Phase I study of weekly (day 1 and 8) docetaxel in combination with capecitabine in patients with advanced solid malignancies

Purpose Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in a number of tumor types, but at the expense of significant toxicity. To improve the therapeutic index, we evaluated a weekly regimen of docetaxel in combination with capecitabine, and determined the maximum tolerated dose, toxicities and pharmacokinetics of this combination.Patients and methods Patients with advanced solid malignancies were treated with docetaxel on days 1 and 8, and capecitabine, twice daily on days 1–14, of an every-21-day cycle. Pharmacokinetics of docetaxel were assessed on days 1 and 8 of the first cycle of chemotherapy.Results Enrolled in the study were 25 patients. The most frequent toxicities were asthenia, hand-foot syndrome and mucositis. Inability to deliver at least 75% of the planned doses of both drugs during the first two cycles of chemotherapy was noted at dose levels 2, 3 and 4. Dose level 1 (docetaxel 30 mg/m² and capecitabine 825 mg/m² twice daily) is the recommended dose for phase II studies. Five patients experienced a partial response, and eight patients had stabilization of disease. Coadministration of capecitabine did not alter the pharmacokinetics of docetaxel.Conclusion The regimen consisting of docetaxel 30 mg/m² (days 1, 8) and capecitabine 825 mg/m² twice daily (days 1–14) was well tolerated. Capecitabine did not alter pharmacokinetics of docetaxel. Further testing of this regimen in tumor-specific trials, especially gastric, lung and breast cancer, is warranted.Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, May 2003, Chicago, IL.     

Phase I study of docetaxel and cyclophosphamide in patients with advanced or recurrent breast cancer

BACKGROUND: A phase I clinical study of combination chemotherapy with docetaxel and cyclophosphamide (CPA) was performed to determine the maximum tolerated dose (MTD), the incidence and severity of toxicities and the pharmacokinetics in patients with advanced or recurrent breast cancer. METHODS: Docetaxel was administered by intravenous drip infusion over 60 minutes, followed by intravenous bolus injection of CPA every 3-4 weeks. The dosage of docetaxel/CPA was 40/200, 40/400, 50/400, or 60/400 mg/m(2)/day. RESULTS: Fifteen patients were enrolled and received a total of 33 cycles of the combined therapy. The dose limiting toxicities (DLTs) were leukopenia, neutropenia and thrombocytopenia. The MTD was estimated to be docetaxel 60 mg/m(2) in combination with CPA 400 mg/m(2) per day. Plasma clearance of both drugs was similar regardless of dose. The recommended doses of docetaxel/CPA for a phase Utrial are 50/400 mg/m(2)/day every 3-4 weeks. CONCLUSION: The MTD of this combined therapy was docetaxel 60 mg/m(2) and CPA 400 mg/m(2). Neutropenia and leukopeina were common and severe. It is important to stress the need for modification of the dosing scheme.     

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer

Purpose

To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer.

Methods

Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m², respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m² to the MTD.

Results

A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m². All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12–66%) in 13 chemotherapy-naïve patients.

Conclusions

A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m² of docetaxel, 30 mg/m² of cisplatin and 1,500 mg/m² of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial.     

A single-institute phase I/II trial combining nedaplatin dose escalation with a fixed dose of docetaxel for induction chemotherapy of oral squamous cell carcinoma

The purpose of this clinical trial was to assess the toxicity and efficacy of docetaxel plus nedaplatin induction chemotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). Twenty-one patients were enrolled in this phase I/II clinical study. The toxicities, response rates, and the maximum tolerated dose of nedaplatin that could be safely given preoperatively were assessed. Patients received escalating doses of nedaplatin (60, 70, 80, 90 mg/m²) combined with a fixed dose of docetaxel (60 mg/m²) on day one. Dose-limiting toxicity (DLT), grade 4 leukopenia lasting for two days or more, was seen in one patient at dose level 3; no other DLT was observed at any dose level. The overall response rate was 66.7%. The response rate was 100% at nedaplatin dose level 4, while that at dose level 1 was low (33.3%). Given these results, the recommended dose of nedaplatin in this regimen combined with fixed dose docetaxel (60 mg/m²) was determined to be 90 mg/m². Docetaxel 60 mg/m² plus nedaplatin 90 mg/m² induction chemotherapy can be recommended for patients with locally advanced oral squamous cell carcinoma. Based on these results, an early phase II clinical study using this dose level was conducted; docetaxel plus nedaplatin induction chemotherapy appears to be a useful regimen for the treatment of OSCC. A late phase II clinical study is warranted.     

A phase I dose-escalation study of docetaxel with granulocyte colony-stimulating factor support in patients with solid tumours.

BACKGROUND: Docetaxel is a widely active cytotoxic agent. The principal dose-limiting toxicities (DLTs) of the 3-weekly regimen are neutropenia and febrile neutropenia. Use of prophylactic granulocyte colony-stimulating factor (G-CSF) may allow higher doses of docetaxel to be administered with potentially greater anticancer efficacy. The objectives of this study were to determine the maximum tolerated dose (MTD) and toxicity profile of docetaxel given with G-CSF support. PATIENTS AND METHODS: Eligible patients had solid tumours and were aged 18-75 years with a WHO performance status of up to 2. Strict criteria for liver function were followed. Patients may have received one previous regimen of chemotherapy in addition to adjuvant chemotherapy. Cohorts of three to six patients received docetaxel over 60-90 min every 3 weeks, commencing at 110 mg/m(2) and escalating at 10 mg/m(2) increments. Patients also received G-CSF 5 micro g/kg/day until neutrophil recovery. A 3-day corticosteroid prophylaxis was given. RESULTS: Twenty-nine patients with median age 55 years (range 29-75) were included. Fourteen (48%) had previously received chemotherapy. At the 170 mg/m(2) dose level (the MTD), two of three patients had DLTs and 160 mg/m(2) was determined to be the recommended dose. The principal DLTs were skin and neurosensory toxicity. Asthenia was frequent, especially at dose levels >/=140 mg/m(2). Grade 4 neutropenia occurred in only 10 patients (35%) and was not dose related, with febrile neutropenia in three patients (10%). CONCLUSIONS: Docetaxel may be escalated considerably above standard doses when administered with G-CSF support. The recommended dose for phase II studies is 160 mg/m(2). With escalated-dose docetaxel, DLTs were non-haematological and qualitatively similar to the toxicity profile at standard doses.     

Phase I/II study of S-1 combined with weekly docetaxel in patients with metastatic gastric carcinoma

We designed a phase I/II trial of S-1 combined with weekly docetaxel to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in metastatic gastric carcinoma (MGC). Patients with measurable disease received S-1 orally b.i.d. on days 1-14 and docetaxel intravenously on days 1 and 8 every 3 weeks. In phase I (n=30), each cohort received escalating doses of S-1 (30-45 mg m(-2) b.i.d.) and docetaxel (25-40 mg m(-2)); MTD was 45 mg m(-2) b.i.d. S-1/35 mg m(-2) docetaxel and RD was 40 mg m(-2) b.i.d. S-1/35 mg m(-2) docetaxel. Dose-limiting toxicities included grade 3 elevated liver enzymes, gastric perforation, grade 3 diarrhoea/fatigue, febrile neutropenia with grade 3 anorexia/fatigue, and neutropenic infection with grade 3 stomatitis/anorexia. In phase II (n=52), the overall response rate was 66.7% (95% confidence interval (CI): 53.8-79.6%) and the median time to progression and overall survival were 6.5 months (95% CI: 4.9-8.1) and 13.7 months (95% CI: 9.9-17.5), respectively. The most common grade 3/4 toxicity was neutropenia (29.4%), and febrile neutropenia/neutropenic infection occurred in 19.6% of patients. Non-haematological toxicities were generally mild. There was one treatment-related death due to pneumonitis. S-1 combined with weekly docetaxel is active in MGC with moderate toxicities.     

Phase I study of docetaxel and topotecan in patients with solid tumors

Purpose: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies. Methods: DOC was administered first at 60 mg/m² without G-CSF and at 60, 70, and 80 mg/m² with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2, 4, 6, etc.). TOPO 0.75 mg/m² was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 μg was administered subcutaneously (s.c.) on days 5–14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h for a total of six doses starting on the day before DOC infusion. Results: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m², respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort II with DOC and TOPO doses of 60 and 0.75 mg/m², respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80 and 0.75 mg/m², respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m² and delivered with TOPO 0.75 mg/m² and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of 12 weeks (range 9–18 weeks). Administration of TOPO on days 1–4 and DOC on day 4 resulted in increased neutropenia. Conclusions: DOC 80 mg/m² given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m² given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m² with TOPO 0.75 mg/m² given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 μg s.c. on days 5–14. The alternative schedule with DOC given on day 4 and TOPO on days 1–4 is not recommended. Received: 18 February 2000 / Accepted: 19 July 2000     

Phase I clinical and pharmacokinetic trial of docetaxel and irinotecan administered on a weekly schedule

Background Docetaxel and irinotecan are synergistic agents with a broad spectrum of activity but overlapping myelosuppression. The study was designed to maintain dose intensity while limiting myelosuppression. The objectives of this study were to determine the maximal tolerated dose (MTD) of the combination of docetaxel and irinotecan administered weekly for four consecutive weeks every 42 days, to describe toxicities of this regimen, and to perform a pharmacokinetic analysis to evaluate changes in drug disposition as a function of dose as well as repeated dosing.Methods Adult patients with advanced solid tumors were treated with docetaxel followed by irinotecan. Doses of 30/50, 35/50, 35/66, 30/57, 30/65, 30/80 mg/m², respectively, were studied. Pharmacokinetics of docetaxel, irinotecan and SN-38 in plasma were determined on days 1 and 22 by a high-performance liquid chromatography (HPLC) assay.Results A total of 35 patients were treated. The MTD was docetaxel 30 mg/m² plus irinotecan 65 mg/m². Diarrhea was the dose-limiting toxicity; myelosuppression and other non-hematological toxicities were uncommon and mild. There were no significant differences in pharmacokinetic parameters between day 1 and day 22 (n=20). Five objective responses (breast, stomach and unknown primary) were observed among 30 evaluable patients. In addition, eight patients achieved stable disease.Conclusions The combination of weekly docetaxel and irinotecan is a well tolerated regimen and should be explored in phase II trials. This schedule maintains dose intensity and has limited myelosuppression.     

Vinorelbine/docetaxel combination treatment of metastatic breast cancer: a phase I study

Purpose The aim of this study was to investigate the combination of vinorelbine (VRL) alternating intravenous (i.v.) and oral in combination with docetaxel (DCT) as first-line chemotherapy of patients with metastatic breast cancer. Patients and methods Tested doses were 60 or 70 mg m⁻² given on day 1 for DCT, 20 to 25 mg m⁻² for i.v. VRL on day 1, 60 mg m⁻² on day 8 or day 15 for oral VRL. Day 1 was administered every 3 weeks. Three to six patients were treated per dose level. Results The median age of the 30 treated patients was 60 years. Four patients were non evaluable for the maximum tolerated dose (MTD) and were replaced. Reported dose-limiting toxicities were 11 omissions of oral VRL for neutropenia, two cases of febrile neutropenia and two grade 4 neutropenia ≥7 days. Dose levels using DCT doses >60 mg m⁻² and/or i.v. VRL doses >20 mg m⁻² met the criteria for MTD. Most frequent toxicities were febrile neutropenia in seven patients and neutropenic infection in four patients (one fatal). Therefore, the recommended schedule was established at i.v. VRL 20 mg m⁻² with DCT 60 mg m⁻² on day 1 and oral VRL 60 mg m⁻² given on day 15 every 3 weeks. At this recommended schedule, only one of six patients experienced febrile neutropenia. Among 22 patients evaluable for tumour response, 2 complete and 10 partial responses were reported. Pharmacokinetics of combined VRL and DCT demonstrated the absence of mutual interaction. Conclusions This phase I study established the recommended doses and schedules of the combination alternating i.v. and oral VRL with DCT, this recommended regimen being further explored in a phase II study.     

Cisplatin plus weekly CPT-11/docetaxel in advanced esophagogastric cancer: a phase I study with pharmacogenetic assessment of XPD, XRCC3 and UGT1A1 polymorphisms

Purpose  A multicenter phase I trial to establish the recommended dose of CPT-11/docetaxel plus cisplatin in advanced esophagogastric cancer patients and to correlate the efficacy and toxicity with genetic polymorphisms in DNA repair genes (XPD and XRCC3) and the UGT1A1 gene. Methods  Four dose levels with a fixed dose of cisplatin (60 mg/m²), day 1, and dose-escalation of CPT-11 (50–70 mg/m²) and docetaxel (25–30 mg/m²), days 1 and 8, every 3 weeks were planned. Polymorphisms of XPD (Asp312Asn and Lys751Gln), XRCC3 (Thr241Met) and UGT1A1*28 were examined in baseline peripheral blood. Results  Twenty-eight patients were included at three different dose levels. Dose-limiting toxicities were febrile neutropenia and diarrhea; the recommended dose was established at CPT-11 60 mg/m² and docetaxel 25 mg/m² plus cisplatin 60 mg/m². Objective response was observed in 13 patients (50%). Median time to progression was 6.6 months, and median survival was 11.3 months. Median time to progression was 9.7 months for patients harboring the XRCC3 Met241Met genotype versus 8.4 months for patients with Thr241Met and 3.1 months for those with Thr241Thr (P = .04). Conclusions  CPT-11/docetaxel plus cisplatin is active in patients with advanced esophagogastric cancer. XRCC3 Met241Thr polymorphisms could be a useful marker to predict prognosis in patients treated with a cisplatin-based chemotherapy. However, these results are required to be confirmed with a great number of patients.     

A dose escalation study of weekly docetaxel in patients with advanced solid tumors

Purpose: To determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of weekly administration of docetaxel for three consecutive weeks every 4 weeks in patients with advanced solid tumors. Patients and methods: A total of 26 patients with malignant tumors refractory to conventional treatment were enrolled in this phase I study; their median age was 62 years. Of the 26 patients, 16 (62%) had previously received more than one chemotherapy regimen and 17 (65%) had previously received taxanes in a 3-week schedule. Docetaxel was administered after appropriate premedication at escalating doses (starting dose 30 mg/m²) as a 1-h i.v. infusion for three consecutive weeks in cycles of 4 weeks. Results: A total of 68 chemotherapy cycles were administered with a median of three cycles per patient (range one to six). The DLT was reached at 45 mg/m² per week and the dose-limiting events were grade 4 neutropenia, febrile neutropenia, and treatment delay due to incomplete hematologic recovery. The MTD was defined at a dose of 42 mg/m²/week. Grade 3/4 neutropenia occurred in seven patients (27%) (10% of cycles), and four patients (15%) developed febrile neutropenia. There were no deaths due to sepsis. Grade 2 peripheral neurotoxicity was observed in two patients (8%), grade 2 and 3 fatigue in 14 (54%), grade 2 edema in seven (27%), mild allergic reactions in two (8%) and lacrimation in three (12%). One (4%) complete response and eight (35%) partial responses (overall response rate 39%) were observed in 23 evaluable patients. Stable disease and progressive disease were observed in six patients (26%) and eight patients (35%), respectively. All responses were observed in patients with metastatic breast cancer, one of whom had progressed on paclitaxel-based and two of whom had progressed on docetaxel-based chemotherapy. Conclusions: The weekly administration of docetaxel for three consecutive weeks every 28 days is a feasible schedule with a favorable toxicity profile, and can be given on an outpatient basis. Moreover, this schedule of docetaxel administration seems to have an enhanced efficacy, especially in patients with advanced breast cancer who have failed front-line taxane-based chemotherapy. Received: 27 February 2000 / Accepted: 28 July 2000     

A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer

BACKGROUND:

Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction.

METHODS:

Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40‐75 mg/m² intravenously on day 1 of a 21‐day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21‐day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose‐limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts.

RESULTS:

Fifteen patients were treated. Dose‐limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m². Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination.

CONCLUSIONS:

Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs. Cancer 2012. © 2011 American Cancer Society.     

Phase II study of vinorelbine (alternating intravenous and oral) in combination with docetaxel as first-line chemotherapy in metastatic breast cancer

Purpose  Combination of intravenous (i.v.) vinorelbine and docetaxel was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated in first-line treatment a regimen alternating i.v. and oral vinorelbine in combination with docetaxel. Patients and methods  Forty-nine patients (median age, 53 years) with MBC received a maximum of 6 cycles consisting of i.v. vinorelbine 20 mg/m2 plus docetaxel 60 mg/m2 given on day 1, and oral vinorelbine 60 mg/m2 on day 15 every 3 weeks in an open-label, multicentre phase II study (recommended dose established in phase I study [1]). Results  Sixty-three percent of the patient had received prior adjuvant chemotherapy and 78% presented visceral involvement. Twenty-four responses were documented and validated by an independent panel review, yielding response rates of 49% (95% CI: 34–64) in the 49 enrolled patients and 55.8% (95% CI: 40–71) in the 43 evaluable patients. Median duration of response was 9.4 months. Median progression-free survival and median overall survival were 5.5 and 33.2 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, four patients having experienced febrile neutropenia and one having developed neutropenic infection. Other frequently reported adverse events included alopecia, fatigue, stomatitis, constipation, diarrhoea and nausea, which were rarely severe. Conclusions  This regimen alternating oral and i.v. vinorelbine in combination with docetaxel is effective and manageable. Vinorelbine i.v. per oral day 1 per day 15-docetaxel day 1 every 3 weeks represents a convenient option to combine docetaxel and vinorelbine for the palliative treatment of MBC.     

A phase II study of weekly docetaxel as salvage chemotherapy for advanced gastric cancer

Background:Docetaxel has shown some activity in advanced gastriccancer. Recent phase I studies found low hematologic toxicity and a favourabletoxicity profile when docetaxel was administered on a weekly schedule. In thisstudy, we explored the activity of weekly docetaxel in patients with advancedgastric cancer who failed first-line chemotherapy. Materials and methods:Patients with stable or progressing diseaseafter first-line chemotherapy received 36 mg/m² weekly docetaxel.One cycle consisted of six administrations followed by a two-weeks rest,patients were re-evaluated at week eight. The optimal two-stage design wasadopted for early stopping of the trial if responses were one or less in 21patients (<20% response rate with and errorprobabilities 0.05 and 0.010 respectively). Results:Twenty-one patients have been enrolled and they are fullyevaluable for response and toxicity. One patient achieved partial response,8 patients had stable disease and 12 patients progressed. Median overallsurvival from the onset of salvage chemotherapy was 3.5 months. Hematologictoxicity was observed in two patients who experienced grade III leukopenia.Beginning from the third week of treatment, most of the patients (90%)showed grade II asthenia which resulted the commonest side-effect. Conclusions:This schedule of weekly docetaxel did not showsignificant activity in pretreated patients with advanced gastric cancer.     

Front-line treatment of metastatic breast cancer with docetaxel and epirubicin: A multicenter dose-escalation study

Purpose: To determine the maximum tolerable dose (MTD) and the dose-limiting toxicity (DLT) of docetaxel (D) in combination with epirubicin (Epi) in patients with advanced breast cancer.Patients and methods: Forty-seven chemotherapy-naïve metastatic breast cancer patients aged <75 years with PS (WHO) 0–2 and adequate bone marrow, renal, liver and cardiac function, were enrolled in the study. Epi was given as a five-min bolus i.v. infusion on day 1 (d1) in escalated doses with increments of 10 mg/m2; D was given in a one-hour infusion after appropriate premedication on either day 1 or on day 2 in escalated doses with increments of 10 mg/m2. The patients' median age was 60 years, 42 (89%) had a PS (WHO) 0–1, 16 (34%) were premenopausal and 25 (53%) had visceral disease.Results: When the two drugs were given on the same day, the MTD1 was reached at the doses of Epi 60 mg/m2 and D 80 mg/m2; administration of G-CSF could not result in a dose intensification. When the drugs were given on two consecutive days, the MTD2 was reached at the doses of Epi 80 mg/m2 (d1) and D 90 mg/m2 (d2). The dose-limiting events were febrile neutropenia and grade 4 neutropenia, which developed in 30 (64%) patients during the study; among 227 delivered cycles grade 3–4 neutropenia occurred in 64 (28%) cycles but only 22 (10%) of them were complicated by fever. There were no septic deaths. Grade 1–2 neurosensory toxicity occurred in nine (19%) patients, mild edema in eight (17%) and allergic reactions in five (11%). Four (9%) patients presented a greater than 10% decrease of LVEF and treatment discontinuation was required in two of them; none of the patients developed congestive heart failure. Nevertheless, one patient suddenly died 10 days after treatment initiation of myocardial ischemia, and this death is considered treatment-related. Five (14.7%) complete and thirteen (38.2%) partial responses (ORR: 53.9%; 95% confidence interval: 36.1%–69.7%) were observed in 34 evaluable patients. Ten (29.4%) and six (17.6%) patients had stable and progressive disease, respectively. The median duration of response and time to tumor progression were five and seven months, respectively. The median survival has not yet been reached.Conclusions: The combination of epirubicin and docetaxel is a feasible and well tolerated regimen, but the MTD depends on the administration schedule of the drugs.     

A phase I trial of celecoxib in combination with docetaxel and irinotecan in patients with advanced cancer

Purpose This phase I study was conducted to determine the safety, tolerability and maximum tolerated dose of the combination of celecoxib, a selective cyclooxygenase-2 inhibitor, with docetaxel and irinotecan, in patients with advanced solid tumors.Patients and methods Patients with solid tumors received one of three escalating dose levels of daily celecoxib in combination with docetaxel and irinotecan administered on days 1 and 8 of an every 21-day cycle. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria (NCI CTC) and recorded as maximum grade per patient for each treatment cycle.Results A total of 19 patients received 90 cycles of treatment through three dose levels. Dose-limiting toxicities were nausea and diarrhea. The most common treatment-related toxicities in all cycles of treatment were alopecia, fatigue, diarrhea, nausea, vomiting, anemia, anorexia, and edema.. The maximum tolerated dose was established at celecoxib 400 mg twice a day continuously, weekly docetaxel 30 mg/m² and irinotecan 50 mg/m² for 2 weeks every 21 days. Disease stabilization (five or more cycles) was documented in eight patients.Conclusion The combination of celecoxib with docetaxel and irinotecan did not ameliorate irinotecan-induced diarrhea. Although prolonged disease stabilization was achieved in some patients, we do not recommend combining celecoxib with docetaxel and irinotecan because of lack of activity and the side effect profile of this combination.This work was supported by Grants from the Pfizer Corporation and Aventis Corporation.     

周剂量多西紫杉醇联合卡培他滨二线治疗晚期食管癌的临床观察

目的　观察周剂量多西紫杉醇联合卡培他滨二线治疗晚期食管癌的疗效和安全性。方法　２８例经顺铂加氟尿嘧啶方案一线化疗失败的晚期食管癌患者,应用多西紫杉醇２５ｍｇ／ｍ^２,静脉滴注１ｈ,ｄ_１、ｄ_８、ｄ_１５,卡培他滨（希罗达）１５００ｍｇ／ｍ^２,分每日２次口服,ｄ_１～ｄ_１４,２８天为１周期。结果　２８例患者中２６例可评价疗效,获ＣＲ１例,ＰＲ１０例,ＳＤ８例,ＰＤ７例,总有效率（ＣＲ＋ＰＲ）为３９.３％。所有患者中位疾病进展时间（ＴＴＰ）为４.２个月（９５％ＣＩ：１.６～６.０个月）,中位生存时间（ＯＳ）为７.８个月（９５％ＣＩ：６.３～９.３个月）。主要毒副反应为骨髓抑制,出现３～４级中性粒细胞减少１２例（４２.９％）,３级贫血５例（１７.９％）,３级血小板减少３例（１０.７％）,无治疗相关性死亡。结论　周剂量多西紫杉醇联合卡培他滨二线治疗晚期食管癌有一定疗效,患者耐受性较好,值得临床进一步研究。     

周剂量多西紫杉醇联合顺铂和5-氟尿嘧啶治疗晚期胃癌

  目的 观察周剂量多西紫杉醇联合顺铂（DDP）、5-氟尿嘧啶（5-Fu）治疗晚期胃癌的临床疗效和毒副作用。方法 晚期胃癌患者28例，给予多西紫杉醇35 mg／m2，静脉滴注1 h，第1、8、15天；DDP 75 mg／m2，均分第1 ~ 3天静脉滴注，5-Fu 500 mg／m2，24 h中心静脉置泵持续滴注，第1 ~ 5天，28 d为1个周期。化疗2 ~ 6个周期后按WHO实体瘤疗效评价标准（RECIST）评定疗效，按WHO标准评价不良反应。结果 全组28例均可评价疗效，其中完全缓解（CR）2例，部分缓解（PR）13例，稳定（SD）7例，近期客观有效率53.4 %，中位疾病进展时间（TTP）为8.7个月，中位生存期（MS）为11.8个月，1年生存率为47.8 %。主要不良反应为骨髓抑制和胃肠道反应。但Ⅲ ~ Ⅳ度发生率较低。结论 周剂量多西紫杉醇联合DDP和5-Fu治疗晚期胃癌疗效较好，患者毒副作用轻，耐受性好，值得进一步推广使用。     

A phase II study of weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer

Background:

Docetaxel plus cisplatin and 5-fluorouracil has become a new standard for treating advanced gastric cancer. However, high rates of severe neutropenia limit its application. Modification of the regimen could be the solution to get similar activity but less myelosuppression.

Methods:

Patients with histologically confirmed, locally advanced, or recurrent/metastatic gastric adenocarcinoma without previous chemotherapy were enrolled. This regimen consisted of docetaxel (Tyxan, TTY, Taipei, Taiwan) 30-min infusion at a dose of 36 mg m⁻², followed by cisplatin 30 mg m⁻² infusion over 1 h on days 1 and 8, and oral tegafur/uracil 300 mg m⁻² per day plus leucovorin 90 mg per day on days 1–14, every 3 weeks. Tumour response was evaluated after every 2 cycles of treatment.

Results:

From August 2007 to March 2009, 45 patients were enrolled. The median age was 56 years (range: 22–75). Among the 40 patients evaluable for tumour response, one achieved a complete response, 22 had partial responses and 11 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 58% (95% CI: 41–74%) and 53% (95% CI: 38–68%), respectively. The disease control rates in these populations were 85% (95% CI: 70–94%) and 82% (95% CI: 68–92%), respectively. In the ITT analysis, the median time to progression and overall survival were 6.8 and 13.9 months, respectively. Major grade 3–4 toxicities were neutropenia (51%), anaemia (22%), diarrhoea (16%), and infections (20%). No patient died of treatment-related toxicities.

Conclusion:

Concurrent weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin are effective and well tolerated in the treatment of advanced gastric cancer.     

Phase I/II trial of weekly docetaxel and concomitant radiotherapy for squamous cell carcinoma of the head and neck

Background A phase I/II trial of concurrent docetaxel and radiation for head and neck cancer was conducted to estimate the recommended dose schedule of docetaxel, and then to evaluate the therapeutic benefit.Methods Patients received radiation in 2.0-Gy single daily fractions to a total dose of 60Gy. Docetaxel was administered weekly for 6 consecutive weeks.Results Docetaxel 15mg/m² was considered the maximum tolerated dose (MTD). The recommended dose was decided as 10mg/m². The phase II study was conducted using docetaxel at 10mg/m². Thirty-nine patients were enrolled. The overall response rate was 96.9%. The prognosis of the complete response (CR) patients was significantly better than that of the partial response (PR) patients. Grade 3 or 4 adverse events consisted of lymphopenia, stomatitis, and anorexia. Thirty-two of the 35 eligible patients showed high compliance, of over 90%, and their toxicities were manageable.Conclusion Even low-dose docetaxel shows a strong effect in combination with radiation, with a high survival rate in CR patients. The effect on survival will be assessed by further follow-up.Yukio Inuyama for the Japan Cooperative Head and Neck Oncology Group (JCHNOG)