Ann Thorac Cardiovasc Surg 2011; 17: 58 62 Case Report Prognostic Factors of Pathologic Stage IB Non-small Cell Lung Cancer Motoki Yano, MD, Hidefumi Sasaki, MD, Satoru Moriyama, MD, Osamu Kawano MD, Yu Hikosaka, MD, and Yoshitaka Fujii, MD Purpose: In pathologic IB (pib) non-small cell lung cancer, especially in adenocarcinoma, adjuvant chemotherapy with uracil-tegafur is widely recognized as being effective. The aim of this study was to determine the prognostic factors of pib disease. Patients and Methods: Sixty patients who were diagnosed with pib disease between 2004 and 2007 were retrospectively analyzed. Results: Of 60 patients, 22 (36.7%) opted for surgery plus adjuvant chemotherapy with uracil-tegafur, whereas 38 (63.3%) opted for surgery only. The oral administration dose of uracil-tegafur was 400 mg/body. Compliance of adjuvant chemotherapy with uracil-tegafur was 65.5% in 12 months, 57.3% in 24 months. Adjuvant chemotherapy was interrupted in 11 patients because of the recurrence of disease in 3 patients and adverse reaction in 8 patients. Anorexia was the most common adverse reaction. The larger tumor diameter (5cm<) and p2 pleural invasion were the worse prognostic factors in disease free survival in a univariate analysis and a multivariate analysis (hazard ratio = 0.26 and 0.25; p = 0.028 and 0.032, respectively). Conclusion: The prognosis of the patients with pleural invasion and a tumor diameter >5cm was poor, and these, partly support the forthcoming classification. Key words: lung cancer, adjuvant chemotherapy, tegafur Introduction Adjuvant chemotherapy has been proven to be beneficial for survival in patients with resected non-small cell lung cancer (NSCLC). 1 3) Uracil-tegafur has been approved for the treatment of patients with NSCLC and Departments of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan Received: July 10, 2009; Accepted: October 8, 2009 Corresponding author: Motoki Yano, MD. Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan Email: motoki@med.nagoya-cu.ac.jp 2011 The Editorial Committee of Annals of Thoracic and Cardiovascular Surgery. All rights reserved. extensively examined for use in adjuvant chemotherapy in Japan. It has been shown that surgery and adjuvant chemotherapy with uracil-tegafur provided a survival advantage over only surgery. 4 7) Especially in patients with pathologic stage IB adenocarcinoma, the efficacy of adjuvant chemotherapy with uracil-tegafur was higher than in the other stages. However, pathological IB disease has been recognized as heterogeneous. In the forthcoming edition of staging classification for lung carcinoma by International Association for the Study of Lung Cancer (IASLC) (version 7), the present pathologic stage IB disease will be classified into pib, piia, and piib according to the maximum diameter of the tumor. 8) Since the stage classification is being revised, a review of the former evidence is necessary. The aim of this study was to determine the prognostic factors of pib disease. 58 Ann Thorac Cardiovasc Surg Vol. 17, No. 1 (2011)
Pathologic Stage IB Non-small Cell Lung Cancer Patients and Methods Patients and Treatment We reviewed surgically resected patients with lung carcinoma who were treated at Nagoya City University Hospital between January 2004 and December 2007 and 61 patients were diagnosed with pathologic stage IB disease underwent complete tumor resection. One patient who received postoperative adjuvant therapy uracil-tegafur was excluded from the study, and the remaining 60 patients were eligible for this study. All 60 patients were given an explaination about the predicted benefit and adverse reactions of adjuvant therapy with uracil-tegafur. Permission from the institutional review board and informed consent from each patient were obtained. The daily oral administration dose was 400 mg per body, and treatment was initiated within 1 month postoperatively. Administration of uracil-tegafur for 2 years was regarded as complete, and patients were allowed to take the drug for up to 2 years. Adverse events arising from adjuvant chemotherapy were identified from the medical records and graded according to the Common Terminology Criteria for Adverse Events version 3.References Statistical Analyses Disease free survival was used to evaluate the efficacy of adjuvant chemotherapy of uracil-tegafur. The differences of significance among categorized groups were compared using χ 2. Univariate and multivariate analyses of disease-free survival were carried out with the Kaplan-Meier method using the log-rank test and the Cox proportional hazards model, respectively. All statistical tests were two sided, and p<0.05 was considered statistically significant. Results Patient and clinicopathological characteristics The patient characteristics were as follows. The median age was 69 years (range, 21 to 85 years); 35 patients were male, and 25, female. Thirty-six patients were current or former smokers, and 24 patients had never smoked. Most common histopathological types were adenocarcinoma (n = 36) and squamous cell carcinoma (n = 15). Nine patients were diagnosed as having other histological types or combined types with adenocarcinoma and other histological types. The maximal tumor diameter was within 5 cm in 48 patients and over 5 cm in 12 patients. Obvious tumor invasion of the visceral pleura (p2) was observable in 8 patients. Epidermal growth factor receptor (EGFR) gene mutation status was analyzed in 57 tumors. Detail procedures of EGFR gene mutation analysis have been reported previously. A point mutation of L858R in exon 21 was found in 6 cases. Several types of deletion mutants in exon 19 were found in these 8 cases. The other 43 tumors were wild type of the EGFR gene. Compliance, survival and adjuvant chemotherapy with uracil-tegafur All 60 patients received an explanation about the predicted benefit and adverse reactions of adjuvant therapy with uracil-tegafur. Of 60 patients, 22 (36.7%) consented to take uracil-tegafur as adjuvant chemotherapy, whereas 38 (63.3%) did not consent and underwent surgery only. The background of patients with or without adjuvant therapy with uracil-tegafur is shown in Table 1. In the group with adjuvant chemotherapy, the ratios of younger and female patients were higher. Also, the EGFR gene mutation was often found. Compliance of adjuvant chemotherapy with uraciltegafur was calculated excluding 3 patients with a recurrence of disease. The rate of compliance was 71.4% in 6 months, 65.5% in 12 months, and 57.3% in 24 months (Fig. 1). Seven patients completed the 2-year regimen of adjuvant chemotherapy. Administration was continuing and not completed in 4 patients. Adjuvant chemotherapy was stopped in 11 patients because of the recurrence in 3 patients and adverse reaction in 8 patients. Anorexia was the most common adverse reaction and graded 1 in 3 patients and graded 2 in 2 patients. Other adverse reactions were grade 2 serum glutamic oxaloacetic transaminase elevation in 1 patient, grade 2 rash in 1 patient, and grade 2 pneumonitis in 1 patient. By December 2008, 7 (11.7%) of 60 patients (2 with adjuvant chemotherapy and 5 with surgery alone) had died, with a median follow-up time among the surviving patients of 24.7 months for the adjuvant chemotherapy group and 23.9 months for the control group. Overall survival was 85.8% in 2 and 4 years after the operation. Disease free survival was 85.4% in 2 years and 70.5% in 4 years. Clinicopathological factors that influenced prognosis were analyzed (Table 1); gender, age, pathological type, and EGFR gene mutation status, did not significantly alter the prognosis. Adjuvant chemotherapy of uracil- Ann Thorac Cardiovasc Surg Vol. 17, No. 1 (2011) 59
Yano M et al. Table 1 Univariate analysis of prognostic factors in patients characteristics. Characteristics No. of patients 2-years disease p free survival (%) Age 0.573 <65 21 84.7 65 39 85.9 Gender 0.613 Male 35 81.9 Female 25 90.2 Pathological types 0.260 adenocarcinoma 36 93.2 other types 24 73.1 Tumor diameter 0.017 <5cm 48 89.5 5cm 12 73.1 Pleural invasion 0.019 p0+1 51 87.4 p2 9 76.2 Adjuvant chemotherapy 0.357 + 22 78.9-38 89.3 In the selected 41 patients with both smaller diameter ( 5cm) and p0 or p1 pleural factor, the disease free survival of the group with adjuvant chemotherapy of uraciltegafur was better compared to the group who had only surgery; however, the difference did not reach statistical significance (p = 0.504, not shown). Discussion Fig. 1 Kaplan-Meier plot of compliance of uracil-tegafur in 22 patients. tegafur did not improve the prognosis in relation to any of these. The larger tumor diameter (5cm<) (Fig. 2) and p2 pleural invasion (Fig. 3) were factors for a poor prognosis in disease free survival in a univariate analysis (p = 0.017 and 0.019, respectively). To compare p0 vs. p1 and p2, we found that there was no difference in disease free survival (p = 0.229). In a multivariate analysis, a larger tumor diameter (5cm<) and p2 pleural invasion were independent factors for a poor prognosis (hazard ratio = 0.26 and 0.25; 95% CI, 0.08 to 0.86 and 0.07 to 0.89; p = 0.028 and 0.032, respectively). In pathologic IB non-small cell lung cancer, especially in adenocarcinoma, adjuvant chemotherapy with uraciltegafur has been widely recognized as being effective. In a previous study, Kato et al. reported that adjuvant chemotherapy with uracil-tegafur improved overall survival in stage I adenocarcinoma, especially in T2 disease. 6) The hazard ratio was 0.48 for the T2N0 adenocarcinoma of patients who received uracil-tegafur. Park et al. reported that adjuvant chemotherapy with uracil-tegafur improved disease-free survival. 9) In the present study, we have shown a low compliance of adjuvant chemotherapy with uracil-tegafur. Kato et al. reported that the compliance of uracil-tegafur in 498 patients was 61% in 24 months. 6) The compliance of uracil-tegafur in our patients was similar (57.5%). They reported a low rate of severe adverse reactions as we did. The main adverse reactions were anorexia and nausea, thus, patients lost their motivation to continue treatment and compliance fell to around 60%. In daily medical treatment, we should rec- 60 Ann Thorac Cardiovasc Surg Vol. 17, No. 1 (2011)
Table 2 Multivariate analysis of prognostic factors Variable HR 95% CI p Tumor diameter <5cm vs 5cm 0.26 0.08 to 0.86 0.028 Pleural invasion p0+1 vs p2 0.25 0.07 to 0.89 0.032 Pathologic Stage IB Non-small Cell Lung Cancer Fig. 2 Disease free survival of all 60 patients stratified by maximal tumor diameter status. Fig. 3 Disease free survival of all 60 patients stratified by visceral pleural invasion status. ognize these facts anew and we have to encourage the patients to continue adjuvant chemotherapy with maintenance of their motivation. We have also shown the heterogeneity of pib disease in prognosis. The patients with both smaller diameter (T 5cm) and p0 or p1 pleural factor had a better prognosis. In the forthcoming IASLC staging classification, patients with a larger tumor diameter (5cm<T) will be classified into stage IIA or IIB. 8) Our data supports the new classification. Park et al. reported prognostic factors for disease free survival in completely resected pt2n0 non-small cell lung cancer, 9) and they also proposed that visceral pleural invasion was an independent poor prognostic factor, which our data also confirms.. It is easy to imagine that patients with clinopathological factors such as a larger tumor diameter (5cm<T) or p2 pleural invasion require the more powerful platinum-based regimen of adjuvant chemotherapy. In the efficacy of adjuvant chemotherapy with uraciltegafur, molecular biological analysis has been reported. Suehisa et al reported that the EGFR mutation status influenced the clinical benefit of adjuvant chemotherapy with uracil-tegafur in patients with resected lung adenocarcinoma. 10) Adjuvant chemotherapy with uracil-tegafur in the patients with EGFR wild-type was more effective than in patients with the same EGFR wild-type who had only surgery, and they could not show efficacy of adjuvant chemotherapy with uracil-tegafur in the patients Ann Thorac Cardiovasc Surg Vol. 17, No. 1 (2011) 61
Yano M et al. with an EGFR mutation. In another biological analysis, Miyoshi et al. reported a relation between the efficacy of uracil-tegafur and thymidylate synthase (TS). 11) Adjuvant chemotherapy with uracil-tegafur might improve the survival of NSCLC patients when TS levels in tumor tissues are low. In a study of colorectal cancer, Ogata et al. reported that matrix metalloproteinase 9 (MMP-9) decreased the effect of uracil-tegafur. 12) Tanaka et al. reported that postoperative adjuvant therapy for NSCLC had a larger effect on the prolonged survival of patients with tumors having a high apoptotic index compared to patients with tumors having a low apoptotic index. 13) In further studies, an appropriate combination of clinical and molecular biological analyses may determine which patient population might benefit the most from adjuvant chemotherapy. In conclusion, the prognosis of the patients with a tumor diameter >5cm and pleural invasion was poor, and these facts partly support the forthcoming classification. References 1) Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, et al. International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350: 351 60. 2) Winton T, Livingston R, Johnson D, Rigas J, Johnston M, et al. National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs. observation in resected nonsmall-cell lung cancer. N Engl J Med 2005; 352: 2589 97. 3) Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, et al. 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. Lancet Oncol 2006; 7: 719 27. 4) Tanaka F, Miyahara R, Ohtake Y, Yanagihara K, Fukuse T, et al. Advantage of post-operative oral administration of UFT (tegafur and uracil) for completely resected p-stage I-IIIa non-small cell lung cancer (NSCLC). Eur J Cardiothorac Surg 1998; 14: 256 62. 5) Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, et al. Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: Reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 2004; 22: 3860 7. 6) Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004; 350: 1713 21. 7) Hamada C, Tanaka F, Ohta M, Fujimura S, Kodama K, et al. Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer. J Clin Oncol 2005; 23: 4999 5006. 8) Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, et al. International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007; 2: 706 14. 9) Park I, Chung KY, Kim KD, Kim DJ. Prognostic factors for disease-free survival in pt2n0 non-small cell lung cancer. Asian Cardiovasc Thorac Ann 2006; 14: 139 44. 10) Suehisa H, Toyooka S, Hotta K, Uchida A, Soh J, et al. Epidermal growth factor receptor mutation status and adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. J Clin Oncol 2007; 25: 3952 7. 11) Miyoshi T, Kondo K, Toba H, Yoshida M, Fujino H, et al. Predictive value of thymidylate synthase and dihydropyrimidine dehydrogenase expression in tumor tissue, regarding the efficacy of postoperatively administered UFT (tegafur+uracil) in patients with non-small cell lung cancer. Anticancer Res 2007 ; 27: 2641 8. 12) Ogata Y, Matono K, Sasatomi T, Ishibashi N, Ohkita A, et al. The MMP-9 expression determined the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer. Cancer Chemother Pharmacol 2004; 57: 577 83. 13) Tanaka F, Otake Y, Yanagihara K, Yamada T, Miyahara R, et al. Apoptosis and p53 status predict the efficacy of postoperative administration of UFT in non-small cell lung cancer. Br J Cancer 2001; 84: 263 9. 62 Ann Thorac Cardiovasc Surg Vol. 17, No. 1 (2011)