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Randomized, Phase III Study of Weekly Paclitaxel in Combination With Carboplatin Versus Standard Every-3-Weeks Administration of Carboplatin and Paclitaxel for Patients With Previously Untreated Advanced Non–Small-Cell Lung Cancer

Chandra P. Belani, Suresh Ramalingam, Michael C. Perry, Renato V. LaRocca, David Rinaldi, Preston S. Gable, William J. Tester

From the Penn State Cancer Institute, Hershey; University of Pittsburgh Cancer Institute, Pittsburgh; Albert Einstein Medical Center, Philadelphia, PA; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO; Kentuckiana Cancer Institute, Louisville, KY; Louisiana Oncology Associates, Lafayette, LA; and Naval Medical Center, San Diego, CA

Corresponding author: Chandra P. Belani, MD, Penn State Cancer Institute, H072, 500 University Drive, PO Box 850, Hershey, PA 77030; e-mail: cbelani{at}psu.edu

	ABSTRACT

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Purpose To compare the efficacy and safety of weekly paclitaxel in combination with carboplatin administered every 4 weeks to the standard regimen of paclitaxel and carboplatin administered every 3 weeks for the treatment of patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods Four hundred forty-four patients with previously untreated stage IIIB/IV NSCLC were randomly assigned to either arm 1 (n = 223), paclitaxel 100 mg/m² weekly for 3 of 4 weeks with carboplatin area under the curve (AUC) = 6 mg/mL · min on day 1 of each 4 week cycle, or arm 2 (n = 221), paclitaxel 225 mg/m² and carboplatin AUC = 6 on day 1 of each 3-week cycle. After four cycles of therapy, patients in both treatment arms were eligible to continue weekly paclitaxel (70 mg/m², 3 of 4 weeks) as maintenance therapy until unacceptable toxicity or disease progression.

Results The objective response rate was 27.6% for arm 1 and 19.2% for arm 2. Median time to progression (TTP) was 18.4 and median survival (MS) was 38.6 weeks for arm 1. For arm 2, the median TTP and MS were 16.7 weeks and 42.9 weeks respectively. Grade 3/4 anemia was more common with arm 1, although grade 2/3 neuropathy and arthralgia were less common. The remainder of the toxicities were similar between the two arms.

Conclusion All efficacy parameters were similar between the two treatment arms. The favorable nonhematologic toxicity profile of arm 1 makes this an alternative treatment option for patients with advanced NSCLC.

	INTRODUCTION

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Lung cancer is the leading cause of cancer-related mortality in the United States. More than 213,000 cases of lung cancer will be diagnosed in the year 2007 in the US.¹ More than 80% of patients have non–small-cell lung cancer (NSCLC) histology.² Approximately 40% present with stage IIIB (with pleural/pericardial effusion) or stage IV disease (advanced or metastatic disease).¹ For patients with advanced/metastatic NSCLC, systemic chemotherapy constitutes the standard of care. Both qualitative and quantitative benefits are noted with platinum-based two-drug combinations for advanced NSCLC patients with a good performance status (PS; Eastern Cooperative Oncology Group [ECOG] PS 0 or 1).³

The combination of carboplatin and paclitaxel is the most commonly used regimen for the treatment of advanced NSCLC in the United States. Its efficacy has been established by randomized phase III studies.^4-6 The ECOG study that compared four commonly used regimens (cisplatin/paclitaxel, cisplatin/docetaxel, cisplatin/gemcitabine, and carboplatin/paclitaxel) for front-line therapy of advanced NSCLC⁶ demonstrated similar efficacy including response rate, median survival, and 1-year survival for all four regimens. Carboplatin/paclitaxel was chosen as the reference regimen for the next ECOG trial based on its favorable therapeutic index. The results of a Southwest Oncology Group study also demonstrated a favorable tolerability profile for the carboplatin/paclitaxel regimen compared with cisplatin/vinorelbine.⁵

The most common toxicities associated with the carboplatin/paclitaxel regimen are neuropathy, arthralgia, myalgia, and myelosuppression. Efforts to improve the tolerability profile of this regimen have focused on administration of lower doses of paclitaxel (175 to 200 mg/m²) or by administering paclitaxel on a weekly schedule.⁷ We initially conducted a randomized phase II study to compare three different weekly schedules of the carboplatin/paclitaxel regimen for patients with advanced NSCLC.⁸ Administration of paclitaxel on a weekly basis for 3 weeks out of 4 (3-weekly), in combination with carboplatin on day 1 of every 4-week cycle was associated with the most favorable therapeutic index (response rate, 32%; median survival, 49 weeks; 1-year survival, 47%) among the three regimens tested in the study. On the basis of these results, we conducted a randomized phase III study to compare the efficacy and safety of the weekly regimen with the standard 3-weekly schedule of carboplatin and paclitaxel for patients with advanced NSCLC.

In the earlier phase II study, patients who were randomly assigned to weekly paclitaxel as maintenance therapy after combination therapy had a longer time to disease progression (TTP) and greater median survival compared with patients randomly assigned to observation^8. Therefore, the present study also evaluated the role of maintenance therapy for patients who responded to initial therapy with weekly paclitaxel in each arm.

	PATIENTS AND METHODS

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Patients
Patients age 18 years or older, with histologically or cytologically confirmed inoperable stage IIIB (malignant pleural or pericardial effusion) or IV non–small-cell lung cancer were eligible. Other eligibility criteria included presence of measurable disease, ECOG PS of 0 to 2, life expectancy of at least12 weeks, adequate hematologic (absolute neutrophil count [ANC] 1,500/mm³ and platelets 100,000/mm³), hepatic (bilirubin 1.5x upper limit of normal [ULN], AST/ALT 2.5 x ULN), and renal (serum creatinine 2 mg/dL) function. Patients who received prior chemotherapy were excluded. Prior radiation therapy or major surgery was to be completed at least 3 weeks before enrollment, and the patient was required to be completely recovered from all adverse effects. Patients with neuropathy, active serious infection, or other serious underlying medical conditions were ineligible. The study protocol was approved by institutional review boards with jurisdiction over the specific sites that registered patients onto the study, and all patients provided informed consent before enrollment.

Pretreatment evaluations included medical history, physical examination, ECOG PS, ECG, radiologic tumor assessment, CBC with differential, and serum chemistry (AST, ALT, bilirubin, alkaline phosphatase, glucose, and creatinine). Imaging studies of brain and bone scans were performed as clinically indicated. Women of childbearing potential had to test negative via urine or serum pregnancy test within 7 days before treatment.

Treatment Plan
On enrollment, patients were randomly assigned to: arm 1, paclitaxel 100 mg/m² weekly for 3 of 4 weeks (3-weekly) with carboplatin area under the curve (AUC) = 6 mg/mL · min on day 1 of each 4-week cycle; or arm 2, paclitaxel (225 mg/m²) and carboplatin (AUC = 6) on day 1 of each of 21-day cycle. Treatment was continued up to a maximum of four cycles. Premedications for paclitaxel were (30-60 minutes before administration): intravenous (IV) dexamethasone 20 mg, IV diphenhydramine 50 mg, and a histamine receptor 2 (H₂) blocker (such as IV cimetidine 300 mg or ranitidine 50 mg). Patients in arm 1 who did not experience a hypersensitivity reaction to paclitaxel during the first cycle could have their premedications altered to the following: IV dexamethasone 8 to 10 mg, IV diphenhydramine 25 mg, and an H₂ blocker as described herein.

Patients with a complete response (CR), partial response (PR), or stable disease (SD) after four cycles of therapy in either arms of the study could proceed to the maintenance phase of weekly paclitaxel therapy. Each paclitaxel cycle consisted of 70 mg/m² weekly for 3 of 4 weeks. Patients were premedicated as described for the initial therapy phase. Maintenance therapy continued until disease progression, development of intercurrent illness, intolerable toxicity, patient refusal of further treatment, or investigator decision to terminate treatment.

A maximum of two dose-level reductions was permitted per patient in the initial phase, but only one reduction was allowed during the maintenance phase. During the initial phase, the dose of carboplatin was reduced to achieve AUC of 5 and 4 mg/mL · min, respectively, with each reduction. In arm 1, paclitaxel dose was reduced to 85 mg/m² and 70 mg/m², respectively, with each reduction. In arm 2, paclitaxel was reduced to 200 mg/m² and 150 mg/m², respectively, with each reduction. For the maintenance phase, paclitaxel dose could be reduced to 50 mg/m². Both paclitaxel and carboplatin were reduced by one dose level if the ANC nadir was no more than 800/µL and/or the platelet count was 50,000/µL or lower. Paclitaxel was reduced by one dose level for grade 2 neuropathy, and patients were removed from the study for grade 3 or worse neuropathy. Paclitaxel was withheld for grade 3 fatigue, arthralgias, or myalgias until resolution to no worse than grade 2, then resumed with a reduction of dose by one level. Paclitaxel was decreased by one dose level for bilirubin levels between 1.5 and 2.0 mg/dL, or withheld for levels higher than 2.0 mg/dL until resolution to no more than 2.0 mg/dL, then restarted at one dose level lower. For all other grade 3 or 4 toxicities, treatment was withheld until resolution to no worse than grade 2; treatment was then resumed with study medications reduced by one dose level.

Assessment of Efficacy and Safety
Response assessments were performed every two cycles (ie, every 8 weeks for arm 1, every 6 weeks for arm 2) during the initial therapy phase of the study and every 12 weeks during the maintenance phase. Responses were confirmed with repeat assessments no less than 4 weeks after the initial claim of response. Responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.⁹ Toxicities were graded using the National Cancer Institute Common Toxicity Criteria Version 2.

Statistical Analysis
The primary efficacy end point was overall patient survival. The survival rate was evaluated at 1, 2, 3, 4, and 6 months, and at 1 and 2 years for each of the dosing arms and for each phase of the study. The secondary efficacy end points were the objective response rate (ORR) for the initial phase and the median TTP for both the initial and maintenance phases. The estimated sample size was 444 patients (222 per treatment arm of the initial therapy phase) to ensure detection of a survival difference between arms 1 and 2 with 80% power. This was based on the assumption of a median survival of 8 months in the control arm and 10.8 months with the experimental regimen.

Patient demographics and baseline history were summarized by treatment arm, with descriptive statistics for continuous measures and counts and frequencies for categoric variables. The ORR was defined as the percentage of patients achieving a CR or PR at the end of the initial therapy phase. TTP was characterized using Kaplan-Meier equations and summarized using descriptive statistics. Overall survival rates for both the initial therapy and maintenance phases were also characterized with Kaplan-Meier methods. Toxicities by grade were tabulated by each treatment arm during the initial and maintenance phases.

To adjust for prognostic factors (including ECOG PS, disease stage, age category [ 70 and < 70 years], and duration since diagnosis), multivariate analyses of patient survival and TTP were conducted, adjusting for these factors. ORR was also summarized by subgroup according to the prognostic factors described.

	RESULTS

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Patient Characteristics
Between October 13, 2000, and June 14, 2004, 444 patients (n = 223 for arm 1 and n = 221 for arm 2) were enrolled onto the initial therapy phase of the study at 68 sites across the United States (Fig 1). ^10,11 Patient baseline characteristics for the initial therapy phase are summarized in Table 1. There was a slightly higher representation of women in arm 1 (40% v 35%). More than 80% of the patients had stage IV disease in both arms. Adenocarcinoma was the most common histological subtype and was seen in approximately 57% of patients in both arms. Patients with an ECOG PS of 2 accounted for 12% and 10% of the patients in arms 1 and 2, respectively.

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard 3-weekly administration of carboplatin and paclitaxel for patients with previously untreated advanced non–small-cell lung cancer.

After all protocol therapy was discontinued, 56% of patients in arm 1% and 60% in arm 2 received salvage therapy with either docetaxel, gemcitabine, or gefitinib. Other poststudy treatment modalities included radiotherapy (33% for patients in both arms), hormonal therapy (1%), immunotherapy (2%), and surgery (4%). Thirty-four percent of patients in arm 1% and 27% in arm 2 did not receive any poststudy therapy.

Efficacy
The median survival duration was 38.6 weeks for patients in arm 1 and 42.9 weeks for those in arm 2 (Fig 2). One- and 2-year survival rates were 37.8% and 16.2%, respectively, for arm 1 and 41.3% and 17.6% for arm 2. The ORR (CR + PR) observed for arms 1 and 2 were 27.6% and 19.2%, respectively (Table 3). The difference in response rate was significant (P = .037). Median TTP was 18.4 weeks for arm 1 and 16.7 weeks for arm 2 (Fig 3). For the patients who went on to receive maintenance therapy with weekly paclitaxel, median TTP was 33 weeks for those from arm 1 and 29 weeks for those from arm 2.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Patient survival by Kaplan-Meier method (initial phase).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Time to disease progression by Kaplan-Meier method (initial phase).

Safety
Table 4 provides a summary of grade 3 and 4 toxicities experienced by at least 3% of patients in the initial phase of treatment. Neutropenia was the most common hematologic toxicity (13% and 16% in arms 1 and 2, respectively). Anemia was more common in arm 1 (8% v 3%, P = .026). Febrile neutropenia was rare (1% in arm 1 and 3% in arm 2).

A total of 141 patients received maintenance therapy. Grade 4 neutropenia was noted in 2.1% of the patients during the maintenance phase. The following grade 3 toxicities were noted during maintenance therapy: anemia (0.7%), neuropathy (2.1%), arthralgia (2.1%), fatigue (2.8%), dyspnea (2.1%), and abdominal pain (2.1%). Progression of disease was the most common reason for discontinuation of maintenance therapy (64%), and approximately 5.7% discontinued because of toxicity.

	DISCUSSION

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The experimental regimen of this phase III trial was developed with the intent of improving the therapeutic index of the combination of carboplatin and paclitaxel. Administration of paclitaxel on a weekly schedule has distinct theoretical advantages because higher dose-intensity of therapy can be achieved. Furthermore, continuous low-dose paclitaxel exhibits potent anti-angiogenic and pro-apoptotic effects in preclinical models.¹²

The median survival and response rates with the standard 3-weekly regimen in our study is similar to that in other phase III studies with the combination of carboplatin and paclitaxel in advanced NSCLC.⁶ Although the differences in the duration of treatment cycle between the two arms (4 and 3 weeks, respectively, for arms 1 and 2) could have contributed to differences in median TTP, the overall survival and 1-year survival results are comparable between the two arms. The lower incidence of grade 2/3 neuropathy was achieved with the weekly paclitaxel regimen despite the same dose-intensity of paclitaxel on both the arms.

Ukena et al¹³ randomly assigned 320 patients to treatment with standard doses of carboplatin (AUC = 6 mg/mL · min) and paclitaxel (200 mg/m²) or the same two drugs administered on a weekly schedule (carboplatin AUC = 2 mg/mL · min/wk; paclitaxel 100 mg/m²/wk, for 6 weeks followed by 2 weeks off). Similar to our study, they noted a lower incidence of grade 2 or worse sensory neuropathy (42% v 63%) with the weekly regimen. Grade 2 or worse neutropenia was also less common with the weekly schedule (35% v 53%). Socinski et al¹⁴ evaluated a slightly different schedule of carboplatin and weekly paclitaxel in a randomized phase II study. In the weekly arm, paclitaxel was administered at 75 mg/m²/wk on a continuous basis for 12 weeks, whereas carboplatin (AUC = 6 mg/mL · min) was administered on day 1 every 3 weeks, and this was compared with the regimen of standard carboplatin and paclitaxel every 3 weeks as in our study. Although efficacy was similar between the two arms, myalgia/arthralgia was less common with the weekly arm, and there was a trend toward a lower incidence of neuropathy and neutropenia. Furthermore, patients in the standard arm reported significantly more taxane-related adverse effects on the Functional Assessment of Cancer Therapy (FACT) taxane subscale. Taken together, the weekly regimen of paclitaxel in combination with carboplatin can be considered an evidence-based therapeutic option for front-line therapy of advanced NSCLC.

Another objective of our study was to evaluate the feasibility of maintenance therapy with weekly paclitaxel after four cycles of combination chemotherapy. Four cycles of combination chemotherapy are considered optimal for patients with advanced-stage NSCLC. Continuation of combination chemotherapy beyond four to six cycles results in cumulative toxicity without any improvement in efficacy.^15,16 This raises the question of whether administration of a single agent as maintenance therapy might be beneficial because it is associated with minimal cumulative toxicity. In our randomized phase II study with weekly paclitaxel regimens, patients randomly assigned to maintenance weekly paclitaxel seemed to have improved efficacy.⁸ Therefore, we included weekly paclitaxel as maintenance therapy for patients in both arms of the study after four cycles of combination therapy. Although only approximately 70% of the eligible patients received maintenance therapy, it was tolerated well overall. In the absence of a control arm, we cannot determine whether maintenance therapy contributed to overall survival. However, the feasibility of a single agent as maintenance therapy provides the proof of principle to evaluate promising single-agent chemotherapy or targeted agents as potential candidates for maintenance therapy.

Recently, the addition of bevacizumab to the regimen of carboplatin and paclitaxel resulted in improved survival for patients with advanced nonsquamous NSCLC.¹⁷ However, there were modest additions to the toxicity profile with a higher incidence of neutropenia, with the three-drug combination. This illustrates the need to establish chemotherapy platforms with the most favorable therapeutic index to combine molecularly targeted agents without excessive increase in toxicity. The results of our phase III study demonstrate that the weekly regimen of paclitaxel in combination with carboplatin is well suited to serve as the backbone for addition of targeted agents based on its favorable therapeutic index. Furthermore, this regimen is also well suited for evaluation in the treatment of special populations such as the elderly and those with a poor performance status (ECOG PS 2).

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Renato V. LaRocca, Bristol-Myers Squibb (C) Stock Ownership: None Honoraria: Renato V. LaRocca, Bristol-Myers Squibb Research Funding: Michael C. Perry, Bristol-Myers Squibb; Renato V. LaRocca, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: None

	Author Contributions

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Conception and design: Chandra P. Belani

Administrative support: Chandra P. Belani

Provision of study materials or patients: Chandra P. Belani, Suresh Ramalingam, Michael C. Perry, Renato V. LaRocca, David Rinaldi, Preston S. Gable, William J. Tester

Collection and assembly of data: Chandra P. Belani, Suresh Ramalingam, Michael C. Perry, Renato V. LaRocca, David Rinaldi, Preston S. Gable, William J. Tester

Data analysis and interpretation: Chandra P. Belani, Suresh Ramalingam

Manuscript writing: Chandra P. Belani, Suresh Ramalingam

Final approval of manuscript: Chandra P. Belani, Suresh Ramalingam, Michael C. Perry, Renato V. LaRocca, David Rinaldi, Preston S. Gable, William J. Tester

	NOTES

 
Supported in part by a grant from Bristol-Myers Squibb Company.

Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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3. Ramalingam S, Belani CP: State-of-the-art chemotherapy for advanced non-small cell lung cancer. Semin Oncol 31:68-74, 2004[Medline]

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5. Kelly K, Crowley J, Bunn PA Jr, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non–small-cell lung cancer: A Southwest Oncology Group trial. J Clin Oncol 19:3210-3218, 2001[Abstract/Free Full Text]

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8. Belani CP, Barstis J, Perry MC, et al: Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. J Clin Oncol 21:2933-2939, 2003[Abstract/Free Full Text]

9. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

10. Moher D, Schulz KF, Altman DG: The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 357:1191-1194, 2001[CrossRef][Medline]

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14. Socinski MA, Ivanova A, Bakri K, et al: A randomized phase II trial comparing every 3-weeks carboplatin/paclitaxel with every 3-weeks carboplatin and weekly paclitaxel in advanced non-small cell lung cancer. Ann Oncol 17:104-109, 2006[Abstract/Free Full Text]

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Submitted July 17, 2007; accepted October 11, 2007.

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