|Year : 2017 | Volume
| Issue : 4 | Page : 702-706
Surgical treatment is an effective approach for patients with synchronous multiple primary lung cancers
Yue Peng, Wangang Ren, Hui Wang, Meng Li, Zhen Feng, Zhongmin Peng
Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, P. R. China
|Date of Web Publication||13-Sep-2017|
Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province
P. R. China
Source of Support: None, Conflict of Interest: None
Objective: The detection rate of synchronous multiple primary lung cancers (SMPLC) showed an increasing trend year by year. In an attempt to identify the optimal treatment strategy for SMPLC, we retrospectively analyzed our surgical treatment outcomes of a series of patients with SMPLC.
Materials and Methods: A total of 43 SMPLC patients who met the modified Martini-Melamed criteria and with clinical data retained between November 2012 and July 2016 underwent complete resection without any preoperative induction therapy at the Department of Thoracic Surgery, Shandong Provincial Hospital. The relationships between gender, age, family history of cancer, the number of tumors, the location of tumors, tumor size, tumor histology, regional lymph node metastasis, type of surgery, pathological stage, epidermal growth factor receptor (EGFR) mutation, mortality, and survival were further analyzed.
Results: Among the 43 patients, 29 (67.4%) patients had ipsilateral tumors, whereas 14 (32.6%) patients had contralateral tumors. Nine patients with contralateral tumors underwent one-stage surgical treatment, with mean postoperative hospitalization days of 9.8. EGFR mutations were detected in 5 patients with synchronous multiple primary lung adenocarcinomas (SMPLA) for each lesion independently. The results showed different tumors in the same patient could carry different EGFR mutations. The 1- and 3-year overall survival (OS) rates were 97.0% and 76.7%, respectively. Larger maximal tumor dimension (P = 0.015), advanced pN stage (P = 0.002), advanced pT stage (P = 0.046), advanced TNM stage (P = 0.013), and postoperative adjuvant chemotherapy (P = 0.025) were correlated with poor OS.
Conclusions: SMPLC could be considered to be a local disease rather than the systemic disease. Surgical treatment is an effective approach for patients with SMPLC. Mutational status of EGFR could be used as a diagnostic criterion, especially in patients with SMPLA.
Keywords: Epidermal growth factor receptor, lung cancer, synchronous multiple primary lung cancers
|How to cite this article:|
Peng Y, Ren W, Wang H, Li M, Feng Z, Peng Z. Surgical treatment is an effective approach for patients with synchronous multiple primary lung cancers. J Can Res Ther 2017;13:702-6
|How to cite this URL:|
Peng Y, Ren W, Wang H, Li M, Feng Z, Peng Z. Surgical treatment is an effective approach for patients with synchronous multiple primary lung cancers. J Can Res Ther [serial online] 2017 [cited 2018 Nov 16];13:702-6. Available from: http://www.cancerjournal.net/text.asp?2017/13/4/702/214463
Yue Peng and Wangang Ren contributed equally to this work.
| > Introduction|| |
With the development of detection technique such as computed tomography (CT), positron emission tomography (PET) scan, the detection rate of multiple primary lung cancers (MPLC) showed an increasing trend year by year. It is reported in recent years 0.2%–8.0% of patients who underwent surgical treatment with nonsmall lung cancers were finally diagnosed as MPLC.,,, MPLC consists of synchronous MPLC (SMPLC) and metachronous MPLC.
It was in 1924 that MPLC was first reported by Beyreuther. Then in 1975, Martini and Melamed set the first diagnostic criteria for MPLC. The diagnostic criteria can help us differentiate MPLC from intrapulmonary metastases. The American College of Chest Physicians (ACCP) made supplement and revision for the criteria of Martini-Melamed. The molecular genetic diagnosis was first introduced to identify multiple lesions with the same pathological type in 2003. In the past 92 years, nevertheless, none of the Union for International Cancer Control (UICC), American Joint Committee on Cancer (AJCC), National Comprehensive Cancer Network (NCCN), ACCP, and International Association for the Study of Lung Cancer (IASLC) has made treatment standard for MPLC.
However, the 7th (2009) and 8th (2015) edition TNM classification for lung cancer still classified separate tumor nodules in the same lobe as T3, in the ipsilateral lung but different lobes as T4 and in the contralateral lung as M1a., In these classifications, multiple nodules were still treated as intrapulmonary metastases or recurrence. Thus, many patients with MPLC were over staged as III/IV stage and finally lost the opportunity to undergo surgical treatment. These patients could only receive palliative therapy such as radiotherapy and chemotherapy. In this study, we retrospectively studied the surgical treatment outcome of 43 patients with SMPLC, in an attempt to identify the optimal treatment strategy for SMPLC.
| > Materials and Methods|| |
Between November 2012 and July 2016, 43 patients with clinical data retained at present underwent complete resection without any preoperative induction therapy for SMPLC at the Department of Thoracic Surgery, Shandong Provincial Hospital. All patients met the modified criteria of Martini and Melamed for the diagnosis of SMPLC:, (1) tumors with different histology; (2) tumors with different histologic subtypes (such as ratio of acinar and papillary percentage for adenocarcinomas [ADC]); (3) tumors with similar histology arising from separate carcinoma in situ (such as different segment, lobe, or lung), with no carcinoma at the common lymphatic drainage site, with no extrapulmonary metastases and (4) Tumors with different molecular genetic characteristics. Informed consent was obtained from all individual participants included in the study.
All lung cancer patients in our hospital underwent a series of preoperative routine checkup for clinical stages, including chest X-rays, thoracic CT, cranial magnetic resonance image (MRI) or CT, bone scintigraphy, abdominal ultrasonography, cardiac ultrasonography, and pulmonary function test. Some patients underwent PET/CT scan. According to each patient's clinical stage, location of all lesions, preoperative comorbidities, cardiopulmonary function, and estimated postoperative pulmonary function test, we evaluate the tolerance levels of operation for each patient and make final surgical treatment strategy.
Our basic surgical treatment strategy: (1) Maximum resection of tumors and maximum reservation of health lung tissue; (2) The main lesion (central lung cancer or tumor with the highest TNM stage) should be resected first; (3) All tumors in ipsilateral chest, single-stage surgical procedures should be performed if possible; (4) For tumors in contralateral lung, we performed single-stage or two-stage pulmonary resection, which is decided by the tolerance levels of patients. Our surgical procedures include lobectomy, sublobectomy (segmentectomy or wedge resection), and pneumonectomy. The surgical approaches include thoracotomy and video-assisted thoracoscopic surgery (VATS). Some patients select thoracotomy because they cannot afford the expense of VATS.
Postoperative pathological stages
According to postoperative histopathological examinations, we staged every lesion independently using the 8th edition TNM classification for each patient. Each tumor was staged. We considered the most advanced disease stage of all tumors as the patient's disease stage.
After surgery, outpatient follow-up was conducted once every 3 months during the first 2 years, every 6 months during the following 3 years and once every year 5 years later. Outpatient follow-up visits included recording of symptoms and findings of examinations such as thoracic CT, tumor marker, abdominal ultrasonography, cranial MRI, and bone scintigraphy, if necessary.
Overall survival (OS) was defined as the time from initial surgery to death or the last follow-up. Disease-free survival (DFS) was defined as the time from initial surgery to the date of death or recurrence or distant metastases or the last follow-up. The last follow-up checkpoint was November 15, 2016. The Kaplan–Meier method was used to estimate survival, with the log-rank test to determine significance. Cox proportional hazard model was used to estimate the treatment effect with adjustment for prognostic factors for survival. The value of P < 0.05 was considered statistically significant.
| > Results|| |
The overall demographic characteristics of the 43 SMPLC patients are shown in [Table 1]. Among the 43 patients, 17 (39.5%) were man and 26 (60.5%) were woman. The median age was 58 years (range from 39 to 76). There were 12 (27.9%) smokers, and 31 (72.1%) patients never smoked. Seven (16.3%) patients had a family history of cancer.
|Table 1: Univariate analysis of prognostic factors related to overall survival and disease-free survival of the 43 synchronous multiple primary lung cancer patients|
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Surgical and pathological details are summarized in [Table 2]. Surgical treatment was successfully performed in all the 43 SMPLC patients with no mortality. Twenty-nine (67.4%) patients underwent VATS and 12 (27.9%) patients through thoracotomy. The other 2 (4.7%) patients underwent VATS for one side and thoracotomy for another side. Thirty-eight (88.4%) patients (including 9 patients with contralateral tumors) underwent single-stage surgical treatment, whereas the other 5 (11.6%) patients underwent two-stage surgical treatment.
|Table 2: Surgical managements and pathological details of 43 synchronous multiple primary lung cancer patients|
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Tumor characteristics and postoperative pathology
Among the 43 SMPLC patients, 101 tumors were found and resected through surgical operations. There were 34 (79.1%) patients with 2 tumors, 5 (11.6%) patients with 3 tumors, 2 (4.7%) patients with 4 tumors, and 2 (4.7%) patients with 5 tumors. A total of 29 (67.4%) patients had ipsilateral tumors, whereas the other 14 (32.6%) patients had contralateral tumors. The median size of the maximum diameter of the tumors in each patient was 2.5 cm (range, 1.3–5 cm). Multiple ADC were present in 38 (88.4%) patients.
The TNM stage is detailed in [Table 1]. Among the 43 patients, 22 patients underwent gene detection, including 17 patients detecting for main cancer only and 5 patients for each lesion independently [Table 3]. The results showed different tumors in the same patient could carry different epidermal growth factor receptor (EGFR) mutations. Twenty (46.5%) patients underwent adjuvant therapy in which 15 patients underwent 4–6 cycles of platinum-based adjuvant chemotherapy and 5 patients select only target therapy.
|Table 3: Mutational status of epidermal growth factor receptor in 5 patients detected for each lesion independently|
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The median follow-up duration was 22.3 months (range from 4 to 47.9 months). The follow-up rate was 95.3%. The 1- and 3-year OS rates were 97.0% and 76.7%, respectively, whereas the 1-year and 3 years DFS rate were 92.1% and 57.9%, respectively.
[Table 1] shows the results of univariate analysis of prognostic factors related to OS and DFS of the 43 SMPLC patients. Larger maximal tumor dimension (P = 0.015), advanced pN stage (P = 0.002), advanced pT stage (P = 0.046), advanced TNM stage (P = 0.013), and postoperative adjuvant chemotherapy (P = 0.025) were correlated with poor OS, whereas larger maximal tumor dimension (P = 0.002), not all ADC histologic type (P = 0.002), advanced pT stage (P = 0.025) and postoperative adjuvant chemotherapy (P = 0.027) were correlated with poor DFS. Independent prognostic predictors for DFS and OS cannot be identified in the multivariable analysis. [Figure 1] shows the overall survival of the 43 SMPLC patients according to TNM stage.
|Figure 1: Overall survival of the 43 SMPLC patients according to TNM stage (8th edition)|
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| > Discussion|| |
There are no systematic and authoritative treatment guidelines for SMPLC. However, for MPLC patients with high risk of becoming symptomatic, lymph nodes staged pN0 or pN1, and without metastasis out chest, parenchymal sparing resections are preferred, if definitive local therapy is possible. Surgery should keep the rule of maximum resection of tumors and minimum resection of normal lung tissue. A large number of patients with MPLC were over staged as II/III/IV stage. Among them, many patients even lost the opportunity to undergo surgical treatment. In previous studies for SMPLC, the 3- and 5-year OS rates were ranged from 40.0% to 92.0%,,, and 34%–77.6%,,,,,,,, which are much better than recurrence or distant metastases cancers. In this study, the 1- and 3-year OS rate were 100% and 76.7%, whereas the 1- and 3-year DFS rate were 92.1% and 57.9%, respectively.
Previous publications reported pneumonectomy should be avoided as far as possible given the poor prognosis.,, However, in our study, a 76-year-old patient with one central lung cancer of squamous cell carcinoma in the right upper lobe and one peripheral lung cancer of ADC in the right lower lobe underwent pneumonectomy. Recurrence occurred 24 months later, and the patient died 47.1 months after surgery. The value of pneumonectomy for SMPLC patients need further study. In previous reports, for patients with tumors in the contralateral lung, separate or delayed resections are much safer than one-stage surgical operation. In this study, 9 patients with contralateral tumors underwent one-stage surgical treatment through bilateral thoracotomy. The mean postoperative hospitalization days was 9.8 (range from 8 to 12 days) which was longer than patients underwent surgeries in the ipsilateral lung (average 8.5 days, range from 3 to 14 days), but there is no statistical difference between the two group (P = 0.865). On the basis of our experience, single-stage surgical treatment can be considered for high selected patients with contralateral tumors.
For surgical treatment outcomes in our study, patients with all lesions of ADC had favorable DFS, whereas advanced pT stage, larger maximal tumor dimension, and lymph nodes metastases were correlated with poor OS and DFS. Several studies have shown the similar results.,,,, We also found that tumor numbers and location, gender, smoking status, family history were not significantly correlated with OS and DFS. However, Zhang et al. reported that female gender, family history of cancer, tumors in contralateral lung correlated with better survival., One possible explanation is because of the difference sample size among these studies.
Adjuvant therapy for SMPLC is controversial at present. Some studies suggested that adjuvant chemotherapy could improve prognosis. However in these studies, the majority of patients had lymph node metastases., Opposite trend was present in our study. Fifteen patients underwent postoperative adjuvant chemotherapy had a worse prognosis than the other 28 patients without chemotherapy. A possible explanation is because these 15 patients had advanced TNM stages.
According to the NCCN guideline, patients with lung ADC should undergo gene detection, such as EGFR and ALK. In our experience, SMPLC with different gene mutation status could be regarded as multiple primary. In our study, 5 patients underwent gene detection for every lesion independently. The results of the 5 patients showed different tumors in the same patient could carry different EGFR mutations. Mutational status of EGFR may be used as a diagnostic criterion especially in patients with ADC. However recently, Gerlinger et al. found that intratumoral heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. In patients with SMPLC, tissues are from different tumor lesions and tumor heterogeneity can also be present. Chen et al. reported that the overall discordance rate of EGFR mutation heterogeneity in Asian patients multiple pulmonary nodules are significantly higher. Hence, it is worth discussing when using mutational status of EGFR to distinguish synchronous multiple primary lung adenocarcinomas (SMPLA) from intrapulmonary metastases.
Finally, our study had several limitations. First, the sample size was too small, and the patient selection was biased because this was a single-center, retrospective study. Second, we did not compare patients with SMPLC who underwent surgery with patients who only received chemotherapy, radiotherapy, or palliative therapy. Finally, EGFR mutation was not assessed in all patients at the diagnosis of multiple primary lung ADC.
| > Conclusions|| |
On the basis of our experience, SMPLC could be considered as a local disease rather than the systemic disease. Surgical treatment is an effective approach for patients with SMPLC. Mutational status of EGFR could be used as a diagnostic criterion, especially in patients with SMPLA.
This work was supported financially by Science and Technology Progress Project of Shandong Province (Grant 2012GSF11826).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Takamochi K, Oh S, Matsuoka J, Suzuki K. Clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras. Lung Cancer 2012;75:313-20.
Gazdar AF, Minna JD. Multifocal lung cancers – Clonality vs. field cancerization and does it matter? J Natl Cancer Inst 2009;101:541-3.
Girard N, Ostrovnaya I, Lau C, Park B, Ladanyi M, Finley D, et al.
Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. Clin Cancer Res 2009;15:5184-90.
Warth A, Macher-Goeppinger S, Muley T, Thomas M, Hoffmann H, Schnabel PA, et al.
Clonality of multifocal nonsmall cell lung cancer: Implications for staging and therapy. Eur Respir J 2012;39:1437-42.
Yu YC, Hsu PK, Yeh YC, Huang CS, Hsieh CC, Chou TY, et al.
Surgical results of synchronous multiple primary lung cancers: Similar to the stage-matched solitary primary lung cancers? Ann Thorac Surg 2013;96:1966-74.
Beyreuther H. Multiplicität von carcinomen bei einem fall von sog.“schneeberger” lungenkrebs mit tuberkulose. Virchows Archiv 1924;250:230-43.
Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975;70:606-12.
Detterbeck FC, Jones DR, Kernstine KH, Naunheim KS. Special treatment issues[J]. Chest 2003;123(1):244S-58S.
Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, 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.
Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, et al.
The IASLC Lung Cancer Staging Project: Proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol 2016;11:39-51.
Kozower BD, Larner JM, Detterbeck FC, Jones DR. Special treatment issues in non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd
ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143 5 Suppl: e369S-99S.
Fabian T, Bryant AS, Mouhlas AL, Federico JA, Cerfolio RJ. Survival after resection of synchronous non-small cell lung cancer. J Thorac Cardiovasc Surg 2011;142:547-53.
Dai L, Yang HL, Yan WP, Liang Z, Xiong HC, Kang XZ, et al.
The equivalent efficacy of multiple operations for multiple primary lung cancer and a single operation for single primary lung cancer. J Thorac Dis 2016;8:855-61.
Ishikawa Y, Nakayama H, Ito H, Yokose T, Tsuboi M, Nishii T, et al.
Surgical treatment for synchronous primary lung adenocarcinomas. Ann Thorac Surg 2014;98:1983-8.
Chang YL, Wu CT, Lee YC. Surgical treatment of synchronous multiple primary lung cancers: Experience of 92 patients. J Thorac Cardiovasc Surg 2007;134:630-7.
Trousse D, Barlesi F, Loundou A, Tasei AM, Doddoli C, Giudicelli R, et al.
Synchronous multiple primary lung cancer: An increasing clinical occurrence requiring multidisciplinary management. J Thorac Cardiovasc Surg 2007;133:1193-200.
Zhang Z, Gao S, Mao Y, Mu J, Xue Q, Feng X, et al.
Surgical outcomes of synchronous multiple primary non-small cell lung cancers. Sci Rep 2016;6:23252.
Kocaturk CI, Gunluoglu MZ, Cansever L, Demir A, Cinar U, Dincer SI, et al.
Survival and prognostic factors in surgically resected synchronous multiple primary lung cancers. Eur J Cardiothorac Surg 2011;39:160-6.
Jung EJ, Lee JH, Jeon K, Koh WJ, Suh GY, Chung MP, et al.
Treatment outcomes for patients with synchronous multiple primary non-small cell lung cancer. Lung Cancer 2011;73:237-42.
Liu M, He W, Yang J, Jiang G. Surgical treatment of synchronous multiple primary lung cancers: A retrospective analysis of 122 patients. J Thorac Dis 2016;8:1197-204.
Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al.
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883-892.
Chen ZY, Zhong WZ, Zhang XC, Su J, Yang XN, Chen ZH, et al.
EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas. Oncologist 2012;17:978-85.
[Table 1], [Table 2], [Table 3]