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The French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) conducted a multicenter phase II study of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to evaluate the efficacy and side effects of this combination in pretreated advanced ovarian cancer. Patients with progressive ovarian carcinoma during or after platinum-based chemotherapy received paclitaxel 175 mg/m2 intravenously over 3 hours followed by intravenous carboplatin over 30 minutes every 4 weeks. The dose of carboplatin was calculated using a projected area under the concentration-time curve of 5 mg/mL x min. Of the 50 patients entered, 50 were evaluable for toxicity and 42 for response. There were eight complete and 10 partial responses, for an overall response rate of 43% (95% confidence interval, 28% to 56%). Overall response rates in platinum refractory patients and in those with early (> or = 3 and < 12 months) and late (> or = 12 months) relapse was 28%, 33%, and 71%, respectively. Median response duration, progression-free survival, and overall survivals were 8, 6, and 14 months, respectively. The most frequent and severe toxicity was myelosuppression. Grades 3 and 4 neutropenia occurred in 30% and 23% of cycles, and granulocyte colony-stimulating factor was administered in 6%. Only one case of neutropenic fever was observed. Grades 3 and 4 thrombocytopenia occurred in 3% and 1% of cycles, respectively. Alopecia and moderate nausea or vomiting were frequent. Transitory peripheral neuropathy was present in 45% of patients but was severe in only one patient. One early death was observed due to progressive disease and possibly to therapy. The combination of paclitaxel 175 mg/m2 as a 3-hour infusion and carboplatin dosed to an area under the concentration-time curve of 5 is an effective therapy in patients previously treated with platinum-based chemotherapy and may be administered safely to outpatients who relapse after one or two lines of chemotherapy.
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PMID:Efficacy and safety of the combination paclitaxel/carboplatin in patients with previously treated advanced ovarian carcinoma: a multicenter French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens phase II study. 934 19

The combination of cyclophosphamide (CY) and etoposide is synergistic, spares bone marrow stem cells and can be given repeatedly in high doses without stem cell support. Thirteen patients with non-Hodgkin's lymphoma (n = 8) or Hodgkin's disease (n = 5), received high-dose chemotherapy (HDC). Median age was 32 years (24-52). Male to female ratio was 10:3. All the patients were in advanced-stage. Karnofsky score prior to HDC was 60% (range 40-90). Six patients showed primary refractoriness and 7 had resistant relapse. HDC consisted of CY 1,500 mg/m2/day and etoposide 300 mg/m2/day, both for 4 days. rhG-CSF was started 24 h after the last dose of chemotherapy as a continuous intravenous infusion at a dose of 0.01 mg/kg/day and stopped when the leukocyte count reached 1 x 10(9)/1 on 3 consecutive days. Overall, 69% (9/13) of patients responded to HDC. Four achieved CR and 5 achieved PR. Two of the patients showed disease progression. The other 2 died during the early period of HDC. Neutrophil and platelet recovery after HDC were 8 (6-16) and 10 (4-14) days, respectively. The major nonhematological toxicities were nausea-vomiting (100%) and diarrhea (61%). The median follow-up was 204 (7-600) days. Two patients relapsed 48 and 185 days after HDC. Eight patients are still alive, 7 progression free. The progression-free survival is 220 (40-285) days. In conclusion, HDC + granulocyte colony-stimulating factor (G-CSF), without stem cell support seems to be promising in refractory or resistant relapse lymphoma patients bringing the need for randomized studies to show the cost effectiveness of HDC + G-CSF compared to HDC + autologous stem cell support.
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PMID:Use of high-dose chemotherapy plus granulocyte colony-stimulating factor for the salvage of refractory or resistant-relapse lymphoma patients without stem cell support. 935 43

The purpose of this study was to evaluate the safety and feasibility of front-line high-dose sequential (HDS) chemotherapy with peripheral blood stem cell (PBSC) transplantation in patients with newly diagnosed high-risk non-Hodgkin's lymphoma (NHL). Thirty-two patients with high-risk NHL (defined by the age-adjusted international index) underwent HDS chemotherapy followed by PBSC transplantation and consolidative radiotherapy. Twenty-eight patients (88%) had intermediate/high grade NHL and four patients (12%) had small noncleaved or lymphoblastic lymphoma. Twenty-four patients were classified as high-intermediate-risk (two risk factors) and eight patients were classified as high-risk (three risk factors). The five phases of HDS (see Fig. 1) consisted of Phase I (adriamycin, vincristine, and prednisone); Phase II (cyclophosphamide, filgrastim [G-CSF], and PBSC harvest); Phase III (methotrexate, leucovorin, vincristine; Phase IV (etoposide, filgrastim [G-CSF]); and Phase V (mitoxantrone, melphalan, autologous peripheral blood stem cell infusion, and filgrastim [G-CSF]). Radiation therapy was given to sites of previous bulk disease, 2400 cGy, (D + 30-100)]. Toxicity, engraftment, hospital utilization, overall survival, and relapse-free survival were evaluated. The high-dose sequential chemotherapeutic regimen was well tolerated. Treatment-related mortality was 6.25% with two deaths occurring secondary to sepsis and one death was caused by progressive disease. The major toxicity in Phase I-IV was grade 3 nausea/vomiting. The major toxicity in Phase V was grade 3 or 4 nausea/vomiting and mucositis. The median follow-up is 18.8 months (range 4-44 months). The overall survival (OS) and relapse-free survival (RFS) at 18 months for all patients were 78% (95% CI 37-90%) and 67% (95% CI 46-88%), respectively. The OS at 18 months for all patients, excluding the four patients with either small noncleaved or lymphoblastic lymphoma, was 82% (95% CI 65-98%) vs. 30% (95% CI 0-86%) (p = 0.0059). One patient in this latter group remains alive at 6 months follow-up. The RFS for all patients, excluding the four patients with either small noncleaved or lymphoblastic lymphoma, was 78% (95% CI 58-97%) vs. 0% (95% CI 0-0%) (p = 0.0004). High-dose sequential chemotherapy with initial PBSC transplantation is well tolerated and appears effective in high-risk NHL. Superior results were noted in patients with intermediate grade versus those with small noncleaved or lymphoblastic NHL.
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PMID:A phase II multicenter trial of high-dose sequential chemotherapy and peripheral blood stem cell transplantation as initial therapy for patients with high-risk non-Hodgkin's lymphoma. 936 Jul 83

THP-COPBLM including pirarubicin (THP), which is thought to be less toxic than doxorubicin, was used to treat non-Hodgkin's lymphoma (NHL) and the remission rate and adverse effects were studied in 26 patients older than 70 years. Complete remission (CR) was achieved in 19 patients (73.1%) and partial remission in three (11.5%). Classified by stages, CR was achieved in seven out of nine stage II patients and 12 out of 17 stage III, IV patients. The 2-year survival rate was 60.3%. Grade 3 or higher adverse effects included leukopenia in eight patients (30.8%), anemia in three (11.5%), thrombocytopenia in two (7.7%) and nausea/vomiting in 1 (3.8%). The THP-COPBLM regimen appears useful for the treatment of NHL in elderly patients. The regimen was seldom associated with gastrointestinal symptoms and cardiotoxicity. Despite the administration of granulocyte colony-stimulating factor (G-CSF), however, the white blood cell count decreased in many patients, suggesting the necessity for further study of this regimen to modify the dose of THP.
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PMID:THP-COPBLM (pirarubicin, cyclophosphamide, vincristine, prednisone, bleomycin and procarbazine) regimen combined with granulocyte colony-stimulating factor (G-CSF) for non-Hodgkin's lymphoma in elderly patients: a prospective study. 936 12

We performed a phase II study to evaluate the activity and toxicity of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin as first-line treatment in patients with recurrent or metastatic head and neck cancer. From March 1994 until August 1996, 49 patients were treated with paclitaxel 200 mg/m2 by 3-hour infusion followed by carboplatin at an area under the concentration-time curve of 7 mg/mL x min; treatment was requested every 4 weeks. Granulocyte colony-stimulating factor was administered prophylactically on days 2 to 12 of each cycle. The study included 41 men and eight women, with a median age of 57 years (range, 23 to 73 years). Most of the patients were symptomatic and had locoregional disease. Primary sites included nasopharynx (14 patients), oropharynx (six), oral cavity (four), hypopharynx (three), larynx (20), paranasal sinuses (one), and unknown (one). After the completion of treatment, four patients (8%; 95% confidence interval, 0% to 16%) achieved a complete response and 12 (24%; 95% confidence interval, 12% to 37%) achieved a partial response. Grade 3/4 toxicities included anemia (2%) and leukopenia, thrombocytopenia, nausea/vomiting, diarrhea, and stomatitis (4% each). After a median follow-up of 15.3 months, median time to progression was 5.7 months (range, 0.5 to 29.8+ months) and median survival was 13.3 months (range, 0.5 to 30.2+ months). In our ongoing study in a similar patient population, gemcitabine was substituted for carboplatin.
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PMID:Paclitaxel in combination with carboplatin or gemcitabine for the treatment of advanced head and neck cancer. 942 62

The purpose of this study was to develop a less toxic outpatient chemotherapy regimen for mobilizing peripheral blood stem cells (PBSC). Three hundred eighteen patients with newly diagnosed stage II-III breast cancer who had received conventional dose adjuvant chemotherapy were randomized to receive intermediate-dose cyclophosphamide (2 g/m2), etoposide (600 mg/m2), and granulocyte colony-stimulating factor (G-CSF) 6 micrograms/kg/day (ID-Cy, n = 162) or high-dose cyclophosphamide (4 g/m2) and the same doses of etoposide and G-CSF (HD-Cy, n = 156) followed by collection of PBSC. Three hundred seventeen of 318 patients had apheresis performed, and 315 received high-dose chemotherapy (HDC) followed by PBSC support. The median numbers of CD34+ cells collected in a median of two apheresis following ID-Cy and HD-Cy were 19.9 and 22.2 x 10(6)/kg, respectively (p = 0.04). The fractions of patients achieving CD34+ cell doses > or = 2.5 or > or = 5.0 x 10(6)/kg were not different between the two regimens. More patients receiving HD-Cy had grade 3-4 nausea (p = 0.001), vomiting (p = 0.03), and mucositis (p = 0.04). The fractions of patients having a neutrophil nadir < 0.5 x 10(9)/L following ID-Cy and HD-Cy were 0.83 and 0.95, respectively (p = < 0.001). The fractions of patients having a platelet nadir < 25 x 10(9)/L following ID-Cy and HD-Cy were 0.13 and 0.51, respectively (p = < 0.001). More patients in the HD-Cy group received platelet (p < 0.001) and red blood cell (p < 0.001) transfusions and were admitted to the hospital more frequently (p = 0.03) than patients receiving ID-Cy. Three hundred fifteen patients received HDC followed by infusion of PBSC. There were no significant differences in the incidence of transplant-related death or early survival between patients receiving ID-Cy or HD-Cy followed by HDC. It was concluded that a regimen of Cy 2 g/m2 with etoposide and G-CSF was effective for mobilization of PBSC with low morbidity and resource utilization in patients with limited prior chemotherapy exposure.
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PMID:A randomized trial of two doses of cyclophosphamide with etoposide and G-CSF for mobilization of peripheral blood stem cells in 318 patients with stage II-III breast cancer. 959 71

A phase II trial was performed to investigate the efficacy and tolerance of vinorelbine (VNB), 5-fluorouracil (5-FU), l-leucovorin (LLV) and recombinant human granulocyte colony-stimulating factor (G-CSF) in advanced breast cancer. Between August 1994 and October 1996, 53 patients entered this trial. Thirty-seven patients were previously untreated and 16 patients had failed previous palliative chemotherapy with (n = 12) or without anthracyclines (n = 4). Therapy consisted of VNB 40 mg m(-2) diluted in 250 ml of saline infused over 30 min on days 1 and 14 and LLV 100 mg m(-2) administered by intravenous bolus injection and 5-FU 400 mg m(-2) diluted in 500 ml of saline infused over 2 h, both given on days 1-5 every 4 weeks. G-CSF was administered at 5 microg kg(-1) day(-1) subcutaneously on days 6-10 during each cycle. Treatment was continued in cases of response or stable disease until a total of six courses were completed. The overall response rate was 59% for chemotherapeutically naive patients (95% confidence interval 42-75%), including five complete responses (CR; 13%) and 17 partial responses (PR; 46%); ten patients (27%) had stable disease (SD) and only five (14%) progressed (PD). Second-line chemotherapy with this regimen resulted in 3/16 (19%) objective remissions, but nine patients had SD and four had PD. The median time to progression was 10.5 months (range 2-23) in previously untreated patients and 7.0 months (range 2-19) in those who had failed prior chemotherapy. After a median follow-up time of 14 months, 29 patients (55%) are still alive with metastatic disease; median survival has not been reached yet. The dose-limiting toxicity was myelosuppression: WHO grade III and IV neutropenia occurred in 15 (28%) and four patients (8%), and was complicated by septicaemia in two; grade III anaemia and thrombocytopenia were noted in four (8%) and three (6%) patients respectively. Severe (WHO grade 3) non-haematological toxicities included stomatitis in 6% and nausea/vomiting and alopecia in 2% each. Our data suggest that the combination of vinorelbine, 5-fluorouracil and l-leucovorin plus G-CSF is an effective first line regimen for treatment of advanced breast cancer. Overall toxicity was modest, with myelosuppression being the dose-limiting side-effect. Other severe adverse reactions were uncommon.
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PMID:Effective treatment of advanced breast cancer with vinorelbine, 5-fluorouracil and l-leucovorin plus human granulocyte colony-stimulating factor. 974 9

The purpose of this study was to determine the maximally tolerated dose of doxorubicin administered during two cycles of intensive chemotherapy with cyclophosphamide and doxorubicin without stem cell support in patients with advanced cancer and to assess the cumulative cardiac toxicity of the regimen by noninvasive radionuclide imaging and by pre-and postchemotherapy endomyocardial biopsies. Thirty-eight patients (thirty-six with high risk or metastatic breast cancer) were treated in a dose-escalation trial using a fixed dose of i.v. cyclophosphamide (4.2 g/m2) administered over 2 h on day 5 and escalating doses of doxorubicin (50-175 mg/m2) given as a 96-h continuous i.v. infusion on days 1-4, using Filgrastim (granulocyte colony-stimulating factor) for hematological support beginning on day 6. All patients underwent pretreatment, and 28 patients underwent postchemotherapy endomyocardial biopsies. Twenty-nine of 38 patients received two cycles of treatment (median number of days between cycles, 44; range, 34-62). Twenty-one patients had received doxorubicin previously at cumulative dose levels </=150 mg/m2; all patients had pretreatment endomyocardial biopsy scores less than 1. One patient treated at the highest dose level of doxorubicin (175 mg/m2) developed symptoms of mild congestive heart failure following two cycles of chemotherapy. Pre- and posttreatment radionuclide ejection fractions were 65 and 45%, respectively; this patient had a posttreatment endomyocardial biopsy score of 1 (damage to <5% of myocytes). One additional patient at this dose level had an asymptomatic biopsy score of 1, with a decrease in ejection fraction from 62 to 43%; this recovered to 58% 5 months after completion of chemotherapy. Six additional patients treated at lower dose levels had abnormal posttreatment endomyocardial biopsies without abnormal posttreatment ejection fractions. Nine patients received only one cycle of chemotherapy: five patients due to decreased cardiac ejection fraction following cycle 1 (two of these patients had normal endomyocardial biopsies, and two patients had biopsy scores of 1); one patient secondary to tumor progression following cycle one; one patient due to persistently detectable Clostridium difficile toxin in the stool; one patient refused cycle two; and one patient died following cycle one of complications related to sepsis. A single patient experienced a grand mal seizure associated with orthostatic hypotension, which was considered the dose-limiting toxicity. The median duration (over two cycles) of granulocytopenia (absolute granulocyte count <500/microliter) at the maximally tolerated dose level of 150 mg/m2 was 8.5 days (range, 5-13 days), and the median duration of thrombocytopenia (platelets <20,000/microliter) was 2.5 days (range, 0-9 days). The median duration of hospitalization including chemotherapy administration was 23 days (range, 19-36 days). Other toxicities included stomatitis, fever, diarrhea, and emesis. One patient developed acute leukemia 54 months posttreatment. We conclude that two courses of high-dose cyclophosphamide and doxorubicin using granulocyte colony-stimulating factor are feasible and safe with tolerable myocardial toxicity as evidenced by serial endomyocardial biopsies. The dose-limiting toxicity encountered was a grand mal seizure. The recommended Phase II dose is doxorubicin 150 mg/m2 administered as a 96-h infusion on days 1-4, with cyclophosphamide 4. 2 g/m2 on day 5 and G-CSF 5 microgram/kg/day started on day 6 and administered until the total WBC is above 10,000/microliter for three consecutive days.
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PMID:High-dose infusional doxorubicin and cyclophosphamide: a feasibility study of tandem high-dose chemotherapy cycles without stem cell support. 981 32

Multiple studies have shown that leucovorin-fluorouracil regimens are modestly superior to fluorouracil alone in the treatment of advanced colorectal cancer. Laboratory data suggest that iododeoxyuridine could further enhance the efficacy of leucovorin-fluorouracil regimens. This report describes the Phase I clinical evaluation of a leucovorin-fluorouracil-iododeoxyuridine chemotherapy regimen. Twenty-four patients received treatment with leucovorin (500 mg/m2), fluorouracil (500 mg/m2), and iododeoxyuridine (escalating doses) on days 1 and 8 of a 21-day cycle. The maximum tolerated dose of iododeoxyuridine was 1200 mg/m2, with a recommended Phase II dose of 1000 mg/m2. Myelosuppression (leukopenia) was dose limiting; other commonly observed treatment toxicities were nausea/vomiting, mucositis, and hyperlacrimation. Although the 1200 mg/m2 dose was tolerated during the initial few cycles of therapy, chronic administration could not be maintained secondary to dose-limiting neutropenia. Since neutropenia was dose limiting, in a follow-up study, 10 patients received a modified regimen (treatment on days 1 and 6 instead of days 1 and 8) with the addition of granulocyte colony-stimulating factor (days 8-19). The addition of granulocyte colony-stimulating factor, however, did not permit further escalation of the iododeoxyuridine dose. Three partial responses and six minor responses were observed. Phase II studies of this regimen are ongoing in advanced colorectal and advanced pancreatic cancer to determine response rates in these diseases.
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PMID:Biochemical modulation in the treatment of advanced cancer: a study of combined leucovorin, fluorouracil, and iododeoxyuridine. 981 23

Autologous peripheral blood stem cell transplantation following myeloablative chemotherapy is being increasingly utilized in the treatment of a variety of malignancies. We administered busulfan 16 mg/kg orally, thiotepa 500-700 mg/m2 i.v., and carboplatin 800-1000 mg/m2 i.v. to 56 women with metastatic carcinoma of the breast. Autologous peripheral blood stem cells, which had been collected after a combination of chemotherapy and granulocyte colony-stimulating factor, were infused on day 0. The major toxicities of the conditioning regimen included severe pancytopenia, stomatitis, nausea, emesis, diarrhea, fever, and infection. Transplant-related mortality was 1.8%. The incidence of opportunistic viral infections was 42.9%. Fourteen individuals achieved a complete response. The actuarial survival at 1223 days was 13.7% for the entire group of patients; the actuarial survival at 1009 days was 39.3% among complete responders. The functional status of the immune system was determined following transplantation in a subset of patients. Peripheral blood mononuclear cells were obtained before and after stem cell infusion, and were analyzed phenotypically and functionally. Proliferative and interleukin-2 synthetic ability of these cells was assessed following stimulation with phytohemagglutinin and anti-CD3 antibody. The response to influenza peptides was also ascertained. Proliferative and interleukin-2 synthetic capacity was markedly impaired for over a year. Memory response was virtually absent for up to 2 years following transplantation. The prolonged and marked immunosuppression following this myeloablative regimen was associated with a high incidence of opportunistic viral infections, and may have contributed to disease relapse and progression especially in patients who failed to achieve a complete response following transplantation.
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PMID:Myeloablative chemotherapy with autologous peripheral blood stem cell transplantation for metastatic breast cancer: immunologic consequences affecting clinical outcome. 1051 93


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