Cisplatin plus continuous infusion vinorelbine for the treatment of advanced non-small cell lung cancer: a phase I-II study

Backbround In this Phase I/II trial, the maximum-tolerated dose (MTD) and activity of cisplatin plus vinorelbine (VRL) administered in continuous in-fusion as first-line treatment of advanced non small cell lung cancer (NSCLC) was determined in 12 consecutive chemotherapy-naive patients with advanced NSCLC. Patients and methods The dose of cisplatin was 100 mg/m² in all patients, and vinorelbine was administered as an initial intravenous (iv) bolus of 8 mg/m² on day 1 followed by a 4-day continuous iv infusion at 4 different 24 h dose levels (DLs) to be repeated every 21 days. All 12 patients (47 cycles) were evaluable for response and toxicity. Results The MTD was 8 mg/m² bolus followed by a continuous iv infusion of 8 mg/m² per day over 4 days. The dose limiting toxicities (DLT) were febrile neutropenia in 4 patients and grade 3 mucositis in 1 patient. There was less neuro-toxicity and compared to the weekly bolus scheme. There was no significant cumulative toxicity after 3 cycles. Partial responses were observed in 6 patients; an overall response rate of 50% (95% CI: 30–65%). Median time to progression was 5,5 months (95% CI: 1,5–11 months) and median survival was 11 months (95% CI: 5–20 months). Conclusions The results demonstrate that, in this setting of first-line treatment of NSCLC, cisplatin plus vinorelbine at 8 mg/m² bolus followed by a continuous infusion of 8 mg/m² per day over 4 days is the recommended schedule. Further trials would be useful to establish activity of this combination.     

A phase 2 trial of whole-brain radiotherapy combined with intravenous chemotherapy in patients with brain metastases from breast cancer

BACKGROUND

A study was conducted to determine the efficacy, tolerability, and safety of concurrent cisplatin and vinorelbine chemotherapy and radiotherapy in patients with previously untreated brain metastases from breast cancer.

METHODS

Twenty‐five patients with untreated brain metastases from breast cancer were treated with cisplatin (at a dose of 20 mg/m²/day, Days 1‐5) and vinorelbine (6‐mg/m² bolus on Day 1 and 6 mg/m²/day continuous infusion on Days 1‐5) chemotherapy combined with concurrent 30‐gray fractionated external‐beam radiotherapy. Chemotherapy was given at 3‐week intervals for a total of 4 cycles. Primary endpoint was the rate of radiologic response of brain metastases.

RESULTS

Complete response in the brain was observed in 3 patients, and partial response was noted in 16 patients, yielding a 76% response rate in the brain. The overall systemic response rate was 44%. Progression‐free and overall survival were 3.7 months and 6.5 months, respectively. Overall toxicity was acceptable; nonhematologic grade 3‐4 events were noted in 5 (20%) patients, and there were no toxic deaths.

CONCLUSIONS

Concurrent chemoradiation with cisplatin and vinorelbine for brain metastases from breast cancer appears to be active and well tolerated. Cancer 2008. © 2008 American Cancer Society.     

Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma

BackgroundWe aimed to investigate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC).Patients and methodsIt was a Simon two-stage designed trial. Chemotherapy-naive patients with recurrent or metastatic disease were enrolled. The regimen was sorafenib 400 mg orally b.i.d., cisplatin 80 mg/m² i.v. day 1, and 5-FU 1000 mg/m²/day CIV for 4 days, repeated every 21 days. After a maximum of six cycles of chemotherapy, patients received maintenance of sorafenib.ResultsIn total, 54 patients were enrolled. The objective response rate reached 77.8%, including 1 complete response and 41 partial responses. The median progression-free survival was 7.2 months (95% CI 6.8–8.4 months), and the median overall survival was 11.8 months (95% CI 10.6–18.7 months). Major toxic effects included hand–foot skin reaction, myelosuppression, and gastrointestinal (GI) reaction. The incidence of hemorrhage was 22.2%, and one patient with liver metastases died of GI bleeding. Contrast-enhanced ultrasonography was carried out in a subset of patients with liver metastases.ConclusionCombination of sorafenib, cisplatin (80 mg/m²) and 5-FU (3000 mg/m²) was tolerable and feasible in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and 5-FU with standard dose of cisplatin plus 5-FU in NPC are warranted.     

Daily times four vinorelbine plus cisplatin in advanced non-small-cell lung cancer: A phase II trial of a novel schedule

Purpose: To evaluate the efficacy of a novel multiday schedule of vinorelbine and cisplatin in patients with advanced NSCLC.Patients and methods: Thirty patients were enrolled, including 27 patients with stage IV disease, and 11 patients with performance status of 2. They received a maximum of four chemotherapy cycles with cisplatin 20 mg/m²/day and vinorelbine 15 mg/m²/day intravenously (i.v.) for four consecutive days, every three weeks, with prophylactic filgrastim.Results: Sixteen patients responded (53%, 95% confidence interval (95% CI): 34%–72%), including two complete and fourteen partial confirmed responses. Median survival for all patients was 8.1 months, with actuarial one-year and two-year survival rates of 40% and 15%. Despite prophylactic filgrastim, the delivered vinorelbine dose intensity of 16.8 mg/m²/week caused febrile neutropenia in 48% of patients (16% of cycles), resulting in one treatment-related death. Common nonhematologic toxicities included delayed emesis, asthenia, and constipation.Conclusions: This multiday vinorelbine–cisplatin schedule is highly active against advanced NSCLC but results in frequent neutropenic complications. The myelotoxicity and antitumor efficacy of vinorelbine in NSCLC patients may be schedule-dependent.     

Sequential chemotherapy of cisplatin and vinorelbine followed by paclitaxel and gemcitabine in advanced non-small-cell lung cancer. A single institution phase II study

BACKGROUND: To determine the activity and safety of a sequential regimen of cisplatin and vinorelbine followed by paclitaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Treatment was two cycles of cisplatin 80 mg/m(2) on day 1 and vinorelbine 30 mg/m(2) on days 1 and 8 every 3 weeks followed by two cycles of paclitaxel 175 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8 every 3 weeks. RESULTS: Fifty-five patients with inoperable NSCLC, performance status 2 or less were enrolled, including 19 patients with brain lesions. There were 23 partial responses (42%; 95% confidence interval 29-55). The median time to progression and overall survival were 5.8 and 10.3 months, respectively (6.5 and 12.8 in the patient subset without brain metastases). One-year survival rate was 47.5%. Grade III/IV neutropenia was the major side effect; it occurred in 56% of patients and was mainly limited to the first two chemotherapy cycles with cisplatin and vinorelbine. CONCLUSIONS: Sequential combination of cisplatin and vinorelbine followed by paclitaxel and gemcitabine is a manageable and active regimen for patients with NSCLC. It deserves to be tested against a standard two-drug scheme in a phase III trial.     

Long‐term results of concurrent chemoradiotherapy using cisplatin and vinorelbine for stage III non‐small‐cell lung cancer

Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non‐small cell lung cancer (NSCLC). The long‐term feasibility and efficacy of vinorelbine and cisplatin with concurrent thoracic radiotherapy were investigated. Eighteen patients received cisplatin (80 mg/m²) on day 1 and vinorelbine (20 mg/m² in level 1, and 25 mg/m² in level 2) on days 1 and 8 every 4 weeks for four cycles in a phase I trial. Ninety‐three patients received the same chemotherapy regimen except for the fixed vinorelbine (20 mg/m²) dosage and consolidation therapy with docetaxel (60 mg/m², every 3 weeks). The thoracic radiotherapy consisted of a single dose of 2 Gy once daily to a total dose of 60 Gy. A total of 111 patients were analyzed in the present study: male/female, 91/20; median age, 60 years; stage IIIA/IIIB, 50/61; and squamous/non‐squamous histology, 26/85. The 3‐, 5‐, and 7‐year overall survival rates (95% CI) were 43.2% (33.9–52.2), 25.2% (17.6–33.5), and 23.2% (15.8–31.4), respectively. The median progression‐free survival and median survival time (95% CI) were 13.5 (10.1–16.7) months and 30.0 (24.3–38.8) months, respectively. Four patients (4%) experienced Grade 5 pulmonary toxicities from 4.4 to 9.4 months after the start of treatment. In conclusion, approximately 15% of patients with unresectable stage III NSCLC could be cured with chemoradiotherapy without severe late toxicities after 10 months of follow‐up. Although based on the data from highly selected population participated in phase I and phase II trial, this analysis would strengthen and confirm the previous reports concerning concurrent chemoradiotherapy with third generation cytotoxic agents. (Cancer Sci 2013; 104: 93–97)     

Sequential chemotherapy with paclitaxel plus cisplatin, followed by vinorelbine, followed by gemcitabine in advanced non-small cell lung cancer: an Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 001)

Aim of this study was to determine the activity and toxicity of a sequential chemotherapy regimen in advanced non-small cell lung cancer (NSCLC). Fifty-one previously untreated stage IIIB/IV NSCLC patients were enrolled to receive two cycles of cisplatin plus paclitaxel (80/175 mg/m(2) every 21 days), followed by two cycles of vinorelbine (30 mg/m(2) on days 1 and 8 every 21 days), followed by two cycles of gemcitabine (1000 mg/m(2) on days 1, 8, and 15 every 28 days). Forty-one patients (82%) completed the planned six cycles. Grade 3-4 neutropenia was the major toxicity (41% of patients) and it was mainly associated with vinorelbine administration. Response rate after cisplatin plus paclitaxel was 18%; this percentage increased to 41% after vinorelbine, and it reached 43% upon completion of the entire six cycle treatment program. Median survival time was 14.4 months, 1-year survival rate was 53%, and 2-year survival rate was 18%. Median time to disease progression was 6.8 months. This sequential chemotherapy regimen is feasible and active in patients with advanced NSCLC. This pilot experience provides the basis for an ongoing randomized phase III trial comparing our sequential regimen versus cisplatin plus gemcitabine.     

Multicenter phase II study of combination chemotherapy with capecitabine and intravenous vinorelbine in patients with pretreated metastatic breast cancer

Background: Capecitabine and i.v. vinorelbine are both active in metastatic breast cancer with non‐overlapping toxicities. This study examined the efficacy and safety of the combination of these agents in patients with pretreated metastatic breast cancer. Methods: Patients previously treated for breast cancer, maximum of one prior metastatic regimen, received capecitabine 1000 mg/m² b.d. for days 1–14 and vinorelbine 25 mg/m² i.v. days 1 and 8 every 21 days. All patients had measurable disease and adequate baseline organ function. The primary endpoint was response and secondary endpoints time to progression, duration of response, survival and safety. Results: Twenty‐two patients (median age 56 years) received a median of six cycles. All patients had received anthracyclines and 64% taxanes. Objective responses were seen in 7/21 (33%, 95% confidence interval [CI] 18–57%), with two complete responses; stable disease was seen in 5/21 (24%, 95% CI 8–42%). Median duration of response was 6.9 months (95% CI 4.7–13.1), time to progression was 5.8 months (95% CI 2.8–6.8) and survival was 13.5 months (95% CI 6.9–19.9). The median dose intensity of vinorelbine was 75% of the intended dose and of capecitabine 85% of intended dose. The main toxicity was myelosuppression including 16 episodes of G3–4 neutropenia in 11 patients (50%). Other toxicities were generally mild to moderate. Conclusion: The combination of capecitabine and i.v. vinorelbine is active and well tolerated in patients with pretreated metastatic breast cancer. The recent availability of oral vinorelbine provides an opportunity to explore a fully oral combination.     

A Cisplatin and Vinorelbine (NP) Regimen as a Postoperative Adjuvant Chemotherapy for Completely Resected Breast Cancers in China: Final Results of a Phase II Clinical Trial

Objective: To evaluate the efficacy and toxicity of cisplatin and vinorelbine (NP) for postoperative adjuvantchemotherapy of completely resected breast cancers. Methods: Between September 1994 and April 2005, 91Chinese breast cancer patients, with pathologically-confirmed adenocarcinoma in Jiangsu Cancer Hospitaland Research Institute, were enrolled. They received postoperative vinorelbine at 25mg/m2 on days 1 and 8,and cisplatin 25mg/m2 on days 1 to 3, this regimen being repeated every 3 weeks. Results: Median age was 49years (range, 25-69 years). A ccording to the TNM stage system, stage Ⅰ, Ⅱ, ⅢA patients accounted for 7.7%,58.2% and 34.1%, respectively. The median number of chemotherapy cycles was 4.5 (range, 1-8), over half ofthe patients receiving 4 to 6 NP cycles. After a median follow-up of 48 months, 11 deaths and 29 relapses weredocumented. Median disease-free survival was 45 months, with disease-free and overall survival at 5 years being76% and 88.7%, respectively. All patients could be evaluated with regard to toxicity, 17 (18.7%) developing gradeⅢ neutropenia during treatment, but all recovering after recombinant human granulocyte colony stimulatingfactor (G-CSF) injection, 3 suffering thrombocytopenia (3.3%), 5 anemia (5.5%) and 5 nausea/vomiting (5.5%).No treatment related deaths occurred. Conclusions: NP is an effective and feasible treatment for completelyresected breast cancer cases at the doses tested. A randomized clinical trial is now needed to compare NP withother conventional regimens.     

Biweekly regimen of cisplatin, gemcitabine and vinorelbine for advanced non-small-cell lung cancer

Purpose: Improving chemotherapeutic efficacy in non-small cell lung cancer (NSCLC) will require the development of new strategies to better use currently available agents. To assess the efficacy and safety of a biweekly regimen of cisplatin, gemcitabine and vinorelbine for advanced non-small-cell lung cancer. Methods: Patients with selected stage IIIb (pleural effusion)/stage IV NSCLC, performance status of 0–2 and normal organ function were eligible. Treatment consisted of cisplatin 100 mg/m² on day 1 plus gemcitabine, 1,000 mg/m² and vinorelbine 25 mg/m² on days 1 and 15 every 28 days. Results: Of the 40 patients enrolled and assessable for response, there were five (12.5%) with confirmed complete response and 14 (35%) with a confirmed partial response for an overall response rate of 47.5%. Nine patients had stable disease while 12 (30%) progressed. Median progression-free survival and overall survival for all patients were 6.3 and 11.1 months, respectively. Toxicity was principally hematologic, with grade 3–4 neutropenia in 30%, and grade 3–4 nausea/vomiting in 22.5%. There were no treatment-related deaths. Conclusions: The biweekly regimen of cisplatin, gemcitabine and vinorelbine is associated with a high rate of response, lesser toxicity than other three-drug regimens and no benefit of survival. Therefore, the regimen under study may be an appealing alternative when considering other treatment modalities for advanced lung cancer, such as neoadjuvant therapy.     

Hepatic arterial infusion chemotherapy for liver metastases from breast cancer

Between 1985 and 1992, 56 patients with unresectable liver metastases from breast cancer were treated by repeated hepatic arterial infusion chemotherapy employing an implantable port system. 5-Fluorouracil (5-FU) at 330 mg/m² per week, Adriamycin (ADR) at 20 mg/m² every 4 weeks, and mitomycin C (MMC) at 2.7 mg/m² every 2 weeks were given to 42 patients. The remaining 14 patients received 5-FU at 330 mg/m² per week and epirubicin (EPIR) at 20 mg/m² every 2 weeks. As a rule, the treatment was performed on an outpatient basis. The side effects and complications observed included myelosuppression (41%), hepatic arterial occlusion (23%), and gastric mucositis (20%), but no major toxicity was encountered. The response rate (CR+PR) of the evaluated patients as determined from CT scans was 81%. The overall median survival period was 12.5 months. Only 14% of the patients died due to regrowth of liver metastases, and in 70% of the total cases, death due to liver metastases was avoided by this treatment. Thus, repeated hepatic arterial infusion chemotherapy for liver metastases from breast cancer might be capable of prolonging the survival of patients via avoidance of death due to the liver metastases.Work presented at the Third International Symposium on Treatment of Liver Cancer, Seoul, Korea, 12–13 February 1993     

Full dose paclitaxel plus vinorelbine as salvage chemotherapy in anthracycline-resistant advanced breast cancer: a phase II study

This phase II trial studied the efficacy and toxicity of full dose paclitaxel plus vinorelbine, as salvage chemotherapy in patients with metastatic breast cancer resistant to anthracyclines. Patients received vinorelbine (30 mg/m2) followed 1 hour later by full dose paclitaxel (175 mg/m2) every 3 weeks for a maximum of 8 cycles or until disease progression. Because of the heavy pretreatment of the patients, prophylactic granulocyte-colony stimulating factor (5 microg/kg) was administered daily for 5-10 days. To minimize potentially cumulative neurotoxicity due to both agents, amifostine was given prior to chemotherapy. Thirty-four patients: 8 with tumors primary resistant and 26 with tumors recurring within 3-6 months after anthracycline treatment, were evaluable for efficacy and toxicity. Objective responses occurred in 11 patients [32%; 95% confidence interval (CI): 16.3-47.7%), all partial responses. Responses were observed in lung and liver. The median response duration was 4 months (range 3-7), median time to progression was 5 months (range 3-9) and median overall survival was 8 months (range 4-24). Neutropenia was dose limiting (35% grade 3-4 toxicity). The left ventricular ejection fraction, measured and followed in 18 patients, fell less than 20% below baseline level in 9 patients (50%), but only one patient developed congestive cardiac failure. The paclitaxel-vinorelbine regimen was moderately tolerated and moderately effective in poor prognosis breast cancer patients with visceral metastases and tumors resistant to anthracyclines. The combination at these doses and schedules should be considered in the design of regimens for advanced breast cancer.     

Phase II interventional study (N0337) of capecitabine in combination with vinorelbine and trastuzumab for first- or second-line treatment of HER2-positive metastatic breast cancer: a north central cancer treatment group trial

BackgroundWe conducted a multiinstitutional phase II study of capecitabine in combination with vinorelbine and trastuzumab in patients eligible to receive first- or second-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive (HER2⁺) metastatic breast cancer (MBC).Patients and MethodsThe study was designed to test that the true confirmed response rate (CRR) was at most 45% vs. a true CRR of at least 65%. Between March 2005 and June 2008, eligible patients received capecitabine 825 mg/m² orally on days 1 to 14, vinorelbine 25 mg/m² intravenously on days 1 and 8 every 3 weeks, and trastuzumab 8 mg/kg intravenously on day 1 week 1 and 6 mg/kg every 3 weeks. The main outcome measure was CRR.ResultsOf 47 women accrued, 45 were evaluable. This design required at least 25 confirmed responses in the 45 evaluable patients for the treatment to be considered promising. Thirty women (67%) achieved a confirmed response; 25 women (56%) had a confirmed partial response (PR); 5 women (11%) had confirmed complete responses (CRs). Median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 8.4-16.7 months). Median overall survival was 28.5 months (95% CI, 24.8-36.4 months).ConclusionsThis triplet combination demonstrated promising activity in patients with HER2⁺ MBC.     

A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer

BackgroundThe Breast Cancer Study Group of the Hellenic Oncology Research Group conducted a phase III trial of single-agent capecitabine versus the vinorelbine/gemcitabine doublet in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. The primary objective was to demonstrate superiority of combination treatment in terms of progression-free survival (PFS).Patients and methodsWomen with MBC were randomly assigned to receive either capecitabine (Cap arm: 1250 mg/m² twice daily, on days 1–14) or vinorelbine/gemcitabine doublet (VG arm: vinorelbine 25 mg/m²; gemcitabine 1000 mg/m²; both drugs on days 1 and 15).ResultsSeventy-four women were treated on each arm and median PFS was 5.4 versus 5.2 months (P = 0.736), for VG and Cap, respectively. Median overall survival was 20.4 months for the VG arm and 22.4 months for the Cap arm (P = 0.319). Overall response rate was 28.4% in the VG arm and 24.3% in the Cap arm (P = 0.576). Both regimens were generally well tolerated. Neutropenia and fatigue were more common with VG arm and hand–foot syndrome with Cap arm.ConclusionsThis trial failed to demonstrate superiority of vinorelbine/gemcitabine doublet over single-agent capecitabine in terms of PFS. Given the favorable toxicity and convenience of oral administration, single-agent capecitabine is recommended for compliant patients.     

卡培他滨联合多西他赛或长春瑞滨治疗乳腺癌肝转移的临床观察及疗效分析

  目的  探讨含卡培他滨不同化疗方案治疗乳腺癌肝转移的疗效及不良反应。  方法  收集2000年1月至2011年12月中国医学科学院肿瘤医院收治的163例使用多西他赛/卡培他滨或长春瑞滨/卡培他滨治疗的乳腺癌肝转移患者,回顾性分析临床特点,探讨两种方案的不良反应及疗效。  结果  全组共纳入163例患者,接受多西他赛/卡培他滨治疗109例（66.9%）,长春瑞滨/卡培他滨组54例（33.1%）。多西他赛/卡培他滨组可评价疗效病例中CR 4例、PR 55例、SD 25例、PD 22例,不详3例,客观有效率为54.1%（59/109）,临床获益率77.1%（84/109）;长春瑞滨/卡培他滨组可评价疗效病例中CR 1例、PR 26例、SD 11例、PD 13例,不详3例,客观有效率为50.0%（27/54）,临床获益率为70.4%（38/54）。在3~4级血液学不良反应方面长春瑞滨/卡培他滨组发生率为42.6%（23/54）,3~4级非血液学不良反应主要表现为手足综合征1例（18.9%）、胃肠道反应2例（3.8%）,均高于多西他赛/卡培他滨治疗组。多西他赛/卡培他滨中位无疾病进展时间（progression free survival,PFS）为8个月,中位肝转移后生存（overall survival after liver metastases,LMS）为26个月,中位转移后生存（post metastasis survival,MSR）为30个月;长春瑞滨/卡培他滨组中位PFS为6个月,中位LMS为20个月,中位MSR为28个月。多西他赛联合卡培他滨方案在PFS、LMS以及MSR均较长春瑞滨联合卡培他滨方案延长,但无显著性差异。  结论  含卡培他滨化疗方案应用乳腺癌肝转移治疗耐受性良好,其中多西他赛/卡培他滨方案在疗效和耐受性方面可能优于长春瑞滨/卡培他滨方案。      

Biweekly vinorelbine and tegafur/uracil in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: GEICAM 2000–02 phase II study

Introduction

To assess the efficacy and safety profile of biweekly vinorelbine and tegafur/uracil (UFT) as treatment in patients with metastatic breast cancer previously treated with anthracyclines and taxanes.

Patients and methods

Patients with histologically confirmed breast cancer, measurable disease, no more than one prior chemotherapy regimen for metastatic disease, an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate bone marrow, renal and liver function were eligible. Patients received vinorelbine (30 mg/m² on day 1) and UFT (250 mg/m² daily) every two weeks for 12 cycles unless progression or unacceptable toxicity was observed.

Results

Thirty-seven patients were included and received 311 cycles of chemotherapy. Efficacy and toxicity analyses were carried out on an intention-to-treat basis. The overall response rate was 35% (95% CI: 20–53). With a median follow-up of 18.6 months (95% CI: 1.0–74.3), the median time to progression was 7.0 months (96% CI: 5.2–8.9) and the median overall survival was 19.4 months (95% CI: 11.1–27.8). The most common severe toxicities were neutropenia (38% of patients) and asthenia (11% of patients).

Conclusion

The combination of biweekly vinorelbine and UFT in patients with metastatic breast cancer pretreated with anthracyclines and taxanes is a well tolerated and effective regimen. AEMPS Trial Registration No.: 00-0534.     

Phase II study of vinorelbine administered by 96-hour infusion in patients with advanced breast carcinoma.

BACKGROUND: Vinorelbine given by weekly bolus injection is active and less toxic than bolus vinblastine in the treatment of patients with metastatic breast carcinoma. Vinblastine given by 5-day continuous infusion showed a steep dose-response curve. Pharmacokinetic studies of vinorelbine showed that it is possible to achieve a comparable antitumor effect with a smaller amount of the drug if it is given by continuous infusion. The purpose of this study was to determine the efficacy of vinorelbine given by 96-hour continuous infusion to patients with refractory metastatic breast carcinoma patients. METHODS: Between May 1996 and August 1997, 47 patients with metastatic breast carcinoma were registered into the study. All patients previously had received doxorubicin and 70% had undergone prior paclitaxel treatment. Approximately 56% of the patients had >/=2 metastatic sites. All patients received vinorelbine according to the following dose schedule: 8 mg bolus followed by 11 mg/m(2) by continuous infusion over 24 hours every 4 days every 3 weeks. RESULTS: Forty-four patients were evaluable for response. A total of 193 cycles were administered. The overall response rate was 16% (2 patients achieved a complete response and 5 patients achieved a partial response). The median duration of response was 4.3 months and the median overall survival was 8.6 months. Patients with visceral metastases and/or multiple sites of involvement had shorter durations of response than patients with only soft tissue disease or single-site metastasis (3.1 months vs. 4. 9 months) and shorter overall survival (8.1 months vs. 12 months). Dose reductions were necessary due to cumulative stomatitis and/or fatigue in 12 cycles and neutropenia and/or infection in 13 cycles. CONCLUSIONS: Due to toxicity, a revised maximum tolerated dose for continuous infusion vinorelbine is proposed by the authors: 8 mg intravenously over 10 minutes followed by 10 mg/m(2) by continuous infusion over 24 hours every 4 days. The current dose schedule did not offer an advantage either in response rates or survival over the weekly vinorelbine bolus injection in doxorubicin-resistant and paclitaxel-resistant patients.     

Pemetrexed

? Pemetrexed inhibits several folate-dependent enzymes, thereby inhibiting both thymidine synthesis and purine nucleotide synthesis. ? The median survival time of patients with NSCLC treated with pemetrexed 500 mg/m² monotherapy every 21 days versus docetaxel 75 mg/m² every 21 days in a second-line setting was 8.3 and 7.9 months (hazard ratio = 0.99, 95% CI 0.82-1.20, with a preset 95% CI upper limit of <1.11) in a phase III randomized, nonblind, multicenter trial (n = 571). In a phase III randomized, single-blind, multicenter trial (n = 448) in chemotherapy-naive patients with malignant pleural mesothelioma (MPM), pemetrexed 500 mg/m² plus cisplatin 75 mg/m² every 21 days was better in terms of median survival time (12.1 vs 9.3 months; hazard ratio 0.77, p < 0.05) and tumor response rates (41.3% vs 16.7%, p < 0.001) than cisplatin 75 mg/m² every 21 days. ? During the MPM trial, a protocol change required all patients to receive supplementation with oral folic acid daily and intravenous cyanocobalamin once every 9 weeks (i.e. supplementation) because of pemetrexed toxicity. ? Pemetrexed was generally well tolerated as monotherapy in patients with advanced NSCLC and as combination therapy in patients with MPM if supplemented. In patients with NSCLC, neutropenia, alopecia, and fatigue were the most common adverse events, whereas in patients with MPM they were neutropenia, leukopenia, nausea, and vomiting. Severe toxicities in pemetrexed recipients in the NSCLC trial were infrequent.

Phase II study of the combination of vinorelbine and cisplatin in advanced non-small-cell lung cancer

Purpose To evaluate the efficacy and safety of combination chemotherapy with cisplatin and vinorelbine for the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC).Patients and methods Eligible patients were those with measurable NSCLC. They were treated with two or more cycles of a regimen consisting of vinorelbine 25 mg/m² on days 1 and 8 and cisplatin 80 mg/m² on day 1 every 3 weeks.Results A total of 45 patients were enrolled. The response rate was 51.1% (23/45; 95% CI 35.8% to 66.3%). The median survival was 286 days with a 1-year survival rate of 40%. The median number of treatment cycles was 2. The major toxic effect was neutropenia of grade 3 or higher (84%). Nonhematological toxicities, including vomiting (62%), were mild (grade 2 or less). There were no treatment-related deaths.Conclusion The high response rate and good tolerability proved this combination therapy to be a safe and effective treatment for advanced NSCLC.This work was supported in part by a grant-in-aid from the Ministry of Health and Welfare (Tokyo, Japan) and from the Second Term Comprehensive 10-Year Strategy for Cancer Control.     

Corrigendum

On page 44 of the above-mentioned article, the third paragraphin the left-hand column is incorrect and should read as follows: Studies combining vinorelbine and cisplatin are shown in Table2. The overall response rate with this combination is 38.2%± 7.5% with durations of response ranging between 5 and12 months and a median survival of 38.8 ± 12 weeks. Insome of the reported studies the dose of cisplatin has beendivided [31, 33, 37] in an effort to improve the tolerance ofthis aspect of the combination and there is no apparent reductionin efficacy as a result of this. A large phase III trial conductedby SWOG including 432 patients [40] in which vinorelbine (25mg/m² every week) in combination with cisplatin (100 mg/m² everyfour weeks) was compared to cisplatin alone (100 mg/m² everyfour weeks). Results showed a significant advantage with regardto one year and two years survival rate among patients receivingthe combination (36% and 20%) compared to 20% and 6% survivalamong patients receiving cisplatin alone. In addition to itsadvantage in one and two years survival rate, vinorelbine pluscisplatin also proved to be superior to cisplatin in mediansurvival (eight months vs. six months, P = 0.0018) and progressionfree survival (four months vs. two months, P = 0.00001). Ina further phase III study comparing vinorelbine–cisplatinwith vindesine–mitomycin–cisplatin response rateswere similar (38% vs. 41%) but the three drug combination producedmuch more haematological toxicity [41]. A report in which across-over between vinorelbine–cisplatin and vindesine–cisplatinwas included in the design for those patients who did not respondto initial therapy showed that not only did vinorelbine–cisplatinproduce a better initial response rate (31.1% vs. 8.9%) butit was also a more active salvage therapy after patients hadreceived vindesine–cisplatin without benefit as theirinitial treatment [42].