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G. Darling

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    GR 01 - Management of Challenging Clinical Scenarios in Localized Lung Cancer (ID 14)

    • Event: WCLC 2015
    • Type: Grand Rounds
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 4
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      GR01.01 - T4 NSCLC Involving the Great Vessels: Role for resection? (ID 1828)

      14:20 - 14:40  |  Author(s): D. Harpole

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Usually NSCLC tumors that have invaded the central/mediastinal vascular structures are considered unresectable, and staged as T4 locally-advanced NSCLC and are treated with concurrent platinum-based chemotherapy and thoracic radiation with curative intent (60+Gy). However, subsets of good functional status patients with limited involvement (clinically node-negative; T4N0) have been selectively treated with surgical resection before or after additional therapy. This has been most commonly employed for tumor invasion at the base of one of the pulmonary veins with extension into the proximal left atrium or for right upper lobe tumors with segmental involvement of the superior vena cava. Smaller series exist for resection of lung tumors having primary extension into the cardiac chambers and aortic arch. There are no prospective trials, only manuscripts that detail decades-long retrospective single institution series. This presentation will review the literature and surgical approaches to NSCLC involving the great vessel with and without circulatory support. Surgical management of lung cancer invading the aorta or the superior vena cava. Misthos P, Papagiannakis G, Kokotsakis J, Lazopoulos G, Skouteli E, Lioulias A. Lung Cancer. 2007 May;56(2):223-7. Epub 2007 Jan 16. Extended resection of the left atrium, great vessels, or both for lung cancer. Tsuchiya R, Asamura H, Kondo H, Goya T, Naruke T. Ann Thorac Surg. 1994;57(4):960-5 Results of superior vena cava resection for lung cancer. Analysis of prognostic factors. Spaggiari L, Magdeleinat P, Kondo H, Thomas P, Leon ME, Rollet G, Regnard JF, Tsuchiya R, Pastorino U. Lung Cancer. 2004 Jun;44(3):339-46. 15 years single center experience with surgical resection of the superior vena cava for non-small cell lung cancer. Shargall Y, de Perrot M, Keshavjee S, Darling G, Ginsberg R, Johnston M, Pierre A, Waddell TK. Lung Cancer. 2004:357-63 Superior vena cava resection for lung and mediastinal malignancies: a single-center experience with 70 cases. Spaggiari L, Leo F, Veronesi G, Solli P, Galetta D, Tatani B, Petrella F, Radice D. Ann Thorac Surg. 2007 Jan;83(1):223-9; discussion 229-30 Left atrial resection for T4 lung cancer without cardiopulmonary bypass: technical aspects and outcomes. Galvaing G, Tardy MM, Cassagnes L, Da Costa V, Chadeyras JB, Naamee A, Bailly P, Filaire E, Pereira B, Filaire M. Ann Thorac Surg. 2014 May;97(5):1708-13 Results of primary surgery with T4 non-small cell lung cancer during a 25-year period in a single center: the benefit is worth the risk. Yildizeli B, Dartevelle PG, Fadel E, Mussot S, Chapelier A. Ann Thorac Surg. 2008 Oct;86(4):1065-75; Twelve-year experience with left atrial resection in the treatment of non-small cell lung cancer. Ratto GB, Costa R, Vassallo G, Alloisio A, Maineri P, Bruzzi P. Ann Thorac Surg. 2004 Jul;78(1):234-7. Review. Survival after extended resection for mediastinal advanced lung cancer: lessons learned on 167 consecutive cases. Spaggiari L, Tessitore A, Casiraghi M, Guarize J, Solli P, Borri A, Gasparri R Petrella F, Maisonneuve P, Galetta D. Ann Thorac Surg. 2013;95(5):1717-25 Superior vena caval resection in lung cancer. Lee DS, Flores RM. Thorac Surg Clin. 2014 Nov;24(4):441-7

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      GR01.02 - Should All Lung Tumors Invading the Chest Wall Be Treated Like Pancoast Tumors? (ID 1829)

      14:40 - 15:00  |  Author(s): B. Stiles

      • Abstract
      • Presentation

      Abstract:
      Chest wall involvement is rare in patients with non-small cell lung cancer (NSCLC), occurring in <8% of patients (1). Invasion of the chest wall accords a T3 designation in both the 7[th] and in the newly proposed 8[th] edition TNM staging systems (2). The overall five-year survival for patients with clinically staged T3N0 NSCLC is approximately 45% (2). With clinically suspected nodal disease, even limited to N1 stations, survival is markedly worse. While cT3N2 NSCLC patients are designated stage IIIA and typically given neoadjuvant therapy, optimal treatment protocols are less clear for cT3N0 or even for cT3N1 patients with chest wall tumors, despite the fact that cT3N1 patients are also classified stage IIIA. An en bloc surgical resection of the involved lung and of the chest wall with or without adjuvant therapy has historically been the treatment algorithm of choice for these patients. Little data exists to determine whether neoadjuvant chemotherapy or chemoradiation might be beneficial in this setting. In contrast, the preferred treatment algorithm for a unique subset of chest wall tumors, Pancoast tumors, has been clearly defined (1). These T3 or T4 superior sulcus tumors arise in the apex of the lung and invade the chest wall at the level of the first rib or above, often with involvement of the brachial plexus, subclavian vessels, or spine. For these patients with clinical T3-4N0-1 disease, two carefully conducted prospective, multi-institutional trials demonstrated that induction chemoradiation therapy was associated with high rates of pathological response, improved resectability, and increased survival over historical controls (3,4). In the Southwest Oncology Group Trial 9416 (Intergroup Trial 0160), following neoadjuvant cisplatin and etoposide with concurrent radiation (45 Gy), 61% of patients had either a pathologic complete response or minimal microscopic residual tumor (3). Among all patients undergoing surgery, 94% were able to undergo an R0 resection. Patients with pathologic complete response had a marked advantage in five year overall survival (median survival not reached for complete responders versus 30 months for those with residual disease). Overall survival of the entire cohort was 44%, but was 54% after complete resection. Similar results were found in a multi-institutional trial from Japan (JCOG 9806), in which 21% of patients experienced a complete pathologic response following neoadjuvant therapy with mitomycin, vindesine, and cisplatin and concurrent radiation of 45 Gy (4). Among surgical patients, 89% underwent an R0 resection. Overall five-year survival for the cohort exceeded 50%, with survival of complete responders again especially favorable. The successful adoption of neoadjuvant therapy followed by surgery for Pancoast tumors raised the question of whether a similar induction strategy should be used in patients with other T3 chest wall tumors outside of the superior sulcus. Previous reports have suggested that prognostic factors for survival in patients with chest wall tumors include lymph node status and depth of chest wall invasion, but also completeness of surgical resection and completion of chemotherapy (5,6). It seems logical that neoadjuvant chemotherapy or chemoradiation may facilitate an R0 resection and that such therapy may be better tolerated preoperatively in patients undergoing potentially morbid chest wall resections. Along those lines, a prospective phase II study of trimodality therapy was performed in Japan (CJLSG 0801) for patients with T3N0 or T3N1 NSCLC involving the chest wall (7). Fifty-one patients were entered into the study, among whom 49 (96%) completed neoadjuvant cisplatin and vinorelbine with concurrent radiation (40 Gy) and among whom 44 (92%) underwent complete resection. Similar to prospective studies in NSCLC patients with superior sulcus tumors, in resected tumors there was a high rate of complete pathological response (25%) and of only minimal residual disease (65%). Treatment was relatively safe. However, one patient did die during neoadjuvant therapy secondary to infection following neutropenia and seven additional patients (16%) experienced grade 4 toxicity. Despite this, 86% of patients completed the induction regimen. Among the 29 patients (66%) who went on to surgery, 5 patients experiencing major complications and there was 1 postoperative mortality. Although median follow up was only 16 months, the 2-year overall and progression-free survival rates were excellent at 85% and 71% respectively. While the results of CJLSG 0801 perhaps make a compelling argument to treat chest wall tumors with neoadjuvant therapy prior to resection, several caveats must be considered. From previous studies, it would seem that nodal disease is the strongest indicator of the need for systemic therapy. However, previously reported rates of nodal disease for chest wall tumors are generally only between 20-40% (5). The rate of nodal disease reported in a recently published review of a Japanese registry of chest wall tumors was only 27% (8). These patients without nodal disease will not clearly benefit from systemic therapy. Furthermore, as opposed to Pancoast tumors, the rate of complete resection of chest wall tumors outside the superior sulcus is high even without neoadjuvant therapy, 88% in the Japanese registry study (8). This ability to obtain an R0 resection calls into question the need to include radiation therapy in the preoperative treatment regimen for most cT3N0 patients, given the potential added morbidity. In conclusion, it would seem most reasonable to utilize neoadjuvant therapy in chest wall tumors with clinical N1 nodal disease. These patients are designated as stage IIIA and need chemotherapy as part of their treatment regimen. Neoadjuvant therapy prior to surgery makes sense, although care should be taken to avoid complications that may prevent surgical resection. For T3N0 patients, the treatment algorithm is less clear. Conceptually, large bulky tumors in which it is expected that difficulty in obtaining negative margins surgically would seem to be good candidates for chemotherapy and radiation preoperatively. Further studies need to explicitly compare neoadjuvant versus adjuvant chemotherapy for T3N0 chest wall tumors and need to better evaluate whether there is any beneficial role of radiation in this challenging group of NSCLC patients. 1. Kozower BD, Larner JM, Detterbeck FC, Jones DR. Special treatment issues in non-small cell lung cancer, diagnosis and management of lung cancer 3[rd] ed: American College of of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5):e3696S-e399S. 2. Rami-Porta R, Bolejack V, Crowley J et al. Proposals for the Revisions of the T descriptors in the forthcoming eight edition of the TNM classification for lung cancer. J Thorac Oncol 2015;10:990-1003. 3. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007;25:313-318. 4. Kunitoh H, Kato H, Tsuboi M, et al. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group Trial 9806. J Clin Oncol 2008;26:644-649. 5. Riquet M, Arame A, Le Pimpec Barthes F. Non-small cell lung cancer invading the chest wall. Thorac Surg Clin 2010;20:519-527. 6. Lee CY, Syun CS, Lee JG, et al. The prognostic factors of resected non-small cell lung cancer with chest wall invasion. World J Surg Onc 2012;10:9. 7. Kawaguchi K, Yokoi K, Niwa H, et al. Trimodality therapy for lung cancer with chest wall invasion: initial results of a phase II study. Ann Thorac Surg 2014;98:1184-91. 8. Kawaguchi K, Miyaoka E, Asamura H, et al. Modern surgical results of lung cancer involving neighboring structures: a retrospective analysis of 531 pT3 cases in a Japanese Lung Cancer Resistry Study. J Thorac Cardiovasc Surg 2012;144:431-7.

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      GR01.03 - T4 Lung Tumors According to the New Classification - What Is the Role of Surgery? (ID 1830)

      15:00 - 15:20  |  Author(s): D. Boffa

      • Abstract
      • Presentation

      Abstract:
      Surgical resection offers the best chance of cure for most patients with localized non-small lung cancer (NSCLC). However, the risk-benefit deliberation for surgery becomes less clear in patients with more locally advanced tumors (T4), because the procedures are typically more dangerous (higher risk) and the patient’s prognosis is worse (benefit less clear). That being said, surgery remains a curative option for a significant proportion of patients with T4 tumors. In order to minimize risk and maximize benefit, surgeons should select patients with 1) T4 tumors that can be removed safely, 2) T4 tumors that can be completely removed (R0) and 3) patients that are less likely to experience early systemic failure. The group of T4 NSCLC tumors that have historically been amenable to safe surgical resection include those that invade the spine, trachea, esophagus great vessels, and atrium. The 7[th] edition of the lung cancer stage classification system expanded the T4 designation to include tumors that involve a nodule in a separate ipsilateral pulmonary lobe. The recently released proposal for the 8[th] edition of the lung cancer stage classification system has moved tumors greater than 7cm in maximum diameter and tumors that invade the diaphragm to the T4 category. We have previously stated that changes in staging nomenclature should NOT be taken as justification for changing the way a patient is treated (because the revision only considers prognosis without any regard to treatment). However, these additional members of the T4 staging group pose the same risk-benefit conundrum that the others members pose and are discussed. Global health should be assessed as this is a critical component to the surgical risk calculation for patients. This typically includes an assessment of comorbid condition severity, pulmonary function testing, exercise testing and cardiopulmonary stress testing in patients at risk for cardiac disease. Strategies for safe removal of T4 tumors typically center around preparation for the unexpected. The supporting services should be alerted to not only the planned elements of the case but also possible needs in the event of a more extensive resection. The anesthesia team should be prepared to deal with abrupt bleeding (e.g. appropriate intravenous access that is located away from vessels that are likely to be clamped), the need for alternate ventilation strategies (e.g. jet ventilation). Any surgical specialty that could support an extended resection (e.g. spine service) should be alerted to the possibility. Surgeons should adjust their surgical approach to not only address what is apparent, but possible occult involvement of neighboring structures. Incisions should be placed in a way that allows the surgeon the flexibility to extend the planned resection. If possible, entrance should preserve tissues that can be used to treat surgical complications (e.g. preserving muscle for later use as a muscle flap). The exposure should allow for proximal and distal control of neighboring vessels, the use of cross table ventilation and the urgent use of cardiopulmonary bypass. Complete resection (removing all gross and microscopic disease) is of paramount importance, as the survival of patients is severely compromised by a positive surgical margin. While positive margins are an unfortunate reality to cancer surgery, every effort should be made to estimate the likelihood that a negative surgical margin can be obtained. At times this involves an exploratory phase of the resection (occasionally a minimally invasive approach to start) in order to assess the extent of local involvement (because imaging is notoriously inaccurate for determining the extent of local invasion). Finally the multi-disciplinary team must attempt to select patients that are less likely to develop early systemic failure, as these patients will not benefit from resection. This is of course not knowable with any degree of certainty but an estimate is helpful. Patients should undergo a thorough staging evaluation (brain imaging, PET scanning). While not an absolute contraindication for surgical resection, surgeons should be cognizant of other staging parameters that further compromise the patient’s potential for long-term survival. Most notably this would include the patient’s mediastinal lymph node status. The presence of mediastinal lymph node metastases (N2) is a further indication of the patient’s risk for systemic failure, and is an overall poor prognosticator. While prognosis does not alone define treatment, the patient’s overall prognosis should be considered when attempting to justify surgical risk (which is typically increased for T4 tumor resection). For this reason, it is recommended that surgeons refrain from resecting of T4 tumors associated with N2 disease as their default approach, and rather develop a strategy that attempts to allow patients to declare their potential for early failure. One strategy would be to offer the patient curative-intent nonsurgical therapy (chemoradiation) and observe the patient for a “local only” recurrence. In conclusion, surgical resection of T4 tumors is reasonable and effective in highly selected NSCLC patients. The onus is on surgeons and multidisciplinary care teams to attempt to identify the patients most likely to benefit and least likely to be harmed by surgery.

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      GR01.04 - Salvage Surgery After Definitive Chemoradiation Therapy (CRT) (ID 1831)

      15:20 - 15:40  |  Author(s): E. Vallieres

      • Abstract
      • Presentation
      • Slides

      Abstract:
      After definitive CRT, approximately 25-30% of patients with stage III disease will fail at their primary site while the regional and systemic fields are under control. As a result, the question of whether some of these patients may potentially benefit from salvage resection of their primary site is often brought up at multidisciplinary tumor boards. The largest published series is from Duke who reported earlier this year on 31 patients in 17 years who underwent lobectomy after definitive radiation therapy (RT), 29 of whom had also received concurrent chemotherapy. Median dose of RT was 60Gy, ranging from 40 to more than 70. The median interval in between completion of the RT and the lobectomy was 18 weeks, ranging from 8 to 111. The majority of these resections were done open though, to their credit, 6 were done VATS without conversion. There was no operative mortality and 48% patients experienced some complications, only a third of these being major. There were no post op bronchopleural fistulae (BPF) despite only a third of patients having their stumps covered: 30/31 achieved an R0 resection, 19/31 had viable tumor in the specimen as histological confirmation of recurrence / persistent disease was not mandated before resection. Median follow-up (f-up) was 26 months and the median OS was 60 months: 20 months if persistent tumor was present in the resected specimen. For the patients who went to salvage resection for recurrent disease (n=3: DFIs being 240, 300 and 700 days) the OS was 9 months, significantly less than the 26 months of those who had persistent disease after RT. The 5 y survival was 31%, 0 if N1-2 disease was present at resection or if salvage was done for relapse, but very small numbers… (1) In 2013, the Yale group reported on 14 patients in 6 years who underwent salvage resection for biopsy proven persistent/ recurrent T disease after definitive CRT. Most underwent lobectomies (9), 2 pneumonectomies. 36% underwent stump coverage. There was no mortality at 90 days, 43% experienced some complication, including 1 ARDS and I BPF. Median post op survival was 9 months, mean 2 year survival was 49%.(2) Bauman in 2008 reported on 24 patients in 8 years who underwent salvage resection after RT, mean dose of 64 Gy (59 to 70), 22 had received concurrent chemo. The interval from completion of RT to surgery ranged from 5 to 94 weeks (median 21). Most underwent lobectomies but 10 were pneumonectomies, including 4 right sided. 19/24 had stump coverage, 16 by omentopexy. Median OR time was 5.5 hours. There was one post op death due to ARDS, 58% experienced some complications, no BPF. 80% of specimen had viable tumor, 2 had R1 resections, 11/24 had N1-2. Median f-up was 29 months, median OS was 30 months, 43 months if PET information/changes led to salvage resection. The estimated 3 year survival was 47%: 2 patients had were found to have brain metastases within 2 months of the salvage resection, neither had had brain imaging in the re-evaluation leading to salvage surgery.(3) Personal opinion (4): the preoperative evaluation of such candidates should always include fresh CT PET, brain MRI and PFTs including a DCO as well as a quantitative perfusion scan as the possibilities of pneumonectomy are not insignificant in this population. Smoking cessation is mandatory. The location of the tumor at presentation also matters: it may be technically much more difficult to perform a lobectomy for centrally radiated lesions. Though not the topic at hand, in my experience, the technical challenges to salvage after SABR pale in comparison as usually the hilar structures are relatively intact after SABR. These surgeries can be challenging and I would encourage that one obtain as much information as possible upfront before going to resection. This includes that one attempt to obtain histological confirmation of viable cancer before undertaking these surgeries. We now know that after RT, particularly after SABR, the PET information may be falsely positive. Along the same lines, I will get EBUS sampling of the mediastinal and hilar lymph nodes before resection. If negative, I will add mediastinoscopy evaluation even in those who had mediastinoscopy at presentation. (5) Intraoperatively, you need to communicate with anesthesia that these patients do not tolerate excess IV fluid well at all as a result of having had their mediastinum radiated. We prepare/ harvest the intercostal muscle bundle at entry. Early circumferential control of the proximal PA and PVs early on is also favored… just in case. Intrapericardial access to the PVs often helps when the hilum is fibrosed, in such instances, open division of the lobar bronchus will often help accessing the lobar PA branches, particularly with the RUL. We cover all of our stumps with the prepared intercostal bundle. Post-operatively, IV fluid restriction remains a priority. Patients whose left hilar dissection was difficult are kept fasting until the left recurrent nerve function is evaluated or judged to be intact. Any concern prompts immediate laryngoscopic evaluation and temporary medialization of any suspicious “lazy” vocal cord follows. The literature on the topic is sparse and all retrospective but we can conclude from its review that: in experienced hands, such resections can be performed safely with acceptable morbidity, such resections, particularly if one is attempting to perform less than a pneumonectomy can be technically challenging and that selection of the patients who may benefit the most from such surgery is not easy. References: Yang CJ, Meyerhoff RR, Stephens SJ, et al. Long-Term Outcomes of Lobectomy for Non-Small Cell Lung Cancer After Definitive Radiation Treatment. Ann Thorac Surg 2015; 99:1914–20 Kuzmik GA, Detterbeck FC, Decker RH, et al. Pulmonary resections following prior definitive chemoradiation therapy are associated with acceptable survival Eur J Card-Thorac Surg 44 (2013) e66–e70 Bauman JE, Mulligan MS, Martins RG, et al. Salvage Lung Resection After Definitive Radiation (>59 Gy) for Non-Small Cell Lung Cancer: Surgicaland Oncologic OutcomesAnn Thorac Surg 2008;86:1632–9 Page B, Blitz M, Louie BE, et al. Pulmonary Resection of NSCLC can be performed safely following definitive chemoradiotherapy. Oral presentation 13th World Conference on Lung Cancer, San Francisco, CA August 1[st] 2009, J Thorac Oncol. 4(9) Supplement 1:S301, September 2009 Louie BE, Kapur S, Farivar AS, et al. Safety and Utility of Mediastinoscopy in Non-Small Cell Lung Cancer in a Complex Mediastinum, Ann Thorac Surgery 92(1): 278-83, 2011

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Author of

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    MINI 20 - Surgery (ID 137)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      MINI20.14 - Discussant for MINI20.10, MINI20.11, MINI20.12, MINI20.13 (ID 3479)

      18:00 - 18:10  |  Author(s): G. Darling

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 34 - Quality/Survival/Prognosis in Localized Lung Cancer (ID 153)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      ORAL34.05 - Survival Implications of Variation in the Lymph Node (LN) Count in ACOSOG Z0030 (Alliance) (ID 654)

      17:28 - 17:39  |  Author(s): G. Darling

      • Abstract
      • Presentation

      Background:
      Variation in the thoroughness and accuracy of pathologic lymph node (LN) staging may contribute to within-stage variation in survival after curative-intent resection of non-small-cell lung cancer. Accurate staging mandates effective collaboration between surgeons and pathologists. ACOSOG Z0030 tightly controlled surgeon practice, but not pathology practice. We tested the impact of the thoroughness of pathologic examination (using the number of examined LNs as a surrogate) on detection of LN metastasis and survival.

      Methods:
      We reanalyzed the mediastinal LN dissection arm of ACOSOG Z0030, using linear regression to examine the clinical and demographic factors associated with LN count, Cox proportional hazards models to determine the association between the number of LNs examined and survival of patients with pN0 and pN1 disease, and logistic regression to determine association of number of LN examined and the discovery of unexpected N2 LN metastasis. Overall (OS) and recurrence-free survival (RFS), were analyzed without and with adjustment for T-category.

      Results:
      The 524 patients, had a mean age of 66.8 years, and were 52% male. Forty-four percent had adenocarcinoma, 27% squamous, 4% large cell, and 25% ‘other’ histology; 96% had T1/2 disease. Four hundred and thirty-nine (84%) were pN0, 63 (12%) pN1, and 21 (4%) pN2. In patients with pN0, pN1, and pN2 respectively, the mean number of mediastinal LNs examined was 13.5, 12.9, and 17.4; station 10 LNs were 2.4, 2.7, and 2.5; station 11-14 LNs were 4.6, 6.2, and 6.2; total LNs (from all stations) were 19.7, 21.3, 25. Tumor histology and pN-category were the only factors associated with the number of LNs examined: patients with squamous histology tended to have the most number of non-hilar N1 LNs examined (p<0.001); patients with pN1/N2 had more non-hilar N1 nodes than those with pN0 (p=0.005); those with pN2 had more N2 nodes examined than those with pN0 or pN1 (p=0.085). There was a consistent association between the number of LNs examined and survival. Patients with pN0 had better OS (HR 0.96; p=0.12) and RFS (HR 0.97; p=0.2) with examination of more non-hilar nodes; patients with pN1, had better OS and RFS with increased examination of LNs from N2 (OS HR=0.96, p=0.059; RFS HR=0.95, p=0.03) and all stations (OS HR=0.97, p=0.048; RFS HR=0.96, p==0.012). Adjustment for T-category strengthened these relationships between the number of LNs, pN-stage and survival. The likelihood of discovering N2 disease was associated with increased examination of LNs from mediastinal (odds ratio=1.04; p=0.035) and all stations (OR=1.03; p=0.035).

      Conclusion:
      Despite uniformly thorough surgical hilar/mediastinal LN harvesting, the number of LNs examined was associated with the likelihood of detecting nodal metastasis, and survival. Patients with more LNs examined were more likely to have LN metastasis, examination of more LNs was associated with better survival in patients within the same pN-category. This may indicate an effect of variable thoroughness in pathologic examination processes on the accuracy and prognostic value of the pathology nodal staging system. Heterogeneity in the cancer immune response may be an alternative hypothesis to explain these findings.

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