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^®     

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     

Prospective study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing

Background. Paclitaxel-induced peripheral neuropathy (PN) may be severeand dose-limiting at initial doses 275 mg/M², but itsneurotoxicity at doses 250 mg/M² has been incompletelycharacterized. The purposes of this study were to characterize and quantifypaclitaxel-induced PN and to determine the utility of quantitative sensorytesting (QST). Methods. We prospectively examined clinically and by QST 37women with metastatic breast cancer, treated with paclitaxel (200–250mg/m2) (average number of cycles = 7.3 over an average of 20.1weeks). QST included thermal threshold (TT) and vibration threshold (VT).Results. Paresthesias appeared in 31 (84%) patients after an averageof 1.7 cycles and an average cumulative dose of 371.5 mg/M². Symptomsoccurred after the first or second dose in 26 (84%) patients and thenstabilized in 10 (32%), improved in 13 (42%) despite continuedtreatment, resolved completely in 6 (19%), and were progressive in 2(7%). Paclitaxel was discontinued in only 1 (3%) patientbecause of neurotoxicity and no patient required dose reduction because ofPN. Thirty-six (97%) developed signs of PN. The most sensitive QSTwas great toe VT but QST did not predict or identify subclinical PN in anypatient. Neurologic syndromes other than PN developed in 12 (32%)patients, and 7 were due to metastatic cancer. Conclusions. 1)Paclitaxel-induced PN is mostly sensory, and begins after the first orsecond dose. At these doses the neuropathy is mild, and rarelydose-limiting. 2) QST quantified the neuropathy but was less sensitive thanthe clinical examination. 3) Knowledge of the features of paclitaxel's PNallows it to be differentiated from other neurologic syndromes which maysignal tumor progression.     

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     

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     

Primary therapy of multiple myeloma with paclitaxel (Taxol)

BACKGROUND: The treatment of multiple myeloma remains unsatisfactory andnew active agents are needed. Paclitaxel is effective againsta variety of solid tumors and we assessed the utility againstmultiple myeloma. PATIENTS AND METHODS: From March 1993 to May 1994, we treated 33 patients with newlydiagnosed multiple myeloma with paclitaxel given intravenouslyat a dose of 125 mg/m² over 24 hours (13 patients) or at a doseof 135 mg/m² over 3 hours (20 patients). RESULTS: Five of 33 patients responded (15%; 95% CI: 5 to 32%) with anunmaintained remission of 3–11+ months. Severe but reversibleneutropenia was the major dose limiting toxicity, but myalgiasand alopecia were also common. CONCLUSIONS: Paclitaxel was slightly active against multiple myeloma. Whetherhigher doses or new analogues of this agent can produce superiorresults requires further study. multiple myeloma, paclitaxel     

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     

Phase I and pharmacokinetic study of polymeric micelle-formulated paclitaxel in adult Chinese patients with advanced solid tumors

Purpose

Polymeric micelle-formulated paclitaxel (PM paclitaxel) is a nanoscale drug delivery compound. This study investigated the maximum tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetic (PK) profile of PM paclitaxel in Chinese patients with treatment-refractory advanced or relapsed solid tumors.

Methods

Dose escalation of PM paclitaxel followed the standard ‘3 + 3’ rule, starting at 175 mg/m². PM paclitaxel was administered over 3 h every 3 weeks. Patients were treated until disease progression, intolerance, death, or consent withdrawal. Blood samples were collected for PK testing.

Results

All 23 patients were evaluable for toxicity. Neutropenia, neuropathy, and myalgia were the most common toxicities; acute hypersensitivity reaction was not observed. One of six patients at dose level 4 (350 mg/m²) and two of six patients at dose level 5 (390 mg/m²) developed grade 4 neutropenia. The MTD was 350 mg/m². No patients discontinued treatment because of neuropathy. Partial response was seen in five of 20 patients (25 %) who had response assessment, three of whom had prior exposure to taxanes (two were heavily pretreated). Ten patients (50 %) had stable disease at cycle 2 and only five patients (25 %) had disease progression. The area under the curve and the maximum concentration of paclitaxel increased with escalating doses, suggesting that PM paclitaxel has linear PKs.

Conclusions

The main dose-limiting toxicity for PM paclitaxel was neutropenia, and the recommended dose for phase II study is 300 mg/m². PM paclitaxel is superior to conventional paclitaxel for its simplified premedication regimen and delivery of a higher paclitaxel dose without increased neuropathy.     

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     

Dose-finding study of paclitaxel and cyclophosphamide in advanced breast cancer

Background: The toxicity profile of prolonged infusions of paclitaxel incombination with cyclophosphamide in metastatic breast cancer has already beendefined. The objective of this dose-finding study was to determine the maximumtolerable doses (MTDs) of shorter (three-hour) infusions of paclitaxel incombination with i.v. bolus cyclophosphamide in patients who had previouslyreceived a maximum of one chemotherapy for advanced breast carcinoma. The MTDof the same regimen with granulocyte colony-stimulating factor (G-CSF) supportwas then established.Patients and methods: Eighty women with metastatic breast cancer receiveda total of 352 fully evaluable courses of therapy. The starting doses werepaclitaxel 135 mg/m² and cyclophosphamide 750mg/m² given every three weeks. At least three patients weretreated at each dose level and if there were dose-limiting toxic effectsduring the first cycles three additional patients were entered. G-CSF support(5µg/kg s.c.) was added to the second cycle if specific dose-limitingtoxicitieshad occurred during the first cycle. The MTD was defined as the dose level atwhich more than two of six patients presented dose-limiting toxicities duringthe first cycle.Results: Febrile neutropenia (n = 4) and severe thrombocytopenia (n = 1)defined the MTDs of paclitaxel as 200 mg/m² and ofcyclophosphamide as 2,000 mg/m², with or without G-CSF inpatients with and, respectively, without prior chemotherapy for advanceddisease. Non-hematologic toxicity was moderate. Recommended doses were 200mg/m² of paclitaxel and 1,750 mg/m² ofcyclophosphamide with or without G-CSF in patients with and, respectively,without prior chemotherapy. The overall response rate was 25% and50%, respectively, in patients with and without prior chemotherapy formetastatic disease. Complete remissions (9%) were reported only inpatients without prior chemotherapy; antitumour activity in women withanthracycline-resistant disease, with an 8% response rate (95%CI: 1%–26%), was poor.Conclusions: Paclitaxel at 200 mg/m² and cyclophosphamideat 1,750 mg/m² can be safely administered every three weeksto women with advanced breast cancer. The moderate antitumour activityobserved with the schedule tested argues against its use as initial therapyfor advanced breast cancer.     

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     

Bilateral facial nerve palsy secondary to the administration of high-dose paclitaxel

Bilateral facial nerve palsy is an uncommon occurrence. We describe a case of bilateral facial nerve palsy secondary to a single cycle of high-dose paclitaxel therapy (825 mg/m²), in a woman with breast cancer. Prior to her high-dose therapy, she had a residual grade 2 peripheral neuropathy following treatment with ten cycles of standard-dose paclitaxel (total dose 3200 mg). The features of the peripheral neuropathy due to standard-dose paclitaxel, which can be both motor and sensory, are well described. Cumulative paclitaxel dose is considered a risk factor for development of the neuropathy. Although facial nerve palsy secondary to paclitaxel is not previously reported, other cranial nerve toxicity has been described. Consistent with reports of the reversibility of paclitaxel-induced peripheral neuropathy, the facial nerve palsies in our patient resolved over 23 months. Ongoing studies of high-dose paclitaxel warrant close attention to its cumulative neurotoxic effects, particularly in patients previously treated with neurotoxic chemotherapy.     

Phase I trial of bi-weekly paclitaxel and gemcitabine as second-line therapy for patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy

A phase I study was conducted to evaluate the maximum tolerated dose, feasibility, and efficacy of biweekly-administered paclitaxel and gemcitabine in patients with non-small-cell lung cancer (NSCLC) who had prevously been treated with platinum-based chemotherapy. In a dose-escalation study, 18 patients, under 75 yr old, with unresectable NSCLC that had relapsed or was resistant after platinum-containing chemotherapy with performance status of 0–2 were enrolled. Patients were treated with paclitaxel and gemcitabine biweekly. The dose escalation levels of paclitaxel (mg/m²) at a fixed dose of gemcitabine 1000 mg/m² were 110 (level 1), 130 (level 2), 150 (level 3), and 170 (level 4), respectively. All patients were eligible for evaluation of toxicities. At level 4, one patient developed an infection with grade 3 neutropenia and two other patients developed severe neurotoxicity (over grade 3). Thus, the recommended dose for phase II was paclitaxel 150 mg/m² and gemcitabine 1000 mg/m² due to dose-limiting toxicities including neutropenia and peripheral neurotoxicity. Partial response was seen in 4 cases of the 18 assessable patients, with an overall response of 22%. Bi-weekly paclitaxel and gemcitabine is feasible and appears to be an efficacious combination chemotherapy as second-line chemotherapy in refractory and recurrent patients with NSCL C who had been previously exposed to platinum-containing chemotherapy.     

Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines

BACKGROUND: Oxaliplatin (^L-OHP) is a platinum complex that possesses activityagainst human and murine cells in vitro and in vivo, includingcolorectal carcinoma-derived cell lines, and cells that havebeen selected for resistance to cisplatin. We report two consecutivephase H trials of ^L-OHP for treatment of patients with advancedcolorectal carcinoma. Patients and methods: Fifty-eight patients were entered in studyI, and 51 patients in study II. All of the patients had tumorprogression when they were treated, prior to their enrolment,with a fluoropyrimidine-containing regimen. In both trials treatmentconsisted of ^L-OHP, 130 mg/m² by i.v. infusion for two hours;the treatment was repeated every 21 days. RESULTS: Response to therapy: Study I: Fifty-five patients were assessedfor response. The response rate was 11% (95% CI, 0.03–0.19).Study II: All 51 patients were assessed for response. The responserate was 10% (95% CI, 0.017–0.18). The overall responserate for the 106 evaluated patients was 10% (95% CI, 0.046–0.16).Times to disease progression in responders were 4, 4, 4.5+,5, 5, 6, 6, 6, 6+, 9, and 13 months. The dose-limiting toxiceffect was sensory peripheral neuropathy. The incidence of severeperipheral neuropathy grades was: Study I: grade 3, 23% of patients,and grade 4, 8% of patients. Study II: grade 3, 14% of patients,and grade 4, 4% of patients. Severe neuropathy had a favorablecourse in all of the patients who had long-term neurologic follow-up.Diarrhea and myeloid impairment were minor. CONCLUSION: ^L-OHP produced modest, but definite antitumor activity in patientswith advanced colorectal carcinoma who were previously resistantto chemotherapy including fluoropyrirnidines. Toxicity is withinacceptable limits of tolerance at the dose and schedule of oxaliplatinused in this trial. advanced colorectal carcinoma, oxaliplatin, phase II study     

A phase I study of doxifluridine combined with weekly paclitaxel for metastatic gastric cancer

Purpose Based on the synergistic effect in preclinical studies, a phase I clinical trial for the combination of paclitaxel and doxifluridine (an intermetabolite of capecitabine) was performed to determine the recommended dose for the treatment of patients with metastatic gastric cancer.Methods The dose of paclitaxel was increased from 60 mg/m² at level 1 to 90 mg/m² at level 5. It was administered as a 1-h infusion on days 1 and 8. The dose of doxifluridine was fixed at 600 mg/m² per day up to level 3, and escalated to 800 mg/m² per day at levels 4 and 5. It was administered orally for 2 weeks. The treatment was repeated every 3 weeks.Results A total of 28 patients were enrolled. No dose-limiting toxicity (DLT) was observed at levels 1 and 2 (paclitaxel 70 mg/m²). A DLT of grade 4 neutropenia lasting for more than 4 days was observed in one patient at level 3 (paclitaxel 80 mg/m²). In addition, the first five of six patients in this group experienced grade 3 neutropenia during the first treatment cycle. A further six patients were added in order to confirm the safety of this dosage level, and no more DLTs except for grade 3 nausea in one patient were observed in the second cohort. No DLT was seen in three patients at level 4 (paclitaxel 80 mg/m²). DLTs (grade 3 neuropathy in one patient and a treatment delay of the second cycle for more than 1 week due to grade 3 neutropenia in another) were observed in two out of six patients at level 5 (paclitaxel 90 mg/m²), and this dose level was determined as the maximum tolerated dose. The tumor response rate was 42% (95% confidence interval 20–67%) in 19 patients with measurable lesions.Conclusions The recommended dose was determined as 80 mg/m² of paclitaxel (days 1 and 8) and 800 mg/m² of doxifluridine (days 1–14) every 3 weeks. The results of this phase I study are encouraging and a phase II trial is thus warranted.     

Phase I Trial of Nedaplatin and Paclitaxel for Patients with Non-Small Cell Lung Cancer

Abstract

A phase I study was conducted to evaluate the maximum tolerated dose and feasibility of combination with nedaplatin (NDP) and paclitaxel in patients with nonsmall cell lung cancer (NSCLC). Fifteen patients under 75 years old, with unresectable NSCLC who had not previously received chemotherapy or radiotherapy, with a performance status of 0-1, were enrolled. The dose escalation levels (NDP/Paclitaxel; mg/m² day 1) were 80/150 (level 1), 80/180 (level 2), 90/180 (level 3) and repeated every 28 days. All patients receiving level 3 had dose-limiting toxicity. One patient developed grade 4 neutropenia with infection, two had incomplete recovery of neutropenia and thrombocytopenia by the 28th day after the first cycle of chemotherapy. Non-hematologic toxicities, including nephrotoxicity, nausea/vomiting, alopecia, and hypersensitivity reaction, were tolerated. Three of the 15 patients achieved partial responses. We concluded that the recommended dose was paclitaxel 180 and NDP 80 mg/m² due to the hematologic toxicity.     

Peripheral neuropathy due to paclitaxel: study of the temporal relationships between the therapeutic schedule and the clinical quantitative score (QST) and comparison with neurophysiological findings

Peripheral neuropathy (PN) is one of the most common and dose-limiting side effects of paclitaxel, a chemiotherapeutic drug of proven efficacy in various tumours. We investigated the pathophysiological features of the PN and the temporal relationships between the development of the symptoms and signs associated with paclitaxel administration in two groups of patients with breast cancer: group A received paclitaxel alone (total cumulative dose range: 950–2,475 mg/m²), and group B paclitaxel and adriamycin (total cumulative dose range: 700–2,800 mg/m²). A codified assessment scoring clinical sensory and motor functions according to the Common Toxicity Scale and neurophysiological measurements were made before treatment, after the third and sixth cycles, and at the end of therapy. A total neuropathy score (TNS) included selected clinical and neurophysiological parameters. Both positive and negative sensory and motor symptoms and signs of PN developed during therapy, the most common being painful paresthesias, global areflexia and distal weakess. The neurophysiological study showed an early onset, length-independent and progressive sensory defect, and delayed, distal and length-dependent motor deficits. The neuropathy progressed faster in group A than in group B but, after therapy, most of the patients were TNS grade 2 regardless of their group. The temporal relationships between the PN and paclitaxel were robustly characterised, and thus provide reference data and a model for testing the efficacy of drugs designed to provide neuroprotection.     

Phase II trial of docetaxel (Taxotere(R)) in metastatic colorectal carcinoma

BACKGROUND:: Docetaxel (Taxotere^®) is prepared from a non-cytotoxic precursorextracted from the needles of the Taxus baccata. Preclinicalinvestigations have demonstrated that docetaxel is very activein colon adenocarcinoma murine models. Phase I studies revealedgranulocytopenia to be the dose-limiting toxicity. Initial clinicaltrials also demonstrated docetaxel's activity in ovarian, breast,and non-small cell lung cancer. Because of this encouragingpreclinical and clinical activity, we initiated a phase II studyof docetaxel in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS:: Docetaxel, 100 mg/m², was administered as a 1-hour intravenousinfusion every 21 days. Nineteen patients were entered on thetrial. All patients had measurable disease and had not receivedprior chemotherapy for metastatic disease. RESULTS:: No complete or partial responses were observed. Granulocytopeniawas the dose-limiting toxic effect. Seventeen patients had grade4 granulocytopenia; 8 of these patients received antibioticsfor neutropenic fevers. Twelve patients experienced hypersensitivityreactions, and 15 patients experienced cutaneous toxic reactions.One patient demonstrated evidence of fluid retention. CONCLUSIONS:: Administered at the stated dose and schedule, docetaxel haslittle activity against metastatic colorectal carcinomas. Thetoxicity profile, consisting of granulocytopenia, hypersensitivityreactions, cutaneous reactions, and edema, has been previouslydescribed in patients receiving docetaxel. docetaxel, Taxotere^®, paclitaxel, Taxol^®, colorectal carcinomas, colon carcinoma, rectal carcinoma     

Progressive paresthesias after cessation of therapy with very high-dose cisplatin

Summary Control of cisplatin-induced nephrotoxicity and nausea/vomiting has enabled the development of very high-dose cisplatin regimens (monthly total dose, 200 mg/m²). Neurotoxicity is now recognized to be the dose-limiting toxicity of these regimens. However, during a pilot study involving 5 mg/m² vinblastine and 100 mg/m² cisplatin given every 28 days on days 1 and 8 for the treatment of advanced non-small-cell lung cancer, we noted a high incidence of progressive peripheral neuropathy, which continued for several months after the discontinuation of cisplatin chemotherapy. Of the six patients treated, four received at least three cycles of therapy (median total cisplatin dose, 685 mg/m²; range, 500–725 mg/m²). All four patients developed a progressive peripheral neuropathy, with a worsening of toxicity by 1–3 grades over the 2–3 months after cisplatin discontinuation. One patient progressed from grade I (mild paresthesia) to grade IV (inability to ambulate) over a period of 3 months after the discontinuation of therapy. Stricter rules for early dose deescalation and discontinuation may be required for very high-dose cisplatin regimens. Delayed progressive neuropathy should be recognized as a possible late complication of this form of therapy.