change event-free survival. Yet, only 57% of all patients were qualified as complete responders after MOPP/ABV (a regimen abandoned in the United States due to high toxicity, including leukemia induction27), and only 45% were randomly assigned in this study. One third of the patients were deemed partial responders after MOPP/ABV; they all received IFRT of 30 Gy. Radiation was of high benefit for them; as a result, their survival matched the CR group. There were more cases of secondary leukemia in the CR group that received RT (4.6%) than in the group of CR patients that did not receive RT (0.6%). This high leukemia rate supposedly explained the borderline (P = .05) decrease in overall survival for this group; it served as the main argument of the accompanied editorial against using RT altogether.2 However, one of the details that De Vita did not notice is that in the large PR group of 244 patients that have all received even more RT than the CR patients, only two developed leukemia (0.8%) and no increase in other malignancies was documented. Assertions based on conflicting small number of events and a likely statistical fluke should be made more carefully. Modern Mini-Radiotherapy Versus Radical Radiation of the Past: Should We Expect the Same Long-Term Toxicity Profile? In the 1960s and 1970s, radiation was the primary, and at times the only, curative modality for HL. It was used alone or with adjuvant MOPP for early and advanced-stage HL. Bulky sites were covered with large radiation field margins, and occasionally even the lungs and the liver were intentionally irradiated. The standard field was total lymphoid irradiation. Its giant size compensated for the lack of good imaging information. The dose was also maximized (the standard dose at Stanford was 44 Gy) and often treatment was given in a technique that delivered even higher doses anteriorly, to the heart and breast. The involved-field radiation therapy (IFRT) that is used now is considerably smaller; the radiation is limited to the involved site and is often tailored to include only the reduced postchemotherapy volume.28 It is estimated that in comparison to total lymphoid irradiation, the average involved field will reduce the irradiated volume by more than 80%. This is particularly relevant to irradiation of the breast, heart, and lungs. With the old indiscriminate mantle field radiotherapy, most of the breast tissue was irradiated. Most breast exposure resulted from the routine irradiation of the axillae and most second breast cancers indeed developed in the outer part of the breast. Yet, approximately, two thirds of women with early-stage HD do not require radiation of the axillae, and additional protection to the upper and medial aspects of the breast can now be provided by further reducing field size using careful computed tomography-based planning that usually allows for smaller mediastinal volumes, particularly after chemotherapy.29 We can now avoid irradiating the breast in most women and substantially reduce exposure of the heart and lungs. The large fields of the past limited the radiation technique to simple opposed anterior and posterior fields. The conversion to smaller and better defined radiation volumes allows the utilization of more conformal radiation therapy, based on better imaging, computerized planning programs, and when indicated, advanced tools such as intensity modulated radiotherapy (IMRT).30 Modern breakthroughs in radiotherapy technology that have been implemented recently in HL have already demonstrated better sparing of the heart and coronary arteries. They provide increased accuracy, avoid normal organs, and thus improve the therapeutic ratio.30,31 Recent studies clearly indicate that the risk of secondary solid tumor induction is radiation-dose related. This was carefully analyzed for secondary breast and lung cancers as well as for other tumors.11,12,32,33 It was also demonstrated that the risk of lung cancer and leukemia after chemotherapy alone is chemotherapy-dose related.11,34,35 Some claim that any radiation dose in HL has significant second cancer risk, although the case-control studies do not support this argument.29 It will take more years of careful follow-up of patients in randomized studies to display the full magnitude of risk tapering by current reduction of radiation field and dose. The encouraging news is that early indicators of decreasing toxicity have already emerged. In the Duke University study published in this issue of the Journal,7 two groups of patients with early-stage HL were treated with different radiation approaches over the same period. One group received radiotherapy alone, given to extended fields with a median dose of 38 Gy, and the second group received chemotherapy followed by involved-field low-dose (median of 25 Gy) radiotherapy. While 12 patients developed second tumors in the first group and eight of them died, no second tumors were detected in the second group. The median follow-up was 11.7 years and 8.1 years, respectively. Similar observations with an even longer follow-up were made by the Yale group.36 In the randomized study from Milan, comparing ABVD x 4 followed by sub-total lymphoid irradiation to ABVD x 4 followed by only IFRT, three patients developed second cancers after sub-total lymphoid irradiation and no second cancers were detected after IFRT. Median follow-up was 10 years.16 The GHSG also compared IFRT with a larger field RT (both with same chemotherapy). In the short follow-up of 54 months, the frequency of second cancer was 2.8% and 4.5%, respectively.19 This is an encouraging trend that may become statistically significant with more follow-up. Implying that risk rates related to past radical radiotherapy are relevant to current reduced RT is potentially misleading and unnecessarily alarming to the patient. Full disclosure and a more balanced discussion of the established current treatment standards should be encouraged. Substituting Radiation With More Chemotherapy: What Is At Stake? Studies have shown that it is possible to compensate for the benefit derived from adding radiation by using longer and more intense chemotherapy. But intensive and/or longer chemotherapy carries a high price, often unjustified. The intergroup MOPP/ABV hybrid (with no RT) trial was closed early because of high risk of acute and delayed toxicity (leukemia and lung cancers),27 escalated BEACOPP displayed a high risk of etoposide-related leukemia,35 and when gemcitabine was added to ABV or BEACOPP, unacceptable toxic mortality was reported.37,38 Six or eight cycles of ABVD carry more risk of bleomycin pulmonary toxicity than only two or four cycles used safely and effectively in a combined modality program.39 Furthermore, we are still in need of reassuring long-term follow-up data from series of patients treated with chemotherapy alone: these data hardly exist. It took more than two decades and careful follow-up of thousands of HL survivors treated with radiation alone or with combined modality to learn about risks of second solid tumors and cardiac morbidity. Replacing the small RT component of a mild combined modality program with more chemotherapy carries risks of known, and yet unknown complications. It shifts the therapeutic ratio in the wrong direction. We should strive to improve the safety of our effective treatments for HL, but singling radiotherapy as the source of all morbidity and replacing it with potentially worse or yet untested alternatives is taking the wrong route or throwing out the baby with the bathwater. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Author Contributions
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Kaplan H: The radical radiotherapy of Hodgkin's disease. Radiology 78:553-561, 1962[Medline] 10. DeVita V, Serpick A, Carbone P: Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med 73:881-895, 1970[Medline] 11. Travis LB, Gospodarowicz M, Curtis RE, et al: Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst 94:182-192, 2002 12. van Leeuwen FE, Klokman WJ, Stovall M, et al: Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst 95:971-980, 2003 13. Ng AK, Bernardo MP, Weller E, et al: Long-term survival and competing causes of death in patients with early-stage Hodgkin's disease treated at age 50 or younger. J Clin Oncol 20:2101-2108, 2002 14. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992[Abstract] 15. Press OW, LeBlanc M, Lichter AS, et al: Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin's disease. J Clin Oncol 19:4238-4244, 2001 16. Bonadonna G, Bonfante V, Viviani S, et al: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: Long-term results. J Clin Oncol 22:2835-2841, 2004 17. Loeffler M, Diehl V, Pfreundschuh M, et al: Dose-response relationship of complementary radiotherapy following four cycles of combination chemotherapy in intermediate-stage Hodgkin's disease. J Clin Oncol 15:2275-2287, 1997 18. Diehl V, Brillant C, Engert A, et al: HD10: Investigating reduction of combined modality treatment intensity in early stage Hodgkin's lymphoma. Interim analysis of a randomized trial of the German Hodgkin Study Group (GHSG). J Clin Oncol 23: 561s, 2005 (supp 1; abstr 6506) 19. Engert A, Schiller P, Josting A, et al: Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: Results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 21:3601-3608, 2003 20. Ferme C, Eghbali H, Hagenbeek A, et al: MOPP/ABV hybrid and irradiation in unfavorable supradiaphragmatic clinical stages I-II Hodgkin's disease: Comparison of three treatment modalities. Preliminary results of the EORTC-GELA H8-U randomized trial in 995 patients. Blood 96:A576, 2000 21. Eghbali H, Brice P, Creemers G-Y, et al: Comparison of three radiation dose levels after EBVP regimen in favorable supradiaphragmatic clinical stages (CS) I-II Hodgkin’s Lymphoma (HL): Preliminary results of the EORTC-GELA H9-F trial. Blood106:240a, 2005 (abstr 814) 22. 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Nachman JB, Sposto R, Herzog P, et al: Randomized comparison of lowdose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20:3765-3771, 2002 26. Aleman BM, Raemaekers JM, Tirelli U, et al: Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med 348:2396-2406, 2003 27. Duggan DB, Petroni GR, Johnson JL, et al: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: Report of an intergroup trial. J Clin Oncol 21:607-614, 2003 28. Yahalom J, Mauch P: The involved field is back: Issues in delineating the radiation field in Hodgkin's disease. Ann Oncol 13:79-83, 2002 (suppl 1)[Abstract] 29. Yahalom J: Breast cancer after Hodgkin disease: Hope for a safer cure. JAMA 290:529-531, 2003 30. Goodman KA, Toner S, Hunt M, et al: Intensity modulated radiation therapy in the treatment of lymphoma involving the mediastinum. Int J Radiat Oncol Biol Phys 62:198-206, 2005[Medline] 31. Girinsky T, Pichenot C, Beaudre A, et al: Is intensity-modulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy for mediastinal masses in patients with Hodgkin's disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes? Int J Radiat Oncol Biol Phys 64:218-226, 2005[Medline] 32. Travis LB, Hill DA, Dores GM, et al: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290:465-475, 2003 33. Kuttesch JF Jr, Wexler LH, Marcus RB, et al: Second malignancies after Ewing's sarcoma: Radiation dose-dependency of secondary sarcomas. J Clin Oncol 14:2818-2825, 1996 34. Lorigan P, Radford J, Howell A, et al: Lung cancer after treatment for Hodgkin's lymphoma: A systematic review. Lancet Oncol 6:773-779, 2005[CrossRef][Medline] 35. Josting A, Wiedenmann S, Franklin J, et al: Secondary myeloid leukemia and myelodysplastic syndromes in patients treated for Hodgkin's disease: A report from the German Hodgkin's Lymphoma Study Group. J Clin Oncol 21:3440-3446, 2003 36. Salloum E, Doria R, Schubert W, et al: Second solid tumors in patients with Hodgkin's disease cured after radiation or chemotherapy plus adjuvant low-dose radiation. J Clin Oncol 14:2435-2443, 1996[Abstract] 37. Friedberg JW, Neuberg D, Kim H, et al: Gemcitabine added to doxorubicin, bleomycin, and vinblastine for the treatment of de novo Hodgkin disease: Unacceptable acute pulmonary toxicity. Cancer 98:978-982, 2003[CrossRef][Medline] 38. Bredenfeld H, Franklin J, Nogova L, et al: Severe pulmonary toxicity in patients with advanced-stage Hodgkin's disease treated with a modified bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine (BEACOPP) regimen is probably related to the combination of gemcitabine and bleomycin: A report of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 22:2424-2429, 2004 39. Martin WG, Ristow KM, Habermann TM, et al: Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma. J Clin Oncol 23:7614-7620, 2005 zlj-044396.xml Related Article
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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