Ifosfamide plus paclitaxel in advanced non-small-cell lung cancer: A phase I study

BACKGROUND:: ifosfamide and paclitaxel are active drugs in the managementof non-small-cell lung cancer. We have performed a phase I studyusing a fixed dose of ifosfamide with escalating doses of paclitaxel,with G-CSF support, in an effort to determine the maximum tolerateddose (MTD) of paclitaxel in this combination, and to describethe dose-limiting toxicities of the combination at the recommendedphase II dose of paclitaxel. We also studied the feasibilityof delivering the paclitaxel as a one-hour infusion at the recommended phase II dose. PATIENTS AND METHODS:: Thirty-one patients were treated, 25 with stage IV disease,and 6 with stage IIIB disease. Ifosfamide was administered ata dose of 1.6 g/m² i.v. bolus daily x 3 days, with mesna uroprotection.Paclitaxel was administered as a 24-hour infusion at dose levelsof 135, 170, 200, 250, and 300 mg/m² six patients were treatedwith a one-hour infusion, at a dose of 250 mg/m² G-CSF, 5 µ/kg,was administered subcutaneously on days 4 through 10, or untilthe absolute neutrophil count exceeded 4000/µl. Cycleswere repeated every 21 days. RESULTS:: The dose-limiting toxicity was granulocytopenia, which increasedwith increasing dose levels of paclitaxel. The MTD was 300 mg/m²of paclitaxel, and the recommended phase II dose 250 mg/m² administeredas a 24-hour infusion. Other toxicities were generally mild,with only 5 patients demonstrating grade 3 neurotoxicity and5 with grade 3 thrombocytopenia. Partial responses were seenin seven patients (23%), all in the 18 patients who receiveddose levels of 250 mg/m² or higher. CONCLUSIONS:: Ifosfamide plus paclitaxel is an active treatment regimen inadvanced non-small-cell lung cancer, and compares favorablywith the results of cisplatin-based chemotherapy. A phase IIstudy is in progress by the Cancer and Leukemia Group B, inan effort to better characterize the tolerance of the regimen,as well as its effect on tumor response and survival. non-small-cell lung cancer, chemotherapy, ifosfamide/paclitaxel     

Paclitaxel and vinorelbine in anthracycline-pretreated breast cancer: A phase II study

BACKGROUND:: Paclitaxel and vinorelbine are active in advanced breast cancerpretreated with anthracyclines We therefore conducted a phaseII study to define the toxicity and activity of paclitaxel andvinorelbine administered in combination. PATIENTS AND METHODS:: Our patient population consisted of 37 patients with metastaticbreast cancer, 35 of whom had received prior chemotherapy includinganthracyclines. The treatment regimen included vinorelbine (25mg/m² i.v.) followed by paclitaxel (135 mg/m² i.v. as a 3-hourinfusion) on day 1; vinorelbine was repeated on day 8 in thefirst 14 patients and on day 3 in the remaining 23 patients. RESULTS:: Because of grade 4 neutropenia, the second dose of vinorelbinewas reduced or omitted in 88% of the courses on the days 1 and8 schedule and in 48% of the courses on the days 1 and 3 schedule.As a consequence the administered dose intensity of vinorelbinewas significantly higher on the days 1 and 3 schedule (13 mg/m²/wkversus 8.3 mg/m²/wk, P = 0.005). The overall response rate was38% (95% CI: 22–55); four responses have been observedin the ten patients with absolute anthracycline resistance.The median duration of response was 6.5 months. CONCLUSIONS:: The combination of paclitaxel and vinorelbine is a feasibleand active salvage regimen in advanced breast cancer patientspretreated with anthracyclines. breast cancer, paclitaxel, vinorelbine     

Paclitaxel-induced neuropathy

Background: Paclitaxel (Taxol®) is a new antineoplasticagent derived from the bark of the western yew, Taxus brevifolia,with important activity against several tumors such as ovariancancer, breast cancer, lung cancer and head and neck cancer.Because it promotes microtubule assembly, neuropathy occursas one of its toxic side effects. Our purpose was to evaluatethe incidence, severity, dose-dependency and reversibility ofpaclitaxel-induced neuropathy. Patients and methods: We prospectivelystudied 27 patients treated with single-agent paclitaxel atthree dose levels. Paclitaxel was administered by 3-hour intravenousinfusion every three weeks in all patients, and if possible,all were evaluated neurologically before paclitaxel, after everyother cycle and after discontinuation of therapy. We used astandardized questionnaire and neurologic examination with emphasison neuropathic symptoms and signs. The severity of symptomsand signs was scored. Quantitatively, vibratory perception threshold(vibrameter) and grip strength (dynamometer) were measured.Results: Six, 14 and seven patients were treated with 135 mg/m²,175 mg/m² and 250–300 mg/m², respectively. Neuropathicsymptoms occurred in 50%, 79% and 100%, neuropathic signs in83%, 86% and 100%, and dose-limiting neurotoxicity in 0%, 21%and 71% of patients, respectively. Neurotoxicity progressedwith higher cumulative dose and was more pronounced with higherdose per course. Paclitaxel-induced neuropathy was predominantlysensory in character, though minor motor signs were present.Follow-up data of 12 patients after discontinuation of paclitaxeltherapy showed that paclitaxel-induced neuropathy is at leastpartially reversible. Conclusions: Paclitaxel-induced neuropathyis a dose-dependent phenomenon, occurring with higher cumulativedose and higher dose per cycle. Using 3-weekly 3-hour infusionsof paclitaxel, dose-limiting neurotoxicity can be expected inpatients treated with 250 mg/m² or more each cycle. dose-dependency, neuropathy, paclitaxel, reversibility     

Phase I study of paclitaxel (TaxolTM) and ifosfamide in previously untreated patients with advanced non-small-cell lung cancer: A study of the National Cancer Institute of Canada Clinical Trials Group

BACKGROUND:: Paclitaxel (Taxol^TM) and ifosfamide are among the most activesingle agents for the treatment of non-small-cell lung cancer.We undertook this phase I dose escalation study to determinethe maximum tolerated doses of these drugs which could be administeredwithout growth factors to untreated patients with tumours ofthis type. PATIENTS AND METHODS:: Forty patients with advanced non-small-cell lung cancer weretreated with a 3-hour infusion of paclitaxel and a 1-hour infusionof ifosfamide every 3 weeks. Groups of 3 patients were enteredat escalating dose levels in traditional phase I design. Startingdoses were paclitaxel, 100 mg/m², and ifosfamide 3 g/m², andall patients received premedication with dexamethasone, diphenhydramineand a 5-HT3 blocker. Dose escalation occurred only after fulltoxicity assessment for 2 cycles for all patients in the doselevel. RESULTS:: Dose escalation of paclitaxel continued to 225 mg/m² withoutdose-limiting toxicity, but further escalation was not attemptedbecause of the known likelihood of neurotoxicity above thislevel. Instead, ifosfamide was increased to 4 g/m² for the finallevel. At these doses, dose-limiting myelosuppression was notseen, and there was only 1 episode of febrile neutropenia in164 treatment cycles. Drug-related toxicities of ifosfamideincluded gross hematuria and confusion in 1 patient each, andpaclitaxel-related symptoms included flu-like syndrome in mostpatients, mild to moderate arthralgia and/or myalgia in 8 and25 patients, respectively, parasthesiae in 15 patients and mildto moderate hypersensitivity reactions in 15 patients each.Partial response was seen in 20.5% of patients (CI 9.3%–36.5%). CONCLUSIONS:: The frequency of tumour cell detection in peripheral blood frompatients with advanced disease was lower than previously reported.It may be only small numbers of circulating tumour cells arepresent at any one time in the peripheral blood of patientswith malignant melanoma. If this is the case increased samplingwill improve detection fre quency. Alternatively, disseminationof melanoma through peripheral blood may be a rare event. Inour experience, RT PCR for tyrosinase mRNA as a staging testfor melanoma patients must be interpreted cautiously. Out-patient paclitaxel given over 3 hours and single-dose ifosfamideover 1 hour may be combined safely without the need for hematopoieticgrowth factors for the treatment of patients with non-small-celllung cancer. The recommended doses for phase II study are paclitaxel,225 mg/m² and ifosfamide, 4 g/m² every 3 weeks. chemotherapy, ifosfamide, non-small-cell lung cancer, paclitaxel     

A phase I investigation of the sequential use of methotrexate and paclitaxel with and without G-CSF for the treatment of solid tumors

BACKGROUND: Paclitaxel is a novel agent with significant activity in severalsolid tumors. Preclinical data suggested that methotrexate priorto pacitaxel would be synergistic. To determine the qualitativeand quantitative toxicity of this regimen we performed a phaseI study in patients with solid tumors. PATIENTS AND METHODS: Patients with solid tumors previously treated with no more thantwo prior chemotherapy regimens were given methotrexate intravenouslyon day 1, followed by pacitaxel, as a 24-hour infusion on day2. The starting dose (level ‘0’) was 40 mg/m formethotrexate and 135 mg/m for paditaxel. RESULTS: After achieving a maximum tolerated dose, additional patientswere enrolled with the addition of G-CSF 5 µg/kg/d ondays 4–13. At the starting dose level, dose-limit ingtoxicity consisting of neutropenic fever occurred in 3 of 4patients. At dose level–1, methotrexate 30 mg/m² and paclitaxel110 mg/m² neutropenic fever occurred in 7 of 10 patients duringthe first course. At dose level–2, methotrexate 23 mg/m²and paclitaxel 85 mg/m² neutropenic fever occurred in 1 of 7patients. To abrogate the neutropenia we explored the same combinationwith the addition of G-CSF. Neutropenic fever remained the onlydose-limiting toxicity. At dose level ‘0’ with G-CSF,1 of 7 patients developed doselimiting toxicity. At dose level1 plus G—CSF, methotrexate 40 mg/m² and pacitaxel 170mg/m² dose-limiting neutropenic fever occurred in 4 of 6 patients.Partial responses occurred in 4 of 41 patients entered on thisstudy. Pharmacokinetic data suggested that methotrexate didnot increase pacitaxel levels. CONCLUSION: The combination of methotrexate and paci taxel is feasible,but neutropenic fever, even with the addition of G—CSFprevents further escalations of paclitaxel beyond 135 mg/m²following methotrexate. phase I, methotrexate, paclitaxel, solid tumors     

A phase I study of bi-weekly paclitaxel/cisplatin as initial therapy for advanced ovarian cancer: A study of the National Cancer Institute of Canada Clinical Trials Group

PURPOSE:: Given the potential for improved outcomes, a phase I trial wasinitiated to develop a paclitaxel/cisplatin regimen that couldbe delivered every two weeks to women with newly diagnosed advancedovarian cancer. PATIENTS AND METHODS:: From 1992 to 1994, 29 (28 eligible) patients were enrolled ina dose-seeking trial. All received 60 mg/m² of cisplatin precededby paclitaxel infused over three hours. The paclitaxel dosewas excalated from an initial level of 90 mg/m² by 10 mg/m²increments in successive cohorts of patients. RESULTS:: At 1^{20 mg/m}2 of paclitaxel, the dose-limiting toxicity was granulocytopeniawhich prevented retreatment on time. The recommended dose levelwas therefore paclitaxel 110 mg/m² infused over three hourswith cisplatin 60 mg/m², repeated bi-weekly for eight cycles. CONCLUSION:: This bi-weekly schedule of paclitaxel/cisplatin provides noadvantage in terms of dose-intensity nor total dose of paclitaxelin comparison to more common regimens given tri-weekly. cisplatin, ovarian cancer, paclitaxel, phase I study     

Paclitaxel/cisplatin in advanced non-small-cell lung cancer (NSCLC)

Background: Paclitaxel (Taxol^®) as single agent has shownpromising activity in advanced non-small-cell lung cancer (NSCLC).Because paclitaxel lends itself to combination with other anticancerdrugs, we have determined the efficacy of paclitaxel combinedwith cisplatin in patients with advanced NSCLC in a phase IItrial Patients and methods: Twenty patients with NSCLC stage IIIBor IV were treated with paclitaxel (175 mg/m²) as a 3-hour infusionafter standard premedication on day 1 and cisplatin (50 mg/m²daily) on days 1 and 2. Treatment was repeated every 3 weeks Results: All 20 patients were evaluable for response and toxiceffects. Partial responses were seen in 7 (35%) patients andno change in 9 (45%) patients. Major side effects included leukopenia,anemia, alopecia and dose-limiting neurotoxicity chemotherapy, cisplatin, neurotoxicity, non-small-cell lung cancer, paclitaxel, phase II trial, Taxol^®     

Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors

Purpose: Paclitaxel and gemcitabine possess broad spectra of clinical activity, distinct mechanisms of cytotoxicity, and are differentially affected by mutations in cell-cycle regulatory proteins, such as bcl-2. This phase I trial was designed to identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of paclitaxel and gemcitabine when both drugs were given together on a once-every-two-week schedule in patients with solid tumors.Patients and methods: A total of 37 patients were treated at nine different dose levels ranging from paclitaxel 75–175 mg/m² administered over three hours followed by gemcitabine 1500–3500 mg/m² administered over 30–60 minutes. Both drugs were administered on day 1 of a 14-day cycle. Dose escalation was performed in a stepwise manner in which the dose of one drug was escalated while the dose of the other drug was kept constant.Results: Dose limiting toxicity (DLT) was observed at dose level 9: paclitaxel 175 mg/m² and gemcitabine 3500 mg/m² in the form of grade 4 neutropenia lasting for 5 days (one patient) and grade 3 elevation of alanine aminotransferase (AST/SGPT) (one patient). An analysis of delivered dose intensity (DI) over the first three cycles revealed that higher dosages of both drugs were delivered at dose level 7, paclitaxel 150 mg/m² and gemcitabine 3000 mg/m² dose level, than at the MTD, dose level 8, paclitaxel 150 mg/m² and gemcitabine 3500 mg/m². Partial responses were confirmed in two patients with transitional cell carcinoma (one of the bladder, one of the renal pelvis) and in one patient with adenocarcinoma of unknown primary.Conclusions: Paclitaxel and gemcitabine is a promising drug combination that can be administered safely and repetitively on an every-other-week schedule. Using this drug administration schedule, the recommended phase II dose is paclitaxel 150 mg/m² and gemcitabine 3000 mg/m².     

Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic

BACKGROUND:: Pacitaxel has shown activity in metastatic breast cancer, includinganthracycline-resistant breast cancer. The efficacy, toxicityand optimal scheduling of the combina tion of the two drugsneeds to be defined. PATIENTS AND METHODS:: Thirty women with advanced breast cancer who had undergone atmost one prior adjuvant chemotherapy regimen, were treated atthree different dose levels with doxorubicin (50, 60 and 60mg/m²) followed 30 minutes later by paclitaxel (155, 175 and200 mg/m², respectively) every 3 weeks. RESULTS:: The overall response rate was 83% (95% CI: 64–94), with24% of patients achieving CR. The median response duration forcomplete responders was 11 months (range 4–14+) and mediansurvival 18 months (range 3–28+). Two hundred sixty-fivetreatment courses were given (median 9, range 3–13) andthe median cumulative dose of doxorubicin was 369 mg/m² (range114–550). The main toxicities were neutropenia, parestesia,nausea/vomiting, alopecia, myalgia and cardiotoxicity. Fifteenpatients (50%) had reductions of left ventricular ejection fractionto below normal levels and 6 of these patients (20%) developedcongestive heart failure. CONCLUSIONS:: The combination of doxorubicin and paclitaxel is highly active,but is accompanied by the dose-limiting toxic effects of neutropenia,neuropathy and cardiotoxicity. advanced breast cancer, cardiotoxicity, doxorubicin, paclitaxel     

Clinical phase II evaluation of paclitaxel in combination with cisplatin in metastatic or recurrent squamous cell carcinoma of the head and neck

Background: Paclitaxel as single agent has shown marked activity in several malignancies. The aim of the present phase II trial was to determine the activity of paclitaxel/cisplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck.Patients and methods: 200 mg/m² paclitaxel was administered over three hours followed by cisplatin (100 mg/m²), repeated every 22 days. Twenty-eight patients were entered and received a total of 99 cycles (median 2, range 1–6). All patients were evaluable for toxicity, and 25 for response.Results: Hematologic toxicities included leukopenia CTC grade 3 in 13 patients, and grade 4 in five patients, neutropenia grade 3 in nine patients, and grade 4 in eigth patients, grade 3 anemia and grade 2 thrombocytopenia in one patient each. Non-hematologic toxicities included hypotension grade 2 (six patients), grade 3 (four patients), and grade 4 (two patients). A decline in renal function was observed in 15 courses and 10 patients, leading to a median delay of 2.5 days. Neurosensory and neuromotor toxicity grade 1 were observed in 13 patients (grade 2: 12 patients; grade 3: one patient), myalgia grade 3 in one patient, asthenia grade 3 in two and grade 4 in one patient. Partial responses were observed in 12 patients for an overall response rate of 48% (95% CI: 28%–68%) with a median response duration of 6.5 months (range 1-10 months). Stable disease was observed in seven patients, of who two also had clinical benefit.Conclusions: Paclitaxel 200 mg/m² administered over three hours combined with cisplatin 100 mg/m² is an active regimen warranting further evaluation.     

Paclitaxel and gemcitabine combination in a biweekly schedule in patients with advanced non small-cell lung cancer: a phase i study

Purpose: This phase I study was designed to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of the paclitaxel–gemcitabine combination in a biweekly schedule in chemotherapy-naive patients with advanced non small-cell lung cancer (NSCLC). Patients and methods: Treatment was administered on an outpatient basis every 2 weeks: paclitaxel over a 1-h IV infusion and gemcitabine as a 30-min IV infusion immediately following paclitaxel. Results: Twenty-nine patients were treated at six different dose levels, ranging from paclitaxel 135–175 mg/m² and gemcitabine 1,500–3,000 mg/m². A total of 198 cycles were administered (median 7, range 1–13). DLTs in the first two cycles were grade 4 neutropenia and myocardial ischemia at the dose level paclitaxel/gemcitabine 150/2,000 mg/m², febrile neutropenia and grade 4 neutropenia at the dose level paclitaxel/gemcitabine 175/2,500 mg/m², fatal pneumonitis, sudden death and grade 3 neutropenia at the dose level paclitaxel/gemcitabine 175/3,000 mg/m². The MTD was paclitaxel 175 mg/m² and gemcitabine 2,500 mg/m². The average dose intensity at this dose level was 98%. The overall intent-to-treat response rate was 35.7% (95% confidence interval [CI] 17.97% - 53.47%). Overall median survival was 36 weeks (95% CI, 24-48). Conclusion: Paclitaxel and gemcitabine can be safely administered at a high dose intensity on an every-other-week schedule. The recommended phase II dose is paclitaxel 175 mg/m² and gemcitabine 2,500 mg/m².     

Multi-day fractionated administration schedule for paclitaxel

PURPOSE: To establish the feasibility of fractionating paclitaxel administrationby utilizing daily one-hour infusions for three, four or fivedays with dose escalating to determine the patterns of hematologicand non hematologic toxicities. PATIENTS AND METHODS: Forty patients received 87 courses of daily fractionated paclitaxelfor three, four or five days; cycles were repeated every 21days. Six patients received concomitant daily cisplatin. Themedian number of cycles delivered per patient was two with arange of one to six. RESULTS: Cumulative doses per cycle ranged from 120 mg/m² to 250 mg/m²with 25% of the cycles delivering 200 mg/m² or more. Ten cycles(11.5%) were associated with dose limiting neutropenia (grade3 [7 cycles]; grade 4 [3 cycles]). No hypersensitivity reactionswere observed and no patient required cytokine support. No patientrequired hos-pitalization. CONCLUSION: Administering paclitaxel on a daily fractioned schedule in anambulatory setting is logistically feasible; does not requirepremedication; is associated with a toxicity pattern similarto single day schedules (e.g. 24-hour or three-hour infusion);is capable of delivering a higher dose per cycle than published96- or 120-hour infusion schedules; and could possibly be escalatedto doses higher than 250 mg/m² in carefully selected patients.The optimal dose rate for five-day multifrac-tionated administrationof paclitaxel is 40 to 50 mg/m²/d or a cumulative cycle doseof 200 to 250 mg/m² and does not require cytokine usage. Addingcisplatin on a fractionated daily schedule may accentuate theneurotoxicity associated with both agents. A prospective comparisonof four-day fractionated vs. four-day continuous infusionalpaclitaxel has been proposed as a randomized study to determineclinical differences in response, dose intensity and toxicity. paclitaxel, schedule-dependent administration     

Dose intensification of cisplatin chemotherapy through biweekly administration

PURPOSE: Dose intensity (DI, expressed in mg/m²wk) may be an importantfactor in the clinical use of cisplatin (DDP). We have exploredthe shortening of the cycle interval as a way to increase theDI of DDP. PATIENTS AND METHODS: DDP 180 mg/m² was given intravenously (i.v.) over 4 hours; sodiumthiosulfate (STS) was given i.v. in the opposite arm at a loadingdose of 4 g/m², followed by 12 g/m² over 6 hours. Each cyclewas repeated every two weeks. Seventy-five cycles were administeredto 28 patients in this clinical trial. RESULTS: In 19 patients who received 2 or more cycles of chemotherapy,a delay of three or more days was required on 17/66 courses(26%); the mean DDP DI actually received by these patients was83 mg/m²/wk (88% of the planned DI). The major side effect wasototoxicity; this occurred in 9 patients (33%), but none requireda hearing aid. Myelosuppression was moderate with thrombocytopeniagreater than neutropenia. Nephrotoxicity (creatinine > 2mg/dl) occurred on only 2 cycles (3%). Three patients (11%)developed symptoms of peripheral neuropathy. In 23 evaluablepatients, the overall response rate was 39%. CONCLUSION: It is feasible to give 180 mg/m² of DDP and STS every two weekswith tolerable nephrotoxicity but without blocking other typesof toxicity, such as myelosuppression and ototoxicity. The shorteningof cycle intervals resulted in a markedly increased DI. biweekly, cisplatin, high-dose intensity chemotherapy     

A randomized phase 2 trial comparing 3‐hour versus 96‐hour infusion schedules of paclitaxel for the treatment of metastatic breast cancer

BACKGROUND:

This study was performed to compare efficacy and toxicity profiles of paclitaxel using 3‐hour versus 96‐hour infusion schedules.

METHODS:

Patients with metastatic breast cancer (MBC) were randomly assigned to receive paclitaxel starting at a dose of 250 mg/m² intravenously (iv) over 3 hours every 21 days or paclitaxel starting at a dose of 140 mg/m² iv over 96 hours every 21 days. Stratification variables included number of prior chemotherapy regimens and previous response to anthracyclines. Response was assessed every 2 cycles using bidimensional measurements. Patients were allowed to cross over at disease progression or therapy intolerance.

RESULTS:

A total of 214 patients received therapy (107 patients per arm). Response rates were similar: 23.4% in the 3‐hour arm and 29.9% in the 96‐hour arm (P = .28). The median duration of response (8.9 months vs 5.7 months; P = .75) and progression‐free survival (5.0 months vs 3.8 months; P = .17) slightly favored the 96‐hour arm. Overall survival was slightly longer in the 3‐hour arm (14.2 months vs 12.7 months; P = .57). One patient who crossed over to the 96‐hour arm (N = 18) developed a partial response; no response was noted with crossover to the 3‐hour arm (N = 10). Myalgia/arthralgia and neuropathy were more frequent in the 3‐hour arm, whereas mucositis, neutropenic fever/infection, and diarrhea were more common in the 96‐hour arm.

CONCLUSIONS:

Paclitaxel given by 3‐hour or 96‐hour infusion was active in MBC. The 96‐hour paclitaxel regimen did not significantly improve response or time to disease progression, was more cumbersome to administer, and was associated with greater myelosuppression (but less neuropathy and myalgia) compared with the 3‐hour schedule. Cancer 2010. © 2010 American Cancer Society.     

A phase I study of sequential vinorelbine followed by paclitaxel

Background: In vitro experiments suggest that administration of vinorelbine preceding paclitaxel results in synergistic cytotoxic effects. A phase I dose escalation trial of vinorelbine daily × 3 with paclitaxel on day 3 repeated every 28 days in metastatic breast cancer patients was completed.Patients and methods: Female patients, PS 0–2, without evidence of CNS disease or prior neuropathies were treated with vinorelbine at dose levels 7, 10, 13 mg/m² per day and paclitaxel over three hours at dose levels of 135, 175, and 200 mg/m².Results: Twenty-eight patients with six dose levels were studied. At dose level 1, patients developed intolerable but reversible neutropenia. Subsequent dose levels required filgrastim. Dose limiting toxicities were myalgia and fatigue at vinorelbine 13 mg/m² /day and paclitaxel 200 mg/m². Neuropathy was minor. Twelve of twenty-five patients with measurable disease had a rapid response which did not correlate with dose level.Conclusions: Sequential administration of these two agents demonstrates activity in breast cancer patients. Phase II dosing on this schedule should be vinorelbine 13 mg/m²/day × 3 and paclitaxel 175 mg/m². With proper selection of patients, concern about neurologic toxicity should not impede future trials of vinorelbine with paclitaxel.     

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.     

Salvage Therapy with Capecitabine Plus Weekly Paclitaxel in Heavily Pretreated Advanced Breast Cancer

Background:The combination of intravenous paclitaxel (three-times weekly administration at a dose of 175 mg/m²) and oral capecitabine has been shown to be highly active in the treatment of advanced or metastatic breast cancer. Currently, there is much interest in the use of relatively low dose weekly paclitaxel infusions in this clinical setting. Aim:To assess the activity and safety of capecitabine plus weekly paclitaxel at a dose of 60 mg/m²in heavily pretreated metastatic breast cancer patients. Patients and methods:Patients were required to have pretreated metastatic breast cancer with measurable/ evaluable disease and a performance status of 0–2 (Eastern Cooperative Oncology Group score). Capecitabine was administered orally at a dosage of 1000 mg/m²twice daily on days 1–14, followed by a 7-day rest period. Paclitaxel was administered as a 1-hour intravenous infusion on a weekly basis at a dose of 60 mg/m². Twenty-one days of therapy represented one cycle. Results:The hypothesis of activity of the capecitabine-paclitaxel combination at the level of clinical interest (40% response rate) was accepted when the 15th response was observed and 33 patients were enrolled. The median progression-free survival and median overall survival estimates were 9.2 and 19.6 months, respectively. Therapy was generally well tolerated and manageable on an outpatient basis. The following grade 3/4 adverse events were observed: hand-foot syndrome (21.2%), neutropenia (12.1%), anemia, nausea/vomiting, stomatitis/ mucositis, and nail disorders (all occurred in 9.0%), and vascular/coagulation disorders (<1%). Conclusions:Oral capecitabine plus weekly paclitaxel at a dose of 60 mg/m²has a favorable activity and tolerability profile and is suitable for the treatment of heavily pretreated advanced breast cancer patients.     

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.     

Outpatient weekly high-dose continuous-infusion 5-fluorouracil plus oral leucovorin in advanced colorectal cancer. A phase II trial

BACKGROUND:: Background: In a previous phase I–II trial we showed thatmaximum tolerable dose (MTD) of 5-fluorouracil (5-FU) a weekly48-hour continuous infusion (CI) was 3.5 g/m². In a subsequentconfirmative phase II trial with 85 evaluable patients, a 38.5%response rate was obtained, and a median survival of 12 months.These data were comparable to those achieved by biochemicalmodulation of 5-FU with leucovorin. On this basis we attemptedto modulate high-dose 5-FU (3 g/m²) with oral leucovorin (LV)but the regimen too toxic and the dose had to be reduced. Anew phase II trial with 2 g/m²/week plus oral leucovorin wasplanned. PATIENTS AND METHODS:: From July 1992 to June 1994, 110 previously untreated patientswith advanced, measurable colorectal cancer were included ina multicenter study. The patients received, on an outpatientbasis, 5-FU 2 g/m² by continuous infusion for 48 hours oncea week until progression or the appearance of toxic effects.Oral leucovorin (60 mg every six hours) was also given duringthe 5-FU infusion. RESULTS:: Patients received a median dose intensity of 5-FU of 1.6 g/m²/week(range 0.9–2). Three complete responses and 36 partialresponses were observed. The overall response rate was 37.5%(95% CI, 28% to 46.8%), the median time to progression 7.4 monthsand median survival 14.5 months. W.H.O. grade 3 diarrhea occurredin 27 patients (24.5%); grade 3 mucositis was observed in 9(8.1%) patients and grade 4 in one. Grade 3 nausea and vomitingwas reported in 13 (11.7%) patients, while grade 3 hand-footsyndrome was detected in only 5 (4.5%). Grade 4 leukopenia occurredin one patient and grade 3–4 thrombocytopenia in two. CONCLUSION:: Oral leucovorin modulation of weekly 48-hour continuous infusionof 5-FU at 2 g/m² is an active regimen, with diarrhea and mucositisas the main limiting toxic effects. Its antitumor activity doesnot seem superior to that obtained with a weekly 48-hour continuousinfusion of 5-FU alone at a dose of 3.5 g/m². advanced colorectal cancer, biochemical modulation, continuous infusion, fluorouracil, phase II trial     

Biweekly paclitaxel and cisplatin in patients with advanced head and neck carcinoma

Background: Cisplatin is an active drug in head and neck cancer. Paclitaxel seems a promising drug. This article reports a phase II assessment of the combination of the two.Patients and methods: Twenty-three patients were treated with paclitaxel 90 mg/m² over three hours plus cisplatin 60 mg/m² every other week. Sixteen patients had locoregional disease and seven had metastatic disease. None of the patients had previously been treated with chemotherapy. Nine patients had had radiotherapy to the target lesions.Results: One patient was not evaluable for response. Partial responses were observed in 32% of evaluable patients. Toxicity included asthenia (56%), neutropenia, peripheral neuropathy, anemia and vomiting.Conclusions: The overall response rate observed in this study does not seem to justify the use of this chemotherapy regimen in the palliative setting.