Sequential combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: carboplatin and gemcitabine followed by paclitaxel.

BACKGROUND: The objective of this Phase II study was to evaluate the concept of sequential chemotherapy in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC) by the administration of carboplatin plus gemcitabine followed by of paclitaxel. METHODS: Patients with Stage IIIB (pleural effusion) or Stage IV NSCLC and a Southwest Oncology Group (SWOG) performance status (PS) of 0--2 were eligible. Therapy consisted of three cycles of carboplatin (area under the concentration-time curve = 5.5 mg/mL per minute) on Day 1 and gemcitabine 1000 mg/m(2) on Days 1 and 8 every 21 days followed by three cycles of paclitaxel 225 mg/m(2) every 21 days. RESULTS: Of the 37 eligible patients, 81% had Stage IV disease, and 27% had a PS of 2; all were assessable for survival and toxicity; 32 patients were assessable for response. After treatment with carboplatin plus gemcitabine, there were no complete responses (CRs) and eight partial responses (PRs) (response rate [RR], 25%; 95% confidence interval [95% CI], 11--43%). The best overall response was two CRs and eight PRs (RR, 31%; 95% CI, 16--50%). The median survival time was 9.5 months, the 1-year survival rate was 36% (95% CI, 26--44%), the 2-year survival rate was 11% (95% CI, 3--25%), and the median time to disease progression was 4.9 months. The median survivals were 11.2 months for patients with a PS of 0--1 and 6.4 months for patients with a PS of 2. Noncumulative, reversible thrombocytopenia was the principal toxicity with carboplatin/gemcitabine therapy. Paclitaxel therapy was well tolerated, and moderate (Grade 3) neutropenia was the primary toxic effect. One cardiac death occurred, possibly related to paclitaxel. CONCLUSIONS: This study is the first to evaluate planned sequential chemotherapy in patients with NSCLC. Carboplatin plus gemcitabine followed by paclitaxel was well tolerated and resulted in promising survival in this patient population. This pilot experience forms the basis for an ongoing SWOG trial. Cancer 2001;92:146-52. Published 2001 American Cancer Society.     

Randomized phase II study of carboplatin/paclitaxel followed by gemcitabine versus carboplatin/gemcitabine followed by docetaxel in patients with advanced nonsmall cell lung cancer

PURPOSE: To evaluate the chemotherapeutic regimens suitable for the outpatient settings, we conducted a randomized phase II study of carboplatin/paclitaxel followed by gemcitabine versus carboplatin/gemcitabine followed by docetaxel. METHODS: Group CP(n=25): carboplatin AUC 6.0 day 1 and paclitaxel 70 mg/m2 day 1, 8, 15 every 4 weeks followed by gemcitabine 1.0 g/m2 day 1, 8, 15 every 4 weeks; group CG(n=26): carboplatin AUC 2.0 and gemcitabine 0.8 g/m2 day 1, 8 every 3 weeks followed by docetaxel 60 mg/m2 day 1, 8 every 3 weeks. RESULTS: The response rate of the first line therapy was 18.0% in group CP and 21.7% in group CG and that of the second line therapy was 10.0% and 14.3%, respectively. Time to progression of the first line therapy was 4.0 months in group CP and 4.3 months in group CG, that of the second line therapy was 2.1 months and 2.8 months, respectively. The median survival time was 10.9 months in group CP and 10.3 months in group CG. No statistically significant differences were documented in the response rate, time to progression, and overall survival between these two groups. Severe hematologic toxicity was rare in both groups and no symptomatic peripheral neuropathy was documented in carboplatin/paclitaxel therapy. CONCLUSION: Carboplatin /paclitaxel followed by gemcitabine and carboplatin/gemcitabine followed by docetaxel were well tolerated and equal in efficacy. Both regimens in this study seemed to be suitable for the outpatient settings because of their mild hematologic toxicity and peripheral neuropathy.     

Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours

Background:

This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours.

Methods:

In all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin.

Results:

Two patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade⩾3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination.

Conclusion:

Axitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug–drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.     

Efficacy of modified regimen with attenuated doses of paclitaxel plus carboplatin combination chemotherapy in elderly and/or weak patients with advanced non-small cell lung cancer

PURPOSE: We conducted this study to evaluate the activity and toxicity of a combination regimen of paclitaxel plus carboplatin in patients with advanced NSCLC aged 65 years or older and/or in those with an ECOG performance status (PS) 2. MATERIALS AND METHODS: Chemotherapy-naive patients with unresectable pathologically-proven NSCLC and of either age >or=65 or ECOG PS 2 were eligible. Patients received modified regimen with attenuated doses of paclitaxel (135 mg/m(2) i.v. for 3 h D1) and carboplatin (AUC=5, D1) every 3 weeks. RESULTS: Thirty-five patients were enrolled. Nineteen patients were aged 65 or older (54%) and 26 patients (74%) were ECOG PS 2. The objective response rate was 40% with 14 partial responses. The median time to progression was 22 weeks. Grade 3 leucopenia occurred in 1 cycle and one case of neutropenic fever. CONCLUSIONS: The modified regimen with attenuated doses of paclitaxel plus carboplatin combination chemotherapy was effective and well tolerated in patients with advanced NSCLC aged 65 years or older and/or in those with ECOG PS 2.     

Phase II study of 24-hour infusion of paclitaxel (Intaxel) with carboplatin in advanced non-small cell lung cancer

PURPOSE: To determine the activity and toxicity of combined 24-hour infusion of paclitaxel with carboplatin in advanced non-small cell lung cancer. PATIENTS AND METHODS: Eligibility required measurable disease; stage III B with malignant pleural effusion or stage IV disease, with a performance status (PS) of ECOG 0-2. Chemotherapy consisted of 24 hours continuous infusion of paclitaxel at 135 mg/m(2) on day 1, followed by carboplatin (AUC=6) on day 2. Treatment was repeated at 3-week intervals for a total of 6 cycles. RESULTS: Thirty-nine patients were enrolled. Twenty six patients were male and 13 female, with a median age of 57 years (range, 38 to 72). Six patients (15%) had stage III B and 33 (85%) had stage IV. PS 0-1/2 was 67%/33%. A total of 131 cycles was administered and the median number of cycles was 4 (range, 2-6). Grade 3-4 neutropenia, grade 3-4 leukopenia and grade 3 anemia occurred in 3%, 3% and 23%, respectively. One patient (3%) developed febrile neutropenia. Grade 3 diarrhea occurred in 3 patients (8%). Other non-hematologic toxicities were mild including mucositis and skin rash. The overall response rate was 15%. Median survival was 8 months (range 6-9.5 months) and 1-year survival rate was 20%. CONCLUSIONS: The combined 24-hour infusion of paclitaxel (Intaxel) with carboplatin is a feasible and well-tolerated regimen in the treatment of advanced NSCLC patients.     

Gemcitabine Plus Paclitaxel as Second-line Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Purpose: The aim of this retrospective study was to determine response rates, progression-free survival(PFS), overall survival (OS) and toxicity of gemcitabine and paclitaxel combinations with advanced or metastaticnon-small cell lung cancer patients (NSCLC) who have progressive disease after platinum-based first-linechemotherapy. Methods: We retrospectively evaluated the file records of patients treated with gemcitabine pluspaclitaxel in advanced or metastatic NSCLC cases in a second-line setting. The chemotherapy schedule was asfollows: gemcitabine 1500 mg/m2 and paclitaxel 150 mg/m2 administered every two weeks. Results: Forty-eightpatients (45 male, 3 female) were evaluated; stage IIIB/IV 6/42; PS0, 8.3%, PS1, 72.9%, PS2, 18.8%; medianage, 56 years old (range 38-76). Six (12.5%) patients showed a partial response (PR), 13 (27.1%) stable disease(SD), and 27 (56.3%) progressive disease (PD). The median OS was 6.63 months (95% CI 4.0-9.2); the medianPFS was 2.7 months (95% CI 1.8-3.6). Grade 3 and 4 hematologic toxicities, including neutropenia (n=4, 8.4%),and anemia (n=3, 6.3%) were encountered, but no grade 3 or 4 thrombocytopenia. One patient developed febrileneutropenia. There were no interruption for reasons of toxicity and no exitus related to therapy. Conclusion:The combination of two-weekly gemcitabine plus paclitaxel was an effective and well-tolerated second-linechemotherapy regimen for advanced or metastatic NSCLC patients previously treated with platinum-containingchemotherapy. Although the most common and dose limiting toxicities were neutropenia and neuropathy, thisregimen was tolerated well by the patients.     

Does chemotherapy have a role as palliative therapy for unfit or elderly patients with non-small-cell lung cancer?

Elderly patients and younger "unfit" patients with poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) (> or = 2) suffering from advanced non-small-cell lung cancer (NSCLC) are two different populations--both of which require palliative treatments. Elderly patients frequently experience progressive decline of organ function and multiple comorbidities, which need to be considered when choosing therapy. ECOG 1594 showed that advanced NSCLC patients with an ECOG PS of 2 did not tolerate platinum-based chemotherapy (cisplatin/paclitaxel, carboplatin/paclitaxel, cisplatin/docetaxel, carboplatin/paclitaxel). These data confirm that treatments designed specifically for this patient subset are needed. Single-agent chemotherapy seems to be a reasonable approach, and non-platinum-based combination chemotherapy should also be investigated. The oncology community has become increasingly aware of the magnitude of the problem of cancer in the elderly. More than 30% of lung cancers arise in patients > or = 70 years old. Elderly patients tolerate chemotherapy poorly, according to the few published papers, and are not considered eligible for aggressive cisplatin-based chemotherapy in clinical practice. A phase III randomized trial (ELVIS [Elderly Lung Cancer Vinorelbine Italian Study]) demonstrated survival and quality-of-life benefits with single-agent vinorelbine versus best supportive care. Among the newer drugs, gemcitabine has demonstrated activity and low toxicity in phase II studies. With this background, we performed a randomized, multicenter phase III trial (MILES [Multicenter Italian Lung Cancer in the Elderly Study]) in 707 advanced NSCLC elderly patients. The MILES study compared single-agent chemotherapy with vinorelbine or gemcitabine versus polychemotherapy with gemcitabine plus vinorelbine. Results showed no benefit in response rate, time to progression, survival, and quality of life for the combination. Single-agent chemotherapy remains the standard treatment approach for elderly NSCLC patients with advanced disease.     

Sequential versus concurrent paclitaxel and carboplatin for the treatment of advanced non-small cell lung cancer in elderly patients and patients with poor performance status: results of two Phase II, multicenter trials

The primary objective of these trials was to determine the 1-year survival of advanced non-small cell lung cancer (ANSCLC) patients (> or =70 years with PS 0-2 or > or =18 years with PS 2) receiving sequential paclitaxel and carboplatin (P --> C) or concurrent P + C. The secondary objectives were assessment of toxicities and quality of life. A total of 121 patients with NSCLC were treated. P--> C patients received paclitaxel (80 mg/m(2)) weekly x 3, followed by 1 week of rest; these 4-week cycles were repeated until relapse. At relapse, patients received carboplatin (AUC = 5, IV) on Day 1 of each 3-week cycle until evidence of further progression or lack of improvement. P + C patients received paclitaxel (80 mg/m(2)) and carboplatin (AUC = 2), weekly x 3, followed by 1 week of rest, until relapse. Patients in both studies were premedicated prior to paclitaxel administration. Sequential P + C resulted in a median survival of 8.2 months (range: <1-18.8) and P + C patients had a median survival of 9.2 months (range: <1-22.0). In both groups (P--> C) and P + C), the 1-year survival was 31%. For patients treated sequentially, treatment-related AEs (TRAE, > or =Grade 3) included fatigue (7%), neuropathy (5%), and leukopenia and diarrhea (3%, each). Grade 4 AEs were limited to neutropenia, febrile neutropenia, and sepsis (1 episode each). For patients receiving concurrent P + C, TRAE included neutropenia and leukopenia (15%, each) and shortness of breath and bilateral bone pain (10%, each). Leukopenia (n = 2) and neutropenia (n = 1) were the only Grade 4 events reported. The analysis of quality of life (QOL) questionnaires indicated that there were no obvious differences between treatment groups during the study. These drugs and treatment schema were well-tolerated when administered in the community setting and resulted in survival rates that were similar to what is reported in the literature with combination therapy administered to "high risk" patients. Finding the optimal chemotherapy regimen, that can be tolerated, remains a challenge in elderly patients.     

Gemcitabine and vinorelbine as second-line therapy in non-small-cell lung cancer after prior treatment with taxane+platinum-based regimens

Treatment options in patients with recurrent non-small-cell lung cancer (NSCLC) remain limited as a result of the poor activity of older agents after platinum-based therapy. The present phase II study aimed to evaluate the combination of gemcitabine and vinorelbine in patients with relapsed NSCLC after pretreatment with taxane+platinum-based regimens, since gemcitabine has demonstrated activity in that setting and the combination has been well tolerated in previous phase I/II studies. Patients with advanced NSCLC (stages III/IV), World Health Organization (WHO), Performance Status (PS) < or = 2, prior platinum+taxane-based chemotherapy and unimpaired haematopoietic and organ function were eligible. Chemotherapy was administered as follows: vinorelbine 25 mg/m(2) followed by gemcitabine 1000 mg/m(2), both administered on days 1 and 8, recycled every 3 weeks. 40 patients were entered and 39 were evaluable for response and all 40 for toxicity: median age was 61 years (range 50-72 years), median PS=1 (range 0-2), gender ratio=37 males/3 females, stages at initial diagnoses were IIIA=2, IIIB=14, IV=24. Metastatic sites included: lymph nodes: 23, bone: 4, liver: 5, brain: 4, lung nodules: 9, adrenals: 8, pleural effusion: 4. 22 patients had prior paclitaxel/ifosfamide/cisplatin treatment. Objective responses were; partial response (PR): 9/40 (22.5%), stable disease (SD): 13/40 (32.5%) and progressive disease (PD) 18/40 (45%). The median time-to-progression (TTP) was 4.5 months (range 1-17 months) and median survival 7 months (range 2-17+ months). 1-year survival was 17%. Grade 3 neutropenia was seen in 33% of patients. There was no grade 4 neutropenia and no episodes of febrile neutropenia. No grade 3/4 thrombocytopenia or grade 3/4 other non-haematological toxicities were observed. The combination of gemcitabine/vinorelbine is active and well tolerated in patients with advanced NSCLC failing prior taxane/platinum therapy. This regimen represents a tolerable and effective combination to apply in the palliative treatment of relapsed NSCLC.     

Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers

Background We investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel. Methods Paclitaxel was administered at 175 mg/m² or 150 mg/m² to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1(ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated. Results Total body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-μM concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel. Conclusion The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.     

Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours

Background:

As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel.

Methods:

Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m⁻² q3w, paclitaxel 80 mg m⁻² every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m⁻² q3w. The primary endpoint was safety/tolerability.

Results:

A total of 116 patients received saracatinib 125 (N=20), 175 (N=44), 225 (N=40), 250 (N=9), or 300 mg (N=3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade ⩾3 asthenic AEs (all causality) was dose-related (125 mg, 10% 175 mg, 20% ⩾225 mg, 33%), and grade ⩾3 neutropenia occurred more commonly at doses ⩾225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w.

Conclusion:

Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.     

A phase II study of biweekly paclitaxel (P) and gemcitabine (G), followed by maintenance weekly paclitaxel in elderly patients with advanced non-small cell lung cancer (NSCLC)

BACKGROUND: This phase II study was conducted to evaluate the efficacy and safety of a novel combination of paclitaxel (P) and gemcitabine (G) in an every 2 weeks schedule followed by weekly paclitaxel (P) as first-line treatment in elderly patients with locally advanced or metastatic NSCLC. METHODS: Elderly patients (> or =65 years of age) with 1997 TNM stage IIIB (pleural effusion)/stage IV NSCLC, performance status (PS) of 0-2 and normal organ function were eligible. Therapy consisted of P at 150 mg/m(2) and G at 2000 mg/m(2) administered every 2 weeks for 3 cycles followed, in progression-free patients, by P at 80 mg/m(2) every week for 6 consecutive weeks every 8 weeks for 2 cycles. RESULTS: Fifty-three eligible patients were enrolled: M/F 51/2; stage IIIB/IV 8/45; PS 0, 40%, PS 1 51%, PS 2 9%; median age, 73 years (range 67-82). The overall response rate was 32% (95% confidence interval [CI]: 19-45). The median overall survival was 7 months (95% CI: 5-9); the median progression-free survival was 5 months (95% CI: 3-6); and the 1- and 2-year survivals were 28.3% and 10.1%, respectively. Both phases of the treatment protocol were well tolerated. CONCLUSIONS: Biweekly P/G followed by weekly P is well tolerated and active as first-line therapy for elderly NSCLC patients.     

Paclitaxel, carboplatin, and gemcitabine in the treatment of patients with advanced transitional cell carcinoma of the urothelium

BACKGROUND: The objective of the current study was to evaluate the efficacy and toxicity of combination chemotherapy with paclitaxel, carboplatin, and gemcitabine in patients with advanced urothelial carcinoma. METHODS: Patients with metastatic or locally unresectable transitional cell carcinoma of the urothelium who had received either no or one previous systemic chemotherapy regimen were eligible. All patients received chemotherapy with intravenous paclitaxel at a dose of 200 mg/m(2) on Day 1, intravenous carboplatin at an area under the serum concentration-time curve of 5.0 on Day 1, and intravenous gemcitabine at a dose of 1000 mg/m(2) on Days 1 and 8. Treatment courses were repeated every 21 days. Patients were evaluated for response after they completed two treatment courses; patients who achieved an objective response and stable disease continued treatment for a total of six courses or until tumor progression. RESULTS: Sixty patients were treated between January 2000 and September 2003. Thirty-five patients (58%) had > or = 1 visceral sites of metastases, and only 4 patients (7%) had received any previous systemic chemotherapy. Twenty-six patients (43%) had achieved objective responses to treatment (12% complete responses). The median actuarial survival was 11 months, and the actuarial 1-year and 2-year survival rates were 46% and 27%, respectively. Myelosuppression was the most frequent toxicity, and Grade 3-4 neutropenia (using the National Cancer Institute Common Toxicity Criteria [version 2.0]) occurred in 72% of patients (46% of courses). Ten patients were hospitalized for the treatment of neutropenia and fever, and 1 patient died of treatment-related causes. Nonhematologic toxicities were relatively uncommon. CONCLUSIONS: The combination of paclitaxel, carboplatin, and gemcitabine was an active and tolerable regimen for patients with advanced urothelial carcinoma. However, the regimen was more toxic and showed no obvious incremental increase in efficacy compared retrospectively with various two-drug regimens.     

Rational drug sequencing of paclitaxel, gemcitabine and carboplatin in patients with untreated stage IV and select stage IIIB non-small cell lung cancer

INTRODUCTION: To conduct a phase II study evaluating the efficacy of rationally sequenced paclitaxel, gemcitabine, and carboplatin in patients with stage IV or select stage IIIB non-small cell lung cancer (NSCLC). METHODS: Patients with select stages IIIB (pleural effusion) and IV NSCLC with an ECOG performance status of 0-1 and no prior chemotherapy for their disease were eligible to participate. Treatment was delivered as follows: paclitaxel at 70 mg/m2 followed by gemcitabine at 300 mg/m2 on day 1, with carboplatin (AUC 5) on day 2 of a 28-day cycle. Response was assessed after every two cycles of therapy. The primary endpoint of this trial was response rate, with secondary endpoints of time to progression and 1 year overall survival. RESULTS: Twenty patients were enrolled on protocol, one of whom never received chemotherapy. The median number of cycles delivered was 3 (range 0-8). A partial response rate of 42% (8/19; 95% CI: 20-67%) and a stable disease rate of 11% (2/19; 95% CI: 1-33%) were observed. The median overall survival time was 9.6 months (95% CI: 4.6-16.6), with a 1 year overall survival rate of 42.1% (95% CI: 24.9-71.3%). Eight patients (42%) stopped treatment due to toxicity. CONCLUSION: Paclitaxel followed by gemcitabine and then carboplatin is an active, albeit complex, regimen in the treatment of patients with advanced NSCLC with insufficient advantage to justify continuation of this regimen.     

Long-term follow-up of patients treated with paclitaxel/carboplatin-based chemotherapy for advanced non-small-cell lung cancer: sequential phase II trials of the Minnie Pearl Cancer Research Network.

PURPOSE: To provide long-term follow-up on the survival of patients with advanced non-small-cell lung cancer treated with paclitaxel/carboplatin-based regimens in a multicenter, community-based setting. PATIENTS AND METHODS: Between March 1995 and April 1998, 321 patients with newly diagnosed stage IIIB or IV non-small-cell lung cancer were treated on sequential phase II trials with the following combination regimens: paclitaxel/carboplatin, paclitaxel/carboplatin/gemcitabine, and paclitaxel/carboplatin/vinorelbine. Details of these three regimens and patient populations have been previously reported. Responding and stable patients continued treatment until tumor progression or for a recommended six treatment courses. RESULTS: After a median follow-up of 58 months (minimum follow-up, 40 months), the median survival for the entire group of patients was 8.6 months, with actual 1-, 2-, and 3-year survival rates of 40%, 19%, and 7%, respectively. The actuarial 4-year survival rate for the entire group was 4%. No statistically significant differences in survival were seen among the three regimens. Administration of all three regimens was feasible in a community-based setting; however, myelosuppression and hospitalizations for treatment of neutropenia/fever were more frequent with the three-drug regimens. CONCLUSION: Paclitaxel/carboplatin-based regimens, in addition to prolonging median survival and improving 1-year survival, result in substantial improvements in the 2-year survival of patients with advanced non-small-cell lung cancer when compared retrospectively with supportive care or traditional cisplatin-based regimens. In these sequential phase II trials, we did not demonstrate any advantages of three-drug regimens when compared with paclitaxel/carboplatin. Because few patients remain alive after 4 years with any of these chemotherapy regimens, future treatment improvements will require the introduction of novel agents.     

Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer.

PURPOSE: To determine the efficacy and toxicity of the drug combination of carboplatin, paclitaxel, and gemcitabine in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: Patients eligible included those with advanced urothelial malignancy of any histology, no previous chemotherapy for metastatic disease, Southwest Oncology Group performance status of 2 or less, serum creatinine levels of 2 mg/dL or less, and adequate bone marrow and hepatic function. Treatment consisted of paclitaxel 200 mg/m2, carboplatin (target area under the curve = 5) on day 1, and gemcitabine 800 mg/m2 on days 1 and 8, repeated every 21 days. RESULTS: Forty-nine patients (44 men and five women) were enrolled; the patients' median age was 63 years, and their median creatinine clearance was 78 mL/min (range, 26 to 165 mL/min). Forty-three patients had transitional cell carcinoma, and six had squamous cell carcinoma or mixed histology. Ten patients had metastases to lymph nodes only, six had locally advanced disease, four had locally recurrent disease, 24 patients had visceral metastases, and five had soft tissue metastases. Twenty-one patients had disease in one site, 16 in two sites, and 12 in three sites. A total of 272 cycles were administered (median, six cycles; range, 1 to 15 cycles). Major toxicities were grade 3 and 4 neutropenia in 17 and 19 patients, respectively; grade 3 and 4 thrombocytopenia in 15 and six patients, respectively; grade 3 and 4 anemia in 10 and two patients, respectively; grade 3 neuropathy in four patients; and diarrhea in two patients. The incidence of febrile neutropenia was 1.4%; no patients died of drug toxicity. Forty-seven of the 49 patients were assessable for response. Fifteen (32%) patients experienced a complete response, and 17 (36%) patients experienced a partial response (32 of 47 patients, 68%; 95% confidence interval, 56.27 to 82.86). Responses were seen in all sites, including 15 (68%) of 22 patients with visceral metastases. The median survival was 14.7 months, with a 1-year survival of 59%. CONCLUSION: Combination paclitaxel, carboplatin, and gemcitabine is active; an encouraging number of patients with advanced urothelial carcinoma treated with this regimen experienced complete remission.     

Paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients

To evaluate the validity of administration of paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with gynecologic cancer, we explored the efficacy and safety of these regimens. From October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin with or without THP-ADR pursuant to the chart we prepared originally as first line chemotherapy in patients with gynecologic cancer. Eleven elderly patients (age > 70 years) and 62 younger patients (age < 70 years) were entered into the present study. Paclitaxel was administered as a 3-hour intravenous (i.v.) infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over 60 minutes at dosages of area under the curve (AUC) 3 to 5, administered intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p = 0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin with THP-ADR. The overall response rates were equivalent among elderly and younger patients (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin without THP-ADR was applied safely to elderly patients.     

Induction chemotherapy followed by concurrent chemoradiation for patients with non-operable stage III non-small-cell lung cancer

Combined modality treatment with chemotherapy (CT) and radiotherapy (RT) in stage III non-small-cell lung cancer is considered as standard therapy. As concomitant CT appears to be beneficial, the choice of anticancer agents and the role of induction chemotherapy is still unresolved. We present our experience based on an induction CT scheme with carboplatin plus paclitaxel followed by RT and concomitant CT. 31 patients with non-operable stage IIIA or IIIB NSCLC without pleural effusion were included in this study: 30 males, 1 female; median age 66 years (range: 50-81); 32% with non-operable stage IIIA and 68% with stage IIIB without pleural effusion; 61% squamous cell carcinoma, 32% adenocarcinoma and 7% other histologies. Regarding performance status (PS), 9.7% PS 0 and 90% PS 1 were included. Patients received 3 courses of induction CT with carboplatin AUC=6 and paclitaxel 175 mg/m(2), administrated i.v. on day 1 of each 21-day cycle, followed by thoracic irradiation (total dose 60-65 Gy, daily fractions 1.8-2 Gy) with two concurrent courses of carboplatin/paclitaxel. 16.2% of the patients achieved complete response, 48.4% partial response, 25.8% stable disease and 9.6% progression of disease. Median progression-free and overall survival was 12 and 18 months, respectively. The most frequent haematological toxicities were grade (G) 3 anaemia in 19.3%, G3 neutropenia in 9.6% and G4 neutropenia in 12.9%. Esophageal G2 toxicity (RTOG) was observed in 28.1% of cases. The induction CT followed by concomitant chemoradiation used in this study appears feasible, safe and effective when administered to an unselected inoperable NSCLC stage III patient cohort in the everyday routine clinical practice. Further, our results are comparable to previously published phase III studies.     

Topotecan and carboplatin in patients with platinum-sensitive recurrent ovarian cancer. Results of a multicenter NOGGO: phase I/II study

OBJECTIVE: Second-line treatment with paclitaxel and carboplatin enhances survival of women with platinum-sensitive recurrent ovarian cancer (ROC). However, because of its cumulative neurotoxicity, there is a strong demand for platinum-combinations with better therapeutic index. Because of its pharmacological properties, topotecan is a good adjunct to carboplatin in this setting, but its safety and efficacy remains to be defined. METHODS: Patients with platinum-sensitive ROC were eligible in this multicenter phase I/II study, stratified according to treatment-free interval (TFI). Dose level 0 consisted of topotecan 1 mg/m(2)/d1-3/q21d plus carboplatin AUC5/d3/q21d. DLT was defined as grade > or =3 neutropenia or thrombocytopenia or grade > or =3 non-hematological toxicity excluding alopecia, nausea and vomiting, accompanied by a treatment delay >1 week. RESULTS: From June 2004 to August 2005, 26 patients were enrolled, receiving a total of 145 cycles of chemotherapy. MTD was reached at topotecan 0.75 mg/m(2) and carboplatin AUC5. We observed a single grade 4 leucopenia. There were 3 (12%), 15 (58%) and 8 (31%) events of grade 3/4 hematological anaemia, leucopenia, and thrombocytopenia. Response rate was 67% (95% CI 43-85), median progression-free survival 9.5 months (95% CI 7.3-12.0), median overall survival 19.4 months (95% CI 12.3-26.9). None of the toxicity or efficacy endpoints were associated with TFI. CONCLUSION: Topotecan and carboplatin is a well tolerated novel doublet option for women with platinum sensitive ROC. We encourage further studies on this approach, but to limit the doses of topotecan to 0.75 mg/m(2)/d1-3 and carboplatin AUC 5/d3.     

Paclitaxel/Carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research Network

PURPOSE: This prospective randomized study compared overall survival (OS) in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) when treated with the platinum agent-based triple drug combination of paclitaxel/carboplatin/gemcitabine (PCG) versus the nonplatinum agent-based doublet drug combination of gemcitabine/vinorelbine. PATIENTS AND METHODS: Advanced (stages IIIB, IV, and recurrent) chemotherapy-naive patients with NSCLC and performance status 0-2 were randomly assigned to the PCG arm (paclitaxel 200 mg/m(2) on day 1, carboplatin area under the concentration-time curve of 5 on day 1, and gemcitabine 1000 mg/m(2) on days 1 and 8, every 21 days) or to the gemcitabine/vinorelbine arm (gemcitabine 1000 mg/m(2) on days 1, 8, and 15 and vinorelbine 25 mg/m(2) on days 1, 8, and 15, every 28 days). RESULTS: A total of 337 patients were randomly assigned to the 2 arms. The median time to progression was 6 months for PCG and 3.9 months for gemcitabine/vinorelbine with 1- and 2-year progression-free survival rates of 13% and 2% versus 14% and 4% (P = .324 log rank). Median OS for PCG was 10.3 months versus 10.7 months for gemcitabine/vinorelbine with 1-, 2-, and 3-year OS rates of 38%, 12%, and 2% versus 45%, 12%, and 6%, respectively (P = 0.269 log rank). Grade 3/4 thrombocytopenia, nausea/vomiting, myalgia/arthralgia, and neuropathy were significantly greater in the PCG arm. CONCLUSION: There was no difference in OS or progression-free survival when comparing PCG and gemcitabine/vinorelbine, and gemcitabine/vinorelbine was significantly less toxic. Gemcitabine/vinorelbine is a reasonable nonplatinum agent-based doublet therapy for patients with advanced NSCLC.