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© 2002 American Society for Clinical Oncology
Reducing Treatment-Related Morbidity and Mortality in Early-Stage Hodgkin’s Disease and Why the Recent Southwest Oncology Group Trial Is Not the Way to GoDuke University Medical Center, Durham, NC For several decades patients with stage IA and IIA Hodgkin’s disease have enjoyed cure rates of 90% or greater after initial therapy with subtotal nodal irradiation (STLI).1-5 With this treatment, approximately 95% of patients will achieve complete response. Of those achieving complete response, approximately 80% will never relapse; 20% will relapse but most of these will be subsequently cured (salvaged) with combination chemotherapy (with or without additional radiotherapy). Thus, the overall cure rate of Hodgkin’s disease in IA and IIA patients is 90% or greater when the initial treatment strategy is STLI. This highly favorable outcome is tempered by the reality of long-term morbidity and mortality brought about by treatment. Radiation oncologists have been diligent regarding long-term follow-up of these patients and reporting of the data and complications observed. Valuable and sobering knowledge has thus been gained. The thesis of this editorial is that research should be focused on developing less toxic therapies (particularly less long-term toxicity) that preserve the high cure rates accomplished with full-dose large-field radiation. There are three major complication issues, two associated with the radiotherapy and one with staging laparotomy which had been performed in most of the patients in the above referenced series. A brief word about staging laparotomy: the procedure was introduced in the 1960s at Stanford University and elsewhere.6-9 Its purpose was the detection of occult disease in the abdomen; if found, either radiotherapy fields were enlarged or chemotherapy was added to the treatment program or both. Approximately 25% to 30% of patients who were stage I or IIA after complete clinical staging had abdominal disease after laparotomy, such disease being mostly in the spleen, leading to continuing enthusiasm for this procedure for some years. Its decline/demise resulted from the following three factors: (1) increasing confidence in the ability of chemotherapy to eradicate occult abdominal disease or to salvage relapsing patients10-12; (2) the probability that STLI encompassing the spleen and para-aortic lymph nodes as well as the mantle field would eradicate occult disease in the spleen and upper abdominal nodes2; and (3) the morbidity and mortality of staging laparotomy.13-15 Mortality is estimated at 1% to 2%.13 It derives primarily from late sepsis in splenectomized patients but also includes the small amount of acute mortality deriving from any major abdominal surgery. Overwhelming sepsis in splenectomized patients is only partially prevented by the use of vaccine such as Pneumovax (Merck & Co., West Point, PA) or Haemophilus influenzae.16,17 There are additionally the problems of nonfatal severe sepsis, intestinal obstruction secondary to adhesions from the surgery, wound infections, and other complications common to major abdominal surgery. All of the above, but particularly the ability of chemotherapy to eradicate occult disease, has combined to markedly decrease the use of staging laparotomy. Of much more significance are the two major long-term problems associated with radiotherapy in these patients, namely second malignancies and heart disease. Both of these topics have been written about at length and are the subject of a number of excellent reviews,18-27 so I will only summarize them briefly. The carcinogenic potential of radiotherapy has been well known for decades. In Hodgkin’s disease patients treated with STLI in which large volumes received significant doses, the long-term frequency of a second malignancy has been alarming. The actuarial frequency is estimated at approximately 1% per year with no sign as yet of a plateau in this rate. The relative risk is estimated as ranging from 2 to 6. The risk may be worse in younger patients, particularly for the development of breast cancer.28 The relationship of radiotherapy dose to carcinogenesis is complex.29 There tends to be a linear increase with dose up to a certain level (approximately 20 to 30 Gy). The incidence of malignancies then plateaus and may even decrease with a higher dose, at least in experimental systems. In humans, this is less well defined and may vary with the type of tumor under consideration. For example, sarcoma induction seems to require a higher dose than adenocarcinoma or squamous cell carcinoma.30 Increased volume of normal tissue irradiated almost certainly leads to an increased frequency of second malignancies. Our experience with low-dose involved-field radiotherapy in combination with multiagent chemotherapy showed no increased risk of a second malignancy with a follow-up to 25 years.31 The explanation is uncertain. A decrease in prescribed radiotherapy dose reduces not only the primary beam dose but also scattered dose. The latter may affect a large volume of tissue and may be as important as the primary beam in secondary carcinogenesis. Thus, although reducing the prescribed primary beam dose from 40 to 20 Gy might theoretically not change the frequency of second malignancies, the accompanying scattered dose reduction from approximately 5 to 10 Gy to approximately 2.5 to 5 Gy might be very significant. Our hypothesis is that low-dose limited-field radiotherapy will be less carcinogenic than conventional-dose large-field radiotherapy (ie, STLI). Late effects of radiotherapy on the heart primarily include coronary artery disease and pericarditis.21 The relative risk is approximately 4 for any cardiac disease in radiated patients. Cardiac complications are clearly dose related; the more dose, the higher the frequency. In the Stanford series, few adverse cardiac effects were seen below 40 Gy, but in our personal experience, myocardial infarctions, both fatal and nonfatal, have been encountered in the range of 35 to 40 Gy. Radiation pericarditis is encountered much less frequently now with better field shaping, left ventricular blocking, and reduction in the dose from 44 to 40 Gy or less. Coronary artery disease, however, remains a concern, because the coronary arteries are still included in the usual mantle or modified mantle field, even with field shaping and blocking of a portion of the left ventricle. With these issues in mind, consider now the recently published Southwest Oncology Group trial of STLI with or without chemotherapy32 and others of similar design. The rationale for this trial, according to the authors, was to modify the treatment of early-stage Hodgkin’s disease by the introduction of combination chemotherapy and omission of staging laparotomy to decrease long-term morbidity and mortality. It is highly unlikely that improvement in the cure rate of Hodgkin’s disease would ever be demonstrated, given the already high cure rate of greater than 90% with STLI alone. A survival advantage might be demonstrated if long-term treatment–related deaths were reduced in one arm. The Southwest Oncology Group trial design was a phase III study. Eligible patients included those with clinical stage IA and IIA disease. Staging laparotomy was not performed in either arm. Patients were randomized to receive chemotherapy with doxorubicin and vinblastine or none. This was followed by STLI to a dose of 36 to 40 Gy in both arms irrespective of the response to chemotherapy. The outcome of this trial, unfortunately, was predictable. A survival benefit for the combined-modality therapy arm was not apparent with short follow-up and is unlikely with longer follow-up, given the already high survival of patients treated with radiotherapy alone. Although a benefit in failure-free survival was seen, this has been observed in several other studies as well, usually without translation into a long-term survival benefit because of the ability of combination chemotherapy to effectively salvage patients who relapse with Hodgkin’s disease after initial radiation treatment.12,33 Long-term toxicity data are not yet available. There will obviously be no toxicity from staging laparotomy. There can be no reduction in second malignancies or adverse cardiac events, however, because chemotherapy has been added to full-dose extended-field radiotherapy. The latter is the same in both arms. (A possible exception is if chemotherapy shrinks tumor masses, such as in the mediastinum, allowing for a reduced radiotherapy volume.) The important message, I believe, is this: if the goal for treating early-stage Hodgkin’s disease is reduced treatment toxicity and maintenance of high cure rates, multiagent chemotherapy should not be combined with full-dose and field radiotherapy. This cannot reduce toxicity. A more appropriate program is, perhaps, a limited number of cycles (four) of a known effective combination such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), combined with reduced-dose involved-field radiation, usually a modified mantle (eliminating the axillary areas from the field reduces the breast dose considerably, an obviously important consideration in young women, as well as scattered lung dose). Because much of the long-term radiotherapy toxicity is from the mantle field (eg, cardiovascular, breast cancer, and hypothyroidism), full-dose mantle radiotherapy in conjunction with four cycles of ABVD is also not an optimal strategy. Reduction in radiotherapy toxicity is likely to require a lower dose as well as a decrease in volumes treated. For many years we have argued that doses of radiation can be reduced in the presence of effective chemotherapy.34 That has been demonstrated repeatedly in a number of solid tumors such as carcinoma of the head and neck,35 esophagus,36 and anus.36 Studies in pediatric Hodgkin’s disease have long joined combination chemotherapy with low-dose radiation in all disease stages with excellent local control and survival reported.37-39 Phase III trials in adult Hodgkin’s disease now confirm the efficacy of 20 Gy versus 40 Gy combined with chemotherapy for local control and survival.40 Phase II studies in diffuse large B-cell lymphoma suggest chemotherapy followed by 30 Gy is as effective as larger doses of radiation,41 although there is not universal agreement on this conclusion.42 Radiation dose reduction should nonetheless be strongly considered when combining chemotherapy and radiation in lymphomas when there has been an excellent response to the former. It is an assumption that radiation doses can be reduced in combination with four cycles of ABVD as opposed to six, but probably valid. Confirmatory phase III trials are in progress. In conclusion, the reduction of treatment-induced morbidity and mortality in Hodgkin’s disease patients with maintenance of high cure rates is a very important goal. Strategies to do so, however, must be quite carefully chosen to stand a reasonable chance of success. Additionally, the long-term consequences of chemotherapy (beyond 10 years) remain uncharted territory requiring careful follow-up of these patients, probably over their lifetimes. REFERENCES 1. Cosset JM, Mauch PM: The role of radiotherapy for early stage Hodgkin’s disease: limitations and perspectives. Ann Oncol 9: S57-S62, 1998 (suppl 5) 2. Gospodarowicz MK, Sutcliffe SB, Bergsagel DE, et al: Radiation therapy in clinical stage I and II Hodgkin’s disease: The Princess Margaret Hospital Lymphoma Group. Eur J Cancer 28A: 1841-1846, 1992[CrossRef] 3. Hoppe RT: Radiation therapy in the management of Hodgkin’s disease. Semin Oncol 17: 704-715, 1990[Medline]
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Mauch P, Tarbell N, Weinstein H, et al: Stage IA and IIA supradiaphragmatic Hodgkin’s disease: Prognostic factors in surgically staged patients treated with mantle and paraaortic irradiation. J Clin Oncol 6: 1576-1583, 1988 5. Mendenhall NP: The role of radiation in the management of Hodgkin’s disease: An update. Cancer Invest 17: 47-55, 1999[Medline] 6. Glatstein E, Guernsey JM, Rosenberg SA, et al: The value of laparotomy and splenectomy in the staging of Hodgkin’s disease. Cancer 24: 709-718, 1969[CrossRef][Medline] 7. Leibenhaut MH, Hoppe RT, Efron B, et al: Prognostic indicators of laparotomy findings in clinical stage I-II supradiaphragmatic Hodgkin’s disease. J Clin Oncol 7: 81-91, 1989[Abstract] 8. Mauch P, Larson D, Osteen R, et al: Prognostic factors for positive surgical staging in patients with Hodgkin’s disease. J Clin Oncol 8: 257-265, 1990[Abstract] 9. Prosnitz LR, Nuland SB, Kligerman MM: Role of laparotomy and splenectomy in the management of Hodgkin’s disease. Cancer 29: 44-50, 1972[CrossRef][Medline] 10. Bonadonna G, Valagussa P: Influence of clinical trials on current treatment strategy for Hodgkin’s disease. Int J Radiat Oncol Biol Phys 19: 209-218, 1990[Medline]
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Rosenberg SA: The management of Hodgkin’s disease: Half a century of change—The Kaplan Memorial Lecture. Ann Oncol 7: 555-560, 1996 13. Jockovich M, Mendenhall NP, Sombeck MD, et al: Long-term complications of laparotomy in Hodgkin’s disease. Ann Surg 219:615-621; discussion 621-624, 1994 14. Morris DM, Coleman JJ, Slawson RG, et al: Effect of postoperative radiotherapy on the development of small bowel obstruction in patients undergoing staging laparotomy for Hodgkin’s disease. Am J Clin Oncol 8: 463-467, 1985[Medline] 15. Cosset JM, Henry-Amar M, Burgers JM, et al: Late radiation injuries of the gastrointestinal tract in the H2 and H5 EORTC Hodgkin’s disease trials: Emphasis on the role of exploratory laparotomy and fractionation. Radiother Oncol 13: 61-68, 1988[CrossRef][Medline]
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Molrine DC, George S, Tarbell N, et al: Antibody responses to polysaccharide and polysaccharide-conjugate vaccines after treatment of Hodgkin disease. Ann Intern Med 123: 828-834, 1995 17. Siber GR, Gorham C, Martin P, et al: Antibody response to pretreatment immunization and post-treatment boosting with bacterial polysaccharide vaccines in patients with Hodgkin’s disease. Ann Intern Med 104: 467-475, 1986 18. Boivin JF, Hutchison GB, Lubin JH, et al: Coronary artery disease mortality in patients treated for Hodgkin’s disease. Cancer 69: 1241-1247, 1992[Medline]
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Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol 11: 1208-1215, 1993 22. Hancock SL, Hoppe RT: Long-term complications of treatment and causes of mortality after Hodgkin’s disease. Semin Radiat Oncol 6: 225-242, 1996[CrossRef][Medline] 23. Kaldor JM, Day NE, Band P, et al: Second malignancies following testicular cancer, ovarian cancer and Hodgkin’s disease: An international collaborative study among cancer registries. Int J Cancer 39: 571-585, 1987[Medline] 24. Mauch PM, Kalish LA, Marcus KC, et al: Long-term survival in Hodgkin’s disease. Cancer J Sci Am 1: 33-42, 1995[Medline]
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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 33. Cosset JM, Henry-Amar M, Meerwaldt JH, et al: The EORTC trials for limited stage Hodgkin’s disease: The EORTC Lymphoma Cooperative Group. Eur J Cancer 28A: 1847-1850, 1992[CrossRef] 34. Prosnitz LR, Farber LR, Kapp DS, et al: Combined modality therapy for advanced Hodgkin’s disease: 15-year follow-up data. J Clin Oncol 6: 603-612, 1988[Abstract] 35. Brizel DM: Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma. Semin Radiat Oncol 8: 237-246, 1998[CrossRef][Medline]
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Shenkier TN, Voss N, Fairey R, et al: Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: An 18-year experience from the British Columbia Cancer Agency. J Clin Oncol 20: 197-204, 2002 42. Wilder RB, Tucker SL, Ha CS, et al: Dose-response analysis for radiotherapy delivered to patients with intermediate-grade and large-cell immunoblastic lymphomas that have completely responded to CHOP-based induction chemotherapy. Int J Radiat Oncol Biol Phys 49: 17-22, 2001[CrossRef][Medline] This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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