Intensification of adjuvant chemotherapy: 5-year results of a randomized trial comparing conventional doxorubicin and cyclophosphamide with high-dose mitoxantrone and cyclophosphamide with filgrastim in operable breast cancer with 10 or more involved axillary nodes.

PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes. PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m(2) plus cyclophosphamide 600 mg/m(2), with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates. RESULTS: There were no significant differences in DFS (P =.44), DDFS (P =.67), or OS (P =.99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P =.01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P <.001). CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m(2) with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.     

Paclitaxel and carboplatin in the treatment of small-cell lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: a non-cross-resistant schedule.

PURPOSE: To evaluate the efficacy of paclitaxel and carboplatin (PC) in small-cell lung cancer (SCLC) patients resistant to cyclophosphamide, doxorubicin, and etoposide (CDE). PATIENTS AND METHODS: We performed a phase II study with PC in SCLC patients who relapsed within 3 months after first-line treatment with CDE. Paclitaxel administration (175 mg/m2 by a 3-hour intravenous infusion) was followed by a 30-minute infusion of carboplatin (area under the curve 7; Chatelut formula) once every 3 weeks for five cycles. Dexamethasone, clemastine, and ranitidine were standard premedication before every cycle. RESULTS: Included were 35 patients (median age, 59 years; 16 with limited disease and 19 with extensive disease; Eastern Cooperative Oncology Group performance status of < or = 1; median time off treatment 6 weeks) who were previously treated with CDE (n = 33), oral etoposide (n = 2), and reinduction CDE (n = 15); only one patient had received three CDE treatments of five cycles. The CDE regimen was followed by local thoracic radiotherapy in seven patients. Hematologic toxicity of grade 3 or 4, for leukopenia was 27% and 6%, for thrombocytopenia 21% and 13%, and for anemia 17% and 0%, respectively, for a total of 132 cycles. Two patients had neutropenic fever; no toxic death occurred. Nonhematologic toxicity was paresthesia CTC grade 3, diarrhea grade 4, and myalgia grade 3 in one patient each. Reversible paresthesia (CTC grade 1 and 2) in toes and fingers was reported in 69% of patients. Thirty-four patients were assessable for response: complete response in two patients, partial response in 23 patients, stable disease in eight patients, and progressive disease in one patient (response rate, 73.5%; 95% confidence interval, 59% to 88%). One patient was found to have atypical carcinoid at pathologic review and was excluded. Median time to progression was 21 weeks (range, 3 to 40 weeks). Median survival was 31 weeks (range, 6 to 112 weeks). One-year survival was 9%. CONCLUSION: Second-line PC in CDE-resistant SCLC patients yields a high response rate and seems non-cross-resistant to CDE. Toxicity was mild in these poor-prognosis patients.     

A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group

To assess the effect of dose escalation in the treatment of small-cell lung cancer (SCLC), 298 patients with extensive-stage disease were treated with either conventional-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1 mg/m2), (CDCAV); or high-dose cyclophosphamide (1,200 mg/m2), doxorubicin (70 mg/m2), and vincristine (1 mg/m2) (HDCAV). No dose attenuation was allowed during the initial three cycles of therapy in either treatment arm. All patients received CDCAV in cycles 4 through 6, during which time dosages were adjusted according to granulocyte and platelet nadirs. No additional chemotherapy was administered until disease progression or relapse was documented. Complete responses were more frequent with HDCAV (22% v 12%; P = .045). However, overall response rate (63% v 53%) and median survival (29.3 v 34.7 weeks) were not significantly different (P greater than .05). HDCAV was substantially more toxic than CDCAV, causing more episodes of life-threatening leukopenia (ie, granulocytes less than 500/microL; 79% v 40%; P less than .05) and infections (15% v 4%; P less than .05). Dose intensification of cyclophosphamide and doxorubicin during induction chemotherapy did not produce any survival benefit compared with conventional dosages of these agents in SCLC patients with extensive-stage disease.     

Etoposide plus cisplatin with or without the combination of 4'-epidoxorubicin plus cyclophosphamide in treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study

BACKGROUND: The combination of etoposide plus cisplatin (EP) is considered to be standard therapy for small-cell lung cancer (SCLC). To determine whether drug intensification improves survival of patients with extensive SCLC, we compared this treatment with a four-drug regimen containing EP plus cyclophosphamide and 4'-epidoxorubicin (PCDE). METHODS: In a phase III clinical trial organized by the French Federation of Cancer Institutes, patients were randomly assigned to receive either EP (n = 109; etoposide at a dose of 100 mg/m(2) on days 1-3 plus cisplatin at 100 mg/m(2) on day 2) or PCDE (n = 117; etoposide and cisplatin given as in EP plus cyclophosphamide at 400 mg/m(2) on days 1-3 and 4'-epidoxorubicin at 40 mg/m(2) on day 1) every 4 weeks. Both groups received a total of six cycles. Survival differences were analyzed by Wilcoxon and log-rank tests. Associations of treatment group and putative prognostic variables with survival were tested in the Cox proportional hazards model. Quality of life was assessed from the responses to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (C30, health status and lung cancer module 13). All statistical tests were two-sided. RESULTS: Patients in the PCDE arm had a statistically significant higher frequency of combined complete plus partial responses compared with those in the EP arm (21% plus 55% versus 13% plus 48%, respectively; P =.02 for difference in combined objective responses). Patients in the PCDE arm survived longer than those in the EP arm (1-year survival rate: 40% and 29%, respectively; median survival: 10.5 and 9.3 months, respectively; log-rank P =.0067). In the Cox model, the relative risk of death for patients in the PCDE arm compared with those in the EP arm was 0.70 (95% confidence interval = 0.51 to 0.95); the disease also progressed more slowly in patients in the PCDE arm. Hematologic toxicity was higher in the PCDE arm (22% with documented infections compared with 8% in the EP arm; P =.0038), and the toxicity-related death rate was 9% in the PCDE arm versus 5.5% in the EP arm (P =.22). The global health status showed similar improvement in both arms during treatment. CONCLUSION: Compared with the EP regimen, the PCDE regimen yielded higher response rates and better survival rates in patients with extensive SCLC without affecting the quality of life of the patients during chemotherapy.     

The addition of cisplatin to cyclophosphamide-doxorubicin-etoposide combination chemotherapy in the treatment of patients with small cell lung carcinoma: A randomized study of 457 patients. "Petites Cellules" Group

BACKGROUND: To assess whether the addition of cisplatin (100 mg/m(2) administered intravenously on Day 1) to CDE (cyclophosphamide [1000 mg/m(2) on Day 1], doxorubicin [45 mg/m(2) on Day 1], and etoposide [150 mg/m(2) on Days 1 and 2] combination is useful in the treatment of patients with small cell lung carcinoma (SCLC). METHODS: In a multicenter clinical trial, 457 patients were randomized from May 1988 to March 1993 to receive either CDE (n = 228) or cisplatin-CDE (PCDE, n = 229) chemotherapy every 4 weeks for 6 cycles. As patients with limited SCLC were included in a concomitant trial assessing thoracic radiotherapy, the current study mainly included patients with extensive stage (79%) or limited stage disease and a contraindication for thoracic radiotherapy. RESULTS: The objective response rate was higher in the cisplatin-CDE group (72%) than in the CDE group (53%) (P = 0.0001). The median overall survival was similar for the groups that received CDE (266 days) and PCDE (271 days) (P = 0.93, log rank test). A higher fatal neutropenia rate was observed in the PCDE group (n = 23) than in the CDE group (n = 4) (P < 0.001, log rank test), mainly for patients with extensive disease (n = 26; P = 0.015, log rank test). CONCLUSIONS: The addition of cisplatin to a CDE regimen is toxic to patients with extensive SCLC and does not improve overall survival. The PCDE combination must be avoided for patients with extensive SCLC; CDE or cisplatin-etoposide combinations remain standard chemotherapy for these patients. The PCDE combination associated with granulocyte-colony stimulating factors could only be assessed in patients with good prognoses.     

Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up.

PURPOSE: To investigate whether chemotherapy with etoposide and cisplatin (EP) is superior to cyclophosphamide, epirubicin, and vincristine (CEV) in small-cell lung cancer (SCLC). PATIENTS AND METHODS: A total of 436 eligible patients were randomized to chemotherapy with EP (n = 218) or CEV (n = 218). Patients were stratified according to extent of disease (limited disease [LD], n = 214; extensive disease [ED], n = 222). The EP group received five courses of etoposide 100 mg/m(2) intravenously (IV) and cisplatin 75 mg/m(2) IV on day 1, followed by oral etoposide 200 mg/m(2) daily on days 2 to 4. The CEV group received five courses of epirubicin 50 mg/m(2), cyclophosphamide 1,000 mg/m(2), and vincristine 2 mg, all IV on day 1. In addition, LD patients received thoracic radiotherapy concurrent with chemotherapy cycle 3, and those achieving complete remission during the treatment period received prophylactic cranial irradiation. RESULTS: The treatment groups were well balanced with regard to age, sex, and prognostic factors such as weight loss, and performance status. The 2- and 5-year survival rates in the EP arm (14% and 5%, P =.0004) were significantly higher compared with those in the CEV arm (6% and 2%). Among LD patients, median survival time was 14.5 months versus 9.7 months in the EP and CEV arms, respectively (P =.001). The 2- and 5-year survival rates of 25% and 10% in the EP arm compared with 8% and 3% in the CEV arm (P =.0001). For ED patients, there was no significant survival difference between the treatment arms. Quality-of-life assessments revealed no major differences between the randomized groups. CONCLUSION: EP is superior to CEV in LD-SCLC patients. In ED-SCLC patients, the benefits of EP and CEV chemotherapy seem equivalent, with similar survival time and quality of life.     

Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Trial (E1494).

PURPOSE: To determine the effectiveness of an infusional chemotherapy regimen in patients with HIV-associated lymphoma treated before and after the use of highly active antiretroviral therapy (HAART) in routine clinical practice. PATIENTS AND METHODS: Ninety-eight assessable patients with HIV-associated intermediate- or high-grade non-Hodgkin's lymphoma received cyclophosphamide 200 mg/m(2)/d, doxorubicin 12.5 mg/m(2)/d, and etoposide 60 mg/m(2)/d (CDE) given by continuous intravenous infusion for 4 days (96 hours) every 4 weeks plus filgrastim. Concurrent antiretroviral treatment consisted of the nucleoside analog didanosine in the first 43 patients enrolled before December 1996 (pre-HAART group), or HAART in the remaining 55 patients enrolled after that time (HAART group). RESULTS: Complete response occurred in 44 patients (45%; 95% CI, 35% to 55%). Failure-free survival and overall survival (OS) at 2 years was 36% (95% CI, 26% to 46%) and 43% (95% CI, 33% to 53%), respectively. At the time of the analysis, 30% in the pre-HAART group were alive compared with 47% in the HAART group; when adjusted for varying length of follow-up, patients in the HAART group had improved OS (P =.039). Patients in the HAART group experienced less grade 4 nonhematologic toxicity (22% v 42%; P =.037), thrombocytopenia (31% v 52%; P =.033), and anemia (9% v 27%; P =.021), and had fewer treatment-associated deaths (0% v 10%; P =.013). CONCLUSION: Infusional CDE is an effective and potentially curative regimen for patients with HIV-associated lymphoma. Patients treated in the HAART era have less chemotherapy-associated toxicity and improved survival.     

Etoposide combined with cyclophosphamide plus vincristine compared with doxorubicin plus cyclophosphamide plus vincristine and with high-dose cyclophosphamide plus vincristine in the treatment of small-cell carcinoma of the lung: a randomized trial of the Bristol Lung Cancer Study Group

A total of 353 patients with previously untreated small-cell lung cancer (SCLC) were accrued in this multicenter trial. Patients were randomly assigned to receive one of the following three regimens: cyclophosphamide 1,000 mg/m2 intravenously (IV) day 1, vincristine 1.4 mg/m2 IV day 1, and etoposide 50 mg/m2 IV day 1, followed by etoposide 100 mg/m2/day orally days 2 through 5 (CEV); cyclophosphamide 1,000 mg/m2 IV day 1, vincristine 1.4 mg/m2 IV day 1, and doxorubicin 50 mg/m2 IV day 1 (CAV); cyclophosphamide 2,000 mg/m2 day 1 and vincristine 1.4 mg/m2 IV day 1 (CV). Cycles were repeated every 3 weeks. Treatment groups were comparable with respect to extent of disease, age, sex, performance status, and metastatic sites. No significant differences in response rates, response duration, or survival could be detected in limited disease, although there appeared to be a trend favoring CEV. Among extensive-disease patients, response duration on the CEV regimen was longer than on the CV regimen or the CAV program (P less than .001). The superiority of the CEV regimen was also demonstrated in the survival analysis in which differences attained statistical significance (P = .01). In this group the median survival was increased from 29 weeks on CV to 31 weeks on CAV and 39 weeks on CEV. Myelosuppression was the most frequent toxicity. It was more severe with CV than CEV or CAV. Most nonhematologic side effects were comparable among the three treatment groups. However, the high doses of cyclophosphamide in the CV regimen produced a higher incidence of hemorrhagic cystitis than in the CEV or CAV programs (P less than .001). Cardiotoxicity only occurred in the CAV group (P = .05). The addition of etoposide to the CV regimen resulted in significantly longer response duration and survival without increased toxicity. Similarly, the substitution of etoposide for the doxorubicin in the CAV regimen was associated with prolonged survival and reduced cardiotoxicity.     

Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732.

PURPOSE: To determine, in a randomized comparison, whether the addition of paclitaxel to etoposide and cisplatin improves the time to progression and overall survival in patients with extensive small-cell lung cancer (SCLC) compared with standard etoposide and cisplatin and to compare the regimens' toxicity. PATIENTS AND METHODS: Eligible patients (N=587) with untreated extensive SCLC were randomly assigned to receive either cisplatin 80 mg/m2 on day 1 and etoposide 80 mg/m2 on days 1 through 3 administered every 3 weeks for six cycles (EP) or cisplatin 80 mg/m2 on day 1, paclitaxel 175 mg/m2 over 4 hours on day 1, and etoposide 80 mg/m2 on days 1 to 3 followed by recombinant human granulocyte colony-stimulating factor on days 4 to 18 administered every 3 weeks for six cycles (PET). RESULTS: Reporting of demographics, response, and survival included 565 patients, of whom 282 were randomly assigned to receive EP and 283 were assigned to receive PET. Overall response rates were 68% for the EP arm and 75% for the PET arm. Median failure-free survival time was 5.9 months for the EP arm and 6 months for the PET arm (P = .179). Median overall survival time was 9.9 months for patients on EP and 10.6 months for patients on PET (P = .169). Toxic deaths occurred in 2.4% of the patients on EP and 6.5% of patients on PET. CONCLUSION: PET did not improve the time to progression or survival in patients with extensive SCLC compared with EP alone and was associated with unacceptable toxicity.     

Randomized phase III trial of standard timed doxorubicin plus cisplatin versus circadian timed doxorubicin plus cisplatin in stage III and IV or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study.

PURPOSE: To determine if circadian timed (CT) chemotherapy results in improved response, progression-free survival (PFS), overall survival (OS), and lower toxicity, when compared with standard timed (ST) chemotherapy. Materials and METHODS: Eligibility criteria were stage III, IV, or recurrent endometrial cancer with poor potential for cure by radiation therapy or surgery; measurable disease; and no prior chemotherapy. Therapy was randomized to schedules of ST doxorubicin 60 mg/m2 plus cisplatin 60 mg/m2, or CT doxorubicin 60 mg/m2 at 6:00 am plus cisplatin 60 mg/m2 at 6:00 pm. Cycles were repeated every 3 weeks to a maximum of eight cycles. RESULTS: The ST arm included 169 patients, and the CT arm included 173 patients. The objective response rate (complete responses plus partial responses) was 46% in the ST group compared with 49% in the CT group (P =.26, one tail). Median PFS and OS were 6.5 and 11.2 months, respectively, in the ST group; and 5.9 and 13.2 months, respectively, in the CT group (PFS: P =.31; OS: P =.21, one tail). Median total doses were 209 mg/m2 doxorubicin and 349 mg/m2 cisplatin in the ST group, versus 246 mg/m2 doxorubicin and 354 mg/m2 cisplatin in the CT group. Grade 3 or 4 leukopenia occurred in 73% of patients in the ST arm and in 63% of patients in the CT arm. There were eight treatment-related deaths. CONCLUSION: In this trial, no significant benefit in terms of response rate, PFS or OS, or toxicity profile was observed with CT doxorubicin plus cisplatin in patients with advanced or recurrent endometrial carcinoma.     

Phase I trial of infusional cyclophosphamide, doxorubicin, and etoposide plus granulocyte-macrophage colony stimulating factor (GM-CSF) in non-hodgkin’s lymphoma

PURPOSE: To determine the recommended phase II dose (RPTD) of a 96-h continuous intravenous infusion (CIVI) of cyclophosphamide (200, 300, or 400 mg/m2/d) and etoposide (60 or 90 mg/m2/d) when used in conjunction with doxorubicin (12.5 mg/m2/d) (CDE) given every 28 d plus granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with poor prognosis non-Hodgkin's lymphoma (Group A), and the same regimen given every 21 d (Group B). METHODS: In Group A, infusional CDE was repeated every 28 d, GM-CSF (250 microg/m2) was given subcutaneously from d 6 until neutrophil recovery, with dose escalation in cohorts of three to six evaluable patients. The RPTD of cyclophosphamide and etoposide established in Group A was then used with CDE given every 3 wk (Group B) with GM-CSF given on d 6-20, and dose escalation was attempted again. RESULTS: In Group A, the RPTD of cyclophosphamide and etoposide were 300 mg/m2/d and 90 mg/m2/d, respectively; prolonged neutropenia was the dose-limiting toxicity. In Group B, use of GM-CSF on d 6-20 did not facilitate dose escalation above the RPTD established in Group A. Complete response occurred in 13/26 patients (50%) with no prior chemotherapy, and in 4/16 patients (25%) who had relapsed after prior chemotherapy. CONCLUSIONS: Because of the increase in dose and dose-density afforded by the administration of GM-CSF, the relative dose intensity was increased by twofold for cyclophosphamide (400 vs 200 mg/m2/wk) and etoposide (120 vs 60 mg/m2/wk), and by 1.3-fold for doxorubicin (16.7 vs 12.5 mg/m2/wk).     

Dose-intensive weekly alternating chemotherapy for patients with small cell lung cancer: randomized trial, can it improve survival of patients with good prognostic factors?

We conducted a randomized trial of dose-intensive weekly alternating chemotherapy (CAV/PE-W) and standard alternating chemotherapy (CAV/PE) in small cell lung cancer (SCLC) patients with good prognostic factors. A total of 76 patients with SCLC was randomized. The CAV/PE-W consisted of 4 alternating cycles of cyclophosphamide: 500 mg/m2, doxorubicin: 30 mg/m2, and vincristine: 1 mg/m2 (day 1) and cisplatin: 50 mg/m2 (day 8) and etoposide: 75 mg/m2 (days 8 and 9). The CAV/PE consisted of 2 alternating cycles of cyclophosphamide: 800 mg/m2, doxorubicin: 50 mg/m2, and vincristine: 1.4 mg/m2 (day 1), cisplatin: 100 mg/m2 (day 22) and etoposide: 100 mg/m2 (days 22, 23 and 24). Eligibility criteria were no prior therapy, no active concomitant malignancy, ECOG PS of 0 or 1, age < or =75, adequate hematologic functions and no brain metastasis. The complete response (CR) rate for CAV/PE-W (14/38, 36.8%) was significantly higher than that for CAV/PE (6/38, 15.8%, chi2; p=0. 032). However, the response rate in patients on CAV/PE-W (36/38, 94. 7%) was not significantly higher than the rate for CAV/PE (31/38, 81. 6%, chi2; p=0.076). Progression-free survival for patients on CAV/PE-W was significantly longer than that of patients on CAV/PE (41.4 weeks vs. 21.3 weeks, log-rank; p=0.0007, generalized Wilcoxon; p=0.0034) as was overall median survival (67.0 weeks vs. 51.2 weeks, log-rank; p=0.028). Actual dose-intensity of CAV/PE-W was 1.74 times that of CAV/PE. Hematological toxicities were equally frequent and G-CSF contributes to treatment efficacy by allowing administration of dose-intensive chemotherapy. The CAV/PE-W achieved a higher CR rate and longer survival, than the CAV/PE.     

Dose-finding and pharmacological study of ifosfamide in combination with paclitaxel and carboplatin in resistant small-cell lung cancer

Background:To find the maximum tolerated dose forifosfamide in combination with paclitaxel and carboplatin in small-celllung cancer patients (SCLC), who are resistant to cyclophosphamide,doxorubicin and etoposide (CDE). Patients and methods:Different dose schedules of ifosfamidewere combined with fixed doses of paclitaxel 175 mg/m² andcarboplatin AUC 6 mg/ml · min. Included were 30patients, with a median age of 60 years, and median time off priorcytotoxic treatment of 8 weeks. All patients were previously treatedwith CDE and 11 had received re-induction CDE. Results:Dose limiting toxicity of our schedule waspersistent thrombocytopenia. None of the patients developed neutropenicfever. Non-haematological toxicity was mild, although twotreatment-related deaths occurred. Fifty-four percent of patients had apartial response and median survival time was twenty-five weeks. Conclusions:The maximum tolerated dose of this combinationfor patients with resistant SCLC is ifosfamide 2000 mg/m² incombination with paclitaxel 175 mg/m² and carboplatin AUC 6mg/ml · min administered on the first day of a 21-daycycle.     

Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group.

PURPOSE: This randomized multicenter study was designed to compare the activity of a high-dose doxorubicin-containing chemotherapy regimen with a conventional standard-dose regimen in adult patients with advanced soft tissue sarcomas (ASTS). PATIENTS AND METHODS: Between 1992 and 1995, 314 patients were randomized to receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m(2) on day 1) and ifosfamide (5 g/m(2) on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m(2) on day 1), the same ifosfamide dose, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; sargramostim, 250 microgram/m(2) on days 3 to 16); all courses were repeated every 3 weeks. RESULTS: The median age of the 294 eligible patients was 50 years. They received a median of five chemotherapy cycles. The median dose and relative doxorubicin dose-intensity achieved were 245 mg and 97% in arm A and 360 mg and 99% in arm B, respectively. Thirty-eight percent and 23% of patients presented with leiomyosarcomas and liver metastases, respectively. Objective responses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P =.65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively. Progression-free survival (PFS) was significantly longer in the intensive arm (P =.03). The median duration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm. There was no difference in overall survival (P =.98) between the two therapeutic arms. Toxicities were manageable in both arms. A grade 3/4 neutropenia and infection occurred in 92% and 4.6% of patients in arm A, respectively, and in 90% and 16.6% in arm B, respectively. Grade 3/4 thrombocytopenia was more frequent in arm B. CONCLUSION: The use of rhGM-CSF allowed safe escalation of chemotherapy doses. Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS. The low complete response rate, the high incidence of leiomyosarcomas, and liver metastases may in part explain these results. However, the lengthening of the PFS in the intensive arm, because of the quality of stable disease and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS.     

Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma

BACKGROUND: This randomized controlled trial was to determine whether a combination chemotherapy regimen that contains anthracycline (doxorubicin and cyclophosphamide [AC]) is superior to the conventional cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] combination in premenopausal women with axillary lymph node positive Stage II breast carcinoma. METHODS: Premenopausal women with lymph node positive breast carcinoma were stratified according to age (younger than 35 or 35 years or older) and the number of positive axillary lymph nodes (1-3, 4-9, or >/= 10) and then randomly assigned to receive either doxorubicin 40 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously (i.v.) every 3 weeks or cyclophosphamide 100 mg/m(2) orally on Days 1 through 14, methotrexate 40 mg/m(2) and 5-fluorouracil 500 mg/m(2) i.v. on Days 1 and 8 every 4 weeks. Both arms were scheduled for six cycles. RESULTS: The median follow-up was 57 months. Eighteen of the 55 AC patients developed recurrence compared with 16 of the 69 CMF patients. The corresponding 5-year recurrence free survival rates were 64% and 78%, respectively (P = 0.12). The site of the first recurrence for AC patients was locoregional in 7%, distant in 22%, and combined in 4%. The corresponding data for the CMF arm were 4%, 16%, and 3%, respectively. Six AC patients died compared with 9 CMF patients. The corresponding 5-year survival rates were 90% and 86%, respectively (P = 0.96). More leukopenia (52%, mostly Grade 1-2) occurred in the CMF arm than in the AC arm (33%, P = 0.001), but no febrile episode was accompanied with leukopenia. CONCLUSIONS: This study showed no difference between AC and CMF with respect to both disease free and overall survival rates in premenopausal women with axillary lymph node positive breast carcinoma.     

Maintenance daily oral etoposide versus no further therapy following induction chemotherapy with etoposide plus ifosfamide plus cisplatin in extensive small-cell lung cancer: a Hoosier Oncology Group randomized study.

BACKGROUND: We performed this phase III study to determine whether the addition of 3 months of oral etoposide in non-progressing patients with extensive small-cell lung cancer (SCLC) treated with four cycles of etoposide plus ifosfamide plus cisplatin (VIP) improves progression-free survival (PFS) or overall survival. PATIENTS AND METHODS: Patients with extensive SCLC with a Karnofsky performance score (KPS) > or =50, adequate renal function and bone marrow reserve were eligible. Patients with CNS metastasis were eligible and received concurrent whole-brain radiotherapy. All patients received etoposide 75 mg/m2, ifosfamide 1.2 g/m2 and cisplatin 20 mg/m2 intravenously on days 1-4 every 3 weeks for four cycles. Non-progressing patients were randomized to oral etoposide 50 mg/m2 for 21 consecutive days every 4 weeks for three courses versus no further therapy until progression. RESULTS: From September 1993 to June 1998, 233 patients were entered and treated with VIP with 144 non-progressing patients subsequently randomized to oral etoposide (n = 72) or observation (n = 72). Minimum follow up for all patients is 2 years. Toxicity with oral etoposide was mild. There was an improvement in median PFS favoring the maintenance arm of 8.23 versus 6.5 months (P = 0.0018). There was a trend towards an improvement in median (12.2 versus 11.2 months), 1-year (51.4% versus 40.3%), 2-year (16.7% versus 6.9%) and 3-year (9.1% versus 1.9%) survival (P = 0.0704) favoring the maintenance arm. CONCLUSIONS: Three months of oral etoposide in non-progressing patients with extensive SCLC was associated with a significant improvement in PFS and a trend towards improved overall survival.     

Comparison of 2 cisplatin and etoposide dosages in relapsing small cell lung cancer]

The synergistic combination of cisplatinum and etoposide appears as the best second line treatment in patients relapsing from small cell lung carcinoma (SCLC). In order to test the dose-effect relationship of cisplatinum and etoposide in this situation, we have performed a randomised phase II trial comparing 2 five-day regimens: cisplatinum 20 mg/m2/day+etoposide 60 mg/m2/day (arm A) versus cisplatinum 40 mg/m2/day+etoposide 100 mg/m2/day (arm B) every 4 weeks. Thirty-seven patients were included (arm A: 18, arm B: 19), and 32 were considered to be eligible (arm A: 15, arm B: 17). Eight patients were non evaluable, five of them because of toxic death occurring prior to the second course (arm A: one from neutropenia; arm B: three from neutropenia and one from thrombopenia). The two groups were well balanced with regard to the main prognostic factors (age, sex, performance status, LDH level, response to induction chemotherapy). An objective response was observed in 10/24 evaluable patients (arm A: 4, arm B: 6) and was considered as complete in one patient in arm A and in 2 pts in arm B; these two patients presented with cerebral metastases and their response lasted 9 and 15 weeks respectively. The mean duration of response was 11 weeks in arm A and 10.5 weeks in arm B. The median actuarial survival of the overall population of eligible patients was 15 weeks: 13 weeks in arm A and 16.5 weeks in arm B. The study was discontinued because of the 23.5% toxic deaths rate in the high doses arm in this heavily pre-treated population of patients. However, the high response rate (54% overall, 35% considering toxic death as a failure) is impressive and presents evidence for the dose/effect relationship in SCLC.     

Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial.

PURPOSE: This phase III trial compared the efficacy and safety of doxorubicin and paclitaxel (AT) to 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line therapy for women with metastatic breast cancer. PATIENTS AND METHODS: A total of 267 women with metastatic breast cancer were randomized to receive either AT (doxorubicin 50 mg/m(2) followed 24 hours later by paclitaxel 220 mg/m(2)) or FAC (5-fluorouracil 500 mg/m(2), doxorubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2)), each administered every 3 weeks for up to eight cycles. Patients had to have measurable disease and an Eastern Cooperative Oncology Group performance status of 0 to 2. Only one prior non-anthracycline, nontaxane-containing adjuvant chemotherapy regimen was allowed. RESULTS: Overall response rates for patients randomized to AT and FAC were 68% and 55%, respectively (P =.032). Median time to progression and overall survival were significantly longer for AT compared with FAC (time to progression 8.3 months v 6.2 months [P =.034]; overall survival 23.3 months v 18.3 months [P =.013]). Therapy was generally well-tolerated (median of eight cycles delivered in each arm). Grade 3 or 4 neutropenia was more common with AT than with FAC (89% v 65%; P <.001); however, the incidence of fever and infection was low. Grade 3 or 4 arthralgia and myalgia, peripheral neuropathy, and diarrhea were more common with AT, whereas nausea and vomiting were more common with FAC. The incidence of cardiotoxicity was low in both arms. CONCLUSION: AT conferred a significant advantage in response rate, time to progression, and overall survival compared with FAC. Treatment was well-tolerated with no unexpected toxicities.     

Sequential versus alternating chemotherapy for high-grade non-Hodgkin's lymphomas: preliminary results of a phase III multicentre trial

In a multicentre phase III trial 105 previously untreated patients with high-grade non-Hodgkin's lymphomas stage II-IV were randomized to receive either 4 cycles of CHOEP (cyclophosphamide 750 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1, vincristine 2 mg i.v. day 1, etoposide 100 mg/m2 i.v. days 3-5, prednisolone 100 mg p.o. days 1-5) (treatment arm A), or 4 cycles of chemotherapy with hCHOP (cyclophosphamide 1,200 mg/m2 i.v. day 1, doxorubicin 40 mg/m2 i.v. days 1 + 2, vincristine 2 mg i.v. day 1, prednisolone 100 mg p.o. days 1-5) alternating with IVEP (ifosfamide 1,500 mg/m2 i.v. days 1-5, vindesine 3 mg/m2 i.v. day 1, etoposide 120 mg/m2 i.v. days 3-5, prednisolone 100 mg p.o. days 1-5) in treatment arm B. After 4 cycles of chemotherapy an involved field irradiation with a total dose of 35 Gy was given to all patients demonstrated to be in complete or partial remission without persisting extranodal disease. A complete response (CR) was seen in 86/105 patients (82%) with 88% CR in arm A vs. 76% CR in arm B. During a median follow-up of 11 months (range 2-31 months) 13 patients relapsed (6 patients arm A, 7 patients arm B). The overall survival at 30 months is projected to be 72% vs. 83% for arm A and B respectively. Disease-free survival is projected to be 78% in arm A and 45% in arm B at 28 months. So far, the differences in CR, survival and disease-free survival are not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)