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Paclitaxel Plus Carboplatin Versus Gemcitabine Plus Paclitaxel in Advanced Non–Small-Cell Lung Cancer: A Phase III Randomized Trial

From the Second Medical Oncology Department, Hygeia Hospital, Athens, Greece.

Address reprint requests to Paris A. Kosmidis, MD, 2nd Medical Oncology Department, Hygeia Hospital, 2 An Tsoha & Vas Sofias Ave, 11521 Athens, Greece; email: parkosmi{at}otenet.gr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: We conducted this randomized study comparing the activity and toxicity of paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to paclitaxel 200 mg/m² on day 1 plus either carboplatin at an area under the concentration-time curve of 6 on day 1 (group A) or gemcitabine 1,000 mg/m² on days 1 and 8 (group B) every 3 weeks. A retrospective cost analysis was conducted using Student’s t test to compare independent samples between groups.

RESULTS: A total of 509 patients (group A, 252 patients; group B, 257 patients) were enrolled; all characteristics were well balanced. The median survival time was 10.4 months (95% confidence interval [CI], 8.8 to 12 months) for group A and 9.8 months (95% CI, 8.0 to 11.7 months) for group B (P = .32). Respective 1-year survival rates were 41.7% and 41.4%. The response rate for group A was 28.0% (2% complete response [CR], 26% partial response [PR] [95% CI, 22% to 34%]), and the response rate for group B was 35.0% (5% CR, 30% PR) [95% CI, 29% to 41%]) (P = .12). Toxicity was mild. Grades 3/4 neutropenia, thrombocytopenia, and anemia for groups A and B were seen in 15% and 15%, 2% and 1%, and 5% and 2%, respectively. The mean total cost (outpatient clinic visits plus chemotherapy drug fee) for group A ( 7,612.64) versus group B ( 7,484.77) was not statistically significant (P < .66).

CONCLUSION: The PG combination is as equally active and well tolerated as the PC combination in patients with advanced NSCLC.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
LUNG CANCER IS one of the most common malignancies in the world¹ and remains the leading cause of cancer-related deaths in Western countries.^2,3 The incidence is increasing especially among women, in whom lung cancer is now the leading cause of cancer death in the United States.⁴ Patients with advanced disease who receive best supportive care survive for a few months, and approximately 90% do not survive 1 year.¹

Chemotherapy affords only a marginal survival advantage in non–small-cell lung cancer (NSCLC). Results from different meta-analyses have shown that platinum-based combination chemotherapy regimens prolong survival in patients with advanced NSCLC when compared with best supportive care.^5,6 During the past few years, several drugs with novel mechanisms of action and significant activity against NSCLC have been identified, including paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan, and tirapazamine.⁷

Gemcitabine as single-agent therapy has been studied extensively and has shown response rates of approximately 20% in patients with chemotherapy-naive advanced NSCLC.^8-10 Gemcitabine has also shown preclinical and clinical evidence of synergism with cisplatin, with remission rates of 52% to 54% for the combination in phase II trials.^11-12

Paclitaxel has produced overall response rates ranging from 20% to 42% in previously untreated patients with advanced NSCLC, with a 1-year survival rate of approximately 40%.^13-16 The combination of paclitaxel and cisplatin has produced good responses in both chemotherapy-naive and previously treated patients with NSCLC, with neurotoxicity found to be the dose-limiting factor.^17,18

Carboplatin, a cisplatin analog, has produced the best 1-year survival rate with the lowest toxicity as a single agent in a five-arm Eastern Cooperative Oncology Group (ECOG) study.¹⁹ Carboplatin is less nephrotoxic and less emetogenic than cisplatin and it lacks neurotoxicity, but has an overall efficacy that is comparable to cisplatin, with improved patient convenience because of the ease with which it can be administered.^20,21

When paclitaxel and carboplatin are combined, response rates range from 27% to 62%, median survival time from 10 to 12 months, and 1-year survival time from 22% to 54% without major toxicity.^21-25 The combination of paclitaxel and gemcitabine is of particular interest among the nonplatinum combinations because of the agents’ differing mechanisms of action, nonoverlapping toxicities, and activity. Paclitaxel possibly enhances the antitumor activity of gemcitabine and the combination has an additive effect .²⁶ Several phase I and II studies using a gemcitabine-paclitaxel combination in previously untreated patients with NSCLC have shown responses from 24% to 47%, with mild toxicity.^27-29

On the basis of these studies, the Hellenic Cooperative Oncology Group (HeCOG) initiated a phase III, randomized, multicenter trial to compare the commonly used paclitaxel and carboplatin (PC) combination with the nonplatinum paclitaxel and gemcitabine (PG) combination. The primary objective was to determine overall survival and 1-year survival times. The secondary objective was to assess response, time to progression (TTP), and toxicity profiles of both combinations in the treatment of patients with advanced inoperable NSCLC.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
Chemotherapy-naive patients were required to be older than 18 years of age with histologically documented, inoperable, recurrent, or metastatic NSCLC (inoperable stage IIIa, IIIb [including mediastinal nodes and/or pleural effusion], or IV carcinoma), respectively, according to the American Joint Committee on Cancer criteria on cancer staging). An ECOG performance status (PS) of 0 to 2 was required. Other requirements included measurable or assessable disease in nonirradiated fields, unless subsequent disease was documented, and a life expectancy of at least 12 weeks. Patients with stable brain metastasis were eligible. In addition, patients must have had adequate bone marrow reserve and normal kidney and liver functions.

Patients with active infection and a history of other neoplasms (except for basal carcinoma of the skin or carcinoma-in-situ of the cervix) were excluded from the study. Also excluded were patients previously treated with cytotoxic chemotherapy and those with active cardiac disease or pre-existing motor or sensory neuropathy (World Health Organization [WHO] grade 3 or 4). Women of childbearing age were required to have a pregnancy test within 48 hours of study enrollment. Before receiving study treatment, patients must have signed an informed consent document according to the Declaration of Helsinki and the HeCOG institutional policies.

Treatment Plan
Eligible patients were randomized to one of two groups. Group A comprised patients who received paclitaxel 200 mg/m² on day 1 as a 3-hour intravenous infusion, followed by carboplatin at an area under the time-concentration curve (AUC) of 6 according to the Calvert formula²⁰ as a 1-hour intravenous infusion. Patients in group B received the same doses and administration of paclitaxel, followed by gemcitabine 1,000 mg/m² as a 30-minute intravenous infusion on days 1 and 8 of each cycle. Paclitaxel was always given before carboplatin or gemcitabine administration with the following premedication and antiemetic prophylaxis: dexamethasone 20 mg orally 12 hours and intravenously 1 hour before paclitaxel; diphenhydramine 50 mg intravenously 30 minutes before paclitaxel and cimetidine 30 minutes before paclitaxel. Also, ondansetron was given 16 mg intravenously 15 minutes before chemotherapy followed by 8 mg bid orally for the next 3 days.

Treatment was repeated every 3 weeks. If the patient did not demonstrate progressive disease, treatment was continued for up to a total of six cycles. If the patient demonstrated a response, treatment was continued at the physician’s discretion. Patients with stage IIIa or IIIb disease who had responded to chemotherapy received poststudy local radiotherapy.

Treatment Modifications
In the event of hematologic and severe nonhematologic toxicities that occurred at any time during treatment, patients were treated at four dose levels (0, -1, -2, and -3) as follows. Patients were started at dose level 0, in which they received paclitaxel 200 mg/m² plus carboplatin AUC 6 (group A) or gemcitabine 1,000 mg/m² (group B). If WHO grade 3 neutropenia and/or thrombocytopenia, grade 2 neurotoxicity and hepatotoxicity, or grade 3 diarrhea occurred, doses of both drugs were decreased to level -1 (group A, paclitaxel 175 mg/m² and carboplatin AUC 5; group B, paclitaxel 175 mg/m² and gemcitabine 900 mg/m²). If grade 4 neutropenia and/or thrombocytopenia or grade 3 hepatotoxicity occurred, the drugs were administered at dose level -2 (group A, paclitaxel 150 mg/m² and carboplatin AUC 4; group B, paclitaxel 150 mg/m² and gemcitabine 800 mg/m²). If neutropenic fever was observed, doses were further decreased to level -3 (group A, paclitaxel 140 mg/m² and carboplatin AUC 4; group B, paclitaxel 140 mg/m² and gemcitabine 700 mg/m²). Once patients were assigned to a lower dose level, no dose re-escalation was permitted for these individuals.

For patients who did not achieve hematologic recovery on the scheduled day of treatment, a complete blood count was taken twice weekly until the absolute neutrophil count (ANC) reached 2,000/µL and the platelet count reached 100,000/L. If hematologic recovery was still not achieved by day 35 of treatment, the patient was withdrawn from the study. Patients were also discontinued from treatment if they had symptomatic arrhythmia or atrioventricular block (except first degree), grade 3 neurotoxicity, or grade 4 hepatotoxicity that was not reversible within 15 days. These modifications were necessary for the safety of our patients, on the basis of our previous protocols in our group.

Baseline and Treatment Assessments
Disease staging and response were assessed by clinical examination, chest x-ray, and computed tomographic (CT) scans. Baseline assessment included complete medical history and physical examination, complete blood count, and serum chemistry panel. Bidimensionally measurable disease was determined by imaging procedures (chest x-ray, ultrasonography, CT scanning, magnetic resonance imaging). Abdominal CT scanning, liver or adrenal ultrasound tests, and bone scanning was performed at the discretion of the treating physician. Tumor assessments (measurements) for response were performed at least every 6 weeks; chest x-rays were repeated every 3 weeks. All histopathology slides were reviewed by the same group of pathologists (ie, those associated with HeCOG-affiliated hospitals).

Eligible patients who received at least two cycles of combination chemotherapy were considered assessable for response. Eligible patients who received at least one cycle of chemotherapy were assessable for toxicity. Standard WHO criteria were followed for definition of response. TTP was defined as the interval from the initiation of chemotherapy to disease progression, and survival was defined as the interval from the initiation of chemotherapy until death. Toxicity was evaluated according to the WHO grading system.

Statistical Analysis
Randomization was performed centrally at the office of the HeCOG. Patients were assigned to one of the two arms using the center as a stratifying factor. Using a significance level of .05 and assuming a constant hazard ratio of .67, there is a 95% probability of detecting a significant difference between regimens when 404 deaths are observed. Taking into consideration a 10% withdrawal rate, 440 patients were needed to enter the study to detect a 50% increase in median survival, to a control median of 11 months. The study accrual rate was estimated at 150 patients per year, and the maximum study duration was estimated at 3.0 years.

Treatment-arm values for survival and TTP were compared using the log-rank test. The Kaplan-Meier method was used for estimating time-to-event measures. The primary response comparisons were derived from the cohort of patients assessable for response and were performed using the linear association ² test and Fisher’s exact test. Multivariate logistic regression analysis and a backward selection procedure were applied to evaluate the best prognostic factors for the likelihood of 1-year survival. Toxicity data were reported for all patients and compared between arms by a linear association ² test. All reported P values were generated from a two-sided analysis via the SPSS 8.0 system (SPSS, Inc, Chicago, IL).

At the end of the study, we performed a retrospective analysis of the cost attributed to each arm. Outpatient clinic expenses and chemotherapy drug costs were the two factors examined. For every factor affecting the analysis, descriptive statistics were calculated and Student’s t tests for independent samples were performed between groups for the same factor.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
A total of 509 patients, 252 in group A and 257 in group B, were enrolled from 19 institutions between February 1998 and September 2000. All pretreatment patient and disease characteristics (Tables 1 and 2, respectively) were well balanced across the two groups of the study. The majority of patients were male smokers with good PS and limited weight loss. Most of the tumors were poorly differentiated squamous or adenocarcinoma.

Median overall survival and TTP for groups A and B were not significantly different. As shown in Fig 1, overall median survival time was 10.4 months (95% CI, 8.8 to 12 months) for group A and 9.8 months (95% CI, 8.0 to 11.7 months) for group B (P = .32). Median TTP was 6.3 months (95% CI, 5.6 to 7.1 months) and 6.1 months (95% CI, 5.4 to 6.8 months) (P = .36) for groups A and B, respectively (Fig 2).

View larger version (12K): [in this window] [in a new window]   Fig 1. Median survival time curve for groups A and B (P = .32). Solid line represents group A and dashed line represents group B.

View larger version (12K): [in this window] [in a new window]   Fig 2. Median time to progression curve for groups A and B (P = .36). Solid line represents group A and dashed line represents group B.

View larger version (20K): [in this window] [in a new window]   Fig 3. Effect of PS on survival in each group (P < .001).

View larger version (23K): [in this window] [in a new window]   Fig 4. Effect of tumor-node-metastasis system stage on survival in group A (P = .01) and group B (P = .05).

The multivariate analysis indicated that PS (P < .0001) and bone (P = .001), supraclavicular lymph node (P < .0001), and liver (P < .0001) involvement are significant prognostic factors for 1-year survival. Histology type (adenocarcinoma v squamous) did not affect overall survival (P = .22). Treatment did not affect survival (P = .33). The same analysis for TTP again identified PS (P < .0001) and bone (P = .007) and supraclavicular lymph node involvement (P = .001), but also the number of metastatic sites (P = .01), as significant prognostic factors.

Response
A total of 49 patients (25 in group A and 24 in group B) were considered nonassessable for response: 19 (10 in group A and nine in group B) because of voluntary withdrawal, four (three in group A and one in group B) because of toxicity allergic reactions during the first course of chemotherapy that resulted in withdrawal, five (three in group A and two in group B) because of early progressive disease, and 21 (11 in group A and 10 in group B) because of failed entry criteria. Thus, a total of 238 patients in group A and 241 in group B were assessable for response.

Patients in group A had five complete responses and 62 partial responses, and patients in group B had 11 complete responses and 73 partial responses. Thus, the overall response rate was 28% (2% complete responders, 26% partial responders) (95% CI, 22% to 34%) in group A and 35% (5% complete responders, 30% partial responders) (95% CI, 29% to 41%) in group B. Overall response rates were not significantly different between groups (P = .12).

The overall response rates for all patients combined with stage III and IV disease, respectively, were 36% (95% CI, 31% to 49%) and 29% (95% CI, 22% to 35%) (P = .10). Patients with a PS of 2 had a poor response rate of 11% (95% CI, 0% to 20%), whereas patients with a PS of 0 or 1 had an overall response rate of 34% (95% CI, 30% to 41%) (P < .0001).

Toxicity
The treatment was generally well tolerated in both groups, and no hospitalizations were required. Overall, the hematologic toxicity profiles of groups A and B were similar (Table 3). There were no toxic deaths.

Nonhematologic toxicity was also mild in both groups (Table 3). Fever, which was usually of a low grade, was related mainly to gemcitabine administration and lasted a few hours. Fever caused by infection, related to neutropenia, was noted in 3% of patients in both groups combined (1% in group A and 2% in B). The incidence of nausea and vomiting was low in both groups, with grade 3 occurring in 4.3% of group A and 6.5% of group B. Grade 3 neurotoxicity was reported in 8% and 6% of patients in groups A and B, respectively, and occurred more frequently after the third cycle of chemotherapy. Alopecia was universal, with 54% and 53% of patients having grade 3/4 alopecia in groups A and B, respectively. Although infrequent (1% of all patients), arthralgia and myalgia, which were also related to paclitaxel therapy, were observed between the second and fourth day after infusion; however, these were generally mild and the patients responded partially to nonsteroidal anti-inflammatory agents. Grade 3/4 allergic reactions related to paclitaxel therapy appeared during the second cycle of chemotherapy in 1% and 2% of patients in groups A and B, respectively. Although the patients responded to antiallergic treatment consisting of steroids and adrenaline, these events necessitated discontinuation of treatment. The hematologic and nonhematologic toxicity of patients with a PS of 0 to 1 was not different from those with a PS of 2.

Drug Delivery
A total of 1,154 and 1,089 cycles of chemotherapy were given to patients in groups A and B, respectively. The median number of cycles completed was six (range, one to nine cycles) in group A and five (range, one to nine cycles) in group B. Very few patients received more than six cycles (20 patients in group A and 12 in group B) because of continuous shrinkage of the tumor. The median duration of treatment for groups A and B, respectively, was 18 weeks (range, three to 31 weeks) and 18 weeks (range, three to 26 weeks).

The relative dose-intensity of paclitaxel was 0.94 for group A and 0.89 for group B. The relative dose-intensity of gemcitabine was 0.89 and the median cumulative dose of carboplatin was 2,852 mg. The percentage of cycles that were delayed was 12% for group A and 17% for group B. These delays were caused by leukopenia.

Cost
A total of 472 patients, 232 in group A and 240 in group B, were retrospectively analyzed for cost at the end of the study. In terms of outpatient clinic visit days, patients in group A required significantly fewer days (mean, 4.9 days) than those in group B (mean, 8.8 days) (P < .05). Accordingly, outpatient clinic expenses were significantly higher for group B (mean, 515.0) than those for group A (mean, 289.7) (P < .05). Patients in group A were given more paclitaxel (mean, 1,659 mg) than those in group B (mean, 1,520 mg) (P < .05), but gemcitabine for patients in group B was more costly (mean, 1,423.5) than that for carboplatin in group A (mean, 1,275.4) (P = .01). Thus, the difference between the two groups in total chemotherapy drug cost was insignificant (P = .21). In particular, when all expenses (total drug and outpatient clinic costs) were combined, there was no significant difference between groups (P = .66) (Table 4).

View this table: [in this window] [in a new window]   Table 4. Cost () and Time Expended in Receiving Treatment

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The overall response rates for the PG and PC regimens were 35% and 28%, respectively. Although the activity produced by PG was higher, the difference between groups was not significant. Responses were seen in all metastatic sites of disease. Response rates were not significantly different between patients with stage III versus stage IV disease, but were significantly higher for patients with a PS of 0 to 1 versus those with a PS of 2 (P < .0001). In the latter group, only 11% of patients responded, which indicates that this subgroup of NSCLC patients with reduced PS requires a different treatment approach. In the ECOG 1594 trial, the response rate, TTP, median survival, and 1-year survival for patients with a PS of 2 who received PC were 13%, 1.5 months, 4.6 months, and 13.3%, respectively.³⁰

Overall, toxicity was mild and well tolerated in patients in both treatment groups (Table 3) and actually did not require hospitalization. Grade 3/4 neutropenia was transient, short-lasting, and did not lead to sepsis; thrombocytopenia was negligible. No toxic death was reported. Toxicity in patients with a PS of 2 was not different in comparison to those with a PS of 0 to 1, as it was reported also in the ECOG 1594 trial.³⁰

Different platinum-based combinations have similar activities.^31,32 It seems that nonplatinum combinations also have similar activities.^33,34

One important issue regarding the selection of the proper regimen is cost. In this study, we attempted to analyze the expenses for each group retrospectively, although we recognize that this is not the most scientifically rigorous method of cost analysis. However, taking into account the similarity in effectiveness and toxicity between the two groups and the fact that actually no hospitalization or supportive measures were required, it seemed logical to base the cost mainly on outpatient clinic visits and chemotherapy drug expenses. The outpatient clinic cost was significantly higher for patients receiving PG (P < .05), but the chemotherapy drug costs were not significantly different between groups (P = .21). This might be explained by the fact that patients in the PC group received more chemotherapy cycles and a higher dose-intensity of paclitaxel than patients in the PG group. The total expenses, which included chemotherapy drug costs and outpatient clinic cost, were not significantly different (P = .66) between the two groups (Table 4).

In summary, the nonplatinum PG combination demonstrated activity and a toxicity profile similar to the commonly used PC combination. The survival of patients with a PS of 2 was lower in both combinations. Although the PG combination required more outpatient clinic visits, its overall drug cost and, in particular, its total expenses were similar to that of the PC combination.

APPENDIX
The following medical oncologists from the HeCOG-affiliated network institutions also participated in this study: D. Bafaloukos, Metaxa Cancer Hospital, Piraeus; C. Papadimitriou, Alexandra Hospital, Athens; A. Onyenadum, Rio University Hospital, Patra; G. Aravantinos, Ag. Anargiroi Hospital, Athens; C. Stergiou, Theagenio Hospital, Thessaloniki; E. Timotheadou, AHEPA Hospital, Thessaloniki; C. Christodoulou, Medical Center, Athens; N. Xiros, Evagelismos Hospital, Athens; D. Tsavdaridis, IKA, Thessaloniki; G. Samelis, Ippokratio Hospital, Athens; N. Pavlakis, Air Force Hospital, Athens; C. Syrigos, Sotiria Hospital, Athens; E. Razi, Hygeia Hospital, Athens; and D. Pectasidis, Metaxa Cancer Hospital, Piraeus.

	ACKNOWLEDGMENTS

 
We thank U. Dafni, PhD, for the statistical analysis, Aris Triantafillidis for the data management, and Vivi Triantafillou for her secretarial assistance.

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Submitted December 21, 2001; accepted May 22, 2002.

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