Prospective randomized trial to evaluate two delayed granulocyte colony stimulating factor administration schedules after high-dose cytarabine therapy in adult patients with acute lymphoblastic leukemia.

In acute lymphoblastic leukemia (ALL), treatment with granulocyte colony stimulating factor (G-CSF) during remission induction shortens granulocytopenia and may decrease morbidity due to infections. However, the optimal timing of G-CSF administration after chemotherapy is not known. In a prospective randomized multi-center study, adult ALL patients were treated with high-dose ARA-C [HDAC, 3 g/m(2) bid (1 g/m(2) bid for T-ALL) days 1-4] and mitoxantrone (MI 10 mg/m(2) days 3-5). They were randomized to receive recombinant human G-CSF (Lenograstim) 263 micro g/day SC starting either from day 12 (Group 1) or day 17 (Group 2). Fifty-five patients (41 male, 14 female) with a median age of 34 years (range: 18-55 years) were enrolled into the study; 50 patients were evaluable. The median duration of neutropenia <500/ micro l after HDAC/MI was 12 days (range: 7-22 days) in the early G-CSF Group 1 and also 12 days (range: 4-22 days) in the late G-CSF Group 2; this was shorter than in the historical control group (15 days, range: 4-43 days, n=46) where the patients received identical cytotoxic treatment without G-CSF. Seventeen infections were observed in 14 patients in Group 1 (47%) and 13 infections in 10 patients in Group 2 (50%) compared to 27 infections in 49 patients of the historical control (54%). In Group 1, the patients received a median of 11 injections with G-CSF (range: 7-22) compared to 7 injections (range: 4-19) in Group 2. The total administered dose of G-CSF in Group 2 was significantly reduced by 40% ( P<0.0001). The delayed start of G-CSF after HDAC/MI in ALL achieves the same clinical benefit compared to the earlier initiation of G-CSF. The reduction of treatment costs by reducing the total G-CSF dose may be important in future treatment with this hematopoietic growth factor.

IL-2 in combination with IFN- alpha and 5-FU versus tamoxifen in metastatic renal cell carcinoma: long-term results of a controlled randomized clinical trial.

We conducted a prospectively randomized clinical trial to compare the efficacy and safety of subcutaneous interferon-alpha2a, subcutaneous interleukin-2 and intravenous 5-fluorouracil as home therapy against oral tamoxifen in 78 patients with progressive metastatic renal cell carcinoma. Treatment courses consisted of interferon-alpha2a 5 x 10(6) IU m(-2), day 1 weeks 1 + 4; days 1, 3, 5 weeks 2 + 3; 10 x 10(6) IU m(-2), days 1, 3, 5 weeks 5-8; interleukin-2 10 x 10(6) IU m(-2), twice daily days 3-5 weeks 1 + 4; 5 x 10(6) IU m(-2), days 1, 3, 5 weeks 2 + 3; and 5-fluorouracil 1000 mg m(-2), day 1 weeks 5-8. The tamoxifen group received tamoxifen 80 mg twice daily over 8 weeks. Among 41 patients treated with interleukin-2, interferon-alpha2a and 5-fluorouracil there were 7 complete (17.1%) and 9 partial responders (21.9%), with an overall objective response rate of 39.1% (95% CI, 24.2-55.5). An additional 15 patients (36.6%) were stable throughout therapy. The overall survival was 24 months (range 5-76+). In 37 patients receiving tamoxifen no objective remissions occurred. 13 patients (35.1%) had stable disease and 24 patients (64.9%) showed continued disease progression. The overall survival was 13 months (range 3-73+). In summary, this home-based therapy regimen of interferon-alpha2a, interleukin-2 and 5-fluorouracil demonstrated significant therapeutic efficacy in patients with progressive renal cell carcinoma when compared to hormonal therapy.

ASHAP--an effective salvage therapy for recurrent and refractory malignant lymphomas.

BACKGROUND: This study was performed to examine the efficacy and toxicity of the combination of adriamycin (ADR), methylprednisolone (solumedrol), cytarabine (Ara-C), and cisplatin (CDDP) in patients with recurrent and refractory malignant lymphomas. PATIENTS AND METHODS: Sixty-five patients with Hodgkin's disease (HD) (n=14) or non-Hodgkin's lymphomas (NHL) (n = 51) were enrolled in the study. The ASHAP therapy consisted of ADR (40 mg/m2 by continuous infusion (CI) over 96 h), methylprednisolone (500 mg i.v., days 1-5), Ara-C (2 g/m2 as a 2-h infusion on day 5), and CDDP (100 mg/m2 by CI over 96 h). RESULTS: Twenty-five patients (38%) achieved complete remission (CR) and 20 (31%) were taken into partial remission (PR) for an overall response rate of 69%. Thirty-two patients with CR or PR following ASHAP underwent high-dose therapy (HDT) with subsequent hematopoietic stem cell transplantation. After a median follow-up of 52 months, 13 patients are in continuous CR (CCR), the 3-year event-free survival (EFS) was 30% for responders and 21% for all patients. The median overall survival (OS) was 12 months (range 0-70 months), and the OS rate after 3 years was 32%. Unfavorable prognostic factors for EFS and OS by univariate analysis were an elevated value of the serum lactate dehydrogenase and refractory lymphoma. The most frequently observed side effects following ASHAP were leukocytopenia and thrombocytopenia of World Health Organization (WHO) grades III/IV in approximately 80% of all courses. Non-hematological toxicities such as gastrointestinal side effects, infections, mucositis, renal and neurotoxicity occurred more rarely and reached WHO grades III/IV only occasionally. No treatment-related mortality with ASHAP was observed. CONCLUSIONS: ASHAP is an effective and moderately toxic salvage therapy for patients with recurrent or refractory HD and NHL. The results in patients responding to ASHAP and afterwards undergoing HDT with stem cell support are comparable with other established protocols and indicate an improvement in survival if HDT is carried out as intensification.

Gemcitabine and cisplatin in the treatment of advanced or metastatic pancreatic cancer.

BACKGROUND: This phase II study was initiated to determine the efficacy and safety of gemcitabine plus cisplatin in patients with pancreatic cancer. PATIENTS AND METHODS: Gemcitabine 1000 mg/m2 was given on days 1, 8, and 15 of a 28-day schedule, and cisplatin 50 mg/m2 on days 1 and 15 to chemonaive patients with locally advanced or metastatic pancreatic cancer. RESULTS: Of the 41 patients enrolled (median age 57, and 61% male), median Karnofsky performance status was 80%. Patients received a median of 4.2 cycles (range 1-11). In 35 evaluable patients, one complete response (CR) and three partial responses (PR) were observed, for an overall response rate of 11% (95% confidence interval (95% CI): 3.2% -26.7%). Stable disease (SD) > 3 months occurred in 20 (57%) patients; 6 survived > or = 1 year. Median time to progressive disease was 4.3 months (95% CI: 3.0-5.7 months). For all patients, median survival was 8.2 months (95% CI: 6.1-10.6 months) with a one-year survival rate of 27%. Therapy was well tolerated. Grade 3-4 neutropenia (no grade 3-4 infection), thrombocytopenia (no bleeding), nausea/vomiting, and alopecia were reported in 29%, 13%, and 2.6% of patients, respectively. CONCLUSIONS: The combination of gemcitabine and cisplatin is a moderately active treatment for patients with locally advanced and metastatic pancreatic cancer without compromising tolerability.

The use of dose-intensified chemotherapy in the treatment of metastatic nonseminomatous testicular germ cell tumors. German Testicular Cancer Study Group.

With the use of a cisplatin-based chemotherapy, metastatic testicular cancer has become a model for a highly curable malignant disease. Current data show that 70% to 80% of patients with this disease will achieve long-term survival following cisplatin/etoposide/bleomycin therapy. The role of high-dose chemotherapy with autologous stem cell support is being investigated in metastatic germ cell cancer in attempts to improve outcome for patients whose disease relapses after standard-dose chemotherapy and for those who present initially with advanced metastatic disease. Prognostic categories for patients receiving high-dose salvage chemotherapy have recently been developed: cisplatin-refractory disease, beta-human chorionic gonadotropin values greater than 1,000 U/L, and primary mediastinal germ cell tumors are factors characterizing patients who will derive less benefit from high-dose chemotherapy than those with chemosensitive disease at relapse. While standard-dose salvage chemotherapy achieves only a 20% long-term survival rate, high-dose salvage chemotherapy may yield a cure rate of approximately 40%. A randomized study comparing high-dose therapy with conventional-dose therapy (IT94 coordinated by the European Group for Blood and Marrow Transplantation) in patients with relapsed disease is ongoing to substantiate this observation. The use of dose-intensive therapy as first-line treatment is currently being studied by several institutions. High-dose therapy may be better tolerated when used first line compared with its use in the salvage situation, and may also achieve a rapid initial cell kill before cytostatic drug resistance develops. The German Testicular Cancer Study Group has developed a sequential high-dose combination regimen of cisplatin/etoposide/ifosfamide given with granulocyte colony-stimulating factor and peripheral blood stem cell support for four cycles every 3 weeks. This ongoing study, started in 1990, had accrued 218 patients with advanced testicular germ cell tumors as of June 1997. Of 141 evaluable patients receiving dose levels 1 through 5, 82 (58%) have achieved complete remission with no evidence of disease and 32 (23%) have achieved partial remission with marker normalization. The early death rate was 8%. Overall and event-free survival rates at 2 years are 78% and 73%, respectively, with a projected 5-year overall survival rate of 74%. Despite favorable preliminary results, this approach cannot be considered standard treatment. Currently, high-dose chemotherapy with peripheral blood stem cell transplantation should be administered to patients with testicular cancer only within controlled clinical trials to allow long-term cure rates and treatment-related late side effects to be evaluated.

Detection of melanoma cells in peripheral blood stem cell harvests of patients with progressive metastatic malignant melanoma.

The detection of melanocyte-specific messenger RNA in patients with malignant melanoma suggests the potential contamination of peripheral blood stem cell (PBSC) harvests by neoplastic cells. In this study, the melanocyte-specific transcripts of tyrosinase and Melan-A/MART-1 were used to detect neoplastic cells in PBSC harvests of nine metastatic malignant melanoma patients. Only one patient's PBSC harvest tested positive for tyrosinase. All harvests were negative for Melan-A/MART-1. Our results suggest that contamination of PBSC harvests with neoplastic cells may not contribute to disease progression following high-dose chemotherapy in advanced malignant melanoma.

[Patient questionnaire for an epidemiologic cancer registry--results of an initial trial]. / Patientenfragebogen für ein epidemiologisches Krebsregister-Ergebnisse eines erstmaligen Einsatzes.

For the first time a patient questionnaire was employed for an epidemiologic cancer registry to complete special history data routinely. After a successful pretest in 1995 it is being employed in the region Weser-Ems (Lower Saxony) since March 1996. The quality criterion completeness increased compared to the previously used sheet for history data, which had be filled in by the doctor. The quota of missing questionnaires is 10% and may be lowered by efficient measures. The occupational data should be used critically for comparison with other data sources (e.g. Bundesanstalt für Arbeit [BfA]) or studies, because the code used by the BfA has been designed for other purposes and cannot be applied to investigations of occupational cancer risks. The geographical relation to cancer will be difficult to estimate because of the obvious mobility of the people.

[Interdisciplinary guidelines: cholelithiasis]. / Interdisziplinäre Leitlinien: Cholelithiasis.

Quality management in internal medicine and surgery is especially difficult because of the magnitude of these two subjects. Between the years 1994 and 1996, the German scientific societies of internal medicine developed the manual "Rationelle Diagnostik und Therapie in der Inneren Medizin". The cooperation of colleagues was most helpful when the interests of several internal branches were involved. An even greater challenge is the development of interdisciplinary internal and surgical guidelines, which are presented here for cholelithiasis.