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Ann Thorac Surg 2001;71:309-313
© 2001 The Society of Thoracic Surgeons

Original article: general thoracic

Survival after resection of metachronous non–small cell lung cancer in 127 patients

Marcel Th.M. van Rens, MDa, Pieter Zanen, MDa, Aart Brutel de la Rivière, MDd, Hans R.J. Elbers, MDb, Henry A. van Swieten, MDc, Jules M.M. van den Bosch, MDa

a Department of Pulmonary Diseases, Sint Antonius Hospital, Nieuwegein, The Netherlands
b Department of Pathology, Sint Antonius Hospital, Nieuwegein, The Netherlands
c Department of Thoracic Surgery, Sint Antonius Hospital, Nieuwegein, The Netherlands
d Department of Thoracic Surgery, University Medical Center, Utrecht, The Netherlands

Accepted for publication May 2, 2000.

Address reprint requests to Dr van Rens, MD, Sint Antonius Hospital, Department of Pulmonary Diseases, PO Box 2500, 3430 EM Nieuwegein, The Netherlands
e-mail: antolong{at}knmg.nl


   Abstract
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 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. In a number of patients with treated primary non–small cell lung cancer (NSCLC) a second primary tumor will be diagnosed. Our experience with surgery in these patients was analyzed and possible prognostic parameters were defined.

Methods. Patients with metachronous NSCLC (n = 127) who underwent resection from 1970 through 1997 were analyzed. All tumors were classified postsurgically. Median interval between the tumors was 3.7 years. Actuarial survival time was estimated and risk factors influencing survival were evaluated.

Results. Overall 5-year survival after the first resection was 70% and after the second resection was 26%. Patients with stage IA of the second primary tumor did have a significantly better survival (p < 0.005) as compared with patients with higher staged second primaries. Stage of second primary tumor and age were significant predictors of survival, whereas stage of first tumor, interval between resections, histology, and type of resection were not.

Conclusions. Survival of patients with metachronous NSCLC and resection of both tumors is high, but poorer than after resection of the first tumor. Irrespective of the interval, patients with stage IA second primary tumor may benefit more from pulmonary resection.


   Introduction
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 Abstract
 Introduction
Material and methods
 Results
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 References
 
Pulmonary resection remains the most effective treatment for patients with non–small cell lung cancer (NSCLC) with limited disease [1, 2]. Following the therapeutic procedure in single lung cancer patients, some patients with multiple lung cancer are offered surgery [3–9]. The incidence of multiple lung cancer ranges from 1% to 10% [3, 7–9]. According to the criteria of Martini and Melamed [3], multiple lung cancer is divided by time into synchronous and metachronous lung cancer [3]. If tumors do not present simultaneously, one deals with metachronous lung cancer. Restrictions have been made when tumors are histologically identical. Histologically identical tumors that do not present simultaneously are categorized as metachronous only if the interval exceeds 2 years or if tumors are located in the lungs or lobes without common lymphatics [3] (Table 1).


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  		Table 1. Criteria for Metachronous Lung Cancer According to Martini and Melamed [3] Tumors Not Simultaneously Present

 
We analyzed our patients with metachronous lung cancer who underwent resection for both tumors to find out which subpopulation of patients may benefit most from this therapy.


   Material and methods
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 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
In the 28-year-period of 1970 through 1997, a total of 3,086 patients underwent pulmonary resection for NSCLC. In this period, 127 patients underwent pulmonary resection for metachronous NSCLC, without pretreatment. Criteria for metachronous lung cancer were derived from Martini and Melamed [3]. In each patient both resections were performed in the Sint Antonius Hospital, Nieuwegein, the Netherlands. Characteristics of the patients are presented in Table 2. Tumors were classified postsurgically according to the 1997 Staging System [1]. Histologic typing was done according World Health Organization classification [10].


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  		Table 2. Characteristics of Patients With Metachronous NSCLC (n = 127)

 
The majority of the patients were male and had been operated before the age of 65 years for the first tumor, whereas the second resection was done at more than 65 years of age in two thirds of the cases. The interval between the resection of both tumors ranged from 5 months to 21 years. In 29% of the patients a second primary tumor was diagnosed in the second or third year after the first resection. Squamous cell cancer predominated in men for the first tumor as well as for second primary tumor (76% and 68%, respectively). In women, adenocarcinoma predominated for both tumors (each 45%). None of the patients had bronchoalveolar lung cancer.

The majority of the patients (57%) underwent surgery for stage I disease for the first as well as for the second primary tumor. A total of 81 (64%) patients were treated for a second primary tumor in the other lung and 46 patients in the same lung. For the second primary tumor, 38 patients (of whom 17 patients had stage I disease) underwent completion pneumonectomy, and another 38 patients (of whom 33 patients had stage I disease) underwent a limited resection such as a wedge or segmental resection. Patients aged more than 65 years were more often treated by limited resection and less often by completion pneumonectomy than younger patients. Before surgery most patients underwent a repeat cervical mediastinoscopy or parasternal mediastinotomy, whereas during resection mediastinal lymph node sampling was performed.

Using the Kaplan-Meier method [11], survival was estimated from date of operation, excluding deaths within 30 days after operation. Survival comparisons of different discriminative factors were tested for significance by the log rank test [12]. Differences were considered significant when the p value was less than 0.05. Several factors were subsequently evaluated using the Cox proportional hazard model and Cox regression analysis method [13]. The following variables were used as categorical variables with two classes: stage (stage IA vs >= IB); age (< 65 years vs >= 65 years); histology (identical vs different); and type of resection (limited [like segmental or wedge resection] vs not limited). Interval between the resections was used as a continuous variable.


   Results
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 Material and methods
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Within 30 days after the second operation 6 (4.7%) patients died; therefore, 121 patients were evaluated after second resection. As of January 1, 2000, 14 patients were alive; ie, survival after the second resection ranging from 2.1 to 18.1 years (median 8.5 years).

After the first resection, overall 5-year survival was 70%. It is notable that 78 of these 121 patients had a disease-free interval of less than 5 years, and 43 of more than 5 years. Patients with stage IA first tumor (n = 46) had a 5-year survival of 82% after the first operation, whereas no patients with stage IIIA tumor (n = 3) survived 5 years (Table 3). Five-year survival after the second resection was 26%. Five-year survival in patients with stage IA second primary tumor was 40%. These latter patients (n = 48) did have a significantly better survival compared with patients with higher staged second primary tumors (n = 73). No significant differences in survival were observed within the group of higher staged (>= IB) second primary tumors (Table 4, Fig 1).


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  		Table 3. Survival Rates (Cumulative Percent Surviving) in Different Stages After First Resectiona

 

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  		Table 4. Survival Rates (Cumulative Percent Surviving) in Different Stages After Second Resectiona

 


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  		Fig 1. Estimated survival after second resection of patients with second tumor stage IA (broken line) and patients with higher staged second tumor (solid line) (p < 0.005) (+ censored cases; patients who are alive and in follow-up as of January 1, 2000).

 
At each observed interval between the first and second resection, survival after the second resection showed a wide range, as depicted in Figure 2. At shorter intervals short survival periods are noted frequently, and a long interval does not predict a long survival in individual patients. Nevertheless Kaplan-Meier analysis demonstrated a significant difference (p < 0.02) in survival if patients were divided into those with short and long intervals; patients with an interval of less than 1.0 years (n = 17) have a poorer survival. However, this observation is biased by the high incidence of higher staged patients (76% vs 58% in patients with increased [> 1 year] interval). Furthermore, no difference was found in the survival of patients with identical versus different histology. Survival of patients with limited resection did not differ significantly compared with that of patients with (bi)lobectomy or completion pneumonectomy.



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  		Fig 2. Scatter plot showing relationship of interval and survival after second resection. Patients with stage IA disease are designated as {circ}; patients with higher staged (>=IB) second primary tumors are marked as {triangledown}. Filled circles and triangles indicate patients alive. Dotted line represents cut-off point at 1 year.

 
Cox regression analysis showed stage of second primary tumor (p < 0.003) and age (p < 0.04) were significant predictors of survival. The hazard ratio of patients with stage IB or greater of the second primary tumor is 1.89 compared with that of patients with stage IA disease (Table 5). Nonsignificant predictors of survival included stage of first tumor (p = 0.38), interval (p = 0.61), histology (p = 0.41), and type of second resection (p = 0.94).


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  		Table 5. Cox Proportional Hazards Model of Factors Associated With Postoperative Survival After Resection in Patients With Metachronous Lung Cancer

 

   Comment
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 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Patients who underwent resection for lung cancer are at risk for developing a second primary tumor. In our hospital, more than 4% of the patients who underwent resection for lung cancer underwent surgery for a second primary tumor. The incidence is probably underestimated because not all patients with second primary tumor are offered surgery again and a number of patients are still in follow-up.

A 5-year survival after the second resection of 26% is comparable to values reported: Faber [5], 33%; Verhagen and associates [7], 31%; Angeletti and coworkers [14], 25.9%, and Rosengart and associates [15], 23%. Overall survival after the second resection is low compared with that of patients who underwent resection for one tumor: Overall 5-year survival after resection in patients with primary NSCLC (including stages I to IIIA) ranges from 41.4% to 48.9% [1, 2]. In general these studies comprise patients in whom second primaries are detected after resection of the first tumor, which will have an impact on overall (reported) survival. This makes a comparison of survival hazardous. Although this is not the theme of the present study, we may illustrate this by comparison of survival after resection of single and metachronous NSCLC, as shown in Figure 3. We used for this illustration our database comprising 2,507 evaluable patients with primary NSCLC who underwent surgery from 1970 through 1997 [2]. The poorer survival after the second resection may suggest that the first tumor still has an impact on survival after the second resection. Therefore, the stage of the first tumor and the interval between resections are variables of interest. The majority (78%) of the patients had stage I disease at the first resection, and our data show that stage of the first tumor has no impact on survival after second resection, as was also found by Rosengart and colleagues [15]. Patients with a short interval between the resections may have a poor prognosis [7], which is implicit in the definition of metachronous cancer [3]. However, Cox regression analysis demonstrated that the interval (as a continuous variable) between resections has no predictive power on prognosis. Martini and Melamed [3] defined the criteria for multiple lung cancer. An interval of 2 years is obligatory for the diagnosis of a metachronous tumor when histologically identical. The time interval of 2 years is arbitrarily chosen and probably determined to be rather confident to exclude metastatic disease. In the present study we only included metachronous patients according these criteria. Because no difference was found in the survival of patients with identical and different histology and the interval did not affect survival either, the criteria of Martini and Melamed may be appropriate. On the other hand, the latter observation opens the discussion as to at which exact interval patients with multiple tumors of identical histology can also be categorized as being definitely "metachronous" when the interval is less than 2 years.



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  		Fig 3. Survival after resection of first tumor (*) in patients with metachronous cancer is indicated by the broken line, and survival after resection of single lung cancer patients by the solid line. Survival after resection of second tumor (**) in patients with metachronous cancer is represented by the solid line. (+ censored cases; patients alive).

 
As staging has proved to be important in predicting prognosis in single lung cancer [1], it would also be likely to be valuable in predicting prognosis in second primaries. Kaplan-Meier analysis demonstrated that patients with stage IA disease of second primary tumor have a better prognosis as compared with patients with higher staged second primaries. Cox regression analysis demonstrated that multiple variables predict the prognosis of patients who underwent resection for second lung cancer. Stage of second primary tumor and age were significant predictors of survival, whereas histology, stage of first tumor, interval, and type of resection were not. In a previous study we also reported a significantly poorer survival of patients with more than 65 years of age who underwent resection for primary NSCLC. The difference may be caused by an overall lower life expectancy [2].

The majority of patients were operated on for stage I second primary tumor and in 31% of these patients a limited resection was performed. Cox regression showed that the type of resection was not a factor predictive of survival. This may support the use of limited resection in treatment of metachronous lung cancer patients. When this observation is confirmed, especially patients with impaired residual lung function and greater age will be more freely included for surgery if a second primary tumor is diagnosed.

As patients with a stage IA second primary tumor have a better prognosis after resection, it is mandatory to have close surveillance of patients who have undergone resection for a primary NSCLC. Routine roentgenography may not be sufficient but low-radiation computed tomography of the thorax may be the appropriate tool, as suggested in screening for primary lung cancer [16]. Although bronchoscopy is an invasive technique and only visualizes well the endobronchial system until the fifth generation, new modalities such as lung imaging fluorescence endoscopy may be worthwhile for follow-up, either alone or combined with sputum cytology [17].

In conclusion, the interval after the first resection and the stage of the first tumor should not be decisive factors when considering surgery. As patients with stage IA second primary tumor show favorable survival rates, a close surveillance of patients who have undergone resection for NSCLC is proposed. Even patients greater than 65 years or with small residual lung function should be considered candidates for surgery.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Mountain C.F. Revisions in the international system for staging lung cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]
  2. Van Rens M.Th.M., Brutel de la Rivière A., Elbers H.R.J., Van Den Bosch J.M.M. Prognostic assessment of 2,361 patients who underwent pulmonary resection for non-small cell lung cancer stage I, II and IIIA. Chest 2000;117:374-379.[Abstract/Free Full Text]
  3. Martini N., Melamed M.R. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975;70:606-611.[Abstract]
  4. Adebonojo S.A., Moritz D.M., Danby C.A. The results of modern surgical therapy for multiple primary lung cancers. Chest 1997;112:693-701.[Abstract/Free Full Text]
  5. Faber L.P. Resection for second and third primary lung cancer. Semin Surg Oncol 1993;9:135-141.[Medline]
  6. Deschamps C., Pairolero P.C., Trastek V.F., Payne W.S. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1990;99:769-778.[Abstract]
  7. Verhagen A.F., Van De Wal H.J., Cox A.L., Lacquet L.K. Surgical treatment of multiple lung cancers. Thorac Cardiovasc Surgeon 1989;37:107-111.[Medline]
  8. Smith R.A., Nigam B.K., Thompson J.M. Second primary lung carcinoma. Thorax 1976;31:507-516.[Abstract/Free Full Text]
  9. Ribet M., Dambron P. Multiple primary lung cancers. Eur J Cardiothorac Surg 1995;9:231-236.[Abstract/Free Full Text]
  10. WHO. Histologic typing of lung tumors, 2nd ed. Geneva, Switzerland: World Health Organization, 1981.
  11. Kaplan E.L., Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481.
  12. Peto R., Peto J. Asymptotically efficient rank invariant test procedures. J Stat Soc 1972;135:185-198.
  13. Cox D.R. Regression models and life tables. J R Stat Soc 1972;34:187-220.
  14. Angeletti C.A., Mussi A., Janni A., et al. Second primary lung cancer and relapse: treatment and follow-up. Eur J Cardiothorac Surg 1995;9:607-611.[Abstract/Free Full Text]
  15. Rosengart T.K., Martini N., Ghosn P., Burt M. Multiple primary lung carcinomas: prognosis and treatment. Ann Thorac Surg 1991;52:773-779.[Abstract/Free Full Text]
  16. Henschke C.I., McCauley D.I., Yankelevitz D.F., et al. Early Lung Cancer Action Project: overall design and findings from baselinescreening. Lancet 1999;354:99-105.[Medline]
  17. Lam S., MacAulay C., Palcic B. Detection and localization of early lung cancer by imaging techniques. Chest 1993;103:12S-14S.[Abstract/Free Full Text]



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