Phase I-II study of gemcitabine and paclitaxel in pretreated patients with stage IIIB-IV non-small cell lung cancer

Gemcitabine and paclitaxel are among the most active new agents in non-small cell lung cancer (NSCLC) and are worth considering for second-line chemotherapy. In this phase I–II study, we combined gemcitabine and paclitaxel for second-line treatment of advanced NSCLC. Gemcitabine doses were kept fixed at 1000 mg/m² on day 1 and 8, and paclitaxel doses were escalated from 90 mg/m² on day 1 of the 21-day cycle. Thirty-seven patients were treated at six different dose levels. Grade 4 neutropenia was dose-limiting toxicity (DLT), since it occurred in two out of six patients treated at paclitaxel 240 mg/m²; the paclitaxel dose level just below (210 mg/m²) was selected for phase II evaluation. Non-hematologic toxicity was mild. One complete response (CR) (3%) and 13 partial responses (PR) (36%) were observed in 36 evaluable patients for an overall response rate of 39% (95% C.I., 23–57%). Median duration of response was 35 weeks (range, 8–102). All of the observed objective responses occurred in the 19 patients who had previously responded to the first-line therapy. Median survival was 40 weeks (range, 8–108 weeks). The combination of gemcitabine and paclitaxel is a feasible, well-tolerated, and active scheme for second-line treatment of advanced NSCLC; further evaluation, at least in selected patients, such as those previously responding to first-line chemotherapy, is definitely warranted.     

Paclitaxel and Mitoxantrone in the Treatment of Metastatic Breast Cancer: A Phase II Trial of the Minnie Pearl Cancer Research Network

Background and rationale: The combination of paclitaxel and doxorubicin is highly active in the treatment of metastatic breast cancer, but is associated with substantial toxicity. In this phase II trial, we evaluated the combination of paclitaxel and mitoxantrone in an attempt to maintain efficacy and improve tolerability of this regimen.

Patients and methods: Sixty-three patients with metastatic breast cancer were treated with paclitaxel 200 mg/m², 1 hr IV infusion, and mitoxantrone 10 mg/m² IV, every 21 days. Responding patients received at least six courses of therapy. Ninety-three percent of patients in this trial were receiving first-line treatment for metastatic breast cancer; 62% of patients had received previous adjuvant chemotherapy, and 26% had received previous doxorubicin.

Results: Objective responses were seen in 24 of 61 evaluable patients (39%). Median response duration was 9 months (range 4-37+ months); actuarial 1-, 2-, and 3-year survivals were 62, 32, and 25%, respectively. The treatment was generally well tolerated; 78% of patients had grade 3 or 4 leukopenia at sometime during their treatment course, but only 14 hospitalizations for neutropenia and fever were necessary (4% of courses). Grade 3 fatigue was experienced by 30% of patients. Cardiotoxicity was not observed.

Conclusions: The combination of paclitaxel and mitoxantrone is active, easily administered, and well tolerated in the treatment of metastatic breast cancer. Its activity appears similar to several other taxane-based combination regimens recently evaluated for the treatment of advanced breast cancer.     

Phase II trial of 96-hour paclitaxel in previously treated patients with advanced esophageal cancer

Background. A 96-hour infusion schedule of paclitaxel demonstrates tolerability and antitumor activity in lung cancer and breast cancer refractory to short-duration infusion paclitaxel. Given the activity of paclitaxel in esophageal cancer, a phase II trial of 96-hour infusion paclitaxel in esophageal cancer was undertaken. Methods. Both adenocarcinoma and squamous cell histology were included. Paclitaxel was administered at 140 mg/m² over 96 hours every 21 days. Patients who had metastatic disease to the liver and transaminases greater than two times normal value received 120 mg/m². Response to treatment was evaluated after the first two cycles and subsequently every third cycle.  Results. Ten men and four women were entered. All were eligible for response and had stage IV disease. Thirteen patients were previously treated. All 13 received prior short-duration paclitaxel-containing chemotherapy regimens. Eleven patients had adenocarcinoma and three squamous cell cancer. Patients completed a mean of two cycles (range one to eight) prior to disease progression. No major responses were observed. Toxicity was minimal and included grade 3/4 neutropenia in 14% of patients. One patient with adenocarcinoma demonstrated stable disease for 28 weeks.  Conclusion. No major activity was observed in a population of previously treated patients. Ninety-six-hour paclitaxel in metastatic esophageal cancer is generally well tolerated with minimal toxicity; however, it is ineffective in previously treated patients. Further evaluation of this schedule of paclitaxel in combination with concurrent radiotherapy, where its radiosensitizing potential may be useful, is ongoing in locally advanced esophageal cancer.     

Phase II study of gemcitabine plus paclitaxel in metastatic breast cancer patients with prior anthracycline exposure

Chemotherapy provides palliation and modest prolongation of symptom-free survival in metastatic breast cancer. Taxane containing regimens are commonly considered to be among the initials in metastatic setting due to earlier use of anthracyclines in the course of breast cancer. Therefore, we conducted this Phase II study to assess efficacy and safety of gemcitabine plus paclitaxel (GT) combination therapy in anthracycline pretreated metastatic first-line setting. Patients and Methods: The study enrolled 26 women with pathologically confirmed and measurable metastatic breast cancer who were previously treated with anthracycline but no prior chemotherapy for metastatic disease. Twenty six and twenty four patients were eligible for toxicity and efficacy evaluations respectively. Mean age was 47.3 years and median ECOG performance status was 0. Twenty patients (76.9 percent) had visceral metastases, most commonly located in liver and lung. Treatment schedule was as follows: paclitaxel 175 mg/m² was administered intravenously in 3 hours on Day 1 and gemcitabine 1000 mg/m² was administered intravenously in 30 minutes on Day 1 after paclitaxel application, and on Day 8 every 21 days. Results: Objective response rate was 41.7 percent (95 percent CI: 21.9-61.4) with 16.7 percent (95 percent CI: 1.7-31.6 percent) CR, and 25.0 percent (95 percent CI: 7.6-42.3 percent) PR. Median time to progression and overall survival were 9.6 and 14.5 months, respectively. Grade 3-4 toxicity was observed in 34.6 percent (9) patients. Treatment of two patients was discontinued due to toxicity, consisting of Grade 3 hypersensitivity reactions and Grade 4 infections in one patient each. Dose reductions due to myelotoxicity were performed in 4 (15.3 percent) patients. Hematologic toxicities were generally manageable with appropriate dose modifications and supportive care. Conclusion: Gemcitabine and paclitaxel combination regimen is effective and has manageable toxicity profile as first line metastatic setting.     

Protracted Continuous Infusion of 5-Fluorouracil in Combination with Doxorubicin, Vincristine, and Oral Cyclophospharnide in Advanced Breast Cancer

Several studies suggest that protracted continuous Infusion constitutes an important way to optimize the dose and the efficacy of 5-fluorouracil (5-FU) in metastatic cancer. Eighty-three women aged 27-76 (median age 55) with metastatic breast cancer were treated every 4 weeks with a continuous ambulatory venous infusion of 5-FU 350 mg/m²/day and oral cyclophosphamide 100 mg/m²/day over 15 days. The continuous therapy was associated with a weekly administration of vincristine (0.8 mg/m²) and doxorubicin (15 mg/m²) on day 1, day 8, and day 15. Cycles were repeated every 28 days. Thirty-four patients were treated in first-line metastatic chemotherapy and 49 in second-line. Toxicities included: mucositis (grade ≤ 2) 23%, diarrhea (grade ≤ 2) 7%, a hand-foot syndrome (grade ≤ 2) 9%, alopecia (grade 3) 21%, neurological (grade ≤ 2) 4%, grade 3 and 4 leukopenia 29%, and grade 3 and 4 thrombopenia 8%. Heart toxicity was only 3%. Catheter infection was observed in 1 case and 7 patients experienced thrombosis. The overall objective response rate (OR) was 48% and the complete response rate was 23%. The median duration of response was 10 months. The median survival was 16 months. Activity was better in naive than pretreated women (respectively, 55% and 42% of OR, p = 0.21). Analysis of responses according to the metastatic sites shows the pronounced efficacy on soft tissus diseases (skin recurrences 42%, lymph nodes 52%), and also in visceral metastases (hepatic 36%, lung 34%).     

A Phase I—II Study of Cyclophosphamide, Epidoxorubicin, Levofolinic Acid/5-Fluorouracil and Recombinant Human Granulocyte Colony Stimulating Factor in Metastatic Breast Carcinoma

Thirty patients with measurable metastatic breast carcinoma were treated with a combination of cyclophosphamide 600 mg/m² on day 1, levofolinic acid 100 mg/m² plus 5-fluorouracil 375 mg/m² on days 1-3, and epidoxorubicin (EDXR) in three refracted doses on days 1-3 with G-CSF rescue for 10 days. In the phase I part of the study, groups of 3 patients received EDXR 20, 25, 30, 35, and 40 mg/m²/day until the dose limiting toxicity (DLT) was reached. At the dose of 40mg/m²/day prolonged grade 4 leukopenia, severe proctitis, and grade 3 diarrhea represented the DLT. All subsequent partients were treated at the maximal tolerated dose of EDXR (35 mg/m²/day). In the group of 18 patients treated at 35 mg/m²/day the overall response rate was 78%, with 22% CR and 56% PR. Four patients did not respond. Objective responses were seen at all tumor sites including bone and viscera, which usually are rather chemotherapy insensitive. Toxicity was generally acceptable. Although the response rate was quite high, the duration of objective tumor regression and patients' survival were not impressive. In conclusion, we do not recommend routine use of such an aggressive regimen for palliation of advanced breast cancer. Results of the present and similar studies may, however, be useful for planning of neoadjuvant or adjuvant trials with curative intent.     

A phase II study with CPT-11 plus leucovorin and bolus IV 5-fluorouracil in patients with advanced colorectal carcinoma

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m² (7 patients) or 70 mg/m² (48 patients). After completion of CPT-11 infusion, LV 200 mg/m² was administered over 2 hr followed immediately by 5-FU 450 mg/m², IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m² weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m². Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m². Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.     

Weekly paclitaxel infusion as salvage therapy in ovarian cancer

The majority of women diagnosed with epithelial ovarian cancer will have persistent or recurrent disease after initial treatment. We evaluated response and toxicity in women with advanced stage disease given salvage paclitaxel as a low-dose, weekly infusion. We performed a retrospective review of 22 women with advanced stage epithelial ovarian (19 women) or primary peritoneal carcinoma (3 women) who had received low-dose, weekly paclitaxel salvage therapy. All women had refractory, persistent, or recurrent disease following first-line treatment with paclitaxel and platin chemotherapy. Response and toxicity were assessed. Measurable disease present on physical or radiologic exam and serum carbohydrate antigen-125 levels were used to assess disease response. Overall response rate to low-dose, weekly paclitaxel salvage therapy was 50% (27% complete, 23% partial). Median progression-free interval (PFI) in responders was 27 weeks (range, 14-68 weeks). Stabilization of disease occurred in an additional 27% of patients with a median PFI of 22 weeks (range, 15-89 weeks). No difference in response was detected between the 7 women with platin-sensitive disease and the 15 women with platin-resistant disease (P=0.19). The median dose of paclitaxel was 80 mg/m² (range, 60-80 mg/m²). During a total of 325 weeks of paclitaxel treatment (median per patient, 12 weeks; range, 6-49 weeks), 13 treatment delays occurred (hematologic indication, 9; nonhematologic indication, 4). No cases of grade 4 hematologic toxicity, sepsis, or worsening neuropathy were documented. Weekly paclitaxel infusion given as salvage therapy results in significant clinical response, even in women previously treated with paclitaxel. The regimen is well tolerated with no cases of grade 4 neutropenia or worsening neuropathy in our population.     

Paclitaxel and gemcitabine, as first-line chemotherapy, combined with trastuzumab in patients with advanced breast cancer: a phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG)

Purpose: Advanced breast cancer (ABC) is an incurable disease. Standard first-line treatment for patients with HER-2/neu overexpressing tumors includes the combination of the humanized monoclonal antibody trastuzumab with chemotherapy, mainly paclitaxel. This combination is the first to demonstrate a survival advantage in this group of patients. To improve on these results, we investigated a triplet, paclitaxel-gemcitabine-trastuzumab (TGH), in a phase II study. Patients and Methods: Patients with ABC were accrued to the study. Treatment consisted of paclitaxel 80 mg/m²/week, gemcitabine 1000 mg/m² every 2 weeks, and trastuzumab 4 mg/kg loading dose and then 2 mg/kg/week. Patients were treated on study for a total of 12 weeks. Response evaluation was performed at the end of the 12 weeks. Continuation of treatment beyond the 12 weeks was left to the discretion of the investigator. Primary study endpoint was response. Toxicity assessment and survival were secondary endpoints. Results: Between November 2000 and May 2002, 40 patients were accrued and 32 patients completed all 12 weeks of therapy. One patient died of septic shock during therapy. Grade III and IV neutropenia was seen in 12.5% of cases each. Grade III anemia was seen in two patients, and grade III and IV thrombocytopenia in three and two patients, respectively. Both paclitaxel and gemcitabine were delivered at 86% of the planned dose intensity. Six patients achieved a complete response (CR) and 15 a partial response for an overall response rate of 52.5%. An additional 25% demonstrated stable disease and 20% progressive disease. Median duration of response was 14 months. All six patients who achieved CR are still in CR for 6 to 19 months. After a median follow up of 12.2 months, 19 patients have progressed and 7 have died. Median time to progression is 13.7 months, whereas median survival has not been reached. Conclusion: TGH is a well-tolerated and effective regimen for the first-line treatment of ABC. Randomized comparison between paclitaxel, trastuzumab, and triplets are warranted.     

Mitoxantrone and paclitaxel combination chemotherapy in metastatic breast cancer

This study evaluated mitoxantrone and paclitaxel combination chemotherapy in the treatment of patients with metastatic breast cancer. Thirty-seven patients who had developed progressive disease after prior chemotherapy were treated with mitoxantrone (14 mg/m²) and paclitaxel (150 mg/m²) every 21 days for a maximum of six cycles. The most frequent grade 3 or 4 nonhematological toxicities were fever and nausea. Grade 4 neutropenia occurred in 71% of patients. Cardiotoxicity occurred in 2 patients, both of whom had previously received doxorubicin. Objective response was achieved in 35% of patients (5% complete response and 30% partial response) and 41% had stable disease. Median time to disease progression and median survival were 6 and 12 months, respectively. The percent of patients with an objective response was not different for those who had received prior doxorubicin or had chemotherapy in the preceding 6 months. This regimen appears to be effective and well tolerated as salvage therapy and merits further evaluation.     

Phase II study of paclitaxel combined with vinorelbine in patients with advanced breast cancer

Paclitaxel and vinorelbine are two drugs active against breast cancer. A phase II study was initiated with the aim of assessing the efficacy and feasibility of the combination. Twenty-six patients presenting with advanced breast cancer with a taxane- and vinorelbine-free line of chemotherapy were included and treated with vinorelbine (20 mg/m2 on D1, D15), followed by paclitaxel (175 mg/m2 on D1), every 3 weeks. A 48% (95% CI: 35-61) response rate was obtained in the 23 patients evaluable for response. Vinorelbine was administered on D15, as scheduled, in 72% of cycles. The main toxicity observed was grade III to IV neutropenia in 73% of patients. Febrile neutropenia was reported in three patients. Disease-free survival was 118 days, and overall median survival was 361 days. This combination of paclitaxel and vinorelbine is feasible and effective in patients with early relapse or previously treated with first-line chemotherapy for metastatic disease.     

A phase II study of weekly alternating chemotherapy in extensive-stage small cell lung cancer

Despite the recent development of new chemotherapeutic agents with activity in small cell lung cancer (SCLC), the long-term prognosis of patients with extensive-stage disease remains poor and has not improved in the past 20 years. The present study was designed to evaluate the activity and toxicity of weekly, alternating-regimen chemotherapy in patients with extensive-stage SCLC. Patients with previously untreated extensive-stage SCLC and performance status 0-2 were treated with cyclophosphamide 250 mg/m², etoposide 100 mg/m², and cisplatin 50 mg/m² on day 1; vincristine 1 mg/m² on day 8; and ifosfamide 1.2 gm/m² on days 8 and 9 with the entire treatment repeated every 14 days. Eighteen patients received chemotherapy for a median of 14 weeks (range, 1-35 weeks). Seventeen patients (94%) required dose delays and 16 patients (89%) required at least one dose reduction due to toxicity. Twelve patients (67%) exhibited an objective response (1 complete response, 11 partial response) with a median duration of response of 18 weeks (range, 8-32 weeks). Median survival was 33 weeks (range, 1-57 weeks) with a 1-year survival rate of 22%. Toxicity was primarily hematologic, including grade 3-4 leukopenia (82% of patients) and anemia (53% of patients). Only 2 patients developed grade 3 peripheral neuropathy and none exhibited grade 3-4 renal insufficiency. This regimen of weekly alternating combination chemotherapy resulted in tolerable toxicity as well as response and survival rates comparable to those achieved with standard chemotherapy in patients with extensive-stage SCLC. However, weekly chemotherapy regimens for the treatment of SCLC remain investigational.     

Phase I trial of gemcitabine and paclitaxel in advanced solid tumors

Purpose. Gemcitabine and paclitaxel are chemotherapeutic agents with clinical antitumor activity in a broad range of malignant solid tumors. Because of preclinical synergy, unique mechanisms of action and resistance, and nonoverlapping toxicities, gemcitabine and paclitaxel combinations are attractive for testing in clinical trials. Prior weekly gemcitabine and paclitaxel regimens administered on a 28-day cycle have been limited by cumulative hematological toxicity on day 15, thus reducing the planned gemcitabine dose intensity. We therefore conducted a phase I trial of a 21-day schedule of weekly gemcitabine and paclitaxel to determine the tolerability, maximum tolerated dose (MTD), and preliminary estimates of efficacy of this regimen. Patients and Methods. Forty-one patients with advanced malignant solid tumors were accrued. Gemcitabine was given at a fixed dose of 1000 mg/m² while paclitaxel was administered at an initial dose of 60 mg/m², then escalated by 15 mg/m² increments over seven dose levels to a prospectively planned maximum dose of 150 mg/m². Both agents were infused intravenously on days one and eight every 21 days. At least three patients were enrolled per dose level. No intrapatient dose escalation was allowed. Results. All patients were assessable for toxicity and 31 were assessable for response. The regimen was generally well-tolerated. Dose-limiting thrombocytopenia was observed in one patient at a paclitaxel dose of 135 mg/m²/week (dose level 6). After expansion of this dose level by 14 additional patients, no further dose-limiting toxicities were observed although one patient at dose level seven died of neutropenic sepsis after completing three cycles. There were eight partial responders for an overall response proportion of 26% (95% CI: 11, 41). Twelve patients (39%) had stable disease. Conclusion. This 21-day schedule of gemcitabine and paclitaxel is safe, well-tolerated, and active. The recommended phase II dose is gemcitabine 1000 mg/m² and paclitaxel 150 mg/m² on days one and eight every 21 days. The antitumor activity observed with this regimen warrants further investigation.     

A case responding to weekly paclitaxel therapy as second-line chemotherapy for gastric cancer previously treated with TS-1

A 58-year-old male patient with the recurrence of para-aortic lymphnodes after TS-1 treatment was treated by a weekly infusion of paclitaxel as second-line chemotherapy. Paclitaxel was administered at a weekly dose of 70 mg/m2/day for three weeks followed by a one week interval. After 2 courses, the tumor was reduced, and the reduction was judged as PR. Moreover, after 5 courses, the tumor was more remarkably reduced and the reduction was judged as CR. The grade 2 leukopenia, neutropenia, and grade 1 alopecia were observed as adverse events. Recently, we treated 11 patients of advanced or recurrent gastric cancers with measurable lesions, using the weekly paclitaxel therapy after TS-1 treatment. The response rate was 36.4%. The median duration of PR was 130 days. Therefore, a weekly paclitaxel regimen was considered to be one of the promising regimens for advanced or recurrent gastric cancer as the second-line chemotherapy after TS-1 treatment.     

Role of epirubicin in advanced breast cancer

Anthracyclines were first introduced for the treatment of metastatic breast cancer in the 1970s and are still among the most active single agents for the treatment of this disease. Unfortunately, their clinical value is limited by late-onset ventricular dysfunction. Epirubicin, an anthracycline analogue, does not eliminate the risk of cardiotoxicity but is less cardiotoxic and myelotoxic than doxorubicin at equimolar doses, thereby allowing the safe administration of cumulative doses between 950 and 1000 mg/m2. The inclusion of epirubicin in combination regimens, such as fluorouracil/epirubicin/cyclophosphamide (FEC), has been shown to be safe and active as first-line treatment for metastatic breast cancer. In the past few years, new drugs, including taxanes, have shown a high level of activity as single agents in the treatment of advanced breast cancer. Doxorubicin/paclitaxel combinations have shown high overall response rates (90%) as first-line chemotherapy of advanced breast cancer; however, congestive heart failure has been reported in up to 20% of patients. Epirubicin/paclitaxel combinations have been associated with grade 3 cardiotoxicity (6%) in only one study. We report findings of a trial of combination epirubicin/paclitaxel as first-line treatment of advanced breast cancer, with overall response rates (ORRs) of 84% and a complete response (CR) rate of 19%. Achieving a CR to first-line chemotherapy for advanced breast cancer appears to predict survival, and adding an active drug with a different mechanism of action and nonoverlapping toxicity might increase the percentage of CRs. We therefore tested the feasibility and activity of 6 to 8 courses of first-line treatment with a three-drug combination (gemcitabine 1000 mg/m2 days 1 and 4, epirubicin 90 mg/m2 day 1, and paclitaxel 175 mg/ m2 over 3 hours on day 1) in a phase II study of 36 metastatic breast cancer patients. Treatment was well tolerated, with an ORR of 92% (95% confidence interval: 77.53%-98.25%) and a CR of 31%. In considering retreating patients who progress or relapse after receiving an anthracycline-/taxane-containing regimen with the same active drugs, epirubicin appears ideal in both the adjuvant and metastatic breast cancer settings.     

Weekly docetaxel/paclitaxel in pretreated metastatic breast cancer

The purpose of our study was to evaluate the feasibility and efficacy of weekly docetaxel/paclitaxel in pretreated advanced breast cancer patients. Twenty-six patients with metastatic breast cancer were included in this study. Three different schedules of treatment were administered. The starting schedule, A1, consisted of docetaxel 60 mg/m2 on day 1 plus paclitaxel 60 mg/m2 over 1 hour, weekly for 18 weeks; this schedule was considered feasible if at least 70% of the planned doses were given on time and without reduction. Schedule A2 consisted of the same doses administered on days 1 and 8 every 3 weeks, and schedule B consisted of docetaxel 25 mg/m2 followed by paclitaxel 40 mg/m2 for 1 hour on days 1 and 8 every 3 weeks for a total of 6 cycles. All patients had received prior anthracyclines, and 19 patients were pretreated with taxanes. Seventy-seven percent of patients had received at least 2 prior lines of chemotherapy. Twenty-five patients are assessable for toxicity and efficacy. A total of 109 cycles of chemotherapy have been administered, with a median of 4 cycles per patient (range, 1-8 cycles). The median delivered dose intensity was 27 mg/m2/week for paclitaxel (range, 18-50 mg/m2/week) and 17 mg/m2/week (range, 12-39 mg/m2/week) for docetaxel. Six patients received schedule A1. This schedule was considered not feasible due to neutropenia grade > 2, mucositis, and diarrhea grade 2, which required dose reduction/omission in 33% of administrations. For this reason, treatment in the following 5 patients was omitted on day 15 (schedule A2). Schedule B was found to be more feasible with 16% of dose reductions/omissions. The overall response rate was 68% (95% CI, 50%-86%) with a median duration of response of 10 months (range, 2-18+ months). Treatment was well tolerated; myelosuppression was rare and grade 3 cutaneous toxicity was observed in only 2 patients. In conclusion, weekly docetaxel/paclitaxel is active at low dosages and was well tolerated as salvage chemotherapy in metastatic breast cancer. This regimen represents a valid option as a salvage treatment in taxane- and anthracycline-pretreated patients.     

Cisplatin and Ifosfamide in Patients with Advanced Squamous Cell Carcinoma of the Uterine Cervix A phase II trial

Thirty patients with advanced squamous cell carcinoma of the cervix were included in a phase II study with cisplatin (DDP) and ifosfamide (IF)/mesna. They received a median of 4 courses of chemotherapy and were all evaluable for response and toxicity. Each cycle consisted of 2 500 mg/m² IF i.v. days 1-5; mesna 500 mg/m² i.v. at hours 0 and 2, and 1 000 mg/m² per os at hours 6 and 10, days 1-5; DDP 20 mg/m² i.v., days 1-5. Cycles were repeated every 4 weeks. One patient obtained CR and 14 PR giving an overall response rate of 50%. Mean duration of response was 21 months. Anemia grade 3 developed in 7 patients, leukopenia grade 3 in 9 patients and grade 4 in one patient; thrombopenia grade 3 in 2; creatinine clearance grade 3 in one; CNS grade 3 in one and cystitis grade 3 in one patient. Overall median survival time was about 25 + months (3-63 +); after a follow-up of 70 months, 11 patients (37%) are still alive with a median survival of 31 + months. IF plus DDP seems to be a good combination for treatment of advanced cervical cancer, with acceptable tolerance and response rate.     

白蛋白结合型紫杉醇联合奈达铂一线治疗晚期食管癌患者的临床观察

背景与目的：化疗是晚期食管癌患者的主要治疗手段,但目前尚没有标准的一线治疗方案,通过白蛋白结合型紫杉醇联合奈达铂方案治疗晚期食管癌,评价其临床疗效及安全性。方法：收集2016年2月—2019年2月之间在长海医院诊治的晚期食管癌并有可评价病灶的患者31例,一线予以白蛋白结合型紫杉醇联合奈达铂方案化疗,具体用药为：白蛋白结合型紫杉醇130 mg/m ² ,第1、8天;奈达铂70 mg/m ² ,第1天;每3周重复。采用实体瘤疗效评价标准（Response Evaluation Criteria in Solid Tumors,RECIST）1.1标准评估疗效,按照美国国立癌症研究所通用毒性标准（National Cancer Institute Common Toxicity Criteria,NCI-CTC）5.0评估不良反应。结果：全部31例患者均可评价疗效,其中完全缓解（complete response,CR）1例（3.2%）,部分缓解（partial response,PR）20例（64.5%）,疾病稳定（stable disease,SD）9例（29.0%）,疾病进展（progressive disease,PD）1例（3.2%）,客观缓解率（objective response rate,ORR）为67.7%,疾病控制率（disease control rate,DCR）为96.8%,中位无进展生存期（progression-free survival,PFS）为9.4个月。常见不良反应主要包括骨髓抑制、感觉神经病变、关节酸痛、肌肉酸痛、消化道反应及脱发,无毒性相关死亡病例。结论：白蛋白结合型紫杉醇联合奈达铂一线治疗晚期食管癌疗效较好,不良反应患者可耐受,值得进一步推广。     

Phase I study of weekly vinorelbine in combination with weekly paclitaxel in adult patients with advanced refractory cancer

Vinorelbine and paclitaxel are highly active antineoplastic agents. Preclinical data indicate a potential for antitumor synergy for a number of common tumor types when they are combined. We investigated a novel weekly schedule of both agents. Eighteen patients with advanced cancer were entered onto this phase I trial. Vinorelbine and paclitaxel were given weekly in combination for 6 consecutive weeks, followed by a 2-week break. Sequential cohorts of patients were treated at two dose levels: Vinorelbine 22.5 mg/m² followed by paclitaxel 40 mg/m² and Vinorelbine 22.5 mg/m² followed by paclitaxel 60 mg/m². Ten patients completed at least one 8-week course of therapy. Neutropenic myelosuppression was dose limiting at level II. Neurotoxicity was not dose limiting. Objective responses were seen in patients with esophageal, lung, and breast cancer and suggest that this is an active regimen worthy of further investigation in selected diseases. Phase II trials of this regimen are in progress.     

Taxanes as first-line therapy for advanced non-small cell lung cancer: a systematic review and practice guideline

This evidence-based practice guideline on the use of paclitaxel (Taxol^®) or docetaxel (Taxotere^®) as first-line treatment for patients with advanced non-small cell lung cancer who are candidates for palliative first-line chemotherapy is based on a systematic search and review of literature published in full or in abstract form between 1985 and April 2005. Forty-five randomized trials, including 11 abstracts, were reviewed and clinicians in the province of Ontario, Canada, provided feedback on a draft version of the guideline. Two phase III trials detected a statistically significant survival advantage for a taxane (paclitaxel or docetaxel) with best supportive care versus best supportive care alone. Among the nine fully published phase III trials comparing platinum-based chemotherapies, taxane-platinum combinations achieved higher response rates compared with older chemotherapy combinations, although significantly longer survival was observed only for docetaxel-cisplatin compared with vindesine-cisplatin. Response rates and survival were generally not significantly different for taxane-platinum combinations compared with other current chemotherapy combinations, although the toxicity profile of the regimens varied. However, in one large trial, improved tumor response and modest survival and quality of life benefits were associated with docetaxel-cisplatin compared with vinorelbine-cisplatin. No statistically significant survival differences were detected in the three fully published phase III trials comparing a taxane-gemcitabine combination with a taxane-platinum regimen.

Recommendations: (i) paclitaxel or docetaxel combined with cisplatin is recommended as one of a number of chemotherapy options for the first-line treatment of advanced non-small cell lung cancer in patients with a good performance status; (ii) carboplatin may be combined with a taxane if a patient is unable or unwilling to take cisplatin; (iii) a taxane-gemcitabine combination may be considered for patients with a contraindication to cisplatin and carboplatin; (iv) no firm recommendation can be made on the optimal dose and schedule of taxane-based chemotherapy; however, commonly used regimens include cisplatin 75 mg/m² combined with either docetaxel 75 mg/m² or paclitaxel 135 mg/m² (24-h infusion) and carboplatin AUC 6 combined with paclitaxel 225 mg/m² (3-h infusion); (v) a single-agent taxane may be used if combination chemotherapy is considered inappropriate.