Japanese Journal of Clinical Oncology Advance Access published online on January 12, 2009
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn147
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© The Author (2009). Published by Oxford University Press. All rights reserved
Evaluation of the Safety and Compliance of 3-Week Cycles of Vinorelbine on Days 1 and 8 and Cisplatin on Day 1 as Adjuvant Chemotherapy in Japanese Patients with Completely Resected Pathological Stage IB to IIIA Non-small Cell Lung Cancer: A Retrospective Study
1 Division of Thoracic Oncology
2 Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
For reprints and all correspondence: Nobuyuki Yamamoto, Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Nagaizumi, Shizuoka 411-8777, Japan. E-mail: n.yamamoto{at}scchr.jp
Received August 25, 2008; accepted December 1, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Objective: With regard to adjuvant chemotherapy for non-small-cell lung cancer, the usefulness of combined chemotherapy with cisplatin (CDDP) and vinorelbine (VNR) has been reported. However, poor compliance has been reported with VNR administered weekly by the conventional method for 16 consecutive weeks, and there is no report on the safety and compliance of adjuvant chemotherapy with CDDP and VNR in Japanese patients.
Methods: The subjects were 25 non-small-cell lung cancer patients who received CDDP and VNR as adjuvant chemotherapy at the Shizuoka Cancer Center between April 2005 and April 2008. The treatment schedule included combined treatment, with CDDP at 80 mg/m2 administered on Day 1 and VNR at 25 mg/m2 administered on Days 1 and 8. The treatment was repeated every 3 weeks, and each 3-week treatment schedule was designated as one cycle. A total of four cycles were administered.
Results: The main adverse events were Grade 3 or more severe neutropenia (76%), anemia (12%), anorexia (12%) and nausea (12%). Thus, the adverse events were mostly mild. There were no treatment-related deaths. The rate of completion of the four cycles was 92%. The mean dose of CDDP and VNR was 312 and 195 mg/m2, respectively. The mean dose administered of either drug was 97.5% of the scheduled dose.
Conclusion: This study was retrospective and had some limitations, for example, non-hematological toxicity would be evaluated milder. However, it was considered that adjuvant chemotherapy with CDDP administered on Day 1 and VNR administered on Days 1 and 8 every 3 weeks was safe, and that the rate of completion of the four cycles was also satisfactory in Japanese patients.
Key Words: adjuvant chemotherapy • non-small-cell lung cancer • cisplatin • vinorelbine • Japanese patients • safety • compliance
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The radical treatment for clinical stages IA–IIB and part of IIIA non-small cell lung cancer (NSCLC) is a surgical resection. However, 40–70% of patients with pathological stage IB to IIIA NSCLC who are treated by surgical resection develop recurrence and show a fatal outcome (1). Recurrence in these cases occurs even when all the lesions that are detectable by diagnostic imaging are totally resected; therefore, they have been considered to be caused by micrometastatic lesions already present at the time of resection. Based on the recognition of such lesions as the possible cause of recurrence, there have been some attempts to administer postoperative adjuvant chemotherapy to selected patients of NSCLC with the aim of reducing the mortality associated with postoperative recurrence.
Before 2000, most clinical studies on postoperative adjuvant chemotherapy have failed to demonstrate its usefulness for survival (2–5). In these studies, the chemotherapeutic regimen included drugs that existed before the development of third-generation drugs, and the number of patients included was small. These factors seem to have had an influence on the failure of the treatments reported from the studies. In 1995, a meta-analysis of many previous clinical studies on postoperative adjuvant chemotherapy was performed, which suggested the usefulness of this strategy, because an improvement in the 5-year survival rate in the postoperative adjuvant chemotherapy group by 5% was observed as compared with that in the course observation group (P = 0.08) (6). Since the publication of this report, many studies have been conducted to investigate the usefulness of postoperative adjuvant chemotherapy, as follows: International Lung Cancer Trial (IALT) based on cisplatin (CDDP) (7); JBR 10 trial by the combined use of CDDP and vinorelbine (VNR); Adjuvant Navelbine International Trialist Association (ANITA) trial by the combined use of CDDP and VNR (8,9). The JBR 10 trial showed that CV (CDDP+VNR) improved the 5-year survival rate by 15% in patients with pathological stage IB to IIB NSCLC. The ANITA trial showed that CV improved the 5-year survival rate by 8.6% in patients with pathological stage IB to IIIA NSCLC. On the other hand, the Cancer and Leukemia Group B (CALGB) 9633 trial showed that combined therapy with carboplatin and paclitaxel improved the 4-year survival rate by 12% in patients with pathological stage IB NSCLC (10). A longer-term follow-up study, however, revealed no statistically significant improvement in the survival rate (11).
Based on the results of these studies, CDDP-based regimens, particularly CV, have been recommended as postoperative adjuvant chemotherapy for NSCLC (12). In the JBR 10 trial and ANITA trial, VNR was administered weekly for 16 weeks, and the median dose of VNR could be administered in only 52% of the patients. Gebbia et al. (13), who conducted a Phase III study of combined use of CDDP at 100 mg/m2 administered on Day 1 plus VNR at 25 mg/m2 administered on Days 1, 8 and 15 every 4 weeks and combined use of CDDP at 80 mg/m2 administered on Day 1 plus VNR at 30 mg/m2 administered on Days 1 and 8 every 3 weeks for Stage IIIB/IV NSCLC reported the absence of any significant difference in the survival period or the efficacy rate between the 3- and 4-week cycles of CV described above, and that the 3-week cycle showed excellent safety. It has also been confirmed that the combined use of CDDP at 80 mg/m2 administered on Day 1 plus VNR at 25 mg/m2 administered on Days 1 and 8 every 3 weeks is effective for Stage IIIB/IV NSCLC in Japanese patients (14). However, there is no report on the safety and compliance of postoperative adjuvant chemotherapy with CV administered in this schedule in Japanese patients.
Under these circumstances, we retrospectively assessed the safety and compliance of postoperative adjuvant chemotherapy with CDDP at 80 mg/m2 administered on Day 1 plus VNR at 25 mg/m2 administered on Days 1 and 8 every 3 weeks in Japanese patients.
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PATIENTS AND METHODS |
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There were 26 patients with histopathologically or cytologically diagnosed NSCLC between April 2005 and April 2008 at the Shizuoka Cancer Center, who underwent surgical complete resection and then received postoperative adjuvant chemotherapy with the CV regimen. Based on the inclusion criteria [(i) age
18 years, (ii) pathological stage IB to IIIA and (iii) performance status (PS), 0–2] and exclusion criteria [(i) double cancer, (ii) serious complications such as active infectious diseases, serious heart diseases, poorly controlled hypertension/diabetes mellitus and radiologically distinct interstitial pneumonia and (iii) prior chemotherapy] for the study, 25 patients were included as subjects for the present study and one patient was excluded because of prior neo-adjuvant chemotherapy. CDDP at 80 mg/m2 was administered on Day 1 and VNR at 25 mg/m2 was administered on Days 1 and 8. The combined use of these drugs was repeated every 3 weeks, and each 3-week treatment schedule was designated as one cycle. As a rule, patients were in the hospital from Day 1 to 3 of chemotherapy and thereafter they were discharged and administered VNR on Day 8 in outpatient setting. A total of four cycles were administered. In regard to the antiemetic therapy, granisetron plus dexamethasone were used according to the ASCO guidelines. Granulocyte colony-stimulating factor was used when patients with febrile neutropenia or Grade 4 neutropenia were judged as requiring its administration by the physician-in-charge. Dose reduction of the anticancer drugs was based on the judgment of the respective physicians-in-charge, but, as a rule, when Grade 3 or more severe non-hematotoxicity or Grade 4 hematotoxicity appeared, the doses of CDDP and VNR in the subsequent cycles were reduced to 60 and 20 mg/m2, respectively. If further dose reduction was required, the treatment was discontinued. Complete blood count and biochemistry were usually examined at least once per week. These patients were examined for the patient background characteristics, adverse events, treatment compliance and relapse-free survival. Adverse events were evaluated until 4 weeks after the completion of chemotherapy according to the Common Terminology Criteria for Adverse Events (CTCAE) Version. 3.0. Relapse-free survival was defined as time from the first administration of adjuvant chemotherapy to relapse or death, and calculated using Kaplan–Meier method.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Table 1 shows the patient characteristics. The number of male patients, 18 (72%), was larger than that of the female patients, and the median age of the patients was 62 years. The number of patients with Stage IIIA was the largest, that is, 10 (40%). In relation to the histological type of the lesions,
2/3 of all the patients had adenocarcinoma. Most of the patients had undergone lobectomy as the surgical procedure, and most had a PS of 0. The interval from the operation to the start of this treatment ranged from 29 to 79 days, with a median of 41 days.
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All the four cycles could be completed in 23 of the 25 patients (92%). The treatment was discontinued in two of the 25 patients (8%); it was discontinued after one cycle because of prolonged myelosuppression in one patient, and the Day 8 dose in the fourth cycle was omitted because of Grade 3 neutropenia and the study period ended without its administration because of prolonged myelosuppression in the other patient. There was no patient in whom the treatment was discontinued because of treatment rejection by the patient, recurrence or death. The mean cumulative dose of CDDP and VNR was 312 (97.5% of the scheduled dose) and 195 mg/m2 (97.5% of the scheduled dose), respectively.
Table 2 shows the adverse events. The Grade 3 or 4 adverse events observed in the patients included neutropenia in 76%, leukopenia in 20%, anemia in 12%, anorexia in 12% and nausea in 12% of the patients. The dose needed to be reduced because of the development of adverse events in five patients. The reasons for dose reduction were Grade 3 elevation of AST and ALT in first cycle in one patient, Grade 3 fatigue and Grade 4 neutropenia in second cycle in another patient, Grade 4 neutropenia and Grade 1 elevation of the serum creatinine in first cycle in another patient, Grade 3 febrile neutropenia and Grade 1 elevation of the serum creatinine in first cycle in another patient, Grade 1 elevation of the serum creatinine in third cycle in the other patient. There was no patient who died within 30 days of the treatment, or there were no treatment-related deaths.
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The Kaplan–Meier curve of relapse-free survival is shown in Figure 1. There were seven events and all of them were relapse. Median relapse-free survival had not been reached. Estimated 1 year relapse-free survival was 67.3%. One patient died because of disease progression after relapse of lung cancer.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The major trials on postoperative adjuvant therapy using the combination regimen of CDDP and VNR include the JBR 10 trial and the ANITA trial. In the present study, CDDP at 80 mg/m2 was administered on Day 1 and VNR at 25 mg/m2 was administered on Days 1 and 8 every 3 weeks, and each 3-week treatment schedule was designated as one cycle. In the JBR 10 trial, CDDP at 50 mg/m2 was administered on Days 1 and 8 and VNR at 30 mg/m2 was administered on Days 1, 8, 15 and 22 every 4 weeks, and each 4-week treatment schedule was designated as one cycle. In this trial, however, the dose of VNR was reduced to 25 mg/m2 because of the appearance of an adverse event, neutropenia, immediately after the start of the trial. In the ANITA trial, CDDP at 100 mg/m2 was administered on Day 1 and VNR at 30 mg/m2 was administered on Days 1, 8, 15 and 22 every 4 weeks, and each 4-week treatment schedule was designated as 1 cycle.
With regard to the patient characteristics, the gender distribution in this study was approximately the same as that in the JBR 10 trial, and the proportion of female patients was higher in this study than in the ANITA trial. The age of the patients was mostly the same in all the trials. In the JBR 10 trial, Stage IIIA NSCLC was not included in the inclusion criteria. The proportion of patients with Stage IB was lower in this study than in the ANITA trial. The reason for the lower proportion of the patients with Stage IB NSCLC in this study seems to be that an alternative choice of UFT for Stage-IB adenocarcinoma is available in Japan, and the results of the meta-analysis by lung adjuvant CDDP evaluation (LACE) (15) did not indicate the usefulness of CDDP-based postoperative chemotherapy for Stage IB patients. With regard to the histological type, the proportion of adenocarcinoma patients was higher in this study than in both the JBR 10 trial and the ANITA trial. In the ANITA trial in particular, the proportion of patients with squamous cell carcinoma was high. The proportions of the patients treated by lobectomy and that of patients with a favorable PS were higher in this study (Table 3). Taking into consideration the treatment schedule and the patient characteristics, this study was comparable to the JBR 10 trial and the ANITA trial in terms of the incidence of adverse events and the compliance (Table 4). There were no significant differences among the trials in terms of the incidence of Grade 3 and 4 adverse events, i.e. of hematological toxicities such as neutropenia and anemia and non-hematological toxicities such as nausea, vomiting, anorexia and febrile neutropenia, although the frequency of fatigue tended to be markedly lower in this study.
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High compliance was observed in this study as compared with that in the JBR 10 trial and ANITA trial, and there were no treatment-related deaths. Of the reasons for treatment discontinuation in the JBR 10 trial, treatment rejection by the patient and toxicity accounted for 29% and 13%, respectively (16). These observations suggest that the low frequency of treatment rejection by the patients in this study might have been the reason for the high compliance, and in turn, the reason for the low frequency of rejection of treatment by the patients could have been that the fatigue was mild. However, there is the possibility that non-hematological toxicity was evaluated milder in retrospective setting and that more patients rejected treatment continuation in the JBR 10 trial and ANITA trial because the benefit of adjuvant chemotherapy had not been demonstrated at that time. With regard to the relationships of the PS and surgical stress to compliance, there was no correlation between the surgical stress and compliance in the ANITA trial. In the JBR 10 trial, on the other hand, a correlation was noted between surgical stress and compliance, but not between surgical stress and the PS. In this study, however, there were many patients who showed favorable PS and only slight surgical stress, and the proportion of the patients rejecting treatment was also low, presumably because of the mild toxicity. These factors were estimated to account for the high compliance. The difference in the socio-cultural characteristics between the Japanese and Western populations may also have had an influence on the high compliance.
There was a better trend of overall survival in favor of higher total CDDP dose in LACE (15). On the other hand, there was no significant interaction between total CDDP dose and overall survival in IALT (17). The total of CDDP and VNR dose in this study was comparable to those in JBR 10 trial as the mean cumulative dose of CDDP was 275 mg/m2 and the mean cumulative dose of VNR was 199 mg/m2 in JBR 10 trial (15).
CDDP at 80 mg/m2 administered on Day 1 plus VNR at 25 mg/m2 administered on Days 1 and 8 every 3 weeks is effective and commonly used for Stage IIIB/IV NSCLC in Japanese patients (14). Major grade 3 or 4 adverse events of this chemotherapeutic regimen for Stage IIIB/IV NSCLC in Japanese patients were neutropenia in 88%, anemia in 30%, anorexia in 21%, febrile neutropenia in 18% and nausea in 14% of the patients (14). Adverse events in this study were milder because PS and main organ function would be better in adjuvant setting than in advanced and metastatic settings.
All the above-described study observations indicate that postoperative combined adjuvant chemotherapy with CDDP administered on Day 1 and VNR administered on Days 1 and 8 every 3 weeks is safe and that the rate of completion of treatment is also satisfactory in Japanese patients.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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