Solid tumors in patients treated for Hodgkin's disease: a report from the German Hodgkin Lymphoma Study Group.

BACKGROUND: Long-term survivors of successfully treated Hodgkin's disease (HD) are at risk for late complications. Among these, secondary solid tumors are most serious because they are often fatal. The aim of this retrospective analysis was to assess the incidence, relative risk and risk factors of secondary solid tumors in HD patients registered in the database of the German Hodgkin Lymphoma Study Group (GHSG). PATIENTS AND METHODS: From 1983 to 1998, the GHSG conducted three generations of clinical trials for early, intermediate and advanced stage HD (HD1-HD9) involving a total of 5367 patients. Data on incidence, risk factors and relative risk were updated in March 2003. RESULTS: A total of 127 patients with secondary solid tumors were identified. Among these, lung cancer (23.6%), colorectal cancer (20.5%) and breast cancer (10.2%) were the most frequent. After a median follow-up of 72 months the cumulative risk of developing a solid tumor was 2%, with an overall relative risk (RR) of 2.4 (lung cancer, 3.8; colorectal cancer, 3.2; breast cancer, 1.9). For most patients (n=67; 52.8%) developing a secondary solid tumor, treatment modality consisted of chemotherapy combined with radiotherapy in extended field technique (RR = 3.3). CONCLUSIONS: With a median follow-up of 72 months, there were 127 patients developing solid tumors out of a total of 5367 HD patients treated in the GHSG studies HD1-HD9. The cumulative risk of 2% is expected to increase over time due to the rather short median observation time and slow progression of solid malignancies.

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.

The role of ifosfamide in the treatment of relapsed and refractory lymphoma.

Ifosfamide is an alkylating agent with proven efficacy in the treatment of solid tumours and malignant lymphomas. Because it causes only mild to moderate myelosuppression, ifosfamide is often used in combination regimens with other agents. Ifosfamide has been mainly used in therapy of lymphoma as a component of salvage regimens, but high-dose ifosfamide is also effective in the mobilization of peripheral stem cells for treatment of patients with relapsed or refractory lymphoma with regimens containing autologous stem cell transplantation. Based on promising data with a new combination regimen containing idarubicin, etoposide and ifosfamide (IIVP-16) in patients with poor-risk non-Hodgkin's lymphoma, we have performed a phase II study using DIZE (dexamethasone 20 mg i.v. days 1-4, idarubicin 8 mg/m2 i.v. days 1 + 2, ifosfamide 1.0 g/m2 continuous infusion (c.i.) days 1-4, and etoposide 160 mg/m2 c.i. days 1-4) in patients with relapsed or refractory Hodgkin's and non-Hodgkin's lymphoma. In 43 evaluable patients, the response rate was 58%, including 11 complete remissions (CR) and 14 partial remissions (PR). The mean duration of response was 8 months (1-30). Myelosuppression was generally mild with mean duration of neutropenia < 1000/microL of 2.5 days (range 0-18) and thrombocytopenia < 25,000/microL of 1.5 days (0-17). Thus, DIZE is an effective and safe regimen for pretreated patients with aggressive lymphoma. These results appear to compare favourably with other salvage regimens such as IMVP-16 or DHAP. In conclusion, salvage regimens containing ifosfamide can play an important role in patients who are not eligible for high-dose chemotherapies. Moreover, ifosfamide might also have a role in reducing tumour burden and selecting those patients who qualify for HDCT.

Abdominal lymphoma staging: is MR imaging with T2-weighted turbo-spin-echo sequence a diagnostic alternative to contrast-enhanced spiral CT?

PURPOSE: To evaluate the diagnostic value of MR imaging in abdominal lymphoma staging, in comparison with that of the established spiral CT, within the context of a prospective study. METHODS: 50 patients with non-Hodgkin (n = 27) and Hodgkin lymphoma (n = 23) were examined with a plain T2-weighted TSE sequence (parameters: TE 90 ms, TR >2.500 ms, slice thickness 8 mm, slice interval 0.8 mm, ETL 20, NEX 4), and with spiral CT following oral and intravenous administration of contrast agent. RESULTS: Both CT and MR imaging agreed in showing abdominal lymphomas in 34/50 cases. The size of the detected lymphomas was between 1.5-9 cm (mean: 4.3 +/-2.2 cm). In the analysis of the individual lymph node sites, CT showed involvement of the paraaortic lymph nodes in 29/50 patients, compared with 28/50 in MRI, and involvement of the portal lymph nodes in 15/50, compared with 12/50. Both techniques showed the iliac lymph nodes in 21/50 patients, the inguinal lymph nodes in 10/50, and the mesenteric lymph nodes in 11/50. Both techniques also showed focal organ lesions in 12/50 cases. CONCLUSIONS: In the staging of abdominal lymphomas, MR imaging with a T2-weighted TSE sequence can be regarded as equal to spiral CT in the detection of lymph adenopathy and the demonstration of focal organ lesions. In addition to the absence of ionizing radiation, the advantage of MR imaging is that there is no necessity for oral or intravenous administration of contrast agent.

Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study.

PURPOSE: To explore the use of gemcitabine for the treatment of patients with relapsing or refractory Hodgkin's disease. PATIENTS AND METHODS: Eligible patients had measurable disease and more than one previous chemotherapy regimen. Patients previously treated with high-dose chemotherapy with autologous bone marrow or peripheral stem-cell support were not included. Gemcitabine, 1,250 mg/m(2), was administered as a 30-minute intravenous infusion on days 1, 8, and 15 of each 28-day cycle of therapy. The dosing schedule remained fixed, and any dose of gemcitabine that could not be given on time was omitted. Patients who had not experienced any hematologic or nonhematologic toxicity after one complete cycle of therapy were permitted to have subsequent doses increased by 20%: that is, from 1, 250 mg/m(2) to 1,500 mg/m(2). RESULTS: Of the 23 enrolled patients, 22 were assessable for response; all 23 patients were included in the efficacy analysis. Disease status for two patients (9%) reached a state of complete remission, and seven patients (30%) achieved a partial response, for an overall response rate of 39% (95% confidence interval, 19.7% to 61.5%). The likelihood of achieving a response was not influenced by a patients' main pretreatment characteristics or by their response to their last prior chemotherapy. The median duration of response was 6.7 months (range, 2 to 33+ months), and the median overall survival time was 10.7 months (range, 4 to 34.7+ months). In general, toxicities were mild; no treatment-related deaths occurred, and only one life-threatening adverse event was reported for this study. CONCLUSION: Gemcitabine was shown to be active in heavily pretreated patients with Hodgkin's disease, producing a response rate of 39%. Additionally, drug-related toxicities were mild, which thus suggests the possible inclusion of gemcitabine in an earlier phase of treatment.

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.