A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma

The purpose of this study was to compare the response rate, overall and 1-year survival in patients with advanced melanoma treated with a standard therapy, dacarbazine and interferon-alpha (DTIC/IFN), or combination chemotherapy, consisting of dacarbazine, BCNU, cisplatin and tamoxifen (DBCT). Treatment toxicity and time spent in hospital were secondary end points. One hundred and five patients (of whom 100 were eligible) were randomized to receive either DTIC/IFN or DBCT. The trial was designed to detect a 25% absolute difference in response rate or in 1-year survival with 80% power. There was no significant difference in response rate: this was 17.3% with DTIC/IFN and 26.4% with DBCT. Median overall survival was similar at 199 and 202 days respectively. One-year survival rate favoured standard treatment (30.6 vs 22.6%), but did not differ significantly between arms. DBCT was associated with significantly greater haematological toxicity, and a greater need for time spent in hospital (5.75 days/treatment cycle vs 2.29 with dacarbazine and interferon). DBCT combination therapy cannot be recommended as standard treatment for advanced melanoma. Dacarbazine remains the standard chemotherapy for this condition.     

Phase II randomized study of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine alone in advanced melanoma patients

This randomized phase II trial was performed to define the activity and toxicity of the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP) and tamoxifen (DBDT regimen) versus DTIC alone in patients with metastatic melanoma. Sixty patients with metastatic melanoma were randomly assigned to receive BCNU 150 mg/m2 intravenously (i.v.) on day 1, cisplatin 25 mg/m2 i.v. daily on days 1 to 3, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and tamoxifen 160 mg orally daily for 7 days prior to chemotherapy (DBDT arm; arm A). Treatment cycles were repeated every 28 days, while BCNU was given every two cycles. The DTIC arm (arm B) patients received DTIC alone 1200 mg/m2 i.v. on day 1, repeated every 21 days. Patients were evaluated every two cycles; responding patients continued the treatment for a maximum of 12 cycles. The overall response rate was 26% in the DBDT arm and 5% in the DTIC arm. Complete responses were 2.5% for DBDT and 0% for DTIC. The median progression-free survival and the median survival were 4 and 9 months, respectively for DBDT, and 2 and 7 months for DTIC. DBDT was associated with significant haematological toxicity: 33% of the patients experienced a grade III or IV neutropenia and 28% a grade III or IV thrombocytopenia. In conclusion, the overall response rate obtained with DBDT was greater than that obtained with DTIC alone; however, this combination increases toxicity with limited impact on overall survival.     

Experience with interferon alpha 2b combined with dacarbazine in the treatment of metastatic malignant melanoma

A prospectively randomized trial was undertaken to compare dacarbazine (DTIC) alone with DTIC plus interferon in patients with metastatic malignant melanoma. Of the 73 patients who entered on the study, 36 were randomized to receive DTIC alone and 37 were randomized to receive the combination DTIC plus interferon. The two sections were well balanced. There was more toxicity on the combination section, but no life threatening toxicity. The overall response rate for patients on DTIC was 20% (two complete and five partial responses)(95% CI 7–39%) and for patients on DTIC plus interferon was 50% (13 complete and four partial responses)(95% CI 26–72%) (p=0.007). The median time to treatment failure, was significantly more in favour of the combination treatment (9versus 2.5 months;p < 0.01, Mantel-Cox). The median survival of 16.7versus 8 months was in favor of the combination treatment (p < 0.01). The reasons for the improved results with the combination treatment are discussed. The Eastern Cooperative Oncology Group is currently, based on the results of this study, investigating the role of interferon combinations in metastatic malignant melanoma     

Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma

Purpose: A phase II study was undertaken to determine the efficacy oftirapazamine (TPZ) combined with cisplatin (cDDP) in patients with metastaticmelanoma.Patients and methods: Between June 1994 and November 1995, 48 patients withmetastatic melanoma were treated with TPZ (260 mg/m²,administered intravenously over two hours) followed in one-hour by cDDP (75mg/m² over one hour) every 21 days. Sixteen patients hadreceived prior chemotherapy, and 13 of these had failed to respond to priorcDDP. None of the patients had symptomatic brain metastasis.Results: Nine patients had partial responses, with an overall response rateof 19% (95% confidence interval (95% CI) of9%–33%). The median duration of response was six months.None of the responders had received prior chemotherapy. Responses were seenin 8 (33%, confidence interval of 16%–55%) of 24patients with primary cutaneous melanoma who had received no priorchemotherapy and in the only patient with previously untreated conjunctivalmelanoma. There were no responders among the seven patients with choroidalmelanoma and 16 patients with previously treated cutaneous melanoma. Twopatients with partial responses were rendered free of gross disease surgicallythree months after completing eight courses of TPZ-cDDP; they remain free oftumor recurrence. Responses were seen in lymph nodes (27%), lung(26%), skin (20%), adrenal gland (20%), soft tissues(17%) and liver (17%). Common toxicities included muscle cramps,fatigue, gastrointestinal effects and peripheral neuropathy. Fatigue, nausea,vomiting, anorexia, and muscle cramps were grade 3 or 4 in less than10% of the courses. Neutropenia and thrombocytopenia were rare.Conclusion: The TPZ-cDDP combination has definite activity againstchemotherapy-naïve patients with cutaneous melanoma and warrant furtherstudies in combination with other cytotoxic agents.     

Cyclosporine A, alpha-lnterferon and interleukin-2 following chemotherapy with BCNU, DTIC, cisplatin, and tamoxifen: a phase II study in advanced melanoma

Preclinical data suggest that one method of inducing autoimmunity to tumor is the administration and subsequent withdrawal of cyclosporine A following chemotherapy and that this effect may be enhanced with interferon and interleukin-2. Consequently, we performed a phase II trial in patients with advanced melanoma to explore this approach. Thirty-three patients were treated with BCNU (150 mg/m2 iv every 8 weeks), cisplatin (25 mg/m2 iv days 1-3) every 4 weeks, DTIC (220 mg/m2 iv days 1-3 every 4 weeks) along with tamoxifen (10 mg po BID days 1-4). Cyclosporine A at 3 mg/kg/day in two divided doses was given on days 4-21, alpha-interferon 1 million units/m2 subcutaneously every other day on days 4-21 and interleukin-2 1 million units/m2 BID subcutaneously days 21-28 were also given. Of the 33 patients, 3 patients (9%) had complete response and 8 patients (24%) had a partial response for a total response rate of 33% (95% confidence interval 18-52%). Median duration of response was 17 months (range 3+ to 24+ months). Six patients continue to show no signs of tumor progression for 3+, 5+, 10+, 24+, 60+, and 72+ months. Toxicity was generally well tolerated and included myelosuppression and fatigue. This regimen is feasible and generally tolerable and has produced an antitumor response rate comparable with inpatient biochemotherapy regimens.     

Phase II study of decarbazine (DTIC) in malignant melanoma. DTIC Research Group

A phase II study of DTIC was carried out with a response rate (CR and PR) of 24.2%. Metastases to liver, lymph nodes and subcutaneous tissues were susceptible to the drug. Most of the adverse reactions observed were upper gastrointestinal symptoms such as nausea in 15.4%, vomiting in 5.8% and anorexia in 3.8%. Alterations in white blood cells, red blood cells or platelets exceeding Grade 2 were not observed. As for biochemistry, GOT was increased in 25.0% and GPT in 28.2%. However, these were mild and transient changes, disappearing in 3 to 4 weeks. The results seem to reproduce those of various U.S. group studies.     

GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): A phase I trial in melanoma

Background:Ineffective tumour antigen processing is recognisedas an important cause of failure of immunotherapy in melanoma. GM-CSF mayaugment the cytotoxic lymphocyte response by activating antigen-presentingcells. This study evaluates a schedule combining GM-CSF with biochemotherapy. Patients and methods:Nineteen patients with advanced malignantmelanoma received cisplatin (25 mg/m² days 1–3), dacarbazine(220 mg/m² days 1–3), interleukin-2 (9 MIU/m²/24h)and interferon-2b (5 MIU/m²) both days 6–10 and days17–21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF wasgiven in escalating doses to three cohorts: 1) 450 µg/m² days4–5 and 15–16; 2) as 1) plus 225 µg/m² days6–10 and 17–21; 3) 450 µg/m² days 4–10 and15–21. Each cycle was 28 days. Results:Constitutional side effects were the majornon-haematological toxicity and lymphopaenia the main haematological toxicity.Six patients responded (32%, 95% confidence interval:13%–57%), two patients had complete remission. There wasan apparent trend for increasing responses with increasing GM-CSF dose; zeroof six responses in cohort 1, two of seven in cohort 2 and three of six incohort 3 (P = 0.016). Median overall survival was 6.2 months.Increasing GM-CSF doses significantly increased serum concentrations ofneopterin and TNF-. Conclusions:The combination of GM-CSF with biochemotherapy isfeasible and there appears to be a dose-response relationship with GM-CSF interms of host immunological response, and possibly clinical efficacy.     

Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma.

The purpose of this study was to evaluate in a randomized phase II trial the efficacy and toxicity of combination biochemotherapy compared with chemotherapy alone in patients with metastatic melanoma. Sixty-five patients with metastatic melanoma (ECOG performance status 0 or 1) were randomized to receive intravenous BCNU 100 mg m(-2) (day 1, alternate courses), cisplatin 25 mg m(-2) (days 1-3), DTIC 220 mg m(-2) (days 1-3) and oral tamoxifen 40 mg (BCDT regimen) with (n = 35) or without (n = 30) subcutaneous interleukin 2 (IL-2) 18 x 10(6) iu t.d.s. (day - 2), 9 x 10(6) iu b.d. (day - 1 and 0) and interferon 2 alpha (IFN-alpha) 9 MU (days 1-3). Evidence for immune activation was determined by flow cytometric analysis of peripheral blood lymphocytes. Treatment was repeated every 4 weeks up to six courses depending on response. The overall response rate of BCDT with IL-2/IFN-alpha was 23% [95% confidence interval (CI) 10-40%] with one complete response (CR) and seven partial responses (PR), and for BCDT alone 27% (95% CI 12-46%) with eight PRs; the median durations of response were 2.8 months and 2.5 months respectively. Sites of response were similar in both groups. There was no difference between the two groups in progression-free survival or overall survival (median survival 5 months for BCDT with IL-2/IFNalpha and 5.5 months for BCDT alone). Although 3 days of subcutaneous IL-2 resulted in significant lymphopenia, evidence of immune activation was indicated by a significant rise in the percentage of CD56- (NK cells) and CD3/HLA-DR-positive (activated T cells) subsets, without any change in the percentage of CD4 or CD4 T-cell subsets. Toxicity assessment revealed a significantly higher incidence of severe thrombocytopenia in patients treated with combination chemotherapy than with chemotherapy alone (37% vs 13%, P = 0.03) and a higher incidence of grade 3/4 flu-like symptoms (20% vs 10%) and fatigue (26% vs 13%). The addition of subcutaneous IL-2 and IFNalpha to BCDT chemotherapy in a randomized phase II trial resulted in immune activation but did not improve response rates in patients with metastatic melanoma, and indeed may increase some treatment-related toxicity.     

Combination chemotherapy with vinblastine, BCNU and cisplatin in advanced malignant melanoma

A combination chemotherapy including vinblastine (6 mg/m2 i.v. days 1-2), BCNU (100 mg/m2 i.v. day 3), and cisplatin (50 mg/m2 i.v. day 5) was given as salvage treatment in 46 consecutive, previously treated patients affected by metastatic malignant melanoma. Courses were planned every 4 weeks provided that a complete bone marrow recovery occurred, otherwise they were delayed for 1-2 additional weeks. Objective responses (3 CRs and 10 PRs) were observed in 13/46 (28%) patients; 12 cases had stable disease and 21 patients progressive disease during treatment. Median duration of response was 13 months (range, 5-18), and median survival was 11 months (range, 3-20) for all patients. Nausea and vomiting were the most distressing side effects, whereas a grade I leukopenia caused a delayed treatment in 90% of patients. In conclusion, the combination chemotherapy was moderately toxic and did not seem to give substantially better results than obtained with other reported regimens.     

Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas

Purpose: Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen. Methods: Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m² infused over 180 min followed by DTIC 500 mg/m² (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2′,2′-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions. Results: Twenty-six patients received a total of 158 cycles (mean four cycles, range 1–18). Grade 3–4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or γ-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0–24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine. Conclusions: Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.J. Fra and R. Losa contributed equally to this work.     

Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity. RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived > or = 1 year.There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm. CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.     

Combination therapy for advanced malignant melanoma with BCNU,pseudomonas vaccine,and heparin

A study was undertaken to investigate the addition of heparin and pseudomonas vaccine to BCNU in the treatment of patients with progressive malignant melanoma refractory to front-line therapeutic regimens containing DTIC. Out of 27 evaluable patients, there was one partial remission (4%), and an additional ten patients (41%) had at least stable disease with a median survival time of 39 weeks compared to 15 weeks for those with progressive disease. The therapy was well tolerated. A schedule of pseudomonas vaccine that seemed to be tolerated has been established.     

Phase II trial of procarbazine, vincristine and lomustine (POC) chemotherapy in metastatic cutaneous malignant melanoma

40 patients with symptomatic metastatic melanoma were treated with procarbazine, vincristine and lomustine (POC). 4 patients had received chemotherapy previously. Responses were seen in 8 patients (20%), 4 of whom had a complete remission. All responding patients had some rumour shrinkage after one cycle. The median duration of response was 27 weeks, with 2 patients remaining in complete remission at 6 and 6.5 years. The median survival for the whole group was 22 weeks, whilst that of the responding patients was 35 weeks. Using conventional anti-emetics, the principal toxicities were nausea and vomiting, severe in 15% of cycles. Other nonhaematological toxicity was uncommon. Neutropenia (WHO grade 3 or 4) occurred in 11% of cycles and thrombocytopenia in 8%. The response rate of metastatic melanoma to POC chemotherapy was similar to other cytotoxic regimens though toxicity, other than nausea and vomiting, was minimal. The rapid response allows patients with unresponsive disease to be identified early, avoiding continuing toxicity.     

Risk and outcome in metastatic malignant melanoma patients receiving DTIC, cisplatin, BCNU and tamoxifen followed by immunotherapy with interleukin 2 and interferon alpha2a.

Combined chemo-/immunotherapy has shown high objective response rates and a significant though small proportion of long-term complete responders in metastatic malignant melanoma. The purpose of this study was to determine response rates, freedom from treatment failure (FFTF) and overall survival in patients with advanced metastatic malignant melanoma treated with combined chemo-/immunotherapy, and to determine the value of a prognostic model for prediction of treatment outcome, FFTF and survival. Sixty-nine patients with metastatic malignant melanoma received combined chemo-/immunotherapy consisting of up to four cycles of DTIC (220 mg m(-2) i.v. days 1-3), cisplatin (35 mg m(-2) i.v. days 1-3), BCNU (150 mg m(-2) i.v. day 1, cycles 1 and 3 only) and tamoxifen (20 mg orally, daily). Two cycles of chemotherapy were followed by 6 weeks of outpatient immunotherapy with combined interleukin 2 (20 x 10(6) IU m(-2) days 3-5, weeks 1 and 4; 5 x 10(6) IU m(-2) days 1, 3, 5, weeks 2, 3, 5, 6) and interferon-alpha (6 x 10(6) IU m(-2) s.c. day 1, weeks 1 and 4; days 1, 3, 5, weeks 2, 3, 5, 6). All patients were evaluated on an intention-to-treat basis. Of 69 patients entered in the study, seven achieved complete remissions and 20 reached partial remissions with an objective response rate of 39% (95% confidence interval 28-52%). Median survival was 11 months, median FFTF was 5 months. Seven patients achieved ongoing long-term remissions, with maximum survival of 58 + months, and maximum FFTF of 58 + months. By Kaplan-Meier survival analysis and two-proportional Cox regression analysis, pretreatment performance status and serum lactic dehydrogenase were statistically significant and independent predictors of survival; risk groups could be defined as (a) the absence of both or (b) the presence of either one or both of these risk factors. Whereas survival and response were significantly influenced by patient risk, no influence could be demonstrated for FFTF. This combined outpatient chemo-/immunotherapy is feasible and results in objective response rates and survival similar to earlier trials. Pretreatment risk, as defined by serum lactate dehydrogenase (LDH) and performance status, has a significant impact on treatment outcome and patient survival.     

Chemoimmunohormonal therapy with carmustine,dacarbazine, cisplatin,tamoxifen, and interferon for metastatic melanoma: a prospective phase II study

The objective of this study was to investigate the efficacy of our treatment regimen in metastatic melanoma. Thirty patients entered the study after undergoing a thorough metastatic workup. Treatment protocol included carmustine (BCNU) (150 mg/m(2) IV, day 1) every 6 weeks, dacarbazine (DTIC) (220 mg/m(2) IV, days 1-3), and cisplatin (25 mg/m(2) IV, days 1-3) every 3 weeks, interferon A-2B (6 x 10(6) U/m daily s.c. on days 4-8 and 16-20) and tamoxifen 20 mg/day for 6 weeks. Among 29 evaluable patients, overall response was seen in 15 (52%) and complete response in 5 (17%) patients. Median duration of partial response was 4 months (range, 1-12 months); of complete response was 8 months (range, 2-14 months). Complete response continues in two patients with lung metastases. Median survival time was 8.7 months. Side effects were tolerable. Four (13%) patients developed neutropenic fever, and platelet transfusions were required in five (17%) patients. One patient died of neutropenic sepsis. Thrombocytopenia caused prolongation of the median interval between the first and second courses, and drug doses were reduced in the second course in 8 of 26 (31%) patients. Our chemoimmunohormonal regimen is efficient in metastatic malignant melanoma and can induce durable remission. Severe thrombocytopenia leads to a reduction of carmustine dose in a new protocol.     

Phase II study of dibromodulcitol and BCNU in metastatic malignant melanoma

Dibromodulcitol (DBD) and BCNU were administered to 20 patients with metastatic malignant melanoma who had not received prior chemotherapy. One complete and three partial responses were noted; duration of response was short. Dose limiting toxicity was thrombocytopenia. DBD and BCNU do not appear to improve response over single agent therapy for disseminated melanoma.     

Phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma.

PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m(2) given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and (1/2) normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m(2) IV for 1 hour in 500 mL of dextrose and (1/2) NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m(2) IV for 2 to 3 hours in 750 to 1,000 mL of dextrose and 5% water on day 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P =.429) and overall survival (P =.545) were not found to differ by treatment. CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.     

Treatment of metastatic malignant melanoma with 24 hours continuous venous infusion of dacarbazine and cisplatin

Twenty consecutive patients with metastatic malignant melanoma were treated with a combination of 24 hours continuous infusion of dacarbazine (250 mg/m2) and cisplatin (20 mg/m2) for 5 days every 3 weeks. One patient (5%) achieved a complete response (CR) and 3 patients (15%) obtained a partial response (PR) with an overall response rate of 20%. Minimal response was observed in 5 other patients (25%). Complete response duration was 8 months. Median response duration of partial responders was 7 months. Median survival of all responders (CR+PR) was 8.5 months. Toxicity was mild to moderate.     

Phase II study of bleomycin,actinomycin D,DTIC and vindesine in disseminated malignant melanoma

Twenty-seven patients with disseminated malignant melanoma were treated with combination chemotherapy consisting of bleomycin, actinomycin D, DTIC and vindesine. There were 4 complete responses in patients with pulmonary metastasis, 5 patients had a partial remission, 2 of them had mainly lung lesions. Toxicity consisted mainly of leuco- and thrombocytopenia of short duration and sporadic severe mucositis.