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Current clinical trials for the treatment of adult advanced‐stage Hodgkin's disease: GELA experiences
Symposium article
Annals of Oncology 13 (Supplement 1): 96–97, 2002 DOI: 10.1093/annonc/mdf619
Current clinical trials for the treatment of adult advanced-stage Hodgkin’s disease: GELA experiences C. Fermé*, N. Mounier & M. Diviné On behalf of the Groupe d’Études des Lymphomes de l’Adulte (GELA) Service d’Hématologie, Institut Gustave Roussy, Villejuif, France
Background: The optimal treatment for patients with advanced Hodgkin’s disease (HD) responding to initial chemotherapy (CT) and an intensive salvage therapy for those who fail to respond completely after initial treatment were evaluated prospectively. Patients and methods: The Groupe d’études des Lymphomes de l’Adulte H89 trial compared two cycles of CT with (sub)total nodal irradiation (RT) as consolidation treatments for patients with stage IIIB/IV HD with a complete response (CR) or good partial response (PR) after six cycles of CT. Early salvage therapy, including intensified cytoreductive CT and high-dose CT with autologous stem-cell transplantation, was integrated into the trial for patients who had failed to respond completely or relapsed after initial treatment. Results: The study does not demonstrate any advantage of RT over CT as consolidation treatment at the time of CT-induced CR or good PR. Early intensive therapy improves the outcomes of patients with PR and those who relapsed with unfavourable factors. This strategy remains unsatisfactory for patients with primary refractory disease and chemoresistant disease. Conclusion: Based on first intensification of conventional-dose CT, in the next trial (EORTC–GELA Intergroup Study), four escalated bleomycin–etoposide–doxorubicin–cyclophosphamide–procarbazine– prednisone (BEACOPP) followed by four baseline BEACOPP are compared with the eight doxorubicin–bleomycin–vinblastine–dacarbazine standard with no RT for patients who achieve CR/CRuncertain after initial CT. Key words: advanced stages, high-dose therapy, Hodgkin’s disease
Patients with advanced-stage Hodgkin’s disease (HD) who have achieved a complete response (CR) after six cycles of a doxorubicin-containing regimen can receive consolidation treatment with chemotherapy (CT) or radiotherapy. Highdose CT with autologous stem-cell transplantation (autoSCT) might be a strategy to improve the outcome of patients who fail to achieve a CR or good partial response (PR) to initial CT. In 1989, the Groupe d’études des Lymphomes de l’Adulte (GELA) designed a randomised study to compare two consolidation treatment procedures consisting of either two additional cycles of CT or (sub)total nodal irradiation (RT), for patients who had achieved a CR or PR of at least 75% after six cycles of CT [1]. Patients with a response of <75%, progressive HD after induction CT or relapse were submitted to early intensive therapy including intensified cytoreductive CT with mitoguazone, ifosfamide, vinorelbine and etoposide (MINE)
*Correspondence to: Dr C. Fermé, Service d’Hématologie, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. Tel: +33-1-42-11-45-07; Fax: +33-1-42-11-52-72; E-mail: [email protected] © 2002 European Society for Medical Oncology
monthly for two to three cycles, followed by high-dose CT with carmustine–etoposide–cytarabine–melphalan and autoSCT. Between July 1989 and December 1996, 559 patients with stage IIIB–IV HD, aged between 15 and 65 years, were randomised to receive six cycles of doxorubicin–bleomycin– vinblastine–procarbazine–prednisone (ABVPP) (n = 267) or chlormethine–vincristine–procarbazine–prednisone–doxorubicin–bleomycin–vinblastine (MOPP/ABV) hybrid (n = 266). The median follow-up was 48 months. The 5-year eventfree survival (EFS) estimate of the 533 eligible patients was 62% [95% confidence interval (CI) 58% to 66%] and the overall survival (OS) estimate was 79% (95% CI 75% to 84%). The 5-year OS of patients treated with MOPP/ABV or ABVPP was 79% (95% CI 73% to 95%) and 80% (95% CI 74% to 86%), respectively. A total of 418 patients were randomised for consolidation treatment, either two further cycles of CT (n = 208) or RT (n = 210). The 5-year EFS was 70% (95% CI 64% to 76%) after CT and 72% (95% CI 66% to 78%) after RT consolidation. A significant qualitative interaction between the induction and consolidation treatments
97 was found for overall survival. Among 533 patients enrolled in the H89 trial, 82 patients had large mediastinal mass (mediastinum/thorax ratio >0.33), and 61 responders (74%) were randomised for consolidation. The 5-year OS (96% versus 97%; log-rank test P = 0.97) and EFS (66% versus 84%; P = 0.12) did not differ significantly for patients receiving consolidation with CT or RT, respectively [2]. Of 533 patients, all 157 patients with induction failure (n = 67), PR of <75% (n = 22) or relapse (n = 68) were analysed [3]. The 5-year OS values were 30, 72 and 76% for the induction failure, PR and relapse groups, respectively (P = 0.0001); for the 101 patients given high-dose CT it was 71%, and for the 48 patients treated without high-dose CT it was 32% (P = 0.0001). Multivariate analysis using the time-dependent Cox model indicated that B symptoms at progression, salvage without high-dose CT and chemoresistant disease before high-dose CT were significantly associated with shorter OS. When the International Pronostic Score (IPS) for advanced HD is applied to the H89 trial, the 5-year survival estimates were 95% (95% CI 93% to 97%) for patients with IPS 0–2 and 70% (95% CI 64% to 76%) for patients with IPS ≥3 (P <0.0001). The 5-year FF2F estimates were 75% (95% CI 69% to 81%) for patients with IPS 0–2 and 54% (95% CI 48% to 60%) for patients with IPS ≥3 (P <0.0001). The 5-year EFS for all 92 patients treated with eight cycles of MOPP/ABV hybrid was 74% (95% CI 69% to 79%). After this treatment, the 5-year EFS was 87% (95% CI 73% to 100%) for patients with IPS 0–2, and 67% (95% CI 55% to 79%) for patients with IPS ≥3 (P = 0.03). The results of H89 trial showed that RT was not superior to CT consolidation for patients with advanced-stage HD who have achieved a response of at least 75% after six cycles of a doxorubicin-containing regimen, and led our group to prefer eight cycles of CT as standard treatment when a CR/CRuncertain has been obtained after six cycles. Our policy, including early intensive therapy for patients who failed to
respond completely to induction CT, improves the outcomes of patients with PR and those who relapsed with unfavourable prognostic factors. However, for patients with primary refractory disease and chemoresistant disease, this strategy remains unsatisfactory. Therefore, efforts have to be made to improve disease control in all patients with advanced-stage, even in patients with IPS 0–2. Considering the German Hodgkin Study Group experience with escalated bleomycin–etoposide– doxorubicin–cyclophosphamide–procarbazine–prednisone (BEACOPP), which supports first intensification of conventional-dose chemotherapy, the GELA and the EORTC Lymphoma Group decided to evaluate whether a superior 3-year EFS difference could be observed with four escalated BEACOPP followed by four baseline BEACOPP compared with the eight doxorubicin–bleomycin–vinblastine–dacarbazine standard with no RT for patients who achieve CR/CRuncertain after initial CT. The GELA will stratify the randomisation according to the IPS. The EORTC trial will include only patients with the IPS ≥3. The EORTC–GELA intergroup study (EORTC protocol 20012) is going to be carried out.
References 1. Fermé C, Sebban C, Hennequin C et al. Comparison of chemotherapy to radiotherapy as consolidation of complete or good partial response after six cycles of chemotherapy in patients with advanced Hodgkin’s disease: results of the Groupe d’Études des Lymphomes de l’Adulte H89 trial. Blood 2000; 95: 2246–2252. 2. Brice P, Colin P, Berger F et al. Advanced Hodgkin’s disease with large mediastinal involvement can be treated with 8 cycles of chemotherapy alone after a major response to 6 cycles of chemotherapy: a study of 82 patients from the GELA H89 trial. Cancer 2001; 92: 453– 459. 3. Fermé C, Mounier N, Diviné M et al. Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: results of the Groupe d’Études des Lymphomes de l’Adulte H89 Trial. J Clin Oncol; 2002; 20: 467–475.
Annals of Oncology 13 (Supplement 1): 96–97, 2002 DOI: 10.1093/annonc/mdf619
Current clinical trials for the treatment of adult advanced-stage Hodgkin’s disease: GELA experiences C. Fermé*, N. Mounier & M. Diviné On behalf of the Groupe d’Études des Lymphomes de l’Adulte (GELA) Service d’Hématologie, Institut Gustave Roussy, Villejuif, France
Background: The optimal treatment for patients with advanced Hodgkin’s disease (HD) responding to initial chemotherapy (CT) and an intensive salvage therapy for those who fail to respond completely after initial treatment were evaluated prospectively. Patients and methods: The Groupe d’études des Lymphomes de l’Adulte H89 trial compared two cycles of CT with (sub)total nodal irradiation (RT) as consolidation treatments for patients with stage IIIB/IV HD with a complete response (CR) or good partial response (PR) after six cycles of CT. Early salvage therapy, including intensified cytoreductive CT and high-dose CT with autologous stem-cell transplantation, was integrated into the trial for patients who had failed to respond completely or relapsed after initial treatment. Results: The study does not demonstrate any advantage of RT over CT as consolidation treatment at the time of CT-induced CR or good PR. Early intensive therapy improves the outcomes of patients with PR and those who relapsed with unfavourable factors. This strategy remains unsatisfactory for patients with primary refractory disease and chemoresistant disease. Conclusion: Based on first intensification of conventional-dose CT, in the next trial (EORTC–GELA Intergroup Study), four escalated bleomycin–etoposide–doxorubicin–cyclophosphamide–procarbazine– prednisone (BEACOPP) followed by four baseline BEACOPP are compared with the eight doxorubicin–bleomycin–vinblastine–dacarbazine standard with no RT for patients who achieve CR/CRuncertain after initial CT. Key words: advanced stages, high-dose therapy, Hodgkin’s disease
Patients with advanced-stage Hodgkin’s disease (HD) who have achieved a complete response (CR) after six cycles of a doxorubicin-containing regimen can receive consolidation treatment with chemotherapy (CT) or radiotherapy. Highdose CT with autologous stem-cell transplantation (autoSCT) might be a strategy to improve the outcome of patients who fail to achieve a CR or good partial response (PR) to initial CT. In 1989, the Groupe d’études des Lymphomes de l’Adulte (GELA) designed a randomised study to compare two consolidation treatment procedures consisting of either two additional cycles of CT or (sub)total nodal irradiation (RT), for patients who had achieved a CR or PR of at least 75% after six cycles of CT [1]. Patients with a response of <75%, progressive HD after induction CT or relapse were submitted to early intensive therapy including intensified cytoreductive CT with mitoguazone, ifosfamide, vinorelbine and etoposide (MINE)
*Correspondence to: Dr C. Fermé, Service d’Hématologie, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. Tel: +33-1-42-11-45-07; Fax: +33-1-42-11-52-72; E-mail: [email protected] © 2002 European Society for Medical Oncology
monthly for two to three cycles, followed by high-dose CT with carmustine–etoposide–cytarabine–melphalan and autoSCT. Between July 1989 and December 1996, 559 patients with stage IIIB–IV HD, aged between 15 and 65 years, were randomised to receive six cycles of doxorubicin–bleomycin– vinblastine–procarbazine–prednisone (ABVPP) (n = 267) or chlormethine–vincristine–procarbazine–prednisone–doxorubicin–bleomycin–vinblastine (MOPP/ABV) hybrid (n = 266). The median follow-up was 48 months. The 5-year eventfree survival (EFS) estimate of the 533 eligible patients was 62% [95% confidence interval (CI) 58% to 66%] and the overall survival (OS) estimate was 79% (95% CI 75% to 84%). The 5-year OS of patients treated with MOPP/ABV or ABVPP was 79% (95% CI 73% to 95%) and 80% (95% CI 74% to 86%), respectively. A total of 418 patients were randomised for consolidation treatment, either two further cycles of CT (n = 208) or RT (n = 210). The 5-year EFS was 70% (95% CI 64% to 76%) after CT and 72% (95% CI 66% to 78%) after RT consolidation. A significant qualitative interaction between the induction and consolidation treatments
97 was found for overall survival. Among 533 patients enrolled in the H89 trial, 82 patients had large mediastinal mass (mediastinum/thorax ratio >0.33), and 61 responders (74%) were randomised for consolidation. The 5-year OS (96% versus 97%; log-rank test P = 0.97) and EFS (66% versus 84%; P = 0.12) did not differ significantly for patients receiving consolidation with CT or RT, respectively [2]. Of 533 patients, all 157 patients with induction failure (n = 67), PR of <75% (n = 22) or relapse (n = 68) were analysed [3]. The 5-year OS values were 30, 72 and 76% for the induction failure, PR and relapse groups, respectively (P = 0.0001); for the 101 patients given high-dose CT it was 71%, and for the 48 patients treated without high-dose CT it was 32% (P = 0.0001). Multivariate analysis using the time-dependent Cox model indicated that B symptoms at progression, salvage without high-dose CT and chemoresistant disease before high-dose CT were significantly associated with shorter OS. When the International Pronostic Score (IPS) for advanced HD is applied to the H89 trial, the 5-year survival estimates were 95% (95% CI 93% to 97%) for patients with IPS 0–2 and 70% (95% CI 64% to 76%) for patients with IPS ≥3 (P <0.0001). The 5-year FF2F estimates were 75% (95% CI 69% to 81%) for patients with IPS 0–2 and 54% (95% CI 48% to 60%) for patients with IPS ≥3 (P <0.0001). The 5-year EFS for all 92 patients treated with eight cycles of MOPP/ABV hybrid was 74% (95% CI 69% to 79%). After this treatment, the 5-year EFS was 87% (95% CI 73% to 100%) for patients with IPS 0–2, and 67% (95% CI 55% to 79%) for patients with IPS ≥3 (P = 0.03). The results of H89 trial showed that RT was not superior to CT consolidation for patients with advanced-stage HD who have achieved a response of at least 75% after six cycles of a doxorubicin-containing regimen, and led our group to prefer eight cycles of CT as standard treatment when a CR/CRuncertain has been obtained after six cycles. Our policy, including early intensive therapy for patients who failed to
respond completely to induction CT, improves the outcomes of patients with PR and those who relapsed with unfavourable prognostic factors. However, for patients with primary refractory disease and chemoresistant disease, this strategy remains unsatisfactory. Therefore, efforts have to be made to improve disease control in all patients with advanced-stage, even in patients with IPS 0–2. Considering the German Hodgkin Study Group experience with escalated bleomycin–etoposide– doxorubicin–cyclophosphamide–procarbazine–prednisone (BEACOPP), which supports first intensification of conventional-dose chemotherapy, the GELA and the EORTC Lymphoma Group decided to evaluate whether a superior 3-year EFS difference could be observed with four escalated BEACOPP followed by four baseline BEACOPP compared with the eight doxorubicin–bleomycin–vinblastine–dacarbazine standard with no RT for patients who achieve CR/CRuncertain after initial CT. The GELA will stratify the randomisation according to the IPS. The EORTC trial will include only patients with the IPS ≥3. The EORTC–GELA intergroup study (EORTC protocol 20012) is going to be carried out.
References 1. Fermé C, Sebban C, Hennequin C et al. Comparison of chemotherapy to radiotherapy as consolidation of complete or good partial response after six cycles of chemotherapy in patients with advanced Hodgkin’s disease: results of the Groupe d’Études des Lymphomes de l’Adulte H89 trial. Blood 2000; 95: 2246–2252. 2. Brice P, Colin P, Berger F et al. Advanced Hodgkin’s disease with large mediastinal involvement can be treated with 8 cycles of chemotherapy alone after a major response to 6 cycles of chemotherapy: a study of 82 patients from the GELA H89 trial. Cancer 2001; 92: 453– 459. 3. Fermé C, Mounier N, Diviné M et al. Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: results of the Groupe d’Études des Lymphomes de l’Adulte H89 Trial. J Clin Oncol; 2002; 20: 467–475.