Surgical treatment of primary lung cancer with synchronous brain metastases

OBJECTIVES: The role of surgical resection for brain metastases from non-small cell lung cancer is evolving. Although resection of primary lung cancer and metachronous brain metastases is superior to other treatment modalities in prolonging survival and disease-free interval, resection of the primary non-small cell lung cancer and synchronous brain metastases is controversial. METHODS: From January 1975 to December 1997, 220 patients underwent surgical treatment for brain metastases from non-small cell lung cancer at our institution. Twenty-eight (12.7%) of these patients underwent surgical resection of synchronous brain metastases and the primary non-small cell lung cancer. RESULTS: The group comprised 18 men and 10 women. Median age was 57 years (range 35-71 years). Twenty-two (78.6%) patients had neurologic symptoms. Craniotomy was performed first in all 28 patients. Median time between craniotomy and thoracotomy was 14 days (range 4-840 days). Pneumonectomy was performed in 4 patients, bilobectomy in 4, lobectomy in 18, and wedge excision in 2. Postoperative complications developed in 6 (21.4%) patients. Cell type was adenocarcinoma in 11 patients, squamous cell carcinoma in 9, and large cell carcinoma in 8. After pulmonary resection, 17 patients had no evidence of lymph node metastases (N0), 5 had hilar metastases (N1), and 6 had mediastinal metastases (N2). Twenty-four (85.7%) patients received postoperative adjuvant therapy. Follow-up was complete in all patients for a median of 24 months (range 2-104 months). Median survival was 24 months (range 2-104). Survival at 1, 2, and 5 years was 64.3%, 54.0%, and 21.4%, respectively. The presence of thoracic lymph node metastases (N1 or N2) significantly affected 5-year survival (P =.001). CONCLUSION: Although the overall survival for patients who have brain metastases from non-small cell lung cancer is poor, surgical resection may prove beneficial in a select group of patients with synchronous brain metastases and lung cancer without lymph node metastases.     

A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209)

OBJECTIVE: We performed a prospective randomized trial in patients with potentially resectable stage IIIA N2 non-small cell lung cancer to confirm the efficacy of induction chemotherapy before surgical resection. METHODS: Patients with stage IIIA N2 non-small cell lung cancer, all with histologically or cytologically confirmed metastases to the ipsilateral mediastinal lymph nodes, were randomly assigned to receive either three cycles of induction chemotherapy (cisplatin at 80 mg/m(2) on 1 day and vindesine at 3 mg/m(2) on 2 days) followed by surgery or surgery alone. RESULTS: This trial was prematurely terminated because the accrual rate was too slow, which lowered the study's statistical power considerably. From June 1993 through April 1998, a total of 62 patients were enrolled, and 31 patients were assigned to each treatment group. The objective clinical response rate of induction chemotherapy was 28%. Complete resection was achieved in 20 patients in the induction chemotherapy group (65%) and 24 in the surgery alone group (77%). Median follow-up was 6.2 years. Median overall survivals were 17 months for the induction group and 16 months for the surgery alone group. The estimated 1-, 3-, and 5-year survivals, respectively, were 68% (95% confidence interval 51%-85%), 23% (95% confidence interval 8%-38%), and 10% (95% confidence interval 0%-20%) for the induction chemotherapy group and 65% (95% confidence interval 48%-82%), 26% (95% confidence interval 11%-41%), and 22% (95% confidence interval 7%-37%) for the surgery alone group. There was no statistically significant difference in survival between the groups (P =.5274). Treatment-related death was not observed in either group. CONCLUSION: This randomized trial to compare induction chemotherapy (cisplatin and vindesine) followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer did not demonstrate a survival difference between the groups, although this may have been because the statistical power was limited.     

Results of surgical intervention for p-stage IIIA (N2) non-small cell lung cancer: acceptable prognosis predicted by complete resection in patients with single N2 disease with primary tumor in the upper lobe

OBJECTIVES: Non-small cell lung cancer with mediastinal lymph node involvement is a heterogeneous entity different from single mediastinal lymph node metastasis to multiple nodes or extranodal disease. The objective of this study was to identify the subpopulation of patients with N2 disease who can benefit from surgical intervention. METHODS: We reviewed 219 consecutive patients with N2 non-small cell lung cancer treated with a thoracotomy between November 1980 and June 2002 and retrospectively analyzed 154 of those who had p-stage IIIA disease and underwent a complete resection. Age, sex, side (right or left), histology, location (upper or middle-lower lobe), tumor size, c-N factor, and N2 level (single or multiple) were used as prognostic variables. RESULTS: The 3- and 5-year survivals were 45.3% and 28.1%, respectively, in patients with p-stage IIIA (N2) disease. Survival for those with single N2 non-small cell lung cancer was significantly better than in those with multiple N2 disease (P =.0001), and patients with a tumor in the upper lobe showed a significantly longer survival than those with middle-lower lobe involvement (P =.0467). The 3- and 5-year survivals for patients with single N2 disease with a primary tumor in the upper lobe were 74.9% and 53.5%, respectively. A multivariate analysis with Cox regression identified 5 predictors of better prognosis: younger age, squamous cell carcinoma as determined by histology, primary tumor location in the upper lobe, c-N0 status, and a single station of mediastinal node metastasis. CONCLUSION: Our results suggest that of the heterogeneity of N2 diseases, patients with single N2 disease with non-small cell lung cancer in the upper lobe are good candidates for pulmonary resection.     

ⅢA-N2期非小细胞肺癌纵隔淋巴结跳跃式转移的临床和预后分析

目的 探讨ⅢA-N2期非小细胞肺癌(NSCLC)纵隔淋巴结跳跃式转移的临床病理特征和分布规律,并分析跳跃转移对生存期的影响.方法 回顾性分析2000年1月至2004年12月478例行手术并经病理证实的ⅢA-N2期非小细胞肺癌患者的临床资料,分为跳跃转移组和非跳跃转移组,分析两组的临床病理特征,N2分布情况以及对生存期的影响并进行统计学分析.结果 全组N2跳跃转移的发生率为40.6%,与性别和吸烟情况有关(χ2=5.340,p=0.021和χ2=7.143,P=0.008),且鳞状细胞癌易发生跳跃转移(χ2=7.602,P=0.022),上叶较下叶更易发生跳跃转移(χ2=5.097,P=0.024),上纵隔淋巴结区为跳跃转移好发区(χ2=7.046,P=0.030).跳跃转移时,右上肺癌易转移至2、3、4组淋巴结,右中和右下肺癌则易转移至7组淋巴结;左上肺癌时,71.7%的转移N2淋巴结位于5、6组淋巴结,而左下肺癌则较易转移至7、9组淋巴结.跳跃转移组5年生存率优于非跳跃转移组(22.1%比13.6%,P=0.001),生存分析显示,跳跃转移是影响N2患者生存期的独立因素.结论 在N2期NSCLC中,跳跃转移易发生于肺上叶以及上纵隔区.跳跃转移可作为ⅢA-N2期NSCLC的一个亚群,具有更高的生存率.     

Prognosis of completely resected pN2 non-small cell lung carcinomas: What is the significant node that affects survival?

OBJECTIVE: We analyzed the effect of the station of mediastinal metastasis with regard to the location of the primary tumor on the prognosis in patients with non-small cell lung cancer. METHODS: Of 956 consecutive patients who underwent operation for primary lung carcinoma between 1986 and 1996, 760 patients (79.5%) were diagnosed as having non- small cell carcinoma and were subjected to complete removal of hilar and mediastinal lymph nodes together with the primary tumor. RESULTS: The status of lymph node involvement was N0 in 480 patients (63.2%), N1 in 139 patients (18.3%), and N2 in 141 patients (18.6%). The 5- and 10-year survival of patients with N2 disease were 26% and 17%, respectively. Neither cell type nor the extent of procedure was a significant survival determinant. Patients having involvement of subcarinal nodes from upper-lobe tumors had a significantly worse prognosis than those patients with metastases only to the upper mediastinal or aortic nodes (P =.003). Patients with nodal involvement of the upper mediastinum from lower-lobe tumors had a significantly worse survival than those patients with metastases limited to the lower mediastinum (P =.039). Furthermore, patients with involvement of the aortic nodes alone from left upper-lobe tumors had a significantly better survival than those patients with metastasis to the upper or lower mediastinum beyond the aortic region (P =.044). CONCLUSIONS: When mediastinal metastasis is limited to upper nodes from upper-lobe tumor, to lower nodes from lower-lobe tumor, or to aortic nodes from left upper-lobe tumor, acceptable survival could be expected after radical resection.     

Pathologic N1 non-small cell lung cancer: correlation between pattern of lymphatic spread and prognosis

OBJECTIVES: Patients with N1 non-small cell lung cancer represent a heterogeneous population with varying long-term survivals. Prognosis and pattern of recurrence seem to be particularly affected by the level of lymph node involvement. METHODS: From 1990 to 1995, a total of 1954 consecutive patients underwent surgical resection for non-small cell lung cancer: 549 (28%) had ipsilateral pulmonary lymph node metastases (N1). The hospital survivors (n = 535) were reviewed. Three levels of lymph node metastases (hilar, interlobar, and lobar) were identified according to the new Regional Lymph Node Classification for Lung Cancer Staging and differentiated from lymph node involvement on the basis of direct invasion. RESULTS: 1 The overall 5-year survival of patients with N1 disease was 40%. Survival was related in the univariate analysis to T classification, level-type of N1 involvement, number of involved nodes, multilevel involvement, Karnofsky Index, R status, and adjuvant therapy. In the multivariate analysis, only T classification and level-type of N1 involvement clearly showed statistical power (P =.000 and P =.001, respectively). The pattern of cancer relapse according to level-type of N1 involvement differed significantly: hilar N1 disease recurred at distant sites in 41% of patients and locoregionally in 12% of patients, whereas N1 disease by direct invasion occurred in 24% and 17% of patients, respectively (P =.030). CONCLUSIONS: Metastases to ipsilateral hilar, interlobar, or both, lymph nodes are associated with a poorer prognosis compared with metastases in intralobar lymph nodes or with lymph node involvement by means of direct invasion. Although surgical resection remains the mainstay of treatment, the high rate of tumor recurrence in both groups mandates further randomized studies with multimodality therapy approaches.     

Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: results of a prospective randomized trial.

OBJECTIVE: To evaluate the effectiveness of lymphadenectomy in the treatment of non-small cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: The extent of lymphadenectomy in the treatment of NSCLC is still a matter of controversy. Although some centers perform mediastinal lymph node sampling (LS) with resection of only suspicious lymph nodes, others recommend a radical, systematic mediastinal lymphadenectomy (LA) to improve survival and to achieve a better staging. METHODS: In a controlled, prospective, randomized clinical trial, the effects of LA on recurrence rates and survival were analyzed, comparing LS and LA in 169 patients with operable NSCLC. RESULTS: After a median follow-up of 47 months, LA did not improve survival in the overall group of patients (hazard ratio: 0.78; 95% confidence interval: 0.47-1.24). Although recurrences rates tended to be reduced among patients who underwent LA, these decreases were not statistically significant (hazard ratio: 0.82; 95% confidence interval: 0.54-1.27). However, analysis of subgroups of patients according to histopathologic lymph node staging revealed that LA appears to prolong relapse-free survival (p = 0.037) with a borderline effect on overall survival (p = 0.058) in patients with limited lymph node involvement (pN1 disease or pN2 disease with involvement of only one lymph node level); in patients with pN0 disease, no survival benefit was observed. CONCLUSIONS: Radical systematic mediastinal lymphadenectomy does not influence disease-free or overall survival in patients with NSCLC and without overt lymph node involvement. However, a small subgroup of patients with limited mediastinal lymph node metastases might benefit from a systematic lymphadenectomy.     

Comparison of mutational changes in involved N1 lymph nodes with those in primary tumors in stage II non-small cell lung cancer: a pilot study

OBJECTIVES: Surgical resection is the standard treatment for stage II non-small cell lung cancer, but recurrence rates approach 60%. This study compared mutational changes in involved lymph nodes and primary tumors from patients with stage II non-small cell lung cancer to determine whether risk factors for recurrence could be identified. METHODS: Forty patients with resected stage II non-small cell lung cancer (excluding T3 N0 disease) were studied. Microdissection was performed on primary tumors and lymph nodes. Analysis was performed across 9 genomic loci by using polymerase chain reaction amplification. The ratio of fractional allelic loss between involved lymph nodes and primary tumors was used to stratify patients into high-risk (fractional allelic loss ratio of >or=1) and low-risk (fractional allelic loss ratio of <1) groups. RESULTS: The median age of the patients was 68 years (range, 42-85 years). Median follow-up was 30 months. Fractional allelic loss was greater in patients with squamous carcinomas compared with that in adenocarcinomas, but survival was similar (35 vs 39 months). The median survival was 35 months in high-risk patients and was not reached in low-risk patients (P =.3). Disease-free survival was 24 months in high-risk patients and was not reached in low-risk patients (P =.35). In the subset with adenocarcinoma (n = 18), median survival was 24 months in the high-risk group; no deaths occurred in low-risk patients (P =.01). Also, disease-free survival was 14 months in high-risk patients and was not reached in the low-risk patients (P =.05). CONCLUSIONS: Squamous cancers demonstrate greater mutational changes than adenocarcinomas; this does not affect outcome. The patients with low-risk adenocarcinomas demonstrated superior outcomes compared with those of other patients. These results should be confirmed in larger studies.     

Border between N1 and N2 stations in lung carcinoma: lessons from lymph node metastatic patterns of lower lobe tumors

OBJECTIVE: Distinction of lymph node stations is one of the most crucial topics still not entirely resolved by many lung cancer surgeons. The nodes around the junction of the hilum and mediastinum are key points at issue. We examined the spread pattern of lymph node metastases, investigated the prognosis according to the level of the involved nodes, and conclusively analyzed the border between N1 and N2 stations. METHODS: We reviewed the records of 604 consecutive patients who underwent complete resection for non-small cell lung carcinoma of the lower lobe. RESULTS: There were 390 patients (64.6%) with N0 disease, 127 (21.0%) with N1, and 87 (14.4%) with N2. Whereas 11.3% of patients with right N2 disease had skip metastases limited to the subcarinal nodes, 32.6% of patients with left N2 disease had skip metastases, of which 64.2% had involvement of N2 station nodes, except the subcarinal ones. The overall 5-year survivals of patients with N0, N1, and N2 disease were 71.0%, 50.8%, and 16.7%, respectively (N0 vs N1 P = .0001, N1 vs N2, P < .0001). Although there were no significant differences in survival according to the side of the tumor among patients with N0 or N1 disease, patients with a left N2 tumor had a worse prognosis than those with a right N2 tumor (P = .0387). The overall 5-year survivals of patients with N0, intralobar N1, hilar N1, lower mediastinal N2, and upper mediastinal N2 disease were 71.0%, 60.1%, 38.8%, 24.8%, and 0%, respectively. Significant differences were observed between intralobar N1 and hilar N1 disease ( P = .0489), hilar N1 and lower mediastinal N2 disease (P = .0158), and lower and upper mediastinal N2 disease (P = .0446). Also, the 5-year survivals of patients with involvement up to station 11, up to station 10, and up to station 7 were 41.4%, 37.9% and 37.7%, respectively (difference not significant). CONCLUSIONS: N1 and N2 diseases appeared as a combination of subgroups: intralobar N1 disease, hilar N1 disease, lower mediastinal N2 disease, and upper mediastinal N2 disease. Interestingly, the survivals of patients with involvement up to interlobar nodes (station 11), main bronchus nodes (station 10), and subcarinal nodes (station 7) were identical. These data constitute the basis for a larger investigation to develop a lymph node map in lung cancer.     

Resection of multifocal non-small cell lung cancer when the bronchioloalveolar subtype is involved

OBJECTIVE: Bronchioloalveolar lung cancer is commonly multifocal and can also present with other non-small cell types. The staging and treatment of multifocal non-small cell cancer are controversial. We evaluated the current staging of multifocal bronchioloalveolar carcinoma and the therapeutic effectiveness of resection when this tumor type is involved. METHODS: We reviewed our experience between 1992 and 2000 with complete pulmonary resections for bronchioloalveolar carcinoma. Kaplan-Meier survival curves were calculated from the dates of pulmonary resection. RESULTS: Among 73 patients with bronchioloalveolar carcinoma, 14 patients, 7 male and 7 female with a mean age of 65 years (51-87 years), had multifocal lesions without lymph node metastases. Follow-up was 100% for a median of 5 years (range 2.6-8.5 years). Tumor distribution was unilateral in 9 patients and bilateral in 5 patients. The multifocal nature of the disease was discovered intraoperatively in 4 patients. Nine patients had 2 lesions, 4 patients had 3 lesions, and 1 patient had innumerable discrete foci in a single lobe. Operative mortality was 0. Postoperatively, 10 patients were staged pIIIB or pIV on the basis of multiple foci of similar morphology; 4 patients had some differences in histology (implying multiple stage 1 primaries). The median survival time to death from cancer was 14 months (141 days-5.6 years). The overall 5-year survival after resection of multifocal bronchioloalveolar carcinoma was 64%. Unilateral or bilateral distribution had no impact on survival. CONCLUSIONS: The current staging system is not prognostic for multifocal bronchioloalveolar carcinoma without lymph node metastases. Complete resection of multifocal non-small cell lung cancer when bronchioloalveolar carcinoma is a component may achieve survivals similar to that of stage I and II unifocal non-small cell lung cancer. When bronchioloalveolar carcinoma is believed to be one of the cell types in multifocal disease without lymph node metastases, consideration should be given to surgical resection.     

Validation of pN2 sub-classifications in patients with pathological stage IIIA N2 non-small cell lung cancer

Optimal surgical treatment for patients with stage IIIA N2 non-small cell lung cancer (NSCLC) remains a matter of debate, because of the outcomes. The outcomes may be affected from variations in patterns of lymph node metastasis. As the patterns of lymph node sub-classifications, multiple station metastases of mediastinal lymph nodes (MN2), highest metastasis of the mediastinal lymph nodes (HM), distribution of metastatic nodes (skip N2 or non-skip N2), and clinical (c-) N factor have been cited. We investigated these factors for patients with pathological stage IIIA (pIIIA) N2 NSCLC. We reviewed 121 consecutive patients with pIIIA N2 who underwent complete resection. Age, gender, tumor laterality, histology, lobe location of the tumor, c-T factor, pathological (p-) T factor, c-N factor, MN2, HM and skip N2 condition were used as prognostic variables. Overall five-year survival rate was 41.8%. Based on log-rank testing, c-T factor (P = 0.022), p-T factor (P = 0.0002), c-N factor (P = 0.009), HM (P = 0.019) and skip N2 (P = 0.030) were identified as significantly prognostic. Using these variables, p-T factor, c-N factor and skip N2 showed significance and independence on Cox multivariate analysis. The sub-classification of lymph node metastasis in patients with p-stage IIIA N2 NSCLC has clinical implications for the prognosis.     

The pattern of mediastinal nodal involvement in lung cancer according to tumor-located lobe]

To clarify the pathway of the metastases from each pulmonary lobe to mediastinal nodes, we examined the pattern of mediastinal nodal involvement in 462 resected pN2 non-small cell lung cancer. Carcinomas of the right upper lobe frequently involved #3 (78/133) and #4 (70/133) nodes, whereas those of the right middle or lower lobe frequently metastasized to #7 nodes (18/23 and 86/113, respectively). On the other hand, carcinoma of left upper lobe frequently involved #5 nodes (81/118), whereas those of the left lower lobe most frequently metastasized to #7 nodes (50/75). Of 462 pN2 patients, 95 (20.6%) had skip metastases to the mediastinal nodes. Skip metastasis was observed more frequently in carcinomas of right upper and middle lobe. One of the reasons of skip metastasis may be the direct lymph drainage through subpleural space to mediastinum.     

Stage III non-small cell lung cancer and metachronous brain metastases

OBJECTIVES: This study was undertaken to identify management strategies that maximize survival of patients with stage III non-small cell lung cancer and metachronous brain metastases and to determine whether any apparent improved survival was due to treatment or simply to patient selection. METHODS: Treatment evaluations of both primary non-small cell lung cancer and brain metastases were performed in 91 patients. Optimal treatment was identified by multivariable analysis. Propensity scoring and multivariable analysis were used to separate treatment benefit from patient selection. RESULTS: Risk-unadjusted median, 12-, and 24-month survivals were 5.2 months, 22%, and 10%, respectively. Younger age (P =.006), good performance status (P =.003), stage IIIA (P =.001), lung resection (P =.02), no other systemic metastases at time of diagnosis of brain metastases (P =.02), and either metastasectomy (P <.001) or stereotactic radiosurgery (P <.001) predicted best survival. However, metastasectomy or stereotactic radiosurgery was more common after lung resection (P =.02) and in patients with good performance status (P =.006), no other systemic metastases at time of diagnosis of brain metastases (P =.01), and fewer brain metastases (P <.001), suggesting that the patients with the best risk profile were selected for aggressive therapy of both lung primary and brain metastases. Despite this selection, analysis of propensity-matched patients demonstrated the benefit of lung resection and metastasectomy or stereotactic radiosurgery (P <.001). CONCLUSIONS: Younger patients with resected stage IIIA non-small cell lung cancer who have isolated metachronous brain metastases and good performance status do best when treated with metastasectomy or stereotactic radiosurgery. This survival benefit is a brain treatment effect, not the result of selecting the best patients for aggressive therapy.     

Impact of comorbidity on survival after surgical resection in patients with stage I non-small cell lung cancer

OBJECTIVE: As the mean age in patients with non-small cell lung cancer increases, the proportion of patients with serious comorbidity who are considered for surgical resection also increases. Patients with non-small cell lung cancer have been shown to have a higher burden of comorbidity than do patients with tumors of other sites, such as breast, prostate, colon, and head and neck. The goal of this review was to determine the impact of comorbidity on postoperative and long-term survival after surgical resection in patients with stage I non-small cell lung cancer. METHODS: A database analysis of our hospital's tumor registry included 451 patients who underwent surgical resection for pathologic stage I non-small cell lung cancer between January 1, 1994, and December 31, 1999. Comorbidity severity was prospectively determined with the Kaplan-Feinstein Index. Survival data were collected for each patient from the date of operation, with a mean duration of follow-up of 35.7 months. Bivariate statistics and Cox proportional hazards model analyses were used. RESULTS: The mean age was 64.4 years, and 249 (55%) patients were male. The distribution of overall comorbidity severity was none, 142 (31.5%); mild, 150 (33.3%); moderate, 115 (25.5%); and severe, 44 (9.8%). The overall in-hospital mortality was 2.2% (n = 10/451). There was a nonsignificant trend toward higher hospital mortality with greater comorbidity: none, 0.7% (n = 1/142); mild, 3.3% (n = 5/150); moderate, 0.9% (n = 1/115); and severe, 6.8% (n = 3/44, P =.055). Kaplan-Meier estimated survivals at 3 years for each level of comorbidity were as follows: none, 85.6%; mild, 74.8%; moderate, 68.8%; and severe, 70.0% (P <.002). After adjustment for age, sex, T status, and tumor histologic type, the relative risks of death as a function of comorbidity were mild, 1.44 (95% confidence interval 0.89-2.34); moderate, 2.28 (95% confidence interval 1.43-3.65); and severe; 1.94 (95% confidence interval 1.023-3.70). CONCLUSIONS: Comorbidity has a significant impact on survival after surgical resection of patients with stage I non-small cell lung cancer. These data may help to explain the lower than expected survival results for patients after surgical resection for stage I non-small cell lung cancer.     

Prognostic factors in patients with ipsilateral pulmonary metastasis from non-small cell lung cancer.

OBJECTIVE: Pulmonary metastasis of non-small cell lung cancer is classified as an advanced disease stage, with limited indications for surgical treatment. However, the prognosis of patients with pulmonary metastasis of non-small cell lung cancer is better than that of patients with distant metastases. The purpose of the present study was to analyze and detect possible prognostic factors in surgically treated patients with ipsilateral pulmonary metastasis of non-small cell lung cancer. METHODS: Among 1198 patients with non-small cell lung cancer who underwent surgery at Kurashiki Central Hospital (Okayama, Japan) from April 1982 to March 2004, a total of 48 (4.0%) patients with pathologically diagnosed ipsilateral pulmonary metastasis were retrospectively evaluated. The median follow-up time was 20.5 months (range 1-103 months) and 37 patients (77.1%) were completely followed up until their death or more than 5 years after the operation. RESULTS: Among the 48 patients, 31 (64.6%) patients had metastatic nodules in the same lobe as the primary tumor (PM1) and 17 (35.4%) patients had metastatic nodules in different ipsilateral lobes (PM2). There was no significant difference in survival between patients with PM1 and the other patients with pT4-stage IIIB, or between patients with ipsilateral PM2 and the other patients with stage IV. Univariate analysis of postoperative survival stratified according to clinicopathologic factors revealed significant differences for the radicality of resection (complete vs. incomplete), tumor size (0-30 vs. >30mm) and pathological nodal (pN) factor (among pN0, pN1 and pN2-3). Multivariate analysis revealed that tumor size (0-30 vs. >30mm) and pN factor (pN0-1 vs. pN2-3) were independent prognostic factors. CONCLUSIONS: The results of our study suggest that undergoing a complete resection, having a tumor size of 30mm or less and having no mediastinal lymph node metastases were better prognostic factors for surgically treated patients with ipsilateral pulmonary metastasis of non-small cell lung cancer.     

Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer. Eastern Cooperative Oncology Group

BACKGROUND: Mediastinal lymph node dissection (MLND) is an integral part of surgery for non-small cell lung cancer (NSCLC). To compare the impact of systematic sampling (SS) and complete MLND on the identification of mediastinal lymph node metastases and patient survival, the Eastern Cooperative Oncology Group (ECOG) stratified patients by type of MLND before participation in ECOG 3590 (a randomized prospective trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC). METHODS: Eligibility requirements for study entry included a thorough investigation of the mediastinal lymph nodes with either SS or complete MLND. The former was defined as removal of at least one lymph node at levels 4, 7, and 10 during a right thoracotomy and at levels 5 and/or 6 and 7 during a left thoracotomy, while the latter required complete removal of all lymph nodes at those levels. RESULTS: Three hundred seventy-three eligible patients were accrued to the study. Among the 187 patients who underwent SS, N1 disease was identified in 40% and N2 disease in 60%. This was not significantly different than the 41% of N1 disease and 59% of N2 disease found among the 186 patients who underwent complete MLND. Among the 222 patients with N2 metastases, multiple levels of N2 disease were documented in 30% of patients who underwent complete MLND and in 12% of patients who had SS (p = 0.001). Median survival was 57.5 months for those patients who had undergone complete MLND and 29.2 months for those patients who had SS (p = 0.004). However, the survival advantage was limited to patients with right lung tumors (66.4 months vs 24.5 months, p<0.001). CONCLUSIONS: In this nonrandomized comparison, SS was as efficacious as complete MLND in staging patients with NSCLC. However, complete MLND identified significantly more levels of N2 disease. Furthermore, complete MLND was associated with improved survival with right NSCLC when compared with SS.     

Prognostic factors in surgically resected N2 non-small cell lung cancer: the importance of patterns of mediastinal lymph nodes metastases.

OBJECTIVE: Patients with non-small cell lung cancer (NSCLC) with metastases to ipsilateral mediastinal lymph nodes (N2) are an heterogeneous group of patients as regard to prognosis and treatment. Indication and timing of surgery remain controversial. The present study investigates the prognostic factors, in order to identify homogenous subgroups of patients. METHODS: Histologically proven N2-NSCLC patients, who underwent a complete surgical resection were retrospectively reviewed. Clinical and pathological features were reported and analyzed, and survival study was performed. RESULTS: One hundred eighty-three patients were analyzed. Overall 1.3 and 5 years survival rates were, respectively, 70, 35 and 20%, with a median survival time of 24 months. Univariate analysis showed a significant better prognosis for: incidental N2 respect to clinical N2 (5-years 35.4 vs 17.4%); single level lymph node involvement respect to multiple levels (5-years 23.8 vs 14.7%); metastases to superior mediastinal or aortic nodes respect to lower mediastinal nodes (5-years 32 and 24.3 vs 16.3%); right upper lobe tumors with superior mediastinal nodes and left upper lobe tumors with aortic nodes respect to lower lobes tumors with lower mediastinal nodes (5-years 31.8 and 26.9 vs 15.7%). Skip metastases had not a significant survival advantage respect to continuous lymphatic spread. N2 clinical status, the number of levels involved and the two specific patterns of lymphatic spread resulted significant prognostic factors at multivariate analysis. CONCLUSIONS: Clinical N2 status, number of lymph nodes levels involved and specific patterns of lymphatic spread identify homogenous subgroups of patients that can be proposed for different therapeutic strategies.     

The prognostic significance of intranodal isolated tumor cells and micrometastases in patients with non-small cell carcinoma of the lung

OBJECTIVE: To study whether isolated tumor cells and micrometastases, as defined by the current American Joint Committee on Cancer criteria for extrapulmonary neoplasms, have prognostic value for patients with resected non-small cell carcinoma of the lung. METHODS: Intrathoracic lymph nodes (n = 1063) from 60 patients with non-small cell carcinoma of the lung were studied for the presence of metastases with serial histologic sections and keratin immunostains. Metastases were classified as isolated tumor cells, pN1mi, pN1, pN2mi, and pN2. Isolated tumor cells were smaller than 0.2 mm, while pN1mi and pN2mi measured 0.2 mm to 2 mm. Survival analysis was performed, stratifying by nodal status and stage. RESULTS: Isolated tumor cells were detected in 11 lymph nodes from 5 of 33 pN0 patients and in 9 pN1 and pN2 patients. The lymph nodes from 3 patients were reclassified as pN1mi. No pN2mi were detected. A survival model based on a stratification of the cohort into stages I to III was significant (chi-square = 7.426, df = 2, P =.024) but demonstrated considerable overlap between the survival curves of stage I and II patients. A model stratifying isolated tumor cells and pN1mi into stage I disease was significant (chi-square = 7.985, df = 2, P =.018) and showed no overlap between the survival curves of stage I and II patients. There were no significant survival function differences between patients with pN0, isolated tumor cells, and pN1mi. CONCLUSIONS: Patients with non-small cell carcinoma of the lung with isolated tumor cells and pN1mi have similar survivals to those with pN0, consistent with the findings reported for breast cancer patients. Future larger studies of patients with non-small cell carcinoma of the lung are needed to confirm whether current American Joint Committee on Cancer staging criteria should be modified to include the pN1mi category.     

Accuracy and survival of repeat mediastinoscopy after induction therapy for non-small cell lung cancer in a combined series of 104 patients

Objective: Precise restaging of non-small cell lung cancer after induction therapy is of utmost importance. Remediastinoscopy remains a controversial procedure. In a combined, updated series of two thoracic centres, accuracy and survival of remediastinoscopy were determined. Methods: From November 1994 to August 2005, remediastinoscopy was performed in 104 patients (98 men, 6 women) after induction therapy for locally advanced non-small cell lung cancer. Mean age was 64.3 years (range 38–85). Neoadjuvant chemotherapy was given in 79 patients and chemoradiotherapy in 25. Follow-up data were completed in January 2007. Results: Remediastinoscopy was technically feasible in all patients except for one who died due to perioperative haemorrhage. Remediastinoscopy was positive in 40 patients and negative in 64; the latter group underwent thoracotomy. There were 17 false-negative remediastinoscopies. Sensitivity of remediastinoscopy was 71%, specificity 100% and accuracy 84%. Follow-up was complete for all patients. Sixty-nine died, mostly of distant metastases. Median survival time for the whole group was 18 months (95% confidence interval 11–25). Median survival time in patients with a positive remediastinoscopy was 14 months (95% confidence interval 8–20), with a negative remediastinoscopy 28 months (95% confidence interval 15–41) and with a false-negative remediastinoscopy 24 months (95% confidence interval 3–45). In univariate analysis the difference between positive and negative remediastinoscopies was highly significant (p = 0.001). In a multivariate analysis including sex, age, histology, centre, and nodal status at remediastinoscopy, only nodal status was a significant independent prognostic factor (p = 0.008). Conclusions: Remediastinoscopy is a valuable restaging procedure after induction therapy. Persisting mediastinal nodal involvement proven at remediastinoscopy heralds a poor prognosis.     

Sentinel node sampling limits lymphadenectomy in stage I non-small cell lung cancer.

OBJECTIVE: It is controversial whether a systematic mediastinal lymph node dissection (MLND) needs to be performed in all patients with stage I lung cancer. The present study was done to examine the new sentinel lymph nodes hypothesis based on the lobe of the primary tumor. METHODS: In our first study, the lymph node (LN) metastases were assessed in 291 stage I non-small cell lung cancer (NSCLC) patients who had a major lung resection with a systematic mediastinal lymph node dissection. We evaluated the validity of using our new sentinel lymph nodes method based on the lobe of the primary tumor as follows: the pretracheal (#3), tracheobronchial (#4), and hilar nodes (#10) for right upper lobe tumors; #4, subcarinal (#7), and #10 for middle lobe tumors; the subaortic (#5), paraaortic (#6), and #10 for left upper lobe tumors; and the #7, #10, and interlobar nodes (#11) for tumors in either lower lobes. In the second study, we performed a lobectomy with new sentinel node sampling in 64 patients with preoperative complications. If all of the sampling nodes showed no metastases on frozen section diagnosis, systematic node dissections were not performed. RESULTS: Six of 291 patients in the first study had skip metastases that did not involve the new sentinel nodes; 5 of the 6 patients had macroscopic pleural invasion. Thus, we defined pleural invasion as an exclusion criterion for the second study. In the second study, the median follow-up time was 39 months. Metastatic lymph nodes were detected in 11 of 64 patients. Fifty-three patients (83%) had no metastasis in the sampled nodes, and, therefore, a mediastinal lymph node dissection was not done. The morbidity rate in the sampling group was 36%, and there was no mortality. In the sampling group, local recurrences were observed in two patients, distant metastases in eight, and carcinomatous pleuritis in one; the overall 5-year survival rate was 82%. CONCLUSIONS: We found that it is possible to perform a less invasive lymphadenectomy for patients with stage I lung cancer using intra-operative sampling of new sentinel lymph nodes.