Dose-response relationship of complementary radiotherapy following four cycles of combination chemotherapy in intermediate-stage Hodgkin's disease.

PURPOSE: To determine the appropriate irradiation dose after four cycles of modern combination chemotherapy in nonbulky involved field (IF/BF) and noninvolved extended-field (EF/IF) sites in patients with intermediate-stage Hodgkin's disease (HD). MATERIALS AND METHODS: HD patients in stage I to IIIA with a large mediastinal mass, E stage, or massive spleen involvement were treated with two double cycles of alternating cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) plus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by EF irradiation in two successive trials (HD1 and HD5). In the HD1 trial (1983 to 1988), 146 patients who responded to chemotherapy were randomized to receive 20 Gy (70 patients) or 40 Gy (76 patients) of EF irradiation in all fields outside bulky disease sites. A cohort of 111 patients who fulfilled the same inclusion criteria in the subsequent trial HD5 (1988 to 1993) were treated with 30 Gy. Bulky disease always received 40 Gy. RESULTS: Freedom-from-treatment-failure (FFTF) and survival (SV) curves showed no differences between the 20-, 30-, and 40-Gy groups. However, acute toxicities were more frequent in the 40-Gy arm. Analysis of relapse patterns showed that 18 of 26 relapsing patients either failed to respond in initial bulky sites (n = 5) or had an extranodal relapse (n = 9) or both (n = 4). After 5 years, the cumulative risk for relapse in bulky sites is 10%, despite 40 Gy of radiation. CONCLUSION: Our results strongly suggest that there is no relevant radiotherapy dose effect in the range between 20 Gy and 40 Gy in IF/BF and EF/IF after 4 months of modern polychemotherapy in patients with intermediate-stage HD. Relapse patterns indicate that patients destined to relapse need more systemic, rather than local, treatment. Based on our data, we conclude that 20 Gy is sufficient in EF/IF of intermediate-stage HD following four cycles of modern polychemotherapy.

Prognosis of high dose chemotherapy/autologous bone marrow transplantation candidates not receiving this treatment after failure of primary therapy of Hodgkin's disease.

In a multicenter study on the therapy of Hodgkin's disease, in 88 out of 297 patients with primary advanced stages IIIB/IV, a failure to the treatment with the alternating chemotherapy COPP/ABVD +/- radiation was recorded. The cause of failure was as follows: tumor progression under current therapy (PD) 23/88, partial response at the end of therapy (PR) 28/88, early nodal relapses 13/88, late nodal relapses 16/88, extranodal relapses 7/88, undetermined localization 1/88.36 months after manifestation of the failure to treatment, 45% of all patients were still alive. In cases of primary PD the prognosis was the worst of all. Only 1/23 of these patients received a long-term continuous complete remission (cCR) with the salvage therapy. 11 patients with only a nodal relapse received a cCR with irradiation alone. These cases could be regarded as low risk relapses. For the high risk relapse group (n = 57) an indication for high dose chemotherapy with subsequent autologous bone marrow transplantation (HDC/ABMT) would have been imperative, following the present-day definition. The probability of survival of these patients who, however, only received a conventional salvage therapy was up to 38% (95% confidence interval 22-54%). Comparing these data with the literature our results seem not to be substantially worse than those for patients who underwent HDC/ABMT. Only in a randomized comparison can the decision be made on whether HDC/ABMT would be superior to high dose conventional chemotherapy supported by hematopoietic growth factors. It is suggested that such a therapy study be performed as soon as possible.

[Recurrence of Hodgkin's disease after advanced primary stages. German Hodgkin's Study Group]. / Morbus-Hodgkin-Rezidive nach primär fortgeschrittenen Stadien. Deutsche Hodgkin-Studiengruppe.

In a multicentre study on the treatment of Hodgkin's disease, 88 out of 297 patients with primary advanced stages IIIB/IV failed to respond to alternating COPP/ABVD chemotherapy +/- radiotherapy. They may be broken down as follows: tumour progression under current therapy (PD) 23/28, partial remission at the end of treatment (PR) 28/88, early nodal recurrence 13/88, late nodal recurrence 15/88, extranodal recurrence 7/88, unclear localisation 1/88. Thirty-six months after noting failure of treatment, 45% of all patients were still alive. The prognosis was poorest in the case of primary PD. Only 1/23 of these patients experience lasting complete remission thanks to salvage treatment (cCR). Eleven patients with an exclusively nodal recurrence experienced a cCR on treatment with radiation alone, and may be considered a low-risk recurrence group. For a high-risk recurrence group (n = 57), indication for high-dose chemotherapy with subsequent autologous bone marrow transplantation (HDC/ABMT) should have been recognized on the basis of the present definition. The survival probability of these patients, who only received conventional salvage treatment, was 38% after 30 months (95% confidence limit, 22 to 54%). These data would not appear to be appreciably poorer than those reported in the literature for comparable patients receiving HDC/ABMT. Only a randomized comparison would be capable of showing whether HDC/ABMT is superior to high-dose conventional chemotherapy with haematopoietic growth factors. It is proposed that such a therapeutic trial should be initiated as soon as possible.

Risk factor adapted treatment of Hodgkin's lymphoma: strategies and perspectives.

In a national multicenter trial in the Federal Republic of Germany, patients with Hodgkin's lymphoma in stages I, II and IIIA presenting with large mediastinal tumor (MT), extranodal (E), or massive spleen (S) involvement received a combined modality treatment with 2x (COPP + ABVD) followed by 20 or 40 Gy EF radiation (HD1 protocol). By October 1987, 89 patients aged 15-60 years had finished therapy and were evaluable for response. Of these 74 (83%) achieved complete remission (CR). After 3 years freedom from treatment failure (FFTF) is 80% (+/- 8%, 95% confidence interval) and survival (SV) 92% (+/- 6%, 95% confidence interval). In a univariate and multivariate analysis using FFTF as endpoint we could not identify any particularly prominent prognostic risk factor among the following examined: stage, constitutional symptoms, MT, E stage, S involvement, age, sex, histology, laparotomy, erythrocyte sedimentation rate (ESR), leukocytes, lymphocytes, and alkaline phosphatase (AP). These data suggest that the inclusion criteria have selected a fairly homogeneous group of patients with respect to prognosis. In a separate trial (HD3 protocol) patients in stages IIIB/IV received induction chemotherapy with 3x (COPP + ABVD). Patients in complete remission (CR) received consolidation therapy by either radiotherapy (20 Gy IF) or further chemotherapy (COPP + ABVD). Patients not in CR received salvage therapy (40Gy in the case of persisting nodal disease, or else 4x CEVD chemotherapy). By October 1987, 137 patients had finished therapy and were evaluable for response. Of these 86 (63%) achieved CR after induction chemotherapy. Including salvage therapy a total of 104 patients (76%) achieved CR. After 3 years FFTF is 56% (+/- 10%, 95% confidence interval) and SV 84% (+/- 8%, 95% confidence interval). Univariate and multivariate prognostic risk factor analyses were performed using FFTF as endpoint. Sex, age, stage, splenectomy, bone marrow, and liver and bone involvement had no prognostic impact. In contrast, a pretreatment erythrocyte sedimentation rate (ESR) above 80 mm/h and a serum alkaline phosphatase (AP) above 230 IU/ml each appeared as significant prognostic factors (P less than 0.01; relative risk, 2.3). The two parameters can be combined to separate two groups (A: ESR and AP both low; B: ESR and/or AP high) which differ significantly for FFTF (P less than 0.001) and survival (P less than 0.04). The decision for risk-adapted treatment requires identification of groups of patients in the frame of specified diagnostic and therapeutic strategies.(ABSTRACT TRUNCATED AT 400 WORDS)