泰索帝每周给药联合顺铂一线治疗晚期非小细胞肺癌的临床研究

目的确定泰索帝每周给药联合顺铂治疗晚期非小细胞肺癌的最大耐受剂量（MTD）和剂量限制毒性（DLT）,观察其疗效（RR）和安全性,并进行药代动力学研究。方法泰索帝每周给药,连用3周,休息1周,顺铂每周期的第1天给药;每28d为1个治疗周期。顺铂的剂量为75mg／m^2。泰索帝在Ⅰ期临床阶段共有4个剂量组：25mg／m^2、30mg／m^2、35mg／m^2和40mg／m^2,每个剂量组至少人选3例患者。在Ⅱ期临床阶段,根据Ⅰ期临床推荐剂量,泰索帝35mg／m^2每周给药。药代动力学为第一周期第1天和第15天抽取血样待分析。根据Ⅰ期临床研究推荐剂量,进行Ⅱ期临床研究。结果Ⅰ期临床的15例患者中,有14例可评价疗效,其中5例部分缓解,有效率为35．7％,其中位生存时间16个月（范围5-40个月）。1、2、3年生存率分别为73．3％、26．6％和20．0％。中位疾病进展时间9个月（6～14个月）。Ⅱ期临床研究的83例初治的晚期非小细胞肺癌患者共接受了216个周期的化疗,可评价者75例。有1例患者完全缓解,22例患者部分缓解,占全部人组病例的27．7％（23／83）,占可评价病例的30．7％（23／75）;其中位生存时间为10．7个月（范围3—34个月）,1年生存率为48．6％。主要不良反应为Ⅲ-Ⅳ度的粒细胞减少以及乏力、指甲毒性及液体潴留。结论泰索帝（35mg／m^2）每周给药联合顺铂（75mg／m^2）作为一线方案治疗晚期非小细胞肺癌,疗效较好,骨髓毒性较小。     

Phase II study of weekly docetaxel combined with cisplatin in patients with advanced non-small-cell lung cancer

Purpose To evaluate the safety and efficacy of the combination of cisplatin on day 1 and docetaxel on days 1, 8 and 15 every 4 weeks for the treatment of previously untreated patients with non-small-cell lung cancer (NSCLC).Patients and methods A group of 38 patients with advanced or metastatic NSCLC who had not received prior treatment and who were aged under 75 years were enrolled. The patients received intravenous infusions of docetaxel (25 mg/m², days 1, 8, 15) and cisplatin (80 mg/m², day 1), followed by a week of rest.Results Six patients had grade 3/4 neutropenia (18%), but there were no episodes of neutropenic fever. Nonhematologic toxicities were also mild. There were 12 partial responses for an objective response rate of 31.6%. The median survival was 11.8 months, and the 1-year survival rate was 46.5%.Conclusion Cisplatin combined with weekly administration of docetaxel is efficacious against NSCLC with low hematotoxicity, and this schedule may be an alternative for the treatment of NSCLC.     

High incidence of pulmonary toxicity of weekly docetaxel and gemcitabine in patients with non-small cell lung cancer: results of a dose-finding study

PURPOSE: To determine the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLTs) of the weekly administration of docetaxel and gemcitabine as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-na?ve patients with histologically or cytologically confirmed unresectable stage III(B) or IV NSCLC were enrolled onto the study. Escalated doses of gemcitabine (starting dose 700 mg/m(2) per week) and docetaxel (starting dose 30 mg/m(2) per week) were given on a weekly basis for three consecutive weeks in cycles of 4 weeks. RESULTS: Twenty-six patients received a total of 94 chemotherapy cycles. At the doses of docetaxel 40 mg/m(2) per week and gemcitabine 1000 mg/m(2) per week, the MTD had not yet been reached. However, the study was prematurely closed because of a high incidence of severe pulmonary adverse events. Six (23%) patients developed fever and pulmonary dysfunction (severe dyspnea, hypoxia in association with diffuse interstitial pneumonitis), which was fatal in two of them. No risk factors were identified contributing to these pulmonary adverse events; four patients had a low absolute number of peripheral blood CD4+ lymphocytes. Grade 3/4 neutropenia occurred in five (19%) patients and grade 3/4 anemia in two (8%). CONCLUSION: The weekly administration of gemcitabine and docetaxel in patients with advanced NSCLC is associated with a high incidence of severe pulmonary toxicity, which does not seem to be dose-related. The regimen cannot be used outside a clinical protocol.     

Phase II randomised trial comparing docetaxel given every 3 weeks with weekly schedule as second-line therapy in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Taxotere (docetaxel) at the dose of 75 mg/m(2) every 3 weeks is a standard therapy for pretreated non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the safety profile of two schedules of docetaxel administration (every 3 weeks versus weekly) in patients with pretreated NSCLC. PATIENTS AND METHODS: From February 2000 to February 2001, 125 patients with locally advanced or metastatic NSCLC were randomised after failure of a previous platinum-based regimen to receive either docetaxel 75 mg/m(2) administered every 3 weeks (Dq3w) or docetaxel 40 mg/m(2) given weekly for 6 weeks followed by 2 weeks of rest (Dqw). Safety evaluations focused on grade 3-4 neutropenia, febrile neutropenia, nausea-vomiting and asthenia. RESULTS: Patients' characteristics were well balanced between arms. The most common National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3-4 toxicity was neutropenia, which occurred in 48.4% of Dq3w patients versus 15.9% of Dqw patients (P=0.001). In addition, febrile neutropenia were observed in 6.5% of patients in Dq3w versus 0% in Dqw. Grade 3-4 asthenia was more frequent in Dqw. Other non-haematological toxicities were very rare. Regarding efficacy, there was a trend towards a better disease control rate in Dq3w: 32.2% versus 25.4% in Dqw. Median time to progression and survival were rather similar in both arms, respectively: 2.1 months (range 2-3.2) and 5.8 months (range 4.0-7.0) in Dq3w and 1.8 months (range 1.6-2.3) and 5.5 months (range 3.7-6.6) in Dqw. CONCLUSIONS: While both schedules had a favourable safety profile, a significant lower rate of severe neutropenia was observed in the weekly arm. Both regimens had similar efficacy. The weekly regimen could be considered as a good alternative for patients at risk of severe neutropenia.     

Docetaxel and cisplatin as induction chemotherapy in patients with pathologically-proven stage IIIA N2 non-small cell lung cancer: a phase II study of the European organization for research and treatment of cancer (EORTC 08984)

The objective of this phase II study was to document activity and toxicity of docetaxel and cisplatin as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) before definitive local treatment. Forty-six chemotherapy-nai ve patients (median age 60 years) were included. Treatment consisted of 3 cycles of docetaxel (85 mg/m2 on day 1), followed by cisplatin (40 mg/m2/day on days 1 and 2) every 21 days. Grade 3-4 leukopenia and neutropenia occurred in 45.7% and 65.2% of the patients, respectively. Among 8 cases of febrile neutropenia (17.4%), one (2.2%) resulted in early death. Common grade 3-4 non-haematological toxicities were nausea (17.4%) and vomiting (13%). Eighty-five percent of the patients received three courses; six stopped prematurely due to toxicity, one due to protocol violation. Response rate was the primary endpoint of this study. Considering eligible patients (n=40), 18 responses (1 complete and 17 partial responses) were observed (response rate 45%; 95% Confidence interval (CI): 29.3%-61.5%). In stage IIIA-N2 NSCLC patients, docetaxel-cisplatin could be administered and demonstrated manageable toxicity with modest efficacy.     

Phase I trial of weekly docetaxel in elderly patients with non-small cell lung cancer

Recent experience with weekly administration of docetaxel has demonstrated less myelotoxicity and suggested that this regimen holds promise for elderly patients at the high risk of myelosuppression. However, in this phase I trial of weekly docetaxel conducted only in elderly patients (70 years old or more) with non-small cell lung cancer (NSCLC), the toxicity profile was markedly different from that in previous reports. The dose-limiting toxicities were neutropenia, diarrhea and infection, all of which were observed at a dose of 30 mg/m(2)/week and the maximum-tolerated dose by protocol definition was 30 mg/m(2)/week. Although other hematological and non-hematological toxicities observed in this treatment were generally moderate and were well tolerated by elderly patients with NSCLC, the risk of myelosuppression still requires careful attention.     

Randomized phase II trial of two different schedules of docetaxel plus cisplatin as first-line therapy in advanced nonsmall cell lung cancer

BACKGROUND: There is increasing interest in the use of a weekly administration of docetaxel as a way of reducing its hematologic toxicity. The purpose of the current randomized study was to evaluate the toxicity and efficacy of docetaxel plus cisplatin combination on 2 schedules in patients with previously untreated, advanced nonsmall-cell lung cancer (NSCLC). METHODS: Consenting patients with advanced NSCLC were randomized to receive first-line chemotherapy with cisplatin 75 mg/m(2) on Day 1, plus 3-weekly (75 mg/m(2) on Day 1) or weekly (35 mg/m(2) on Days 1, 8, and 15 of a 4-week cycle) docetaxel, for up to 6 cycles. RESULTS: Of 86 patients accrued, 41 patients were treated with 3-weekly and 43 with weekly docetaxel plus cisplatin. The most frequent grade 3/4 toxicity in the 3-weekly arm was neutropenia (56% of patients). In those receiving the weekly regimen, the frequent grade 3/4 toxicities were fatigue (44%) and nausea/vomiting (35%). The overall response rate was 40% with the 3-weekly and 39% with the weekly arm (P = .74). The median progression-free survival was 4.3 months in the 3-weekly arm and 3.9 months in the weekly arm (P = .08) and the median survival was 10.3 and 10.0 months, respectively (P = .76). Quality of life data showed no relevant difference between the arms. CONCLUSIONS: The weekly schedule of docetaxel plus cisplatin combination as first-line chemotherapy for advanced NSCLC, while feasible, has no clear advantage over the standard 3-weekly regimen.     

Phase I trial of weekly docetaxel combined with cisplatin in patients with non-small cell lung cancer

The phase I study was conducted to evaluate the maximum tolerated dose (MTD) and toxicity of weekly administered docetaxel combined with cisplatin in patients with non-small-cell lung cancer (NSCLC). In a dose escalation study, 22 patients, under 75 years old, with unresectable and metastatic untreated NSCLC with performance status (0-1) were enrolled. Patients were treated with cisplatin (day 1) and weekly docetaxel (days 1, 8, 15). Dose escalation levels in mg/m(2) were for cisplatin and docetaxel; 70 and 15 (level 1), 80 and 15 (level 2), 80 and 20 (level 3), 80 and 25 (level 4), 80 and 30 (level 5), respectively. Chemotherapy was repeated for at least two cycles every 28 days. All patients were assessable for toxicities. Although grade 3 neutropenia occurred in one case in level 4, there were no significant modifications of chemotherapy schedule until level 4. Grade 3 neutropenia occurred in all cases receiving level 5. One patient developed an infection, and two had incomplete recovery of neutropenia by the 28th day after the first cycle of chemotherapy. Nonhematological toxicities, including nephrotoxicity, nausea/vomiting, alopecia and hypersensitivity reaction, were tolerable. However, one case developed severe hyponatremia. Among 21 patients evaluable for response, eight cases achieved partial response, thus the overall response was 39%. Weekly administration of docetaxel at 25 mg/m(2) (days 1, 8, 15) combined with cisplatin 80 mg/m(2) (day 1) is recommended for phase II studies. The responses observed in the present study suggest an identical high degree of activity against NSCLC with less hematotoxicity compared with a standard schedule of cisplatin and docetaxel.     

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.     

Docetaxel-based induction therapy prior to radiotherapy with or without docetaxel for non-small-cell lung cancer

This trial aimed to assess the feasibility and tumour control of concurrent chemoradiotherapy or radiotherapy alone after docetaxel-based induction chemotherapy in locally advanced non-small-cell lung cancer (NSCLC). Patients with stage IIIA/IIIB NSCLC received two 21-day cycles of induction chemotherapy with docetaxel (85 mg m(-2), day 1) plus cisplatin (40 mg m(-2), days 1 and 2). Patients without disease progression on day 43 were randomised to radiotherapy (2 Gy for 5 days week(-1); total 60 Gy) alone or with docetaxel 20 mg m(-2) once weekly every 6 weeks. Of 108 patients who received induction chemotherapy, 104 were evaluable for response. After induction chemotherapy, the overall response rate (ORR) was 44%; 91 (88%) patients had no disease progression and 89 were subsequently randomised to local treatment. After randomised therapy, the ORR was 53% (chemoradiotherapy 58%; radiotherapy 48%). Median survival and time to progression were 14.9 and 7.8 months, respectively, for chemoradiotherapy and 14.0 and 7.5 months, respectively, for radiotherapy. The most common toxicities during induction chemotherapy and randomised therapy were grades 3-4 neutropenia and grade 3 lymphocytopenia, respectively. Docetaxel-cisplatin induction therapy followed by concurrent docetaxel and thoracic radiotherapy is a feasible treatment option, showing good clinical activity and tolerability, for locally advanced NSCLC.     

A parallel dose-escalation study of weekly and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors.

PURPOSE: To establish maximum tolerated dose (MTD) and tolerability of two schedules of bortezomib in combination with cisplatin and gemcitabine as first-line treatment of patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients were assigned to increasing doses of bortezomib days 1 and 8 (weekly schedule) or days 1, 4, 8, and 11 (twice-weekly schedule), in addition to gemcitabine 1,000 mg/m(2) days 1 and 8 and cisplatin 70 mg/m(2) day 1, every 21 days. Maximum of six cycles. Plasma pharmacokinetics of cisplatin and gemcitabine were determined at MTD. RESULTS: Thirty-four patients were enrolled of whom 27 had non-small cell lung cancer (NSCLC). Diarrhea, neutropenia, and thrombocytopenia were dose-limiting toxicities leading to an MTD of bortezomib 1.0 mg/m(2) in the weekly schedule. Febrile neutropenia and thrombocytopenia with bleeding were dose-limiting toxicities in the twice-weekly schedule, leading to an MTD of bortezomib 1.0 mg/m(2) as well. Most common > or =grade 3 treatment-related toxicities were thrombocytopenia and neutropenia. No grade > or =3 treatment-related sensory neuropathy was reported. Of 34 evaluable patients, 13 achieved partial responses, 17 stable disease, and 4 progressive disease. Response and survival of NSCLC patients treated with twice weekly or weekly bortezomib were similar. However, increased dose intensity of bortezomib led to increased gastrointestinal toxicity as well as myelosuppression. Pharmacokinetic profiles of cisplatin and gemcitabine were not significantly different in patients receiving either schedule. CONCLUSIONS: Weekly bortezomib 1.0 mg/m(2) plus gemcitabine 1,000 mg/m(2) and cisplatin 70 mg/m(2) is the recommended phase 2 schedule, constituting a safe combination, with activity in NSCLC.     

A phase I trial of weekly docetaxel and cisplatinum combined to concurrent hyperfractionated radiotherapy for non-small cell lung cancer and squamous cell carcinoma of head and neck

We conducted a phase I study to evaluate the activity and tolerability of concurrent docetaxel and cisplatinum radiosensitization with hyperfractionated irradiation, in patients with advanced non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN). Nine patients (5 stage III(A) and 4 III(B)) with NSCLC, and 15 with SCCHN (10 stage III and 5 IV) were treated with a b.i.d. hyperfractionated (HF) radiotherapy schedule. The normalized total dose for alpha/beta ratio = 10 Gy was 69.6 Gy for NSCLC and 80.5 Gy for SCCHN patients. The standard dose of cisplatin (10 mg/m(2)) was given combined to docetaxel on a weekly basis. The docetaxel starting dose level was 10 mg/m(2)/week and was escalated by 3 mg/m(2) increments in cohorts of 8 patients (5 SCCHN and 3 NSCLC). DLT (grade 3 malaise) was observed in 4 out of 8 patients treated at the 16 mg/m(2)/week docetaxel dose level. The 13 mg/m(2)/week docetaxel dose level was defined as the MTD causing grade 3 mucositis in 4 out of 8 patients. In total 4 (17%) patients developed grade 3 neutropenia. G-CSF support was given in 1/8, 4/8, and 5/8 patients treated at the 10, 13 and 16 mg/m(2) docetaxel dose levels respectively. Fatigue was the most common adverse event (5/24: 21%) and was responsible for more than 1 week treatment delay in 4 out of 8 patients treated at the 16 mg/m(2)/week docetaxel dose level. Nine (3 NSCLC and 6 SCCHN patients: 37.5%) had treatment delay of 1 week, while 7 (3 NSCLC and 4 SCCHN: 29%) had delays of 2 weeks for combined chemoradiation sequelae. Acute hypersensitivity reactions occurred in 3 (12.5%) patients, and grade 3 mucositis in 2/8, 5/8 and 6/8 patients, treated at 10, 13 and 16 mg/m(2)/week docetaxel dose levels respectively. The overall response rate was 79% (CI = 63-96%) with 33% and 53% CRs for NSCLC and SCCHN patients respectively. There were 3 deaths among 9 NSCLC and 4 among 15 SCCHN patients. Local and/or distant disease recurrences were shown in 4 NSCLC and in 6 SCCHN patients; 5 NSCLC and 9 SCCHN patients are alive with no evidence of tumor progression at 8.5 months mean follow-up time. Radiosensitization with docetaxel and cisplatin given concurrently with HF (b.i.d.) radiotherapy on a weekly basis is a promising approach and the recommended dose for further phase II studies is 10 mg/m(2)/week for both drugs. The antitumor activity shown was significant in both types of tumors. The incorporation of docetaxel in chemoradiotherapy regimens for future treatment of squamous cell carcinoma of the lung and head and neck, merits evaluation in phase II and III trials.     

Prospective randomised phase II study of docetaxel versus paclitaxel administered weekly in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.

BACKGROUND: Docetaxel and paclitaxel have activity in the second-line treatment of non-small-cell lung cancer (NSCLC), and can be administered as weekly schedules. This phase II randomised study was designed to test the efficacy and toxicity of both taxanes in patients with NSCLC previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Patients (n = 71) with documented NSCLC were randomised to receive docetaxel (n = 35 patients; 36 mg/m(2)) or paclitaxel (n = 36 patients; 80 mg/m(2)) as a 1 h weekly infusion for 6 weeks followed by a 2-week rest. The cycles were repeated until disease progression or non-acceptable toxicities occurred. RESULTS: Treatment achieved partial response of one versus five patients, median time-to-progression of 74 versus 68 days, and overall survival of 184 versus 105 days, with docetaxel and paclitaxel, respectively. The most common non-haematological toxicities were (docetaxel versus paclitaxel): grade 3/4 pulmonary toxicity in seven versus one patient; grade 2/3 diarrhoea in nine versus five; and grade 3/4 haematological toxicities occurred in two versus four patients. There were no treatment-related deaths. CONCLUSIONS: Docetaxel and paclitaxel administered weekly have discrete efficacy in patients with NSCLC previously treated with platinum-based chemotherapy. The higher non-haematological toxicity of docetaxel, particularly pulmonary toxicity and diarrhoea, is of concern and warrants further investigation.     

Phase I study of weekly docetaxel and liposomal doxorubicin in patients with advanced solid tumors

PURPOSE: To determine the maximum-tolerated doses (MTDs) and the dose-limiting toxicities (DLTs) of the weekly administration of docetaxel and pegylated liposomal doxorubicin (PEG-LD) in patients with advanced solid tumors. PATIENTS AND METHODS: Forty-eight patients with solid tumors were enrolled in the study. Dose escalations of both drugs were given on a weekly basis for 3 consecutive weeks in cycles of 4 weeks. The starting dose for docetaxel was 20 mg/m(2)/week and for PEG-LD 6 mg/m(2)/week. RESULTS: The MTD was 35 mg/m(2)/week for docetaxel and 14 mg/m(2)/week for PEG-LD. The DLTs at this level were grade 3 diarrhea (n=1 patient) and grade 3 mucositis (n=2 patients). There was no grade 4 hematologic or non-hematologic toxicity. Grade 3 neutropenia and thrombocytopenia occurred only in 1 and 2 patients, respectively. The non-hematologic toxicity was also mild with grade 2/3 fatigue in 8 patients, grade 2/3 neurotoxicity in 4, grade 2/3 mucositis in 8, grade 2/3 diarrhea in 4 and grade 2/3 nausea and vomiting in 5 patients. Two (5.7%) complete and 6 (17%) partial responses (overall response rate=22.7%; 95% confidence interval 9.6--32.4%) were observed among 35 evaluable patients. In 12 (63%) of 19 patients with hormone-refractory prostate cancer, a decline in serum levels of prostate-specific antigen of >50% was observed. CONCLUSIONS: The weekly administration of docetaxel with PEG-LD is a well-tolerated regimen that merits further evaluation.     

A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study

Docetaxel (75 mg m(-2) 3-weekly) is standard second-line treatment in advanced non-small-cell lung cancer (NSCLC) with significant toxicity. To verify whether a weekly schedule (33.3 mg m(-2) for 6 weeks) improved quality of life (QoL), a phase III study was performed with 220 advanced NSCLC patients, < or =75 years, ECOG PS < or =2. QoL was assessed by EORTC questionnaires and the Daily Diary Card (DDC). No difference was found in global QoL scores at 3 weeks. Pain, cough and hair loss significantly favoured the weekly schedule, while diarrhoea was worse. DDC analysis showed that loss of appetite and overall condition were significantly worse in the 3-week arm in the first week, while nausea and loss of appetite were more severe in the weekly arm in the third week. Response rate and survival were similar, hazard ratio of death in the weekly arm being 1.04 (95% CI 0.77-1.39). A 3-weekly docetaxel was more toxic for leukopenia, neutropenia, febrile neutropenia and hair loss; any grade 3-4 haematologic toxicity was significantly more frequent in the standard arm (25 vs 6%). The weekly schedule could be preferred for patients candidate to receive docetaxel as second-line treatment for advanced NSCLC, because of some QoL advantages, lower toxicity and no evidence of strikingly different effect on survival.     

Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer.

BACKGROUND: Pharmacokinetic study has shown that co-administration of cyclosporin A (CsA), which acts as a P-glycoprotein (P-gp) and CYP-3A blocker, resulted in an 8-fold increase in the systemic exposure of oral paclitaxel. Two doses of oral paclitaxel on 1 day in combination with CsA resulted in higher systemic exposure than single dose administration. PATIENTS AND METHODS: In this phase II study, chemona?ve patients with advanced gastric cancer received oral paclitaxel weekly in two doses of 90 mg/m(2) on the same day; CsA (10 mg/kg) was given 30 min before each dose of oral paclitaxel. RESULTS: In 25 patients, the main toxicities were: nausea CTC grade 2/3, 10 patients (40%); vomiting grade 2/3, 4 patients (20%); diarrhea grade 2/3, 6 patients (24%); neutropenia grade 3/4, 5 patients (20%). In the 24 evaluable patients, eight partial responses were observed, resulting in an overall response rate (ORR) of 33% [95% confidence interval (CI) 18% to 52%]. Eleven patients had stable disease (46%) and 5 patients showed progressive disease (21%). The ORR in the total population was 32% (95% CI 17% to 50%). The median time to progression was 16 weeks (95% CI 9-22). Pharmacokinetic analyses revealed that the mean area under the plasma concentration-time curve (AUC) of orally administered paclitaxel (+/- standard deviation) was 3757.6 +/- 939.4 ng.h/ml in week 1 and 3928.4 +/- 1281 ng.h/ml in week 2. The intrapatient variability in the AUC was 12%. CONCLUSIONS: Oral paclitaxel in combination with CsA is both active and safe in chemona?ve patients with advanced gastric cancer. Toxicities were mainly gastrointestinal.     

国产多西紫杉醇治疗非小细胞肺癌的Ⅱ期临床研究

目的 :评价国产多西紫杉醇 (艾素 ,江苏恒瑞医药股份有限公司产品 )单用以及艾素 +顺铂联合化疗方案对非小细胞肺的临床疗效和安全性 ,并以进口多西紫杉醇 (泰索帝 ,安万特公司产品 ) +顺铂联合化疗方案作对照。方法 :患者随机分入艾素单用组 (A组 ) :艾素 75mg/m2 ;艾素 +顺铂组 (B组 ) :艾素 75mg/m2 +顺铂 75mg/m2 ;泰索帝 +顺铂组 (C组 ) :泰索帝 75mg/m2 +顺铂 75mg/m2 ;3组均为每 3周重复。结果 :入组的 115例中 10 4例可评价疗效 ,A、B和C组有效率分别为 8 10 %、2 3 5 3%、2 7 2 7%。B和C组有效率相似。不良反应主要有中性粒细胞减少、贫血、粒细胞减少性发热、其他发热、脱发、恶心呕吐和乏力。C组中性粒细胞减少的发生率高于B组 ,两组间差异有显著性 (P <0 0 5 )。其余不良反应两组相似。结论 :国产多西紫杉醇 (艾素 ) +顺铂与进口多西紫杉醇 (泰索帝 ) +顺铂两联合化疗方案相似 ,对非小细胞肺癌有一定疗效 ,且毒性可耐受。     

A phase I study of weekly docetaxel and cisplatin in advanced non-small cell lung cancer.

This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity of a weekly docetaxel (TXT) and cisplatin (CDDP) combination regimen in advanced non-small cell lung cancer (NSCLC). Patients with stage IIIB or IV NSCLC who were previously untreated were eligible. Docetaxel, at a starting dose of 20 mg m(-2) per week on days 1, 8 and 15, was combined with a fixed dose of cisplatin 80 mg m(-2) on day 1. Docetaxel was increased in 5 mg m(-2) per week steps. Chemotherapy was given in a 4-weeks cycle. Dose-limiting toxicities (DLTs) were defined as grade 3-4 leukopenia, thrombocytopenia, anemia, fever with grade 4 neutropenia and more than grade 2 non-hematologic toxicity, with the exception of nausea, vomiting, and alopecia. Omission of chemotherapy on day 8 and/or 15 was also considered DLT. Eighteen patients were enrolled in this study. Leukopenia, anemia and fatigue were the DLTs. No grade 4 toxicities were seen in any patients. The overall response rate was 44.4% (95% confidence interval, 21.5-67.4%). The recommended dose of TXT to be combined with CDDP 80 mg m(-2) on day 1 is 35 mg m(-2) per week on days 1, 8 and 15. This is a promising regimen, therefore a multicenter phase II study is now under way.     

Weekly docetaxel with concurrent radiotherapy in locally advanced non-small cell lung cancer: a phase I/II study with 5 years' follow-up

This Phase I/II study investigated weekly docetaxel (Taxotere) with concurrent radiotherapy in 42 patients with untreated stage III non-small cell lung cancer (NSCLC). All patients were treated with chest irradiation: 2Gy administered 5 days/week for 5 weeks, to a total of 50Gy. Docetaxel (1-h infusion) was administered on days 1, 8, 22, and 29< or =2 h before radiation fractions 1, 6, 16, and 21 (i.e. every week excluding the third week of treatment). In the Phase I study (n=12), docetaxel was started at 20 mg/m2 per week (n=3) and escalated in 10 mg/m2 increments (30 mg/m2, n=3; 40 mg/m2, n=6). Dose-limiting toxicity (grade 3-4 esophagitis) occurred with docetaxel 40 mg/m2. The Phase II study (n=30), therefore, evaluated docetaxel 30 mg/m2 (considered recommended dose). All patients except one experienced asymptomatic grade 3-4 lymphopenia; four patients (9.5%) had grade 3-4 esophagitis. The overall response rate was 45.5%, with eight (24.2%) complete responses. The median time to progression at the recommended dose of 30 mg/m2 (n=33) was 12.0 months and the median survival time was 13.6 months. The 1-year survival rate was 60.6%. Five patients (one from Phase I and four from Phase II) were alive after >5 years. In conclusion, weekly docetaxel 30 mg/m2 plus radiotherapy is active and well tolerated in stage III NSCLC.     

Phase II study with fractionated schedule of docetaxel and cisplatin in patients with advanced non-small cell lung cancer

Background

Docetaxel and cisplatin combination chemotherapy is established first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). We evaluated a weekly schedule of docetaxel and cisplatin for efficacy and tolerability in patients with chemotherapy-naive NSCLC.

Methods

Patients enrolled in this study had stage IIIB or IV NSCLC with measurable disease, no prior chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2. Treatment consisted of docetaxel 40 mg/m² and cisplatin 35 mg/m² given on D1 and D8 every 3 weeks. Patients were evaluated for response after every 2 cycles of treatment.

Results

Thirty six patients were enrolled, and 35 underwent treatment. Of these, 29 were males and 7 females, median age was 61 years (range, 38–68). About 31 patients had ECOG PS 0-1 and 4 patients had ECOG PS 2. Fifty seven percentage (20/35) of patients had adenocarcinoma and 74.3% (26/35) had stage IV disease. A total of 153 cycles of chemotherapy were administered. Of the 35 patients treated, 17 (48.6%) achieved partial response, 11 (31.4%) showed stable disease, and 6 (17.1%) had progressive disease. Median duration of response was 5.3 months (95% CI: 4.2–6.2 months), and median time to disease progression was 4.6 months (95% CI: 2.9–6.3 months). Estimated overall survival at 1 year was 65.7%. The major hematologic toxicity was myelosuppression. Grade 3 or 4 anemia occurred in 6 cycles, and grade 3 or 4 neutropenia was observed in four cycles. Major non-hematologic toxicities were grade 3 nausea in three patients and grade 3 fatigue in two patients. Three patients developed pneumonia and one patient had infectious colitis. There were no treatment-related deaths in this study.

Conclusions

Weekly schedule of docetaxel and cisplatin as first-line treatment for NSCLC had good efficacy and manageable toxicity.