Abstract
Lessons Learned.
This clinical trial, evaluating the efficacy and safety of a carboplatin plus paclitaxel regimen in a biweekly or weekly schedule instead of the more toxic 3‐weekly administration, showed that the weekly regimen was better in efficacy than the biweekly regimen, with mild toxicities, for patients with non‐small cell lung cancer (NSCLC).
The weekly carboplatin plus paclitaxel regimen could be considered as an alternative to the 3‐weekly regimen in Japanese patients with NSCLC.
Background.
Combination therapy comprising carboplatin (C) and paclitaxel (P) is the most commonly used regimen for the treatment of advanced non‐small cell lung cancer (NSCLC). Common toxicities associated with the regimen, such as neuropathy and myelosuppression, cause its discontinuation. In the present study, we conducted a clinical trial evaluating the efficacy of biweekly (B) and weekly (W) PC therapy to identify the appropriate chemotherapy schedule for Asian patients.
Methods.
Chemonaive patients with IIIB/IV NSCLC and a performance status of 0–1 were randomly assigned to a biweekly regimen (paclitaxel 135 mg/m2 with carboplatin area under the curve [AUC] 3 on days 1 and 15 of every 4 weeks) or to a weekly regimen (paclitaxel 90 mg/m2 on days 1, 8, and 15 with carboplatin AUC 6 on day 1 of every 4 weeks).
Results.
A total of 140 patients were enrolled in the study. The objective response rates (ORRs) were 28.1% (B) and 38.0% (W). The most common toxicity was neutropenia, with incidence rates of 62.0% (B) and 57.8% (W). Progression‐free survivals (PFSs) were 4.3 months (B) and 5.1 months (W), and overall survival durations were 14.2 months (B) and 13.3 months (W).
Conclusion.
The ORR and PFS in the weekly regimen were better than those in the biweekly schedule, although a statistical difference was not observed. The toxicity profile was generally mild for both regimens. The weekly CP regimen was suitable to be considered as an alternative to the current 3‐weekly regimen in NSCLC treatment.
Abstract
经验总结
• 此项临床试验评估了卡铂联合紫杉醇治疗方案的疗效和安全性，用每两周或每周给药代替毒性更大的每三周给药，结果表明，每周治疗方案比每两周治疗方案对非小细胞肺癌(NSCLC)患者的疗效更好，毒性较轻。
• 在日本NSCLC患者中，每周卡铂联合紫杉醇治疗方案可被视为每三周治疗方案的替代 方案。
摘要
背景。包含卡铂(C)和紫杉醇(P)的联合疗法是治疗晚期非小细胞肺癌(NSCLC)最常用的治疗方案。与该治疗方案相关的常见毒性(如神经病变和骨髓抑制)会导致停药。在当前研究中，我们进行了一项临床试验，评估每两周(B)和每周(B)PC 治疗的疗效，以确定适合亚洲患者的化疗时间安排。
方法。将患有 IIIB/IV NSCLC 且体力状态为 0–1 的化疗初治患者随机分配采取每两周治疗方案 [每 4 周的第 1 天和第 15 天，紫杉醇 135 mg/m2，卡铂曲线下面积 (AUC)3 ]或每周治疗方案(每 4 周的第 1、第 8 和第 15 天，紫杉醇 90 mg/m2，每 4 周的第 1 天，卡铂 AUC 6)。
结果。总计有 140 名患者参与研究。客观缓解率(ORRs)分别为 28.1%(B)和 38.0%(W)。最常见的毒性是中性粒细胞减少症，发病率分别为 62.0%(B)和 57.8%(W)。无进展生存期(PFSs)分别为 4.3 个月(B)和 5.1 个月(W)，总生存期分别为 14.2 个月(B)和 13.3 个月(W)。
结论。尽管未观察到统计学差异，但每周治疗方案的 ORR 和 PFS 均好于每两周治疗方案。两种治疗方案的毒性一般都比较轻微。在NSCLC治疗中，每周 CP 治疗方案可作为当前每三周治疗方案的替代方案。
Discussion
Lung cancer is one of the leading causes of death in many Asian countries [1], [2], [3]. For patients with advanced NSCLC, systemic chemotherapy remains the standard care. The combination of C and P is the most commonly used regimen for the treatment of advanced NSCLC, and its efficacy has been established by randomized phase III studies [4], [5], [6]. The Eastern Cooperative Oncology Group (ECOG) study that compared four commonly used regimens for first‐line therapy of advanced NSCLC demonstrated similar efficacy, including median survival and 1‐year survival in all four regimens [6]. A similar clinical trial comparing four different platinum doublets including a CP regimen was performed in Japan [7]. The results of this study demonstrated a favorable tolerability profile and a similar efficacy in the CP regimen (PFS: 4.5 months; OS: 12.3 months). The most common nonhematological toxicities associated with the CP regimen were neuropathy and arthralgia. In particular, severe neuropathy caused the deterioration of daily activity and quality of life. To improve the tolerability profile of this regimen, dose reduction of paclitaxel or administration of paclitaxel on a split schedule has been recommended [8], [9]. Administration of paclitaxel on a weekly basis for 3 out of 4 weeks in combination with carboplatin on day 1 of an every‐4‐week cycle was associated with the most favorable therapeutic index among three regimens tested [9]. A phase III study comparing a weekly PC regimen and a 3‐weekly PC regimen showed a similar efficacy with favorable nonhematologic toxicity in the weekly PC regimen [10]. More frequent grade 3 or 4 neutropenia, febrile neutropenia, and anemia were observed in the Japanese population than in the white population, despite the lower treatment delivery [11]. Because there is a clear ethnic difference in hematological toxicities, we initially conducted a single‐arm phase II study of a CP regimen in which administration of carboplatin and paclitaxel was performed on a biweekly schedule. The dose of the CP regimen was determined by AUC 3 added with 140 mg/m2 according to a phase I study reported previously [12]. The biweekly administration of the CP regimen was associated with favorable therapeutic efficacy (response rate: 35.1%; median survival: 357 days) in the previous phase II study [13]. Moreover, this study showed a reduction in neurotoxicity and myelosuppression compared with the 3‐weekly regimen reported previously [7]. On the basis of these results, we conducted the present randomized phase II study to compare the efficacy and safety of the weekly and biweekly CP regimen for patients with advanced NSCLC.
This phase II study was developed with the intent of reducing toxicity while maintaining efficacy similar to that in the standard 3‐weekly regimen. The ORR was 28.1% in the biweekly arm and 38.0% in the weekly arm (p = .27). Median PFS was 4.3 months in the biweekly arm and 5.1 months in the weekly arm (p = .24). Median OS was 14.2 months in the biweekly arm and 13.3 months in the weekly arm (p = .10). Both regimens had results comparable to the previously described 3‐weekly regimen. There were no statistically significant differences in the primary endpoint ORRs, but the weekly regimen tended to be superior to the biweekly regimen. In the secondary endpoints, the weekly regimen tended to be favorable for PFS and hematologic toxicities, but the biweekly regimen tended to be favorable for OS (Fig. 1), both of which were not statistically significant. For treatment delivery, in the biweekly arm, the average number of cycles was 2.8 and 45% of patients received 4 cycles, and in the weekly arm, the average number of cycles was 3.0 and 53% of patients received 4 cycles. Based on these results, the weekly CP regimen could be considered as an alternative to the 3‐weekly regimen in NSCLC.
Figure 1.
Overall survival (OS) curve by the Kaplan‐Meier method. Solid and dotted lines indicate the biweekly and weekly arms, respectively. The median OS in the biweekly and weekly arms was 14.2 months (95% confidence interval [CI]: 9.9–25.4 months) and 13.3 months (95% CI: 9.9–15.3 months), respectively. No significant differences were noted in either arm (p = .10, log‐rank test).
Trial Information
- Disease
Advanced cancer
- Stage of Disease/Treatment
Metastatic/advanced
- Prior Therapy
None
- Type of Study – 1
Phase II
- Type of Study – 2
Randomized
- Primary Endpoint
Overall response rate
- Secondary Endpoint
Progression‐free survival
- Secondary Endpoint
Overall survival
- Secondary Endpoint
Toxicity
- Additional Details of Endpoints or Study Design
- The primary efficacy endpoint was the ORR. The secondary efficacy endpoints were PFS, OS, and toxicities. The sample size was calculated based on the assumption of an objective response rate of 25% as the threshold and 40% in the experimental regimens to ensure the power of 80%. Patients were stratified by stage and sex at enrollment.
- Patient demographics and baseline history were summarized per treatment arm, with descriptive statistics for continuous measures and counts and frequencies for categorical variables. The ORR was defined as the percentage of patients achieving complete response (CR) or partial response (PR). The difference of the ORR was analyzed by Fisher's exact test. OS and PFS were characterized using Kaplan‐Meier equations and analyzed by log‐rank test. Toxicity by grade was tabulated per treatment arm.
- Investigator's Analysis
Active and should be pursued further
Drug Information for Phase II Biweekly
- Drug 1
- Generic/Working Name
Carboplatin
- Drug Class
Platinum compound
- Dose
AUC 3 mg per mL × minute
- Route
IV
- Schedule of Administration
Biweekly; paclitaxel 135 mg/m2 with carboplatin AUC of 3 mg/mL × minute biweekly for 2 of 4 weeks of each 28‐day cycle
- Drug 2
- Generic/Working Name
Paclitaxel
- Dose
135 mg/m2
- Route
IV
- Schedule of Administration
Biweekly; paclitaxel 135 mg/m2 with carboplatin AUC of 3 mg/mL × minute biweekly for 2 of 4 weeks of each 28‐day cycle
Drug Information for Phase II Weekly
- Drug 1
- Generic/Working Name
Carboplatin
- Trade Name
- Company Name
- Drug Type
- Drug Class
Platinum compound
- Dose
AUC 6 mg per mL × minute
- Route
IV
- Schedule of Administration
Weekly, paclitaxel 90 mg/m2 weekly for 3 of 4 weeks with carboplatin AUC of 6 mg/mL × minute on day 1 of each 28‐day cycle
- Drug 2
- Generic/Working Name
Paclitaxel
- Trade Name
- Company Name
- Drug Type
- Drug Class
- Dose
90 mg/m2
- Route
IV
- Schedule of Administration
Weekly, paclitaxel 90 mg/m2 weekly for 3 of 4 weeks with carboplatin AUC of 6 mg/mL × minute on day 1 of each 28‐day cycle
Patient Characteristics: Phase II Biweekly
- Number of Patients, Male
45
- Number of Patients, Female
19
- Stage
Stage (IIIB/IV); (12/52)
- Age
Median (range): 64
- Number of Prior Systemic Therapies
Median (range): not collected
- Performance Status: ECOG
-
0 — 34
1 — 30
2 — 0
3 — 0
Unknown — 0
- Cancer Types or Histologic Subtypes
-
Adenocarcinoma, 47
Squamous cell carcinoma, 14
NOS, 3
Patient Characteristics: Phase II Weekly
- Number of Patients, Male
48
- Number of Patients, Female
23
- Stage
Stage (IIIB/IV); (13/58)
- Age
Median (range): 66
- Performance Status: ECOG
-
0 — 32
1 — 39
2 — 0
3 — 0
Unknown — 0
- Cancer Types or Histologic Subtypes
-
Adenocarcinoma, 49
Squamous cell carcinoma, 14
NOS, 8
Primary Assessment Method: Phase II Biweekly
- Title
ORR
- Number of Patients Enrolled
64
- Number of Patients Evaluable for Toxicity
64
- Number of Patients Evaluated for Efficacy
64
- Evaluation Method
RECIST 1.0
- Response Assessment CR
n = 0 (0%)
- Response assessment PR
n = 18 (28.1%)
- Response Assessment SD
n = 27 (42.2%)
- Response Assessment PD
n = 16 (25.0%)
- Response Assessment OTHER
n = 3 (4.7%)
- (Median) Duration Assessments PFS
4.3 months, CI: 3.5–5.3
- (Median) Duration Assessments OS
14.2 months, CI: 9.9–25.4
- Outcome Notes
- The ORR was 28.1% in the biweekly arm and 38.0% in the weekly arm (p = .27). Median PFS was 4.3 months in the biweekly arm and 5.1 months in the weekly arm (Fig. 2). No statistical difference in the response rate and PFS in the biweekly and weekly regimens was noted. Median OS was 14.2 months in the biweekly arm and 13.3 months in the weekly arm. OS in the biweekly arm was slightly, but not significantly, longer than that in the weekly arm.
Primary Assessment Method: Phase II Weekly
- Title
ORR
- Number of Patients Enrolled
71
- Number of Patients Evaluable for Toxicity
71
- Number of Patients Evaluated for Efficacy
71
- Evaluation Method
RECIST 1.0
- Response Assessment CR
n = 0 (0%)
- Response Assessment PR
n = 27 (38.0%)
- Response Assessment SD
n = 23 (32.4%)
- Response Assessment PD
n = 12 (16.9%)
- Response Assessment OTHER
n = 9 (12.7%)
- (Median) Duration Assessments PFS
5.1 months, CI: 4.0–6.6
- (Median) Duration Assessments OS
13.3 months, CI: 9.9–15.3
- Outcome Notes
- The ORR was 28.1% in the biweekly arm and 38.0% in the weekly arm (p = .27). Median PFS was 4.3 months in the biweekly arm and 5.1 months in the weekly arm. No statistical difference in the response rate and PFS in the biweekly and weekly regimens was noted. Median OS was 14.2 months in the biweekly arm and 13.3 months in the weekly arm. OS in the biweekly arm was slightly, but not significantly, longer than that in the weekly arm.
Adverse Events: Phase II Biweekly
Neutropenia was the most common hematologic toxicity in total, with no statistical difference between the weekly and biweekly arms. In grade ≥3 toxicities, incidence rates of anemia, leucopenia, and thrombocytopenia were significantly higher in the weekly arm compared with those in the biweekly arm (28.2% vs. 3.1% [p < .01], 35.2% vs. 17.2% [p < .05], and 8.5% vs. 0% [p < .05], respectively). Nonhematological toxicities were generally mild and manageable. However, it is important to note that the frequency of infection was significantly higher in the biweekly arm (1.4% vs. 14.1% [p < .01]).
Abbreviations: AGC, absolute granulocyte count; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; NC/NA, no change from baseline/no adverse event; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; WBC, white blood cell.
Adverse Events: Phase II Weekly
Neutropenia was the most common hematologic toxicity in total, with no statistical difference between the weekly and biweekly arms. In grade ≥3 toxicities, incidence rates of anemia, leucopenia, and thrombocytopenia were significantly higher in the weekly arm compared with those in the biweekly arm (28.2% vs. 3.1% [p < .01], 35.2% vs. 17.2% [p < .05], and 8.5% vs. 0% [p < .05], respectively). Nonhematological toxicities were generally mild and manageable. However, it is important to note that the frequency of infection was significantly higher in the biweekly arm (1.4% vs. 14.1% [p < .01]).
Abbreviations: AGC, absolute granulocyte count; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; NC/NA, no change from baseline/no adverse event; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
- Completion
Study completed
- Investigator's Assessment
Active and should be pursued further
The efficacy and toxicity data of the 3‐weekly carboplatin plus paclitaxel (CP) regimen in the Japanese population is available in several clinical trials, including the FACS trial [7], NEJ002 trial [15], and JO19907 trial [16]. Clinical data of carboplatin plus paclitaxel in Asian populations are available from the reference arm in the IPASS study conducted in nine countries in Asia [17]. The objective response rate (ORR) data in these clinical trials were 32.4% (FACS), 29.0% (NEJ002), 31.0 (JO19907), and 32.2% (IPASS). The ORR of 37.6% in the weekly arm of this study was similar to that reported by the previous clinical trials. The present findings suggest that patients with advanced non‐small cell lung cancer (NSCLC) may obtain a similar efficacy from the split dose of the CP regimen with a weekly schedule. Toxicities associated with this dose were clearly lesser. Hematologic toxicities except anemia and neurotoxicity were mild compared with those in the 3‐weekly CP regimen reported previously [7]. In terms of survival, overall survival (OS) was better in the biweekly arm and correlated inversely with improved progression‐free survival (PFS) in the weekly arm. The discrepancy between OS and PFS data may be due to the difference in poststudy treatment. The prevalence of second‐line chemotherapy was 55% and 59% in the weekly and biweekly arms, respectively. The rate of use of epidermal growth factor receptor tyrosine kinase inhibitors or docetaxel as a second‐line chemotherapy in both arms was not statistically different. Moreover, there was no difference between the actual doses of carboplatin and paclitaxel. Another explanation is that more severe toxicities reduced the survival rate in the weekly arm. As shown in the Adverse Events section, grade 3 or 4 hematological toxicities in the weekly arm were significantly more severe than those in the biweekly arm. The association of chemotherapy‐induced neutropenia and treatment efficacy was reported previously [18], [19].
The addition of bevacizumab to the regimen of carboplatin and paclitaxel was confirmed to improve the survival of patients with advanced nonsquamous NSCLC [20]. However, a higher incidence of neutropenia was reported with the three‐drug combination treatment, especially in older patients [20], [21]. In the Japanese population, a randomized phase II study comparing CP regimens with and without bevacizumab showed a similar toxicity profile [16]. The addition of bevacizumab increased the incidence of grade 4 neutropenia from 57% to 73%. Split doses of paclitaxel may provide a favorable toxic profile compared with the bevacizumab‐based therapy. Carboplatin plus weekly paclitaxel in combination with bevacizumab was well tolerated in patients with metastatic melanoma in a phase II study [22], although comparative data were not available for patients with lung cancer in this setting. The CP regimen with split dose may thus be an alternative with a better toxicity profile for patients with NSCLC. A phase III comparative study with the 3‐weekly regimen has been planned as a future course of action.
Figure
Figure 2.
Progression‐free survival (PFS) curve by the Kaplan‐Meier method. Solid and dotted lines indicate the biweekly and weekly arms, respectively. The median PFS in the biweekly and weekly arms was 4.3 months (95% confidence interval [CI]: 3.5–5.3 months) and 5.1 months (95% CI: 4.0–6.6 months), respectively. No significant differences were noted in either arm (p = .29, log‐rank test).
Acknowledgments
We thank the staff of the Clinical Research Support Center Kyushu for their secretarial assistance and for preparing the manuscript.
Footnotes
ClinicalTrials.gov Identifier: UMIN000036556
Sponsor(s): Clinical Research Support Center Kyushu
Principal Investigator: Koichi Takayama
IRB Approved: Yes
Disclosures
Koichi Takayama: Chugai‐Roche Co., Ono Pharmaceutical Co. (RF), AstraZeneca, Chugai‐Roche Co., MSD‐Merck Co., Eli Lilly Co., Boehringer‐Ingelheim Co., DaiichiSankyo Co. (H); Junji Uchino: AstraZeneca, Eli Lilly Japan K.K. (RF). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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