Hodgkin’s Disease: the Management of “Favorable” Early Stage Disease with Combined Modality Therapy

A major alternative to the use of radiation therapy alone for early stage Hodgkin's disease is combined modality therapy. The concept of combined modality therapy for early stage disease predates the modern combination chemotherapy era by more than a decade. In 1957, Brown and Kaplan wrote: "In October 1953 a new specific program of treatment was inaugurated by one of us (HSK). This consists of the administration of 0.4 mg/kg nitrogen mustard intravenously, in combination with intensive irradiation to the region of involvement. . . . The rationale for the concurrent use of nitrogen mustard in these localized cases is that it might simultaneously control microscopic, clinically undetectable deposits elsewhere and potentiate the effect of radiation locally. The infrequency with which localized cases of Hodgkin's disease occur even in large institutions suggests the need for cooperative studies in which several therapy centers establish comparative treatment series to which patients are assigned at random after clinical evaluation and staging according to a preagreed classification."¹ The litmus test of the concept awaited the introduction of effective combination chemotherapy for Hodgkin's disease, the nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) combination as first reported by Frei and associates in 1966.²

Early studies of combined modality therapy, largely conducted in the 1970s, combined a full course (six months) of MOPP or MOPP-like chemotherapy with high dose involved or extended field irradiation. In general, the conclusions were that, if patients with unfavorable characteristics (eg, large mediastinal masses) were excluded, combined modality programs showed a superior event-free but similar overall survival compared to programs utilizing radiation therapy alone. This observation has been confirmed in a recent meta-analysis of these trials.³ In the absence of a demonstrable survival advantage, combined modality treatment of early stage disease seemed inappropriate at that time, since all patients were being exposed to the toxicities of the combined modalities, including chemotherapy-related sterility and risk for leukemia. Equivalent results could be achieved by using combination chemotherapy as a salvage regimen for the 20% to 25% of patients who relapsed after primary irradiation.

Two factors led to a change in this perception. One was the development of an effective combination chemotherapy regimen (adriamycin, bleomycin, vinblastine, and dacarbazine or ABVD) that was not associated with leukemia or sterility. The other was a growing awareness of radiation-related complications that were appearing only 15 or more years after exposure, including secondary solid tumors and cardiac disease. The absolute risk for developing secondary solid tumors after radiation is 53 per 10,000 patient years (a 5.3% risk per decade, ignoring changes in risk with time).⁴ The relative risk of death from heart disease is 3.1 among patients treated for Hodgkin's disease with mediastinal radiation doses greater than 30 Gy.⁴ Potentially, the risk for both of these serious complications could be reduced by reducing radiation fields and doses, which could be safely accomplished by the use of ABVD or similar chemotherapy.

Thus, the thrust of subsequent trials of combined modality therapy in early stage Hodgkin's disease was to find an optimal combination of chemotherapy and irradiation that limited the risk for long-term toxicity of both modalities without compromising curability. The important variables to be considered included the sequence of therapies, choice of drugs, duration of chemotherapy, extent of radiation fields, and radiation doses.

With respect to sequence, it is always appropriate to initiate treatment with chemotherapy. This has the advantage of treating all sites, including microscopic disease, from the outset. In addition, the reduction of disease that occurs with chemotherapy permits the treatment of smaller radiation volumes. This is especially important with respect to mediastinal disease, since it allows reduction of the lung volume included in the subsequent radiation fields.

The choice of drugs should be based upon efficacy and toxicity. Issues of toxicity relate to selection of drugs and total dosages. For example, nitrogen mustard may be associated with sterility when utilized in the same doses as in MOPP, but the risk may be acceptable when lower doses are employed.

Regarding irradiation fields, when adequate chemotherapy is employed to eradicate microscopic disease, the radiation fields may be limited to the involved regions. This question has been addressed in two clinical trials. At the National Cancer Institute in Milan, 133 patients with CSI-IIA Hodgkin's disease were treated with four cycles of ABVD chemotherapy. Subsequent radiation treatment was randomized between involved and extended fields.⁵ The five-year freedom from progression rate (93% versus 96% with subtotal nodal irradiation or STNI) and overall survival (96% versus 100%) were similar in the two groups. The second trial was by the German Hodgkin's Study Group (GHSG). Its HD8 trial randomized 685 patients to involved or extended field irradiation after four months (two double cycles) of COPP(cyclophosphamide, vincristine, procarbazine, and prednisone)/ABVD.⁶ With a median observation period greater than two years, there was no difference in freedom from treatment failure or overall survival in the two treatment groups

The issue of radiation dose also has been addressed in clinical trials. In the GHSG HD1 and HD5 trials, patients with stage I-IIIA disease received 20, 30, or 40 Gy to non-bulky or uninvolved sites following two double cycles of COPP/ABVD.⁷ Bulky sites (>7.5 cm) always received 40 Gy. There was no difference in outcome for the three different doses.

Current clinical trials for combined modality therapy in favorable prognosis Hodgkin's disease attempt to define the least amount of chemotherapy and irradiation to achieve reliable cure rates.⁸ The EORTC H9 trial employs six months of a "mild" chemotherapy, EBVP I (epirubicin, bleomycin, vinblastine, and prednisone), and randomizes between 20 and 36 Gy involved field. The GHSG HD10 trial includes a double randomization: two versus four cycles of ABVD and 20 versus 30 Gy involved field irradiation. In a pilot study at Stanford, patients are treated with eight weeks of Stanford V chemotherapy followed by 30 Gy involved field irradiation.⁹ Long-term assessment of outcomes and toxicity will be required to define the best regimen for the majority of patients.

Published May 2000