Asian Cardiovasc Thorac Ann 2006;14:139-144
© 2006 Asia Publishing EXchange Ltd
Prognostic Factors for Disease-Free Survival in pT2N0 Non-Small Cell Lung Cancer
Inkyu Park, MD,
Kyung Young Chung, MD,
Kil Dong Kim, MD1,
Dae Joon Kim, MD
Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, South Korea
1 Department of Thoracic and Cardiovascular Surgery, Eulji University School of Medicine, Daejon, South Korea
For reprint information contact: Dae Joon Kim, MD Tel: 82 2 2228 2140 Fax: 82 2 393 6012 Email: kdjcool{at}yumc.yonsei.ac.kr, Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, CPO Box 8044, Seoul 120-752, South Korea.
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ABSTRACT
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To clarify the prognostic factors for disease-free survival in completely resected pT2N0 non-small cell lung cancer, 81 consecutive patients who were treated between 1998 and 2001 were retrospectively reviewed. Follow-up was complete for all patients and the median follow-up time was 37.5 months. The overall 5-year survival rate was 68.6%, and the 5-year disease-free survival rate was 62.5%. Four factors (age, sex, visceral pleural invasion, and administration of tegafur and uracil) were proposed as prognostic factors for disease-free survival by univariate analysis. In multivariate analysis, visceral pleural invasion by the tumor (hazard ratio = 2.709, 95% confidence interval: 1.085 to 6.765, p = 0.033) and administration of tegafur and uracil (hazard ratio = 0.327, 95% confidence interval: 0.147 to 0.730, p = 0.006) were significant factors. Visceral pleural invasion was a prognostic factor for reduced disease-free survival in completely resected pT2N0 non-small cell lung cancer, and postoperative treatment with tegafur and uracil significantly improved disease-free survival.
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INTRODUCTION
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Surgical resection is generally accepted as the treatment of choice for pT2N0 non-small cell lung cancer (NSCLC). Reported survival after surgical resection ranges from 45% to 65% and many prognostic factors have been proposed, including histopathologic type, size of tumor, and visceral pleural invasion.1 Approximately half of the patients with stage I NSCLC who undergo curative resection die of recurrent tumor, predominantly outside the thorax.2 Thus, an important goal is to develop therapeutic strategies that not only control the tumor locally but also decrease the risk of extrathoracic recurrence. Although adjuvant therapy was expected to improve postoperative survival, it was not shown to benefit patients who underwent complete resection in early NSCLC.3 However, recent studies show a significant increase in survival with a platinum-based adjuvant therapy that has acceptable drug toxicity.4,5 Japanese investigators have shown that adjuvant therapy with oral UFT, a combination of tegafur and uracil, may improve overall survival after complete resection of pT2N0 NSCLC.6–8 We examined the prognostic factors for survival after complete resection of pT2N0 NSCLC.
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PATIENTS AND METHODS
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Eighty-seven consecutive patients who underwent complete resection for pathologic stage T2N0 NSCLC between 1998 and 2001 were retrospectively reviewed. Four patients with low-grade malignancy (3 typical carcinoids and 1 mucoepidermoid cancer), one with a second primary lung cancer, and one who died of respiratory failure on postoperative day 17 were excluded from the analysis. Lobectomy was the procedure of choice for pulmonary resection, and radical lymphadenectomy was performed in every patient regardless of its node staging clinically. Complete resection was defined as no residual disease identified microscopically either at the resection margin of the tumor or in the highest mediastinal lymph node dissected. Mediastinoscopy was not routinely performed. Pathologic stages were determined on the basis of histopathologic findings in the resected specimens, according to the current TNM classification revised in 1997.9 Histologic types were diagnosed according to the classification of the World Health Organization.10
Adjuvant therapy consisted of oral administration of UFT (600 mg·day–1) for at least 6 months after surgery (maximum administration period, 2 years). Administration of UFT was scheduled to start within 4 weeks after surgery and discontinued when the patient refused the treatment, significant side effect(s) occurred, or a local or distant relapse was identified. When a relapse was detected, administration of UFT was stopped and systemic intravenous chemotherapy, with or without radiotherapy, was initiated promptly. Follow-up included physical examination and chest radiography every 3 months and chest computed tomography, bone scintigraphy, and abdominal ultrasonography every 6 months for the first 2 years after surgery. From the 3rd to the 5th year postoperatively, follow-up consisted of a physical examination, chest radiograph, chest computed tomography scan, bone scintigraphy, and abdominal ultrasonography every 6 months. Other examinations including positron-emission tomography were performed appropriately when relapse was suspected.
The chi-squared test, Fisher’s exact test, and the Student t test were used to examine variations in patient characteristics. The survival time was counted from the day of surgery, and the 5-year survival rate was calculated using the Kaplan-Meier method. The log-rank test was used to compare the survival curves. Multivariate analysis of the prognostic factors was conducted using Cox’s regression model. When the p-value was less than 0.05, it was concluded that there was a significant difference.
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RESULTS
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There were 66 men and 15 women. Their demographic and surgical details are summarized in Table 1
. UFT was administered to 55 patients (UFT group) and no adjuvant treatment was given to the other 26 patients (surgery-only group). The clinical characteristics of both groups are shown in Table 2. There were no significant differences in age, distribution of sex, histopathologic data, and operation performed between the two groups. In the UFT group, the median period of administration was 74 weeks (range, 12–154 weeks), which was 77.1% of the maximum administration period (96 weeks). Administration of UFT was discontinued early (before 6 months postoperatively) in 7 patients: 2 suffered gastrointestinal complications (nausea, vomiting, and indigestion), 4 were found to have recurrent disease during treatment, and one gave no reason for ceasing medication.
Twenty-three (28%) of the 81 patients suffered a recurrence during follow-up. Intrathoracic recurrences were found in 13 patients and extrathoracic recurrences were noted in 10. Ten recurrences (38%) were in the surgery-only group and 13 (24%) in the UFT group ( p = 0.193). Intrathoracic recurrences affected 4 patients (15%) in the surgery-only group and 9 (16%) in the UFT group. The recurrence was extrathoracic in 6 patients (23%) in the surgery-only group and in 4 (7%) in the UFT group. The median time to recurrence was 10 months in the surgery-only group and 20 months in the UFT group.
The median follow-up time was 37.5 months, and the follow-up was complete in all patients. The overall 5-year survival rate was 68.6%. In subgroup analysis, the 5-year survival rates in the surgery-only and UFT groups were 51.7% and 80.2%, respectively ( p = 0.002; Figure 1). The 5-year disease-free survival rate of all patients was 62.5%. In subgroup analysis, the 5-year disease-free survival rates were 48.5% in the surgery-only group and 69.9% in the UFT group, with a statistically significant difference ( p = 0.026; Figure 2).
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Figure 1. (A) The 5-year overall survival curve, (B) The 5-year survival curves in the UFT group (solid line) and surgery-only groups (dashed line). 5 YSR = 5-year survival rate.
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Figure 2. (A) The overall 5-year disease-free survival curve, (B) The 5-year disease-free survival curves in the UFT group (solid line) and surgery-only groups (dashed line). 5 YSR = 5-year survival rate.
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Univariate analysis of the prognostic factors revealed that age, visceral pleural invasion, and administration of UFT were significant factors affecting disease-free survival (Table 3). In multivariate analysis, visceral pleural invasion and administration of UFT were significant factors determining postoperative disease-free survival (Table 4). Age, sex, tumor size, and histologic type did not significantly affect postoperative disease-free survival. There were no significant interactions among variables at each step of entry into multivariate analysis.
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DISCUSSION
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It seems that the prognostic factors for pathologic T2N0 NSCLC are similar to those for pT1N0 NSCLC, but their significance may diminish as the disease progresses. Many variables such as age, sex, histopathologic type, grade of differentiation, extent of pulmonary resection, and tumor size have been proposed as prognostic factors.1 Visceral pleural invasion is consistently reported to be a significant prognostic factor for reduced survival in completely resected pT2N0 NSCLC.1,11–14 Shimizu and colleagues15 stated that visceral pleural invasion indicates a poor prognosis and tumors greater than 3 cm (T2) with visceral pleura invasion should be upgraded to T3 status. In this study, it was also found that visceral pleural invasion was a significant prognostic factor for shorter disease-free survival in completely resected pT2N0 NSCLC.
Approximately half of the patients die of recurrent disease following curative resection for pT2N0 NSCLC.2 Sixty percent of recurrences develop within the first 2 years after surgery, and the predominant pattern of recurrence is systemic.2 The 5-year survival rate was 95.5% for pT1N0 NSCLC at our institute, but it dropped significantly to 60.3% for pT2N0 NSCLC ( p = 0.001).16 Therefore, the need for a treatment modality to improve the survival outcome of pT2N0 NSCLC has been evident since the late 1990s. Earlier studies with cisplatin-based chemotherapy failed to achieve a significant prolongation of survival.4 Thus, since 1998 we have administrated oral UFT as adjuvant treatment in completely resected pT2N0 NSCLC patients.
UFT is a combination drug that consists of tegafur and uracil in a molar ratio of 1:4. Tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil) is a prodrug that continuously releases 5-fluorouracil (5-FU) and maintains the blood 5-FU concentration. Uracil is added to inhibit degradation of the released 5-FU which is pharmacokinetically not a dose-dependent anti-tumor agent, but a time-dependent agent. It has been proved by in vivo and in vitro studies that 5-FU has a strong anti-tumor effect when in contact over a long time period, even at low drug concentrations.17 Therefore, oral administration of UFT is remarkably effective pharmacologically in terms of continuous maintenance of 5-FU concentration in the blood.18 UFT can be effective in various ways as an adjuvant therapy for patients who have undergone complete tumor resection. Minimal adverse effects of UFT permit long-term oral administration on an outpatient basis. Drug compliance was approximately 80%, which was higher than in a study on cisplatin-based adjuvant therapy (60%).8 In our study, only 2 patients stopped UFT due to gastrointestinal complications at 13 and 17 weeks postoperatively. In the UFT group, the administration period per patient was 77.1% of the maximum administration period, which was similar to that reported by Endo and colleagues.19
Recent studies have shed light on the role of UFT as adjuvant treatment for resected NSCLC. Wada and colleagues6 performed a randomized trial of adjuvant chemotherapy for stage I–III resected NSCLC and showed a prognostic advantage for oral administration of UFT compared to surgery only. Their 5-year survival rates were 64.1% for the UFT group (n = 103) vs. 49.0% for the surgery-only group (n = 98) with a p value of 0.022. In a retrospective study, the 5-year survival rate of the UFT group was significantly better than the surgery-only group (88.6% vs. 72.2%, p = 0.013) of patients with pathologic stage I NSCLC.7 Kato and colleagues8 reported the results of a randomized trial evaluating the efficacy of UFT in 979 patients with pathologic stage I adenocarcinoma. A significant survival benefit was observed in the UFT group ( p = 0.04), but the benefit appeared to be limited to the subgroup with pT2N0 disease. A recent meta-analysis demonstrated that adjuvant chemotherapy with single-agent UFT therapy can improve the survival of stage I–II NSCLC patients (hazard ratio = 0.799, 95% confidence interval: 0.668 to 0.957, p = 0.015).20
In our study, the 5-year survival rate of the UFT group was better than that of the surgery-only group and the 5-year disease-free survival rate of the UFT group was also significantly better than that of the surgery-only group. Although statistical significance was not reached, recurrence tended to be more frequent in the surgery-only group (38.5% vs. 23.6%), and the median time to recurrence was longer in the UFT group (20 vs. 10 months). A relatively lower recurrence rate and improvement of disease-free survival were thought to contribute to the improvement in survival in the UFT group. In multivariate analysis, administration of UFT was the most significant prognostic factor affecting postoperative disease-free survival. This retrospective, non-randomized study has several problems such as selection of the patients in whom UFT was administered and the small number in the study population. However, we observed that visceral pleura invasion was a prognostic factor for shorter disease-free survival, and postoperative oral administration of UFT provided a significant survival benefit with minimal adverse effects in completely resected pT2N0 NSCLC.
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REFERENCES
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- Ambrogi V, Pompeo E, Elia S, Pistolese GR, Mineo TC. The impact of cardiovascular comorbidity on the outcome of surgery for stage I and II non-small-cell lung cancer. Eur J Cardiothorac Surg 2003;23:811–7.[Abstract/Free Full Text]
- Ponn RB, LoCicero J III, Daly BD. Surgical treatment of non-small cell lung cancer. In: Shields TW, LoCicero J III, Ponn RB, Rusch VW, editors. General thoracic surgery. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2004:1548–87.
- Martini N. Surgical treatment of non-small cell lung cancer by stage. Semin Surg Oncol 1990;6:248–54.[Medline]
- Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899–909.[Abstract/Free Full Text]
- Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; 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.[Abstract/Free Full Text]
- Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small cell lung cancer. N Engl J Med 2005;352:2589–97.[Abstract/Free Full Text]
- Wada H, Hitomi S, Teramatsu T. Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. West Japan Study Group for Lung Cancer Surgery. J Clin Oncol 1996;14:1048–54.[Abstract/Free Full Text]
- Tanaka F, Miyahara R, Ohtake Y, Yanagihara K, Fukuse T, Hitomi S, 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;14:256–64.
- Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004;350:1713–21.[Abstract/Free Full Text]
- Mountain C. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710–7.[Abstract/Free Full Text]
- Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, in collaboration with Sobin LH and pathologists from 14 countries. Histological typing of lung and pleural tumors. World Health Organization. International histological classification of tumors. 3rd ed. Berlin: Springer-Verlag, 1999.
- Harpole DH Jr, Herndon JE 2nd, Young WG Jr, Wolfe WG, Sabiston DC Jr. Stage I nonsmall cell lung cancer. A multivariate analysis of treatment methods and patterns of recurrence. Cancer 1995;76:787–96.[Medline]
- Ichinose Y, Yano T, Asoh H, Yokoyama H, Yoshino I, Katsuda Y. Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cadiovasc Surg 1995;110:601–5.[Abstract/Free Full Text]
- Manac’h D, Riquet M, Medioni J, Le Pimpec-Barthes F, Dujon A, Danel C. Visceral pleura invasion by non-small cell lung cancer: an underrated bad prognostic factor. Ann Thorac Surg 2001;71:1088–93.[Abstract/Free Full Text]
- Osaki T, Nagashima A, Yoshimatsu T, Yamada S, Yasumoto K. Visceral pleural involvement in nonsmall cell lung cancer: prognostic significance. Ann Thorac Surg 2004:77:1769–73.[Abstract/Free Full Text]
- Shimizu K, Yoshida J, Nagai K, Nishimura M, Yokose T, Ishii G, et al. Visceral pleural invasion classification in non-small cell lung cancer: a proposal on the basis of outcome assessment. J Thorac Cardiovasc Surg 2004;127:1574–8.[Abstract/Free Full Text]
- Kim K, Chung K, Hong K, Kim D. The surgical results of stage I lung cancer. Korean J Thorac Cardiovasc Surg 1998;31:982–7.
- Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988;6:1653–64.[Abstract/Free Full Text]
- Fujii S, Ikenaka K, Fukushima M, Shirasaka T. Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil. Gann 1978;69:763–72.[Medline]
- Endo C, Saito Y, Iwanami H, Tsushima T, Imai T, Kawamura M, et al. A randomized trial of postoperative UFT therapy in p stage I, II non-small cell lung cancer: North-East Japan Study Group for Lung Cancer Surgery. Lung Cancer 2003;40:181–6.[Medline]
- Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. 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.[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION
