Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial.

BACKGROUND: The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen COPP/ABV/IMEP (cyclophosphamide-vincristine-procarbazine-prednisone-doxorubicin-bleomycin-vinblastine-ifosfamide-methotrexate-etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV, dacarbacine) (CA) in the treatment of advanced-stage Hodgkin's disease (HD). PATIENTS AND METHODS: Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both groups then received consolidating radiotherapy. RESULTS: Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73% and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated with a poor prognosis CONCLUSION: The rapidly alternating hybrid CAI did not give superior results when compared with the standard regimen CA in advanced-stage HD.

Spleen involvement in Hodgkin's lymphoma: assessment and risk profile.

Diagnostic laparotomy is no longer routinely performed in Hodgkin's lymphoma and noninvasive diagnosis of spleen involvement remains uncertain. In order to assess the probability of splenic involvement based on clinical parameters, we retrospectively analyzed data on patients of the German Hodgkin's Lymphoma Study Group (GHSG) who underwent staging laparotomy and for whom splenic weight and size were available. Our study included 376 patients with Hodgkin's lymphoma who underwent staging laparotomy and splenectomy according to the treatment policy of the GHSG between February 1981 and January 1993. Univariate and multivariate analyses of pretherapeutic clinical characteristics and splenic weight were performed in order to predict the probability of splenic involvement. Computed tomographic (CT) images of 25 patients were available and used to correlate radiological splenic size and pathological splenic weight. In 171 of 376 patients spleen involvement was found. Average weight of the spleens was 258 g (+/-257) ranging from 55 to 3290 g. All spleens with a weight above 2000 g showed disease involvement, while those under 150 g were never involved. In the multivariate analysis, splenic weight ( p<0.001), erythrocyte sedimentation rate ( p<0.001), and clinical stage ( p<0.01) were found to be independently prognostic for spleen involvement. Splenic weight was highly correlated with a spleen index defined as the product of length, width, and thickness measured by CT (correlation coefficient: 0.93). By applying the identified risk factors in clinically staged patients spleen involvement can be determined. Spleen weight can be estimated with the help of a spleen index. Above an index of 1000 the probability of spleen involvement is higher than 90%. This might be of outstanding importance for patients being scheduled for involved field radiation.

14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group.

PURPOSE: This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen given in 14-day intervals (BEACOPP-14) with granulocyte colony-stimulating factor (G-CSF) support in advanced Hodgkin's lymphoma. PATIENTS AND METHODS: From July 1997 until March 2000, 94 patients with Hodgkin's lymphoma stage IIB, III, and IV were scheduled to receive eight cycles of BEACOPP-14. Consolidation radiotherapy was administered to regions with initial bulky disease or residual tumor after chemotherapy. RESULTS: All patients were assessable for toxicity and treatment outcome. Eighty-six patients received the planned eight cycles of BEACOPP-14. Consolidation radiotherapy was given in 66 patients. Chemotherapy could generally be administered on schedule. Dose reductions varied among drugs but were generally low. Acute toxicity was moderate, with World Health Organization grade 3/4 leukopenia in 75%, thrombocytopenia in 23%, anemia in 65%, and infection in 12% of patients. A total of 88 patients (94%) achieved a complete remission. Four patients had progressive disease. At a median observation time of 34 months, five patients have relapsed, one patient developed a secondary non-Hodgkin's lymphoma, and three deaths were documented. The overall survival and freedom from treatment failure rates at 34 months were 97% (95% confidence interval [CI], 93% to 100%) and 90% (95% CI, 84% to 97%), respectively. CONCLUSION: Acceleration of the BEACOPP baseline regimen by shortening cycle duration with G-CSF support is feasible and effective with moderate acute toxicity. On the basis of these results, the German Hodgkin's Lymphoma Study Group will compare the BEACOPP-14 regimen with BEACOPP-21 escalated in a prospective multicenter randomized trial.

Male gonadal dysfunction in patients with Hodgkin's disease prior to treatment.

UNLABELLED: Infertility after treatment of patients with Hodgkin's disease (HD) is considered as a side effect of alkylating agent containing chemotherapy regimens. To investigate whether gonadal failure is related primarily to the toxic effect of chemotherapy or rather to the disease itself, we investigated the fertility status before the onset of treatment. PATIENTS AND METHODS: Semen quality and hormonal status were evaluated in 158 patients with first diagnosis of HD enrolled into trials of the German Hodgkin Lymphoma Study Group (GHSG). The median age of the patients was 28 years (range 16-52). Twenty patients (13%) were classified as early stage HD, 63 patients (40%) as intermediate stage, and 75 patients (47%)) as advanced stage according GHSG grading. Sixty-seven patients (42%) showed systemic symptoms. Semen analysis was performed according to WHO guidelines. Follicle-stimulating hormone (FSH) and luteinising hormone (LH) plasma levels were measured by specific double-antibody radio-immune-assay (RIA) methods. RESULTS: Prior to treatment, severe damage of fertility, i.e.. azoospermia and oligoasthenoteratospermia (OAT-syndrome) was found in 13 (8%) and 20 patients (13%), respectively. Thirty-eight patients (24%) had single, i.e., oligo-(O), astheno-(A) or teratospermia-(T), and 40 patients (26%) showed combined damages, i.e., OA, OT or AT. In 47 patients (30%) a normal sperm count was found. Thus, III patients (70%) showed semen abnormalities before the onset of treatment. In a multivariate analysis elevated ESR (P < 0.003) and advanced stage of disease (P < 0.01) could be distinguished as prognostic factors for severe damage of fertility. No correlation was found between pre-therapeutic gonadotropine levels and fertility status. CONCLUSION: Patients with HD have an increased risk for inadequate semen quality even prior to treatment. Infertility is more frequent in patients with elevated ESR and advanced stage of disease. This association demonstrates the predominant influence of the disease on fertility. Assuming HD is the major initial cause for infertility efforts should be made to identify new non-gonadal toxic chemotherapies to be able to regain fertility after effective therapy. Further investigations have to be performed to clarify mechanisms inducing fertility defects in patients with HD.

Dose escalation of cytotoxic drugs using haematopoietic growth factors: a randomized trial to determine the magnitude of increase provided by GM-CSF.

BACKGROUND: The magnitude of chemotherapy dose escalation made possible by the use of recombinant haematopoietic growth factors has not been quantified in a randomized trial. PATIENTS AND METHODS: Patients with refractory or relapsing Hodgkin's disease were randomized to receive the Dexa-BEAM regimen with escalating etoposide doses supported by placebo or granulocyte-macrophage colony-stimulating factor (GM-CSF). Using an adaptive sampling method independently in both arms, the etoposide dose was escalated until the maximal tolerated dose for the first cycle was reached. RESULTS: Thirty patients were randomized to GM-CSF and thirty to placebo. The etoposide dose could be escalated considerably in both treatment arms. Maximal etoposide dose for the first cycle was 1920 mg/m2 for patients receiving GM-CSF and 1160 mg/m2 for patients receiving placebo (P = 0.045 one-sided), corresponding to a 65% higher etoposide dose and a 13% higher dose intensity with GM-CSF. Dose-limiting events were similar in both arms, consisting mainly of prolonged neutropenia and consecutive infections. Treatment efficacy was not different in the two treatment groups. CONCLUSIONS: While GM-CSF permits a somewhat higher dose escalation than placebo, the increase in dose intensity provided by GM-CSF is small. The use of CSF for interval reduction rather than dose escalation is the more effective strategy for dose intensification.

Non-Hodgkin's lymphoma after primary Hodgkin's disease in the German Hodgkin's Lymphoma Study Group: incidence, treatment, and prognosis.

PURPOSE: The cumulative incidence for non-Hodgkin lymphoma's (NHL) after primary Hodgkin's disease (HD) ranges between 1% and 6%. To investigate the course of disease for secondary NHL, we retrospectively analyzed patients treated within clinical trials of the German Hodgkin's Lymphoma Study Group (GHSG) since 1981. PATIENTS AND METHODS: From 1981 to 1998, the GHSG conducted three generations of clinical trials for the treatment of primary HD involving a total of 5,406 patients. Reference histology by an expert panel was obtained for 4,104 of the patients. Data on incidence, treatment, and outcome of secondary NHL were updated in March 1999. RESULTS: At first diagnosis of HD, the pathologists rejected 114 (2.1%) of 5,520 cases initially diagnosed as HD and rediagnosed them as primary NHL. Fifty-two (0.9%) of the remaining 5,406 patients developed a secondary NHL. One patient was excluded from further analyses because of insufficient documentation. Six patients had no further therapy because of patient refusal (n = 1) or rapidly progressive disease (n = 5). For the remaining 45 patients, overall response rate was 43% (36% complete response and 7% partial response). The actuarial 2-year freedom from treatment failure (FFTF) and overall survival (OS) for all patients was 24% and 30%, respectively, and for patients with diffuse large-cell lymphoma, it was 28% and 35%, respectively. Time of occurrence of secondary NHL after first diagnosis of HD and variables employed in the age-adjusted International Prognostic Factor Index (IPFI) significantly influenced treatment outcome. CONCLUSION: In the GHSG, the incidence of secondary NHL with 0.9% is relatively low compared with previously reported series. The prognosis of secondary NHL seems dismal and is significantly influenced by time of occurrence and the age-adjusted IPFI. In a subset of patients with secondary NHL, long-term disease-free survival could be achieved.

Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group.

To determine prognostic factors and treatment outcome, patients with primary progressive Hodgkin lymphoma (HD) registered in the database of the German Hodgkin Lymphoma Study Group (GHSG) were analyzed retrospectively. Detailed records from randomized prospective multicenter trials performed between 1988 and 1998 of 3807 patients recruited in these trials were reviewed. The median age of the 206 patients available was 34 years (range, 16-71). Fifty-seven patients (28%) in intermediate stage and 149 patients (72%) in advanced stage developed progressive disease (PD). One hundred and fifty-three patients (74%) were treated with salvage chemotherapy, 47 patients (23%) with salvage radiotherapy, and 6 patients (3%) did not receive any therapy due to rapid PD. Seventy patients (34%) were treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation. The 5-year freedom from second failure (FF2F) and overall survival (OS) for all patients were 17% and 26%, respectively. The 5-year FF2F and OS for patients treated with HDCT were 31% and 43%, respectively. In multivariate analysis low Karnofsky performance score at the time of progression (P <.0001), age above 50 years (P =.019), and failure to attain a temporary remission on first-line treatment (P =.0003) were significant adverse prognostic factors for OS. Patients with none of these risk factors had a 5-year OS of 55% compared with 0% for patients with all 3 of these unfavorable prognostic factors. Although HDCT is a reasonable option for selected patients with primary progressive HD, the majority did not receive HDCT. Interestingly, salvage radiotherapy gave promising results in patients with localized PD. (Blood. 2000;96:1280-1286)

Dexamethasone, carmustine, etoposide, cytarabine, and melphalan (dexa-BEAM) followed by high-dose chemotherapy and stem cell rescue--a highly effective regimen for patients with refractory or relapsed indolent lymphoma.

We performed a phase II study to determine the efficacy of maximal cytoreductive therapy with up to five cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) for patients with advanced relapsed or refractory indolent lymphoma. Thirty-two patients with primary refractory or relapsed indolent lymphoma were treated with the Dexa-BEAM regimen. Thirteen patients had primary refractory disease, 4 patients partial remission, and 15 patients first or subsequent relapse. Patients achieving PR or CR received HDCT with ASCT. The conditioning regimen used was BEAM (carmustine [BCNU], etoposide, cytarabine, and melphalan). Twenty-two patients responded to Dexa-BEAM resulting in a response rate of 78%. Maximum response was observed after 3.2 (range 2-5) courses. One patient with progressive disease died in septic shock during neutropenia. Nineteen patients with partial or complete remission after Dexa-BEAM received HDCT. Hematopoietic stem cells (HSC) were collected after two cycles of Dexa-BEAM. The median number of CD34+ HSC reinfused was 3.1 x 10(6)/kg (range 1.6-8.2 x 10(6)/kg). There was no transplantation-related death. All patients receiving HDCT achieved complete remission. Overall survival (OS) and freedom from treatment failure (FFTF) for all patients are estimated to be 68% and 65% at two years, respectively. With a mean follow-up of 20 months (range 8-42 months), 16/19 patients receiving HDCT are in continuous complete remission. The Dexa-BEAM regimen is effective in overcoming drug resistance in patients with indolent lymphoma who failed to respond to conventional treatment or who relapsed. The CR rate of 100% of those patients receiving HDCT and ASCT after maximal cytoreductive treatment with Dexa-BEAM suggests the use of HDCT at the time of maximal response.

Dexa-BEAM: an effective regimen for cytoreduction prior to high-dose chemotherapy with autologous stem cell support for patients with relapsed/refractory mantle-cell lymphoma.

Mantle-cell lymphoma (MCL) is not a curable disease using conventional chemotherapy. Patients with MCL have the shortest median time to progression and the shortest median survival of all lymphoma subtypes after first-line treatment. In the present study we determined the efficacy of maximal cytoreductive therapy with up to four cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell support (ASCT) for patients with advanced relapsed or refractory MCL. Nine consecutive patients with relapsed or refractory MCL were included. Three patients had partial remission (PR), three patients progressive disease (PD) upon first line tretment, and three patients first or subsequent relapse. After 2 to four cycles of Dexa-BEAM eight patients achieved complete remission (CR), resulting in a response rate of 88%. Six of 8 patients responding to Dexa-BEAM received high-dose chemotherapy HDCT (BEAM) and autologous hematopoietic stem cell transplantation (ASCT). With a median follow up of 24 months six patients are alive. Five of those six patients are still in contiuous CR (range 13-54 months).

Treatment of primary progressive Hodgkin's and aggressive non-Hodgkin's lymphoma: is there a chance for cure?

PURPOSE: To determine differences in prognosis between primary progressive Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL), we retrospectively analyzed patients with progressive lymphoma who were treated with different salvage chemotherapy regimens including high-dose chemotherapy (HDCT) followed by autologous stem-cell support (ASCT). PATIENTS AND METHODS: One hundred thirty-one patients with primary progressive lymphoma (HD, n = 67; NHL, n = 64) were enrolled. Primary progressive disease was defined as disease progression during first-line chemotherapy or only transient response (complete or partial response lasting

Retrospective assessment of quality of life and treatment outcome in patients with Hodgkin's disease from 1969 to 1994.

We determined the current quality of life (QoL) of patients with Hodgkin's disease treated at the Innsbruck University Hospital between 1969 and 1994 at a mean time of 9.1 +/- 7.0 years after their initial treatment. Further aims of our study were to assess potential differences in objective treatment outcome and QoL between patients treated with chemo-, radio- or combined modality therapy and those enrolled in randomised clinical trials or treated according to standard procedures. The QLQ-C30, a health-related and validated self-report questionnaire developed by the Study Group on Quality of Life of the European Organization for Research and Treatment of Cancer (EORTC) was mailed to a cohort of 194 survivors out of a total of 225 patients with Hodgkin's disease; 126 of them (64.9%) returned the completed questionnaire. The 5- and 10-year overall survival rates for the total group of 225 patients were 94.3% and 84.9%, respectively. Irrespective of stage, higher relapse-free survival rates were observed in patients receiving combined modality treatment (P = 0.025). Five-year relapse-free survival rates were 96.6% for patients enrolled in clinical trials and 82.8% for patients treated outside of randomised studies (P = 0.037 in univariate and P = 0.064 in multivariate analysis). Patients treated with combined modality regimens had reduced QoL scores in comparison with those treated with either radiation or chemotherapy alone, but QoL parameters did not differ between patients enrolled in clinical trials and those treated according to standard procedures. Patients with Hodgkin's disease had an excellent long-term prognosis and very high QoL scores a mean of 9.1 years after treatment of their disease. The improved relapse-free survival rates achieved by combined modality regimens must be carefully weighed against the accompanying reduced QoL, since lower relapse rates did not translate into a survival advantage.

Prognostic factors for subdiaphragmatic involvement in clinical stage I-II supradiaphragmatic Hodgkin's disease: a retrospective analysis of the GHSG.

BACKGROUND: Staging laparotomy and splenectomy were routinely performed in patients with early-stage Hodgkin's disease (HD) qualifying for radiotherapy alone to determine the exact extent of disease. However, staging laparotomy is associated with a considerable number of side effects, warranting more sophisticated diagnostic procedures and new therapy strategies. We retrospectively analyzed patients undergoing staging laparotomy to identify pretherapy risk factors predicting the probability of abdominal disease and to define high-risk groups that might benefit from staging laparotomy and subsequent stage-adjusted treatment. PATIENTS AND METHODS: Between February 1988 and January 1993, 391 patients with CS I-II supradiaphragmatic Hodgkin's disease underwent staging laparotomy and splenectomy according to the treatment policy of the German Hodgkin's Lymphoma Study Group (GHSG) for early stages of Hodgkin's disease. Univariate and multivariate analysis of pretherapeutic clinical characteristics were performed in an attempt to predict staging laparotomy results and to identify risk groups. RESULTS: Of the 391 patients, 81 (21%) had subdiaphragmatic disease. Eighteen percent were upstaged to PS III and three percent to PS IV. By a multivariate model the following parameters were independent risk factors for positive surgical staging: left cervical involvement (P < 0.001), mediastinal involvement (P < 0.009), Karnofsky performance status (P < 0.004) and histology (P < 0.04). In our analysis gender (P < 0.08) and ESR (P < 0.06), often described as of high prognostic value, was not significant. The presence of systemic symptoms, number of involved areas and clinical stage were not associated with abdominal disease, as described in several former publications. To define high-risk groups, which comprise at least 15% of patients of the cohort and have a risk of subdiaphragmatic involvement of > 35%, combinations of only two or three of the predictive factors were analyzed. With respect to these criteria the following subgroups of patients were identified as having a high risk for subdiaphragmatic disease (> 35%): a) left cervical lymph node involvement and no mediastinal involvement (n = 98, observed risk 36%); b) no mediastinal involvement and MC/LD histology (n = 113, observed risk 40%). CONCLUSIONS: We conclude that initial clinical characteristics are predictive for occult abdominal involvement in early clinical stages of Hodgkin's disease. The impact of these risk factors on future therapeutical strategies have to be evaluated.

Favorable outcome of patients with relapsed or refractory Hodgkin's disease treated with high-dose chemotherapy and stem cell rescue at the time of maximal response to conventional salvage therapy (Dex-BEAM).

BACKGROUND: Disease status before high-dose chemotherapy with autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT) is an important predictor of transplantation-related toxicity and event-free survival (EFS) for patients with relapsed or refractory Hodgkin's disease (HD). We performed a phase II study in patients with relapsed or refractory HD to evaluate the feasibility of four cycles of Dexa-BEAM followed by high-dose chemotherapy with ABMT or PBSCT. PATIENTS AND METHODS: Twenty-six patients (median age 30, range 20-40 years) were treated with 2-4 courses of dexamethasone, carmustine, etoposide, cytarabine and melphalan (Dexa-BEAM) as salvage chemotherapy in order to attain maximal response. Patients achieving complete response (CR) or partial response (PR) received high-dose chemotherapy with ABMT or PBSCT. The conditioning regimen used was CVB (cyclophosphamide, carmustine, etoposide). RESULTS: Eighteen patients responded to Dexa-BEAM, resulting in a response rate of 69%. At the time of transplant 16 patients were in CR two patients in PR. At present 14 patients transplanted are in continuous CR (median follow-up 40 months, range 14-60 months). Two patients with PR after four courses of Dexa-BEAM relapsed and died three months posttransplantation. Two patients with CR at the time of transplant relapsed after nine and 13 months respectively. Eight patients had rapid progressive disease after 2-4 cycles of Dexa-BEAM. One patient with progressive disease died in gram-negative sepsis after four cycles of Dexa-BEAM. There was no transplantation-related death. CONCLUSION: These data suggests the use of high-dose chemotherapy followed by stem cell transplantation at the time of maximal response.

Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: a trial of the German Hodgkin's Disease Study Group.

PURPOSE: A prospective phase II study was conducted to evaluate the efficacy of dexamethasone, carmustine, etoposide, cytarabine, and melphalan (Dexa-BEAM) as salvage chemotherapy for patients with Hodgkin's disease. PATIENTS AND METHODS: Fifty-five patients progressing on or relapsing after eight- or 10-drug chemotherapy (cyclophosphamide, vincristine, procarbazine, and prednisone plus doxorubicin, bleomycin, vinblastine, and dacarbazine [COPP+ABVD] or COPP+ABV+ifosfamide, methotrexate, etoposide, and prednisone [IMEP]) were treated with Dexa-BEAM. Patients who responded after two cycles of Dexa-BEAM either continued treatment for another two to three cycles or received high-dose chemotherapy/autologous bone marrow transplantation (HDCT/ABMT) with cyclophosphamide, etoposide, and carmustine (BCNU) (CVB) as conditioning regimen. RESULTS: Seventeen patients (31%) achieved a complete remission and 16 (29%) a partial remission, resulting in a response rate of 60% (95% confidence interval, 46% to 73%). Progressive disease developed in 18 patients. Toxicity of Dexa-BEAM was acceptable with pronounced, but temporary World Health Organization (WHO) grade III/IV granulocytopenia and thrombocytopenia occurring in more than 90% of all courses. Two patients died of sepsis during granulocytopenia. Three prognostic subgroups could be distinguished: (1) patients progressing on initial chemotherapy, (2) patients relapsing within 12 months, and (3) patients with late relapses. The response rates for these groups were 52%, 60%, and 83%, and the median survival duration 12, 29, and 40+ months, respectively. In a nonrandomized comparison, the survival of patients who responded to two cycles of Dexa-BEAM and had additional cycles of Dexa-BEAM (n = 14) was not different from those responding patients who underwent HDCT/ABMT (n = 19). However, the power to detect a 20% survival difference was only 33% in this comparison. CONCLUSION: Dexa-BEAM is an effective salvage treatment for patients with Hodgkin's disease who fail to respond to multidrug chemotherapy. Efficacy and toxicity are comparable to HDCT/ABMT and underline the need for prospective randomized trials to define better the role of HDCT with and without ABMT in these patients.