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© 2003 American Society for Clinical Oncology 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
From the University of Pittsburgh Cancer Institute, Pittsburgh, PA; University of California at Los Angeles Santa, Clarita Cancer Center, Valencia, CA; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO; Kentuckiana Cancer Center, Louisville, KY; Fort Wayne Medical Oncology-Hematology, Fort Wayne, IN; Louisiana Oncology Associates, Lafayette; Louisiana State University Medical Center, Shreveport, LA; and Hematology and Oncology Associates, Jackson, MI. Address reprint requests to Chandra P. Belani, MD, Professor of Medicine, Co-Director, Lung and Thoracic Cancer Program, University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Ave, Ste 570, Pittsburgh, PA 15232; email: belanicp{at}msx.upmc.edu.
Purpose: To explore the efficacy and safety of three regimens of weekly paclitaxel plus carboplatin as initial therapy and the feasibility of subsequent maintenance therapy versus observation in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods: Four hundred one patients were randomly assigned to one of the following arms: arm 1, paclitaxel 100 mg/m2 weekly for 3 of 4 weeks with carboplatin (area under the curve [AUC] = 6) on day 1; arm 2, paclitaxel 100 mg/m2 and carboplatin (AUC = 2) weekly for 3 of 4 weeks; or arm 3, paclitaxel 150 mg/m2 cycle 1 and 100 mg/m2 cycle 2 and carboplatin (AUC = 2) weekly for 6 of 8 weeks. Patients who responded (n = 130) at week 16 were randomly assigned to either weekly paclitaxel therapy (70 mg/m2, 3 of 4 weeks; n = 65) or observation (n = 65). Results: For the 390 assessable patients, the objective response rates observed with initial therapy were 32% for arm 1, 24% for arm 2, and 18% for arm 3. The median time to progression and median survival times were 30 and 49 weeks for arm 1, 21 and 31 weeks for arm 2, and 27 and 40 weeks for arm 3, respectively. The 1-year survival rates were 47% for arm 1, 31% for arm 2, and 41% for arm 3. Conclusion: Arm 1, paclitaxel 100 mg/m2 weekly for 3 of 4 weeks with carboplatin (AUC = 6) administered on day 1, demonstrates the most favorable therapeutic index in patients with advanced NSCLC.
IN 2002, an estimated 169,400 cases of lung cancer were diagnosed (90,200 in men and 79,200 in women), with an estimated 154,900 deaths attributed to lung cancers in the same year.1 Non–small-cell lung cancer (NSCLC) constitutes approximately 80% of all cases of lung cancer.2 Nearly half of all patients with NSCLC are not candidates for curative surgery at the time of diagnosis.3 Those patients who have regionally advanced, unresectable, stage IIIA and IIIB disease are candidates for combined chemotherapy and definitive radiation therapy, or what is generally referred to as multimodality therapy. In patients with stage IV metastatic disease, the primary goals of therapy are improvement in survival and palliation of symptoms to enhance the patient’s quality of life. Meta-analyses of trials comparing platinum-based chemotherapeutic intervention versus observation have demonstrated a modest survival benefit for chemotherapy with overall improvement in quality of life.4–7 The armamentarium of chemotherapy regimens available is beginning to yield better prognoses for patients with advanced disease through the use of agents such as gemcitabine, irinotecan, vinorelbine, carboplatin, and the taxanes. Paclitaxel is a taxane that functions by promoting the assembly of microtubules from tubulin dimers and then stabilizing those microtubules by preventing depolymerization. Stabilization of the microtubules inhibits their rearrangement, a step that must occur to allow normal cell division. In addition, paclitaxel causes the formation of abnormal bundles of microtubules during the cell cycle and has antiangiogenic activity.8–11 The dosing regimen for paclitaxel exists in several different permutations, the most common ones being every-3-week or weekly schedules. Studies using weekly paclitaxel have shown that this schedule is well tolerated and provides a greater dose intensity when compared with the more conventional schedules. Chang et al12 and Akerley et al13 have reported results of trials using the weekly schedule to treat patients with advanced NSCLC; they achieved response rates of 32% and 39%, respectively. The combination of paclitaxel (225 mg/m2) and carboplatin (area under the curve [AUC] = 6) administered every 3 weeks is the most commonly used chemotherapy regimen in the United States for the treatment of advanced and metastatic NSCLC. The response rate with paclitaxel and carboplatin ranges from 17% to 25%, with median survival times averaging approximately 8 months.14–16 Although the regimen is well tolerated, it is associated with a 10% to 17% incidence of neuropathy.14–16 Weekly regimens of paclitaxel in combination with carboplatin were developed in an attempt to increase the overall efficacy and decrease the expected toxicities. Ramanathan et al17 studied the feasibility of weekly paclitaxel plus carboplatin in two different schedules including paclitaxel 100 mg/m2 weekly for 6 of 8 weeks plus carboplatin (AUC = 6) on days 1 and 22, and paclitaxel 100 mg/m2 weekly for 3 of 4 weeks plus carboplatin (AUC = 6) on day 1. It was determined that both schedules were feasible, with the optimal paclitaxel dose ranging from 100 to 125 mg/m2 in combination with full doses of carboplatin. In the Cancer and Leukemia Group B (CALGB) trial reported by Akerley et al,13 the dose of paclitaxel was 150 mg/m2 for 6 out of 8 weeks. This regimen was active in NSCLC but was associated with a 28% incidence of grade 2 and 3 neuropathy. This study was undertaken to determine the optimal schedule for the administration of the paclitaxel and carboplatin combination in the treatment of advanced, stage IIIB and IV NSCLC and incorporates the regimens developed in the aforementioned trials.13,17 The three treatment arms were as follows: arm 1, paclitaxel (100 mg/m2) weekly for 3 of 4 weeks with carboplatin (AUC = 6) on day 1 of each 4-week cycle for a total of four cycles; arm 2, paclitaxel (100 mg/m2) and carboplatin (AUC = 2) weekly for 3 of 4 weeks of each of four 4-week cycles; and arm 3, paclitaxel (150 mg/m2 in cycle 1 and 100 mg/m2 in cycle 2) and carboplatin (AUC = 2) weekly for 6 of 8 weeks for a total of two 8-week cycles. The only difference between arms 1 and 2 was the delivery of carboplatin weekly in arm 2, but carboplatin was delivered at the same dose intensity in both arms. In arm 3, the higher dose of paclitaxel was based on the CALGB trial.13 However, a higher incidence of neuropathy was observed in that arm in the CALGB trial, especially after the first 8-week cycle, so the dose of paclitaxel was intentionally decreased from 150 mg/m2/wk to 100 mg/m2/wk with the second 8-week cycle. The purpose of the trial was to develop the best weekly regimen for comparison with the standard every-3-week regimen.
Patients Patients who were 18 years of age or older and who had histologically or cytologically conformed, inoperable, stage IIIB or IV NSCLC were eligible for enrollment. Patients had to have at least one bidimensionally measurable indicator lesion that had not been previously irradiated. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) had to be 0 to 2, and patients had to have a life expectancy of  12 weeks and adequate hematologic (absolute granulocyte count 1,500/ìL and platelets 100,000/ìL), renal (bilirubin  1.5 x upper limit of normal), and hepatic (AST/ALT 2.5 x upper limit of normal and creatinine 2 mg/dL) function. Prior chemotherapy was not allowed. Prior radiation therapy or major surgery was to be completed at least 3 weeks before enrollment, with the patient fully recovered from all adverse effects. Patients with measurable neuropathy, active serious infection, or other serious underlying medical conditions were ineligible. The protocol was approved by institutional review boards with jurisdiction over the specific sites that registered patients onto the study. Each patient gave written informed consent before enrollment. The following pretreatment evaluations were performed: medical history, physical examination, height and body weight, ECOG PS, ECG, radiologic tumor assessment, complete blood count with differential and platelet counts, hemoglobin, and serum chemistries (AST, ALT, bilirubin, alkaline phosphatase, glucose, and creatinine). Brain computed tomography or magnetic resonance imaging scans and bone scans were performed as clinically indicated. Women of childbearing potential had to have a negative urine or serum pregnancy test within 7 days before treatment.
Treatment Plan Patients with a complete response, partial response, or stable disease at week 16 proceeded on to the maintenance phase of therapy and were randomly assigned to either weekly paclitaxel therapy or observation. 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 (Table 1
Assessment of Efficacy and Safety Response assessments were performed every 8 weeks 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. For measurable disease, complete response was defined as the disappearance of all clinical evidence of tumor. Partial response was a 50% decrease in the sum of the products of measured lesions or a compared increase of 25% in the size of any lesions. There could not be any appearance of new lesions. Stable disease constituted no significant change in disease for at least 4 weeks, including an estimated decrease of less than 50% or estimated increase of less than 25% in the size of any lesion. There could be no appearance of areas of new malignant disease. Progressive disease was an unequivocal increase of 25% in the product of measured lesions. Appearance of new lesions also constituted progressive disease, as well as significant clinical deterioration that could not be attributed to treatment of other medical conditions or the need for radiation therapy.
For assessable disease, complete response was the complete disappearance of all clinically detectable malignant disease. Partial response was defined as a definite improvement in assessable disease estimated to be greater than 50% and agreed on by two study investigators. Stable disease was defined as no significant change in disease for at least 4 weeks, including lesions with an estimated decrease in size of less than 50% or an estimated increase of less than 25%. There could be no appearance of new areas of malignant disease. Progressive disease constituted a definite increase in the area of malignant lesions estimated to be
Statistical Analysis Patient demographics and baseline history were summarized by treatment arm, with descriptive statistics for continuous measures and counts and frequencies for categorical variables. The objective response rate was defined as the percentage of patients achieving a complete response or partial response at the end of the initial therapy phase. Time to disease progression was characterized using the Kaplan-Meier method18 and summarized using descriptive statistics. Overall survival rates for both the initial therapy and maintenance phases were also characterized using Kaplan-Meier method. P values for disease progression and patient survival on arms 2 and 3 were compared with arm 1 and were adjusted for maintenance treatment. Time to disease progression and survival in the maintenance group were adjusted for 16 weeks of initial treatment. Patients were stratified by ECOG PS (0 to 1 or 2) and by disease stage (stage IIIB or IV), and subgroup analyses of objective response rate, disease progression, and patient survival were calculated based on the stratification.
Patient Characteristics Between May 1998 and June 2000, 401 patients (n = 135 in arm 1, n = 132 in arm 2, and n = 134 in arm 3) were enrolled onto the initial therapy phase of the study at 47 community and academic sites in the United States. Patient baseline characteristics for the initial therapy phase (Table 2  ) were comparable across treatment arms. There was a higher percentage of males than females in each treatment arm, with 59% males in arm 1, 65% males in arm 2, and 61% males in arm 3. Median age was 65 years (range, 42 to 87 years) in arm 1, 63 years, (range 35 to 85 years) in arm 2, and 64 years (range, 35 to 83 years) in arm 3. The percentage of patients with an ECOG PS of 0 or 1 to 2 was 86% and 14% in arms 1, 86% and 14% in arm 2, and 85% and 15% in arm 3, respectively.
Three-hundred ninety patients (97%) received treatment and were included in the intent-to-treat analysis. Eleven patients did not receive treatment, including three patients in arm 1, two patients in arm 2, and six patients in arm 3. Of these 11 patients, three were ineligible for the study, and for various reasons, the remaining eight did not receive any study drug. A greater percentage of patients in arm 1 completed all 16 weeks of initial therapy (30% for paclitaxel and 55% for carboplatin) compared with arms 2 and 3 (29% and 22%, respectively, for paclitaxel and 28% and 21%, respectively, for carboplatin). The median number of doses received per patient on arms 1, 2, and 3 were 11, 10, and nine paclitaxel doses and four (administered every 4 weeks), 10, and nine carboplatin doses, respectively. A total of 54.5% of patients received the total planned dose of carboplatin on arm 1 compared with 27.7% of patients on arm 2. The dose intensity of carboplatin was higher during the first 8-week period on arm 3; otherwise, it was the same for the three arms (total dose, AUC = 24). The primary reasons for discontinuation for all patients in the initial therapy phase were progression of disease (31%) and adverse events (15%; Table 3 ).
One-hundred thirty patients (paclitaxel, n = 65; observation, n = 65) were randomly assigned to the maintenance phase within 2 weeks of completion of the initial therapy phase. Patient characteristics did not differ between the two groups (Table 4 ). Fifty-one patients (79%) discontinued paclitaxel treatment during maintenance therapy; the most common reasons were disease progression (39%) and adverse event (22%). Fifty-two patients (80%) completed one full cycle of paclitaxel, but 15 (23%) completed four full cycles. After discontinuation of protocol therapy, patients received additional treatment for their disease as follows: additional chemotherapy (47%), radiotherapy (26%), immunotherapy (1%), and surgery (4%).
Efficacy The objective response rate (complete response + partial response) observed at the end of initial therapy (week 16) was 32% for arm 1, 24% for arm 2, and 18% for arm 3 (Table 5 ). Median time to disease progression was 30 weeks for arm 1, 21 weeks for arm 2, and 27 weeks for arm 3. Median survival time was 49 weeks for arm 1, 31 weeks for arm 2, and 40 weeks for arm 3, and 1-year survival rates were 47% for arm 1, 31% for arm 2, and 41% for arm 3 (Fig 1). Two-year survival rates are listed in Table 5.
Table 6 lists the results of an analysis of the efficacy parameters with the patients stratified by disease stage or PS. Patients on arms 1, 2, and 3 with stage IIIB disease had objective response rates of 32%, 27%, and 25%, respectively, and patients with stage IV disease had objective response rates of 32%, 23%, and 16%, respectively. The median time to disease progression was significantly higher for arm 1 than arm 2 for patients with stage IIIB NSCLC (35 v 18 weeks, P = .018) and ECOG PS 0 to 1 (31 v 21 weeks, P = .007). The median survival time for patients with stage IIIB disease was greater on arm 1 than on arm 2 (68 v 43 weeks, P = .021); it was also greater for patients with an ECOG PS of 2 on arm 1 versus arm 2 (26 v 12 weeks, P = .02). No other subgroup comparisons were significantly different for median time to progression or median survival time. Although the differences were not statistically significant, it is notable that 1-year survival rates were greater for arm 1 than for arms 2 and 3 across all subgroups examined.
Median time to progression and median survival time for those patients who went on to receive either maintenance therapy with paclitaxel or observation are reported in Table 7 . The median times to disease progression were 38 weeks for the paclitaxel arm and 29 weeks for patients on the observation arm. Median survival times and 1-year survival rates (Fig 2) were 75 weeks and 72% on the paclitaxel arm and 60 weeks and 60% on the observation arm, respectively. Two-year survival rates are listed in Table 7.
Age can also be a factor in the prognosis of patients with advanced disease. Therefore, a subgroup analysis of patients less than 70 years of age (n = 279) and 70 years of age or older (n = 111) was also performed. Median time to progression was 29.7 weeks (arm 1), 18.0 weeks (arm 2), and 26.6 weeks (arm 3) for those patients less than 70 years of age and 31.3 weeks (arm 1), 23.1 week (arm 2), and 37.3 weeks (arm 3) for patients 70 years of age or older. In terms of survival, median survival times were 48.4 weeks (arm 1), 33.4 weeks (arm 2), and 39.6 weeks (arm 3) for patients less than 70 years of age and 49.3 weeks (arm 1), 26.3 weeks (arm 2), and 62.6 weeks (arm 3) for patients 70 years of age or older. The 1-year survival rates for the patients less than 70 years were 46.1%, 34.7%, and 37.6% versus 49.9%, 18.8%, and 51.5% for patients 70 years of age or older for arms 1, 2 and 3, respectively.
Safety
Few nonhematologic toxicities were reported (Table 9 ). Grades 3 and 4 neurotoxicity, including neuropathy, peripheral neuritis, neuritis, and paresthesia, were most prevalent in patients on arm 3 (13%), but the incidence was lower for arms 1 and 2, at only 5% and 3%, respectively. There were two (2%) treatment-related deaths on arm 2, three (2%) on arm 3, and none on arm 1. Three patients died of sepsis, one patient had acute respiratory distress syndrome, and one patient had rapidly progressive disease.
Only 130 patients were randomly assigned to maintenance therapy, which consisted of weekly paclitaxel versus observation. During maintenance therapy, 86% of patients in the paclitaxel group reported at least one adverse experience, and 45% reported at least one grade 3 or 4 experience. Grade 3 and 4 hematologic and nonhematologic toxicities reported in the maintenance phase were similar to those reported for the initial therapy phase.
The three weekly regimens of paclitaxel and carboplatin in this study were reasonably well tolerated, and the efficacy results are provocative. The standard every-3-week regimen of paclitaxel and carboplatin results in an objective response rate of 17% to 25%, with a median survival time of 8 months.14–16,19 In this study, arm 1 (paclitaxel 100 mg/m2 weekly for 3 of 4 weeks plus carboplatin AUC = 6 on day 1) demonstrated a response rate of 32% and a median survival time of 49 weeks, with a 1-year survival rate of 47%. Although this is a phase II randomized study not designed to show benefit in survival, it is large enough, with 390 assessable patients, to allow reasonable inferences and comparisons with historical data (Table 10 ). Comparison with the results of studies using the standard every-3-week schedule of paclitaxel and carboplatin indicates that the regimen used in arm 1 of this study achieved the goal of favorable efficacy with a highly tolerable toxicity profile.
Although the dose intensity of carboplatin and paclitaxel in arm 2 was designed to be similar to that of arm 1, arm 1 was associated with overall improved efficacy. This may be in part because of the administration of full-dose carboplatin on arm 1, whereas the true dose intensity of carboplatin on arm 2 was lower because weekly doses of both carboplatin and paclitaxel were omitted on arm 2 because of myelosuppression. Administration of a higher weekly dose of paclitaxel (150 mg/m2), as on arm 3, did not show any additional benefit compared with arm 1. There was a higher incidence of grade 2 and 3 neuropathy (13%) on arm 3 despite reduction in the dose of paclitaxel to 100 mg/m2 after the first 8 weeks of treatment. Thus, more is certainly not better, and the results demonstrate that arm 1 has the best overall efficacy and the most favorable toxicity profile. Patients who achieved complete or partial responses or stable disease with initial therapy were randomly assigned to receive either maintenance therapy with weekly paclitaxel (n = 65) or observation (n = 65). Maintenance therapy with paclitaxel delayed the time to disease progression (38 weeks v 29 weeks) and yielded a greater median survival time (75 weeks v 60 weeks). Despite these interesting results, no definitive statement can be made regarding the role of weekly maintenance treatment with paclitaxel. If the study sample was larger, there is a possibility that a significant effect may have been identified. Therapy beyond three or four cycles with the same regimen may not be beneficial in patients with advanced NSCLC,20–22 but the role of nontoxic, low doses of a single agent in this setting still remains an open question. This study was also not designed to address this issue.
In general, subset analyses yielded no surprises regarding the relationship of stratification factors (ECOG PS and disease stage) and efficacy. An ECOG PS of 2 and stage IV disease typically equate with a poorer prognosis, and in this study, patients in those strata had shorter times to progression and decreased survival times (Table 6 Although cross-arm comparisons are not valid in randomized phase II studies, arm 1 seems to have the best therapeutic index, and both paclitaxel and carboplatin can be administered with ease without substantial toxicity on this schedule and can be given with reasonable efficacy in both patients with an ECOG PS of 2 and elderly patients. This schedule has been chosen for comparison with the standard every-3-week regimen of paclitaxel and carboplatin in a recently completed phase III randomized trial.
Supported by a grant from Bristol-Myers Squibb Company, Princeton, NJ. Previously presented at the Ninth Annual World Conference on Lung Cancer, Tokyo, Japan, September 11–15, 2000, and at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.
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21. Smith IE, O’Brien MER, Talbot DC, et al: Duration of chemotherapy in advanced non-small cell lung cancer: A randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 19:1336–1343, 2001 22. Depierre A, Quoix E, Mercier M, et al: Maintenance chemotherapy in advanced non-small cell lung cancer (NSCLC): A randomized study of vinorelbine (V) versus observation (OB) in patients (pts) responding to induction therapy (French Cooperative Oncology Group). Proc Am Soc Clin Oncol 20:309a, 2001 (abstr 1231) Submitted February 13, 2003; accepted May 15, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
