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Originally published as JCO Early Release 10.1200/JCO.2008.19.0330 on October 14 2008 © 2008 American Society of Clinical Oncology.
Treatment of Stage IIIa Hodgkin's Disease: Long Follow-Up Perspective
Department of Medical Oncology, St Bartholomew's Hospital, London, United Kingdom Meticulous attention to detail, clinical research, and a degree of therapeutic empiricism set the stage for the spectacular improvements generated in the long-term outcome of Hodgkin's disease in the 1960s and 1970s.1-7 The results below are a reflection of this, documenting the commitment of the generation of academic physicians pioneering hematologic oncology 40 years ago. At the time, management was based on the Ann Arbor Staging Classification8 based on the presumed anatomic spread of the disease,9 the outcome potential of megavoltage irradiation, and the assumption that systemic chemotherapy was substantially more toxic—and as yet—unproven in efficacy, hence reserved for advanced disease. It was generally accepted that disease localized to one side of the diaphragm should be treated with irradiation, at least to a mantle or inverted Y field, that advanced and symptomatic disease be treated with cyclical combination chemotherapy, and that asymptomatic nodal disease on both sides of the diaphragm (stage IIIA) receive either total nodal irradiation, chemotherapy, or both. Over time, it became clear that bulky disease and multiple nodal sites were poor prognostic factors, and combined chemoradiotherapy became the treatment of choice for those in whom they were identified. By 1974, at least at St. Bartholomew's Hospital, 40% of patients with stage II disease were being treated this way. The article above reported interim data on a subset of patients, all identified as having pathologic stage IIIA disease on the basis of Ann Arbor Classification, including staging laparotomy, representing approximately 20% of the patients seen during the period in question. In 2008, more than a quarter of a century after the first patient was treated, none have been lost to follow-up. Forty percent are alive in first remission, presumed cured, with an additional 13% currently disease-free in a second remission for more than 3 years. The outcome was the same for both substages (IIIA1, IIIA2) and both combination chemotherapy and total nodal irradiation. This extraordinary improvement over the natural history of the disease, achieved over a short time, is only marred by a less-than-satisfactory overall survival pattern due, at least in part, to late toxicity.
These data mirror the overall outcome of therapy seen in the newly diagnosed population of patients treated at St. Bartholomew's Hospital from 1968 to 1985,10 only 12 having been lost to follow-up. Based on the Ann Arbor Stage, 526 adults were treated with mantle or inverted Y irradiation, combination chemotherapy with mustine, vinblastine, prednisolone, and procarbazine, or combined modality treatment with 55% undergoing laparotomy. The management at recurrence depended on the circumstances, but only included myeloablative chemotherapy in 9 patients. With only 12 lost to follow-up, 49% are alive, 39% in first remission for a minimum of 23 years, and an additional 10% have been in second or subsequent remission for at least 5 years. Twenty percent have died of Hodgkin's disease and 31% have died resulting from other causes (including second malignancy 9%, cardiac event 9%; Table 1; Fig 1). Age and stage were highly statistically significant prognostic factors (P = .001 and P = .001, respectively; Fig 2, Fig 3). Within stage III, both the absence of B symptoms (P
In 2008, both investigation of the patient with Hodgkin's disease and the treatment are substantially different, and better. Lymphography has been replaced by computed axial tomography, to the enormous benefit of the patient in terms of comfort. Laparotomy has become redundant both through the identification of surrogate markers of extensive disease obviating the need for diagnostic splenectomy and lymph node mapping,11 and the increasing use of combined modality therapy, which obviates the necessity for demonstrating limited anatomic spread. The most recent addition to the imaging armamentarium, [18F]fluorodeoxyglucose–positron emission tomography (PET), although of relatively limited additional value in pretreatment staging for most patients (except possibly to identify those with erstwhile PSIIIA disease by virtue of splenic involvement) is likely to play a major role in the rational individualization of therapy on the basis of midtherapy imaging. In terms of therapeutic strategy, there has been a strong trend away from extended field irradiation in favor of either limited chemotherapy and limited irradiation or, whenever possible, chemotherapy alone because of increasing concerns about late second malignancy consequent on irradiation. The attraction of this approach has been increased by the demonstration that doxorubicin, vinblastine, bleomycin, and procarbazine12 is more efficacious13,14 and less likely to cause infertility or second malignancy than alkylating agent-based chemotherapy. Overall treatment has become markedly better with huge improvements in antiemetics and supportive care. With the current strategy of employing ABVD as conventional first-line chemotherapy, the challenge still remains to cure the 20% to 25% of patients for whom initial therapy fails. There is compelling evidence that more intensive therapy has both greater efficacy and greater toxicity, particularly infertility and second malignancy.15 With respect to early-stage disease, it is increasingly clear that irradiation may be omitted for the majority and that PET scanning is likely to be a powerful predictor of the need for additional therapy after standard treatment has been prescribed. Similarly, for those with advanced disease, PET scanning after two cycles is highly predictive of the outcome of a planned six cycles of therapy. It is probable that this early midtherapy prognostication and therapy informing investigation will be of more practical use than a pretreatment decision based on pretreatment clinical features. Philosophical questions remain. In patients who may be at reasonably high risk of treatment failure, should the initial therapy be ABVD, which may be escalated on the basis of persistent PET positivity after two cycles, or should it be intensive (eg, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisolone, and procarbazine) in the first instance, and de-escalated on the basis of a negative PET scan? How risky is early undertreatment of approximately 20% patients (hard to identify), compared with early partial overtreatment of 80%? In the new era, how will salvage therapy succeed? Is the cup half full or half empty? Large international trials are being planned to answer these questions. Phenomenal improvements have been made in the treatment of Hodgkin's disease, such that the design of trials to demonstrate additional improvement is difficult. This fact notwithstanding, even our best current therapies are most unpleasant: we must seek to do better. However, by the time of the 50th birthday of Journal of Clinical Oncology, it will be known whether the advances in the therapy of Hodgkin's disease currently being investigated will be as significant as those introduced in the second half of the last century. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS I thank many of the previous staff at St Bartholomew's Hospital for their leadership and contributions to the care of the patients and the generation of the data, particularly Sir Ronald Bodley Scott, Gordon Hamilton Fairley, Derek Crowther, Peter Wrigley, Arthur Jones, Michael Whitehouse, James Malpas, Simon Sutcliffe, Adrian Timothy, Mark Dorreen, Amit Oza, and Trivadi Ganesan. George Canellos gave kind advice. NOTES published online ahead of print atwww.jco.org on October 13, 2008 REFERENCES 1. Gilbert R: Radiotherapy in Hodgkin's disease (malignant granulomatosis); anatomic and clinical foundations; governing principles; results. AJR Am J Roentgenol 41:198-241, 1939 2. Peters MV: Prophylactic treatment of adjacent areas in Hodgkin's disease. Cancer Res 26:1232-1243, 1966 3. Kaplan HS: The radical radiotherapy of regionally localised Hodgkin's Disease. Radiology 78:553-561, 1962[Medline] 4. Easson EC: Long term results of radical radiotherapy in Hodgkin's disease. Cancer Res 26:1244-1249, 1966 5. DeVita VT Jr, Serpick AA, Carbone PP: Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med 73:881-895, 1970 6. DeVita VT Jr, Simon RM, Hubbard SM, et al: Curability of advanced Hodgkin's Disease with chemotherapy. Ann Intern Med 92:587-595, 1980 7. Sutcliffe SB, Wrigley PF, Peto J, et al: MVPP chemotherapy regimen for advanced Hodgkin's disease. BMJ 1:679, 1978 8. Rosenberg SA: Report of the Committee on the Staging of Hodgkin's Disease. Cancer Res 26:1310, 1966 9. Rosenberg SA, Kaplan HS: Evidence for an orderly progression in the spread of Hodgkin's Disease. Cancer Res 26:1225-1231, 1966 10. Ward R, Wilson A, Plowman N, et al: Efficacy and toxicity of treatment of Hodgkin's Disease: Mature data from a single centre. Haematologia (Budap) 99:26, 2007 (suppl) 11. Tubiana M, Henry-Amar M, Carde P, et al: Towards comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease. The EORTC Lymphoma Group controlled clinical trials: 1964-1987. Blood 73:47-56, 1989 12. Bonadonna G, Zucali R, Montfardini S, et al: Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine and imidazole carboxamine versus MOPP. Cancer 36:252-259, 1975[CrossRef][Medline] 13. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advance Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992[Abstract] 14. Canellos GP, Niedzwiecki D: Long term follow-up of Hodgkin's Disease trial. N Engl J Med 346:1417-1418, 2002 15. Diehl V, Franklin J, Pfreundschuh M, et al: Standard and increased dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 348:2386-2395, 2003
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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.01) and laparotomy staging (P < .01).were favorable factors. 
