Commentary (Connors)-Hodgkin's Disease: Management of First Relapse

The management of Hodgkin's disease presents the clinician with several separate opportunities to intervene effectively. Not only is it possible to treat newly diagnosed patients with the knowledge that the majority will be cured, but also one can approach relapse with cautious optimism. Unlike most human neoplasms, Hodgkin's disease can be regularly cured even after relapse has occurred. The article by Drs. Yuen and Horning reviews available data on the outcome of treatment of first relapse of Hodgkin's disease, and summarizes the evidence indicating that relapsed disease can still be cured.

Drs. Yuen and Horning correctly indicate that patients who have relapsed after irradiation alone require a different treatment strategy and have a different prognosis than those who have relapsed after primary chemotherapy. They ably assemble and critique the available information on the outcome of treatment for these two differing populations, and note the difficulty posed by the small numbers of reports available and the small numbers of patients included in these reports. However, even while acknowledging these limitations, the authors are able to reach reasonable recommendations about the best approach to treating first relapse after irradiation and early relapse after primary chemotherapy. Their more tentative conclusions regarding late relapses after primary chemotherapy reflect the paucity of comparative data, and the authors appropriately leave the matter open. Given the thoroughness and balance of their review, are we clinicians fully equipped to know just what to do when treating Hodgkin's disease in first relapse? The answer is a qualified yes.

Which Matters Are Reasonably Well-Settled?

• Treatment of first relapse after irradiation should consist of the best available chemotherapy, usually a seven- or eight-drug program hybridizing MOPP (mechlorethamine, Oncovin, procarbazine, and prednisone ) and ABVD (Adriamycin, bleomycin, vinblastine, and dexamethasone) [1].
• Patients who experience a first relapse after primary chemotherapy that occurs less than 12 months after primary treatment or that is accompanied by such unfavorable characteristics as B symptoms at relapse or initial stage IV disease should receive high-dose chemotherapy, autologous hematopoietic stem-cell transplantation, and, in selected cases, involved-field irradiation.
• Late relapses after primary chemotherapy, even when not accompanied by other negative prognostic factors, should usually be approached with similar high-dose programs. The authors correctly indicate that we lack firm data to support this recommendation, but what we do have provides at least substantial encouragement.

Unsettled Issues

Several other questions remain unsettled, however, and do arise sufficiently often to deserve comment. First, what is the best approach when the patient with relapsed disease is elderly, infirm, or uncooperative, and thus, is not a candidate for high-dose therapy? Presumably, such patients should receive the most intensive treatment still within their tolerance and willingness to accept.

Second, in an era in which dose intensity is carefully attended to and supported by granulocyte colony-stimu- lating factors, and virtually all patients who receive chemotherapy are treated with ABVD or seven- or eight-drug hybridized regimens, it is less likely that patients who are not cured by their first chemotherapy will be cured by subsequent standard-dose regimens than it might have been in the past. This shift in primary treatment may make observations based on experience from only a few years ago irrelevant.

Finally, the paradigm investigated by Drs. Yuen and Horning may already be out of date. It divides Hodgkin's disease patients into two exclusive groups--those initially treated with radiotherapy alone and those given a prolonged course of chemotherapy. This now increasingly outdated paradigm is based on staging laparotomy. As many clinicians abandon staging laparotomy in favor of combined-modality treatment for early-stage disease, usually with either brief or low-toxicity chemotherapy plus limited-field irradiation [2-4], a new group of patients is emerging-namely, those who have received both chemotherapy and irradiation before their first relapse. The best treatment approach for these patients is currently undefined, although in the absence of applicable data, seven- or eight-drug hybrid chemotherapy regimens are probably the best choice.

Need to Increase Patient Enrollment in Clinical Trials

Drs. Yuen and Horning provide a useful overview of the treatment of Hodgkin's disease in first relapse. They have been hobbled by a lack of data directly applicable to current practice. It is remarkable that the literature to which they could turn is so limited, covering experience with about 1,300 patients. A reasonable estimate of the number of patients experiencing a first relapse of Hodgkin's disease annually in North America alone is 1,500. Combined with those patients managed in Europe and spanning the two decades summarized in their review, the available pool of patients in first relapse probably exceeded 60,000. Thus, in the past, we have entered fewer than 1 patient in 40 into eventually reported trials of treatment for first relapse of Hodgkin's disease. As Drs. Yuen and Horning rightly point out, there is an urgent need to do better in the future.

References:

1. Connors JM: Is cyclical chemotherapy better than standard four-drug chemotherapy for Hodgkin's disease? Yes, in DeVita VT, Hellman S, Rosenberg (eds): Important Advances in Oncology 1993, pp 189-196. Philadelphia, JB Lippincott, 1993.

2. Horning SJ, Hoppe RT, Hancock SL, et al: Vinblastine, bleomycin, and methotrexate: An effective adjuvant in favorable Hodgkin's disease. J Clin Oncol 6:1822-1831, 1988.

3. Klasa RJ, Connors J, Hoskins P, et al: Early stage Hodgkin's disease: Impact of brief chemotherapy together with radiotherapy without staging laparotomy (abstract). Proc Am Soc Clin Oncol 13:372, 1994.

4. Bonfante V, Santoro A, Viviani S, et al: ABVD plus radiotherapy (subtotal nodal vs involved field) in early-stage Hodgkin's disease (abstract). Proc Am Soc Clin Oncol 13:373, 1994.