Second-line chemotherapy with weekly paclitaxel in patients with advanced non-small-cell lung cancer

In this phase II study we assessed the activity and toxicity of weekly paclitaxel in second line treatment of non-small-cell lung cancer. Sixteen patients were included. Disease staging was IV in 12 patients and IIIB in 4. Paclitaxel (80 mg/m²) was administered as a weekly 1 hour infusion. Partial response was observed in two patients, stable disease in 4 and progression in 10. The median progression time was 78 days and the median survival was 160 days. There was not severe toxicity. Weekly infusion of paclitaxel as second-line chemotherapy induces moderate rates of response with excellent tolerance.     

Gemcitabine pharmacokinetics and interaction with paclitaxel in patients with advanced non-small-cell lung cancer

PURPOSE: Gemcitabine administered at a fixed dose rate of 10 mg/m(2) per min has been reported to achieve plasma steady-state concentrations ranging from 10 to 20 microM in patients with acute leukemia. These concentrations have been shown to saturate the intracellular accumulation of the active triphosphate metabolite. We designed this pharmacokinetic study to assess the ability of a fixed dose rate of gemcitabine to achieve the desired steady-state concentration in the absence and presence of paclitaxel in patients with solid tumors. PATIENTS AND METHODS: A group of 14 patients with advanced non-small-cell lung cancer received paclitaxel 110 mg/m(2) over 3 h on days 1 and 8 and gemcitabine 800 mg/m(2) over 80 min on days 1 and 8 every 21 days. Patients received gemcitabine alone on cycle (C) 1, day (D) 1. Pharmacokinetic samples were collected at 0, 15, 30, 45, 60 and 80 min during infusion and 0.25, 0.5, 1, 2, 4, 6, and 8 h after infusion on C1D1, C1D8, C2D1, C4D1 and C6D1. RESULTS: Of 13 patients included in the pharmacokinetic analysis, 61% achieved the desired steady-state concentration (C(ss)) with gemcitabine alone (C1D1), whereas only 0 to 45% of patients achieved the desired C(ss) with paclitaxel and gemcitabine, depending on the treatment cycle. Paclitaxel significantly decreased systemic clearance (Cl(T); P=0.012) and volume of distribution (V(d); P=0.050) and significantly increased C(ss) ( P=0.009). Gemcitabine plasma pharmacokinetic parameters demonstrated great interpatient variability in the absence of paclitaxel (C(ss) 30%, Cl(T) 30%, V(d) 55%). Interpatient and intrapatient variability in gemcitabine pharmacokinetics were not observed when gemcitabine was administered in combination with paclitaxel (P>0.05). CONCLUSIONS: Gemcitabine plasma pharmacokinetic parameters are significantly altered in the presence of paclitaxel.     

Thrombin-activatable fibrinolysis inhibitor levels in patients with non-small-cell lung cancer

BACKGROUND: An increased incidence of thromboembolic events has been described in patients with cancer. Cancer cells are attributed with producing procoagulant substances such as cysteine protease and tissue factor to activate factor X and factor VII, respectively. However, there are limited data on the pathogenesis behind this hypercoagulability state, and the thrombin generation, fibrinolytic system, and coagulation inhibition system during cancer are largely obscure. In this study, we investigated the changes of different steps of coagulation pathway in patients with non-small-cell lung cancer (NSCLC) and compared the data with those of healthy controls. PATIENTS AND METHODS: Forty-four patients with NSCLC and 36 age-matched controls were recruited for this study. Prothrombin fragment 1 + 2 (F 1 + 2) were used as a marker of thrombin generation; thrombin-activatable fibrinolysis inhibitor (TAFI) immunologic activity level was measured for inhibition of the fibrinolytic system, and tissue factor pathway inhibitor (TFPI) activity was assessed for the coagulation inhibition system. In the patient group, the relationships between TAFI activity levels and patient parameters (age, sex, body mass index [BMI], histopathology, and stage) were evaluated. RESULTS: The TAFI activity, F 1 + 2 levels, and TFPI activity were significantly higher in patients with lung cancer than in subjects in the control group (P < .05; P < .0001; and P < .0001; respectively). However, there were no statistically significant associations between TAFI activity levels and patient age, sex, BMI, histopathology, or stage of disease (P > .05). CONCLUSION: In this study, it was clearly shown that patients with lung cancer have hypercoagulable states and that the pathogenesis of thrombotic events in these patients is multifactorial. Increased TFPI is a reflection of thrombin activity in this patient group. Confirmatory studies with larger patient groups should be performed in this population.     

Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2.

PURPOSE: Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect. CONCLUSION: Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.     

Carboplatin in combination with etoposide in inoperable non-small-cell lung cancer (NSCLC)

Carboplatin, a second generation platinum complex, is less nephrotoxic and emetogenic than its parent compound. We have tested the objective response to and the toxicity of the combination carboplatin 330 mg m-2 on day 1 with etoposide 120 mg m-2 on days 1, 3 and 5, administered every 3 weeks in histologically proven inoperable non-small-cell lung cancer (NSCLC) patients with a good performance status. Thirty-one patients entered the study; 29 were evaluable for response, 24 after 3 courses and 5 after 2 courses of chemotherapy. An overall response rate of 21% was found including zero complete response and 6 partial responses. In addition, 3 minor responses (10%), 12 stable diseases (38%), and 9 progressive diseases (39%) were observed. The median survival was 48 weeks, including 68 weeks for non-metastatic (M0) patients and 27 weeks for metastatic (M+) patients. This regimen was well tolerated. Gastrointestinal toxicity never exceeded WHO grade II and renal function remained in the normal range for all cases. Haematological toxicity was low in the majority of the cases; nevertheless it proved to be the dose limiting toxicity as illustrated by two grade III anemia, one grade III leucopenia, one grade III and one grade IV thrombocytopenia. Carboplatin-etoposide combination is not more active, but clearly much less toxic than cisplatin-etoposide in NSCLC.     

Drug distribution and pharmacokinetic/pharmacodynamic relationship of paclitaxel and gemcitabine in patients with non-small-cell lung cancer

Background:Gemcitabine and paclitaxel are two of the mostactive agents in non-small-cell lung cancer (NSCLC), and pharmacologicinvestigation of the combination regimens including these drugs mayoffer a valuable opportunity in treatment optimization. The presentstudy investigates the pharmacokinetics and pharmacodynamics ofpaclitaxel and gemcitabine in chemotherapy-naive patients with advancedNSCLC within a phase I study. Patients and methods:Patients were given i.v. paclitaxel 100 mg/m² byone-hour infusion followed by gemcitabine 1500, 1750 and 2000mg/m² by 30-min administration. Plasma levels of paclitaxel,gemcitabine and its metabolite 2,2-difluorodeoxyuridine(dFdU) were determined by high-performance liquid chromatography (HPLC).Concentration-time curves were modeled by compartmental andnon-compartmental methods and pharmacokinetic/pharmacodynamic (PK/PD)relationships were fitted according to a sigmoid maximum effect(E_max) model. Results:Paclitaxelpharmacokinetics did not change as a result of dosage escalation ofgemcitabine from 1500 to 2000 mg/m². A nonproportionalincrease in gemcitabine peak plasma levels (C_max, from 18.56± 4.94 to 40.85 ± 14.85 µg/ml) and area under theplasma concentration-time curve (AUC, from 9.99 ± 2.75 to 25.01± 9.87 h·µg/ml) at 1500 and 2000mg/m², respectively, was observed, suggesting the occurrenceof saturation kinetics at higher doses. A significant relationshipbetween neutropenia and time of paclitaxel plasma levels 0.05µmol/l was observed, with a predicted time of 10.4 h to decreasecell count by 50%. A correlation was also observed betweenpercentage reduction of platelet count and gemcitabine C_max,with a predicted effective concentration to induce a 50% decreaseof 14.3 µg/ml. Conclusion:This study demonstratesthe lack of interaction between drugs, the nonproportionalpharmacokinetics of gemcitabine at higher doses and the E_maxrelationship of paclitaxel and gemcitabine with neutrophil and plateletcounts, respectively. In addition, gemcitabine 1500 mg/m² isthe recommended dosage in combination with paclitaxel 100mg/m² for future phase II studies, due to its predictablekinetic behaviour and less severe thrombocytopenia than expected.     

Cisplatin-based combination chemotherapy for elderly patients with non-small-cell lung cancer

Purpose: To compare the response rates, toxicities and survival durations of elderly patients (70 years of age or more) with those of younger patients ( less than 70 years of age) with non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. Patients and methods: We analyzed retrospectively the data of 203 assessable patients entered on a prospective randomized trial of cisplatin-based combination chemotherapy. Chemotherapy consisted of three dosage regimens: (1) vindesine and cisplatin (VP); (2) mitomycin, vindesine and cisplatin (MVP); or (3) etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM). Results: A greater proportion of elderly patients had localized disease and more squamous cell carcinoma than non-elderly patients. The overall response rates were 44% in the elderly group and 28% in the non-elderly group. In the EP/VM arm, the response rate was significantly better in the elderly group than in the non-elderly group. The frequency of grade 4 leukocytopenia in the MVP and EP/VM arms in the elderly group was significantly greater than in the non-elderly group (P < 0.05). No differences were found in nonhematological toxicities between the two groups. There was no difference in overall survival between the groups. Conclusion: Elderly patients treated with mitomycin-containing regimens have higher hematologic toxicities than younger patients. The results of this study are consistent with the previously reported pharmaco logic data on mitomycin suggesting altered pharmacokinetics in elderly patients. The improved response rate in the elderly patients was probably because more elderly patients had earlier disease, squamous cell carcinoma and better performance status. Cisplatin-based chemotherapy was tolerable for most elderly NSCLC patients with good performance status. Received: 30 October 1996 / Accepted: 20 March 1997     

吉西他滨联合顺铂治疗32例老年非小细胞肺癌

目的：观察吉西他滨(健择，GEM)与顺铂(DDP)联合化疗对老年非小细胞肺癌(NSCLC)的疗效和毒副反应。方法：老年NSCLC32例，予以GEMl000mg／m^2于第1、8天静脉泵人，DDP70mg／m^2第1天静滴。21天为1周期，按WH0疗效及毒副反应标准评价。结果：32例均化疗2个周期以上，共化疗134个周期，其中完全缓解(CR)1例(3．2％)，部分缓解(PR)13例(40．6％)，稳定(SD)13例(40．6％)，进展(PD)5例(15．6％)，有效率(RR)43．8％。主要毒副反应为骨髓抑制，Ⅲ-Ⅳ度血红蛋白降低周期数占7．5％(10／134)，Ⅲ-Ⅳ度白细胞减少周期数占12．7％(17/134)，Ⅲ—Ⅳ度血小板减少周期数占23．1％(31／134)。结论：GEM联合DDP化疗方案，对老年非小细胞肺癌有一定的客观肿瘤缓解率，毒副反应低，耐受性好，值得在临床推广。     

Response to treatment and prognostic significance of supradiaphragmatic disease in patients with high-grade serous ovarian cancer

ObjectivesThis study was designed to investigate the response to chemotherapy of supradiaphragmatic disease diagnosed by preoperative imaging. As secondary objectives, oncologic outcomes of patients affected by supradiaphragmatic disease and their pattern of recurrence were also evaluated.MethodsData of consecutive patients with newly diagnosed FIGO stage IV (for supradiaphragmatic disease) epithelial ovarian cancer undergoing either primary debulking surgery or neoadjuvant chemotherapy plus interval debulking surgery between 2004 and 2021, were retrospectively collected. All patients were preoperatively evaluated by chest/abdominal CT scan or ¹⁸F-FDG PET/CT preoperatively and at follow-up to evaluate response to chemotherapy. At follow-up visits, site of recurrence diagnosed by imaging techniques was systematically recorded as it occurred. Progression-free and overall survival were measured by using Kaplan-Meier and Cox models.ResultsA total of 130 patients was included in this study with a median (range) follow-up of 32.9 (12.8–176.7) months. Complete or partial response was achieved in most of the patients after 3 cycles (77.7%) and 6 cycles (85.4%) of chemotherapy. At follow-up, recurrence occurred in 96 (73.8%) patients and the main site of recurrence was abdomen only in 64 (66.7%) patients. At multivariate analysis, residual disease after surgery was the only variable influencing survival outcomes.ConclusionsSupradiaphragmatic disease respond to chemotherapy in most patients affected by advanced EOC and recurrence mainly occurs in the abdomen. Results from this study confirms that abdominal optimal cytoreduction is the main surgical goal in the treatment of women affected by FIGO stage IV EOC.     

Dosimetric predictors of radiation esophagitis in patients treated for non-small-cell lung cancer with carboplatin/paclitaxel/radiotherapy

PURPOSE: To establish dosimetric predictors of radiation esophagitis (RE) in patients treated with a combination of carboplatin, paclitaxel, and radiotherapy. METHODS AND MATERIALS: Three-dimensional radiotherapy plans of 26 patients with non-small-cell lung cancer who received 50-60 Gy of radiotherapy concurrently with weekly administration of carboplatin (AUC 2) and paclitaxel (40-45 mg/m(2)) were reviewed in conjunction with RE. The factors analyzed included the following: percentages of organ volumes receiving >40 Gy (V40), >45 Gy (V45), >50 Gy (V50), and >55 Gy (V55); the length of esophagus (total circumference) treated with >40 Gy (LETT40), >45 Gy (LETT45), >50 Gy (LETT50), and >55 Gy (LETT55); the maximum dose in the esophagus (Dmax); and the mean dose in the esophagus (Dmean). Data were obtained on the basis of superposition algorithm. RESULTS: All factors except Dmax showed statistical correlation with RE. Good correlations were shown between RE and LETT45 (rho = 0.714) and V45 (rho = 0.686). CONCLUSIONS: LETT45 and V45 appear to be useful dosimetric predictors of RE. It is also suggested that Dmax does not predict RE.     

Phase I study of TLR9 agonist PF-3512676 in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer

This phase I, open-label study investigated the Toll-like receptor 9 agonist, PF-3512676, in combination with carboplatin and paclitaxel in Japanese patients with advanced, non-small-cell lung cancer (NSCLC). Patients ( n =  12) with treatment-naive stage IIIB or IV NSCLC received single-agent PF-3512676 subcutaneously once during the first 7 days (monotherapy phase) in three escalating dose levels (0.1, 0.2, and 0.4 mg/kg) followed by a combination phase during which patients received 0.1 or 0.2 mg/kg PF-3512676 subcutaneously on days 8 and 15 of each 3-week cycle of carboplatin (area under the curve, 6 mg × min/mL) and paclitaxel (200 mg/m²). Safety and pharmacokinetics of PF-3512676 were assessed during monotherapy and combination therapy phases. PF-3512676 was tolerable as monotherapy or in combination with chemotherapy in patients with NSCLC. Most common treatment-related, non-hematologic adverse events (AEs) throughout the study were injection-site reactions ( n =  12, 100%) and flu-like symptoms ( n =  11, 91.7%) that were each grade 1 or 2 in all but one patient. All patients experienced neutropenia and leukopenia (≥grade 3 in 11 [91.7%] and seven [58.3%] patients, respectively). One patient in dose level 2 had a dose-limiting toxicity: grade 3 rash and grade 3 increase in γ-glutamyltransferase during combination therapy. Mean PF-3512676 half-life ranged from 4.8 to 21.6 h (longer with higher doses). Four (33%) patients had objective responses (one complete response, three partial responses), and seven (58%) patients achieved stable disease. PF-3512676 as monotherapy and in combination with chemotherapy had an acceptable safety profile in Japanese patients with treatment-naive NSCLC. ( Cancer Sci 2009)     

Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer: a phase II study from Indiana University.

Background: Recombinant human angiostatin (rhAngiostatin) functions as a potent inhibitor of angiogenesis. This study combined rhAngiostatin with a standard chemotherapy regimen in patients with advanced non-small-cell lung cancer (NSCLC).Patients and methods: Eligible patients had chemotherapy-naïve stage IIIB (with pleural effusion) or IV NSCLC, performance status (PS) 0 or 1, no history of bleeding, brain metastasis or requirements for anti-coagulation. Patients received carboplatin (AUC 5) intravenously and paclitaxel (175 mg/m²) intravenously day 1 + subcutaneous rhAngiostatin at either 15 mg or 60 mg twice daily. Cycles were repeated every 3 weeks, for up to six cycles. Patients without progression after completing at least four cycles were continued on maintenance rhAngiostatin until disease progression.Results: Patient characteristics (n = 24) were: 16 males, median age 66 years (range 45–78), 54% PS 1, 83.3% stage IV and 62.5% adenocarcinoma. Grade 3/4 toxicities included: fatigue 47.8%, neutropenia 39.1%, dyspnea 39.1%, vascular 26.1% and infection 17.4%. The overall response rate was 39.1%, 39.1% stable disease and 21.7% progressive disease. Median time to progression was 144 days, and 1-year survival was 45.8%.Conclusions: rhAngiostatin in combination with paclitaxel and carboplatin is feasible and results in a high disease control rate in patients with advanced NSCLC.     

Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic interactions in patients with non-small-cell lung cancer.

PURPOSE: To assess possible pharmacokinetic and pharmacodynamic interactions between gemcitabine and paclitaxel in a phase I/II study in non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Eighteen patients with advanced NSCLC received the following in a 3-week schedule: gemcitabine 1,000 mg/m(2) (30 minutes, days 1 and 8) and paclitaxel 150 (n = 9) or 200 mg/m(2) (n = 9) before gemcitabine (3 hours, day 1). Plasma pharmacokinetics and pharmacodynamics in mononuclear cells were studied. RESULTS: Gemcitabine did not influence paclitaxel pharmacokinetics at 150 and 200 mg/m(2) (area under the concentration-time curve [AUC], 7.7 and 8.8 micromol/ L. h, respectively; maximum plasma concentration [C(max)], 3.2 and 4.0 micromol/L, respectively), and paclitaxel did not influence that of gemcitabine (C(max), 30 +/- 3 micromol/L) and 2',2'-difluorodeoxyuridine. Paclitaxel, however, dose-dependently increased the C(max) of gemcitabine triphosphate (dFdCTP), the active metabolite of gemcitabine, from 55 +/- 10 to 106 +/- 16 pmol/10(6) cells.( )No significant difference in the AUC of dFdCTP was observed. Moreover, the gemcitabine-paclitaxel combination significantly increased ribonucleotide levels, most pronounced for adenosine triphosphate (six- to seven-fold). Postinfusion paclitaxel AUC was related to pretreatment hepatic function (bilirubin: r = 0. 79; P <.001) and to the percentage decrease in platelets (r = 0.61; P =.009). The latter was also related to the duration of paclitaxel concentration above 0.1 micromol/L (r = 0.62; P =.007). Gemcitabine C(max )was related to the percentage decrease in platelets (r = 0. 58; P =.01), pretreatment hepatic function (bilirubin: r = 0.77; P <. 001), and to plasma creatinine (r = 0.5; P =.03). The pharmacokinetics and pharmacodynamics were not related to response or survival. CONCLUSION: Gemcitabine and paclitaxel pharmacokinetics were related to the percentage decrease in platelets. Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP accumulation. This might enhance the antitumor activity of gemcitabine.     

紫杉醇和顺铂加放疗同步治疗Ⅲ期非小细胞肺癌临床观察

目的观察同步放化疗治疗局部晚期非小细胞肺癌的近期疗效和急性毒副反应.方法 40例Ⅲ期非小细胞肺癌患者放疗前1周开始化疗,采用每4周休2周方案,紫杉醇80 mg/m2溶于生理盐水500 ml中,第1,8,29,36天给药;顺铂20 mg/m2,第2～6和30～35天;常规放疗2 Gy/次,1次/d,5 d/周,肿瘤灶总剂量66 Gy/7周.结果近期疗效:完全缓解(CR)率为30.0%,部分缓解(PR)率为57.5%,总有效率87.5%.主要毒副反应是急性放射性食管炎和肺炎,放射性食管炎的发生率为52.5%,放射性肺炎为37.5%,但大多数患者经过对症支持治疗均能耐受.结论紫杉醇、顺铂加放疗同步治疗局部晚期非小细胞肺癌,近期疗效肯定,远期疗效和晚期并发症有待进一步观察.     

Phase II study of docetaxel and ifosfamide combination chemotherapy in non-small-cell lung cancer patients failing previous chemotherapy with or without paclitaxel

Docetaxel has shown activity in the treatment of non-small-cell lung cancer (NSCLC) that has failed previous chemotherapy. Ifosfamide is an active alkylating agent used in the first-line treatment of NSCLC. We conducted a phase II study of docetaxel and ifosfamide chemotherapy in two groups (one with and one without previous paclitaxel treatment) of NSCLC patients who had failed previous chemotherapy, to assess the response and toxicity of this combination chemotherapy. Fifty patients were enrolled from June 2000 to December 2001, including 26 patients treated with paclitaxel-containing agents and 24 patients who had never been treated with paclitaxel. Treatment consisted of docetaxel 60 mg/m(2) and ifosfamide 3 g/m(2) intravenous infusion on day 1 of every 3 weeks. Two hundred and thirty-eight cycles of treatment were given, with a median of 5 cycles (range, 1-8 cycles). All patients were evaluable for toxicity profile and response rate. The major toxicity was myelosuppression. Grade 3 or 4 neutropenia occurred in 40 patients (80%) during treatment. Febrile neutropenia occurred in 7 patients (14%). Grade 3 anemia occurred in 2 patients. The majority of patients needed a decrease in the treatment dose due to grade 4 or febrile neutropenia. Interstitial pneumonitis occurred in 3 patients, leading to the death of two. Other toxicities were few and mild in severity. After two cycles of treatment, 5 patients (10%) had a partial response (95% confidence interval 1.7-18.3%), including 2 patients previously treated with paclitaxel and 3 who had not received this treatment. More patients who had been previously treated with paclitaxel suffered from progressive disease than among those who had never been treated with paclitaxel (P = 0.049). The median time to disease progression was 5 months and the median survival was 8.2 months. Median survival was 7.6 and 8.7 months, respectively, in patients with and without previous paclitaxel treatment (P = 0.56). Median survival was 8.7 and 7.6 months in patients receiving docetaxel and ifosfamide as second- and third-line chemotherapy, respectively (P = 0.327). In conclusion, docetaxel and ifosfamide salvage chemotherapy produces a relatively low response rate, low dose intensity, and higher proportion of severe neutropenia in NSCLC. Physicians should be alert to the potential of interstitial pneumonitis. Nevertheless, median survival was of a reasonable duration.     

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

To determine the maximum-tolerated dose (MTD) and the recommended dose (RD) of paclitaxel administered weekly with a fixed dose of cisplatin, and to assess the toxicity and activity of this combination, we conducted a phase I/II trial in patients with advanced non-small-cell lung cancer (NSCLC). In this study, patients with stage IIIB/IV NSCLC were eligible. Paclitaxel, at a starting dose of 40 mg x m(-2) week(-1) on days 1, 8, and 15, was combined with a fixed dose of cisplatin 80 mg x m(-2) on day 1. Chemotherapy was given in a 4-week cycle. In this phase I/II study, 38 patients were enrolled. Dose-limiting toxicities (DLT) were neutropenia, fatigue, and omission of treatment due to leucopenia, thrombocytopenia, or febrile neutropenia. The MTD and RD were estimated to be 70 mg x m(-2). Of the 37 assessable patients, 23 had a partial response and one had a complete response. Overall response rate was 62.1% (95% confidence interval (CI): 46.5-77.7%). The progression-free survival, the median survival time, and the 1-year survival rate were 5.5 months, 13.7 months, and 56.9%, respectively. This regimen is tolerable and very active against advanced NSCLC, and its efficacy should be confirmed in a phase III study.     

Phase I trial of carboplatin and weekly paclitaxel in patients with advanced non-small-cell lung cancer

OBJECTIVE: This study was designed to determine the maximum tolerated dose of paclitaxel administered weekly in combination with carboplatin and to assess its dose limiting toxicity and preliminary activity in patients with previously untreated, advanced non-small-cell lung cancer. METHODS: Carboplatin was administered at a fixed dose that maintained an area under the curve of 6. Paclitaxel was given over 1 h once a week for 3 weeks starting at 60 mg/m(2) and escalated in 10 mg/m(2) increments. RESULTS: Twenty-one patients were treated with six dose levels (60, 70, 80, 90, 100, 110 mg/m(2)) of paclitaxel. The dose limiting toxicity was infection and the maximum tolerated dose was 110 mg/m(2). Nine of 21 (42.9%) patients demonstrated a therapeutic response. CONCLUSION: Weekly paclitaxel and carboplatin were well tolerated. Based on our results, 100 mg/m(2) of paclitaxel for 3 weeks of a 4-week cycle, in combination with carboplatin, was recommended for a phase II study.