Beate Pfistner

Revised Response Criteria for Malignant Lymphoma

PURPOSE Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. METHODS The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations. RESULTS New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkins and Hodgkins lymphoma. Standardized definitions of end points are provided. CONCLUSION We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.

Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial

BACKGROUND High-dose chemotherapy followed by transplantation of autologous haemopoietic stem cells (BEAM-HSCT) is frequently used to treat patients with relapsed Hodgkins disease. We aimed to compare this treatment with conventional aggressive chemotherapy without stem-cell transplantation (Dexa-BEAM). METHODS 161 patients between 16 and 60 years of age with relapsed Hodgkins disease were randomly assigned two cycles of Dexa-BEAM (dexamethasone and carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and transplantation of haemopoietic stem cells. Only patients with chemosensitive disease (complete or partial remission after two courses of Dexa-BEAM) proceeded to further treatment. The primary endpoint was freedom from treatment failure for patients with chemosensitive disease. Analysis was per protocol. FINDINGS 17 patients were excluded from the study after randomisation (ten given Dexa-BEAM and seven given BEAM-HSCT). Median follow-up was 39 months (IQR 3-78). Freedom from treatment failure at 3 years was significantly better for patients given BEAM-HSCT (55%) than for those on Dexa-BEAM (34%; difference -21%, 95% CI -39.87 to -2.13; p=0.019). Overall survival of patients given either treatment did not differ significantly. INTERPRETATION High-dose BEAM and transplantation of haemopoietic stem cells improves freedom from treatment failure in patients with chemosensitive first relapse of Hodgkins disease irrespective of length of initial remission.

Involved-Field Radiotherapy Is Equally Effective and Less Toxic Compared With Extended-Field Radiotherapy After Four Cycles of Chemotherapy in Patients With Early-Stage Unfavorable Hodgkin’s Lymphoma: Results of the HD8 Trial of the German Hodgkin’s Lymphoma Study Group

PURPOSE To investigate whether radiotherapy can be reduced without loss of efficacy from extended field (EF) to involved field (IF) after four cycles of chemotherapy. PATIENTS AND METHODS Between 1993 and 1998, patients with newly diagnosed early-stage unfavorable HD were enrolled onto this multicenter study. Patients were randomly assigned to receive cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) + doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for two cycles followed by radiotherapy of 30 Gy EF + 10 Gy to bulky disease (arm A) or 30 Gy IF + 10 Gy to bulky disease (arm B). RESULTS Of 1,204 patients randomly assigned to treatment, 1,064 patients were informative and eligible for the arm comparison (532 patients in arm A; 532 patients in arm B). The median observation time was 54 months. Five years after random assignment, the overall survival (OSran) for all eligible patients was 91% and freedom from treatment failure (FFTFran) was 83%. Survival rates at 5 years after start of radiotherapy revealed no differences for arms A and B, respectively, in terms of FFTF (85.8% and 84.2%) and OS at 5 years (90.8% and 92.4%). There also were no differences between arms A and B, respectively, in terms of complete remission (98.5% and 97.2%), progressive disease (0.8% and 1.9%), relapse (6.4% and 7.7%), death (8.1% and 6.4%), and secondary neoplasia (4.5% and 2.8%). In contrast, acute side effects including leukopenia, thrombocytopenia, nausea, gastrointestinal toxicity, and pharyngeal toxicity were more frequent in the EF arm. CONCLUSION Radiotherapy volume size reduction from EF to IF after COPP + ABVD chemotherapy for two cycles produces similar results and less toxicity in patients with early-stage unfavorable HD.

Rapidly alternating COPP/ABV/IMEP is not superior to conventional alternating COPP/ABVD in combination with extended-field radiotherapy in intermediate-stage Hodgkin's lymphoma: final results of the German Hodgkin's Lymphoma Study Group Trial HD5.

PURPOSE To investigate whether treatment results in intermediate-stage Hodgkins lymphoma can be improved by rapid application of non-cross-resistant drugs, the 10-drug regimen cyclophosphamide, vincristine, procarbazine, and prednisone (COPP), doxorubicin, bleomycin, and vinblastine (ABV), and ifosfamide, methotrexate, etoposide, and prednisone (IMEP), repeated every 6 weeks, was compared with conventional alternating COPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) administered every 8 weeks. PATIENTS AND METHODS From January 1988 to January 1993, 996 patients in stage I or II Hodgkins lymphoma with at least one risk factor (massive mediastinal tumor, massive spleen involvement, extranodal disease, elevated ESR, or more than two lymph node areas involved) and all patients in stage IIIA Hodgkins lymphoma were randomized to receive two cycles of COPP/ABVD or COPP/ABV/IMEP followed by extended-field radiotherapy. RESULTS Both regimens produced similar rates for treatment responses (complete remission, 93% v 94%), freedom from treatment failure (80% v 79%), and overall survival (88% for both regimens) at a median follow-up time of 7 years. Most serious toxicities during chemotherapy were similar in both regimens. However, World Health Organization grade 3 and 4 leukocytopenia occurred significantly more frequently in the COPP/ABV/IMEP arm (53% v 44% of patients; P =.010). There were no differences in the number of serious infections and toxic deaths during therapy. The number of second malignancies was also the same in both arms (22 each). CONCLUSION Alternating COPP/ABVD and rapid alternating COPP/ABV/IMEP in combination with extended-field radiotherapy are equally effective in intermediate-stage Hodgkins lymphoma and produce excellent long-term treatment results.

Role of Hematotoxicity and Sex in Patients With Hodgkin's Lymphoma: An Analysis From the German Hodgkin Study Group

PURPOSE Several scores have described sex as a prognostic factor in patients with Hodgkins lymphoma (HL). However, little is known how sex-specific factors influence treatment outcome. We systematically investigated sex differences with regard to pretreatment characteristics and therapy-related variables, and examined their influence on the outcome of HL patients. PATIENTS AND METHODS This analysis comprises 4,626 HL patients of all prognostic risk groups who were enrolled onto the multicenter studies HD4 to HD9 of the German Hodgkin Study Group. At 5.5 years, 2,050 female and 2,576 male patients were analyzed. RESULTS Male and female patients had similar prognostic factors. There was more acute chemotherapy-related hematotoxicity in women, especially more severe leucopenia (WHO grade 3/4, 69.9% female and 55.2% male; P < .0001). Importantly, this did not translate into more infections. Female patients had similar response rates but fewer relapses and deaths, leading to a significantly better freedom from treatment failure (FFTF; at 66 months, 81% female [95% CI, 79% to 82%] and 74% male [95% CI, 72% to 76%]). Severe leucopenia during chemotherapy was strongly associated with better FFTF, both for males and females. In addition, when only those patients who developed severe leucopenia within the first two cycles of chemotherapy were included, the factor maintained its protective role. CONCLUSION The protective role of severe leucopenia suggests the testing of a more individualized therapy. In future trials, this therapy may be tailored in a response-adapted manner depending on the individual toxicity profile within the first cycles.

Successful mobilization of peripheral blood stem cells with the DHAP regimen (dexamethasone, cytarabine, cisplatinum) plus granulocyte colony-stimulating factor in patients with relapsed Hodgkin's disease

High-dose chemotherapy followed by autologous stem cell transplantation can improve the outcome of relapsed and refractory Hodgkins disease (HD) patients. The objective of the trial was to determine the mobilizing potential of the DHAP salvage regimen (dexamethasone, cytarabine, cisplatin) for the collection of peripheral blood stem cells (PBSC) in patients with relapsed HD. The target yield of harvesting CD34 + cells was > or =2 x 10(6)/kg in order to support the subsequent myeloablative chemotherapy. Most of the 105 patients included were intensively pre-treated with different combination chemotherapy regimens prior to mobilization. The use of DHAP followed by granulocyte colony-stimulating factor (G-CSF; 10 microg/kg) resulted in the successful collection of adequate numbers of PBSC in 97.1% of patients (102 of 105) with a median harvest of CD34+ cells of 13 x 10(6)/kg (range 2.6 - 85.1). More than 2.0 x 10(6) CD34+ cells/kg were achieved in 65 of 103 (63%) patients after 1 apheresis, the maximum number of aphereses for all patients was 3. It was found that the optimal time of PBSC harvest was at days 13 - 16 after initiating the mobilization regimen. These results demonstrate that the salvage chemotherapy regimen, such as DHAP combined with G-CSF, can be successfully used to mobilize PBSC in HD patients.

Current treatment strategies of the German Hodgkin Study Group (GHSG)

Abstract:  Hodgkins Lymphoma (HL) has developed to one of the best curable human cancers and overall about 80% of patients experience long‐term disease free survival. Therefore, current treatment strategies aim at further improving treatment outcome, thereby trying to by minimize therapy‐induced complications, such as infertility, cardiopulmonary toxicity, and secondary malignancies. Ongoing trials investigate a reduction of chemotherapy in terms of dose or cycles given, and the application of lower radiation doses and smaller radiation fields. For patients with a specific high‐risk profile, new approaches with more intense drug combinations are currently being investigated. Moreover, the advent of effective salvage high‐dose therapy for relapsed disease and a better understanding of prognostic factors have further improved the management of HL. Here, we summarize current strategies of the German Hodgkin Study Group (GHSG) in diagnostics and treatment of primary and relapsed HL, together with recent approaches for specific subgroups of HL patients.

Quality Management for Clinical Trials within the German Competence Network Paediatric Oncology and Haematology

The German ‘Competence Network Paediatric Oncology and Haematology’ aims at improving the structure of paediatric oncology and haematology as a whole, focussing in particular on the quality of clinical trials and study co-ordinating centres. This comprises the following measures: (1) Employment of research and trial assistants in order to improve the quality of documentation and study management in the participating hospitals. (2) Development of an internet portal to provide medical information for non-professionals, for patients and their families as well as for health professionals. (3) The project group ‘Central Trial Support’ supports study centres during the process of writing and examining new treatment protocols so that they are in compliance with the Good Clinical Practice criteria, formal criteria, legal requirements and statutory provisions. This group currently produces a structural standardisation of study protocols and case record forms in order to improve their usability. The ‘Competence Network Malignant Lymphomas’ is a project with similar aims and will be outlined for comparison.

Qualitätssicherungsprozesse in wissenschaftsinitiierten klinischen Studien

ZusammenfassungDurch das 12. Gesetz zur Änderung des Arzneimittelgesetzes (im Folgenden 12. AMG-Novelle) erfolgt eine Umsetzung der europäischen Richtlinie 2001/20/EG in deutsches Recht. Deren Ziel ist die Verankerung der guten klinischen Praxis (Good Clinical Practice, GCP) in die Gesetzgebung als ethischer und wissenschaftlicher Maßstab zur Planung, Durchführung, Dokumentation und Berichterstattung klinischer Studien am Menschen. Nach den ersten Erfahrungen mit der Umsetzung der 12. AMG-Novelle in die Praxis der Studiendurchführung stellt sich die Frage, inwieweit dieses Ziel in der wissenschaftsinitiierten klinischen Forschung erreichbar erscheint und ob die begrenzten finanziellen Mittel weiterhin im notwendigen Ausmaß die Durchführung von nichtkommerziellen klinischen Studien erlauben.AbstractThe 12th Amendment to the German Medicines Law (hereafter 12th AMG Amendment) implements the European Guideline 2001/20/EG into German law. The aim thereby is to establish good clinical practice (GCP) in the legislation as the ethical and scientific standard for planning, executing, documenting and reporting clinical trials on human subjects. Following initial experience with realisation of the 12th AMG Amendment in performing clinical trials, the questions arise: (1) to what extent this aim can be attained in non-commercial clinical research, and (2) whether, given financial constraints, sufficient non-commercial clinical trials can continue to be performed.

Qualitätsmanagement in Therapieoptimierungsstudien der Deutschen Hodgkin Lymphom Studiengruppe (DHSG)

Zulassungsstudien unterliegen strikten Reglements, die beispielsweise in dem Arzneimittelgesetz [2], dem Medizinproduktegesetz [3] und den ICH-Guidelines [4] festgelegt sind. Für Studien zur Optimierung der Standardversorgung, die im Falle medikamentöser Therapien nur zugelassene Arzneimittel einsetzen (Therapieoptimierungsstudien, TOS), sind vom Gesetzgeber keine entsprechend verbindlichen Regularien formuliert worden. Es herrscht jedoch Konsens darüber, dass auch dieser Studientyp der Deklaration von Helsinki und den ICH-Guidelines verpflichtet ist.