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A Multicenter Randomized Controlled Study of Paclitaxel plus Carboplatin versus Oral Uracil-Tegafur as the Adjuvant Chemotherapy in Resected Non–Small Cell Lung Cancer
Corresponding author. Address for correspondence: Shinichi Toyooka, MD, PhD, Department of General Thoracic, Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Department of General Thoracic, Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, JapanDepartment of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
Department of General Thoracic, Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
Department of General Thoracic, Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
We conducted a randomized controlled study to compare the survival benefit of paclitaxel plus carboplatin and oral uracil-tegafur (UFT) as adjuvant chemotherapy in resected NSCLC.
Methods
In an open-label multicenter trial, patients with pathological stage IB to IIIA NSCLC were randomized into a group receiving paclitaxel (175 mg/m2) plus carboplatin (area under the curve 5) every 3 weeks for four cycles (arm A) or a group receiving orally administered UFT (250 mg/m2) daily for 2 years (arm B). The primary and secondary end points were overall survival and relapse-free survival and toxicity, respectively.
Results
Between November 2004 and November 2010, 402 patients from 40 institutions were included (201 in each arm). The median follow-up period was 6.5 years. The 5-year overall survival rate was 70% (95% confidential interval [CI]: 63–76] in arm A versus 73% (95% CI: 66–78) in arm B (hazard ratio = 0.92, 95% CI: 0.55–1.41, p = 0.69). There was no significant difference in the 5-year relapse-free survival rate between arms A and B (56% versus 57% [hazard ratio = 0.92, 95% CI: 0.63–1.34, p = 0.50]). Toxicities were well tolerated and there was no treatment-related death. Toxicities of any grade or grade 4 were significantly more frequent in the paclitaxel plus carboplatin group (95.7% and 22.1%, respectively) than in the UFT group (76.5% and 1.0%, respectively [p < 0.0001 in both]).
Conclusions
As adjuvant chemotherapy, paclitaxel plus carboplatin was no better than UFT in terms of survival among patients with stage IB to IIIA NSCLC tumors who underwent complete resection (UMIN000000810).
Lung cancer is the most common cause of cancer-related death worldwide as well as in Japan. Primary surgery is the first-line treatment for patients with limited NSCLC. Even in patients who undergo complete resection, recurrence often impairs clinical outcome. To prevent recurrence due to micrometastases at the time of surgical resection, adjuvant chemotherapies were introduced.
There have been three major trials examining combinations using platinum-based regimens, mainly platinum plus third-generation anticancer agents, which demonstrated a survival benefit in stage II to III disease compared with surgery alone: the International Adjuvant Lung Trial, the National Cancer Institute of Canada Clinical Trials Group JBR10 trial, and the Adjuvant Navelbine International Trialist Association trial.
Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.
For stage IB disease, adjuvant chemotherapy with paclitaxel plus carboplatin was compared with surgery alone in the Cancer and Leukemia Group B (CALGB) 9633 trial. Although preliminary analyses of the trial presented in 2004 showed that paclitaxel plus carboplatin improved survival in an adjuvant setting, its mature results published in 2008 were unable to prove any advantage of adjuvant therapy in total stage IB disease.
Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study groups.
In an exploratory analysis, adjuvant chemotherapy showed a significant survival advantage in a subset of patients with tumors larger than 4 cm in diameter.
Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study groups.
This suggests that paclitaxel plus carboplatin has a benefit in patients with more progressed stage IB disease rather than as adjuvant chemotherapy in early disease.
In Japan, uracil-tegafur (UFT) alone has been reported to be a beneficial adjuvant strategy for patients with resected NSCLC in stages I to III.
On the other hand, usefulness of adjuvant chemotherapy with the combination of platinum and third-generation anticancer agent confirmed by randomized trials has not been reported in Japanese patients. In 2004, when this study had been conducted, a randomized study comparing adjuvant chemotherapy with UFT and an observational study conducted by the Japan Lung Cancer Research Group also indicated that UFT provides a survival advantage compared with surgery alone for patients with stage IB or stage IA NSCLC (tumor size >2 cm).
Generally, the combination of platinum and a third-generation anticancer agent is considered to have a stronger anticancer effect than UFT in patients with advanced NSCLC.
However, it is unclear whether the platinum plus a third-generation anticancer agent treatment is superior to UFT in adjuvant chemotherapy for completely resected NSCLC.
It is possible that patients who undergo radical surgery are free from cancer cells and are thus already cured without adjuvant therapy. From this point of view, severe adverse effects, especially toxic death due to adjuvant chemotherapy, should be avoided as much as possible. There have been treatment-related deaths in patients treated with cisplatin-based regimens in an adjuvant setting. The incidence of treatment-related deaths in both the International Adjuvant Lung Trial and the JBR10 trial was 0.8, and it was 2.0% in the Adjuvant Navelbine International Trialist Association trial
Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.
Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study groups.
This is consistent with the results of clinical trials in advanced NSCLC showing that paclitaxel plus carboplatin was less toxic and better tolerated than cisplatin-based regimens in North America.
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.
On the basis of these findings, we designed a randomized trial of paclitaxel plus carboplatin and oral UFT in 2004 to evaluate the efficacy and safety of adjuvant chemotherapy in resected stage IB to IIIA NSCLC.
Patients and Methods
Study Design and Patients
This study is an open-label multi-institutional, prospective randomized controlled trial that was conducted on 2004 by the Setouchi Lung Cancer Study Group (as SLCG0401) (University Hospital Medical Information Network Clinical Trial Registry identifier UMIN000000810) to evaluate the efficacy and safety of adjuvant chemotherapy in patients who underwent a complete radical resection for NSCLC in pathological stage IB to IIIA. Disease stage was defined according to the Union for International Cancer Control TNM classification (sixth edition).
Patient enrollment and data collection were performed at each participating institute. The details of the main inclusion and exclusion criteria are listed in Supplementary Tables 1 and 2.
The patients were subsequently randomly assigned to receive either paclitaxel plus carboplatin (arm A) or UFT (arm B) in a 1:1 ratio by using computer-generated random numbers at the Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Aichi, Japan, with the following stratification factors: institution, histologic type (adenocarcinoma versus others), and disease stage (stage IB or II or IIIA) (Fig. 1). The SLCG 0401 data center, the nonprofit organization Epidemiological and Clinical Research Information Network in Kyoto, Japan, anonymized each participant by assignment of a new number and managed all the study data.
Figure 1Study design. Flow diagram of the study. Sixteen patients who had agreed to inclusion in this study ultimately refused the protocol treatment before starting therapy and were followed without any adjuvant therapy (13 and 3 in arms A and B, respectively). Two patients who had been randomly assigned to arm B (uracil-tegafur [UFT] administration) were accidentally treated by using the paclitaxel plus carboplatin protocol (arm A). In the end, 386 patients actually received the protocol treatment (188 in arm A and 198 in arm B, with 190 in the paclitaxel plus carboplatin protocol and 196 in the UFT protocol).
The protocol was approved by the institutional review boards of all the participating institutions. All patients provided written informed consent before enrollment in the trial; consent was obtained from the patients by each investigator at each participating institute.
Treatment and Follow-up
Adjuvant treatment was planned to start within 6 weeks after surgery. In arm A, patients received paclitaxel (175 mg/m2) intravenously over 3 hours followed by a 1-hour infusion of carboplatin (area under the curve [AUC] 5), with each administered on day 1 every 3 weeks for four cycles. In arm B, patients received UFT orally twice or thrice daily every day until 2 years after the start of oral administration; the dose was 300 mg/d when the body surface area was less than 1.40 m2, 400 mg/d for a body surface area of 1.40 to 1.80 m2, and 500 mg/d for a body surface area greater than 1.80 m2.
The details of (1) the criteria for discontinuation, entry, or dose modification of protocol treatments and (2) patient evaluations during and after protocol treatments are provided in the Supplementary Method. Further examination (such as by computed tomography scan, magnetic resonance imaging scan, bone scintigraphy, and abdominal ultrasonography) was performed whenever disease relapse, as defined in the Supplementary Method, was considered.
After the protocol treatment had been completed or terminated, no other adjuvant chemotherapy or radiotherapy for primary disease was permitted unless patients had experienced disease relapse.
Outcome
We defined the rate of overall survival (OS) at 5 years as the primary end point and the rate of relapse-free survival (RFS) and toxicity as secondary end points (each definition and evaluation is presented in the Supplementary Method).
We calculated the relative dose intensity (RDI), which was defined as the ratio of planned dose intensity (mg/wk for pclitazxel or carboplatin; mg/d for UFT) to actual dose intensity received for each drug.
Sample Size
We assumed 5-year OS rates of 60 % and 45 % for arms A and B, respectively, on the basis of the previous report.
According to these rates, we estimated the required number of patients as 186 patients in each arm (α = 0.05 and β = 0.2). Finally, we set the sample size at 400 after considering the potential dropout of patients on account of ineligibility.
Interim analysis of OS and toxicity is planned to be performed when 200 cases have been enrolled in this study without stopping patient enrollment. The interim analysis of OS did not reach the prespecified p value. In addition, no clear difference in toxicity was seen between the two arms. Therefore, the study was continued as planned (Supplementary Method).
Statistical Analysis
The reference arm of this study was arm A (paclitaxel plus carboplatin). All the survival analyses were conducted on the basis of intention to treat. For the primary end point, OS, we applied a stratified Cox proportional hazard model with institution, histologic type (adenocarcinoma versus others), and disease stage (stage IB or II or IIIA) used as stratifying factors. Other survival analyses used stratified Cox proportional hazard models and stratified log-rank tests with the same stratification factors. Differences in incidence of toxicities between the two arms were evaluated by using Fisher’s exact test.
We defined p less than 0.05 as the threshold of statistical significance. All the statistical analyses were executed with STATA software (version14, StataCorp, College Station, TX) and GraphPad Prism 5 (GraphPad Software, La Jolla, CA).
Results
Patient Characteristics
A total of 402 patients were enrolled in this trial from 40 institutions (Supplementary Table 3) in Japan between November 2004 and November 2010 because the expected number of participants was achieved. The details of patient distribution are shown in Figure 1. The baseline characteristics of the patients are summarized in Table 1.
Details of delivery of the chemotherapies are provided in Supplementary Tables 4 and 5. As for the paclitaxel plus carboplatin protocol (n = 190), 163 patients (85.8%) received all four cycles of chemotherapy. During the whole treatment course, 25 patients (13.2%) needed dose reduction and 22 patients (11.6%) needed delay of course. Four patients (2.1%) needed both dose reduction and delay of course. In all, 139 patients (73.2%) received four cycles of chemotherapy at the full dose and 118 patients (62.1%) received four cycles of full-dose chemotherapy without delay.
In those treated with the UFT protocol (n = 196), the initial treatment dose of UFT was either 300 mg (in 39 patients [19.9%]), 400 mg (in 138 patients [70.4%]), 500 mg (in 18 patients [9.2%]), or 600 mg (in one patient [0.5%]). Among them, 142 patients (72.4%) received UFT for 1 year or more and 69 patients (35.2%) received UFT for 2 years (the whole treatment period). The median period of drug administration was 709 days (range 20–866 days). During the entire treatment course, 21 patients (10.7%) needed dose reduction, 16 patients (8.2%) needed a drug holiday, and nine patients (4.6%) needed both dose reduction and delay of course.
The median RDIs of paclitaxel, carboplatin, and UFT were 92.6 % (0.4–102.4), 92.7 % (0.0–106.8), and 87.7 % (2.7–116.0), respectively. Because the whole treatment period of UFT was 2 years, 51 patients (25.3%) experienced relapse of disease (n = 49) or a second malignancy in another organ (n = 2) and stopped the protocol treatment (see Supplementary Table 5). On the other hand, only four patients (2.1%) experienced relapse of disease, and none of the patients experienced a second malignancy during protocol treatment (treatment period of approximately 3 months) in arm A (see Supplementary Table 4).
Toxicity
A summary of the adverse events is shown in Table 2. The patients who suffered from toxicity of any grade were significantly more frequent in the paclitaxel plus carboplatin group (n = 180 [95.7%]) than in the UFT group (n = 150 [76.5%] (p < 0.0001).
The main adverse events in the paclitaxel plus carboplatin group were hematological toxicities, neuropathy, alopecia, and gastrointestinal toxicities, the frequencies of which at any grade of toxicity were more than 30%. On the other hand, there were no adverse events with more than 30% frequency in the UFT group; increased aspartate transaminase, alanine transaminase, lactate dehydrogenase, and total bilirubin level; anemia; and anorexia were the main adverse events in the UFT group, with less than 30% frequency. Severe adverse events of leukopenia and neutropenia (grades 3 or 4) were significantly more frequent in the paclitaxel plus carboplatin group than in the UFT group (42.1% versus 0.5% and 17.4% versus 0%, respectively [p < 0.0001 in each]) (Table 2). Grade 4 toxicities of any kind were also significantly more frequent in the paclitaxel plus carboplatin group (n = 42 [22.1%]) than in the UFT group (n = 2 [1.0%]) (p < 0.0001). There were no treatment-related deaths during the protocol treatment.
As two patients in arm B accidentally received paclitaxel plus carboplatin, we also evaluated the toxicities of arms A (n = 188) and B (n = 198) and found no significant difference in the incidence of toxicities between those in the paclitaxel plus carboplatin group (n = 190) and those in the UFT group (n = 196).
Survival
Survival analyses were performed on the basis of intention to treat. The median follow-up period of all 402 cases was 5.8 years (0.16–11.23) and the median follow-up period for survivors (n = 252) was 6.5 years (1.53–11.23). The 5-year OS rate was 70% (95% confidential interval [CI]: 63–76) for patients in arm A (n = 201) versus 73% (95% CI: 66–78) for those in arm B (n = 201), and this difference was not significant (hazard ratio = 0.92, 95% CI: 0.55–1.41, p = 0.69) (Fig. 2A). Regarding 5-year RFS rate, there was no significant difference between arms A and B (56% [95% CI: 47.4–61.2] versus 57% [95% CI: 50.0–63.7], respectively) (hazard ratio = 0.92, 95% CI: 0.63–1.34, p = 0.50) (Fig. 2B).
Figure 2Kaplan-Meier curves of overall survival (A) and relapse-free survival (B) are shown. This trial was ended at November 2015 because more than 5 years of the follow-up period had been completed in all 402 patients. A total of 12 patients (six in each arm) were lost to follow-up in less than 5 years because they declined further follow-up; their median follow-up period was 4.95 years (range, 1.53– 4.98) CI, confidence interval.
As for pathological stage, the edition of Union for International Cancer Control TNM staging system had been updated from the sixth edition to the seventh edition
during the study period (in 2009). Because pathological stage is one of the stratification factors in this study, we also evaluated the impact of the three types of revised pathological stage (Supplementary Table 6) on clinical outcome and found that OS and RFS rates showed no significant difference between these three classifications (data not shown).
Discussion
When SLCG0401 was under design in early 2004, the evidence of adjuvant chemotherapy for stage I to IIIA NSCLC was limited. The results of two prospective trials of UFT had been published to show survival benefit of treatment in stage IB adenocarcinoma
The number of cases in the former trial is limited. Regarding paclitaxel plus carboplatin, we chose this regimen expecting its superiority to UFT on the basis of the preliminary report for stage IB disease that was presented in 2004 as the latest topic. However, the final report on the paclitaxel plus carboplatin regimen, which was published in 2008, did not demonstrate an advantage as adjuvant therapy in stage IB disease.
Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study groups.
In our study, 228 out of 402 patients (54.3%) were in stage IB, and there were no significant differences in OS and RFS rates between the two groups in the patients with stage IB disease.
In our study, paclitaxel plus carboplatin did not improve survival compared with UFT among patients with completely resected stage IB to IIIA NSCLC. Generally, treatment with platinum plus third-generation antitumor agents is considered to have a strong antitumor effect compared with other regimens, such as cisplatin with second-generation agents or monotherapy with any cytotoxic agent.
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.
Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients.
UFT is generally considered a mild antitumor agent in NSCLC.
Among the platinum-based regimens, vinorelbine plus cisplatin was demonstrated to be associated with favorable prognosis in stage II to III NSCLC compared with surgery alone.
Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.
Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.
Although paclitaxel plus carboplatin did not show a survival advantage in all patients with stage IB disease as a whole compared with surgery alone, it did show a survival benefit in stage IB patients with tumors larger than 4 cm in diameter.
Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study groups.
These data suggest that agents with strong antitumor effects might be suitable for resected NSCLC in a more advanced stage than for early-stage NSCLC. On the other hand, a recent randomized phase II study showed that monotherapy with S-1, a modified oral agent of UFT, for 1 year was preferable to S-1 plus cisplatin for four cycles in resected stage II to IIIA NSCLC, indicating similar RFS and OS with less toxicity.
Randomized phase II study of adjuvant chemotherapy with long-term S-1 versus cisplatin+S-1 in completely resected stage II-IIIA non-small cell lung cancer.
A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial.
suggesting that the efficacy of S-1 plus cisplatin is similar to that of platinum plus a third-generation anticancer agent. These results imply that adjuvant therapy with S-1 monotherapy for 1 year may have efficacy similar to that of platinum plus a third-generation anticancer agent for resected NSCLC. Thus, although it may be a necessary feature in the case of fluorouracil, long-term treatment might also be an important factor for favorable prognosis in patients with completely resected NSCLC.
We selected the doses of 175 mg/m2 for paclitaxel and AUC 5 for carboplatin. These doses are lower than those of the standard regimen. We chose these doses to avoid severe toxicity and to improve patient compliance with the treatment regimen after radical surgery. Although chemotherapy with 225 mg/m2 of paclitaxel and carboplatin, AUC 6, has been reported by a dose escalation study
to be tolerated in Japanese patients with advanced NSCLC, grade 3 or 4 neutropenia was observed in 75% to 88% of patients in two Japanese phase III studies for untreated NSCLC with doses of 200 mg/m2 for paclitaxel and AUC 6 for carboplatin.
Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan.
Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer: results of a West Japan Oncology Group study.
Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan.
Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer: results of a West Japan Oncology Group study.
In phase III trials for advanced NSCLC conducted in North America with paclitaxel, 225 mg/m2, and carboplatin, AUC 6, grade 3 or 4 neutropenia was observed in about 60% of patients.
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.
In the CALGB 9633 study, which was also conducted in North America, adjuvant chemotherapy for patients with resected NSCLC was performed with 200 mg/m2 of paclitaxel and carboplatin AUC 6, and 35% of patients suffered from grade 3 or 4 neutropenia, which was similar to what we observed (42.1%). These results suggest that the tolerability of paclitaxel and carboplatin differs by ethnicity and that Japanese patients experience more toxicity in response to paclitaxel and carboplatin. Thus, we believe that our dose setting is appropriate as adjuvant therapy for Japanese patients with resected NSCLC with regard to toxicity. The toxicity profile of UFT was similar to that in previous reports;
although the rate of toxicity was higher in our study, it is still well tolerated.
Quality of life is an important consideration in the clinical trials related to adjuvant chemotherapy. However, quality of life has not been investigated in this study. As for RDIs, these values were only advisories based on limited information because we had not planned to calculate RDI in this study. These were limitations of this study.
In conclusion, four cycles of paclitaxel plus carboplatin were not better than UFT monotherapy in terms of survival among Japanese patients with resected stage IB to IIIA NSCLC. Although both treatments are feasible, toxicity was milder with UFT than with paclitaxel plus carboplatin.
Acknowledgments
This investigator-initiated trial was supported in part by a grant from Bristol-Myers Squibb and Taiho Pharmaceutical and further supported, in part, by a nonprofit organization, Epidemiological and Clinical Research Information Network. Bristol-Myers Squibb and Taiho Pharmaceutical had no role in the design and conduct of the study or in collection, analysis, or interpretation of the results. We thank all 40 hospitals and institutions for their participation and cooperation (see Supplementary Table 3).
Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.
Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study groups.
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.
Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients.
Randomized phase II study of adjuvant chemotherapy with long-term S-1 versus cisplatin+S-1 in completely resected stage II-IIIA non-small cell lung cancer.
A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial.
Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan.
Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer: results of a West Japan Oncology Group study.
Disclosure: Drs. Toyooka, Okumura, and Date have received honoraria from Taiho Pharmaceutical. Dr. Sakamoto has received honoraria from Tsumura and Chugai Pharmaceutical. Dr. Okada has received fees for speakers bureau participation from Taiho Pharmaceutical and Bristol-Myers Squibb. Dr. Sakamoto has received consulting fees from Takeda Pharmaceutical. Dr. Hotta has received personal fees from AstraZeneca, Ono Pharmaceutical, Boehringer Ingelheim, Nihon Kayaku, Taiho Pharmaceutical, Chugai Pharmaceutical, Novartis, Bristol-Myers Squibb, Eli Lilly Japan, and MSD, and the institute with which he is affiliated has received research funding from Bristol-Myers Squibb, AstraZeneca, Ono Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Astellas, Novartis, Eli Lilly Japan, and MSD. The institutes with which Drs. Toyooka, Okada, and Date are affiliated have received research funding from Taiho Pharmaceutical. The institute with which Dr. Okada is affiliated has received research funding from Bristol-Myers Squibb. The remaining authors declare no conflict of interest.
Ethnic differences in the pharmacokinetics and tolerability of anticancer drugs, especially between Asian and white patients, have been extensively reported. Allelic variants of genes encoding drug-metabolizing enzymes are expressed with different incidences in different ethnic groups.1 Irinotecan is more active in Asian than in white patients because of the single-nucleotide polymorphisms of UDP glucuronosyltransferase gene (UGT1A1), which is responsible for the irinotecan metabolism. Differences in the cellular processing of irinotecan may result in differences in toxicity, compliance, and chemosensitivity.
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