Schedule specific biochemical modulation of 5-fluorouracil in advanced colorectal cancer: A randomized study

Background:We have recently suggested that bolus 5-fluorouracil(5-FU) may work via a RNA directed mechanism while continuous infusion 5-FUmay kill cells via a thymidylate synthase related pathway. It may thus bepossible to selectively modulate each schedule biochemically. We have comparedan alternating regimen of bolus and continuous infusion 5-FU, selectivelymodulated for the schedule of administration, with modulated bolus 5-FU inadvanced colorectal cancer patients. Patients and methods:Two hundred fourteen patients from nineteenItalian centers were randomized to the control arm consisting of biweeklycycles of MTX, 200 mg/m² on day 1, followed by bolus 5-FU 600mg/m² on day 2 and 6-S-leucovorin rescue, or to the experimentalarm consisting of two biweekly cycles of the same regimen as in the controlarm alternated to three weeks of continuous infusion 5-FU (200mg/m² day) + weekly bolus 6-S-leucovorin, 20 mg/m². Results:Nine CR and twenty-seven PR were obtained on one hundredeleven evaluable patients treated in experimental arm (RR = 32%,95% confidence interval (95% CI): 24%–42%),while two CR and eleven PR were observed among one hunderd three evaluablepatients in control arm (RR = 13%, 95% CI:7%–21%). WHO grade 3–4 toxicity occurred in13% of cycles of experimental arm and in 8% of cycles in controlarm. The PFS was significantly longer in experimental arm (6.2 vs. 4.3 months,odds ratio 0.66, P = 0.003), while the overall survival was similarin both arms (14.8 months in experimental arm vs. 14.1 months in control arm);quality of life was similar as well. Eighty percent of patients receivingsecond-line chemotherapy in control arm were treated with continuous infusion5-FU. Conclusions:Alternating, schedule-specific biochemical modulationof FU is more active than MTX 5-FU as first-line treatment of advancedcolorectal cancer. However, the overall survival was similar suggesting thatalternating bolus and infusional 5-FU upfront may be as effective as givingthem in sequence as first- and second-line treatment.     

Unusual Response to Second-Line Single-Agent Gemcitabine in Locally Advanced Primary Leiomyosarcoma of the Lung: A Case Report

Abstract

Primary leiomyosarcomas (LMSs) of the lung are extremely rare malignancies that have been the subject of single or small series of case reports. Today, the gold standard of treatment in patients with locally advanced and metastatic disease includes one of the many possible regimens containing an anthracycline and/or ifosfamide. Few chemotherapy agents are active in the second-line setting. In particular, gemcitabine is considered quite ineffective in the treatment of first- as well as second-line chemotherapy of soft tissue sarcoma and responses to this agent are seldom reported. In this paper, we report a single patient with primary LMS of the lung previously treated with a combination of epirubicin and ifosfamide. The patient responded to second-line chemotherapy with gemcitabine 1250 mg/m² given as a 30-minute infusion on days 1, 8, and 15 of a 28-day cycle and showed an 8-month response duration and negligible toxicity. Gemcitabine may represent an alternative to the best supportive care in patients affected with soft tissue sarcoma who fail first-line chemotherapy.     

A Phase II Study of Ifosfamide,Methotrexate, Etoposide,and Prednisolone for Previously Untreated Stage I/II Extranodal Natural Killer/T‐Cell Lymphoma,Nasal Type: A Multicenter Trial of the Korean Cancer Study Group

Background.

Combination chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) was active as first-line and second-line treatment for extranodal natural killer/T-cell lymphoma (NTCL).

Methods.

Forty-four patients with chemo-naïve stage I/II NTCL were enrolled in a prospective, multicenter, phase II study and received six cycles of IMEP (ifosfamide 1.5 g/m² on days 1–3; methotrextate 30 mg/m² on days 3 and 10; etoposide 100 mg/m² on days 1–3; and prednisolone 60 mg/m² per day on days 1–5) followed by involved field radiotherapy (IFRT).

Results.

Overall response rates were 73% (complete remission [CR] in 11 of 41 evaluable patients [27%]) after IMEP chemotherapy and 78% (CR 18 of 27 evaluable patients [67%]) after IMEP followed by IFRT. Neutropenia and thrombocytopenia were documented in 33 patients (75%) and 7 patients (16%), respectively. Only 8 patients (18%) experienced febrile neutropenia. Three-year progression-free survival (PFS) and overall survival (OS) were 66% and 56%, respectively. High Ki-67 (≥70%) and Ann Arbor stage II independently reduced PFS (p = .004) and OS (p = .001), respectively.

Conclusion.

Due to the high rate of progression during IMEP chemotherapy, IFRT needs to be introduced earlier. Moreover, active chemotherapy including an l-asparaginase-based regimen should be use to reduce systemic treatment failure in stage I/II NTCL.     

Ifosfamide given by continuous-intravenous infusion in association with vinorelbine in patients with anthracycline-resistant metastatic breast cancer: A phase I-II clinical trial

Background: Vinorelbine (VNR) is highly active in metastatic breastcancer (MBC) and has shown an overall response rate of40%–50% as first-line treatment. In vitro, a synergy hasbeen observed between this drug and ifosfamide (IFX). In addition, thepharmacokinetics of IFX suggest that it may have greater activity when givenby continuous-intravenous infusion (C.I.V.I.). The aim of this study was.therefore. to assess the antitumor efficacy and toxicity of the combinationof bolus VNR and C.I.V.I. IFX as second-line therapy inanthracycline-resistant breast cancer patients.Patients and methods: Forty-two patients with MBC who had alreadyreceived anthracycline-based chemotherapy were treated with a regimenconsisting of IFX, by C.I.V.I. for 72 hours and bolus VNR. The courses wererepeated every three weeks for a maximum of eight cycles. Four doseintensification steps were planned: IFX, 1.5 g/m² on days1–3 + VNR, 30 mg/m² on day 1 (six patients); IFX, 2g/m² on days 1–3 + VNR, 25 mg/m² on day 1(six patients); IFX, 1.8 mg/m² on days 1–3 + VNR, 25mg/m² on days 1 and 8 (six patients); IFX, 2g/m² on days 1–3 + VNR, 25 mg/m² on days 1and 8 (24 patients). Sodium-2-mercaptoethane sulfonate (mesna) wasassociated with IFX at an infusion ratio of 1 : 1 and, once the infusion wascompleted, per os every four hours for three times.Results: All of the 42 patients entered were assessable for toxicity, and41 of them for response. Neutropenia was the most frequently-occurringtoxicity, but only five patients at the highest dose level (11.9%)presented grade 4, and none of those at the first three steps. Othersignificant toxic effects were mild (only grade I–II). The medianrelative dose intensity was 95% at the highest dose level and all ofthe treatments were administered on an out-patient basis. The overallresponse rate was 36.5% with a CR rate of 4.8% (two of 41patients, all at the highest dose level) and a PR rate of 31.7% (13of 41 patients). The median response duration was 7.0 months (range2–13 months).Conclusions: The present phase I–II study shows that the IFX and VNRcombination is an active and well-tolerated treatment in MBC and provides analternative to taxanes for patients previously treated with anthracyclines.     

Ifosfamide,mitomycin and radiotherapy in non-small-cell lung cancer

Summary Ifosfamide and mitomycin C are two of the more active single agents in non-small-cell lung cancer (NSCLC). This study evaluates these drugs in combination followed by radiotherapy. A total of 33 ambulatory patients with inoperable NSCLC were treated with 5 g/m² ifosfamide as a 24-h infusion, with the concurrent administration of sodium 2-mercaptoethane sulphonate (mesna; 160% of the ifosfamide dose) and 6 mg/m² mitomycin C given as an i.v. bolus injection on the 2nd day. The median age of the patients was 61 years. In all, 20 patients had limited disease and 13, extensive disease. A total of 30 were assessable for response to chemotherapy, 8 of whom achieved a partial response (PR) and 5, a complete response (CR) (2 were verified bronchoscopically). The overall response rate was thus 43%. All but one response (a PR) were in patients with limited disease (LD). A total of 21 patients, including 13 responders, received thoracic irradiation (30 Gy in 8 fractions over 10 days) following chemotherapy. One PR was converted to a radiological CR. In all, 17 (55%) of the patients were alive at 1 year. All patients suffered chemotherapy-induced alopecia (WHO grade 3), but there were no treatment modifications due to myelosuppression, haemorrhagic cystitis or other toxicity. WHO grade 3 nausea and vomiting were seen in all patients. There was one treatment-related death. Combination therapy using ifosfamide and mitomycin C has useful activity in NSCLC.     

Ifosfamide, methotrexate, and 5-fluorouracil: effective combination in resistant breast cancer

Ifosfamide has definite efficacy in many malignant tumours, including breast cancer. In the present study we substituted cyclophosphamide with ifosfamide in the combination CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) regimen in 25 patients with breast cancer whose disease was refractory to CMF or who had relapsed after previous response. Ifosfamide was given in an i.v. infusion at a dose of 1.2 g/m² daily for 5 days, together with mesna as a uroprotector (at 20% of the ifosfamide dose). Methotrexate was given at a dose of 40 mg/m² and 5-fluorouracil was given at 600 mg/m², both by i.v. push. Courses were repeated every 21 days. The 24 evaluable patients received 3–12 courses (average, 5 courses); results included a complete remission in 3 patients (12.5%) and a partial remission in 3 (12.5%). Among the remaining patients, improvement was seen in 4 (16.6%); stable disease, in 7; and progressive disease, in 7 (29.2%). The complete responses lasted for 11+, 13+, and 15+ months, and partial remissions, for 2, 6, and 9 months. The responses were detected in soft-tissue as well as visceral lesions, but not in bony lesions. The responders remain under follow-up. This study shows the efficacy of ifosfamide-containing chemotherapy in breast cancer. As toxicities were tolerable, higher doses of ifosfamide could safely be used in these patients. Use of this combination as first-line therapy in breast cancer could be considered for a future study.Presented at the Satellite Symposium Ifosfamide in Gynecological Tumors of the 5th European Conference on Clinical Oncology and Cancer Nursing, London, September 3–7, 1989     

Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study

Background: Second-line irinotecan-based chemotherapy is commonly used in metastatic colorectal cancers after first-line oxaliplatin-based chemotherapy. No standard schedule of irinotecan has been established in this situation.Patients and methods: Metastatic colorectal cancer patients included in the OPTIMOX1 phase III study received first-line oxaliplatin-based chemotherapy (FOLFOX). No second line was defined in the protocol, but data concerning second line were prospectively registered. Inclusion criterion was patients receiving an irinotecan-based second-line chemotherapy. Second-line progression-free survival (PFS) and tumor response were evaluated according to type of irinotecan-based regimen administered.Results: A total of 342 patients received irinotecan-based chemotherapy as second-line chemotherapy: FOLFIRI-3 [n = 109, irinotecan 100 mg/m² days 1 and 3 combined with leucovorin (LV) 400 mg/m² day 1 and 46-h continuous 5-fluorouracil (5-FU) 2000 mg/m²], FOLFIRI-1 (n = 112, irinotecan 180 mg/m² day 1 combined with LV 400 mg/m² day 1, 5-FU bolus 400 mg/m² and 46-h continuous 5-FU 2400 mg/m²) and other various irinotecan-based regimens (n = 121). Median second-line PFS was 3.0 months (FOLFIRI-3: 3.7 months; FOLFIRI-1: 3.0 months; other regimens: 2.3 months). In multivariate analysis, FOLFIRI-3 regimen (relative risk 0.43, 95% confidence interval 0.28–0.68, P = 0.0003) and lactate deshydrogenase level at inclusion (P = 0.0006) in OPTIMOX1 were associated with a longer second-line PFS.Conclusion: In unselected patients pretreated with oxaliplatin, PFS in second line appeared to be improved by FOLFIRI-3 regimen.     

Pilot study of daily ifosfamide 1 g/m2 until grade III granulocytopenia as second-line chemotherapy for anthracycline-pretreated advanced soft tissue sarcoma

BACKGROUND AND AIMS: Second-line chemotherapy regimens for advanced soft tissue sarcomas after treatment failure or tumor relapse following anthracyclines are still investigational. The aim of the present study was to assess the activity of ifosfamide with a new schedule for patients with advanced soft tissue sarcoma failing to achieve remission or relapsing following anthracycline-containing regimens; it was attempted to individualize dosages and prevent excessive toxicity. STUDY DESIGN: A second-line chemotherapy regimen of ifosfamide 1 g/m2 daily, with drug withdrawal until the next cycle upon appearance of grade III granulocytopenia, was administered to 21 patients with advanced soft tissue sarcoma. All patients failed to achieve remission or relapsed following a first-line high-dose anthracycline regimen (epirubicin 180 mg/m2 or zorubicin 600 mg/m2 per cycle). The cycles were repeated every four weeks. RESULTS: The median number of cycles applied was three (range, 1-15). The ifosfamide dosage reached was 4-13 g/m2 per cycle, median 5 g/m2. A complete response was achieved in 1/21 patient (5%), no partial responses were observed, 4/21 patients (20%) had stable disease, and 16/21 (75%) had progressive disease. No difference in response and stable disease rates was observed between responders and non-responders to first-line chemotherapy. No difference in the ifosfamide dose reached was noted between patients receiving second-line chemotherapy directly following first-line therapy and those with a time interval between first- and second-line chemotherapy. The granulocytopenia grade III nadir lasted for a median of one day (range, 1-3) and other toxicities including hematological toxicity were mild and infrequent. CONCLUSIONS: In view of the swift regeneration from grade III granulocytopenia, continuation of the study with granulocytopenia grade IV as a limiting factor for ifosfamide dose escalation seems feasible, with the prospect of better efficacy without excessive toxicity.     

Phase II Study of Irinotecan plus Leucovorin and Bolus 5-Fluorouracil as First- or Second-Line Chemotherapy in Patients with Advanced Gastric or Esophageal-Gastric Junction Adenocarcinoma

Abstract

The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU) / leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Treatment consisted of irinotecan 80 mg/m² intravenously (i.v.), followed by LV 200 mg/m² (i.v.) and 5-FU 450 mg/m² as an i.v. bolus, administered weekly for 6 weeks, followed by a 2-week rest period. Thirty-one patients (23 chemo-naïve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 3 toxicity was febrile neutropenia. Grade 3 non-hematological toxicities were rare. There were no treatmentrelated deaths.

The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation would be worthwhile, particularly in elderly or debilitated patients who cannot tolerate aggressive chemotherapy.     

A phase II study of ifosfamide and cisplatin chemotherapy for metastatic or relapsed carcinoma of the cervix

Summary A total of 44 women received a combination of ifosfamide (1.5 g/m² daily x5) and cisplatin (50 mg/m² on day 1 only) as first-line chemotherapy for recurrent or metastatic carcinoma of the cervix. In all, 12/42 (38%) evaluable patients responded, with the median duration of response being 7 months. Bone marrow and gastrointestinal toxicity were frequently severe. There were 3 septic death. Although cisplatin plus ifosfamide is an active combination against this disease, these results suggest that it is no more so than either drug used alone.The London Gynaecology Oncology Group (LGOG) comprising the Departments of Medical Oncology     

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas

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 µg/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 anti-tumor activity of this regimen and a potential improvement in survival.     

High-dose ifosfamide with mesna uroprotection in Ewing's sarcoma

The German Society of Pediatric Oncology (GPO) has studied the efficacy of high-dose ifosfamide with mesna uroprotection in patients with Ewing's sarcoma. A phase II trial of ifosfamide (IFO) (2 g/m² per day, days 1–5) in eight patients with recurrent evaluable disease resulted in three partial and two complete responses lasting from 3 to 12 months (median, 6 months). In a second phase II trial in 15 patients, the combination of IFO and cisplatin (20 mg/m² per day, days 1–5) resulted in 7 partial and 2 complete responses lasting from 3 to 32 months (median, 6 months). Consequently, in 1985 IFO was incorporated into first-line chemotherapy for newly diagnosed patients (replacing cyclophosphamide) and given in combination with vincristine, actinomycin D, and Adriamycin (VAIA) in patients considered to be at high risk for relapse. IFO was given at a dose of 3 g/m per day on days 1 and 2 as a 48-h continuous infusion, in combination with actinomycin D (0.5 mg/m² per day on days 1–3) or Adriamycin (30 mg/m² per day on days 1 and 2). The study was piloted from March to December 1985 and has been open since January 1986; 37 patients were entered during the pilot phase and 65 have been entered in the ongoing main trial since January 1986. At present, Kaplan-Meier disease-free survival projects that disease-free survival in patients with large primary tumors has improved compared with that reported for the previous CESS 81 trial. The toxicity of the VAIA regimen was comparable with that of the conventional vincristine, actinomycin D, cyclophosphamide, and Adriamycin (VACA) regimen used in the previous CESS 81 trial.Presented in part at the 4th European Conference on Clinical Oncology and Cancer Nursing (ECCO-4), Madrid, Spain, November 1–4, 1987     

Salvage chemotherapy with paclitaxel, ifosfamide, and nedaplatin in patients with urothelial cancer who had received prior cisplatin-based therapy

Background and aims: The aim of the present phase II study was to evaluate the efficacy of combination chemotherapy of paclitaxel, ifosfamide, and nedaplatin (PIN regimen) in patients with recurrent urothelial cancer who had been treated with cisplatin-based chemotherapy. Patients/methods: Eligible patients were those with histologically confirmed urothelial cancer who had progressed or relapsed after cisplatin-based chemotherapy. The PIN regimen consisted of paclitaxel 175 mg/m² on day 1; ifosfamide 4.5 g/m2 divided over days 1, 2, and 3; and nedaplatin 70 mg/m² on day 1; PIN was given every 28 days. Results: Among the 32 patients enrolled in the study (median age, 66 years), complete and partial responses were obtained in 5 patients and 19 patients, respectively, with an overall response rate of 75% (95% confidence interval [CI], 59–91%). The median time to progression was 8 months (range, 0–50+ months) and the median survival was 22 months (range, 4–52+ months). The 1- and 2-year overall survival rates were 53.7 and 42.9%, respectively. All patients experienced Grade 3 or 4 neutropenia, while Grade 3 or 4 thrombocytopenia was seen in 8 patients; Grade 3 or 4 anemia was seen in 6 patients; Grade 3 neuropathy was observed in 1 patient, for whom the PIN therapy was discontinued. There were no treatment-related deaths. Conclusion: The PIN combination was highly active and tolerable in previously treated patients with urothelial cancer as a second-line treatment.Research support: none     

FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study

Purpose

The purpose of the present study was to evaluate the activity and the tolerability of the FOLFIRI regimen, administered as second-line chemotherapy in patients with locally advanced or metastatic pancreatic cancer after the failure of a gemcitabine-based regimen.

Methods

Patients with locally advanced/metastatic disease who received a first-line chemotherapy (one line only) with gemcitabine ± platinoid (cisplatin, oxaliplatin) and who had measurable disease conform with the RECIST criteria were eligible for the study. FOLFIRI consists of irinotecan 180 mg/m² iv on day 1, leucovorin (l-form) 200 mg/m² iv on day 1 and 2, 5-FU 400 mg/m² iv bolus on days 1 and 2, and 5-FU 600 mg/m² iv by ci for 22 h on days 1 and 2, repeated every 2 weeks. The primary end point was the response rate.

Results

Among the 50 enrolled patients, 4 partial responses (PR) (8 %) and 14 stable diseases were observed, for a disease control rate of 18/50 (36 %). Forty-one patients (82 %) have been pretreated with cisplatin/oxaliplatin+gemcitabine as first-line chemotherapy. The median progression-free and overall survivals were 3.2 and 5 months, respectively. The 6-month survival rate was 32 %. Grade 3–4 neutropenia and diarrhea occurred in 10 (20 %) and 6 (12 %) patients, respectively.

Conclusion

The FOLFIRI regimen showed a modest clinical activity in this quite heavily pretreated patients’ population with locally advanced or metastatic pancreatic cancer with a manageable toxicity profile.     

Evaluation of the combination 5-fluorouracil, dacarbazine, and epirubicin in patients with advanced well-differentiated neuroendocrine tumors

IntroductionThe aim of this study was to retrospectively analyze the efficacy and safety of the combination of 5-fluorouracil (5-FU), dacarbazine, and epirubicin (FDE) in 39 patients with advanced, well-differentiated neuroendocrine tumors (NETs).Patients and MethodsThe primary sites of the disease were the pancreas (16 cases), gastrointestinal tract (12 cases), and extradigestive sites (11 cases). Out of these, 54% of the patients were chemotherapy naive and 74% were progressive. The treatment was a combination of 5-FU 500 mg/m²/day, dacarbazine 250 mg/m²/day for 5 days, and epirubicin 50 mg/m² on day 1, administered every 21 days. Tumoral response was assessed with response evaluation criteria in solid tumors.ResultsPartial response was seen in 17 out of the 39 patients (44%) and the median response duration was 12 months. The median progression-free survival and overall survival were 11 and 21 months, respectively. Disease control was achieved in 83% of the 29 patients in progression at the beginning of the treatment. Objective responses were 58%, 25%, and 36%, for pancreatic, gastrointestinal, and extradigestive NETs, respectively. The sole grade 3/4 toxicity was hematologic.ConclusionThe FDE regimen is effective in advanced well-differentiated NETs and represents an interesting alternative to streptozocin-based regimens as first- or second-line therapy.     

Ifosfamide in advanced epidermoid head and neck cancer

Summary A total of 37 men with epidermoid head and neck cancer whose disease had recurred following primary treatment (surgery and/or radiotherapy) received first-line chemotherapy with ifosfamide at i. v. doses of 3 g/m² given daily on 3 consecutive days in combination with mesna (600 mg/m²×3 oral daily doses on days 1–3) every 3 weeks. In all, 7 patients showed a partial response and 2 patients achieved a complete response, for an overall objective response rate of 26% (9 of 35 eligible patients; 95% confidence interval, 12.5%–43%). Excluding the 5 early nontoxic deaths observed during the first 3 weeks of therapy, the objective response rate was 30% (9 of 30 patients; 95% confidence interval, 15%–49.5%). Responses were seen in lung metastases (2 patients), lymph nodes (2 patients), skin (3 patients), and cases of local recurrence (5 patients). The median duration of responses was 3 months (range, 2–5 months). The main side effects of ifosfamide were alopecia (83% of patients), emesis (80%), granulocytopenia (23%), and mild mucositis (20%). Two poor-risk patients suffered severe CNS complications that were probably related to treatment. Three patients died due to chemotherapy-related complications (2 patients with CNS toxicity and 1 patient with granulocytopenic sepsis). In conclusion, ifosfamide appears to be an active drug in epidermoid head and neck cancer and merits further evaluation in this disease.     

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer

Purpose: We designed a phase I–II trial of three active agents,paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lungcancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximumtolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2)determine the overall response rate and median survival of patients treatedon this regimen.Patients and methods: We treated cohorts of patients with stage IIIB orIV NSCLC with ifosfamide 1.2–1.6 g/m²/day × 3 andvinorelbine 20–25 mg/m²/day × 3 and escalatingdoses of paclitaxel at 100–175 mg/m² on day 2 with G-CSFsupport on a 21-day cycle. One prior experimental single-agent chemotherapyregimen was allowed.Results: Fifty-six patients, were enrolled on this trial: 27 on the phaseI portion of the study and an additional 29 at the recommended phase II dose(RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel dosesof 175 mg/m² and 150 mg/m² produceddose-limiting myelosuppression, and the RPTD was determined to be paclitaxel135 mg/m² with ifosfamide 1.2 g/m²/day on days1–3 and vinorelbine 20 mg/m²/day on days 1–3 withG-CSF support. The overall response rate was 18%, with a mediansurvival of 6.1 months. Six of 35 patients (17%) treated at the RPTDachieved a partial response to therapy. Grade IV neutropenia was observed in19 of 35 patients at this dose, with eight patients suffering febrileneutropenia.Conclusions: This non-cisplatin-containing three-drug regimen hassubstantial toxicity and low activity in advanced NSCLC, and does not seem toimprove on prior regimens. It is unclear whether the lack of efficacy relatesto an antagonistic reaction between the specific drugs, administrationschedule, or to subtherapeutic doses of the individual agents.     

Ifosfamide given by continuous-intravenous infusion in association with vinorelbine in patients with anthracycline-resistant metastatic breast cancer: A phase I-II clinical trial

Background: Vinorelbine (VNR) is highly active in metastatic breast cancer (MBC) and has shown an overall response rate of 40%-50% as first-line treatment. In vitro, a synergy has been observed between this drug and ifosfamide (IFX). In addition, the pharmacokinetics of IFX suggest that it may have greater activity when given by continuous-intravenous infusion (C.I.V.I.). The aim of this study was therefore to assess the antitumor efficacy and toxicity of the combination of bolus VNR and C.I.V.I. IFX as second-line therapy in anthracycline-resistant breast cancer patients. Patients and methods: Forty-two patients with MBC who had already received anthracycline-based chemotherapy were treated with a regimen consisting of IFX, by C.I.V.I. for 72 hours and bolus VNR. The courses were repeated every three weeks for a maximum of eight cycles. Four dose intensification steps were planned. IFX, 1.5 g/m² on days 1-3 + VNR, 30 mg/m² on day 1 (six patients); IFX, 2 g/m² on days 1-3 + VNR, 25 mg/m² on day 1 (six patients); IFX, 1.8 g/m² on days 1-3 + VNR, 25 mg/m² on days 1 and 8 (six patients); IFX, 2 g/m² on days 1-3 + VNR, 25 mg/m² on days 1 and 8 (24 patients). Sodium-2-mercaptoethane sulfonate (mesna) was associated with IFX at an infusion ratio of 1:1 and, once the infusion was completed, per os every four hours for three times. Results: All of the 42 patients entered were assessable for toxicity, and 41 of them for response. Neutropenia was the most frequently-occurring toxicity, but only five patients at the highest dose level (11.9%) presented grade 4, and none of those at the first three steps. Other significant toxic effects were mild (only grade I-II). The median relative dose intensity was 95% at the highest dose level and all the treatments were administered on an out-patient basis. The overall response rate was 36.5% with a CR rate of 4.8% (two of 41 patients, all at the highest dose level) and a PR rate of 31.7% (13 of 41 patients). The median response duration was 7.0 months (range 2-13 months). Conclusions: The present phase I-II study shows that the IFX and VNR combination is an active and well-tolerated treatment in MBC and provides an alternative to taxanes for patients previously treated with anthracyclines.     

Phase II interventional study (N0337) of capecitabine in combination with vinorelbine and trastuzumab for first- or second-line treatment of HER2-positive metastatic breast cancer: a north central cancer treatment group trial

BackgroundWe conducted a multiinstitutional phase II study of capecitabine in combination with vinorelbine and trastuzumab in patients eligible to receive first- or second-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive (HER2⁺) metastatic breast cancer (MBC).Patients and MethodsThe study was designed to test that the true confirmed response rate (CRR) was at most 45% vs. a true CRR of at least 65%. Between March 2005 and June 2008, eligible patients received capecitabine 825 mg/m² orally on days 1 to 14, vinorelbine 25 mg/m² intravenously on days 1 and 8 every 3 weeks, and trastuzumab 8 mg/kg intravenously on day 1 week 1 and 6 mg/kg every 3 weeks. The main outcome measure was CRR.ResultsOf 47 women accrued, 45 were evaluable. This design required at least 25 confirmed responses in the 45 evaluable patients for the treatment to be considered promising. Thirty women (67%) achieved a confirmed response; 25 women (56%) had a confirmed partial response (PR); 5 women (11%) had confirmed complete responses (CRs). Median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 8.4-16.7 months). Median overall survival was 28.5 months (95% CI, 24.8-36.4 months).ConclusionsThis triplet combination demonstrated promising activity in patients with HER2⁺ MBC.     

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

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