A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study

Purpose We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). Methods Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m² and 30 mg/m², respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m² was conducted and primary objective in the phase II portion was response rate. Results The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m² because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C _max and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. Conclusion These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.     

Cisplatin-paclitaxel weekly schedule in advanced solid tumors: A phase I study

Purpose: The objective of our study was to determine the maximumtolerable doses (MTDs) of both paclitaxel and cisplatin when given in a weeklyschedule alone or simultaneously with G-CSF in advanced solid neoplasms.Patients and methods: Patients with advanced cancer eitherchemotherapy-naïve or resistant to standard treatments receivedpaclitaxel in a three-hour infusion followed by cisplatin, with or without theaddition of r-HuG-CSF (5 µg/kg s.c. days three to five). The startingdoses of CDDP and paclitaxel were 25 mg/m²/week and 45mg/m²/week, respectively. During the first six courses thedosages of the two drugs were alternately escalated by 20% (CDDP = 5mg/m²/week, and paclitaxel 10 mg/m²/week) ateach step until the appearance of dose-limiting toxicity (DLT) in one-thirdor more of the patients enrolled in that cohort.Results: Fifty-five patients with cancer (16 lung, 16 breast, 11ovarian, 7 head and neck, 1 renal, 1 esophageal, 1 cervical, 1 soft-tissuesarcoma, and 1 of unknown primary), 25 of whom were pretreated, were enteredinto the study. A total of 439 weekly courses were delivered. Inchemotherapy-naïve patients, the MTDs of cisplatin and paclitaxel were30 mg/m²/week and 65 mg/m²/week, respectively,in the absence of G-CSF support, which increased to 40mg/m²/week and 85 mg/m²/week, respectively,when G-CSF was given. There were no toxic deaths in this study. Neutropeniawas the main dose-limiting toxicity (100/439 courses), but was seldom severe.Neurotoxicity was quite frequent (18 of 55 patients for the total of 88courses) but never dose-limiting. It was more frequent and clinically relevantin cisplatin-pretreated patients. Overall 18 patients (eight ovarian, fivebreast, three lung, and two head and neck) achieved objective responses.Conclusions: The cisplatin–paclitaxel weekly administrationseems a safe, practical and effective therapeutical approach in patients withadvanced solid neoplasms. Large phase II trials are warranted to accuratelydefine the efficacy of this schedule in cisplatin-paclitaxel sensitive tumors.     

A phase I study of palliative chemoradiation therapy with paclitaxel and cisplatin for local symptoms due to an unresectable primary advanced or locally recurrent gastric adenocarcinoma

Purpose  To establish the maximum tolerated dose and dose-limiting toxicity of chemoradiation with paclitaxel (PTX) and cisplatin (CDDP) for patients with local symptoms due to unresectable primary advanced or locally recurrent gastric adenocarcinoma located at left-upper abdomen. Methods  Chemotherapy consisted of PTX at escalating doses of 40–80 mg/m² per day and CDDP at escalating doses of 20–25 mg/m² per day on days 1, 15, and 29. Concurrent radiation was administered up to a dose of 45 Gy for 5 weeks. Results  A total of nine patients were enrolled, of which six were into level 1 (PTX 60 mg/m² and CDDP 20 mg/m²) and three into level −1 (PTX 50 mg/m² and CDDP 20 mg/m²). At level 1, one patient developed grade 3 fatigue, and the other experienced grade 5 DIC, grade 5 pneumonia, grade 4 thrombocytopenia, grade 3 hyponatremia, and grade 3 esophagitis as dose-limiting toxicities. A palliative effect was observed in eight of nine patients; six of six patients at level 1 and two of three at level −1. Conclusion  PTX 50 mg/m² and CDDP 20 mg/m² given biweekly with concurrent radiation therapy of 45 Gy were well tolerated.     

Phase I–II trial of prolonged gemcitabine infusion plus paclitaxel as a biweekly schedule for advanced breast cancer patients pretreated with anthracyclines

Purpose

Paclitaxel (PACL) plus gemcitabine (GEM) is an effective regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged GEM infusion at a fixed dose rate (FDR) of 10 mg/m²/min produces higher levels of intracellular active metabolites of GEM when compared with a standard 30-min infusion. In the present phase I/II trial, we investigated the association of FDR GEM plus PACL.

Methods

1,200 mg/m² was the dose of GEM recommended for the phase II study, in which patients received PACL at 150 mg/m², followed by FDR GEM at 1,200 mg/m² (total GEM infusion time = 120 min), both drugs administered biweekly.

Results

Forty-two anthracycline-pretreated advanced breast cancer patients with disease recurrence following at least one line of chemotherapy were enrolled. Two (4.8%) and 12 (33.3%) patients experienced a complete and partial response, respectively, for an overall response rate of 38.1% (95% CI 23.4–52.8%). Median progression free survival and overall survival were 5 and 19.9 months, respectively. No statistically significant association was noted between in situ protein expression of RRM1 and BRCA1 (as assessed by immunofluorescence combined with automated quantitative analysis) and response to treatment in 15 patients with tissue available for analysis. Toxicity was mostly mild to moderate, mainly consisting of G3–G4 neutropenia (9.6%) and hypertransaminasemia (9.5%).

Conclusions

Biweekly FDR GEM in combination with PACL is an active and safe regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged infusion regimen of GEM does not seem to improve the efficacy of a standard 30-min infusion.     

Irinotecan (CPT-11) in combination with weekly administration of cisplatin (CDDP) for non-small-cell lung cancer

Purpose: CPT-11 (60 mg/m² on days 1, 8 and 15) in combination with CDDP (80 mg/m² on day 1) has shown promising antitumor activity for non-small-cell lung cancer (NSCLC), but dose-limiting toxicities (DLT) are leukopenia and diarrhea, with a wide variation among patients. To estimate weekly CDDP administration in combination with CPT-11, a phase I study for patients with advanced NSCLC was conducted. Methods: Patients were treated with CPT-11 at a fixed dose of 60 mg/m² together with CDDP at 27 mg/m² (level 1, 6 patients), 33 mg/m² (level 2, 12 patients), and 40 mg/m² (level 3, 6 patients) with 1600 ml hydration on days 1, 8 and 15 over 4 weeks. During the treatment course, drug was not administered on the day it was due in the presence of leukopenia (<3000/ml) and/or diarrhea. Results: The planned administration was completed in 5 of 6 patients at level 1, 6 of 12 patients at level 2, and 2 of 6 patients at level 3. The most common toxicity observed was leukopenia (five patients with grade 3 and one patient with grade 4). Leukopenia was considered to be a DLT, and the maximum tolerated dose (MTD) was level 2. Although there were patients who suffered from diarrhea (four patients with higher than grade 2), diarrhea was judged not to be a DLT with this weekly regimen. Nausea and vomiting were mild. Pharmacokinetic analysis of free platinum from CDDP demonstrated that the area under the curve (AUC) from 33 mg/m² CDDP was 0.92 ± 0.29 g/ml h. In 13 patients evaluated for response, the response rate was 54%. Conclusion: The value of weekly administration of CDDP in combination with CPT-11 was shown by (1) diarrhea not being dose-limiting, (2) mild nausea, (3) well-maintained AUC of free platinum, and (4) promising activity. Received: 4 April 1997 / Accepted: 8 October 1997     

Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-na?ve patients with advanced non-small-cell lung cancer

Background:Gemcitabine (GEM) and paclitaxel (TAX) are active,non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performeda phase I study to determine the maximum-tolerated dose (MTD), antitumoractivity and pharmacokinetics of GEM and TAX given weekly in chemo-naïvepatients with advanced NSCLC. Patients and methods:Escalating doses of GEM (800–2000mg/m²) and TAX (60–100 mg/m²) were administeredon days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasmapharmacokinetics of TAX and GEM was assessed at the three higher dose-levels. Results:Dose-escalation was discontinued in absence of MTDbecause of increased cumulative toxicity leading to dose modification ortreatment delay at levels 6 and 7 (TAX 100 mg/m² plus GEM 1750 and,respectively, 2000 mg/m²). Hematological toxicity included grade4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycleand febrile neutropenia in three cycles. Maximal non-hemathological toxicitywas grade 3 elevation in serum transaminases and grade 2 neuro-sensorytoxicity in 8% and 5% of cycles, respectively. At the two higherdose-levels a non-linear pharmacokinetics of GEM was observed with aremarkable variability of C_max and AUC. No pharmacokineticinteractions were reported. Objectives responses were seen at all dose levels,with an overall response rate of 43% (95% confidence interval(95% CI): 25.5%–62.6%) in 30 evaluable patients. Conclusions:The weekly administration of GEM and TAX is very welltolerated, and has shown promising antitumor activity in NSCLC. In view of thecumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500mg/m² of GEM and 100 mg/m² of TAX are recommended forphase II studies.     

Cisplatin, raltitrexed, levofolinic acid and 5-fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: a phase I-II trial of the Southern Italy Cooperative Oncology Group (SICOG).

Background:The combination of cisplatin (CDDP) and 5-fluorouracil(5-FU) can be regarded as a reference regimen in squamous cell carcinoma ofthe head and neck (SCCHN). Raltitrexed (Tomudex) is a direct and specificthymidilate synthase (TS) inhibitor, which has shown clinical activity againstSCCHN in a previous phase I study, when combined with 5-FU and levo-folinicacid (LFA). Preclinical data support the combination of CDDP and raltitrexed.The aim of the present study was to evaluate the combination of cisplatin,raltitrexed, LFA and 5-FU in a phase I–II study. Patients and methods:Patients with locally advanced or metastaticSCCHN were treated with a combination of cisplatin at the starting dose of 40mg/m², followed by raltitrexed at the starting dose of 2.5mg/m² on day 1; levo-folinic acid at fixed dose of 250mg/m², followed by 5-fluorouracil at the starting dose of 750mg/m² on day 2. Doses of the three cytotoxic agents werealternately escalated up to dose-limiting toxicity (DLT). Treatment wasrecycled every two weeks and given up to a maximum of eight courses; afterchemotherapy, patients with locally advanced disease received a locoregionaltreatment. Results:Forty-five patients were entered into the study. Six doselevels were tested. At CDDP 50 mg/m², raltitrexed 3mg/m², 5-FU 900 mg/m², four out of six patients showedDLT, which was in all cases grade 4 neutropenia. Therefore, this dose levelwas defined as maximum tolerated dose (MTD). CDDP 60 mg/m²,raltitrexed 2.5 mg/m², LFA 250 mg/m², 5-FU 900mg/m² was the dose level recommended for phase II. CDDP,Raltitrexed and 5-FU mean actually delivered dose intensities at the selecteddose level were 26, 1.05, and 378 mg/m²/week, respectively.Neutropenia was the main side effect and was observed even at the lowest doselevels. Non-hematologic side effects were mild. Nine complete responses(20%) and twenty-one partial responses (47%) were observed, foran overall response rate of 67% (95% confidence interval(95% CI): 51%–80%), according to intention to treatanalysis. Fifteen of fifteen patients (100%) treated at the dose levelselected for phase II had an objective response (5 complete responses, 10partial responses). Conclusions:The results of our dose escalation clearlydemonstrate that it is possible to combine CDDP, raltitrexed, and modulated5-FU at effective doses, without unexpected toxicities. The response datapoint to an impressive clinical activity, which will be better defined by anongoing large phase II study.     

Gemcitabine and vinorelbine in pretreated advanced breast cancer: A pilot study

Purpose:Gemcitabine (GEM) and vinorelbine (VNR) are both activeagainst advanced breast cancer (ABC), being able to induce a median ORR of25% and 40%, respectively. Because of their different mechanismof action and good tolerability, the combination of GEM and VNR has beentested in ABC. Patients and methods:Twenty-nine ABC patients pretreated withanthracycline-taxane were treated with GEM 1000 mg/m² on day 1, 8,15, and VNR 25 mg/m² on day 1 and 8 every twenty-eight days.Analysis of toxicity pattern, response rate, TTP and OS were carried out. Results:Twenty-nine patients were enrolled into the trial. TheORR was 48% (95% CI: 29–67): a CR was observed in threepatients (10%; 95% CI: 2–27), while eleven patients(38%; 95 CI: 21–58) achieved PR, eight (28%) had a SD, andseven (24%) progressed. Toxicity was mainly hematological and included:grade 3 leukopenia in 48% of cases without episodes of neutropenicfever, grade 3–4 thrombocytopenia in 10%, and grade 2 anemia in7%. Non-hematological toxicities were mild and rather infrequent. Conclusions:The GEM–VNR combination seems to be active inpretreated ABC with an acceptable toxicity pattern, and may well reppresentan interesting therapeutic choice after anthracycline/taxane regimens.     

Phase II study of vinorelbine and gemcitabine for inoperable stage IIIB-IV non-small-cell lung cancer.

Purpose: To evaluate the efficacy of the combination of vinorelbine and gemcitabine as a non-platinum chemotherapy regimen in patients with inoperable locally-advanced or metastatic non-small-cell lung cancer (NSCLC). Efficacy was assessed primarily in terms of response rate, and secondarily in terms of toxicity, time to progression and survival.Patients and methods: Patients with cytologically- or histologically-proven stage IIIB–IV NSCLC, bi-dimensionally measurable lesions, adequate haematological, hepatic and renal function, WHO performance status 2 and no previous chemotherapy or radiotherapy were eligible. The first 12 patients were entered in a pilot study and received vinorelbine (VNR) 30 mg/m² on days 1, 8, 15 and 22, and gemcitabine (GEM) 1000 mg/m² on days 1, 8 and 15, of a 28-day cycle. Subsequently, patients were entered in a phase II trial of VNR 35 mg/m² and GEM 1200 mg/m² on days 1 and 15 of each 28-day cycle. Treatment consisted of three cycles of the chemotherapy, with a further three cycles for those patients who achieved stable disease or a complete or partial response (CR/PR) to the first three cycles. Patients who had achieved CR or PR after six cycles continued with the treatment until relapse.Results: The dosage and scheduling of VNR and GEM in the pilot study resulted in neutropenia necessitating reductions or delays in treatment, and consequently low dose intensity. The schedule was thus modified to VNR 35 mg/m² and GEM 1200 mg/m² on days 1 and 15 of each 28-day cycle for the phase II trial. Thirty-three patients were enrolled in the phase II trial, and 28 were evaluable for response. The overall intent-to-treat response rate of all 45 patients was 40% (18 of 45), comprising 4 CR (9%) and 14 PR (31%). For the 28 evaluable patients who received the fortnightly chemotherapy the response rate was 46% (13 of 28), CR 11% (3 of 28) and PR 36% (10 of 28). Seven patients (25%) had stable disease. The one-year cumulative survival rate for the 33 patients receiving the fortnightly chemotherapy was 24% and median time-to-progression 4 months (range 1–16 months). Median survival for these patients was eight months. Nine out of twelve patients in the pilot study (75%) suffered grade 3–4 neutropenia. There was one toxic death, attributed to neutropenic fever and sepsis, and two cases of pulmonary embolism. One patient suffered Grade 4 thrombocytopenia. Only eight patients (24%) on the fortnightly schedule suffered grade 3–4 neutropenia, resulting in dose reductions or delays for three of them (9%). None of the patients on the fortnightly schedule suffered thrombocytopenia or anaemia.Conclusions: The fortnightly schedule of gemcitabine and vinorelbine was a well-tolerated out-patient regimen, producing response and survival rates comparable to those of cisplatin combination regimens, but with a more favourable toxicity profile. Gemcitabine and vinorelbine should now be tested in a triplet combination with a taxane as the third drug, or against a platinum-containing regimen in a phase III study.     

A study of the combination of gemcitabine hydrochloride (LY188011) and cisplatin in non-small-cell lung cancer: 3-week schedule

Background. It has been reported that the combination of gemcitabine (LY188011; GEM) and cisplatin (CDDP) in a 4-week schedule showed a high response rate for patients with non-small-cell lung cancer (NSCLC), but GEM could not be administered on day 15 because of increased myelosuppression in many patients. The present study was performed to evaluate the efficacy and safety of GEM and CDDP in a 3-week schedule. Methods. Patients with unresectable NSCLC without prior chemotherapy were enrolled. We administered 1000 mg/m² of GEM on days 1 and 8, and 80 mg/m² of CDDP on day 1. The feasibility of the combination therapy was confirmed in 8 patients, and then 20 more patients were enrolled, to evaluate the efficacy and safety of this combination therapy for all 28 patients. Results. The response rate was 42.9% (12/28) and the median survival time was 12.6 months. Neutropenia, leukopenia, anemia, thrombocytopenia or lymphocytopenia of grade 3 or higher were observed as hematological toxicity, and anorexia, nausea, fatigue, or vomiting of grade 3 were the nonhematological toxicities, but most of these toxicities were of grade 2 or less. For GEM and CDDP, 89% and 91% of the scheduled doses, respectively, were administered. Conclusion. This is the first study of the combination of GEM and CDDP with a 3-week schedule in Japan, and the results showed a low level of myelosuppression, high dose intensity, and high response rate, similar to the results reported in other countries. Accordingly, the combination of GEM and CDDP with a 3-week schedule may be a promising regimen for the treatment of NSCLC in Japan. Received: July 2, 2001 / Accepted: September 17, 2001     

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.     

A phase I/II study of S-1 plus cisplatin in patients with advanced gastric cancer: 2-week S-1 administration regimen

Background The combination of a new oral dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine (S-1) and cisplatin (CDDP) is one of the most active chemotherapy regimens for gastric cancer. However, the optimum schedule for this combination has not yet been determined. This study was conducted to establish the maximum tolerated dose (MTD) and the recommended dose of CDDP when combined with 2-week S-1 administration, and to observe the safety and efficacy of the regimen as treatment for patients with advanced gastric cancer.Methods S-1 was administered orally at a dose of 80mg/m² per day for 2 weeks, followed by a 2-week rest. CDDP was administered intravenously on day 8 of each course; the initial dose of CDDP was 60mg/m² and it was increased in 10-mg/m² increments. Treatment was repeated every 4 weeks unless disease progression was observed.Results Eleven patients were enrolled. The main toxicities were leucopenia, neutropenia, nausea, and anorexia. These toxicities were not severe, and were reversible and manageable. The MTD for CDDP was established as 80mg/m², as 2 of 5 (40%) patients developed dose-limiting toxicity (DLT) at this level. Therefore, the recommended dose of CDDP was determined to be 70mg/m². All 11 patients were evaluable for a response: 8 achieved a partial response and 1 had stable disease. The overall response rate was 73%.Conclusion This regimen is considered to be generally well-tolerated and has substantial antitumor activity.     

Triplet chemotherapy with cisplatin, gemcitabine and vinorelbine for malignant pleural mesothelioma

BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) is expected to increase due to delayed control of occupational exposure to asbestos in Japan. We investigated the use of triplet combination chemotherapy with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR) for the treatment of Japanese patients with MPM. METHODS: From December 2000 to August 2003, 12 patients received the following regimen: CDDP 40 mg/m(2), GEM 800 mg/m(2) and VNR 20 mg/m(2) on days 1 and 8 every 4 weeks. Among the 12 patients, six selected patients underwent an extrapleural pneumonectomy (EP) after a median of three cycles of triplet chemotherapy. RESULTS: The overall response rate for all patients and the response rate for chemotherapy-naive cases were 58 and 67%, respectively. The median survival time and survival rate at 2 years for all patients were 11 months and 50%, respectively. The 2-year survival rates for the patients with and without EP were 83.3 and 16.7%, respectively. CONCLUSIONS: Triplet chemotherapy with CDDP, GEM and VNR was thus found to be highly effective for patients with MPM and its toxicity was manageable. A multi-institutional phase II trial is now being planned to establish the effectiveness of this new regimen in chemotherapy-naive patients with MPM.     

Mitoxantrone plus vinorelbine with granulocyte-colony stimulating factor (G-CSF) support in advanced breast cancer patients. A dose and schedule finding study

Summary Mitoxantrone (MTZ) and vinorelbine (VNR) have shown a good efficacy in advanced breast cancer. We conducted a phase I-II trial to determine the MTDs and best schedule of these drugs, in advanced breast cancer patients, when granulocyte-colony stimulating factor (G-CSF) support was given. The starting dose-intensity level was MTZ 3 mg/m²/week + VNR 15 mg/m²/week; dose was escalated at each step by 1 mg/m²/week for MTZ and 5 mg/m²/week for VNR, until dose limiting toxicity (DLT) developed in 33% or more of the patients at the first course. G-CSF 5 µg/kg/day d 3–13 was administered at each cycle from dose level 2 on. For each dose step we planned 3 different schedules (a = total dose of MTZ on day 1; b = total dose d 1 and 8; c = weekly schedule). At the time of this analysis (December 1993) 43 patients with locoregionally advanced or metastatic breast cancer have entered this study, 23 of whom had received prior chemotherapy other than adjuvant. Toxicity has been primarily hematologic. Non hematologic toxicity never caused interruption of dose escalation.Overall 8 patients developed DLT at the first course. Dose escalation was stopped at level 3 in patients receiving schedules a or b, and in those receiving schedule c the dose was escalated until level 5. The MTD was MTZ 6 mg/m² and VNR 30 mg/m² weekly. Age, dose level, and PS were found to be correlated with neutrophil and platelet nadirs, but dose level was the only independent variable predictive of myelotoxicity at multiple regression analysis.Forty-one patients were evaluable for response. Five complete and 16 partial responses were recorded for a 51% [35–67] overall response rate. This was 67% (12/18) in chemotherapy naive patients as compared to 39% (9/23) in those who had been pretreated.Seven of 21 (33%) patients receiving dose level 1 and 2 responded as compared to 14/20 (70%) patients who received higher dose-intensity (p = 0.02). Dose level and pretreatment were the only variables significantly associated with response rate at multiple logistic analysis.The median TTP was 9.5 months for the entire group. It was significantly better in patients who received a dose level > 2 (15 vs. 7; p = 0.015). However, the chemotherapy dose level did not significantly predict outcome after correction for pretreatment (yes vs. no), at multivariate Cox analysis.In conclusion, G-CSF support allows us to achieve a high dose-intensity of MTZ and VNR. Weekly administration of mitoxantrone is recommended to achieve the maximum dose level.Dose escalation seems to provide a significant gain in terms of response rate, although the low number of patients enrolled and the short follow-up prevents us from drawing any conclusion on its effects on TTP and survival. Further controlled trials of this combination in unpretreated patients with advanced breast cancer are needed to determine whether dose escalation can really improve prognosis.     

S-phase modulation by irinotecan: pilot studies in advanced solid tumors

Two studies of irinotecan (CPT-11) followed 24 h later by an antimetabolite were conducted. The objectives of the studies were: (1) to determine whether the increase in S-phase in tumor cells seen 24 h after CPT-11 administration in animal studies is seen in advanced solid tumors in patients, (2) to determine the dose of CPT-11 required to produce this effect, (3) to compare two methods (immunohistochemistry, IHC, for cyclin A, and DNA flow cytometry, FC) for evaluating S-phase in tumor biopsies from patients, and (4) to establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of CPT-11, given 24 h before gemcitabine (GEM, 1000 mg/m²). In one study CPT-11 was followed 24 h later by 5-fluorouracil (5-FU), 400 mg/m² per week for 4 weeks every 6 weeks. Tumor biopsies were obtained before and 24 h after CPT-11 administration before administration of 5-FU and assayed for S-phase by IHC for cyclin A and by FC. The starting dose of CPT-11 was 80 mg/m² per week with subsequent exploration of 40 and 60 mg/m² per week to establish the dose-effect relationship of the increase in tumor cells in S-phase. In the second study, CPT-11 was given 24 h before GEM 1000 mg/m² per week for 2 weeks every 3 weeks. Doses of 20–80 mg/m² were explored to establish the MTD and DLT and to study tumor cell S-phase in selected patients. CPT-11 80 mg/m² produced a mean increase in S-phase by IHC for cyclin A of 137%. Lesser increases were seen with 40 and 60 mg/m². CPT-11 followed 24 h later by 5-FU 400 mg/m² per week for 4 weeks was well tolerated. In the study of CPT-11 followed by GEM 1000 mg/m², 60 mg/m² of CPT-11 was the MTD.This work was presented in part at the 14th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Frankfurt, Germany, November 2002.     

Functional polymorphisms of the microsomal epoxide hydrolase gene: a reappraisal on a early-onset lung cancer patients series

As concomitant chemoradiotherapy for stage III NSCLC is associated with survival advantage in comparison to a sequential approach, we conducted a phase III randomised study aiming to determine the best sequence and safety of chemotherapy (CT) and chemoradiotherapy (CT-RT), using a regimen with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR). Unresectable stage III NSCLC patients received CDDP (60 mg/m(2)), GEM (1g/m(2), days 1 and 8) and VNR (25mg/m(2), days 1 and 8) with reduced dosage of GEM and VNR during radiotherapy (66Gy). Two cycles of CT with radiotherapy followed by two further cycles of CT alone were administered in arm A or the reverse sequence in arm B. The study was prematurely closed for poor accrual due to administrative problems. Forty-nine eligible patients were randomised. Response rates and median survival times were, respectively 57% (95% CI: 36-78%) and 17 months (95% CI: 9.3-24.6 months) in arm A and 79% (95% CI: 64-94%) and 23.9 months (95% CI: 13.3-34.5 months) in arm B (p>0.05). Chemotherapy dose-intensity was significantly reduced in arm A. Grade 3-4 oesophagitis occurred in 5 patients. One case of grade 5 radiation pneumonitis was observed. In conclusion, chemoradiotherapy with CDDP, GEM and VNR appears feasible as initial treatment or after induction chemotherapy. Consolidation chemoradiotherapy seems less toxic with a better observed response rates and survival although no valid conclusion can be drawn from the comparison of both arms.     

Phase I-II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer

Background Both paclitaxel (TXL) and cisplatin (CDDP) show efficacy against gastric cancer. The aim of this phase I-II study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity and efficacy of combination chemotherapy with these two agents. Methods Nineteen patients entered the phase I part of the study, and 21 patients entered the phase II part. TXL infusions were administered on days 1 and 15, with a fixed 3mg/m² dose of CDDP. Results In the phase I part of the study, we determined dose level 5, which represented a TXL dose of 18mg/m², with CDDP 3mg/m², to be the MTD. The recommended dose (RD) was level 4, with a TXL dose of 16mg/m² with CDDP, 3mg/m². In the phase II part of the study, the response rate was 25.0%; five patients had a partial response, seven had stable disease, 6 had progressive disease, and 2 were not evaluable. Grade 3 or 4 neutropenia was the most common adverse event and occurred in 65% of the patients. During treatment, 25% of the patients received granulocyte colony-stimulating factor, but febrile neutropenia was not shown in any of the patients. Major nonhematological toxicities were nausea/vomiting, anorexia, fatigue, alopecia, and sensory neuropathy. Adverse reactions of grade 3 or 4 were shown by two patients, one with anorexia (5%) and the other with sensory neuropathy (5%). Conclusion The RD was determined to be TXL 14mg/m², with CDDP 3mg/m².     

Feasibility of concurrent cisplatin use during primary and adjuvant chemoradiation therapy: a phase I study in Japanese patients with cancer of the uterine cervix

Background Although the prognostic advantages of concurrent cisplatin (CDDP) chemoradiation therapy (CCRT), for uterine cervical cancer (UCC) has been demonstrated, the feasibility of concurrent CDDP administration has not yet been evaluated. We determined the optimal CDDP dose for both weekly and monthly schedules during primary and adjuvant CCRT in patients with UCC. Methods The study was conducted as a phase I, dose-escalation trial. Concurrent CDDP was started at the dose of 30 mg/m² for the weekly schedule and at 50 mg/m² for the monthly schedule, and the doses were steadily escalated to the maximum tolerated dose (MTD). Results A total of 45 patients with UCC (25 receiving primary CCRT and 20 receiving adjuvant CCRT) were entered in the study. In both the primary and adjuvant CCRT patients, the MTD was observed to be 40 mg/m² for the weekly schedule and 80 mg/m² for the monthly schedule. Dose-limiting toxicity was observed in 10 patients (granulocytopenia in 9 patients and diarrhea in 1 patient). Disease recurrence was confirmed in 6 patients in the primary CCRT group during a mean follow-up period of 22.4 ± 13.2 months, and in patients 3 in the adjuvant CCRT group during a mean follow-up period of 17.7 ± 6.8 months. Conclusion For Japanese patients with UCC receiving primary or adjuvant CCRT therapy, the recommended CDDP dose was determined to be 30 mg/m² for the weekly schedule and 75 mg/m² for the monthly schedule.     

5-fluorouracil,leucovorin, hydroxyurea,and escalating doses of continuous-infusion cisplatin with concomitant radiotherapy: a clinical and pharmacologic study

Summary Cisplatin (CDDP), 5-fluorouracil (5-FU), and hydroxyurea (HU) have individually demonstrated activity against several solid tumors, act synergistically with each other in vitro, and may act as radiation sensitizers. Therefore, we designed a phase I study to determine the maximally tolerated dose of cisplatin as given in addition to our previously described combination of 5-FU, HU, and concomitant radiotherapy (XRT). Patients exhibiting advanced solid tumors requiring palliative XRT were eligible. The regimen consisted of 1 g HU given p.o.b.i.d. on days 1–5,600 mg/m² 5-FU given i.v. daily by continuous infusion (c.i.) on days 1–5, escalating doses of cisplatin starting at 10 mg/m² daily given by c.i. on days 1–5, and involved-field XRT carried out on days 1–5. The cycle was repeated every 14 days until the target XRT dose had been reached. In all, 19 patients were entered at the first dose level, and cumulative grade 3–4 myelosuppression was seen in 16 subjects. As no dose escalation was feasible, the chemotherapy was subsequently altered by using the above regimen for cycles 1, 3, 5, and 7 and substituting the less myelosuppressive regimen of 1 g HU given p.o.b.i.d. on days 1–5, 400 mg/m² 5-FU given i.v. daily by c.i., and 100 mg leucovorin given p.o. 4 h on days 1–5 for cycles 2, 4, and 6. On this alternating program, 28 patients were treated with escalating doses of CDDP. The dose-limiting toxicity was again myelosuppression, which was prohibitive at a CDDP dose of 20 mg/m² daily. In the final phase of the protocol, 30 subjects were treated with the above alternating-cycle regimen at a CDDP dose of 20 mg/m² daily and a decreased HU dose of 500 mg p.o.b.i.d. in an attempt to circumvent the myelosuppression associated with this dose of CDDP. Although severe acute toxicity (cycles 1 and 2) was observed less frequently, cumulative toxicity (all cycles) remained pronounced. The other major toxicity encountered was mucositis, which was particularly pronounced in patients receiving radiation to the head and neck and following leucovorin-containing cycles. Plasma concentrations of free platinum did not correlate with the CDDP dose, possibly due to the narrow range of doses given. Pharmacodynamic modeling demonstrated that the CDDP dose and the HU dose were associated with leukopenia. Antitumor activity was demonstrated in a number of solid tumors, particularly non-small-cell lung cancer and head and neck cancer. Due to the high incidence of severe cumulative toxicity, we recommend further use of this regimen only as part of a curative treatment strategy for patients presenting with locoregionally advanced solid tumors.Supported in part by an American Cancer Society Clinical Oncology Cancer Development Award (to M. J. R.) and by National Cancer Institute grant CA-14599-17     

A phase I trial of gemcitabine, docetaxel and carboplatin administered every 2 weeks as first line treatment in patients with advanced breast cancer

Objective  To determine the maximum tolerated doses (MTDs) and dose limiting toxicities (DLTs) of gemcitabine (GEM), docetaxel (DOC) and carboplatin (CARBO) combination. Patients and methods  A total of 33 previously untreated HER-2 negative patients with stage IIIB-IV breast cancer received escalated doses of GEM, DOC and CARBO all given sequentially on day 1 every 2 weeks. Twenty-three patients (70%) had previously received adjuvant or neoadjuvant chemotherapy. Results  The recommended MTDs are GEM 1,500 mg/m², DOC 50 mg/m² and CARBO 3AUC. Seven dose levels were evaluated and neutropenia was the primary dose-limiting event. Of 319 chemotherapy cycles delivered, grade 3–4 neutropenia occurred in 13.5% of them with two cases of febrile neutropenia. Diarrhea and asthenia were the most common non-hematological toxicities. Three (16%) complete and 6 (32%) partial responses were observed among 19 patients with measurable disease. Conclusion  The biweekly administration of GEM, DOC and CARBO is a well-tolerated regimen which merits further evaluation.