GENERAL THORACIC
Surgical Treatment of Metachronous Second Primary Lung Cancer Jie Yang, MD, Ming Liu, MD, Jie Fan, MD, Nan Song, MD, Wen-xin He, MD, Yu-ling Yang, MD, Yan Xia, MD, and Ge-ning Jiang, MD Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Background. Many studies have demonstrated that patients with metachronous second primary lung cancer (MSPLC) benefit from surgery. Owing to the lack of uniform criteria and prospective randomized trials, the extent of resection remains controversial, and prognostic factors are still not fully clear. The present study aimed to assess surgical treatment of MSPLC and identify prognostic factors of outcome. Methods. This retrospective analysis included 143 patients who underwent surgical resection of MSPLC in our department from January 2006 to December 2011. Predictors of postoperative complications were analyzed with the binary logistic regression method. Survival was analyzed with Kaplan-Meier and Cox regression methods. Results. Operative mortality was 1.4%, and the complication rate was 34.3%. Age more than 70 years was an independent risk factor for postoperative complications. The overall 5-year survival after resection of MSPLC was 54.5%. TNM stage II or higher (p [ 0.025),
20 or more pack-years of smoking (p [ 0.037), and tumor size greater than 2 cm (p [ 0.033) were independent negative prognostic factors for survival. For stage I disease, completion pneumonectomy had a lower 5-year survival rate than others, 44.8% and 65.9, respectively (p [ 0.039); lobectomy and sublobar resection have a 5year survival of 77.1% and 56.7%, respectively (p [ 0.203). Conclusions. Surgical treatment of MSPLC is safe and effective. TNM stage I, tumor size 2 cm or less, or less than 20 pack-years smoking are predictors of improved survival. Sublobar resection is acceptable. For stage I disease, lobectomy tends to be associated with better survival than sublobar resection, although the difference is not significant, and completion pneumonectomy is not recommended. Long-term follow-up is necessary even after curative resection of lung cancer.
T
controversial. Moreover, whether TNM stage can perfectly predict the outcome of MSPLC or whether there are any other factors that may significantly affect survival remains to be investigated. The purpose of this study was to assess surgical treatment of MSPLC and to identify factors that may affect short-term and long-term outcomes.
he risk of a metachronous primary lung cancer (MSPLC) developing after complete resection of a first tumor increases as follow-up time extends [1, 2], and the incidence is estimated to be 1% to 2% per patient per year [3, 4]. With the widespread use of accurate follow-up tools such as multislice spiral computed tomography (CT), positron emission tomography (PET), and the better survival results after resection of primary lung cancer, more and more MSPLCs have been detected. Different from metastases, MSPLC are potentially curative if detected at an early stage. For many years it has been demonstrated that surgical treatment is valuable for MSPLC [5], but there are still issues on which surgeons have not reached an agreement, issues mainly focusing on the extent of resection. Anatomic lobar resection has been considered the standard surgical procedure for patients with primary lung cancer [6]. However, there is still paucity of large randomized trials focusing on MSPLC, and the standard surgical approach has not been identified. Whether atypical resection is applicable to MSPLC remains
Accepted for publication May 7, 2014. Address correspondence to Dr Jiang, 507 Zhengmin Rd, Shanghai 200433, China; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2014;98:1192–8) Ó 2014 by The Society of Thoracic Surgeons
Patients and Methods Approval for the study was obtained from the Ethics Committee of the Shanghai Pulmonary Hospital. A retrospective study was conducted analyzing clinical data of 143 patients who underwent surgery for MSPLC after curative resection of initial lung cancer in our department from January 2006 to December 2011. During this period, 6,741 patients underwent pulmonary resection for lung cancer, and this cohort represented an incidence of 2.1% of the overall series. Another 31 patients who were considered to have a second primary cancer but who did not undergo resection were not included in this analysis. The reasons for not undergoing resection were poor lung function in 12 patients, distant metastatic disease in 8 patients, unresectable tumor in 5 patients, severe comorbidity in 3 patients, refusal to undergo surgery in 2 patients, and advanced age in 1 patient. 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.05.050
The criteria for diagnosis of MSPLC were those described by Martini and Melamed [7] in 1975: (1) histology different; or (2) histology the same, if diseasefree interval between cancers was at least 2 years, or origin was from carcinoma in situ, or second cancer in different lobe or lung but no carcinoma in lymphatics common to both, and no extrapulmonary metastases at time of diagnosis. Eight of the 143 patients did not undergo the first resection in our department, and the original pathology slides from the first lung cancer were obtained and reviewed by pathologists at our institute. All patients were restaged according to the seventh edition of the TNM classification of malignant tumors introduced in 2009 [8]. The interval between tumors was calculated from the date of resection of the prior tumor to the date of detection of the second tumor by imaging. Preoperative evaluation included medical history, physical examination, chest and abdomen CT scan, bronchoscopy, whole-body radionuclide bone scanning, brain magnetic resonance imaging, and lung function. Endobronchial ultrasound-guided transbronchial needle aspiration were performed if imaging indicated N2/N3 disease. Positron emission tomography was applied when it was introduced. The surgical resections were performed by either video-assisted thoracoscopic surgery (VATS) or thoracotomy according to the condition of patients and tumors as well as surgeon preference. All VATS procedures performed in this study were complete VATS, using thoracoscopic visualization only and without rib spreading. Thoracotomies were performed through a posterolateral incision. Extent of resection, including lobectomy (including completion pneumonectomy) and sublobar resection (segmentectomy and wedge resection), was decided based on preoperative and intraoperative evaluation. During lobectomy, lymph nodes were systematically dissected when the lesion was invasive or sampled for noninvasive disease. For patients who underwent sublobar resection, node sampling was performed and sometimes only enlarged or PET-positive nodes were dissected. Operative mortality included deaths from all causes occurring within 30 days of surgery or beyond 30 days but during the same hospitalization period. Postoperative complications were graded according to the Common Terminology Criteria for Adverse Events (version 4.03) [9]. The indication for adjuvant therapy was stage IB in high-risk patients or stage II or higher disease. Highrisk patients included those with poorly differentiated tumors, vascular invasion, wedge resection, tumors greater than 4 cm, visceral pleural involvement, and incomplete lymph node sampling [10].
Follow-Up The timing of surveillance for patients who underwent surgical resection of lung cancer in our center was 3 months after surgery, and thereafter at 6-month intervals until 2 years, and then annually. Survival was calculated from the date of the second resection to the date of the last follow-up or death. Follow-up was complete up to
YANG ET AL SURGICAL TREATMENT OF MSPLC
1193
December 31, 2013. History, physical examination, chest CT, and abdominal ultrasonography were routine examinations in each follow-up visit after 3 months from the date of surgery. Bone scan, brain magnetic resonance imaging, or PET were performed whenever there were indications of distant metastases.
Statistical Analysis Comparative analysis to identify differences was performed with the c2 test or Fisher’s exact test on categorical variables, and Student’s t test or Mann-Whitney U test on continuous variables. Complications were assessed by binary logistic regression. Survival was assessed by the Kaplan-Meier method and log rank test. Cox regression analysis was used to investigate the predictors of long-term survival. Factors analyzed included patient sex, age, comorbidities, smoking history, tumorfree interval, pulmonary function, tumor size, tumor number, ipsilateral or contralateral, surgical approach (VATS versus thoracotomy), extent of resection (lobectomy versus sublobar resection), estimated blood loss, systematic lymph node dissection or sampling, TNM stage, lymph node status, and histology of second primary lung cancer. Variables considered in the multivariate analysis were those with a p value of 0.15 or less in the univariate assessments. A p value of less than 0.05 was considered statistically significant. All statistical analysis was performed with IBM SPSS version 16.0 for Windows (IBM Corporation, Armonk, NY).
Results Patient Characteristics The median age of patients at second intervention was 60 years (range, 35 to 81), with a median tumor-free interval of 34 months (range, 3 to 186). The median size of a second tumor was 2.2 cm (range, 0.3 to 8.5 cm). Table 1 summarizes patient characteristics and clinical data of the first lung cancer. Perioperative findings of the second intervention are shown in Table 2.
Complications and Mortality There were 2 operative deaths (1.4%) in this series, due to respiratory failure (right upper lobectomy for the first tumor, right completion pneumonectomy for the second) and pulmonary embolism (left lower lobe lobectomy for the first tumor, right middle and lower bilobectomy for the second). A total of 54 postoperative complications occurred in 49 patients (34.3%; Table 3). Fourteen patients (9.8%) had grade 3 or higher complications. Univariate analysis revealed that thoracotomy (p ¼ 0.034), completion pneumonectomy (p ¼ 0.005), age more than 70 years (p ¼ 0.024), estimated blood loss greater than 1,000 mL (p ¼ 0.017), and reoperative ipsilateral surgery (p ¼ 0.010) were associated with an increased risk of postoperative complications. In multivariate analysis, age more than 70 years (odds ratio 3.444, 95% confidence interval: 1.318 to 9.002; p ¼ 0.012) was
GENERAL THORACIC
Ann Thorac Surg 2014;98:1192–8
GENERAL THORACIC
1194
YANG ET AL SURGICAL TREATMENT OF MSPLC
Ann Thorac Surg 2014;98:1192–8
Table 1. Patient Characteristics and Clinical Data of First Lung Cancer Variables Sex Male Female Pack-years of smoking 20 2 cm (dotted line); (C) pack-years of smoking 2 cm CI ¼ confidence interval.
Odds Ratio
95% CI
p Value
2.019 1.798 1.935
1.092–3.734 1.019–3.174 1.054–3.554
0.025 0.037 0.033
[7] in 1975. Using this criteria, a MSPLC incidence of 2.1% is similar to that reported by other studies [2,14]. The American College of Chest Physicians lung cancer guidelines set up new criteria in which the interval between tumors with similar histology extended to 4 years [15]. Although no interval limit is mentioned in the Mayo Clinic criteria, a metachronous carcinoma with similar histology was considered primary when the new lesion was solitary and occurred outside the area anatomically contiguous to the previous lung cancer and its regional lymphatics, with no evidence of extrathoracic lung cancer [16]. Many molecular techniques have also been successfully used to distinguish MPSLC from metastasis, such as p53 mutation analysis [17], patterns of loss of heterozygosity of multiple chromosomal loci [18], comet assay for DNA damage [19], and genomic alteration using array comparative genomic hybridization [20], but none of these has been widely used clinically. A more definitive diagnosis may be possible based on routine performance of molecular analysis in the future.
Fig 3. Survival of patients with stage I metachronous second primary lung cancer based on extent of resection: (A) noncompletion pneumonectomy (solid line) and completion pneumonectomy (dotted line); and (B) lobectomy (solid line) and sublobar resection (dotted line).
Whichever criteria or methods are used, the distinction between a new primary lung cancer and recurrence of the original tumor is not as important as determining whether the tumor can be treated with curative intent [7]. If extrapulmonary metastases can be excluded and the patient can tolerate the procedure, we believe surgery should be considered, as most thoracic surgeon [2, 14, 16, 21, 22] recommend, because surgical resection remains the most effective treatment for patients with non-small cell lung cancer [23]. As to the safety of surgery, there were only 2 operative deaths (1.4%) in this series, 1 each after completion pneumonectomy and bilobectomy. Postoperative complications occurred in 34.3% of patients, and 9.8% of patients had grade 3 or higher complications, similar to the results of two Society of Thoracic Surgeons general thoracic database studies, in which 9,033 and 18,800 lung resections were involved, respectively [24, 25]. Hamaji and colleagues [16] of the Mayo Clinic retrospectively analyzed 161
YANG ET AL SURGICAL TREATMENT OF MSPLC
1197
resections of MSPLC, and their data showed that ipsilateral operation and a lower FEV1% were predictors of a higher risk of postoperative complications. In our study, age more than 70 years was the only predictor of postoperative complications in multivariate analysis. Regarding surgical approach, VATS was associated with less risk of postoperative complications, as another study has confirmed [26]. But we must confess that 33 of the 39 patients who underwent VATS had contralateral lung cancer. Surgeons should be prudent in choosing VATS for patients who will undergo ipsilateral reoperation because of a higher risk of pleural adhesions, which may make it too difficult to perform the procedure. A lower FEV1% was not associated with complications in this series, perhaps because all these patients underwent sublobar resection for a second tumor. In this study, we have shown a 5-year survival of 54.5% after resection of MSPLC, which is far better than what would be expected for metastases or local recurrences. In addition, several factors were identified as having a significant effect on survival. TNM stage is the most widely accepted predictor of survival for primary lung cancer. Some studies have revealed that survival after resection of MSPLC is associated with TNM stage [5, 27, 28], whereas others have not mentioned or have failed to find significant differences in survival based on TNM stage [2, 14, 16]. Our study confirms that TNM stage is an important determinant of survival of patients with MSPLC. Furthermore, it is very interesting that tumor size was as significant a predictor as stage in this series. A reasonable explanation is that 43 patients were pathologically NX, and some of them may have been understaged based on clinical staging. The importance of this finding is that tumor size can be a valuable predictor for survival, especially when pathologic node staging is not available. The significant effects of tumor size and packyears of smoking on survival were supported by the study of Hamaji and associates [16], although different diagnostic criteria of MSPLC were used. Regarding the extent of resection, some surgeons reported that sublobar resection is acceptable for MSPLC [2, 16], whereas others consider that anatomic resection is favorable [14, 29]. In our center, the extent of resection is based on the balance of risk and benefit of surgery, and many factors should be considered before determination, including age, pulmonary function, tumor condition, pleural condition, and any other factors that may affect the outcome. Pulmonary function is a very important prognostic factor of lung resection, and preservation of pulmonary reserve should be considered at the time of the first tumor resection, because all patients have a probability of second primary lung cancer developing [2]. According to our current data, sublobar resection is acceptable for the treatment of MSPLC, with a satisfactory survival rate. For stage I disease, which accounts for the majority of MSPLC, lobectomy tends to have better survival than sublobar resection, but the difference is not significant. Completion pneumonectomy is not recommended for patients with stage I MSPLC because of higher risk of complications and the negative effect on long-term survival.
GENERAL THORACIC
Ann Thorac Surg 2014;98:1192–8
GENERAL THORACIC
1198
YANG ET AL SURGICAL TREATMENT OF MSPLC
Many studies have concluded that close long-term follow-up is necessary for patients who have undergone resection of lung cancer [2, 5, 16]. We also recommend long-term follow-up as 22.4% of MSPLC in our series developed more than 5 years after first resection and 15.7%, after more than 10 years. Computed tomography scan is preferred during surveillance for early detection of MSPLC, as the National Cancer Comprehensive Network guideline suggests [10]. There are several limitations of this study. First of all, owing to the retrospective nature of the study and lack of randomization, there is certainly a degree of bias in patient selection and surgeon experience. Second, the characteristics and surgical treatment of the initial lung cancer can also affect patients’ survival, especially for patients with a shorter interval between metachronous tumors, leading to potential bias as well. In conclusion, surgical treatment of MSPLC is safe and offers a good long-term outcome. TNM stage I, tumor size 2 cm or less, and less than 20 pack-years smoking are predictors of improved survival. Sublobar resection is acceptable for the treatment of MSPLC, with a satisfactory survival rate. For stage I disease, lobectomy tends to be associated with better survival than sublobar resection, although the difference is not significant, and completion pneumonectomy is not recommended because of the higher risk of complications and shorter survival. Longterm follow-up is necessary even for patients who have undergone curative surgical resection of lung cancer. Randomized, controlled, and multicenter studies are needed to confirm these findings.
References 1. Thomas PA, Rubinstein L. Malignant disease appearing late after operation for T1 N0 non-small-cell lung cancer. The Lung Cancer Study Group. J Thorac Cardiovasc Surg 1993;106:1053–8. 2. Bae MK, Byun CS, Lee CY, et al. The role of surgical treatment in second primary lung cancer. Ann Thorac Surg 2011;92:256–62. 3. Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335–45. 4. Rubins J, Unger M, Colice GL. Follow-up and surveillance of the lung cancer patient following curative intent therapy: ACCP evidence-based clinical practice guideline (2nd edition). Chest 2007;132(Suppl):355–67. 5. Rosengart TK, Martini N, Ghosn P, et al. Multiple primary lung carcinomas: prognosis and treatment. Ann Thorac Surg 1991;52:773–8. 6. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615–22. 7. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975;70:606–12. 8. Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest 2009;136:260–71. 9. The common terminology criteria for adverse events (CTCAE version 4.03). Available at: http://evs.nci.nih.gov/ ftp1/ctcae/about.html. Accessed February 13, 2014.
Ann Thorac Surg 2014;98:1192–8
10. National Cancer Comprehensive Network. 2013 NCCN guidelines version 2.2013, non-small cell lung cancer. Available at: http://www.nccn.org/professionals/physician_gls/f_ guidelines.asp#nscl. Accessed February 13, 2014. 11. Beyreuther H. [Multipicate von carcinomen bei einem fall von sog: “Schneeberger” lungenkrebs mit tuberculose.] Virchows Arch Pathol Anat 1924;250:230–6. 12. Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 2003;63: 1727–30. 13. Colice GL, Rubins J, Unger M. Follow-up and surveillance of the lung cancer patient following curative-intent therapy. Chest 2003;123(Suppl):272–83. 14. Zuin A, Andriolo LG, Marulli G, et al. Is lobectomy really more effective than sublobar resection in the surgical treatment of second primary lung cancer? Eur J Cardiothorac Surg 2013;44:e120–5. 15. Detterbeck FC, Jones DR, Kernstine KH, et al. Lung cancer. Special treatment issues. Chest 2003;123(Suppl): 244–58. 16. Hamaji M, Allen MS, Cassivi SD, et al. Surgical treatment of metachronous second primary lung cancer after complete resection of non-small cell lung cancer. J Thorac Cardiovasc Surg 2013;145:683–90. 17. van Rens MT, Eijken EJ, Elbers JR, et al. p53 mutation analysis for definite diagnosis of multiple primary lung carcinoma. Cancer 2002;94:188–96. 18. Froio E, D’Adda T, Fellegara G, et al. Three different synchronous primary lung tumours: a case report with extensive genetic analysis and review of the literature. Lung Cancer 2008;59:395–402. 19. Orlow I, Park BJ, Mujumdar U, et al. DNA damage and repair capacity in patients with lung cancer: prediction of multiple primary tumors. J Clin Oncol 2008;26:3560–6. 20. Arai J, Tsuchiya T, Oikawa M, et al. Clinical and molecular analysis of synchronous double lung cancers. Lung Cancer 2012;77:281–7. 21. De Leyn P, Moons J, Vansteenkiste J, et al. Survival after resection of synchronous bilateral lung cancer. Eur J Cardiothorac Surg 2008;34:1215–22. 22. Fabian T, Bryant AS, Mouhlas AL, et al. Survival after resection of synchronous non-small cell lung cancer. J Thorac Cardiovasc Surg 2011;142:547–53. 23. Goldstraw P, Crowley J, Chansky K, et al. 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. 24. Boffa DJ, Allen MS, Grab JD, et al. Data from The Society of Thoracic Surgeons general thoracic surgery database: the surgical management of primary lung tumors. J Thorac Cardiovasc Surg 2008;135:247–54. 25. Kozower BD, Sheng S, O’Brien SM, et al. STS database risk models: predictors of mortality and major morbidity for lung cancer resection. Ann Thorac Surg 2010;90:875–81. 26. Flores RM, Park BJ, Dycoco J, et al. Lobectomy by videoassisted thoracic surgery (VATS) versus thoracotomy for lung cancer. J Thorac Cardiovasc Surg 2009;138:11–8. 27. Aziz TM, Saad RA, Glasser J, et al. The management of second primary lung cancers. A single centre experience in 15 years. Eur J Cardiothorac Surg 2002;21:527–33. 28. Lee BE, Port JL, Stiles BM, et al. TNM stage is the most important determinant of survival in metachronous lung cancer. Ann Thorac Surg 2009;88:1100–5. 29. Doddoli C, Thomas P, Ghez O, et al. Surgical management of metachronous bronchial carcinoma. Eur J Cardiothorac Surg 2001;19:899–903.
Surgical Treatment of Metachronous Second Primary Lung Cancer Jie Yang, MD, Ming Liu, MD, Jie Fan, MD, Nan Song, MD, Wen-xin He, MD, Yu-ling Yang, MD, Yan Xia, MD, and Ge-ning Jiang, MD Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Background. Many studies have demonstrated that patients with metachronous second primary lung cancer (MSPLC) benefit from surgery. Owing to the lack of uniform criteria and prospective randomized trials, the extent of resection remains controversial, and prognostic factors are still not fully clear. The present study aimed to assess surgical treatment of MSPLC and identify prognostic factors of outcome. Methods. This retrospective analysis included 143 patients who underwent surgical resection of MSPLC in our department from January 2006 to December 2011. Predictors of postoperative complications were analyzed with the binary logistic regression method. Survival was analyzed with Kaplan-Meier and Cox regression methods. Results. Operative mortality was 1.4%, and the complication rate was 34.3%. Age more than 70 years was an independent risk factor for postoperative complications. The overall 5-year survival after resection of MSPLC was 54.5%. TNM stage II or higher (p [ 0.025),
20 or more pack-years of smoking (p [ 0.037), and tumor size greater than 2 cm (p [ 0.033) were independent negative prognostic factors for survival. For stage I disease, completion pneumonectomy had a lower 5-year survival rate than others, 44.8% and 65.9, respectively (p [ 0.039); lobectomy and sublobar resection have a 5year survival of 77.1% and 56.7%, respectively (p [ 0.203). Conclusions. Surgical treatment of MSPLC is safe and effective. TNM stage I, tumor size 2 cm or less, or less than 20 pack-years smoking are predictors of improved survival. Sublobar resection is acceptable. For stage I disease, lobectomy tends to be associated with better survival than sublobar resection, although the difference is not significant, and completion pneumonectomy is not recommended. Long-term follow-up is necessary even after curative resection of lung cancer.
T
controversial. Moreover, whether TNM stage can perfectly predict the outcome of MSPLC or whether there are any other factors that may significantly affect survival remains to be investigated. The purpose of this study was to assess surgical treatment of MSPLC and to identify factors that may affect short-term and long-term outcomes.
he risk of a metachronous primary lung cancer (MSPLC) developing after complete resection of a first tumor increases as follow-up time extends [1, 2], and the incidence is estimated to be 1% to 2% per patient per year [3, 4]. With the widespread use of accurate follow-up tools such as multislice spiral computed tomography (CT), positron emission tomography (PET), and the better survival results after resection of primary lung cancer, more and more MSPLCs have been detected. Different from metastases, MSPLC are potentially curative if detected at an early stage. For many years it has been demonstrated that surgical treatment is valuable for MSPLC [5], but there are still issues on which surgeons have not reached an agreement, issues mainly focusing on the extent of resection. Anatomic lobar resection has been considered the standard surgical procedure for patients with primary lung cancer [6]. However, there is still paucity of large randomized trials focusing on MSPLC, and the standard surgical approach has not been identified. Whether atypical resection is applicable to MSPLC remains
Accepted for publication May 7, 2014. Address correspondence to Dr Jiang, 507 Zhengmin Rd, Shanghai 200433, China; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2014;98:1192–8) Ó 2014 by The Society of Thoracic Surgeons
Patients and Methods Approval for the study was obtained from the Ethics Committee of the Shanghai Pulmonary Hospital. A retrospective study was conducted analyzing clinical data of 143 patients who underwent surgery for MSPLC after curative resection of initial lung cancer in our department from January 2006 to December 2011. During this period, 6,741 patients underwent pulmonary resection for lung cancer, and this cohort represented an incidence of 2.1% of the overall series. Another 31 patients who were considered to have a second primary cancer but who did not undergo resection were not included in this analysis. The reasons for not undergoing resection were poor lung function in 12 patients, distant metastatic disease in 8 patients, unresectable tumor in 5 patients, severe comorbidity in 3 patients, refusal to undergo surgery in 2 patients, and advanced age in 1 patient. 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.05.050
The criteria for diagnosis of MSPLC were those described by Martini and Melamed [7] in 1975: (1) histology different; or (2) histology the same, if diseasefree interval between cancers was at least 2 years, or origin was from carcinoma in situ, or second cancer in different lobe or lung but no carcinoma in lymphatics common to both, and no extrapulmonary metastases at time of diagnosis. Eight of the 143 patients did not undergo the first resection in our department, and the original pathology slides from the first lung cancer were obtained and reviewed by pathologists at our institute. All patients were restaged according to the seventh edition of the TNM classification of malignant tumors introduced in 2009 [8]. The interval between tumors was calculated from the date of resection of the prior tumor to the date of detection of the second tumor by imaging. Preoperative evaluation included medical history, physical examination, chest and abdomen CT scan, bronchoscopy, whole-body radionuclide bone scanning, brain magnetic resonance imaging, and lung function. Endobronchial ultrasound-guided transbronchial needle aspiration were performed if imaging indicated N2/N3 disease. Positron emission tomography was applied when it was introduced. The surgical resections were performed by either video-assisted thoracoscopic surgery (VATS) or thoracotomy according to the condition of patients and tumors as well as surgeon preference. All VATS procedures performed in this study were complete VATS, using thoracoscopic visualization only and without rib spreading. Thoracotomies were performed through a posterolateral incision. Extent of resection, including lobectomy (including completion pneumonectomy) and sublobar resection (segmentectomy and wedge resection), was decided based on preoperative and intraoperative evaluation. During lobectomy, lymph nodes were systematically dissected when the lesion was invasive or sampled for noninvasive disease. For patients who underwent sublobar resection, node sampling was performed and sometimes only enlarged or PET-positive nodes were dissected. Operative mortality included deaths from all causes occurring within 30 days of surgery or beyond 30 days but during the same hospitalization period. Postoperative complications were graded according to the Common Terminology Criteria for Adverse Events (version 4.03) [9]. The indication for adjuvant therapy was stage IB in high-risk patients or stage II or higher disease. Highrisk patients included those with poorly differentiated tumors, vascular invasion, wedge resection, tumors greater than 4 cm, visceral pleural involvement, and incomplete lymph node sampling [10].
Follow-Up The timing of surveillance for patients who underwent surgical resection of lung cancer in our center was 3 months after surgery, and thereafter at 6-month intervals until 2 years, and then annually. Survival was calculated from the date of the second resection to the date of the last follow-up or death. Follow-up was complete up to
YANG ET AL SURGICAL TREATMENT OF MSPLC
1193
December 31, 2013. History, physical examination, chest CT, and abdominal ultrasonography were routine examinations in each follow-up visit after 3 months from the date of surgery. Bone scan, brain magnetic resonance imaging, or PET were performed whenever there were indications of distant metastases.
Statistical Analysis Comparative analysis to identify differences was performed with the c2 test or Fisher’s exact test on categorical variables, and Student’s t test or Mann-Whitney U test on continuous variables. Complications were assessed by binary logistic regression. Survival was assessed by the Kaplan-Meier method and log rank test. Cox regression analysis was used to investigate the predictors of long-term survival. Factors analyzed included patient sex, age, comorbidities, smoking history, tumorfree interval, pulmonary function, tumor size, tumor number, ipsilateral or contralateral, surgical approach (VATS versus thoracotomy), extent of resection (lobectomy versus sublobar resection), estimated blood loss, systematic lymph node dissection or sampling, TNM stage, lymph node status, and histology of second primary lung cancer. Variables considered in the multivariate analysis were those with a p value of 0.15 or less in the univariate assessments. A p value of less than 0.05 was considered statistically significant. All statistical analysis was performed with IBM SPSS version 16.0 for Windows (IBM Corporation, Armonk, NY).
Results Patient Characteristics The median age of patients at second intervention was 60 years (range, 35 to 81), with a median tumor-free interval of 34 months (range, 3 to 186). The median size of a second tumor was 2.2 cm (range, 0.3 to 8.5 cm). Table 1 summarizes patient characteristics and clinical data of the first lung cancer. Perioperative findings of the second intervention are shown in Table 2.
Complications and Mortality There were 2 operative deaths (1.4%) in this series, due to respiratory failure (right upper lobectomy for the first tumor, right completion pneumonectomy for the second) and pulmonary embolism (left lower lobe lobectomy for the first tumor, right middle and lower bilobectomy for the second). A total of 54 postoperative complications occurred in 49 patients (34.3%; Table 3). Fourteen patients (9.8%) had grade 3 or higher complications. Univariate analysis revealed that thoracotomy (p ¼ 0.034), completion pneumonectomy (p ¼ 0.005), age more than 70 years (p ¼ 0.024), estimated blood loss greater than 1,000 mL (p ¼ 0.017), and reoperative ipsilateral surgery (p ¼ 0.010) were associated with an increased risk of postoperative complications. In multivariate analysis, age more than 70 years (odds ratio 3.444, 95% confidence interval: 1.318 to 9.002; p ¼ 0.012) was
GENERAL THORACIC
Ann Thorac Surg 2014;98:1192–8
GENERAL THORACIC
1194
YANG ET AL SURGICAL TREATMENT OF MSPLC
Ann Thorac Surg 2014;98:1192–8
Table 1. Patient Characteristics and Clinical Data of First Lung Cancer Variables Sex Male Female Pack-years of smoking 20 2 cm (dotted line); (C) pack-years of smoking 2 cm CI ¼ confidence interval.
Odds Ratio
95% CI
p Value
2.019 1.798 1.935
1.092–3.734 1.019–3.174 1.054–3.554
0.025 0.037 0.033
[7] in 1975. Using this criteria, a MSPLC incidence of 2.1% is similar to that reported by other studies [2,14]. The American College of Chest Physicians lung cancer guidelines set up new criteria in which the interval between tumors with similar histology extended to 4 years [15]. Although no interval limit is mentioned in the Mayo Clinic criteria, a metachronous carcinoma with similar histology was considered primary when the new lesion was solitary and occurred outside the area anatomically contiguous to the previous lung cancer and its regional lymphatics, with no evidence of extrathoracic lung cancer [16]. Many molecular techniques have also been successfully used to distinguish MPSLC from metastasis, such as p53 mutation analysis [17], patterns of loss of heterozygosity of multiple chromosomal loci [18], comet assay for DNA damage [19], and genomic alteration using array comparative genomic hybridization [20], but none of these has been widely used clinically. A more definitive diagnosis may be possible based on routine performance of molecular analysis in the future.
Fig 3. Survival of patients with stage I metachronous second primary lung cancer based on extent of resection: (A) noncompletion pneumonectomy (solid line) and completion pneumonectomy (dotted line); and (B) lobectomy (solid line) and sublobar resection (dotted line).
Whichever criteria or methods are used, the distinction between a new primary lung cancer and recurrence of the original tumor is not as important as determining whether the tumor can be treated with curative intent [7]. If extrapulmonary metastases can be excluded and the patient can tolerate the procedure, we believe surgery should be considered, as most thoracic surgeon [2, 14, 16, 21, 22] recommend, because surgical resection remains the most effective treatment for patients with non-small cell lung cancer [23]. As to the safety of surgery, there were only 2 operative deaths (1.4%) in this series, 1 each after completion pneumonectomy and bilobectomy. Postoperative complications occurred in 34.3% of patients, and 9.8% of patients had grade 3 or higher complications, similar to the results of two Society of Thoracic Surgeons general thoracic database studies, in which 9,033 and 18,800 lung resections were involved, respectively [24, 25]. Hamaji and colleagues [16] of the Mayo Clinic retrospectively analyzed 161
YANG ET AL SURGICAL TREATMENT OF MSPLC
1197
resections of MSPLC, and their data showed that ipsilateral operation and a lower FEV1% were predictors of a higher risk of postoperative complications. In our study, age more than 70 years was the only predictor of postoperative complications in multivariate analysis. Regarding surgical approach, VATS was associated with less risk of postoperative complications, as another study has confirmed [26]. But we must confess that 33 of the 39 patients who underwent VATS had contralateral lung cancer. Surgeons should be prudent in choosing VATS for patients who will undergo ipsilateral reoperation because of a higher risk of pleural adhesions, which may make it too difficult to perform the procedure. A lower FEV1% was not associated with complications in this series, perhaps because all these patients underwent sublobar resection for a second tumor. In this study, we have shown a 5-year survival of 54.5% after resection of MSPLC, which is far better than what would be expected for metastases or local recurrences. In addition, several factors were identified as having a significant effect on survival. TNM stage is the most widely accepted predictor of survival for primary lung cancer. Some studies have revealed that survival after resection of MSPLC is associated with TNM stage [5, 27, 28], whereas others have not mentioned or have failed to find significant differences in survival based on TNM stage [2, 14, 16]. Our study confirms that TNM stage is an important determinant of survival of patients with MSPLC. Furthermore, it is very interesting that tumor size was as significant a predictor as stage in this series. A reasonable explanation is that 43 patients were pathologically NX, and some of them may have been understaged based on clinical staging. The importance of this finding is that tumor size can be a valuable predictor for survival, especially when pathologic node staging is not available. The significant effects of tumor size and packyears of smoking on survival were supported by the study of Hamaji and associates [16], although different diagnostic criteria of MSPLC were used. Regarding the extent of resection, some surgeons reported that sublobar resection is acceptable for MSPLC [2, 16], whereas others consider that anatomic resection is favorable [14, 29]. In our center, the extent of resection is based on the balance of risk and benefit of surgery, and many factors should be considered before determination, including age, pulmonary function, tumor condition, pleural condition, and any other factors that may affect the outcome. Pulmonary function is a very important prognostic factor of lung resection, and preservation of pulmonary reserve should be considered at the time of the first tumor resection, because all patients have a probability of second primary lung cancer developing [2]. According to our current data, sublobar resection is acceptable for the treatment of MSPLC, with a satisfactory survival rate. For stage I disease, which accounts for the majority of MSPLC, lobectomy tends to have better survival than sublobar resection, but the difference is not significant. Completion pneumonectomy is not recommended for patients with stage I MSPLC because of higher risk of complications and the negative effect on long-term survival.
GENERAL THORACIC
Ann Thorac Surg 2014;98:1192–8
GENERAL THORACIC
1198
YANG ET AL SURGICAL TREATMENT OF MSPLC
Many studies have concluded that close long-term follow-up is necessary for patients who have undergone resection of lung cancer [2, 5, 16]. We also recommend long-term follow-up as 22.4% of MSPLC in our series developed more than 5 years after first resection and 15.7%, after more than 10 years. Computed tomography scan is preferred during surveillance for early detection of MSPLC, as the National Cancer Comprehensive Network guideline suggests [10]. There are several limitations of this study. First of all, owing to the retrospective nature of the study and lack of randomization, there is certainly a degree of bias in patient selection and surgeon experience. Second, the characteristics and surgical treatment of the initial lung cancer can also affect patients’ survival, especially for patients with a shorter interval between metachronous tumors, leading to potential bias as well. In conclusion, surgical treatment of MSPLC is safe and offers a good long-term outcome. TNM stage I, tumor size 2 cm or less, and less than 20 pack-years smoking are predictors of improved survival. Sublobar resection is acceptable for the treatment of MSPLC, with a satisfactory survival rate. For stage I disease, lobectomy tends to be associated with better survival than sublobar resection, although the difference is not significant, and completion pneumonectomy is not recommended because of the higher risk of complications and shorter survival. Longterm follow-up is necessary even for patients who have undergone curative surgical resection of lung cancer. Randomized, controlled, and multicenter studies are needed to confirm these findings.
References 1. Thomas PA, Rubinstein L. Malignant disease appearing late after operation for T1 N0 non-small-cell lung cancer. The Lung Cancer Study Group. J Thorac Cardiovasc Surg 1993;106:1053–8. 2. Bae MK, Byun CS, Lee CY, et al. The role of surgical treatment in second primary lung cancer. Ann Thorac Surg 2011;92:256–62. 3. Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335–45. 4. Rubins J, Unger M, Colice GL. Follow-up and surveillance of the lung cancer patient following curative intent therapy: ACCP evidence-based clinical practice guideline (2nd edition). Chest 2007;132(Suppl):355–67. 5. Rosengart TK, Martini N, Ghosn P, et al. Multiple primary lung carcinomas: prognosis and treatment. Ann Thorac Surg 1991;52:773–8. 6. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615–22. 7. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975;70:606–12. 8. Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest 2009;136:260–71. 9. The common terminology criteria for adverse events (CTCAE version 4.03). Available at: http://evs.nci.nih.gov/ ftp1/ctcae/about.html. Accessed February 13, 2014.
Ann Thorac Surg 2014;98:1192–8
10. National Cancer Comprehensive Network. 2013 NCCN guidelines version 2.2013, non-small cell lung cancer. Available at: http://www.nccn.org/professionals/physician_gls/f_ guidelines.asp#nscl. Accessed February 13, 2014. 11. Beyreuther H. [Multipicate von carcinomen bei einem fall von sog: “Schneeberger” lungenkrebs mit tuberculose.] Virchows Arch Pathol Anat 1924;250:230–6. 12. Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 2003;63: 1727–30. 13. Colice GL, Rubins J, Unger M. Follow-up and surveillance of the lung cancer patient following curative-intent therapy. Chest 2003;123(Suppl):272–83. 14. Zuin A, Andriolo LG, Marulli G, et al. Is lobectomy really more effective than sublobar resection in the surgical treatment of second primary lung cancer? Eur J Cardiothorac Surg 2013;44:e120–5. 15. Detterbeck FC, Jones DR, Kernstine KH, et al. Lung cancer. Special treatment issues. Chest 2003;123(Suppl): 244–58. 16. Hamaji M, Allen MS, Cassivi SD, et al. Surgical treatment of metachronous second primary lung cancer after complete resection of non-small cell lung cancer. J Thorac Cardiovasc Surg 2013;145:683–90. 17. van Rens MT, Eijken EJ, Elbers JR, et al. p53 mutation analysis for definite diagnosis of multiple primary lung carcinoma. Cancer 2002;94:188–96. 18. Froio E, D’Adda T, Fellegara G, et al. Three different synchronous primary lung tumours: a case report with extensive genetic analysis and review of the literature. Lung Cancer 2008;59:395–402. 19. Orlow I, Park BJ, Mujumdar U, et al. DNA damage and repair capacity in patients with lung cancer: prediction of multiple primary tumors. J Clin Oncol 2008;26:3560–6. 20. Arai J, Tsuchiya T, Oikawa M, et al. Clinical and molecular analysis of synchronous double lung cancers. Lung Cancer 2012;77:281–7. 21. De Leyn P, Moons J, Vansteenkiste J, et al. Survival after resection of synchronous bilateral lung cancer. Eur J Cardiothorac Surg 2008;34:1215–22. 22. Fabian T, Bryant AS, Mouhlas AL, et al. Survival after resection of synchronous non-small cell lung cancer. J Thorac Cardiovasc Surg 2011;142:547–53. 23. Goldstraw P, Crowley J, Chansky K, et al. 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. 24. Boffa DJ, Allen MS, Grab JD, et al. Data from The Society of Thoracic Surgeons general thoracic surgery database: the surgical management of primary lung tumors. J Thorac Cardiovasc Surg 2008;135:247–54. 25. Kozower BD, Sheng S, O’Brien SM, et al. STS database risk models: predictors of mortality and major morbidity for lung cancer resection. Ann Thorac Surg 2010;90:875–81. 26. Flores RM, Park BJ, Dycoco J, et al. Lobectomy by videoassisted thoracic surgery (VATS) versus thoracotomy for lung cancer. J Thorac Cardiovasc Surg 2009;138:11–8. 27. Aziz TM, Saad RA, Glasser J, et al. The management of second primary lung cancers. A single centre experience in 15 years. Eur J Cardiothorac Surg 2002;21:527–33. 28. Lee BE, Port JL, Stiles BM, et al. TNM stage is the most important determinant of survival in metachronous lung cancer. Ann Thorac Surg 2009;88:1100–5. 29. Doddoli C, Thomas P, Ghez O, et al. Surgical management of metachronous bronchial carcinoma. Eur J Cardiothorac Surg 2001;19:899–903.
