Phase I/II study of the combination of carboplatin and paclitaxel as first-line chemotherapy in patients with advanced epithelial ovarian cancer

Purpose: We performed a phase I/II study evaluating the combination ofpaclitaxel and carboplatin as first-line chemotherapy in patients withadvanced ovarian cancer. The aim of this study was to define a feasible andsafe combination regimen that could be recommended for future phase IIIstudies.Design: This study was a parallel two-arm, non-randomized, open trial. Ina first step, carboplatin was administered at a fixed dose of AUC 5 andpaclitaxel was escalated in 25 mg/m² steps starting at 135mg/m². Paclitaxel was given as a three-hour infusion.Carboplatin was administered on day 1 following paclitaxel in one study armand 24 hours after paclitaxel infusion on day 2 in the other study arm.Carboplatin was escalated to AUC 6 and AUC 7.5 after the MTD for paclitaxelhad been defined. Treatment was repeated every three weeks.Patients: Sixty-one patients with untreated histologically confirmedepithelial ovarian cancer were recruited of whom 59 were found eligible andevaluable for toxicity. Thirty-three patients with bidimensionally measurabledisease were evaluable for tumor response.Results: We could not detect any advantage of the two-day schedule comparedwith the more convenient one-day schedule. Dose limiting toxicities wereneutropenia, thrombocytopenia, and neurotoxicity. Except for two patients,toxicity was acceptable and clinically managable. One patient died ofneutropenic sepsis and one further patient developed grade III peripheralneurotoxicity that did not resolve within two months after chemotherapy hadbeen terminated. Overall objective response rate was 70%. The MTD forpaclitaxel was 185 mg/m² and AUC 6 for carboplatin,respectively. Secondary prophylaxis with G-CSF did not allow further doseescalation and therefore is not generally recommended.Conclusions: Paclitaxel 185 mg/m² given as three-hourinfusion followed by carboplatin AUC 6 is a feasible and safe regimen and canbe recommended for phase III trials. Observed response rates justify furtherevaluation of this combination. A randomized phase III trial comparing athree-hour infusion of paclitaxel 185 mg/m² combined witheither carboplatin AUC 6 or cisplatin 75 mg/m² as first-linechemotherapy of advanced ovarian cancer has recently been initiated by ourgroup.     

Weekly administration of topotecan–paclitaxel as second-line treatment in ovarian cancer

Purpose To investigate the weekly administration of topotecan combined with paclitaxel in pretreated advanced ovarian cancer patients; our objectives were to determine efficacy, toxicity and survival Methods The chemotherapy agents, topotecan and paclitaxel were administered on a weekly basis for 3 consecutive weeks, every 28 days. The plan was to give three courses (each course included three once-weekly infusions). The dose of topotecan was 1.75 mg/m² and of paclitaxel 70 mg/m². Results From January 2004 until January 2006, 45 patients were enrolled in this multicenter trial; 44 patients were evaluable for response and toxicity. The median age was 60 years old (range 39–82 years) and performance status was 0–2. Thirty-nine patients were in stage III and 5 in stage IV. All patients had been pretreated with carboplatin or cisplatin in combination with paclitaxel. Complete and partial responses were seen in 39% of the patients, stable disease in 43% and progressive disease in 18%; median survival time was 9 months, range 2–24+ months, (95% CI: 7.9–10.2). There was a notable absence of grade 3 toxicity except for neutropenia in 11% of the patients. Conclusion The combination of topotecan and paclitaxel administered on a weekly basis is a well-tolerated chemotherapy schedule. The response rate of 39% is quite high for patients with pretreated ovarian cancer.     

A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients

BackgroundIn esophageal cancer (EC) patients who are not eligible for surgery, definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard chemotherapy regimen. Nowadays carboplatin/paclitaxel is also often used. In this study, we compared survival and toxicity rates between both regimens.Patients and methodsThis multicenter study included 102 patients treated in five centers in the Northeast Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU (75 mg/m² and 1 g/m²) and 55 patients carboplatin/paclitaxel (AUC2 and 50 mg/m²).ResultsOverall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group {[P = 0.879, hazard ratio (HR) 0.97 [confidence interval (CI) 0.62–1.51]}, with a median survival of 16.1 (CI 11.8–20.5) and 13.8 months (CI 10.8–16.9). Median disease-free survival (DFS) was comparable [P = 0.760, HR 0.93 (CI 0.60–1.45)] between the cisplatinum/5-FU group [11.1 months (CI 6.9–15.3)] and the carboplatin/paclitaxel group [9.7 months (CI 5.1–14.4)]. Groups were comparable except clinical T stage was higher in the carboplatin/paclitaxel group (P = 0.008). High clinical T stage (cT4) was not related to OS and DFS in a univariate analysis (P = 0.250 and P = 0.201). A higher percentage of patients completed the carboplatin/paclitaxel regimen (82% versus 57%, P = 0.010). Hematological and nonhematological toxicity (≥grade 3) in the carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the cisplatinum/5-FU (19% and 38%, P = 0.001).ConclusionsIn this study, we showed comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared with cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment of cisplatinum/5-FU is a good candidate regimen for further evaluation.     

Long-term results of a randomised phase III trial of weekly versus three-weekly paclitaxel/platinum induction therapy followed by standard or extended three-weekly paclitaxel/platinum in European patients with advanced epithelial ovarian cancer

BackgroundWeekly paclitaxel/carboplatin might improve survival in platinum-resistant epithelial ovarian cancer (EOC). We compared efficacy of first-line weekly to three-weekly paclitaxel/cis- or carboplatin (PCw and PC3w) induction therapy, followed by either three or six PC3w cycles.Patients and methodsIn this multicentre, randomised phase III trial with 2×2 design, patients with FIGO stage IIb–IV EOC were randomised to six cycles PCw (paclitaxel 90 mg/m², cisplatin 70 mg/m² or carboplatin AUC 4) or three cycles PC3w (paclitaxel 175 mg/m², cisplatin 75 mg/m² or carboplatin AUC 6), followed by either three or six cycles PC3w. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were response rate (RR) and toxicity.ResultsOf 267 eligible patients, 133 received PCw and 134 PC3w. The first 105 patients received cisplatin, after protocol amendment the subsequent 162 patients received carboplatin. Weekly cisplatin was less well tolerated than weekly carboplatin. All PC3w cycles were well tolerated. At the end of all treatments, RR was 90.8% with no differences between the treatment arms. After a follow-up of median 10.3 years (range 7.1–14.8), median PFS was 18.5 (95% confidence interval (CI) 15.9–21.0) months for PCw and 16.4 (95% CI 13.5–19.2) months for PC3w (p = 0.78). Median OS was 44.8 (95% CI 33.1–56.5) months for PCw and 41.1 (95% CI 34.4–47.7) months for PC3w (p = 0.98).ConclusionsThere was no benefit in terms of OS, PFS or RR for a weekly regimen nor for extended chemotherapy as first-line treatment for EOC in European patients.     

A phase II,open-label,non-randomized,prospective study assessing paclitaxel,carboplatin and metformin in the treatment of advanced stage ovarian carcinoma

ObjectiveThe purpose of this study was to assess the efficacy and tolerability of a paclitaxel, carboplatin and metformin regimen in the first-line treatment of advanced-stage ovarian, fallopian tube, and primary peritoneal carcinoma.MethodsEligible subjects underwent surgery and 6 cycles of neoadjuvant or adjuvant dose-dense intravenous paclitaxel (80 mg/m²), carboplatin (area under the curve 5 or 6 on Day 1), and oral metformin (850 mg daily). Study participants who completed their primary therapy and attained a clinically defined complete or partial response (PR) were treated with a planned 12 cycles of paclitaxel (135 mg/m² every 21 days) and metformin (850 mg twice daily) maintenance therapy.ResultsThirty subjects received a median of 6 cycles (range, 5–6) of primary induction chemotherapy and were eligible for response evaluation; twenty-three patients exhibited a complete response, while 3 study patients obtained a PR (an overall response rate of 86.7%). Grade 3–4 hematological toxicity included neutropenia (43.3%), thrombocytopenia (10%) and anemia (36.7%). There was no incidence of grade 3–4 neuropathy although 15 patients (50%) developed grade ≤2 neurotoxicity. Additionally, we observed grade ≤2 diarrhea in 20 (66.7%) subjects. The median progression-free survival was 21 months (range, 3–52) and overall median survival was 35 months (range, 15–61). The subjects also received an aggregate 103 cycles (median, 12; range, 6–12) of maintenance chemotherapy.ConclusionThe study results suggest that the combination of paclitaxel, carboplatin and metformin is associated with moderate efficacy and a reasonable toxicity profile.     

Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR)

The combination of carboplatin and topotecan in platinum-sensitive relapsed ovarian cancer could not improve progression-free survival or overall survival compared with established standard regimens.BackgroundRandomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC).Patients and methodsPatients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m²/ days 1–3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points.ResultsA total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4–10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4–27.6 resp. 26.0–36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia.ConclusionThe combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens.     

A phase II study of modified dose-dense paclitaxel and every 4-week carboplatin for the treatment of advanced-stage primary epithelial ovarian, fallopian tube, or peritoneal carcinoma

Purpose

Traditional dose-dense chemotherapy regimens for advanced stage ovarian cancer incorporate weekly paclitaxel on a 21-day cycle and are associated with favorable efficacy but high rates of neutropenia, thrombocytopenia, and anemia. The purpose of this phase II study was to assess the response rate and toxicity of modified dose-dense paclitaxel and every 4-week carboplatin for the treatment of advanced-stage ovarian, fallopian tube, and primary peritoneal carcinoma.

Methods

All eligible patients were treated with 6 cycles of intravenous dose-dense paclitaxel (80 mg/m²) days 1, 8, and 15 and carboplatin (AUC 5 or 6) Day 1 during a 28-day cycle in accordance with an IRB-approved protocol. Patients who had clinically defined stable disease or better with a CA-125 ≤ 35 U/ml following the completion of primary induction therapy were subsequently administered a planned 12 cycles of paclitaxel (135 mg/m²; every 21 days) consolidation therapy.

Results

Eighty-eight patients received at least 3 cycles of induction dose-dense chemotherapy, of whom 76 completed 6 cycles of chemotherapy; the overall response rate was 84.2 % (56.6 % complete response). Fifty-three patients received an aggregate 473 cycles (median = 9; range 1–12) of consolidation chemotherapy. Grade 3–4 hematological toxicity included neutropenia (22.7 %), thrombocytopenia (7.9 %), and anemia (1.1 %). Further, grade 3 neuropathy developed in one (1.1 %) patient. The patients’ median disease-free survival and overall survival were 22.5 and 31.5 months, respectively.

Conclusions

This phase II study suggests that first-line treatment comprising modified dose-dense paclitaxel and monthly carboplatin chemotherapy with paclitaxel consolidation therapy preserves the efficacy of traditional dose-dense chemotherapy, while minimizing hematologic toxicity.     

First-line therapy for ovarian cancer with carboplatin followed by paclitaxel–gemcitabine (SCOTROC5): A feasibility study and comparative analysis of the SCOTROC series

BackgroundWe have conducted a series of four feasibility studies in stage Ic–IV ovarian cancer exploring six sequential first-line schedules with the same entry criteria in a total of 339 patients. Here we present the results of the sixth study, and an analysis of the overall series.MethodsIn this trial patients received 4 cycles of carboplatin AUC 7 every 3 weeks, followed by 4 cycles of concurrent paclitaxel 175 mg/m² (day 1) and gemcitabine 1000 mg/m² (days 1 and 8) every 3 weeks. The primary end-point of the trial was feasibility of administering all cycles of planned chemotherapy to >60% of patients.ResultsFifty-four patients were recruited to the trial between June 05 and June 06. A total of 40 (74.1%) patients received all 8 cycles of treatment. Reasons for early discontinuation included toxicity (n = 8) and disease progression (n = 4). The overall response rate was 73.7%, and the median progression free survival (PFS) was 14.2 months with a median follow-up of 24 months. A comparative analysis of all six regimens from the SCOTROC series suggests that the sequential schedule in which paclitaxel was given weekly (median PFS 19.5 m) is most effective.¹ConclusionThe sequential schedule explored in this trial is feasible, but comparative efficacy analysis suggests that trials involving weekly paclitaxel should be prioritised for further study.     

Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG,phase I,open-label dose-escalation study (IND 179)

BackgroundThe purpose of the study was to assess the safety, tolerability, recommended phase II dose (RPTD), and preliminary antitumor activity of the combination of carboplatin–paclitaxel (Taxol)–temsirolimus.Materials and methods: Patients with solid malignancies suitable for carboplatin–paclitaxel (CP) chemotherapy and two or less prior lines of chemotherapy received 15, 20, or 25 mg of temsirolimus per week with CP given every 21 days. Thirty-eight eligible patients were entered into six dose levels with the first two levels administering temsirolimus on days 8 and 15 and the subsequent four dose levels switching to days 1 and 8 temsirolimus administration.ResultsDays 8 and 15 administration of temsirolimus was not feasible due to myelosuppression on day 15. CP on day 1 with temsirolimus on days 1 and 8 was well tolerated. Dose-limiting toxicity (DLT) was grade 4 thrombocytopenia (n = 2) and grade 3 fatigue (n = 1). Relative dose intensities for carboplatin, paclitaxel, and temsirolimus at the RPTD were 92%, 82%, and 56%, respectively. Non-DLT treatment-related adverse events occurring in >20% of patients included fatigue, mucositis, alopecia, neuropathy, nausea, neutropenia, thrombocytopenia, and infection. Grade 3/4 non-hematological toxicity was rare. Partial responses (PRs) and disease stabilization were seen in 46% and 49% of patients, respectively. Nine of 11 (82%) endometrial cancer patients had objective PRs.Conclusions:Carboplatin–paclitaxel–temsirolimus is well tolerated and the RPTD is carboplatin area under the curve 5 mg/ml/min, paclitaxel 175 mg/m², both given on day 1 with temsirolimus 25 mg on days 1 and 8.     

Carboplatin and Paclitaxel Plus ASA404 as First-Line Chemotherapy for Extensive-Stage Small-Cell Lung Cancer: A Multicenter Single Arm Phase II Trial (SAKK 15/08)

IntroductionSmall-cell lung cancer (SCLC) is a highly vascularized tumor. ASA404 is a tumor vascular disrupting agent. This is the first trial to report the effects of combining chemotherapy with ASA404 in SCLC.MethodsPatients with untreated metastatic SCLC were treated with carboplatin (area under curve, 6) plus paclitaxel (175 mg/m²) plus ASA404 (1800 mg/m²) on day 1 every 21 days for up to 6 cycles. The primary endpoint was the progression-free survival (PFS) rate at 24 weeks.ResultsMedian age was 61 years; 53% were women, 41% had weight loss; and 96% had a performance status of 0-1. Twelve patients completed all 6 cycles, and most adverse events were related to chemotherapy. Median PFS and time to progression were 7.0 months (95% CI, 5.7-9.4 months) and 7.5 months (95% CI, 5.7-9.4 months), respectively. The progression-free survival (PFS) rate at 24 weeks was 41% (95% CI, 18%-65%). The overall response rate was 94%. The median overall survival time was 14.2 months (95% CI, 8.2-16.0 months) and 1-year survival was 57%. The median follow-up time was 17.7 months. Due to negative results with ASA404 in non–small-cell lung cancer trials, the trial was stopped prematurely after 17 of 56 planned patients were being accrued.ConclusionsThis is the first report of a clinical trial with a vascular disrupting agent in SCLC. No unexpected toxicity was observed. PFS was not prolonged with carboplatin and paclitaxel plus ASA404.     

A Phase II Study of Weekly Paclitaxel/Estramustine/Carboplatin in Hormone-Refractory Prostate Cancer

PurposeThe objective of this phase II study was to determine the response rate in patients with hormone-refractory prostate cancer given paclitaxel/estramustine/carboplatin for weeks 1, 2, and 3 of a 4-week cycle.Patients and MethodsEighty-four patients were registered into the trial. Paclitaxel 80 mg/m² and carboplatin area under the curve of 2 were administered intravenously on days 2, 9, and 16, and oral estramustine 280 mg 3 times daily was given on days 1-3, 8-10, and 15-17 for 6 cycles. Eastern Cooperative Oncology Group performance status 0, 1, and 2 was 46%, 41%, and 13%, respectively, and median age was 70 years (range, 53-82 years), with 58 patients (69%) aged > 65 years. The majority of patients (83%) were white. Fifteen patients (18%) had received previous chemotherapy, 61 patients (73%) had undergone previous surgery, and 51 patients (61%) had received previous external-beam radiation therapy.ResultsIntent-to-treat analysis revealed a ≥ 50% prostate-specific antigen decrease rate of 61%. Median survival was 15.3 months. The most frequent grade ≥ 3 toxicities included fatigue (11%), nausea (10%), neutropenia (9%), anemia (6%), and vomiting (6%).ConclusionPaclitaxel/estramustine/carboplatin administered in a weekly regimen is highly effective in the treatment of hormone-refractory prostate cancer and can be administered with reasonable safety in an outpatient setting.     

Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy,erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial

BackgroundAfatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy.Patients and methodsPatients with relapsed/refractory disease following ≥1 line of chemotherapy, and whose tumors had progressed following initial disease control (≥12 weeks) with erlotinib/gefitinib and thereafter afatinib (50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m²/week) or investigator's choice of single-agent chemotherapy. The primary end point was progression-free survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes.ResultsTwo hundred and two patients with progressive disease following clinical benefit from afatinib were randomized to afatinib plus paclitaxel (n = 134) or single-agent chemotherapy (n = 68). PFS (median 5.6 versus 2.8 months, hazard ratio 0.60, P = 0.003) and ORR (32.1% versus 13.2%, P = 0.005) significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-related adverse events were consistent with those previously reported with each agent.ConclusionAfatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy.Trial registration numberNCT01085136 (clinicaltrials.gov).     

A phase II multicenter study of oxaliplatin in combination with paclitaxel in poor prognosis patients who failed cisplatin-based chemotherapy for germ-cell tumors

BackgroundThe aim of this study is to determine feasibility and efficacy of the combination regimen oxaliplatin and paclitaxel in patients with cisplatin (CDDP)-refractory germ-cell tumors (GCT).Patients and methodsPatients with either a cisplatin absolute-refractory GCT defined as progressive disease (PD) during or within 1 month of CDDP administration or with a poor prognosis relapse, defined as PD between the second and the sixth month after CDDP administration, were treated with a combination of oxaliplatin (130 mg/m²) and paclitaxel (175 mg/m²) administered every 21 days. Primary end point was efficacy.ResultsTwenty-seven patients were included. Patients were pretreated with a median of two lines of cisplatin-based chemotherapy (range 1–5). Sixteen patients were absolute refractory. Five patients had relapsed after high-dose chemotherapy plus stem-cell support. There were no complete responses but there was one marker-positive partial response and nine disease stabilization (34, 6%). After a median follow-up of 65 months, two patients are disease-free survivors. Main toxicity was leucocytopenia grade 3/4 in 30% of the patients.ConclusionCombination chemotherapy with oxaliplatin and paclitaxel is feasible with acceptable toxicity and may be effective if combined with additional treatment in patients with CDDP-refractory GCT.     

A randomized phase III trial of combined paclitaxel, carboplatin, and radiation therapy followed by weekly paclitaxel or observation for patients with locally advanced inoperable non-small-cell lung cancer

BackgroundThis study was designed to determine the efficacy and safety of additional maintenance chemotherapy after standard induction chemotherapy/radiation therapy (XRT) in stage III non–small-cell lung cancer (NSCLC). The primary objective was to increase 1-year survival.Patients and MethodsEligible patients (N = 220) had confirmed stage IIIA or IIIB NSCLC, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients received induction chemotherapy (paclitaxel 200 mg/m² + carboplatin AUC = 6/3 weeks) for 2 cycles, followed by paclitaxel 45 mg/m² + carboplatin AUC = 2 weekly ×7 and concurrent daily XRT (cumulative dose = 66.6 Gy in 37 fractions) and then observation or maintenance. Before randomization, 101 patients (46%) discontinued treatment due to progressive disease (n = 34), toxicity (n = 33), patient request (n = 13), death (n = 7), or other (n = 14). The remaining 119 patients were randomly assigned to either “observation” or “maintenance” (6 cycles of paclitaxel 70 mg/m²/wk [3 weeks on/1 week off]); a median of 5 of 6 planned cycles was delivered in the maintenance arm.ResultsFor the observation group vs. the maintenance group, the estimated 1- and 4-year survival rates were 77% vs. 66% and 38% vs. 17% (median, 26.9 months vs. 16.1 months, respectively [P = .07]); the estimated 1- and 4-year performance-free survival (PFS) were 46% vs. 24% and 25% vs. 13% (median, 10.2 months vs. 8.2 months, respectively [P = .04]). Common toxicities were neutropenia, thrombocytopenia, and fatigue.ConclusionMedian survival in both groups surpassed the standard, most notably the 26.9-month survival in the observation group. Maintenance chemotherapy, when added to a regimen of both induction and concurrent chemoradiotherapy, did not improve clinical outcomes, with endpoints favoring the standard arm.     

Phase I dose-finding study of paclitaxel with panitumumab,carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck

BackgroundPanitumumab has the potential to improve the therapeutic ratio of concurrent chemoradiotherapy for squamous cell carcinoma of the head and neck (SCCHN).Patients and methodsThis phase I dose-finding study investigated escalating doses of paclitaxel (Taxol) given concurrently with panitumumab, carboplatin and intensity-modulated radiotherapy (IMRT) for stage III–IVB SCCHN. Untreated patients with oral cavity, oropharynx, larynx, hypopharynx or unknown primaries were eligible. Additional eligibility criteria included measurable disease, good performance status and no contraindication to therapy. Patients received weekly fixed doses of panitumumab and carboplatin plus escalating doses of paclitaxel with IMRT.ResultsNineteen patients were enrolled on to two dose levels (DLs): weekly paclitaxel 15 mg/m² (n = 3) and 30 mg/m² (n = 16). One dose-limiting toxicity occurred in DL 2, which was declared the maximum tolerated dose. All patients experienced mucositis, primarily grade 3 or more. Oral pain, xerostomia, dysphagia, weight loss, dermatitis, nausea and acneiform rash were frequent. All patients had partial response according to RECIST, whereas the overall complete clinical response rate was 95%. At median follow-up of 21 months, 18 of 19 patients (95%) remained disease free.ConclusionsPanitumumab, carboplatin, paclitaxel and IMRT are well tolerated and appear highly active in the treatment of SCCHN. Further study of this regimen in SCCHN is warranted.     

Phase I trial of bi-weekly paclitaxel and gemcitabine as second-line therapy for patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy

A phase I study was conducted to evaluate the maximum tolerated dose, feasibility, and efficacy of biweekly-administered paclitaxel and gemcitabine in patients with non-small-cell lung cancer (NSCLC) who had prevously been treated with platinum-based chemotherapy. In a dose-escalation study, 18 patients, under 75 yr old, with unresectable NSCLC that had relapsed or was resistant after platinum-containing chemotherapy with performance status of 0–2 were enrolled. Patients were treated with paclitaxel and gemcitabine biweekly. The dose escalation levels of paclitaxel (mg/m²) at a fixed dose of gemcitabine 1000 mg/m² were 110 (level 1), 130 (level 2), 150 (level 3), and 170 (level 4), respectively. All patients were eligible for evaluation of toxicities. At level 4, one patient developed an infection with grade 3 neutropenia and two other patients developed severe neurotoxicity (over grade 3). Thus, the recommended dose for phase II was paclitaxel 150 mg/m² and gemcitabine 1000 mg/m² due to dose-limiting toxicities including neutropenia and peripheral neurotoxicity. Partial response was seen in 4 cases of the 18 assessable patients, with an overall response of 22%. Bi-weekly paclitaxel and gemcitabine is feasible and appears to be an efficacious combination chemotherapy as second-line chemotherapy in refractory and recurrent patients with NSCL C who had been previously exposed to platinum-containing chemotherapy.     

A randomized,phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer

BackgroundPaclitaxel–carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen.Patients and methodsA total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m² on days 1 and 8 plus carboplatin area under the concentration–time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m² on days 1 and 8 plus paclitaxel 200 mg/m² on day 1 (GP), or paclitaxel 225 mg/m² plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression.ResultsMedian survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC.ConclusionsNon-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.     

A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma

Background: There is no clear data on the optimum number of coursesof platinum chemotherapy required for treating advanced ovarian cancer. Aprospective randomised trial was performed to compare five with eight coursesof either carboplatin 400 mg/m² or cisplatin 75mg/m² given four-weekly to patients with stage IC–IVovarian cancer.Patients and methods: 255 patients were entered into the study and233 were eligible for randomisation: 118 to five courses and 115 to eightcourses. In each randomisation, half the patients received carboplatin andhalf received cisplatin.Results: The mean number of courses received on the five arm was 4.74and on the eight arm, 6.42, an increase of 35%. The median survival forall patients was 24 months with the median survival for the 156 patients withstage 3 disease being 21 months. No difference was detected in survival (P = 0.53) or time to progresion from initial surgery ( P = 0.29) betweenthe two arms of the trial. False-negative calculations based on a multivariateanalysis show that the trial currently has 95% power for excluding adifference of 10% in favour of the eight course arm at three years.Conclusion: There is insufficient evidence at the present time tojustify more than five courses of first-line single agent platinumchemotherapy in the management of advanced ovarian cancer.     

A phase II study of weekly paclitaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

Purpose: Both paclitaxel (P) and carboplatin (C) have a significant activity in non-small cell lung cancer (NSCLC). Weekly administration of P is active, is dose intense, and has a favorable toxicity profile. To evaluate the efficacy and toxicity of weekly P and C in advanced-stage NSCLC, we initiated this phase II study in patients with advanced NSCLC (III B with pleural effusion and stage IV). Patients and Methods: Eligible patients were treated with paclitaxel 100 mg/m² intravenously (iv) over 1 h followed by carboplatin AUC 2 iv over 30 min. This treatment was administered weekly for 3 of every 4 wk until disease progression or intolerable toxicities. Results: Of the 30 patients enrolled in the study, one patient did not meet the eligibility criteria. Of the remaining 29 patients, 6 did not complete at least two cycles of treatment and hence were not assessable for response. The overall response rate was 43.5% (10/23) (all partial responses). An additional 43.5% had stable disease. The median time to progression was 162 d and the median duration of response was 169 d. Overall survival at 1 yr on intent-to-treat analyses was 44% and median survival was 10.8 mo. We observed the following grade 3/4 toxicities: hypersensitivity to paclitaxel (13%), hypersensitivity to carboplatin (3%), neutropenia (31%), thrombocytopenia (7%); 31% experienced grade 1 neuropathy and 17% experienced grade 2 neuropathy. Conclusions: We conclude that weekly paclitaxel and carboplatin is active and very well tolerated in patients with advanced NSCLC.