Asian Cardiovasc Thorac Ann 2004;12:149-153
© 2004 Asia Publishing EXchange Ltd
Impact of Size, Histology, and Gender on Stage IA Non-Small Cell Lung Cancer
Andrea Campione, MD,
Tommaso Ligabue, MD,
Luca Luzzi, MD,
Claudia Ghiribelli, MD,
Piero Paladini, MD,
Luca Voltolini, MD,
Maurizio Di Bisceglie, MD,
Mario Lonzi, MD,
Giuseppe Gotti, MD
Department of Surgery, Thoracic Surgery Unit, University Hospital of Siena, Siena, Italy
For reprint information contact: Andrea Campione, MD Tel: 39 0577 585 731 Fax: 39 0577 586 168 Email: andikampione{at}yahoo.it Department of Surgery, Thoracic Surgery Unit, University Hospital, Viale Bracci 1, 53100 Siena, Italy.
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ABSTRACT
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The aim of this study was to assess which prognostic factors could influence survival in surgically treated stage IA non-small cell lung cancer. The records of 224 consecutive patients with pathological stage IA after radical surgery were reviewed retrospectively. Overall 1, 3 and 5-year survival rates were 89%, 76%, and 66%. Nearly half of the deaths were unrelated to the original cancer. There was no difference in survival attributable to preoperative pulmonary function, age at operation, or extent of resection. However, patients with limited resections had a higher rate of local recurrence. Survival was better with a smaller size of tumor (= 2 cm), in the female sex, and in cases of bronchoalveolar adenocarcinoma.
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INTRODUCTION
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The prognosis for patients with surgically resected lung cancer has not been satisfactory, and the 5-year survival rate is no more than 67%, even for patients in stage IA.1 Multiple factors might influence the long term survival of patients with primary lung cancer after surgery, and the frequencies of recurrence and new primary cancers vary from one report to another.2 The TNM staging system does not provide information about tumor biology and several reasons account for this: patient typology, inconsistent staging, anatomic variability, tumor morphology, and tumor biology. For these reasons, sub-staging based on molecular biology could be useful in the future.3–5 In addition, postoperative adjuvant therapy in patients with completely resected stage I non-small cell lung cancer (NSCLC) has failed to show a prognostic benefit.6 The aim of this study was to assess which factors affect survival in early stage (pT1N0M0) NSCLC in order to determine whether there is a subset of patients with a poor life expectancy who could be enrolled for further postoperative chemotherapy.
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PATIENTS AND METHODS
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From January 1982 to December 2000, 1575 pulmonary resections for NSCLC were performed in the Department of Thoracic Surgery at Siena and the Thoracic Surgery Unit at Arezzo. The TNM staging system modified in 1997 was used, and preoperative staging was performed with chest, brain, and superior abdominal computed tomography and bone radionuclide scanning.1 There were 224 patients identified with pathologic stage IA NSCLC at definitive histology. The research was approved by the University Review Board. The mean age of the 37 female and 187 male patients was 66.25 years (range, 42–80 years). All patients received a complete resection: pneumonectomy was performed in 2 case, lobectomy in 174, bilobectomy in 9, and sub-lobar resections in 41 patients who had cardiopulmonary impairment. Mediastinal lymph node dissection was carried out in all patients and no adjuvant therapy followed surgical treatment. Histologic evaluation confirmed squamous cancer in 111 (49.6%) cases, adenocarcinoma in 53 (23.7%), bronchoalveolar cell carcinoma in 52 (23.2%), adenosquamous in 3 (1.3%), and large cell carcinoma in 5 (2.2%).
Patient data were analyzed to assess which factors might predict survival, timing and sites of recurrence in stage IA NSCLC. All causes of mortality were considered. Patients who were alive and disease free at the most recent follow-up were censored from this analysis. Follow-up was completed by March 2003, and median follow-up time for the entire group was 64 months (range, 12–84 months). Because of such protracted follow-up, secondary primary NSCLC was excluded from the analysis. Variables analyzed included preoperative pulmonary function, histologic type, extent of surgical resection, age at operation, sex, and tumor size. Survival was calculated using Kaplan and Meyer survival curves, and the difference between curves was analyzed by the log-rank test. The Cox proportional hazards model was used to analyze the influence of 5 variables (with p-value = 0.20 from univariate analysis).
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RESULTS
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Overall 1, 3, and 5-year survival rates were 89%, 76%, and 66% respectively. The median survival period for all patients with pT1N0M0 NSCLC was approximately 108 months (Figure 1
). The overall mortality rate was 36.2% (81 patients). Mortality due to lung cancer was in 18.8% (42 patients): 32 deaths were related to metastasis (bone metastasis in 14, diffusive metastasis in 10, lung metastasis in 3, liver metastasis in 3, brain metastasis in 2), and 10 deaths were due to local relapse. Thirty-nine patients (17.4%) died from other causes with no sign of relapse of the original cancer, thus nearly half of the deaths were unrelated to recurrence of the original cancer (Table 1). Of the 143 (63.8%) patients alive at the end of the study, 135 (60.3%) had no sign of disease and 8 (3.6%) had a recurrence (bone metastasis in 2, lung metastasis in 2, and local relapse in 4), thus the overall relapse rate was 22.3% (50 patients). The mean interval for cancer recurrence was 42 months (range, 1–132 months). Approximately 78% of the first recurrences involved distant sites, and local recurrence accounted for 22%. There was a low incidence of second primary lung cancer (4 cases, 1.8%). Because a more limited resection is usually performed in patients with inadequate respiratory performance, the effect of preoperative respiratory function on survival was assessed. The patients were divided into two groups: group 1 had good respiratory function (Miller classes 0, 1 and 2) and group 2 had poor respiratory function (Miller classes 3 and 4). The analysis showed that there was no difference ( p = 0.27) between groups 1 and 2 in terms of survival (Figure 2).
Distant metastasis were observed more frequently in non-epidermoidal carcinomas. In bone metastasis, non-epidermoidal cancer had a median survival of 108 months for squamous cancer and 85 months for non-squamous cancer. Despite this, statistical analysis did not show any difference in survival ( p = 0.45) between squamous and non-squamous cancer (Figure 3). When bronchoalveolar carcinoma was compared with the other types, the survival curves were different ( p = 0.044). Median survival was 132 months for bronchoalveolar carcinoma and 85 months for the other types (Figure 4). Five-year survival was 88% for bronchoalveolar carcinoma and 54% for other types.
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Figure 4. Difference in survival between bronchoalveolar carcinoma and others. *Subjects at risk immediately postoperatively.
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To determine whether the extent of resection affected survival, patients who underwent standard resections including lobectomy, bilobectomy, and pneumonectomy were compared with those who had limited resection. There was no significant difference ( p = 0.20) between these groups. Median survival after a standard resection was 98 months versus 104 months in those who had limited resections (Figure 5). Despite this result, it was found that sublobar resections had a higher rate of local relapse compared with standard resections (19% versus 2%; p = 0.02). Patients with age < 70 years at operation were compared with those aged = 70 years. The 5-year survival was 71% in the younger group and 60% in the older patients ( p = 0.14). Median survival was 132 and 85 months, respectively (Figure 6). A better prognosis was observed in women ( p = 0.0481) with a 5-year survival of 83.5% compared to 60% in men (Figure 7). However, mortality unrelated to lung cancer was higher in men, representing 55% of their overall mortality, than in women (14% of overall mortality unrelated to lung cancer).
When comparing tumors with a diameter = 2 cm to larger tumors (over 2 cm but less than 3 cm), this study confirmed a better survival in patients with smaller tumors ( p = 0.0109), with 5-year survival of 89.2% versus 52.1% in those with larger tumors. Median survival was 132 and 72 months, respectively (Figure 8).
On multivariate analysis considering tumor size, histology (bronchoalveolar versus others), sex, age (as a continuous variable), and extent of surgery (standard versus limited resections), it was found that larger tumor size and histology other than bronchoalveolar were independent negative prognostic factors for overall survival (Table 2).
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DISCUSSION
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Age at operation, preoperative respiratory function, and the extent of resection do not seem to influence survival. In agreement with other reports, this study showed that systemic recurrence was more frequent than local recurrence.7 As some have argued, distant recurrence of disease is more likely to arise in the early stage with negative nodal involvement (N0), whereas local relapse is more likely to develop in the N1 stage.8 The finding that histology affected survival, with bronchoalveolar carcinoma having a better survival rate than other types, has been noted previously.9,10 The observation that sublobar resections led to more frequent local relapses is possibly due to the fact that limited resections might be preferred in patients with cardiopulmonary impairment, despite the higher risk of relapse.11,12 However, limited resections did not show a worse prognosis than lobectomy in terms of 5-year survival.
It has been noted in other studies on NSCLC that women have a better prognosis.13 However, a report by Sakao and colleagues14 refuted this. On multivariate analysis, sex was not an independent predictive factor, but one report noted an effect due to sex on smaller tumors.15 The finding that better survival was associated with smaller sized tumors (= 2 cm) agrees with the report of Yanagi and colleagues16 but contrasts with the results from several other series.17–19
An important issue is the high rate of bronchoalveolar cancer in this study. Possibly this retrospective analysis may have been affected by the less restrictive classification which was used to label peripheral non-epidermoidal tumors before 1990. It was concluded from these findings that postoperative chemotherapy could not be advocated for any particular subset of patients as the results failed to define those with the worst survival. On the other hand, information from this investigation could be evaluated further by subdividing the T1 stage, because in modern times with advances in imaging techniques, such as spiral computed tomography, the early stages are likely to represent a larger portion of patients.20
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ACKNOWLEDGMENTS
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The work for this paper was supported by University of Siena in "Young Investigators Project" (Progetto Giovani Ricercatori) 2001.
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REFERENCES
|
|---|
- Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest
1997;111:1710–7.[Abstract/Free Full Text]
- Martini N, Bains MS, Burt ME, Zakowski MF, McCormack P, Rusch VW, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg
1995;109:120–9.[Abstract/Free Full Text]
- Nesbitt JC, Putnam JB Jr, Walsh GL, Roth JA, Mountain CF. Survival in early-stage non-small cell lung cancer. Ann Thorac Surg
1995;60:466–72.[Abstract/Free Full Text]
- D’Amico TA, Aloia TA, Moore MB, Herndon JE 2nd, Brooks KR, Lau CL, et al. Molecular biologic substaging of stage I lung cancer according to gender and histology. Ann Thorac Surg
2000;69:882–6.[Abstract/Free Full Text]
- Ohta Y, Tomita Y, Oda M, WatanabeS, Murakami S, Watanabe Y. Tumor angiogenesis and recurrence in stage I non-small cell lung cancer. Ann Thorac Surg
1999;68:1034–8.[Abstract/Free Full Text]
- Feld R, Rubinstein L, Thomas PA. Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small-cell lung cancer. The Lung Cancer Study Group. J Natl Cancer Inst
1993;85:299–306.[Abstract/Free Full Text]
- Little AG, DeMeester TR, Ferguson MK, Skinner DB, Hoffman PC, Skosey C, et al. Modified stage I (T1N0M0, T2N0M0), nonsmall cell lung cancer: treatment results, recurrence patterns, and adjuvant immunotherapy. Surgery
1986;100:621–8.[Medline]
- Immerman SC, Vanecko RM, Fry WA, Head LR, Shields TW. Site of recurrence in patients with stages I and II carcinoma of the lung resected for cure. Ann Thorac Surg
1981;32:23–7.[Abstract]
- Breatnach OS, Kwiatkowski DJ, Finkelstein DM, Godleski J, Sugarbaker DJ, Johnson BE, et al. Bronchioloalveolar carcinoma of the lung: recurrences and survival in patients with stage I disease. J Thorac Cardiovasc Surg
2001;121:42–7.[Medline]
- Rena O, Papalia E, Ruffini E, Casadio C, Filosso PL, Oliaro A, et al. Stage I pure bronchioloalveolar carcinoma: recurrences, survival and comparison with adenocarcinoma of the lung. Eur J Cardio-thorac Surg
2003;23:409–14.[Abstract/Free Full Text]
- Okada M, Yoshikawa K, Hatta T, Tsubota N. Is segmentectomy with lymph node assessment an alternative to lobectomy for non-small cell lung cancer of 2 cm or smaller? Ann Thorac Surg
2001;71:956–60.[Abstract/Free Full Text]
- Warren WH, Faber LP. Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma: five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg
1994;107:1087–94.[Abstract/Free Full Text]
- Alexiou C, Onyeaka CVP, Beggs D, Akar R, Beggs L, Salama FD, et al. Do women live longer following lung resection for carcinoma? Eur J Cardio-thorac Surg
2002;21:319–25.[Abstract/Free Full Text]
- Sakao Y, Sakuragi T, Natsuaki M, Itoh T. Clinicopathological analysis of prognostic factors in clinical IA peripheral adenocarcinoma of the lung. Ann Thorac Surg
2003;75:1113–7.[Abstract/Free Full Text]
- Boyd CA, Thurez RS, LoCicero J III, Huberman M, Boiselle P, Watson A, et al. Is it time to subdivide T1 lesions in resected non small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol
2000;20:310a.
- Yanagi S, Sugiura H, Morikawa T, Kaji M, Okushiba S, Kondo S, et al. Tumor size does not have prognostic significance in stage IA NSCLC. Anticancer Res
2000;20:1155–8.[Medline]
- Motta G, Carbone E, Spinelli E, Nahum MA, Testa T, Flocchini GP. Considerations about tumor size as a factor of prognosis in NSCLC. Ann Ital Chir
1999;70:893–7.[Medline]
- Koike T, Terashima M, Takizawa T, Watanabe T, Kurita Y, Yokoyama A. Clinical analysis of small-sized peripheral lung cancer. J Thorac Cardiovasc Surg
1998;115:1015–20.[Abstract/Free Full Text]
- Patz EF Jr, Rossi S, Harpole DH Jr, Herndon JE, Goodman PC. Correlation of tumor size and survival in patients with stage IA non-small cell lung cancer. Chest
2000;117:1568–71.[Abstract/Free Full Text]
- Gajra A, Newman N, Gamble GP, Abraham NZ, Kohman LJ, Graziano SL. Impact of tumor size on survival in stage IA non-small cell lung cancer: a case for subdividing stage IA disease. Lung Cancer
2003;42:51–7.[Medline]
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ABSTRACT
INTRODUCTION
