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© 2000 American Society for Clinical Oncology Phase III Comparative Study of High-Dose Cisplatin Versus a Combination of Paclitaxel and Cisplatin in Patients With Advanced Non–Small-Cell Lung CancerFrom the Grosshansdorf Hospital, Grosshansdorf; Zentralkrankenhaus Gauting, Gauting, Germany; Meir Hospital, Kfar Saba, Israel; Academisch Ziekenhuis Maastricht, Maastricht, the Netherlands; Helsinki University Hospital, Helsinki, Finland; Ospedale Carlo Forlanini, Rome, Italy; Guy’s Hospital, London, United Kingdom; Centre Hospitalier Universitaire de Brest, Brest, France; Centro Riferimento Oncologico, Aviano, Italy; Bristol-Myers Squibb Pharmaceutical Research Institute, Waterloo, Belgium. Address reprint requests to Ulrich Gatzemeier, MD, Department of Thoracic Oncology, Krankenhaus Grosshansdorf, Wohrendamm 80, Grosshansdorf, 22927, Germany; email pneumo.onko{at}t-online.de
PURPOSE: New effective chemotherapy is needed to improve the outcome of patients with advanced non–small-cell lung cancer (NSCLC). Paclitaxel administered as a single agent or in combination with cisplatin has been shown to be a potentially new useful agent for the treatment of NSCLC. PATIENTS AND METHODS: Between January 1995 and April 1996, 414 patients with stage IIIB or IV NSCLC were randomized to received either a control arm of high-dose cisplatin (100 mg/m2) or a combination of paclitaxel (175 mg/m2, 3-hour infusion) and cisplatin (80 mg/m2) every 21 days. RESULTS: Compared with the cisplatin-only arm, there was a 9% improvement (95% confidence interval, 0% to 19%) in overall response rate for the paclitaxel/cisplatin arm (17% v 26%, respectively; P = .028). Median time to progression was 2.7 and 4.1 months in the control and paclitaxel/cisplatin arm, respectively (P = .026). The study, however, failed to show a significant improvement in median survival for the paclitaxel/cisplatin arm (8.6 months in the control arm v 8.1 months in the paclitaxel/cisplatin arm, P = .862). There was more hematotoxicity, peripheral neuropathy, and arthralgia/myalgia on the paclitaxel/cisplatin arm, whereas the high-dose cisplatin arm produced more ototoxicity, nausea, vomiting, and nephrotoxicity. Quality of life (QOL) was similar overall between the two arms. CONCLUSION: This large randomized phase III trial failed to show a significant improvement in survival for the paclitaxel/cisplatin combination compared with high-dose cisplatin in patients with advanced NSCLC. However, the paclitaxel/cisplatin combination did produce a better clinical response, resulting in an increased time to progression while providing a similar QOL.
LUNG CANCER IS among the most common malignancies in the world and is one of the few cancers that continues to show an increasing incidence. In the early 1990s, more than half a million new cases of lung cancer were diagnosed annually worldwide.1 By the year 2000, the projected number of new cases worldwide is expected to exceed 2 million.2 Approximately three quarters of these lung tumors are of non–small-cell histologic type, which includes adenocarcinoma and squamous and large-cell carcinomas.2-4 Non–small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, and 5-year survival is approximately 10% to 15% when all stages are included.2-5 At the time of initial diagnosis, only 20% to 25% of patients are eligible for potentially curative surgery.4-6 Consequently, the remaining patients are eligible for multimodality treatment that may include surgery, radiotherapy, and/or chemotherapy. However, most patients with late-stage or metastatic disease are treated palliatively. There has been considerable controversy over the benefit of treating advanced NSCLC patients with chemotherapy. However, there is an increasing evidence that treatment with cisplatin-containing regimens has a modest effect on survival.2,4,5 A meta-analysis demonstrated that median survival was improved by approximately 6 weeks in patients treated with combination chemotherapy that included a platinum agent when compared with patients treated with supportive care alone.6 For trials reporting the 1-year survival rate, it seems that treatment with cisplatin-containing regimens results in a 20% to 25% 1-year survival rate compared with approximately 10% for patients treated with supportive care.6 Clearly, new effective chemotherapy agents are essential if the survival rate of patients with advanced NSCLC is to be improved. One of the new potentially useful agents to treat advanced NSCLC is paclitaxel. As a single agent in early phase II trials, paclitaxel produced a 20% to 24% response rate and a 1-year survival rate as high as 42%.7-9 Two early phase I studies with paclitaxel (3-hour infusion) and cisplatin in advanced NSCLC showed that the combination was active.10,11 Moreover, in these trials, the administration of the two-drug combination was well tolerated. An increased incidence of peripheral neuropathy was observed with the administration of high doses of either drugs. These studies established that a dose of paclitaxel 175 mg/m2 (3-hour intravenous [IV] infusion) with cisplatin 80 mg/m2 would be appropriate for phase II studies. Several randomized phase II/III studies have shown that dose-intensive cisplatin was active in patients with advanced NSCLC (Table 1). Based on these studies, which demonstrate response rates in the 4% to 23% range and median survival in the 5 to 9 months range, high-dose cisplatin may be considered an appropriate control arm in phase III trials. Based on the evidence that the combination of paclitaxel and cisplatin is active, safe, and promising in the treatment of patients with advanced NSCLC, this study was initiated in 1995 to compare this regimen with a control arm of high-dose cisplatin.
Patient Eligibility Patients eligible for this study had histologically confirmed stage IIIB or IV NSCLC. Patients were to have measurable or nonmeasurable disease, be between 18 and 75 years old, and have a Karnofsky index performance status of 60 or better. Patients were allowed to have received palliative radiotherapy to less than 30% of the marrow bearing bones more than 4 weeks before study entry. Patients with asymptomatic brain involvement were eligible provided that it was not the only disease site. Adequate baseline bone marrow function and hepatic and renal function were required. Patients were ineligible if they had a history of prior or concomitant malignancy, except for curatively treated nonmelanoma skin cancer or in situ cervical cancer or other cancer cured by surgery alone with a disease-free survival longer than 5 years. Female patients could not be pregnant or lactating. A prior history of atrial or ventricular arrhythmias and/or history of congestive heart failure, even if medically controlled, disqualified patients from study entry. Patients with a prior documented myocardial infarction were also ineligible. Pre-existing motor or sensory neurologic symptoms  grade 2 (World Health Organization [WHO] criteria) were not allowed, nor were active infections or other serious underlying medical conditions that would impair the ability of the patient to receive protocol treatment, including a prior allergic reaction to drugs containing polyoxyethylated castor oil. Written informed consent was to be obtained from each patient, before study entry, and according to the local institutional ethics committee requirements.
Treatment High-dose cisplatin was to be administered in the inpatient or outpatient setting according to the usual practice of the study site. Patients were scheduled to receive cisplatin 100 mg/m2 diluted in 250 mL of normal saline and administered by IV drug infusion over 30 minutes. Prehydration, with at least 1 L of fluid over 4 hours, and posthydration, with a minimum of 2 L, were mandatory. The recommended prophylactic antiemetic medication included dexamethasone, metoclopramide, and lorazepam. Patients may also have received 5-hydroxytryptamine-3 antagonists, per each institution’s policy. Before paclitaxel administration, each patient received premedication consisting of dexamethasone (20 mg orally, 12 hours and 6 hours before paclitaxel), cimetidine (300 mg IV, 30 minutes before paclitaxel), and diphenhydramine (50 mg IV, 30 minutes before paclitaxel). Alternative agents of the same class could be used because some of these recommended compounds were not available in some centers. The total daily dose of paclitaxel (175 mg/m2) was dissolved in 500 mL of dextrose 5% in water or normal saline to a concentration not exceeding 1.2 mg/mL. This solution was administered through a free-flowing IV line over 3 hours, with in-line filtration using a cellulose acetate filter of 0.22-µm pore size. Cisplatin (80 mg/m2) was given 1 hour after paclitaxel. Cisplatin was to be administered as previously described. Treatment in both arms was to be repeated every 21 days or on recovery from hematologic and nonhematologic toxicities. Dose escalation in this study was not planned; reductions in subsequent courses were based on toxicities encountered in the previous treatment course. In absence of disease progression or intolerable toxicity, patients were to remain on protocol treatment for a minimum of three cycles of treatment. Duration of therapy was based on treatment effect reassessed before each course. Evidence of disease progression would lead to treatment discontinuation. Patients with stable disease received up to six cycles of therapy. Patients achieving a partial or complete response were given an additional two courses after the occurrence of the best response. Patients could discontinue protocol treatment in case of unacceptable toxicity, patient’s request, intercurrent illness, pregnancy, or other reasons which would, in the judgement of the investigator, affect assessments of clinical status to a significant degree and require discontinuation of the treatment.
Treatment Evaluation
Responses were defined according to the WHO criteria for measurable and nonmeasurable disease. A complete response was defined as the disappearance of all clinical evidence of active tumor for a minimum of 4 weeks. A partial response was defined as a 50% or greater decrease in the sum of the product of the longest perpendicular diameters of all measurable lesions (or an estimated decrease of 50% for nonmeasurable lesions) lasting at least 4 weeks without appearance of any new lesions and without progression in any disease sites. Stable disease was defined as a decrease of less than 50% in the sum of the products of the longest perpendicular diameters of all measurable sites (or an estimated decrease of less than 50% or increase of < 25% in nonmeasurable sites) or an increase of less than 25% of any lesion without the appearance of any new sites and without progression in any disease sites. Progressive disease represented an increase of Patients recorded their QOL using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life questionnaire (QLQ-C30, version 1.0) and the lung cancer–specific module (LC-13, version 1.0). Both questionnaires were to be administered at randomization (baseline), within 3 days before every cycle, at off study, and after off study therapy every 2 months until progression. All scales from both questionnaires were linearly transformed according to the EORTC recommendations. Each patient who received at least one dose of any study drug was considered assessable for safety. Drug safety was based on laboratory tests and on clinical signs and symptoms experienced during the treatment period.
Statistical Considerations Kaplan-Meier estimates were used in the analysis of all time-to-event variables (survival, time to progression, duration of response). A 95% confidence interval (CI) for the median time to event was computed using the method of Brookmeyer and Crowley.16 The primary comparison for survival and time to progression was a log-rank test stratified by the stratification factors of Karnofsky performance status (80 to 100 v 60 to 70) and stage of disease (IIIB v IV). Response rates were compared using a Cochran-Mantel-Haenszel test17 stratified by the same factors. QOL analysis was performed using the five functional scales, the global health status scale, and the 20-symptom scales, as recommended by the EORTC. For each scale, the difference from baseline was compared between treatment arms with a null hypothesis of equal distributions per time point versus a stochastic ordering alternative (where one treatment is at least as good as the other treatment at each time point and superior in at least one time point) using a nonparametric longitudinal Wei-Johnson test.18 Toxicity was evaluated considering the worst reported event per patient. For each toxicity, treatment arms were compared using Fisher’s exact test for 2 x 2 tables, for occurrence of any toxicity, and for occurrence of severe toxicity.
Patients Characteristics A total of 414 patients were randomized from 35 participating institutions between January 1995 and April 1996. Two hundred seven patients were randomized in both study arms. Patient characteristics of the 414 patients randomized are listed in Table 2. The two groups were comparable with respect to sex and age. All but 43 patients, 15 (7%) in the high-dose cisplatin arm and 28 (14%) in the paclitaxel/cisplatin arm, were symptomatic and had a Karnofsky performance status of 90 or less. Information on weight loss during the 6-month period before study entry was available for 358 patients (86%) and was similar in both arms. Disease characteristics including cell type and stage were comparable between the two treatment groups. Approximately 95% of all randomized patients had uni- and/or bidimensional disease and are included in the response evaluation.
Dosing Of the 414 patients randomized, six patients never received study drugs (one patient in the high-dose cisplatin arm and five patients in the paclitaxel/cisplatin arm). Seven hundred fifty-nine courses of high-dose cisplatin therapy were administered to 206 patients, and 889 courses of paclitaxel/cisplatin therapy were administered to 202 patients. The median number of courses was three in the high-dose cisplatin arm (range, one to nine courses) and five in the paclitaxel/cisplatin arm (range, one to eight courses). The number of courses administered per patient was significantly higher in the paclitaxel/cisplatin arm than in the high-dose cisplatin arm (P = .0002), and thus, the treatment duration was significantly shorter in the high-dose cisplatin arm (median, 9.9 weeks; range, 3.0 to 32.1 weeks) compared with the paclitaxel/cisplatin arm (median, 14.9 weeks; range, 3.0 to 28.1 weeks) (P = .0014). Seven patients in the high-dose cisplatin arm received more than six courses of therapy compared with 16 patients in the paclitaxel/cisplatin arm. The median cumulative dose of cisplatin administered per patient was higher in the paclitaxel/cisplatin arm (342 mg/m2) compared with the high-dose cisplatin arm (302 mg/m2) (P = .172). As expected by virtue of the planned cisplatin dose, the median dose-intensity of cisplatin was significantly higher in the high-dose cisplatin arm than in the paclitaxel/cisplatin arm (32 mg/m2/wk v 26 mg/m2/wk; P = .0001). The relative dose-intensity was similar in both arms. In the high-dose cisplatin arm, 75% of the patients received cisplatin at 90% or greater of the scheduled dose-intensity compared with 74% in the paclitaxel/cisplatin arm.
Survival
Other Efficacy End Points Among the assessable patients, the overall clinical response rate was 17% in the high-dose cisplatin arm (34 of 197 patients; 95% CI, 12% to 23%) and 26% in the paclitaxel/cisplatin arm (50 of 190 patients; 95% CI, 20% to 33%) (Table 3). Of note, three complete responses were observed in the paclitaxel/cisplatin arm and one in the high-dose cisplatin arm. The 9% difference in response rate (95% CI, 0% to 19%) among the two arms was statistically significant (P = .028) (odds ratio for paclitaxel/cisplatin arm over high-dose cisplatin arm, 1.75; 95% CI, 1.06 to 2.88). When all randomized patients are considered (intent-to-treat population), the response rates were 16% (34 of 207 patients; 95% CI, 12% to 22%) and 24% (50 of 207 patients; 95% CI, 18% to 31%) for the high-dose cisplatin arm and the paclitaxel/cisplatin arm, respectively (8% difference; 95% CI, -1% to 17%; P = .047) (odds ratio for paclitaxel/cisplatin over high-dose cisplatin, 1.65; 95% CI, 1.01 to 2.71).
The median time to progression was 2.7 months (95% CI, 2.3 to 3.2 months) in the high-dose cisplatin arm and 4.1 months (95% CI, 3.3 to 4.4 months) in the paclitaxel/cisplatin arm (Fig 2). The difference favoring time to progression in the paclitaxel/cisplatin arm compared with the high-dose cisplatin arm was statistically significant (P = .026). When patients receiving secondary therapy without having evidence of progression are censored, the median time to progression is 3.2 months in the high-dose cisplatin arm (95% CI, 2.4 to 3.9 months) and 4.3 months in the paclitaxel/cisplatin arm (95% CI, 3.5 to 4.6 months). This difference favored the paclitaxel/cisplatin arm but was not statistically significant (P = .085).
More than half of the patients received at least one follow-up therapy (122 of 207 patients [59%] in the high-dose cisplatin arm and 109 of 207 patients [53%] in the paclitaxel/cisplatin arm) (Table 4). Surgery was performed in eight patients, whereas radiotherapy was administered to one third of all patients. Chemotherapy was used more frequently in patients in the high-dose cisplatin arm; 76 patients (37%) received subsequent chemotherapy after high-dose cisplatin compared with 57 patients (28%) in the paclitaxel/cisplatin arm. One third of these patients received another platinum-containing chemotherapy.
Safety All patients who received at least one dose of therapy were considered in this analysis (206 patients in the high-dose cisplatin arm and 202 patients in the paclitaxel/cisplatin arm). It should be noted that patients in the high-dose cisplatin arm received only a median of three treatment courses (759 courses in total), whereas in the paclitaxel/cisplatin combination arm, patients were treated for a median of five courses (889 courses in total). This highly significant imbalance in amount of therapy could bias the incidence and severity of reported safety parameters in favor of high-dose cisplatin because worst toxicity per patient is reported. Neutropenia of any grade and severe neutropenia were observed significantly more frequently in the paclitaxel/cisplatin arm than in the high-dose cisplatin arm (both tests, P < .0001) (Table 5). The median neutrophil nadir counts (worst course) were 2.66 x 109 cells/L in the high-dose cisplatin arm (range, 0.04 to 20.2 x 109 cells/L) and 1.93 x 109 cells/L in the paclitaxel/cisplatin arm (range, 0.00 to 10.1 x 109 cells/L). The more severe neutropenia observed in the patients randomized to the paclitaxel/cisplatin combination did not result in a higher incidence of febrile neutropenia and infections compared with patients in the high-dose cisplatin arm. Overall, the incidence of febrile neutropenia was low (one episode in the high-dose cisplatin arm and eight episodes in the paclitaxel/cisplatin arm, P = .019).
The frequency and severity of thrombocytopenia and anemia was similar in both study arms. Only one patient received a platelet transfusion, and the frequency of RBC transfusions was similar in both arms. Table 6 lists the nonhematologic toxicities associated with the paclitaxel/cisplatin combination and high-dose cisplatin. With the exception of asthenia and nausea/vomiting, the frequency of severe nonhematologic adverse events was low in both study arms. Symptoms of peripheral neuropathy and arthralgia/myalgia were more frequently reported by patients in the paclitaxel/cisplatin arm. It is noteworthy that no grade 4 peripheral neuropathy or myalgia/arthralgia was observed in either treatment arm.
Significantly more patients developed ototoxicity in the high-dose cisplatin arm than in the paclitaxel/cisplatin arm. The greater dose-intensity of cisplatin in patients receiving high-dose cisplatin compared with patients receiving the paclitaxel/cisplatin combination might explain the difference in ototoxicity. Nausea and vomiting were the most frequently reported gastrointestinal manifestations. Significantly more patients experienced nausea/vomiting in the high-dose cisplatin arm compared with the paclitaxel/cisplatin arm. Severe renal toxicity was avoided in this study largely because of a protocol specific request to stop the administration of cisplatin when grade 1 nephrotoxicity was observed.
QOL
In evaluating QOL results in this study, one must consider that patients were treated longer with paclitaxel/cisplatin compared with high-dose cisplatin and, therefore, had more of a chance to experience deterioration in QOL. When comparing the respective changes per treatment period to baseline, differences in the following scales were noted between the treatment arms for all on-study assessments (Table 8): (1) physical function during the first five QOL evaluation periods was frequently improved for the paclitaxel/cisplatin combination, and therefore, the overall comparison resulted in a borderline advantage for the paclitaxel/cisplatin combination; (2) nausea and vomiting were worse in the high-dose cisplatin arm; (3) appetite loss was consistently reported during the QOL evaluation period and was also more severe in the high-dose cisplatin arm; (4) constipation was more frequently reported in the high-dose cisplatin arm; (5) hair loss was more severe and consistently reported throughout the QOL evaluation period for the paclitaxel/cisplatin combination; and (6) peripheral neuropathy was reported more frequently for the paclitaxel/cisplatin combination.
NSCLC continues to be a major health problem in developed countries. Although the incidence in males generally seems to be levelling off, the incidence in females continues to increase. At the time of diagnosis, the majority of patients will be diagnosed with metastatic (stage IV) or locally advanced (stage III) disease. Thoracic radiotherapy, generally considered as standard therapy for inoperable, locally advanced disease, has a limited impact on survival, and most patients will develop distant metastatic disease. Consequently, most patients diagnosed with NSCLC are potential candidates for effective chemotherapy. Among the agents considered active in the treatment of advanced NSCLC, cisplatin has been reported to produce a response rate of up to 20%. Moreover, cisplatin-based combination regimens have demonstrated some improvement in survival when compared with non–platinum-containing regimens. However, there is a definite need for more effective chemotherapy to treat NSCLC. Paclitaxel has been shown to have a unique mechanism of antitumor action; it promotes microtubule assembly and stabilization. The safety profile, as well as the anticancer activity, of paclitaxel in patients with advanced malignancies has been well established. Many single-agent studies demonstrated the activity of paclitaxel in the treatment of advanced NSCLC.7-9,19-26 In combination with cisplatin10,11,27-31 or carboplatin,32-44 paclitaxel has been reported to be safe and to have high activity in NSCLC. The different mechanism of action of the taxanes and the platinum classes would potentially allow to target different cell populations and/or to increase the efficacy against the same cell lines. In January 1995, the current study was initiated to show that the combination of paclitaxel and cisplatin was safe and effective when compared with high-dose cisplatin in a population of advanced NSCLC patients. This multicenter randomized phase III trial was designed for patients with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC previously untreated with chemotherapy. A total of 414 patients from 35 centers in 12 countries were centrally randomized. Pretreatment characteristics were well balanced among the two groups, except number of disease sites. The combination of paclitaxel/cisplatin proved to be easier to administer than high-dose cisplatin, as demonstrated by the higher number of treatment delays in the high-dose cisplatin arm. The median number of courses in the high-dose cisplatin arm was three compared with five in the paclitaxel/cisplatin arm. This resulted in a higher median cumulative dose of cisplatin in the paclitaxel/cisplatin arm despite a higher individual dose of cisplatin in the single-agent arm. The paclitaxel/cisplatin combination was more efficacious than the high-dose cisplatin regimen; significantly more patients achieved a clinical response in the paclitaxel/cisplatin arm than in the high-dose cisplatin arm (P = .028). This difference favoring the paclitaxel/cisplatin arm remained statistically significant after adjustment for a number of potential prognostic factors in a logistic regression model. Time to progression also favored the paclitaxel/cisplatin arm when patients were considered to have progressed, rather than being censored, at the time of start of salvage therapy (P = .026). This more conservative analysis seems justified because the majority of those patients were taken off study for treatment-related toxicities and subsequently received salvage therapy. After adjusting for the same set of prognostic factors, the advantage for the paclitaxel/cisplatin treatment was maintained. The median survival was 8.6 months and 8.1 months for patients enrolled in the high-dose cisplatin and paclitaxel/cisplatin arms, respectively. Although this trial failed to demonstrate a statistically significant superiority for the combination regimen over high-dose cisplatin in terms of survival, the study provided some statistical evidence to state that the survival in the two groups was comparable. In fact, the survival curves were superimposable over the 2-year period. It is interesting to note that in recent studies using cisplatin as a standard arm in randomized studies, in patients with advanced NSCLC, similar median survivals have been reported comparable with those in this study.13,45 In the study by Wozniak et al,13 the median survival for patients receiving cisplatin was 7.6 months, whereas, in the study by Sandler et al,45 the median survival was 6 months. The comparison of survival results from our study with these published reports is difficult because of the difference in dose-intensity of cisplatin and/or because of different patients characteristics (eg, inclusion of patients with better/worse performance status). In addition, in our study, more patients in the high-dose cisplatin than in the paclitaxel/cisplatin arm received salvage chemotherapy before or after disease progression was assessed. However, a cross-over to taxanes in the high-dose cisplatin arm was uncommon. The median survival of patients in the paclitaxel/cisplatin arm in our study is somewhat shorter than in recently published reports using this combination in randomized studies.46,47 In the study by Giaccone et al,46 the median survival for patients receiving the paclitaxel/cisplatin combination was 9.7 months, whereas, in the study by Bonomi et al,47 the median survival was 9.6 to 10 months depending on the paclitaxel dose administered. Of note, in our study, considering only the 168 patients in the paclitaxel/cisplatin arm with good performance status at baseline (performance status, 80 to 100), the median survival was 9.0 months. The protocol was written to avoid severe and irreversible toxicities in this palliative setting and required discontinuation of cisplatin in case of renal toxicity (WHO grade 1), clinical hearing loss or severe paresthesias, and/or mild weakness (WHO grade 2 neurologic toxicity). This and the significantly higher number of courses administered to patients in the paclitaxel/cisplatin arm compared with the high-dose cisplatin arm have to be considered when comparing the safety profile of the two treatment arms. The combination of paclitaxel/cisplatin caused more severe leukopenia and neutropenia compared with high-dose cisplatin. Considering the number of courses, however, there was no imbalance of febrile neutropenia or infection between the two treatments. As expected, hypersensitivity reactions, peripheral neuropathy, arthralgia/myalgia, diarrhea, and alopecia were more frequent in the paclitaxel/cisplatin arm. However, there was no difference in terms of severe (grade 3) events among the two arms. High-dose cisplatin did produce significantly more nausea and vomiting as well as ototoxicity. Overall, patients in the paclitaxel/cisplatin arm reported a similar QOL. Statistically significant differences favoring the paclitaxel/cisplatin combination were noted in the following three QOL scales: nausea/vomiting, loss of appetite, and constipation. In addition, patients in the paclitaxel/cisplatin arm reported an improvement in physical functioning. In contrast, patients in the high-dose cisplatin arm reported less alopecia and less peripheral neuropathy, confirming the findings of the safety analysis. This large randomized phase III trial failed to show a significant improvement in survival for the paclitaxel/cisplatin combination compared with high-dose cisplatin in patients with advanced NSCLC. However, compared with high-dose cisplatin, the paclitaxel/cisplatin combination did produce a better clinical response, resulting in an increased time to progression while providing a similar QOL.
The participating investigators and institutions are as follows: Dr Gatzemeier, Grosshansdorf Hospital, Grosshansdorf; Dr von Pawel, Zentralkrankenhaus Gauting, Gauting; Dr Loddenkemper, Lungerklinik Heckeshorn, Berlin; Dr Huber, Medizinische Klinik Klinikum Innenstadt, Munich, Germany; Dr Gottfried, Meir Hospital, Kfar Saba; Dr Peretz, Hadassah University Hospital, Jerusalem; Dr Sulkes, Beilinson Medical Center, Petah Tiqva, Israel; Dr ten Velde, AZ Maastricht, Maastricht, Netherlands; Dr Mattson, Helsinki University Hospital, Helsinki, Finland; Dr DeMarinis, Dr Pallotta, Ospedale Carlo Forlanini; Dr Salvati, Ospedale Carlo Forlanini, Rome; Dr Lucenti, Dr Monfardini, Centro Riferimento Oncologico, Aviano; Dr Luporini, Ospedale S. Carlo Borromeo, Milan, Italy; Dr Harper, Guy’s Hospital; Dr Rudd, St Bartholomew’s Hospital, London; Dr Talbot, Churchill Hospital, Oxford; Dr Williams, Royal South Hants Hospital, Southampton; Dr Clark, Clatterbridge Centre of Oncology, Merseyside, United Kingdom; Dr Robinet, CHU Brest, Brest; Dr Braun, Hôpital Maillot, Briey; Dr Depierre, CHU Besançon, Besançon; Dr Moro, CHU La Tronche, Grenoble; Dr Breton, Centre Hospitalier Général Belfort, Belfort; Dr Paillot, Hôpital Notre-Dame du Bon Secours, Metz; Dr Quoix, CHU Hôpital Civil, Strasbourg; Dr Wallaert, Hôpital Calmette, Lille, France; Dr Gonzalez-Larriba, Hospital Clinico San Carlos, Madrid; Dr Alberola, Hospital de Sagunto, Valencia, Spain; Dr Gorbunova, Cancer Research Center, Moscow, Russia; Dr Herrmann, Basel Hospital, Basel, Switzerland; Dr Henriksson, Umea University Hospital, Umea, Sweden; Dr Majois, Hôpital de Jolimont, Haine-St-Paul; Dr Humblet, UCL Medical School, Brussels; Dr. Canon, Institut Notre-Dame, Charleroi; Dr Salamon, Clinique Ste Elisabeth, Namur; Mrs Renard, Dr Leroy, Bristol-Myers Squibb’s Pharmaceutical Research Institute, Waterloo, Belgium; Dr Ferrante, Dr Winograd, Bristol-Myers Squibb’s Pharmaceutical Research Institute, Wallingford, CT, United States.
Supported by the Bristol-Myers Squibb Pharmaceutical Research Institute. We thank Fabienne Gérard for her expert technical assistance.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
