Upfront maintenance therapy with arsenic trioxide in acute promyelocytic leukemia provides no benefit for non‐t(15;17) subtype

Aims: The optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved complete remission (CR) and complete consolidation chemotherapy is still controversial. Whether the use of arsenic trioxide (ATO) alone or along with all‐trans retinoic acid (ATRA) improves overall survival (OS) or disease‐free survival (DFS) is still debated. Methods: A retrospective reivew was conducted of 20 patients diagnosed with APL according to the French – American – British system. After achieving CR and receiving consolidation chemotherapy, nine patients were given maintenance therapy for 1 year (ATRA 45 mg/m²/day p.o., mercaptopurine 60 mg/m²/day p.o. and ATO 0.15 mg/kg/day × 5 days/week for six cycles in five patients; ATRA 45 mg/m²/d p.o. alternating with ATO 0.15 mg/kg/day × 5 days/week in 1 patient; ATRA only in three patients). Results: In all patients the rates of CR, 3‐year OS and 5‐year OS were 75, 71 and 57%, respectively. For patients treated with ATO maintenance, the rates were 100% for both 5‐year OS and 5‐year DFS. Four of six patients on ATO maintenance had grade 1 or grade 2 adverse events. Excluding the two patients who died from intracerebral hemorrhage within 4 days after diagnosis, these rates were 85, 82 and 78%, respectively. Conclusion: Upfront ATO maintenance therapy for one year is safe and appears to be effective, with the benefits restricted to patients with APL with t(15;17) translocation. Larger studies will be required to confirm this observation.     

Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia: the APL92 study of the Japan Adult Leukemia Study Group (JALSG)

All-trans-retinoic acid (ATRA) has been incorporated in front-line therapy for newly diagnosed acute promyelocytic leukemia (APL). We conducted a multicenter study of differentiation therapy with ATRA alone or in combination with chemotherapy followed by intensive postremission chemotherapy in patients with APL (the JALSG APL92 study), and analyzed prognostic factors to increase the cure rate in our subsequent trial. From 1992 to 1997, adult patients with newly diagnosed APL received oral ATRA 45 mg/m2 daily alone until complete remission (CR) if initial leukocyte counts were < 3.0x10(9)/l, and ATRA daily plus daunorubicin (DNR) 40 mg/m2x3 days plus enocitabine (BHAC) 200 mg/m2x5 days if leukocyte counts were > or =3.0 x 10(9)/l. If peripheral blasts exceeded 1.0x10(9)/l during therapy, DNRx3 days plus BHACx5 days was added. After CR was achieved, three courses of consolidation and six courses of maintenance/intensification chemotherapy were administered. Of 376 patients enrolled, 369 were evaluable (median age 46 years, range 15-86 years; median leukocyte counts 2.0x10(9)/l), and 333 (90%) achieved CR (94% of patients treated with ATRA alone, 88% with ATRA plus later chemotherapy, 89% with ATRA plus initial chemotherapy, and 86% with ATRA plus initial and later chemotherapy). At a median follow-up of 45 months, the predicted 6-year overall and event-free survival (EFS) rates for all patients were 65% and 52%, respectively. Favorable prognostic factors for CR were younger age, no or mild purpura, high serum total protein level, low lactate dehydrogenase level, and no or mild disseminated intravascular coagulation (DIC). Favorable prognostic factors for EFS were leukocyte counts < 10.0x10(9)/l, mild DIC, and no sepsis during induction therapy. In the JALSG APL97 study, we intensified chemotherapy for patients with leukocyte counts > or =3.0x10(9)/l, and are randomly testing whether further chemotherapy is required for APL patients with negative PCR for PML/retinoic acid receptor alpha in the maintenance phase.     

Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. APL Study Group. Acute promyelocytic leukemia.

The purpose of this study was to assess the safety and efficacy of stem cell transplantation (SCT) mainly autologous SCT as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2). Fifty adult patients with a first relapsed APL, of whom 39 had been previously treated with ATRA, entered a multicenter trial of oral ATRA until complete remission (CR) achievement followed by timed sequential chemotherapy (EMA combining etoposide 200 mg/m2/day for 3 days, mitoxantrone 12 mg/m2/day for 3 days, and cytarabine 500 mg/m2/day for two sequences of 3 days). EMA was started either after CR achievement, or on day 1 of ATRA because of initial white blood cell (WBC) counts >5 x 10(9)/l, or rapidly added to ATRA in order to prevent ATRA syndrome because WBC count increased under ATRA. Forty-five patients (90%, 95% CI 78%-97%) were in CR after induction therapy. Five patients died from infection during aplasia following EMA chemotherapy. Eleven patients who achieved CR had a familial HLA-identical donor and were allografted. The median disease-free survival (DFS) of allografted patients was 8.2 months. The 34 other CR patients were scheduled for autologous peripheral blood (PB) SCT (intent-to-treat group). Actually, autologous transplantation was only carried out in 22 patients (65%) (17 PBSCT and five autologous bone marrow transplantation (BMT)). Reasons for not autografting were early relapse (three patients), severe toxicity of EMA chemotherapy (six patients), and refusal or failure of stem cell harvest (three patients). The 3-year DFS rate of patients actually autografted was 77%. Among the 17 autografted patients still in CR2, nine patients have already reached a longer CR2 than first CR (CR1). Results of detection of PML/RARalpha by RT-PCR after autologous transplantation show negative findings in eight of the nine patients tested. We conclude that (1) ATRA combined to EMA chemotherapy is effective in the treatment of relapsed APL; (2) allogeneic BMT may be too toxic after salvage treatment including EMA intensive chemotherapy; (3) clinical outcome of autografted patients and preliminary molecular results regarding detection of PML/RARalpha after autologous PBSCT are encouraging.     

The development of targeted chemotherapy for CNS lymphoma—a pilot study of the IDARAM regimen

Purpose We have developed and evaluated a CNS-targeted chemotherapy regimen based on the pharmacokinetic properties of the individual drugs in the combination.Patients and methods In a twin-track study, 16 patients with secondary CNS lymphoma (SCNSL) and 8 with primary CNS lymphoma (PCNSL) were treated with IDARAM which comprised idarubicin 10 mg/m² i.v., days 1 and 2; dexamethasone 100 mg, 12-h infusion, days 1, 2 and 3; cytosine arabinoside (ARA-C) 1.0 g/m², 1-h infusion, days 1 and 2; methotrexate 2.0 g/m², 6-h infusion, day 3 (with folinic acid rescue); and cytosine arabinoside 70 mg plus methotrexate 12 mg, intrathecally, days 1 and 8. Two cycles were delivered at 3-weekly intervals. After response assessment, patients received adjuvant cranial radiotherapy (40 Gy over 20 fractions).Results The series comprised 24 patients, 11 male and 13 female. Their median age was 53 years (range 21 to 73 years). Grade 4 neutropenia and thrombocytopenia occurred in the majority of patients treated. Of the eight PCNSL patients, seven achieved complete remission (CR). Four remained in CR at the time of this report with a median duration of follow-up of 25 months (range 11 to 42 months). Of the 16 SCNSL patients, 12 achieved CR. Seven patients remained in CR at the time of this report with a median duration of follow-up of 24 months (range 18 to 57 months).Conclusion This study suggests that IDARAM is an effective regimen in both PCNSL and SCNSL and is suitable for further development and evaluation.This work is presented on behalf of the Central and Southern Lymphoma Group.     

High-dose cyclophosphamide and VP 16 as late dosage intensification therapy for small cell carcinoma of lung

Summary This study investigated the use of late dose intensification therapy (LDIT) with cyclophosphamide (180 mg/kg) and VP 16 (1 g/m²) plus autologous bone marrow rescue in 22 patients with small cell lung cancer (SCLC). These patients were selected from a group of 95 patients who received three courses of a five-drug induction regimen comprising cyclophosphamide (750–1000 mg/m²), adriamycin (40 mg/m²), VP 16 (100 mg/m²) for 3 days, methotrexate (50 mg/m²) and vincristine (2 mg) (CAVMO). There were 16 patients with limited disease, 8 of whom were in complete remission (CR) and 8 in partial remission (PR) after the induction therapy. The other 6 patients had extensive disease; 3 of these achieved CR and 3 PR after induction therapy. Of the 11 patients in PR, 5 responded to LDIT; 3 had a further PR, and 2 CR. Subsequent to LDIT radiotherapy 4000 cGy was given to the primary site in 10 of the 22 patients. Since the start of the study, 19 of the 22 patients have relapsed and died (median survival 11 months), while 3 remain alive and in remission at 11, 11, and 24 moths. Comparison of the survival of patients receiving LDIT with that of an equivalent group (with respect to staging and response to induction chemotherapy) of patients who received induction chemotherapy alone showed no significant difference. In this study, LDIT following conventional induction therapy in patients with chemosensitive tumours did not improve survival.     

Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside,tetrahydrouridine, and carboplatin

Summary Eight patients, of whom four had acute myeloid leukemia (AML) and four had chronic myeloid leukemia (CML) blast crisis, were treated with a combination of cytosine arabinoside (ARA-C: 1,600 mg/m² in three patients, 1,200 mg/m² in five patients), tetrahydrouridine (THU: 2,800 mg/m² in two patients, 2,646 mg/m² in one patient, 2,100 mg/m² in five patients), and carboplatin (900 mg/m² in four patients, 720 mg/m² in one patient, 450 mg/m² in three patients). As a result of this treatment, five of the eight patients became aplastic. Two of the four patients with CML blast crisis reverted to the chronic phase and two of the four patients with acute nonlymphocytic leukemia (ANLL) attained a remission (one partial remission and one complete remission). The major toxicities included myelosuppression, unacceptable hepatotoxicity, and diarrhea. Pharmacokinetics studies revealed that the addition of carboplatin did not significantly change the disposition of ARA-C. ARA-C levels were not significantly changed in comparison with those obtained in a prior study of ARA-C with THU (ARA-C plasma levels at 3 h, 2630±1170 ng/ml).Supported by the Don Monti Memorial Research Foundation     

Single-agent liposomal all-trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M. D. Anderson Cancer Center Series

The present study aimed to investigate single-agent liposomal all-trans retinoic acid (Lipo-ATRA) in untreated acute promyelocytic leukemia (APL). Induction therapy consisted of Lipo-ATRA 90 mg/m2 i.v. every other day. Patients in complete remission (CR) continued to receive Lipo-ATRA 90 mg/m2 i.v. three times a week for 9 months. Idarubicin was added only if a polymerase chain reaction test for promyelocytic leukemia-retinoic acid receptor alpha (sensitivity level, 10(-4)), performed every 3 months from CR, was positive. The results were compared with those of a historical control group treated with oral ATRA and idarubicin. Lipo-ATRA induced CR in 79% of patients; CR rates were 92% and 38% in patients with white blood cell (WBC) counts <10 x 10(9)/L and >10 x 10(9)/L, respectively. Ten of the 26 responders to Lipo-ATRA remain in first CR at a median of 6.4 years, despite never receiving idarubicin; all 10 had initial WBC counts <10 x 10(9)/L. The 5-year survival rate was 76% for patients treated with Lipo-ATRA. Comparisons with oral ATRA+idarubicin as given at M. D. Anderson are confounded because of their historical nature and the absence of ATRA from post-remission therapy in the former group. Nonetheless, a multivariate Cox model identified higher WBC counts and older age, but not treatment (historical vs. Lipo-ATRA), as being predictive of shorter relapse-free and overall survival. Lipo-ATRA can cure patients presenting with WBC counts <10 x 10(9)/L (low risk) without additional therapy, contrary to conventional ATRA, which, when given alone, probably cures no patients. The observation that patients can be cured of APL without the use of chemotherapy should encourage further study of 'targeted' therapy in APL and in other leukemias.     

Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly

We conducted a randomized multicenter trial comparing low-dose cytarabine (LD ARA-C) (20 mg/m2 for 21 days) with an intensive chemotherapy (rubidazone [a daunorubicin-derived agent], 100 mg/m2 for 4 days, ARA-C 200 mg/m2 for 7 days) in 87 patients over 65 years of age with de novo acute nonlymphocytic leukemia (ANLL). Forty-one patients received LD ARA-C and 46 received intensive chemotherapy. The number of complete remissions (CRs) but also of early deaths was higher in the intensive chemotherapy group, while partial remissions (PRs) and failures were more frequent in the LD ARA-C group (P less than .001). Infectious complications during induction treatment were more numerous and more severe in the intensive chemotherapy group (P less than .01). Patients treated with LD ARA-C required fewer RBC transfusions (P less than .02), fewer platelet transfusions (P less than .01), and had a shorter hospital stay for induction treatment (P less than .01). Overall survival and CR duration were not significantly different in either group. In the LD ARA-C group, the survival of patients with PR and those of patients in CRs was identical. We conclude that in a selected group of elderly patients with de novo ANLL a higher number of CRs may be obtained with intensive chemotherapy, but that with LD ARA-C, the number of early deaths is lower, and long-lasting PRs are obtained, resulting in a similar overall survival.     

VAPEC-B chemotherapy in the treatment of aggressive non-Hodgkin's lymphoma: A retrospective analysis of 45 patients

We performed a retrospective analysis on 45 patients who, between January 1989 and October 1993, received VAPEC-B chemotherapy for high and intermediate grade non-Hodgkin's lymphoma. The aim was to assess response and tolerance to treatment. The weekly regimen consisted of: doxorubicin 35 mg/m² i.v. weeks 1,3,5,7,9,11; cyclophosphamide 350 mg/m² i.v. weeks 1, 5, 9; etoposide 100 mg/m² p.o. daily for 5 days, weeks 3,7,11; vincristine 1.4 mg/m² i.v. (2 mg max.) weeks 2, 4, 6, 8, 10; bleomycin 10 mg/m² i.v. weeks 2, 6, 10; methotrexate 12.5 mg i.t. weeks 1, 5, 9; prednisolone 50 mg p.o. daily for 6 weeks, reduced to 25 mg daily for 6 weeks. The patients treated were aged 22–71 years, 34 (75%) had high grade (Working Formulation) non-Hodgkin's lymphoma (NHL); 11 (24%) had intermediate grade NHL; 25 had Stage III/IV disease; and 14 (31%) had marrow involvement. The majority of patients (76%) received VAPEC-B as first line chemotherapy; the remainder received it for relapsing disease. Follow-up time from completion of VAPEC-B chemotherapy ranged from 6 months to 50 months (median 25). VAPEC-B, as first line therapy, induced a complete response (CR) and partial response (PR) in 79% and 18% respectively, whilst 3% had no response to treatment. VAPEC-B used for relapsing disease produced CR and PR in 64% and 27% respectively, whilst 9% failed to respond. Six patients in PR and five patients in CR have subsequently undergone an autologous bone marrow transplant or a peripheral blood stem cell transplant. In the group who received VAPEC-B first line but did not proceed to transplant (27 patients), five relapsed (three with CNS disease who had not had CNS prophylaxis). Tolerance to treatment was measured by WHO toxicity scores. The haemoglobin (Hb) toxicity median score for all patients was grade 1 (Hb 9.5–10.9 g/dl), and the white cell count (WCC), toxicity score was grade 2 (WCC 2.0–2.9 × 10⁹/l). No platelet toxicity was observed. Ten per cent of patients suffered grade 3 severity infections requiring antibiotics and there was one treatment related death. The majority of patients received VAPEC-B on time, however, 24% patients had a 2-week delay.VAPEC-B chemotherapy is an effective regimen for malignant lymphoma, either as a first line or as a salvage treatment. Although chemotherapy was given weekly, the tolerance to treatment was acceptable, thus making this short regimen a good alternative to CHOP chemotherapy.     

Cladribine in the Treatment of Acute Myeloid Leukemia: A Single-Institution Experience

BackgroundDespite advances in novel therapeutics, supportive care, and postremission therapy, the outcome of high-risk and elderly patients as well as those with relapsed/refractory acute myeloid leukemia (AML) remains poor. There is likely still room for improvement through optimizing conventional chemotherapy.Patients and MethodsThrough a pharmacy database search we identified all patients with AML treated at Washington University with cladribine-based regimens.ResultsTwenty-four patients were identified that were treated with 2 cladribine-based regimens: CLAG (cladribine [5 mg/m² days 1-5], cytarabine [2 g/m² days 1-5] and granulocyte colony-stimulating factor [G-CSF; 300 μg subcutaneously (s.c.) days 0-5]) and CLAM (cladribine [5 mg/m² days 1-5], cytarabine [2 g/m² days 1-5], G-CSF [300 mg s.c. days 0-5] and mitoxantrone [10 mg/m² days 1-3]). Complete responses were achieved in 53% of patients given induction chemotherapy and 44% of those given salvage chemotherapy. The regimens were well tolerated with minimal extramedullary toxicity.ConclusionThese data suggest that cladrabine-based regimens should be further explored in both the salvage and first-line setting and might offer an attractive backbone on which to add novel therapies.     

Analysis of efficacy and toxicity of chemotherapy with cisplatin, 5-fluorouracil, methotrexate and leucovorin (PFML) and radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck

Purpose The aim of this study was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), methotrexate (MTX) and leucovorin (LV) (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Methods Seventy-seven patients with previously untreated stages III–IV SCCHN were included in this trial. Patients received two cycles of chemotherapy repeated every 4 weeks. The chemotherapy regimen consisted CDDP (60 mg/m², day 4), 5-FU (600 mg/m² given over 24 h for 5 days, days 1–5), MTX (30 mg/m², day 1) and LV (20 mg/m², days 1–5). Radiation was targeted to begin on the starting day of chemotherapy, day 1. The total radiation dose to the primary site and neck lymph nodes was 70.0 Gy. When grade ≥3 toxicities were observed frequently, radiotherapy and/or chemotherapy were delayed or reduced. Results The main toxicities were mucositis (grade ≥3, 39%), leukocytopenia (grade ≥3, 34%) and neutropenia (grade ≥3, 30%). The overall clinical response rate and the pathological complete response (CR) were 94% (72/77) and 71% (55/77). The primary site CR and neck lymph node CR were 79% (61/77) and 85% (44/52), and 3-year survival rate was 73%. Conclusions This concurrent chemoradiotherapy with PFML was safe and well tolerated. The high CR rate justifies further evaluation of this chemoradiotherapy modality in locally advanced SCCHN patients.     

Epirubicin-containing high-dose chemotherapy followed by autologous hematopoietic progenitor cell transfusion for patients with chemotherapy-sensitive metastatic breast cancer: results of 5-year follow-up

Purpose: Conventional chemotherapy for metastatic breast cancer results in very few long-term survivors. With a view to overcoming this problem, we hypothesized that a higher rate of complete response (CR) would lead to more long-term survivors. Therefore, we conducted a phase II study of epirubicin-containing high-dose chemotherapy (HDC) followed by autologous hematopoietic progenitor cell transfusion in patients who were sensitive to induction chemotherapy. Methods: The induction chemotherapy consisted of doxorubicin 60 mg/m², cyclophosphamide 750 mg/m² and fluorouracil 750 mg/m² on day 1. Supported by G-CSF, this chemotherapy was repeated for at least three cycles at intervals of 2 weeks until the achievement of >50% tumor regression. The HDC comprised epirubicin 120 mg/m² on day 1, cyclophosphamide 60 mg/kg on days 1 to 3 and thiotepa 6 mg/kg on days 1 to 3, followed by autologous bone marrow transplantation and peripheral blood stem cell transfusion. Results: Of 25 patients who achieved a partial response to the induction chemotherapy, 17 were treated with the HDC. Of the 15 patients evaluable for response, 10 achieved a CR (67%), giving an overall CR rate of 43% (10/25). The disease-free survival rate at 5 years was 27%. The median duration of overall survival was 21 months and the overall survival rate at 5 years was 31%. However, the survival curves were not significantly different from those of the historical controls who achieved a CR or PR to conventional chemotherapy. There were three early deaths, one as a consequence of disease progression and two treatment-related (sepsis and heart failure). Diarrhea (grade 3, 76%) and stomatitis (grade 3–4, 29%) were the dose-limiting toxicities. Conclusions: The present study suggests that epirubicin-containing HDC is able to induce a high rate of CR, but its benefit in terms of survival is still unclear. To determine whether HDC can achieve a cure in some patients, further studies in a larger number of patients, with a longer follow-up, are necessary. Received: 23 February 1998 / Accepted: 13 May 1998     

Ifosfamide,Cisplatin and Etoposide (ICE)Combined Chemotherapy with Recombinant Human Granulocyte Colony-Stimulating Factor Support in Small Cell Lung Cancer

Abstract

This study was aimed to evaluate the effect of ifosfamide, cisplatin and etoposide (ICE) combined chemotherapy in small cell lung cancer (SCLC), and to test the feasibility of adding recombinant human granulocyte colony-stimulating factor (rhG-CSF) to aggressive chemotherapy. Thirty consecutive, previously untreated, patients with SCLC (17 with limited disease and 13 with extensive disease) entered this study. The ICE regimen consisted of ifosfamide (I) 4 g/m² i.v. with same dose mesna i.v. on first day, cisplatin (C) 25 mg/m² i.v. on days 1 to 3 and etoposide (E) 100 mg/m² i.v. on days 1 to 3. A total of 30 MU rhG-CSF i.v. were given from day 7 to 14 if WBC were lower than 3000x10⁶/L, neutrophils were lower than 1000x10⁶/L. Overall response (OR) rate was 93% with a complete response (CR) rate of 23%. Median survival was 12 months [95% confidence interval (CI): 11-14] and median response duration was 10 months [95% CI: 8-10]. Thirty-seven percent of patients had grade 3 neu-tropenia, 40% had grade 3 anemia, and 1% had grade 2 thrombocytopenia. Nonhematologic toxicity was mild with nausea and vomiting being the most common. RhG-CSF, which reduced leukopenic nadirs and shortened the neutropenic period, was also well tolerated. This chemotherapy protocol seems to be active, well tolerated and is currently being compared with various conventional chemotherapies.     

Neoadjuvant chemotherapy and operation for invasive masaoke stage III and IVa thymoma

Objective: Evaluation the role of neoadjuvant chemotherapy in invasive thymoma. Methods: 14 patients with invasive thymoma(Masaoka stage III in 12 and IVa in 2) were treated with neoadjuvant chemotherapy by CAVP for 3–4 cycles (cyclophosphamide 600mg/m² D1, adramycin 30mg/m² or epi-adramycin 40mg/m² D1, vincristine 0.6mg/m² D1 or vindestine 3mg/m² D1, D8, cisplatin 30mg/m² D1, 2, 3). After chemotherapy, all patients underwent operation in 1–3 months. We performed 10 sternotomies and 4 anterolateral thoracotomies. Radiotherapy was administrated with total dose 50–60Gy in all patients except for those who were pathologically complete remission. The group was followed up by 6 months to 3 years. Results :After chemotherapy, 5 patients(35.7%) had a complete remission(CR) and 9 patients(64.3%) had a partial remission(PR). At operation, 9 patients had radical resection and 5 had partial resection. Postoperative pathological examination found only fibrosis in 5 patients with CR by chemotherapy. All patients were still alive except 2 patients died from visceral metastasis after 18 months and 2 years respectively. Conclusion: Neoadjuvant chemotherapy can increase the resectability of stage III and IVa invasive thymoma. A longer follow-up and a larger number of patients are needed to determine the impact of this treatment on long-term survival. Biography: Tan Li-jie, (1970–), doctor of medicine, Fudan University Medical College, majors in thoracic surgery.     

A phase III randomized trial of cyclophosphamide,mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide,adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer

Summary One hundred patients with metastatic breast cancer were randomly selected to receive combined chemotherapy treatment with adriamycin (50 mg/m²) or mitoxantrone (12 mg/m²) associated with 5-fluorouracil (600 mg/m²) and cyclophosphamide (600 mg/m²) administered intravenously every 21 days with a maximum of ten cycles. All patients included in this study were under 75 years of age and had ECOG performance status of less than 4. They had not been treated previously with chemotherapy for metastatic disease. Patients treated with adjuvant chemotherapy, which could not have included anthracyclines, had to have relapsed at least 12 months after the completion of therapy. There were no statistically significant differences in pretreatment characteristics or metastatic disease location between the two groups. Ninety-four patients were assessable for response. No differences were observed in response rate or in survival between the groups. The response rate (complete response (CR) and partial response (PR)) was 68% (13% CR and 55% PR for CAF; 0% CR and 68% PR for CNF). Median survival for all patients was 19 months (18 months with CAF and 19 months with CNF). All patients were assessable for toxicity. There were no differences in gastrointestinal and cardiac toxicity. More grade I-II hematologic toxicity episodes (p < 0.001) and treatment delays (p = 0.05) due to leucopenia were observed with the CNF group, and more grade III alopecia (p < 0.001) was observed with the CAF group. Patients received further therapeutic manoeuvres after finishing the study with a sequential treatment consisting of hormonal therapy and chemotherapy with mitomycin (M) -vinblastine (Vbl) (M 10 mg/m² day 1, Vbl 5 mg/m² days 1, 15 and 29; maximum 5 cycles). This chemotherapy treatment was received by 32 patients, with a response rate of 34% and grade III-IV hematologic toxicity of 37%. Treatment with CNF can be considered a good alternative to CAF for first-line treatment of metastatic breast cancer. M-Vbl treatment is useful as second-line treatment in patients with prior adriamycin exposure.     

Doxorubicin,cyclophosphamide and VP16-213 (ACE) in the treatment of small cell lung cancer

Summary Small cell lung cancer requires aggressive combination chemotherapy. The three active agents, doxorubicin (A) 45 mg/m² i.v. day 1, cyclophosphamide (C) 1.0 mg/m² i.v. day 1 and VP16-213 (E) 50 mg/m²/day i.v. days 1–5 were given together. The combination (ACE) was given every 21 days without chest irradiation. One hundred and seventy-four patients have been stratified for extent of disease and randomized on three sequential studies testing ACE vs ACE + MER immunotherapy (38 patients), or ACE vs ACE alternating with CCNU, methotrexate, vincristine and procarbazine (109 patients), or ACE vs ACE II (ACE with continuous VP16-213-100 mg/m²/dayx5 days-27 patients-ongoing). The immunotherapy and the alternating non-cross resistant combination have not proven beneficial with respect to response or survival. The ACE combination, regardless of additional treatments, has produced greater than 90% response overall. In limited disease the complete response (CR) frequency is 65%. The median survival for limited disease overall is 14 months and 18 months for patients achieving CR. In extensive disease the CR frequency is 40% with a median survival of 9 months overall and 13 months for patients achieving CR. Response frequency and survival are identical in the first two studies and 20–30% of patients with limited disease are long-term survivors with one late relapse (>3 years). Patients who achieved CR had a significantly longer survival regardless of other factors such as performance status or extent of disease. Prophylactic cranial irradiation was demonstrated to be useful in prevention or delaying CNS metastases in patients who achieved CR. The third generation study of high-dose VP16-213 infusion seeks to increase the CR frequency. ACE chemotherapy without chest irradiation is a highly effective treatment for all patients with small cell lung cancer and compares favorably with all other studies with or without adjuvant radiotherapy.This investigation was supported in part by PHS Grant Number 1 P50CA 32107-01 awarded by the National Cancer Institute, DHHS     

MiCMA: An alternative treatment for refractory or recurrent Hodgkin's disease

Background:We determined the response rate to MiCMA(mitoxantrone, carboplatinum, methylprednisolone and aracytin) in a group of29 patients with Hodgkin's disease (HD) and poor prognostic factors eitherresistant to first line or relapsing after conventional chemotherapy andsubsequently evaluated the role of autologous stem-cell transplantation (ASCT)in these patients after MiCMA. Patients and methods:The treatment was intended as a brief tumordebulking program before ASCT. Twenty-nine patients with primary refractoryHD or relapsed HD were submitted to two courses of MiCMA (mitoxantrone 10mg/m² day 1; carboplatinum 100 mg/m² days 1–4;aracytin 2 g/m² day 5; methylprednisolone 500 mg/m² days1–5) and subsequently evaluated for response. Those with responding orstable disease, received one or two other courses of MiCMA followed by ASCT. Results: There were 10 complete responses (34% CR), 15partial responses (52% PR) and 4 treatment failures with diseaseprogression (14% PD). In total there were 25 evaluable responses outof 29 patients (86% CR + PR). Myelosuppression was the main toxicityof this treatment. At this time 20 patients (69%) are alive with amedian follow-up of 26.5 months (7–100), 13 patients in CR (45%),8 patients died, 7 of them from disease progression and one due to multi-organfailure, one patient is lost to follow-up. All but one of the patients whoachieved CR after MiCMA are alive. Only the number of extranodal sites wasfound to predict a poor response to MiCMA. Conclusions: A short pre-transplantation treatment with MiCMA isan effective tumor debulking approach in patients with refractory or relapsedHD.     

Thrombosis in patients with acute promyelocytic leukemia treated with and without all-trans retinoic acid

Laboratory evidence of disseminated intravascular coagulation (DIC) and/or fibrinolysis is present in the majority of patients with acute promyelocytic leukemia (APL). Historically, early hemorrhagic death (EHD) occured in 10% to 30% of patients treated with chemotherapy. All-trans retinoic acid (ATRA), a differentiating agent, has a CR rate above 80% in patients, with ATRA-associated leukocytosis. We studied thrombotic events in this population and compared it to patients treated with chemotherapy alone. The results of studies using ATRA in patients with APL were reviewed. Patients received ATRA 45-50 mg/m² orally in two divided doses daily until complete remission. In newly diagnosed patients, Idarubicin 12 mg/m²/day was given intravenously for 4 to 5 days beginning on the fifth day of ATRA therapy or when the white blood cell count (WBC) was over 10×10³/μl. Thrombotic complications were noted in 3 of 31 patients during induction. Two died from thrombotic events during therapy with multiple thromboses documented at autopsy. ATRA syndrome was suspected in 2 of the patients with thromboses and only 1 of the patients without thrombosis. In previous studies, 1 of 25 APL patients treated with chemotherapy alone had thrombotic events during therapy. In conclusion, treatment of APL with ATRA may decrease the incidence of hemorrhagic complications, but does not eliminate thrombosis. While thrombotic events were not significantly increased in patients treated with ATRA, they were more common in patients suspected of having ATRA syndrome.     

Cisplatinum plus Epirubicin Alternated with Cyclophosphamide plus 5-Fluorouracil in Ovarian Cancer

Summary

Fifty-two patients with ovarian cancer (post surgical residual tumor) were treated with the combination of platinum + epirubicin (PE) (P 50mg/m², E 60 mg/m²) alternated with cyclophosphamide + 5-fluorouracil (CF) (C 800 mg/m², F 600 mg/m²). The treatment was repeated every 28 days for a maximum of 10 cycles. Forty-three patients were evaluable for response. Complete remission (CR) was achieved in 13 (30%) patients (evaluated by second-look), while partial remission (PR) was achieved in 6 (14%) patients for a mean duration of 27 and 14 months, respectively. Eleven out of 13 patients with CR and 5 out of the nonevaluable patients are alive and do not show signs of disease after a mean follow-up of 29 + months (range 19-36). The main factors that conditioned complete remission were the tumor residue and performance status of the patient.     

Cisplatin-etoposide and carboplatin-etoposide induction chemotherapy for good-risk patients with germ cell tumor

Background: In an attempt to reduce the toxicity of chemotherapyin good-risk testicular cancer patients the two drug combinations,cisplatin plus etoposide (EP) and carboplatin plus etoposide(EC), have been compared. Methods: Good risk was defined according to the MSKCC and IUcriteria. 39 Patients have been treated with EP (cisplatin 20mg/m² i.v. and etoposide 100 mg/m² i.v. on days 1 to 5), and23 patients received EC (carboplatin 350 mg/m² on day 1 andetoposide 100 mg/m² on days 1 to 5). Four cycles of chemotherapywere given at 21- and 28-day intervals, respectively, with delaysof up to 7 days in istances of leukocyte counts less than 3.0x 10⁹/l or platelet counts less than 100 x 10⁹/l. Results: In the EP group 34 (87%) of 39 patients achieved CR(26 with chemotherapy alone, 8 with additional surgery). Aftera median follow-up of 26 (12–58) months 3 (9%) patientsrelapsed from CR. Currently 38 patients are alive, and 37 (94%)are NED. In the EC group 20 (87%) of 23 patients achieved CR(15 with chemotherapy alone and 5 with additional surgery).After a median follow-up of 45 (26–57) months 6 (30%)patients relapsed from CR. Currently 19 patients are alive and17 (74%) are NED. There was no difference in survival betweenthe two groups (p = 0.13), but in the EC group the relapse ratewas higher (p = 0.052) and the proportion of patients with NEDwas lower (p = 0.03) in comparison with EP. Toxicity in bothgroups was mild and similar, but 3 EP-treated patients presentedhair loss. Conclusions: The study suggests that carboplatin-etoposide combinationtherapy is inferior to cisplatin-etoposide in patients withgood-risk germ cell tumors. chemotherapy, germ cell tumors, good prognosis