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Triple- vs Double-Agent Chemotherapy for Advanced Non–Small-Cell Lung Cancer

Triple- vs Double-Agent Chemotherapy for Advanced Non–Small-Cell Lung Cancer

ABSTRACT: In our previous phase I/II studies, both the cisplatin (Platinol), gemcitabine (Gemzar), and vinorelbine (Navelbine) (PGV), and cisplatin, gemcitabine, and paclitaxel (Taxol) (PGT) regimens produced a median survival of approximately 1 year in patients with advanced non–small-cell lung cancer (NSCLC). The present phase III study compared the median survival of patients treated with these triple-drug regimens to that of patients receiving cisplatin plus vinorelbine (PV) or cisplatin plus gemcitabine (PG). Accrual for the trial began in 1997 and by December 1998, a total of 240 patients (stage IIIB, 98; stage IV, 142) had been enrolled. An interim survival analysis was performed in April 1999. Overall, 151 patients had died. The median survival rates of patients in the PGV, PG, and PV arms were 51, 42, and 35 weeks, respectively. At the time of this analysis, the median survival of patients in the PGT arm could not be assessed; however, the 1-year projected survival rate was 58%. At multivariate Cox analysis, the estimated risk of death for patients receiving PGV compared with those receiving PV was 0.35 (95% CI, 0.16-0.77, P = .0058). Overall response rates were 47% in the PGV arm, 30% in the PG arm, 25% in the PV arm, and 58% in the PGT arm. Severe neutropenia and vomiting were significantly more frequent in patients who received PV than in those who received PGV. The PV regimen produced a significantly shorter survival compared with the PGV combination. Since this difference in survival complied with one of the early stopping rules, accrual in the PV arm was discontinued. Enrollment in the PGV, PG, and PGT arms is ongoing. [ONCOLOGY 14(Suppl 4):35-40, 2000]

Introduction

A number of chemotherapy agents have been shown to be active in
non–small-cell lung cancer (NSCLC).[1,2] However, the long-term
prognosis for patients is still poor. After the results of a recent
meta-analysis,[3] there is wide agreement about the benefit of
including cisplatin (Platinol) in first-line combination treatment of
this disease.

The cisplatin and vinorelbine (Navelbine) (PV),[4,5] cisplatin (or
carbo-platin) and paclitaxel (Taxol) (PT),[6-9] or cisplatin and
gemcitabine (Gemzar) (PG)[10-11] combinations have been widely tested
in the last few years. Although the addition of a new agent to
cisplatin has resulted in improvement in survival when compared with
cisplatin alone, there has been no statistically significant
difference in survival with the use of these “new” regimens
vs the “older” regimens.[9,12-16] However, there is
increasing interest in testing triple-drug combinations including
combinations with at least two new agents.

Our group devised the cisplatin, gemcitabine, and vinorelbine (PGV)
regimen for the management of patients with advanced NSCLC. In this
regimen, we scheduled all three drugs on days 1 and 8 every 3 weeks
so that we were able to deliver a full dose of chemotherapy with
moderate toxicity.[17] This regimen produced more than a 50% overall
response rate, and a 50-week median survival in patients with
advanced NSCLC.[18] Therefore, we embarked on a three-arm phase III
trial to compare this new combination with PV and PG. An interim
analysis was planned when the first 60 patients in each arm were
evaluable for response.

In a parallel phase I/II study, our group also investigated the
cisplatin, gemcitabine, and paclitaxel (PGT) combination[19]
administered every 3 weeks. In this regimen, we used the same doses
of cisplatin and gemcitabine as in the previous trial, and split the
paclitaxel dose on days 1 and 8. In view of the promising antitumor
activity demonstrated by the PGT regimen in this phase II study, we
decided to incorporate this combination in the phase III trial
currently underway. In this article, we present the results of the
interim analysis.

Patients and Methods

Eligibility Criteria

Chemotherapy-naive patients with histologically or cytologically
proven locally advanced (stage IIIB) or metastatic (stage IV) NSCLC
were eligible for this trial. Patients had to be £
70 years of age and have adequate bone marrow function (absolute
neutrophil count ³ 2 × 109/L,
platelet count ³ 100 × 109/L,
and hemoglobin level ³ 10.0 g/L),
adequate liver function (bilirubin level < 2 times the upper limit
of normal, oxaloacetic transaminase enzyme (AST) and/or alanine
aminotransferase (ALT) < 3 times the upper limit of normal,
prothrombin time < 1.5 times control), and creatinine clearance ³
60 mL/min. The presence of severe cardiac arrhythmia or heart
failure, second- or third-degree heart block, or acute myocardial
infarction within 4 months prior to study entry were considered
exclusionary. Central nervous system metastases, if asymptomatic,
were not considered exclusionary.

 Patients were also required to have a performance status £
1 on the Eastern Cooperative Oncology Group (ECOG) scale, and a life
expectancy of at least 12 weeks. All patients gave their written
informed consent, and the trial was approved by the Ethical Committee
for Biologic Research of the National Tumor Institute of Naples.

Pretreatment Evaluation

The pretreatment evaluation included a complete history and physical
examination, electrocardiogram, chest x-ray, respiratory tests,
fiberoptic bronchoscopy, and computed tomography (CT) of the chest,
brain, and upper abdomen. A radionuclide scan of bone was also
performed as necessary to document disease extent. Laboratory studies
included a complete blood cell count with white blood cell
differential and platelet count, full chemistry profile, prothrombin
time, partial thromboplastin and thrombin time, and urinalysis.

Treatment Regimens

Patients were randomized to receive: (1) cisplatin 50 mg/m²,
gemcitabine 1,000 mg/m², and vinorelbine 25 mg/m² on days 1
and 8, with recycling every 3 weeks (PGV arm); (2) cisplatin 100
mg/m² on day 1 and gemcitabine 1,000 mg/m² on days 1, 8,
and 15 every 4 weeks (PG arm); (3) cisplatin 120 mg/m² on days 1
and 29 and vinorelbine 30 mg/m²/week for 10 weeks (PV arm), or
(4) cisplatin 50 mg/m², gemcitabine 1,000 mg/m², and
paclitaxel 125 mg/m² (over 1 hr) on days 1 and 8 every 3 weeks
(PGT arm).

All patients received antiemetic prophylaxis consisting of
HT3-receptor antagonists plus 20 mg of dexamethasone. In the PGT arm,
prophylaxis for hypersensitivity to paclitaxel consisted of
dexamethasone 20 mg intravenously (IV), ranitidine (Zantac) 50 mg IV,
and promethazine 50 mg intramuscularly (IM), administered 30 minutes
before the start of paclitaxel infusion.

Response and Toxicity Evaluation

Study patients underwent assessment for tumor response after a
similar period of induction chemotherapy (after three cycles in the
PGV and PGT arms and two cycles in the PG and PV arms). An additional
two or three cycles, respectively, were administered only in patients
achieving a complete or partial response according to World Health
Organization (WHO) criteria. Chest irradiation was performed (if
indicated) in stage IIIB patients showing stable disease and in
progressing patients when considered useful by the physician.

The WHO grade scale was also used to record toxicity. Toxicity was
assessed prior to each cycle of chemotherapy, and hematologic studies
were performed weekly to determine toxicity at nadir. Data showing
severest toxicity for each patient in all cycles of chemotherapy were
used for toxicity analysis.

Statistical Methods and Study Design

Survival was the primary end point of the study. The study has a
power of 80% to recognize a 50% prolongation in the median survival
of patients receiving the triple-drug regimens when compared with PV
and PG (12 months vs 8 months). Each arm must enroll about 120
people. An interim analysis was planned after the first 60 patients
in each arm had undergone a minimum follow up at 26 weeks. The study
would be concluded early if the triple-drug regimen did not
demonstrate a statistically significant reduction in the risk of
death (P < .44), when compared with either PV or PG (null
hypothesis accepted). We also planned to close accrual early in any
two-drug arm that demonstrated a significant increase in the risk of
death (P < .01) as compared with one or both of the
triple-drug regimens (null hypothesis rejected).[20]

Overall survival was measured from the date of study entry to the
date of death or last follow up. Survival curves were estimated using
the Kaplan-Meier product-limit method,[21] and compared by Cox
analysis,[22] with age (< 65 years vs older), performance status
(0 vs 1), stage (IIIB vs IV), histology (squamous vs others), and
weight loss (> 5% vs < 5% of body weight) as covariates.

Patient accrual in the PGV, PG, and PV arms began in April 1997. From
October 1997 on, patients were also randomly assigned to the PGT arm.
By January 16, 1999, 286 patients were enrolled in the study; 10
patients did not meet the eligibility criteria, and 9 were not
evaluable because of the absence of demographics and follow-up data.
On April 15, 1999, we performed an interim analysis of the survival
of the first 60 evaluable patients in each arm.

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