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Randomized phase 2 study of irinotecan plus cisplatin versus gemcitabine plus vinorelbine as first-line chemotherapy with second-line crossover in patients with advanced nonsmall cell lung cancer
Article first published online: 16 MAY 2008
Copyright © 2008 American Cancer Society
Volume 113, Issue 2, pages 388–395, 15 July 2008
How to Cite
Han, J.-Y., Lee, D. H., Song, J. E., Lee, S. Y., Kim, H. Y., Kim, H. T. and Lee, J. S. (2008), Randomized phase 2 study of irinotecan plus cisplatin versus gemcitabine plus vinorelbine as first-line chemotherapy with second-line crossover in patients with advanced nonsmall cell lung cancer. Cancer, 113: 388–395. doi: 10.1002/cncr.23582
- Issue published online: 8 JUL 2008
- Article first published online: 16 MAY 2008
- Manuscript Accepted: 21 MAR 2008
- Manuscript Revised: 9 JAN 2008
- Manuscript Received: 5 OCT 2007
- National Cancer Center. Grant Numbers: 0210140, 0510140
- nonsmall cell lung cancer
The current study was performed to compare the nonplatinum-based combination of gemcitabine and vinorelbine (GV) with the combination of irinotecan and cisplatin (IP) as first-line chemotherapy with second-line crossover in patients with advanced nonsmall cell lung cancer (NSCLC).
Patients were randomly assigned to received either irinotecan at a dose of 65 mg/m2 plus cisplatin at a dose of 30 mg/m2 (Arm A) or gemcitabine at a dose of 900 mg/m2 plus vinorelbine at a dose of 25 mg/m2 (Arm B), each of which was administered on Days 1 and 8 every 3 weeks as the first-line therapy followed by crossover at the time of disease progression.
A total of 146 patients were enrolled (75 patients in Arm A and 71 patients in Arm B); 138 patients were evaluable for tumor response and toxicity. During first-line therapy, IP was found to result in more grade 2+ nausea and vomiting (toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) (41% vs 12%; P = .0001) and alopecia (36% vs 10%; P = .0003). Pneumonitis was noted only with GV therapy (7% vs 0%; P = .058). During second-line therapy, IP was found to result in more grade 3 diarrhea (17% vs 2%; P = .039) and GV featured more cases of grade 3+ neutropenia (78% vs 40%; P = .0003). IP tended to generate more tumor responses (38% vs 26% as first-line therapy, and 30% vs 13% as second-line therapy) compared with GV. IP also demonstrated a favorable trend in median progression-free survival (4.6 months vs 3.8 months as first-line therapy and 4.5 months vs 2.6 months as second-line therapy) and overall survival (15.9 months vs 13.1 months; P = .3), but this difference was not statistically significant. The majority of patients who were refractory to IP also failed to respond to GV in the second-line setting.
The platinum-based IP regimen appeared to be superior to the GV combination in terms of response rate. However, given the similar survival and better tolerability of the nonplatinum GV regimen, either treatment sequence would appear to be acceptable for the treatment of patients with advanced NSCLC. Cancer 2008. © 2008 American Cancer Society.
Cisplatin-based chemotherapy is currently considered to be the standard treatment for advanced nonsmall cell lung cancer (NSCLC), with modest but statistically significant improved survival without compromising quality of life compared with best supportive care alone.1, 2 However, the cisplatin-related toxicity (including nausea and vomiting, neurotoxicity, and nephrotoxicity) as well as the delivery problems (eg, prolonged hydration and hospitalization) have prompted us to search for alternative regimens. Over the last decade, several third-generation agents such as paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan have been widely adopted. In general, these agents are more tolerable and have single-agent activity that is equal to or greater than that of cisplatin.3 Thereafter, it has become possible to explore more nonplatinum combinations of third-generation agents, such as the regimen of gemcitabine and vinorelbine (GV), in patients with advanced NSCLC.
A recent update of American Society of Clinical Oncology guidelines recommended that any first-line chemotherapy administered to advanced NSCLC patients should be a 2-drug combination regimen and that nonplatinum-containing chemotherapy can be used as an alternative first-line chemotherapy.4 Moreover, a recent meta-analysis demonstrated that although third-generation platinum-containing doublets have better response rates, they also have a higher rate of toxicity, even without providing a significant improvement in survival compared with nonplatinum-containing doublets.5 Given the better tolerability and similar survival rates of nonplatinum regimens, the modern third-generation nonplatinum-containing regimens can be a valid option for first-line therapy in patients with advanced NSCLC.
The GV combination is characterized by a favorable toxicity profile and better tolerability than platinum-based regimens. In phase 2 trials, response rates of 26% to 59% with median survival rates of 8 months to 9 months were reported.6–12 There are several randomized phase 3 trials published to date comparing the GV regimen with cisplatin-based regimens. Gridelli et al.13 compared GV with cisplatin plus vinorelbine or chemotherapy with gemcitabine alone in chemotherapy-naive patients with advanced NSCLC and demonstrated that GV therapy is similar to standard cisplatin-based doublets with respect to palliation as assessed by response rate and quality of life and is less toxic, with no significant difference noted with regard to overall survival (OS). In addition, the German and Swiss Lung Cancer Group compared the GV regimen with GV plus cisplatin (GVP) chemotherapy. They found that the cisplatin-based GVP regimen demonstrated no survival benefit when used as first-line chemotherapy in patients with advanced NSCLC compared with the cisplatin-free GV regimen, which was found to be substantially better tolerated.14 Based on the favorable activity and tolerability of the GV regimen in patients with NSCLC, we conducted a phase 2 randomized trial comparing the nonplatinum-based GV regimen with a cisplatin-based modern doublet, irinotecan plus cisplatin (IP), as the first-line chemotherapy in patients with advanced NSCLC, with crossover occurring at the time of disease progression, to investigate the efficacy, toxicity, and survival of these alternating sequential treatment schedules.
MATERIALS AND METHODS
Eligibility criteria included pathologically confirmed stage IIIB disease with pleural effusions or stage IV NSCLC (determined according to the American Joint Committee on Cancer Staging Manual); age ≥18 years; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; ≥1 bidimensionally measurable lesion; no prior chemotherapy or targeted therapy; adequate hematologic, hepatic, and renal functions defined as a white blood cell count ≥3.5 × 109/L, a platelet count ≥150.0 × 109/L, a serum bilirubin level ≤1.2 times the upper limit of normal, aspartate aminotransferase and alanine aminotransferase levels ≤2.5 times the upper limit of normal of the institutional reference range, and serum creatinine ≤1.4 mg/dL; and no active infection. Patients with brain metastasis were permitted to enter the study unless there were clinically significant neurologic symptoms or signs. Before randomization, all patients provided written informed consent approved by the Institutional Review Board of the National Cancer Center Hospital. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
At the time of study entry, patients were randomly assigned to treatment arms A or B using permuted blocks within strata. Stratification factors included disease stage (stage IIIB vs stage IV), ECOG PS (0 or 1 vs 2), and sex (male vs female).
Patients enrolled onto Arm A (IP) received cisplatin at a dose of 30 mg/m2 as a 30-minute intravenous (iv) infusion followed by irinotecan at a dose of 65 mg/m2 as a 1-hour iv infusion on Days 1 and 8 as the first-line therapy. Patients enrolled onto Arm B (GV) received gemcitabine at a dose of 900 mg/m2 as a 30-minute iv infusion followed by vinorelbine at a dose of 25 mg/m2 as a 10-minute iv infusion on Days 1 and 8 as the first-line therapy. For both treatment arms, cycles were administered every 3 weeks and patients could undergo an unlimited number of treatment cycles until disease progression or unacceptable toxicity occurred. When progressive disease had been documented, patients crossed over to the alternative therapy (GV for Arm A and IP for Arm B) as second-line treatment.
The primary objective of the current study was an assessment of OS for each treatment regimen in patients with NSCLC; secondary objectives were the evaluation of response rate, time to disease progression, and toxicity.
Baseline evaluations conducted before study entry included history and physical examination, assessment of ECOG PS, complete blood count, biochemical profile, electrocardiogram, and serum pregnancy test; assessments were conducted on Day 1 of each treatment cycle and complete blood counts and biochemical profiles were obtained on Days 1, 8, and 15 of each treatment cycle. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0). Response assessment was performed every 3 cycles or whenever clinically indicated. Responses were assessed according to World Health Organization criteria.15
The primary endpoint of this trial was 1-year OS. The trial was designed to detect an absolute 20% increase in the 1-year OS compared with historic controls. The 1-year OS rate for patients treated with cisplatin-based doublet regimens was approximately 40%. Therefore, using the 1995 statistical selection criterion of Strauss and Simon,16 the treatment demonstrating superior 1-year OS would be studied further. The sample size was determined to ensure that if the 1-year OS for 1 treatment was superior by at least 20%, it would be selected with high probability. This study design had a 90% chance of selecting a treatment yielding a 1-year OS of at least 60%, assuming a rate of 40% for the historic control or alternative treatment arm. Sample size based on these calculations stipulated a minimum of 65 patients per arm. Assuming that 10% proved inaccessible, 146 patients were projected for accrual.
Kaplan–Meier curves were used to describe the OS and progression-free survival (PFS), as well as the duration of response. OS was calculated from the first day of treatment until death or last known follow-up. PFS was calculated as the time between the first day of treatment and disease progression, death, or last known follow-up. The duration of response was defined for all responders as the time between the first demonstration of response and subsequent failure (disease progression). The log-rank test and hazards ratios were used to compare the differences in survival.
Between December 2003 and June 2005, 146 patients were accrued (75 in Arm A and 71 in Arm B) and the median follow-up time was 32.3 months. Three of 146 eligible patients had never started protocol therapy (Arm A) and therefore 143 patients were evaluable for survival. After the initiation on Day 1 of the first cycle of treatment, 4 eligible patients were refused further treatment (3 in Arm A and 1 in Arm B). One additional patient in Arm B withdrew from further treatment after Day 1 of the first cycle because of active pulmonary tuberculosis. These patients were unavailable for the assessment of toxicity and response. Therefore, a total of 138 patients (69 patients in each treatment arm) were evaluable for toxicity and response. Among them, 94 patients crossed over to receive alternative second-line treatment (41 in Arm A and 53 in Arm B) when progressive disease was documented, and 87 were evaluable for response (40 patients in Arm A and 47 patients in Arm B).
Baseline demographics were comparable for both arms (Table 1). The median age of the patients was 60 years. Approximately 79% of patients were male and 90% had an ECOG PS of 0 or 1. Approximately 87% had stage IV disease and 19% of patients had disease of squamous histology. There was no statistically significant difference noted between the 2 treatment arms.
|Treatment arm A (IP followed by GV), %||Treatment arm B (GV followed by IP), %||P|
|Early drop-out||6 (3 never started the protocol)||1|
|No. evaluable for toxicity and response||69||69|
|Median age, y||58 (range, 36–75)||60 (range, 33–80)||.613|
|Male||58 (77.3)||58 (81.7)|
|Female||17 (22.7)||13 (18.3)||.515|
|ECOG performance status|
|0–1||67 (89.3)||65 (91.5)|
|2||8 (10.7)||6 (8.5)||.649|
|IIIB||10 (13.3)||9 (12.7)|
|IV||65 (86.7)||62 (87.3)||.906|
|Squamous cell carcinoma||13 (17.3)||15 (21.1)|
|Adenocarcinoma||53 (70.7)||49 (69.0)|
|NSCLC, NOS||9 (12.0)||7 (9.9)||.802|
Objective Tumor Responses and Survival
Objective responses (complete response + partial response) and disease control (complete response + partial response + stable disease) are summarized in Table 2. In the first-line therapy, the overall response rates were 38% (95% confidence interval [95% CI], 26.3–49.1%) for Arm A and 26% (95% CI, 15.7–36.5%) for Arm B. The median response durations were 5.6 months (95% CI, 4.1–7.0 months) for Arm A and 5.8 months (95% CI, 1.0–10.7 months) for Arm B. In the second-line therapy, the overall response rates were 13% (95% CI, 0.7–19.3%) for Arm A and 30% (95% CI, 16.7–42.9%) for Arm B. The median response durations were 5.0 months (95% CI, 2.6–7.5 months) for Arm A and 4.5 months (95% CI, 2.6–6.3 months) for Arm B.
|Treatment arm A (IP followed by GV)||Treatment arm B (GV followed by IP)||P|
|No. (%)||No. (%)|
|First-line||(n = 69)||(n = 69)|
|PR||26 (38)||18 (26)|
|SD||18 (26)||29 (42)|
|PD||25 (36)||22 (32)|
|Overall response (CR + PR)||26 (38)||18 (26)||.144|
|Disease control (CR + PR + SD)||44 (64)||47 (68)||.720|
|Median response duration, mo||5.6||5.8||.766|
|Median PFS, mo||4.6||3.8||.415|
|Second-line||(n = 40)||(n = 47)|
|PR||5 (13)||14 (30)|
|SD||13 (33)||17 (36)|
|PD||22 (55)||16 (34)|
|Overall response (CR + PR)||5 (13)||14 (30)||.052|
|Disease control (CR + PR + SD)||18 (45)||31 (66)||.050|
|Median response duration, mo||5.0||4.5||.699|
|Median PFS, mo||2.6||4.5||.151|
|Overall Survival||(n = 72)||(n = 71)|
|Median OS, mo||15.9||13.1||.285|
|1-y survival rate, %||63.4||56.3|
|2-y survival rate, %||30.5||26.8|
The response to the GV regimen as second-line therapy was found to be correlated with the response to IP as first-line therapy (Table 3). The majority of patients who developed progressive disease while receiving IP as their first-line therapy did not respond to GV as the second-line therapy. In addition, the response to GV as the first-line therapy did not appear to affect the response to IP as the second-line therapy (80.0% vs 28.6%; P = .022).
|Response to second-line therapy||Response to first-line therapy|
|Treatment Arm A (IP Followed by GV)||No.||%||No.||%||No.||%|
|Treatment Arm B (GV Followed by IP)||No.||%||No.||%||No.||%|
Survival data are shown in Table 2. In the first-line treatment, the Kaplan-Meier estimate of PFS for Arm A (IP with crossover to GV) was 4.6 months (95% CI, 3.1–6.1 months) and was 3.8 months (95% CI, 2.9–4.8 months) for Arm B (GV with crossover to IP). In the second-line treatment, the Kaplan-Meier estimate of PFS for Arm A (IP with crossover to GV) was 2.6 months (95% CI, 1.8–3.4 months) and was 4.5 months (95% CI, 3.0–6.1 months) for Arm B (GV with crossover to IP). Figure 1 displays Kaplan-Meier estimates of OS by treatment arm. The median survival was 15.9 months (95% CI, 11.8–20.0 months) for Arm A, with a 1-year survival rate of 63.4% (95% CI, 52.2–74.6%) and a 2-year survival rate of 30.5% (95% CI, 19.7–41.3%). The median survival for Arm B was 13.1 months (95% CI, 10.2–15.9 months), with a 1-year survival rate of 56.3% (95% CI, 44.7–67.9%) and a 2-year survival rate of 26.8% (95% CI, 16.4–37.2%).
The median numbers of treatment cycles as the first-line treatment were 5 cycles (range, 1–20 cycles) for Arm A (IP) and 4 cycles (range, 1–24 cycles) for Arm B (GV). Figure 2 shows exposure to treatment in both arms. Of the 69 patients receiving IP, 47.2% completed >6 cycles of therapy and 11.1% received >10 cycles. Of the 69 treated patients receiving GV, 40.8% completed >6 cycles of therapy and 11.3% received >10 cycles. The median numbers of the second-line treatment cycles were 3 (range, 1–15 cycles) for Arm A (GV) and 4 (range, 1–15 cycles) for Arm B (IP). Of 41 patients receiving GV as second-line treatment, 34.1% completed >6 cycles of therapy and 14.6% received >9 cycles. Of the 53 patients who received IP as second-line therapy, 34.0% completed >6 cycles of therapy and 15.1% received >9 cycles.
Toxicity is summarized in Tables 4 and 5. During the first-line treatment comparing Arm A and Arm B, Arm A (IP) featured more grade 2 or 3 nausea and vomiting (41% vs 12%; P = .0001) and grade 2 alopecia (36% vs 10%; P = .0003). Arm A also demonstrated a trend toward more grade 3 or higher anemia (19% vs 7%; P = .053) whereas patients in Arm B (GV) tended to develop more grade 3 pneumonitis (7% vs 0%; P = .058). During the second-line treatment, Arm A (IP with crossover to GV) featured more grade 3 or higher neutropenia (78% vs 40%; P = .0003). Likewise, for the patients on Arm B (GV with crossover to IP), there was more grade 2 or 3 nausea and vomiting (40% vs 5% P<.0001) and alopecia (44% vs 24%; P = .047). In addition, second-line IP chemotherapy yielded more grade 3 diarrhea (17% vs 2%; P = .039). There were no treatment-related deaths reported in either treatment arm.
|Toxicity, %||Treatment arm A (IP followed by GV)||Treatment arm B (GV followed by IP)||P|
|No. accessible 69||No. accessible 69|
|Grade 3||Grade 4||Grade 3||Grade 4|
|Toxicity, %||Treatment arm A (IP followed by GV)||Treatment arm B (GV followed by IP)||P|
|No. accessible 41||No. accessible 52|
|Grade 3||Grade 4||Grade 3||Grade 4|
At the current time, the standard platinum-based chemotherapy for advanced NSCLC may be challenged by modern nonplatinum-based chemotherapy because of its better tolerability and similar effect on survival. As more patients are treated upfront with nonplatinum-based chemotherapy, platinum-based doublets can be used in the second-line setting.17 Moreover, improved supportive care medications are better able to control or prevent severe platinum-related toxicities, which means that more patients can be treated with platinum-based chemotherapy as a second-line treatment. Currently, in patients with progressive disease and a good PS after first-line chemotherapy, second-line treatment with single-agent docetaxel or pemetrexed is recommended.18–20 However, the response rate to second-line chemotherapy, either docetaxel or pemetrexed, is reported to be <10%. Previously, we conducted a phase 2 study of IP for patients with advanced NSCLC who were previously treated with nonplatinum-based chemotherapy.18–20 The response rate and median survival time of the IP chemotherapy as a second-line treatment were 41% and 9.3 months, respectively. Although grade 3 or 4 neutropenia was the most common toxicity, toxicity was manageable, and 50% of patients completed the planned 6 cycles of IP chemotherapy. These results suggest that IP chemotherapy is active and well tolerated as a second-line therapy for advanced NSCLC patients who are pretreated with nonplatinum-based chemotherapy. Thereafter, we conduced the current randomized, phase 2 study to compare the 2 opposite sequences of chemotherapy: cisplatin-based followed by noncisplatin-based chemotherapy versus noncisplatin-based followed by cisplatin-based chemotherapy. We found that the IP regimen demonstrated a favorable trend with regard to tumor response rate and PFS, particularly in the second-line setting, which resulted in no significant difference in OS between the opposite sequences of chemotherapy. These findings suggest that both treatment sequences appear to be acceptable for the treatment of patients with advanced NSCLC. With regard to toxicity, IP was associated with more alopecia and nausea and vomiting. In the second-line setting, IP was associated with more grade 3 diarrhea whereas GV was associated with more grade 3 or 4 neutropenia. There was no significant increase in the number of cases of febrile neutropenia or treatment-related deaths reported in the IP arm compared with the GV arm. These results also confirm that IP can be safely administered as well as the nonplatinum, GV regimen in both the first-line and second-line settings.
With regard to cross-resistance, it appears that tumor responsiveness to a prior GV regimen had no effect on the antitumor activity of IP in the second-line setting. Conversely, primary disease that was refractory to IP chemotherapy was found to significantly decrease tumor response to nonplatinum GV chemotherapy and the majority of patients who were primarily refractory to IP chemotherapy also failed to respond to GV chemotherapy. The excision repair cross-complementation Group 1 (ERCC1) enzyme plays a central role in the nucleotide excision repair pathway that recognizes and removes cisplatin-induced DNA adducts.22, 23 In a study of 783 individuals with completely resected NSCLC, patients with ERCC1-negative tumors, but not those with ERCC1-positive tumors, appeared to benefit from adjuvant cisplatin-based chemotherapy and experienced prolonged PFS as well as OS. These results suggest that ERCC1 expression levels are inversely associated with the response and survival of patients treated with cisplatin-based chemotherapy.24 Ribonucleotide reductase M1 (RRM1) is a key enzyme involved in DNA synthesis, catalyzing the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. It is the molecular target of gemcitabine and reported data have indicated that higher levels of RRM1 are associated with resistance to gemcitabine.25, 26 Recently, Ceppi et al.27 reported that the ERCC1 mRNA level is an independent prognostic factor for survival in patients with advanced NSCLC who are treated with gemcitabine plus cisplatin. They also found that the RRMI mRNA level is inversely associated with survival on univariate analysis. However, the relevance of the RRMI level was hampered by its significantly high correlation with the ERCC1 level (Rho = 0.6; P < .0001). More recently, Zheng et al.28 also demonstrated that RRMI expression is significantly correlated with ERCC1 expression (Rho = 0.3; P < .001). These findings suggest that disease that is primarily refractory to cisplatin-based chemotherapy may be associated with a high expression of ERCC1 that would be significantly correlated with RRM1 expression and thereafter result in resistance to gemcitabine-based chemotherapy. Therefore, patients with resistance to cisplatin-based chemotherapy do not appear to be appropriate candidates for gemcitabine-based chemotherapy. Further research investigating the expression level of ERCC1 and RRMI in NSCLC is needed to clarify the cross-resistance between these 2 significant agents.
Recently, Fidias et al.29 reported on a study comparing immediate versus delayed second-line docetaxel therapy after 4 cycles of chemotherapy with gemcitabine and carboplatin. The authors found that immediate treatment was associated with a significant benefit in PFS and a favorable trend in OS. They suggested that an immediate transition to second-line therapy may be optional in patients with NSCLC. Therefore, it would be necessary to test whether this finding would hold true for sequential therapy with IP and GV.
In summary, the platinum-based IP regimen appeared to be more effective in terms of response rate in both the first-line and second-line settings. However, given the similar OS and the better tolerability of the GV regimen, either treatment sequence would appear to be acceptable for the treatment of patients with advanced NSCLC. Further investigation of the immediate transition to a sequential setting is needed.
- 13Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2003; 21: 3025–3034., , , et al.
- 15World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. WHO Offset Pub. No. 48. Geneva: World Health Organization; 1979.
- 19Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000; 18: 2354–2362., , , et al.
- 29Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: updated report with survival. Proc Am Soc Clin Oncol. 2007; 25: 388s., , , et al.