Phase I study of cyclophosphamide (NSC 26271) by 72-hour continuous intravenous infusion

A phase I clinical study of cyclophosphamide administered by 72-hour continuous intravenous infusion was conducted in 13 patients with various types of advanced solid tumors to evaluate the drug's toxicity and efficacy. The initial dosage of 300 mg/m2/day X 3 days repeated at 3-week intervals was progressively increased by 150 mg/m2/day-increments to a maximum dosage of 750 mg/m2/day. The dose-limiting toxicities were hematologic and gastrointestinal. Neutropenia was more severe than was thrombocytopenia. The lowest granulocyte count less than 500/mm3 occurred during more than half of the treatment courses at doses of 600 mg/m2 and higher. Severe nausea and vomiting were observed in patients during three of four treatment courses at the 750 mg/m2 dose level. None of the patients had microscopic hematuria or symptoms suggestive of cystitis. Partial response occurred in a patient with parotid cancer metastatic to the lung. Disease stabilization occurred in four patients, while six patients had progression of disease. The recommended starting dosage of cyclophosphamide by continuous intravenous infusion for phase II trials is 600 mg/m2/day X 3 every 3 weeks for patients with good bone marrow reserve.     

Cisplatin-vindesine-mitomycin (MVP) vs cisplatin-ifosfamide-vinorelbine (PIN) vs carboplatin-vinorelbine (CaN) in patients with advanced non-small-cell lung cancer (NSCLC): a FONICAP randomized phase II study. Italian Lung Cancer Task Force (FONICAP)

In the present multicentre randomized phase II trial, the activity and toxicity of three platinum-based combination regimens for the treatment of advanced non-small-cell lung cancer (NSCLC) were evaluated. The three regimens were: MVP (mitomycin-C 6 mg m(-2) on day 1, vindesine 3 mg m(-2) on days 1 and 15, and cisplatin 80 mg m(-2) on day 1 every 28 days), PIN (cisplatin 80 mg m(-2) day 1, ifosfamide 3 g m(-2) day 1 and vinorelbine 25 mg m(-2) day 1 and 8 every 21 days) and CaN (carboplatin 350 mg m(-2) day 1 and vinorelbine 25 mg m(-2) days 1 and 8 every 28 days). A total of 140 chemotherapy-naive patients entered the study; 49 patients were treated with MVP, 48 with PIN and 43 with CaN. Sixty-seven per cent of the patients had stage IV disease. Response rates, calculated on an 'intention to treat' basis, were as follows: MVP, 14.3% (95% CI 5.94-27.2%); PIN, 16.7% (95% CI 7.4-30.2%); and CaN, 14% (95% CI 5.3-27.9%). The overall median survivals were 256, 269 and 243 days for patients treated with MVP, PIN and CaN respectively. Myelosuppression was the most frequent toxicity: grade 3-4 leucopenia was observed in 14.3%, 25% and 18.6% of patients treated with MVP, PIN and CaN respectively. This multicentre phase II randomized trial shows that MVP, PIN and CaN can be administered on an outpatient basis with acceptable toxicities. Unfortunately, the three regimens showed an activity significantly lower than that reported in previous single-institution phase II trials.     

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer

Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study is to characterize the toxicity, pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day schedule to patients with or without prior exposure to nitrosourea (NU). Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5 days, every 4 weeks. Separate dose escalations were carried out in patients, with or without prior exposure to NU. Pharmacokinetic studies were performed during the first cycle of treatment on days 1 and 5. Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days (total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2), respectively. Significant (grade 3 or higher) thrombocytopenia was observed in six patients during cycle 1. The median times to nadir and recovery were 17 and 15 days, respectively. Nonhematological toxicity was generally manageable and consisted of fatigue, nausea, and vomiting. There were two complete responses (one glioma and one melanoma) in patients without prior NU. No objective responses were seen in patients with prior NU treatment. Pharmacokinetic studies showed rapid absorption with a mean time to peak concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min). The area under the curve and the peak plasma concentrations were linear over the dose range of 50-250 mg/m2/day. The mean apparent oral clearances on day 1 for patients with and without prior NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively. Apparent oral clearances on days 1 and 5 were found to differ with respect to NU exposure (P = 0.047). Renal clearance of the parent drug and its metabolism to 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of TMZ elimination. We conclude that TMZ is well tolerated in this oral 5-day schedule with dose-limiting thrombocytopenia and that it has promising activity in glioma and melanoma. The recommended doses for Phase II studies in patients with and without prior NU are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.     

A phase II study of 5-fluorouracil, leucovorin and cisplatin (FLP) for metastatic gastric cancer

The modulation of 5-fluorouracil (5-FU) with folinic acid (leucovorin, LV) is more efficacious than 5-FU alone in the treatment of metastatic colorectal cancer, and the combination of 5-FU with cisplatin is currently one of the most active regimens in advanced gastric cancer. A phase II study was therefore conducted to test the efficacy and toxicity of the combination of 5-FU, LV and cisplatin (FLP) in metastatic gastric cancer. 28 patients entered the study. Metastatic sites were observed in the liver (in 21 patients), the peritoneum (in 8), the lymph nodes (in 7) or the bones (in 1) and a local recurrence was noted in 4 cases. The performance status (using World Health Organisation criteria) was 0 for 13 patients and 1 or 2 for the others. Cycles of treatment were administered every 28 days and consisted of LV 200 mg/m2/day for 5 days followed by 5-FU 400 mg/m2/day for 5 days with cisplatin 100 mg/m2 on day 2. The response rate for the 27 evaluable patients was 51.8% (95% confidence interval (CI), 33-70.6%). There were four complete responses (14.8%) and 10 partial responses (37%). Median survival was 11 months and 4 patients were alive at 2 years. Both response rate and survival were better for patients with a good performance status. The overall toxicity was very low, except for 1 patient who died of dehydration and cardiac failure. In conclusion, the FLP protocol was effective and well tolerated in patients with metastatic gastric cancer.     

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)-L-aspartate in patients with advanced colorectal cancer. Results of a phase II study

Methotrexate (MTX) and N-phosphonacetyl-L-aspartate acid (PALA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU). A phase II study was initiated to evaluate the feasibility, toxicity and efficacy of PALA/MTX and 5-FU in patients with metastatic colorectal cancer. 26 patients received PALA 250 mg/m2 as an intravenous 15-min infusion plus MTX 200 mg/m2 as a 30-min intravenous (i.v.) infusion on day 1 and 5-FU 600 mg/m2 as i.v. push on day 2. Cycles were repeated every 14 days and the 5-FU dose was escalated in the individual patient in steps of 100 mg/m2 for the third, fifth and seventh cycle in the absence of toxicity. 7 patients had received prior 5-FU-based chemotherapy while 19 patients were chemotherapy naive. Objective responses occurred in 23% of patients (1 CR, 5 PR of which 2 were pretreated), no change in 13 patients (50%) and tumour progression (6 patients) or toxic death (one patient) in 27%. Responses lasted for a median of 7 months (range 6-9), the median time to progression was 4 months and median survival 13 months. Toxicity was mainly gastrointestinal with diarrhoea and mucositis, and severe or life threatening in only 3 patients. In 3 patients an increase in serum glucose levels occurred while being treated with PALA/MTX and 5-FU. 2 patients with insulin-dependent diabetes had a 33% increase in insulin requirement and 1 patient with dietary-controlled diabetes died due to a ketoacidotic coma. PALA/MTX/5-FU in this dose and schedule is active in patients with colorectal cancer. Hyperglycaemia may be a potential side-effect of PALA-containing regimens especially in patients with diabetes. Careful monitoring of serum glucose levels in these patients is indicated.     

Loss of biological activity due to Glu-->Arg mutation at residue 11 of the B subunit of cholera toxin

PURPOSE: To determine the maximum tolerated dose, toxicities, and potential antitumor activity of edatrexate (E), an antifolate agent with enhanced in vitro antitumor activity as compared with methotrexate (M), when given in combination with vinblastine, doxorubicin, cisplatin, and filgrastim (G-CSF) to patients with advanced malignancies. PATIENTS AND METHODS: Thirty-seven patients with advanced malignancies were treated with escalating doses of edatrexate in combination with vinblastine (V), doxorubicin (A), cisplatin (C), and filgrastim (EVAC/G-CSF) following three different subsequently developed schedules. Schedule 1 was patterned after the MVAC regimen, a combination chemotherapy program with activity against different epithelial malignancies, and consisted of E, 40 mg/m2/day, days 1/15/22; V, 3 mg/m2/day, days 2/15/22; A, 30 mg/m2/ day, day 2; C, 70 mg/m2/day, day 2; repeated every 28 days. Schedules 2 and 3 were designed to avoid observed dose-limiting toxicity on schedule 1 consisting of transient elevation of serum creatinine levels and delayed myelosuppression. Schedule 2 consisted of E, 40 or 60 mg/ m2/day, days 1 and 15; V, 3 mg/m2/day, days 2 and 15; A, 30 mg/m2/day, day 2; C, 30 mg/m2/day, days 1 and 2; cycled every 28 days. Schedule 3 consisted of E, 60 to 120 mg/m2/day, day 1; V, 3 mg/m2/day, day 2; A, 30 mg/m2/day, day 2; C, 30 mg/m2/day, days 1 and 2; cycled every 21 days. Filgrastim 5 micrograms/kg/day was given to all patients subcutaneously until the absolute neutrophil count was greater than 10,000/microL postnadir. Three patients were treated on schedule 1, 10 on schedule 2 (four at an E dose of 40 mg/m2/day and six at an E dose of 60 mg/m2/day), and 24 on schedule 3 (six at each of the following E dosages: 60, 80, 100, and 120 mg/m2/day). RESULTS: Dose-limiting toxicities of grade 3 to 4 leukopenia and transient elevation of serum creatinine values were observed in two of three patients treated on schedule 1. A dose-limiting toxicity of grade 3 to 4 leukopenia was noted in two of six patients treated on schedule 2 at an edatrexate dose of 60 mg/m2/day. Two of six patients treated on schedule 3 at an edatrexate dose of 120 mg/m2/day had a dose-limiting toxicity of grade 3 stomatitis (one patient) and grade 3 cytopenia (one patient). Nineteen of 37 patients with evaluable or measurable disease had a response to treatment (response rate 51%, 95% confidence intervals = 35%-67%). Nine of 15 patients with metastatic non-small cell lung cancer responded, including one complete remission (response rate 60%, confidence intervals = 35%-85%). A median survival of 517 days (confidence interval = 163-808 days) and a 1-year survival rate of 60% (confidence interval = 35%-85%) was seen in patients with advanced non-small cell lung cancer. CONCLUSIONS: The maximum tolerated dose and the recommended phase II dose of edatrexate is 100 mg/m2/day when administered as part of the EVAC/G-CSF program following schedule 3. Promising antineoplastic activity against non-small cell lung carcinomas was observed, and a phase II study is planned.     

Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen: a cancer and leukemia group B study

Multidrug resistance mediated by P-glycoprotein may be an important cause of chemotherapy failure. Renal cell carcinoma is a disease known to demonstrate a high degree of intrinsic chemotherapy drug resistance, and this has been shown to be related to intrinsic overexpression of P-glycoprotein. Cyclosporine A and tamoxifen have been shown to reverse multidrug resistance in renal cell carcinoma cell lines in vitro. Phase I studies have defined appropriate doses of cyclosporine A and tamoxifen that can be combined with continuous-infusion vinblastine and safely achieve serum levels associated in vitro with resistance reversal. A randomized Phase II study was carried out by the Cancer and Leukemia Group B to evaluate the potential of high doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients with advanced renal cell carcinoma. Patients were treated initially with continuous-infusion vinblastine alone (1.2 mg/m2/day for 4 days or 1.5 mg/m2/day for 5 days); patients with stable or progressive disease were then treated with the same vinblastine regimen, combined with a high-dose regimen of either cyclosporine A (12.5 mg/kg/day for 5 days) or tamoxifen (400 mg/m2 as a loading dose and 300 mg/m2/day for 13 days). Sixty-three patients were randomized to each arm. Eighty patients on both arms were evaluable for response to vinblastine alone; of these, only one patient achieved a partial response. Thirty-three patients went on to be treated with vinblastine and high-dose cyclosporine A. No responses were observed, although four patients with progressive disease on prior vinblastine achieved stabilization of disease after cyclosporine A was added. Addition of cyclosporine resulted in more leukopenia (5% versus 25%) and in transient hyperbilirubinemia (24%) and neurocortical changes (11%). No significant azotemia was observed. Thirty-five patients received high-dose tamoxifen with continuous-infusion vinblastine. One complete remission was seen in a patient who had stable disease only with prior vinblastine alone; no other responses were observed. Leukopenia was not more severe with the addition of tamoxifen to vinblastine, nor was hyperbilirubinemia observed. However, 9% of patients developed transient ataxia with or without neurocortical changes as a result of high-dose tamoxifen therapy, and 11% developed phlebitis. We conclude that advanced renal cell carcinoma is a highly chemoresistant tumor, that continuous-infusion vinblastine has no appreciable activity in the therapy of this disease, and that addition of high doses of cyclosporine A or tamoxifen was not able to modulate this resistance in these patients. Suggestions regarding study design for future drug resistance modulation trials were made based on the design and conduct of this study.     

MRI of hyperpolarized 3He gas in human paranasal sinuses

Relapsed or refractory adult acute lymphoblastic leukemia (ALL) carries a grave prognosis. The most promising strategy for curing these patients is through re-induction chemotherapy followed by successful allogeneic transplant. We studied a new high-dose induction regimen in order to improve the outcome for these patients. Eighteen adult patients with relapsed/refractory ALL were treated on a phase I study of high-dose cytarabine combined with a single escalating dose of idarubicin. Five patients had primary refractory disease and 13 were treated in refractory relapse. Nine patients (50%) had Ph+ ALL. The induction regimen was cytarabine 3 g/m2/day intravenously days 1-5 and idarubicin as a single intravenous dose on day 3. G-CSF 5 microg/kg subcutaneously every 12 h was started on day 7. The initial idarubicin dose was 20 mg/m2 with dose escalations of 10 mg m2. Cohorts of three patients were treated at each idarubicin dose level. Unacceptable toxicity was encountered at 50 mg/m2 with one death from infection and one death from cardiotoxicity in a patient with significant prior anthracycline exposure. There were no instances of grade 4 non-hematologic toxicity encountered at idarubicin doses of 20 mg/m2, 30 mg/m2, or 40 mg/m2. The data suggest a dose-response relationship for increasing doses of idarubicin with 0/3 complete responses (CR) at 20 mg/m2, 1/3 CR at 30 mg/m2, and 7/12 (58%) CR at idarubicin doses > or = 40 mg/m2. We conclude that concomitant administration of cytarabine 3 g/m2/day x 5 and high-dose idarubicin at 40 mg/m2 as a single dose on day 3 can be administered safely to patients with refractory and relapsed ALL.     

New combination therapy with FTM [5-FU, pirarubicin (THP) and MMC] for treatment of inoperable advanced gastric cancer

Clinical usefulness of a new combination FTM therapy consisting of 5-FU, Pirarubicin (THP) and MMC for the treatment of advanced gastric cancers was investigated. 5-FU, THP or MMC was administered at a dose of 600 mg/m2 on day 1, 8, 22 and 29, 30 mg/m2 on days 1 and 22, and 10 mg/m2 on day one only of each course, respectively. Eighteen patients with inoperable advanced gastric cancer were treated with FTM. All drugs were investigated by intravenously by one shot. The tumor response rate was 50% [9 of 18 showed PR]. The survival rate was higher in responders than in nonresponders (18.1% vs 11.1%) (p < 0.05). Side effects in the gastrointestinal tract were minimal. Cardiotoxicity and nephrotoxicity were not detected, but myelosuppression was prominent in most cases. G-CSF was given in sixteen patients (88%), and platelet transfusion was performed in two patients (11%). New combination FTM therapy is an effective treatment regimen even for advanced inoperable gastric cancer.     

Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung cancer (NSCLC)

INTRODUCTION: Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92. METHODS: Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy. RESULTS: Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery. CONCLUSIONS: Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.     

DIZE (dexamethasone, idarubicin, and continuous infusion of ifosfamide and etoposide): an effective and well-tolerated new regimen for patients with relapsed lymphoma

We performed a phase II study of dexamethasone, ifosfamide, idarubicin and etoposide (DIZE) in patients with relapsed or refractory Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL). The regimen consisted of dexamethasone (20 mg i.v. days 1-4), idarubicin (8 mg/m2 i.v. days 1+2), continuous infusion (c.i.) of ifosfamide (1,000 mg/m2 days 1-4), and c.i. etoposide (60 mg/m2 days 1-4). G-CSF (5 microg/kg) was used to support neutrophil recovery from day 5. In older patients (> 60 years) the dosage of idarubicin and ifosfamide was reduced to 75% in the initial cycle. Fourty six patients (pts) were treated with a total of 131 cycles. Sixteen pts were primary resistant and 30 were relapsed. Median age was 54.3 years (range 22-75). The median number of different prior chemotherapies was 1.7 (range 1 to 5). 31/46 (67.4%) pts had advanced disease (stage III or IV); 19/46 had B symptoms. Of 43 evaluable pts the response rate was 58.1% including 11 complete remissions (CR) and 14 partial remissions (PR). Mean duration of response was 8 months (1-30+). DIZE was more effective in relapsed than in refractory high-grade NHL (74 % vs 16.6%; p < 0.001). Of four heavily pretreated pts with HL, one obtained CR and two PR (response rate 75%). Myelosuppression was generally moderate with a mean duration of leukocytopenia < 1,000/microl of 2.5 days (range 0-18) and of thrombocytopenia < 25,000/microl 1.5 days (range 0-17). One patient died of uncontrollable infection in treatment related neutropenia. No other serious toxicities apart from alopecia were observed. We conclude that DIZE is safe and effective in heavily pretreated pts with relapsed lymphoma. The continuous infusion of cytostatic drugs such as that used in the new DIZE protocol might reduce hematotoxicity.     

Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer: a phase II study of the Southern Italy Oncology Group (GOIM)

Lonidamine (LND) is a unique antineoplastic drug derived from indazole-3-carboxylic acid which inhibits oxygen consumption and aerobic glycolysis, interfering with energy metabolism of neoplastic cells. LND has been experimentally shown to potentiate the cytotoxic effects of epirubicin (EPI) in human breast cancer cell lines, cisplatin activity in both platinum-sensitive and -resistant human ovarian carcinoma cell lines, and EPI antineoplastic activity in some recent phase III trials carried out in advanced breast cancer. A multicenter phase II trial was carried out with the combination of cisplatin 60 mg/m2, EPI 100 mg/m2 and LND 450 mg/day p.o. in three refracted doses/day starting 2 days before cisplatin and EPI (day -2 and -1), stopping 2 days after chemotherapy (day 0, +1 and +2). Thirty patients with metastatic breast cancer were enrolled into the study. Twenty-nine patients were evaluable for objective response. The overall response rate accordingly to an intent-to-treat analysis was 73% (95% CL 54-88%). Four patients achieved complete response (13%; 95% CL 4-31%) with a median duration of 9.5 months (range 4-16) and 18 patients had partial response (60%; 95% CL 41-77%) with a median duration of 9.8 months. Stable disease was obtained in five cases (17%) and progressive disease was recorded in three patients. One patient died of progressive cancer before restaging. The overall median survival of the whole series of patients was 14+ months. The most frequent toxicities were represented by gastrointestinal and hematological side effects. The combination of cisplatin + EPI plus oral LND is active against metastatic breast carcinoma. The antineoplastic activity of the cisplatin + EPI + LND regimen is as high as that reported for more aggressive regimens such as the fluorouracil + doxorubicin + cyclophosphamide combinations without an increase in toxic effects.     

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK)

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. PATIENTS AND METHODS: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2 bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 micrograms/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. RESULTS: The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. CONCLUSIONS: The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high antitumor activity of this regimen and a potential improvement in survival.     

Etoposide, epirubicin and cisplatin (EEP) combination in metastatic cancers of the cardia and the stomach. Groupe de recherche en cancérologie du Nord (GRECNO)

This study was aimed to confirm the therapeutic activity of the combination of etoposide, doxorubicin and cisplatin which has shown some clinical efficiency as first line therapy in advanced gastric cancer. Seventeen patients with metastatic gastric cancer were treated with etoposide (120 mg/m2, i.v., on day 5, 6 and 7), epirubicin (20 mg/m2, i.v., on day 1 and 7) and cisplatin (40 mg/m2, i.v., on day 2 and 8), q 4 weeks. In 16 patients evaluable for response, three (19%) obtained a partial response lasting from 93 to 360 days. Fifteen patients were evaluable for toxicity. Main toxicities > grade 2 included anemia (2/15), neutropenia (5/15), alopecia (8/15), fatigue (3/15), diarrhea (2/15), vomiting (2/15). Twenty nine per cent of severe toxic events were documented all along 52 cycles. Therefore we failed to confirm that this regimen could be of clinical efficiency in advanced gastric cancer as regards the benefits/toxicity ratio.     

Long-term follow-up of a randomized post-induction therapy trial in acute myelogenous leukemia (a Southeastern Cancer Study Group trial)

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.     

Recombinant human granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) administered following cytotoxic chemotherapy have a similar ability to mobilize peripheral blood stem cells

The availability of hematopoietic growth factors has greatly facilitated the mobilization and collection of peripheral blood stem cells (PBSC). It was the aim of this double-blind study to compare the PBSC-mobilizing efficacy of recombinant human G-CSF and GM-CSF when administered post-chemotherapy. Twenty-six patients with relapsed Hodgkin's disease were included in the study. Their median age was 31 years (range, 22-59) and 14 patients were males and 12 were females. Patients were pretreated with a median of eight cycles of cytotoxic chemotherapy, while 18 patients had undergone extended field irradiation. The patients received dexamethasone 24 mg days 1-7, melphalan 30 mg/m2 day 3, BCNU 60 mg/m2 day 3, etoposide 75 mg/m2 days 4-7, Ara-C 100 mg/m2 twice daily days 4-7 (Dexa-BEAM). Twelve patients were randomized to receive 5/microg/kg/day G-CSF and 14 patients to receive 5 microg/kg/day GM-CSF, both administered subcutaneously starting on day 1 after the end of Dexa-BEAM. Primary endpoints of the study were the number of CD34+ cells harvested per kg body weight on the occasion of six consecutive leukaphereses and the time needed for hematological reconstitution following autografting. Twenty-one patients completed PBSC collection, and six patients of the G-CSF group and nine of the GM-CSF group were autografted. No difference was observed with respect to the median yield of CFU-GM and CD34+ cells: 32.5 x 10(4)/kg vs 31.3 x 10(4)/kg CFU-GM, and 7.6 x 10(6)/kg vs 5.6 x 10(6)/kg CD34+ cells, for G-CSF and GM-CSF, respectively (U test, P= 0.837 and 0.696). High-dose chemotherapy consisted of cyclophosphamide 1.7 g/m2 days 1-4, BCNU 150 mg/m2 days 1-4, etoposide 400 mg/m2 days 1-4. All patients transplanted with more than 5 x 10(6) CD34+ cells/kg had a rapid platelet recovery (20 x 10(9)/l) between 6 and 11 days and neutrophil recovery (0.5 x 10(9)/1) between 9 and 16 days, while patients transplanted with less than 5 x 10(6)/kg had a delayed reconstitution, regardless of the kind of growth factor used for PBSC mobilization. In conclusion, our data indicate that in patients with Hodgkin's disease G-CSF and GM-CSF given after salvage chemotherapy appear to be not different in their ability to mobilize PBSC resulting in a similar time needed for hematological reconstitution when autografted following high-dose therapy.     

Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma

PURPOSE: To determine whether combination 5-fluorouracil, cisplatin, and interferon alfa, an active regimen in advanced esophageal cancer, is efficacious as induction therapy before esophagectomy. MATERIALS AND METHODS: Forty-four patients with potentially resectable esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma were entered into a phase I/II study of this chemotherapeutic regimen and concurrent external-beam radiotherapy before resection. The initial 16 patients were treated with prolonged-infusion 5-fluorouracil (300 mg/m2 on days 1 to 28), cisplatin (20 mg/m2 on days 1 to 5 and 24 to 28), interferon alfa (3 x 10(6) U/m2 intravenously on days 1 to 5 and 24 to 28; subcutaneous injection every other day on days 6 to 23), and radiation (4000 cGy). The subsequent 28 patients were treated over 21 days with two modifications: dose escalation of 5-fluorouracil (250 to 350 mg/m2) and double-fractionated radiotherapy to a total dose of 4500 cGy. RESULTS: Forty-one patients completed chemoradiotherapy and were evaluable for toxicity. Adverse events were substantial but tolerable, and most toxic episodes were hematologic and gastrointestinal. Three patients died, and one patient had progressive disease before resection. Of the 37 patients eligible for curative resection, 36 had all gross tumor removed. Thirty-three (80%) patients had a major pathologic response: 10 (24%) with no residual tumor and 23 with only microscopic residual tumor. Median survival for all patients was 27 months and for responders was 36 months. CONCLUSIONS: This combination regimen is active but yields results similar to those of other chemoradiotherapy phase II trials; therefore, the contribution of interferon alfa to treatment efficacy remains uncertain. The true worth of preoperative chemoradiotherapy is unknown pending results of phase III trials.     

Insulin-induced lipohypertrophy treated by liposuction

BACKGROUND: The new intercalative agent Mitonafide was shown in early clinical trials to be toxic to the central nervous system when administered as a short intravenous infusion, but not when given as a 120-hour continuous infusion. Thus, clinical development in different tumor types was pursued using only this administration schedule. PATIENTS AND METHODS: Forty-nine patients with previously untreated non-small cell lung cancer (NSCLC) and at least one measurable site received Mitonafide as a 120-hour continuous (5 days) infusion every 3 weeks. The starting dose was 170 mg/m2/day x 5 in the first 26 patients and 200 mg/m2/day x 5 in the remainder. Patients were evaluated for toxicity after each course and for response every two courses and remained on treatment until excessive toxicity or disease progression were observed. A special test, the "Mini-mental state", was used to assess patients' cognitive functions. RESULTS: Of the 49 patients entered, 42 were evaluable for response and toxicity. Toxicity consisted mainly of myelosuppression and no neurologic side effects were observed. Only one patient presented a partial response. CONCLUSIONS: Although definitively safe with this schedule of administration, Mitonafide is not active in NSCLC.     

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.     

New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen

PURPOSE: A regimen of cisplatin, doxorubicin, vincristine, and etoposide (PAVE) was designed for patients with small-cell lung cancer (SCLC) who were older than 65 years, with the following objectives compared with standard chemotherapy regimens: maintain efficacy, diminish toxicity, enhance compliance, and improve chemotherapy administration convenience at an acceptable cost. PATIENTS AND METHODS: The PAVE regimen consisted of cisplatin 30 mg/m2 intravenously (i.v.) day 1; doxorubicin 40 mg/m2 i.v. day 1; vincristine 1.0 mg/m2 i.v. day 1; and etoposide 100 mg/m2 i.v. day 1 and orally days 3 and 5. Cycles were repeated every 3 weeks for four cycles. Patients with limited-stage disease and selected patients with extensive-stage disease received thoracic irradiation delivered concurrently with etoposide-cisplatin (EP) at the time of the second chemotherapy cycle. RESULTS: Sixty-six eligible patients were treated, which included 25 patients with limited-stage disease and 41 patients with extensive-stage disease. Median survival was 70 weeks and 5-year survival was 25% for limited-stage disease. Median survival was 46 weeks for extensive-stage disease. Only one treatment-related death occurred and severe toxicity was infrequent. The median delivered dose-intensity was according to protocol and the mean delivered total dose was 80% of intended. CONCLUSION: The treatment outcome achieved with PAVE in a phase II study of elderly patients compared favorably with published results of standard regimens in patient populations with better prognostic factors. Because the PAVE regimen can be delivered with good compliance, has acceptable toxicity, and is associated with logistic advantages compared with standard regimens, this protocol is suitable for further investigative trials in elderly patients with SCLC.