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Ann Thorac Surg 2009;88:1100-1105. doi:10.1016/j.athoracsur.2009.06.098
© 2009 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

TNM Stage Is the Most Important Determinant of Survival in Metachronous Lung Cancer

Benjamin E. Lee, MD, Jeff L. Port, MD, Brendon M. Stiles, MD, James Saunders, BA, Subroto Paul, MD, Paul C. Lee, MD, Nasser Altorki, MD*

Division of Thoracic Surgery, Department of Cardiothoracic Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York

Accepted for publication June 25, 2009.

* Address correspondence to Dr Altorki, Division of Thoracic Surgery, Department of Cardiothoracic Surgery, New York Presbyterian Hospital-Weill Cornell Medical College, 525 E 68th St, New York, NY 10065 (Email: nkaltork{at}med.cornell.edu).

Presented at the Poster Session of the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Distinguishing a metachronous lung cancer from a metastatic or recurrent lesion in patients with a prior history of non–small cell lung cancer is a challenging task. Previous studies have suggested histologic type and disease-free interval as criteria for diagnosing metachronous lung cancer. These factors may not be as relevant now that current imaging allows for earlier detection of tumors and with the rising incidence of adenocarcinoma. The purpose of this study was to reexamine the factors that determine outcomes in patients with a second primary lung cancer.

Methods: A retrospective review of a prospective lung cancer database was performed to identify patients with metachronous lung cancer. Metachronous lung cancer was defined as any non–small cell lung cancer occurring after a prior resection regardless of disease-free interval or histologic type. The Kaplan-Meier method was used for survival analysis. The Mantel-Cox method was used to compare overall survival. Cox regression was used for multivariate analysis.

Results: Fifty-eight patients had metachronous lung cancer. Overall survival at 5 years was 66% (stage IA, 74%; IB, 59%; all other stages, 0%; p = 0.01). Seventy-two percent (42 of 58 patients) had similar histologic type. There was no difference in overall survival based on similar versus different histologic type (65% versus 73%; p = 0.77). Median disease-free interval was 42 months (range, 8 to 312 months). Disease-free interval was not a significant predictor of overall survival (p = 0.24). The extent of resection included wedge (36%, 21 of 58 patients), segmentectomy (24%, 14 of 58 patients), and lobectomy (40%, 23 of 58 patients), with no difference in overall survival (58% versus 60% versus 75%, respectively; p = 0.32).

Conclusions: These data suggest that early tumor stage is the only significant determinant of survival after surgical treatment of metachronous lung cancer. Neither histologic type nor disease-free interval was of prognostic value. Limited resections may be adequate treatment.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Although lung cancer remains the leading cause of cancer-related deaths in the United States, a significant proportion of newly diagnosed patients present with localized disease that is potentially curable with surgical therapy. Five-year survival for completely resected stage I or II non–small cell lung cancer (NSCLC) is approximately 50% to 70% [1]. These patients are at risk for the development of a metachronous lung cancer (MLC). This risk is cumulative and has been estimated at 1% to 2% per patient, per year of follow-up [2]. Although no standard of care has been established for postoperative surveillance of these patients, our group has previously shown that these patients may be accurately followed with computed tomography in a cost-effective manner [3–5]. Among the patients who present with second lesions, differentiating intrapulmonary metastases and recurrent lung cancer from MLC can be difficult. The traditional criteria for establishing a MLC were previously defined by Martini and Melamed. [6] Tumors were considered MLC if the histologic type was discordant or if the disease-free interval (DFI) was at least 2 years for tumors with a cell type similar to that of the index primary. Patients were also considered to have an MLC if the tumor was associated with carcinoma in situ or arose in a different lobe. However, we propose that in the current era of earlier detection by computed tomographic imaging and the rising incidence of adenocarcinoma, it is reasonable to reevaluate these criteria. The purpose of this paper is to detail our experience with MLC and to identify those prognostic factors that are predictive of survival. We hypothesize that the clinical stage of the MLC is the most important preoperative determinant of survival.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
The Thoracic Surgery Tumor Registry at the Weill Medical College of Cornell University served as the database. A retrospective review of this prospective database was used to identify patients with surgically resected MLC between 1995 and 2008.

After resection of the index primary cancer, all patients were followed according to our institutional guidelines, which included computed tomographic scans obtained postoperatively at 6 and 12 months, and annually thereafter [4, 5]. Metachronous lung cancer was defined as any NSCLC occurring after a prior resection regardless of DFI, tumor location, or histologic type. Patients with two or more lesions and patients with pure bronchoalveolar carcinoma were excluded.

Evaluation of patients with a presumed MLC included, at a minimum, an updated history and physical examination and clinical staging by computed tomographic imaging (Union Internacional Contra la Cancrum/American Joint Committee on Cancer staging scheme). Brain magnetic resonance imaging and positive emission tomography were done in nearly all patients to exclude the presence of widely metastatic disease. Mediastinoscopy was done in only 6 patients because 20 patients had undergone a staging mediastinoscopy at the time of the initial resection and the remaining 32 patients had a systematic mediastinal dissection during the index procedure.

Approval for the review of hospital records was obtained from the institutional review board. Data collected included patient age, sex, stage of the initial lung cancer, the DFI between the time of initial resection and documented MLC, extent of resection, clinical stage of the MLC, and pathologic characteristics of the MLC. Follow-up was obtained through routine office visits or by means of telephone contact. Waiver of patient consent was approved.

Statistical analysis was performed using SPSS statistical software (SPSS; Chicago, IL). Survival was calculated from the time of the second primary lung cancer using the Kaplan-Meier actuarial method. The Mantel-Cox method was used to compare overall survival. A Cox regression was used for multivariate analysis. Results were considered significant at a probability value of 0.05 or less.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
From 1995 to 2008, 58 patients with surgically resected MLC were identified from a total of 1,900 patients who underwent pulmonary resection for NSCLC (3.1%). The median age at presentation of the MLC was 67 years (range, 48 to 86 years) and 35 of 58 (60%) were women (Table 1).


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  		Table 1 Patient Characteristics
 
Characteristics of the Index Primary Lesion
The median tumor size was 3.2 cm. The initial primary NSCLC was predominantly adenocarcinoma (47 of 58 patients). Five patients had squamous histologic presentation, 2 were carcinoid, and 4 were not otherwise specified. The initial pathologic stage of the index lesion was stage I in 42 patients (IA in 25 of 58 patients, 43%; IB in 17 of 58 patients, 29%), IIA/IIB in 6 patients (10%), IIIA in 6 patients (10%), and unknown in 4 patients (Fig 1, Table 2).


Figure 1
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  		Fig 1. Primary and metachronous lung cancer (MLC) histologic characteristics. Note that 72% (42 of 58) had similar histology. (Adeno = adenocarcinoma; AdenoCA = adenocarcinoma.)

 

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  		Table 2 Primary and Metachronous Lung Cancer Tumor Stage (n = 58)
 
Characteristics of the Metachronous Lung Cancer
The median tumor size was 1.5 cm (range, 0.1 to 5.8 cm). The MLC was adenocarcinoma in 48 of 58 patients (83%), squamous in 6 of 58 patients (10%), and large cell or carcinoid in 4 of 58 patients (7%). The pathologic stage of the MLC was predominantly stage I (IA in 43 of 58 patients, 74%; IB in 13 of 58 patients, 22%). One patient each had stage IIA and IIIA disease, respectively (Fig 1, Table 2).

Histologic Concordance
Overall, 42 of 58 patients (72%) had concordant histologic type and 12 of 58 patients (21%) had discordant histologic type. The 5-year survival based on concordant versus discordant histologic type was 65% versus 73% (p = 0.77; Fig 2).


Figure 2
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  		Fig 2. Actuarial survival comparing patients with concordant versus discordant histologic type in metachronous lung cancer. The 5-year survival was 65% for patients with similar histologic type compared with 73% for patients with different histologic type (p = 0.77).

 
Disease-Free Interval
The median DFI was 42 months (range, 8 to 312 months) with 10 patients having a DFI of 24 months or less. Three patients had a DFI of 12 months or less (8, 9, 12 months). Of the 10 patients with a DFI of 24 months or less, 9 had an MLC with a concordant histologic type to the index lesion and all 10 were located in the contralateral lung. Patients with a DFI of 24 months or less had a 5-year survival of 53%, compared with 68% in patients with a DFI greater than 24 months (p = 0.23; Fig 3).


Figure 3
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  		Fig 3. Actuarial survival of metachronous lung cancer patients with a disease-free interval of 24 months or less versus 25 months or more. The 5-year overall survival for patients with a disease-free interval of 24 months or less was 53% compared with 68% for patients with a disease-free interval of 25 months or more (p = 0.23).

 
Location of Metachronous Lung Cancer
Metachronous lung cancer presented in the ipsilateral lung in 17 of 58 patients and in the contralateral lung in 41 of 58 patients (71%). Patients with MLC in the ipsilateral lung had a 5-year survival of 55%, compared with 72% in patients with contralateral lesions (p = 0.80; Fig 4).


Figure 4
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  		Fig 4. Actuarial survival comparing the location of the metachronous lung cancer relative to the primary lesion. The 5-year overall survival for metachronous lung cancer found in the ipsilateral lung versus the contralateral lung was 55% and 72%, respectively (p = 0.80).

 
Extent of Resection
The majority of patients underwent anatomic resection as treatment for their initial NSCLC. There were 50 lobectomies (86%), 2 pneumonectomies (3%), 2 segmentectomies (3%), and 4 wedge resections (7%). In contrast, the extent of surgical resection for the MLC was by lobectomy in 23 of 58 patients (40%), segmentectomy in 14 of 58 patients (24%), and wedge resection in 21 of 58 patients (36%). The 5-year overall survival for lobectomy versus sublobar resection (segmentectomy plus wedge resection) was 75% versus 59%, respectively (p = 0.32; Fig 5).


Figure 5
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  		Fig 5. Actuarial survival comparing extent of metachronous lung cancer resection. The 5-year overall survival for patients undergoing lobectomy was 75% compared with 59% in patients undergoing sublobar resection (p = 0.32).

 
Survival
Overall survival at 5 years was 66% when measured from time of presentation of the MLC. Based on pathologic staging of the MLC, 5-year survival for patients with stage IA (n = 43) was 74% and 59% for patients with stage IB (n = 13), compared with 0% for patients with all other stages (n = 2; p = 0.011). There was no significant difference in survival between patients with stage IA and IB disease (p = 0.90; Fig 6).


Figure 6
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  		Fig 6. Actuarial survival of stage IA versus stage IB for metachronous lung cancer. The 5-year survival for stage IA was 74% and for stage IB was 59% (p = 0.904).

 
In a multivariate analysis of the effects of sex, DFI, histologic type, and pathologic stage on overall survival, pathologic stage emerged as the only significant predictor of overall survival (p = 0.009).


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Approximately 35,000 patients in the United States undergo surgery for lung cancer each year, predominantly for early stage disease [7]. Historically, patients without lymph node metastases can be expected to have 5-year survival rates from 57% to 67% [1]. Recent reports indicate that 5-year survival for patients with stage IA cancer may even approach 80% [9, 10]. These patients are at significant risk to develop an MLC, with an incidence between 1% and 2% per patient, per year [2]. This risk is cumulative over time. For example, in two large series of patients with resected early stage lung cancer followed for 4.2 and 5 years, respectively 8.6% and 11.7% of patients experienced MLC [6, 11]. Distinguishing a metachronous tumor from a recurrent or metastatic lesion arising from the initial tumor may be difficult in this patient population. Historically most groups have used the guidelines proposed by Martini and Melamed [6] that include histopathologic factors and clinical factors, such as DFI and tumor location.

When tumors are of different histologic subtype, a diagnosis of an MLC is seemingly straight-forward. Unfortunately, this frequently is not the case. In our series, more than 70% of MLC had similar histologic type to the index lesion. Clinically, one would then need to rely on pathologic characteristics, such as the presence or absence of carcinoma in situ and presence or absence of cancer cells in common lymphatics, to make a distinction. Although some of this information can be inferred from limited tissue samples obtained from fine-needle aspiration or core biopsies, accurate characterization depends on complete pathologic analysis, which may not be readily available at the time of presurgical evaluation. Regardless, when we examined the overall survival at 5 years, we found no significant difference in patients who had concordant versus discordant histologic type. This supports a recent study that showed no difference in 5-year survival rates in similar versus different histologic classification of metachronous NSCLC [12].

The current study also casts some doubt on the merits of using DFI to differentiate recurrent lung cancer from a metachronous lesion. There was no statistically significant difference in overall survival between patients with a DFI less than 24 months and those with a DFI exceeding 24 months (53% versus 68%; p = 0.23). Interestingly, in the subgroup of MLC patients with a DFI of 24 months or less, 90% (9 of 10 patients) had concordant histologic type. Theoretically these patients, in particular, would not typically be classified as a having an MLC and therefore might not have been evaluated for curative surgical resection. These results support recent reports that showed no difference in survival of patients diagnosed with MLC with a DFI less than or more than 2 years [13]. In our current era of improved lung cancer screening and more advanced and detailed imaging, it is possible that new lesions are being identified at earlier stages of development. Postresection computed tomographic scans at 6 months or even at 1 year have become standard at many centers. This contrasts with historic studies that relied on simple chest radiographs to detect new lesions and thus many lesions were likely not detected until they reached an advanced stage [8, 14–16]. However, one should interpret these findings with some caution as less than 20% of our patients had a DFI less than 2 years. Clearly some patients who experienced a recurrence within the first 12 months were excluded from this study either because of the presence of widely metastatic disease or because they did not meet our strict criteria for inclusion in the study, namely the presence of a single new nodule.

Tumor location was also examined to determine its prognostic value. As almost 90% of our population underwent a lobectomy or pneumonectomy as the initial resection, these patients predominately had a second lesion develop in a different ipsilateral lobe or in the contralateral lung. Again, no significant difference in overall survival based on location of the MLC was found at 5 years.

Altogether, we have not found the individual criteria proposed by Martini and Melamed [6] to be helpful with regard to evaluation and preoperative decision-making in patients with a prior history of a resected NSCLC who have developed a new lung lesion. In fact, by multivariate analysis we found that stage of the MLC was the sole predictor of survival. Similarly, a previous study showed a higher 5-year survival after surgical resection of metachronous stage I tumors, compared with those with more locally advanced stage MLCs [13]. Other recent surgical series also suggest that the subgroup of patients with stage I MLC have improved survival when compared with the group as a whole [15, 17]. Thus, we believe that accurate clinical staging of the new lung lesion in a patient with a prior history of NSCLC is paramount in determining a treatment plan. Moreover, patients who have early stage disease and who have physiologic reserve to tolerate resection should be offered surgery regardless of DFI, histologic similarity, or tumor location.

Finally, the extent of resection (lobectomy, segmentectomy, wedge resection) is often dictated by a patient's physiologic reserve. More than half of our patients (60%) underwent sublobar resection for their MLC. Although patients who underwent lobectomy had the highest 5-year overall survival, this was not statistically significant when compared with segmentectomy or wedge resection. This finding is supported by recent evidence that sublobar resection for small, early stage NSCLC may have equivalent benefit when compared with lobectomy [18–20]. Parenchymal preservation and the morbidity associated with inadequate pulmonary reserve must be considered in patients subjected to multiple lung resections.

One of the major limitations of this study is an inherent selection bias owing to the retrospective design. As only patients who underwent a surgical resection were included, it is reasonable that patients who presented with more advanced disease were not offered surgical resection. This is reflected in the few numbers of patients with advanced-stage MLC. Moreover, patients with insufficient pulmonary reserve also may not have been offered a surgical resection. Ideally, a multicenter prospective study that evaluates and compares the differing treatment modalities for all new lesions in patients with a prior history of NSCLC regardless of DFI or histologic type would be best suited to determine the long-term survival in patients with MLC.

Another major limitation is the small study size, which subjects our analysis to having a possible type 2 statistical error. We contend, however, that this patient cohort represents one of the largest published surgical series of MLC in an era of improved pulmonary imaging modalities. By comparison, the oft-referenced study published by Martini and Melamed [6] in 1975 had only 32 patients with MLC, of which only 19 patients were treated by surgical resection [6]. Thus, we hope that the present study will add to current understanding of MLC and further guide the future treatment algorithms in MLC.

In summary, we conclude that the development of a single metachronous lesion after lung cancer resection does not preclude potentially curative surgical resection in selected patients with adequate pulmonary reserve. Furthermore, we believe that the Martini and Melamed [6] criteria for multiple primary lung cancers, while of historical interest, have little practical or therapeutic utility in evaluating these patients preoperatively. In particular, the histologic type of the second tumor and the DFI appear to have little or no impact on survival. Instead, the most important preoperative determinant of survival is the stage of the metachronous lesion. A collaborative study that substantiates these findings and sets new guidelines for the diagnosis and treatment of MLC would be of considerable interest.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Nesbitt JC, Putnam JB, Walsh GL, Roth JA, Mountain CF. Survival in early-stage non-small cell lung cancer Ann Thorac Surg 1995;60:466-472.[Abstract/Free Full Text]
  2. Johnson BE, Cortazar P, Chute JP. Second lung cancers in patients successfully treated for lung cancer Semin Oncol 1997;24:492-499.[Medline]
  3. Korst RJ, Kansler AL, Port JL, Lee PC, Altorki NK. Accuracy of surveillance computed tomography in detecting recurrent or new primary lung cancer in patients with completely resected lung cancer Ann Thorac Surg 2006;82:1009-1015.[Abstract/Free Full Text]
  4. Kent MS, Korn P, Port JL, Lee PC, Altorki NK, Korst RJ. Cost effectiveness of chest computed tomography after lung cancer resection: a decision analysis model Ann Thorac Surg 2005;80:1215-1222.[Abstract/Free Full Text]
  5. Korst RJ, Gold HT, Kent MS, Port JL, Lee PC, Altorki NK. Surveillance computed tomography after complete resection for non-small cell lung cancer: results and costs J Thorac Cardiovasc Surg 2005;129:652-660.[Abstract/Free Full Text]
  6. Martini N, Melamed MR. Multiple primary lung cancers J Thorac Cardiovasc Surg 1975;70:606-612.[Abstract]
  7. Shaw A, Swaminathan M, Phillips-Bute B, et al. Mortality after lung resection: a 15-year analysis of US hospital discharge data Cancer Therapy 2008;6:787-792.
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  9. 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;42:51-57.[Medline]
  10. Lee PC, Korst RJ, Port JL, Kerem Y, Kansler AL, Altorki NK. Long-term survival and recurrence in patients with resected non-small cell lung cancer 1 cm or less in size J Thorac Cardiovasc Surg 2006;132:1382-1389.[Abstract/Free Full Text]
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  13. Battafarano RJ, Force SD, Meyers BF, et al. Benefits of resection for metachronous lung cancer J Thorac Cardiovasc Surg 2004;127:633-635.[Free Full Text]
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  17. van Rens MT, Zanen P, de la Riviere AB, Elbers HR, van Swieten HA, van den Bosch JM. Survival after resection of metachronous non-small cell lung cancer in 127 patients Ann Thorac Surg 2001;71:309-313.[Abstract/Free Full Text]
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