Implications of Pathologic Complete Response Beyond Mediastinal Nodal Clearance With High-Dose Neoadjuvant Chemoradiation Therapy in Locally Advanced, Non-Small Cell Lung Cancer

Implications of Pathologic Complete Response Beyond Mediastinal Nodal Clearance With High-Dose Neoadjuvant Chemoradiation Therapy in Locally Advanced, Non-Small Cell Lung Cancer

Accepted Manuscript Implications of Pathological Complete Response (pCR) Beyond Mediastinal Nodal Clearance with High-dose Neoadjuvant Chemoradiothera...

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Accepted Manuscript Implications of Pathological Complete Response (pCR) Beyond Mediastinal Nodal Clearance with High-dose Neoadjuvant Chemoradiotherapy (CRT) in Locally Advanced, Non-Small Cell Lung Cancer (LA-NSCLC) Melissa A.L. Vyfhuis, MD, PhD, Whitney M. Burrows, MD, Neha Bhooshan, MD, PhD, Mohan Suntharalingam, MD, MBA, James M. Donahue, MD, Josephine Feliciano, MD, Shahed Badiyan, MD, Elizabeth M. Nichols, MD, Martin J. Edelman, MD, Shamus R. Carr, MD, Joseph Friedberg, MD, Gavin Henry, MD, Shelby Stewart, MD, Ashutosh Sachdeva, MD, Edward M. Pickering, MD, Charles B. Simone, II, MD, Steven J. Feigenberg, MD, Pranshu Mohindra, MD PII:

S0360-3016(18)30250-5

DOI:

10.1016/j.ijrobp.2018.02.003

Reference:

ROB 24781

To appear in:

International Journal of Radiation Oncology • Biology • Physics

Received Date: 4 December 2017 Revised Date:

26 January 2018

Accepted Date: 5 February 2018

Please cite this article as: Vyfhuis MAL, Burrows WM, Bhooshan N, Suntharalingam M, Donahue JM, Feliciano J, Badiyan S, Nichols EM, Edelman MJ, Carr SR, Friedberg J, Henry G, Stewart S, Sachdeva A, Pickering EM, Simone II CB, Feigenberg SJ, Mohindra P, Implications of Pathological Complete Response (pCR) Beyond Mediastinal Nodal Clearance with High-dose Neoadjuvant Chemoradiotherapy (CRT) in Locally Advanced, Non-Small Cell Lung Cancer (LA-NSCLC), International Journal of Radiation Oncology • Biology • Physics (2018), doi: 10.1016/j.ijrobp.2018.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Implications of Pathological Complete Response (pCR) Beyond Mediastinal Nodal Clearance with High-dose Neoadjuvant Chemoradiotherapy (CRT) in Locally Advanced, Non-Small Cell Lung Cancer (LA-NSCLC) Implications of pCR after neoadjuvant chemoradiation in stage III NSCLC

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Melissa A.L. Vyfhuis, MD, PhDa, Whitney M. Burrows, MDb, Neha Bhooshan, MD, PhDa, Mohan Suntharalingam MD, MBAc, James M. Donahue, MDd, Josephine Feliciano, MDe, Shahed Badiyan, MDc, Elizabeth M. Nichols, MDc, Martin J. Edelman, MDf, Shamus R. Carr, MDb Joseph Friedberg, MDb, Gavin Henry, MDb, Shelby Stewart, MDb, Ashutosh Sachdeva, MDg, Edward M. Pickering, MDg, Charles B. Simone, II, MDc, Steven J. Feigenberg, MDh, Pranshu Mohindra, MD c* a

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Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD Division of Thoracic Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD c Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD d Division of Thoracic Surgery, Department of Surgery, University of Alabama at Birmingham School of Medicine, Baltimore, MD e Department of Hematology and Oncology, Johns Hopkins Hospital, Baltimore, MD f Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA g Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD h Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA

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*Corresponding author/Statistical Analysis: Pranshu Mohindra MD, MBBS, DABR Assistant Professor Department of Radiation Oncology University of Maryland School of Medicine 22 S. Greene St., Rm GGJ35 Baltimore, MD 21201 Phone: (410) 328-9155 Fax: (410) 328-5279 Email: [email protected] Conflict of interest: None of the authors have any conflict of interests to disclose. Acknowledgements

We would like to thank Dr. Nancy Knight, PhD for providing editorial guidance on this manuscript as well as Dr. Søren M. Bentzen, PhD, DMSc for his guidance in the statistical analysis.

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Abstract

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Purpose: Mediastinal response guides decision for surgery in LA-NSCLC patients treated with neoadjuvant therapy, where mediastinal nodal clearance (MNC) is strongly associated with improved survival. The added benefit of a pathologic complete response

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(pCR), with no viable tumor in both the mediastinum and primary site is not known, which is the objective of this large, single-institutional analysis using a high-dose

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neoadjuvant chemoradiation (CRT) approach.

Methods and Materials: At our institution, 355 patients with LA-NSCLC were treated with curative intent with definitive CRT (Jan 2000-Dec 2013) of which 111 underwent mediastinal reassessment for possible surgical resection. Ultimately 88 patients received trimodality therapy. χ2 analysis was used to compare categorical variables. The Kaplan-

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Meier analysis was performed to estimate overall survival (OS) and freedom-fromrecurrence (FFR) with cox regression used to determine the absolute hazards.

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Results: Using high-dose neoadjuvant CRT, we observed a MNC rate of 74% (82/111 patients) and pCR rate of 48% (37/77 patients). With a median follow up of 34.2 months

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(range: 3–177 months), MNC resulted in improved OS and FFR on both univariate (OS: Hazard Ratio [HR]:0.455, 95% CI: 0.272–0.763, P=0.004; FFR: HR:0.426, 95% CI: 0.250–0.726, P =0.002) and multivariate analysis (OS: HR:0.460, 95% CI: 0.239–0.699, P =0.001; FFR: HR:0.455, 95% CI: 0.266–0.778, P =0.004). However, pCR did not independently impact OS (P=0.918) or FFR (P=0.474). Conclusion: MNC after CRT continues to be predictive of improved survival for patients undergoing trimodality therapy. However, a pCR at both the primary and mediastinum

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did not further improve survival outcomes. Future therapies should focus on improving MNC to encourage more frequent use of surgery and might justify use of pre-operative

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CRT over chemotherapy alone.

Keywords: Stage III NSCLC, trimodality, mediastinal nodal clearance, complete

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pathologic response

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Introduction Non-small cell lung cancer (NSCLC) accounts for an approximately 87% of all

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lung cancer diagnosis in the United States (US) and 22% of patients present with locally advanced disease.1 Despite evolution in treatment paradigms and technology in stage III NSCLC, overall-survival (OS) remains poor with 5-year rates ranging from 19-36%.2

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Current National Comprehensive Cancer Network (NCCN) guidelines recommend

concurrent chemoradiation (CRT) for curative treatment in the majority of stage III

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NSCLC, reserving surgical resection to those with only minimal nodal disease at time of diagnosis.3 However, rates of local-regional recurrence remains quite high in the nonoperative setting, with an estimated progression-free-survival (PFS) of approximately 5.8 - 11 months 4,5 and local failure rates as high as 30-40% at 2-years.4,6,7

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The addition of surgical resection after CRT remains controversial in stage III NSCLC, although studies have shown a benefit in local control and perhaps OS in carefully selected patients.7–11 A common theme found in these studies is the strong

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correlation of OS with clearance of mediastinal disease (MNC) at time of surgical resection,7,9 regardless of the extent of initial disease at time of diagnosis.10,12,13 In RTOG

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0229, the estimated two-year OS after neoadjuvant CRT was 67% vs. 54% in those patients who did and did not achieve MNC, respectively (P = 0.002).9 A similar trend was seen in the Intergroup 0139 trial, where patients who attained a pN0 response following CRT at the time of surgery had a significant improvement in outcomes when compared to those who had residual disease (pN1-3) or no surgery (5-year estimated OS of 41%, 24% and 8%, respectively).7 While the clinical significance of MNC has been

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consistently established in the literature, the additional benefit of obtaining a complete pathologic response (pCR) in both the nodes and the primary tumor sites after definitive CRT and surgical resection (trimodality therapy) has not been defined. We therefore

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performed a retrospective analysis a large cohort of stage III NSCLC patients treated with curative intent at our institution (Jan 2000 – Dec 2013) to determine if having a pCR

influenced OS or freedom-from-recurrence (FFR) in patients who underwent definitive

Patient Selection

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Materials and Methods

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(≥60 Gy) neoadjuvant doses of CRT.

Under institutional review board (IRB) approval (GCC 1175, “Thoracic Oncology Database”), we assessed all consecutive patients with stage III NSCLC (re-staged

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retrospectively per American Joint Committee on Cancer [AJCC] staging criteria, 7th edition) who were treated with curative intent at our institution between January 2000 and December 2013 to allow time for adequate follow-up assessment. Our institution’s

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general treatment paradigm for LA-NSCLC includes initial imaging and invasive (mediastinoscopy or endobronchial ultrasound guided transbronchial needle aspiration

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[EBUS-TBNA]) staging followed by intent to deliver definitive (≥60 Gy) doses of CRT. Patients then undergo mediastinal resampling to assess for clearance prior to proceeding with surgical resection. We have previously reported on the factors influencing consideration for surgery in these patients (10). Of the 355 patients in our study population, 111 underwent mediastinal reassessment in preparation for possible surgical resection after CRT, and 107 pathology reports were available for review (Figure 1).

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Table 1 summarizes patient demographic, disease and treatment information in our cohort. Briefly, patients in this analysis were assessed by a multi-disciplinary team at presentation and were all planned to receive high-dose CRT (concurrent or sequential)

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(Table 1). Radiation was delivered with either three-dimensional conformal radiation

therapy (3D-CRT) or intensity-modulated radiation treatment (IMRT), the latter being more common after 2009, to a median dose of 63.9 Gy (range: 39.6–70.2Gy, 93.7%

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patients receiving ≥ 60 Gy) delivered in 1.8 or 2 Gy daily fractions. All patients received platinum-based chemotherapy, with weekly carboplatin/paclitaxel (carboplatin, area

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under the curve [AUC] of 2; paclitaxel, 50 mg/m2) for concurrent CRT as the most common (74%) regimen. For patients who initially received weekly carboplatin/paclitaxel with radiation treatment, an additional two cycles of consolidation chemotherapy (carboplatin/paclitaxel; AUC of 5–6/200–225 mg/m2, respectively) was

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given, as tolerated, 4-6 weeks after completing surgical resection. PET/CT imaging was routinely used to assess treatment response after neoadjuvant treatment in the majority (63%) of patients.

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Pathology reports from the nodal resampling, which were typically done at time of surgery, were used to assess the treatment response from the neoadjuvant CRT. Nodal

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reassessment was typically done 6-8 weeks after CRT. Patients were considered to have a MNC if no viable tumor was identified at the time of pre-operative staging. Likewise, pathology reports from the surgical resection were used to get a confirmation of mediastinal clearance and also to ensure absence of viable tumor at the primary site, which constituted a complete pCR. After definitive treatment, patients were generally

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monitored with serial CT or PET/CT scans as clinically indicated every three months for the first year, 4-6 months for the next 2-5 years, then yearly thereafter. Statistical Analysis

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All patients in this study were retrospectively analyzed. OS was calculated from date of diagnosis (i.e. confirmatory biopsy of primary or mediastinal nodes) to the time of death or the date of last follow-up. FFR was determined by date of diagnosis to the time

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of first failure (i.e. distant or local/regional progression). The Kaplan–Meier method was used to plot survival curves and estimate OS and FFR. Log-rank test statistics were used

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to assess levels of statistical significance between selected covariates.

Cox regression with forward modeling selection was used to determine which covariates were significant for OS and FFR on multivariate analysis. Variables analyzed for clinical outcomes included the following: age (<60 vs. ≥60 years; median age), race

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(black vs. non-black), sex, marital status, insurance status (yes vs. no), smoking (packyears), median household income, Eastern Cooperative Oncology Group performance status (ECOG PS) at time of diagnosis (0 vs. ≥1), Charlson comorbidity index score (≤6

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vs. >7; median 6), COPD diagnosis, T-stage, N-stage, overall stage (IIIA vs. IIIB), histological subtype, radiation technique (3D-CRT vs. IMRT), date of diagnosis (divided

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into quartiles based on proportion diagnosed by years: 2000-2002, 2003-2005, 20062009, 2010-2013), MNC achieved (yes vs. no), pCR achieved (yes vs. no), radiation dose (<60 vs. ≥60 Gy), time to mediastinoscopy, type of chemoradiation (concurrent vs. sequential) and use of consolidation chemotherapy. All factors were first analyzed on univariate analysis and if they were predictive for either clinical outcome (entry criteria P = 0.10, exit criteria P > 0.05), they were included in the MVA. SPSS software was used

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for statistical analysis (SPSS Statistics for Windows, Version 21.0., IBM Corporation; Armonk, NY). Results

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Patient population

Table 1 summarizes the cohort’s patient demographic, disease and treatment

characteristics. Approximately two-thirds of the patient population self-identified as

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white, with a median age of 61 years (range: 30-87), the majority of which were married and had an ECOG PS of 0. Nearly 70% of the patients who underwent mediastinal

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reassessment after CRT had clinical N2 (33% of N2 patients had multistation disease) and stage IIIA at time of diagnosis. Mediastinal staging before commencement of CRT consisted of either a mediastinoscopy or EBUS-TBNA in the majority of patients (Table 1).

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Figure 1 summarizes the cohorts MNC and pCR rates after neoadjuvant definitive-dose CRT and surgical resection, respectively. One-hundred and eleven patients underwent nodal reassessment for possible surgical resection. Among the 107 of

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these patients with pathology reports available for review, 82 patients achieved MNC, giving a MNC rate of 73.9% after neoadjuvant CRT. In the entire cohort of 111 patients,

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88 patients underwent surgical resection, 94% of whom received ≥60 Gy with their CRT regimen. From these, 83 surgical pathology reports were accessible at the time of this retrospective study. Surgical resection at the primary site was completed in 77 of the 82 patients who achieved MNC after CRT. Reasons for the 5 patients not undergoing surgical resection were as follows: 2 patients had a primary lesion that was deemed unresectable by the thoracic surgeon and 1 had metastatic disease at restaging (done after

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mediastinal assessment). The reason for lack of surgical resection for two patients could not be ascertained from the available records. Thirty-seven patients attained MNC along with a complete pathologic response at their primary tumor, giving a final pCR rate of

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48% (Figure 1).

Eight patients underwent surgical resection despite nodal disease found at time of nodal reassessment as seen in Figure 1. Reasons for proceeding with trimodality therapy

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in this small cohort was primarily due to the surgeon giving the patient the “benefit of the doubt” secondary to either just microscopic disease found in the mediastinum at the time

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of surgery (N=3) or N1 nodal stations involved with tumor (N=3). In one patient, the primary was contiguous with a cardiophrenic lymph node and thus surgical resection was continued. We were unable to ascertain the reason why the last patient underwent trimodality therapy with positive nodes at the time of surgery given the available records.

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Survival analysis

With a median follow-up of 34.2 months for all patients (n = 111) and 102 months for surviving patients (range: 3 – 177 months), patients with MNC at time of

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nodal reassessment had an improved OS (Figure 2A) and FFR (Figure 2B), when compared to those who did not. The estimated median survival for patients with MNC

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was 61 months vs. 29 months in those who still had residual disease after definitive CRT (unadjusted Hazard Ratio [HR]: 0.455, 95% CI: 0.272 – 0.763, P = 0.004; Figure 2A). Two and five-year OS was 71% and 59%, respectively, in patients who achieved MNC, while corresponding rates for those who did not obtain MNC were 68% and 14%. FFR was also improved with MNC, where the estimated median time to failure was 38 months with MNC and 18 months in those with residual nodal tumor (unadjusted HR: 0.426,

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95% CI: 0.250 – 0.726, P = 0.002; Figure 2B). Two and five-year FFR rates in patients with and without MNC were 53%, 44% and 32%, 8%, respectively. The addition of a complete pathologic response at the primary site after MNC was

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achieved, did not improve OS (Figure 3A) or FFR (Figure 3B). The estimated median

survival and time to recurrence for patients with a pCR and residual tumor at the primary site in the setting of MNC was approximately 61 months (unadjusted HR: 1.032, 95% CI:

0.645 – 2.569, P = 0.474; Figure 3B), respectively.

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0.566 – 1.881, P = 0.918; Figure 3A) and 38 months (unadjusted HR: 1.287, 95% CI:

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MNC was an important predictor for OS and FFR as seen in both univariate (Table 2) and multivariate analysis (Table 3). If mediastinal clearance was achieved, there was an approximate 50% decrease risk of death and disease recurrence as compared to patients who still had residual mediastinal disease (Table 3). Attaining a complete

Failure patterns

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pathologic response continued to have no influence on clinical outcomes in MVA.

Table 4 summarizes failure patterns in patients who attained MNC and in those

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who also achieved a pCR. In those with MNC, over half (53%) of the patients had no failure. The most common failure pattern was distant (30%). Patients who did not

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achieve MNC were 2 and 2.5 times more likely to have distant and locoregional failures, respectively when compared to those patients with MNC (P = 0.001; Table 4). On the other hand, there was no statistically significant difference in failure patterns in patients who did and did not achieve a pCR in both the primary tumor site and mediastinum.

Discussion

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In this retrospective analysis of trimodality therapy utilizing high-dose neoadjuvant CRT for patients with stage III NSCLC, we note a 73.4% rate of MNC and 48% pCR. We demonstrated a survival advantage in patients who were able to attain

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MNC after neoadjuvant therapy, even when accounting for various patient demographic, disease and treatment characteristics (Figure 2; Table 3). This positive association of

MNC on clinical outcomes has also been confirmed in several prospective trials. 7,9,13–16

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Even so, the benefit of a pCR, in both the nodes and primary tumor, was never fully

evaluated in those trials and was the goal of our study. Our study, the largest reported

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institutional analysis of pathological response to neoadjuvant CRT to date, demonstrates that there was no additional benefit (over MNC) on clinical outcomes if patients had a pCR in both the nodes and primary site (Figure 3A and 3B).

This relative lack of prognostic significance of pCR at both mediastinum and

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primary tumor seen in our own analysis and other data suggests that while neoadjuvant treatment is important for regionally/distant metastatic disease, surgical resection, especially with clear margins, attenuates the impact that the CRT response in the primary

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tumor has on clinical outcomes, principally by removing tumor burden and improving local control.7–10 For example, in the Intergroup 0139 study, although local control did

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not translate into an OS benefit with trimodality treatment (most likely due to the high mortality rate seen in patients who received pneumonectomies), an unplanned subset analysis did reveal an OS advantage in those patients who underwent a lobectomy.7 Furthermore, various institutional analyses have depicted an OS advantage to trimodality treatment, especially in the setting of MNC10,11,17, relaying the importance of local control with surgery, but not necessarily the pathologic response at the primary site (Figure 3).

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Our analysis also creates an opportunity to compare pathological outcomes between neoadjuvant CRT versus neoadjuvant chemotherapy alone, which is another approach that is followed by many NCCN institutions for patients with stage III

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NSCLC.18 It has been reported in prior studies that neoadjuvant CRT often results in a

higher rate of MNC (Intergroup 0139: 38%7, RTOG 0229: 63%9, Figure 1: 74% in this study), when compared to more modern-day neoadjuvant chemotherapeutic regimens

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(Betticher et al.: 19%,13 Liao et al.: 12%,15 German Lung Cancer Cooperative Group

Study [GLCCGS]: 20%14).19 In comparison, the pCR reported in large trials evaluating

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neoadjuvant chemotherapy were relatively low at 0% (0/28 patients), 3% (1/30 patients) and 12% (9/73 patients) for the studies by Roth et al.,20 Rosell et al.,21 and Pister et al.22, respectively. The GLCCGS did note that while the addition of CRT did increase mediastinal downstaging and pathologic response, it had no significant impact on OS.14

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The rarity of achieving a pCR in these series would overshadow any statistically significant association between clinical outcomes and a pCR. Our data are the first to show the implication of a pCR after definitive CRT

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followed by surgery in stage III NSCLC; however, like any retrospective analysis, our study has some limitations. For example, there is an inherent selection bias in choosing

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patients for trimodality therapy. In our previous report we noted that race (P< .001), stage (P < .001), performance status (P < .001), age (P < .001), and diagnosis of chronic obstructive pulmonary disease (P = .009) were significant indicators that influenced both the decision to initially choose trimodality therapy at consultation and to actually perform surgical resection. While this can definitely impact survival outcomes comparing those undergoing surgery versus not (trimodality vs. bimodality), it is unlikely to have a large

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impact on the analysis of outcomes within the trimodality cohort based on the pathological response. We have confirmed this in the Cox Regression Model (Table 3). Secondly, histology can also impact response rates to neoadjuvant treatment in NSCLC,

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as squamous cell carcinomas tends to have a greater response when compared to

adenocarcinomas.15 Unfortunately, we were restricted by the histology reported during chart reviews and found that one-third of our cohort was identified as NSCLC “not

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otherwise specified” (Table 1). Thus, we could not find any meaningful difference between histological subtypes and the response to definitive CRT that could have

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impacted clinical outcomes. Furthermore, despite this being a large institutional analysis, due to relative scarcity of patients able to undergo trimodality therapy, the number of patients in each arm may be under-powered to detect a statistically significant difference in OS and FFR between those patients who had a pCR. Finally, due to limitations in

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historical pathological documentation, we were unable to separately analyze microscopic vs. gross residual disease after CRT, which have been previously shown to impact OS in patients undergoing trimodality therapy in esophageal cancer.23

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Nonetheless, our findings indicate that as long as an R0 surgery is performed after neoadjuvant therapy, while maximizing the ability to achieve MNC through the use of

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definitive (≥60 Gy) CRT, the pathologic response at the primary site has little impact on outcomes. Future studies should aim at augmenting the rate of MNC in operable LANSCLC patients thereby maximizing patient selection for trimodality therapy. Our analysis also supports the notion of the relative radioresistance of primary tumors (pCR, 48%) when compared to nodal disease (MNC, 74%) after neoadjuvant treatment. Therefore, in unresectable stage III NSCLC patients treated with bimodality CRT, future

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approaches could evaluate boosting the primary tumor using advanced radiation techniques such as stereotactic body radiotherapy (SBRT),24 IMRT or proton therapy with either a conventional or hypofractionated approach as is currently being investigated

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in LUN005 (ClinicalTrials.gov Identifier: NCT01770418). Another method that can

potentially improve both pCR and MNC could be through the use of immunotherapy

such as nivolumab25 or durvalumab, the latter of which was recently shown to improve

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progression-free survival in stage III NSCLC patients.5 Through the use of patient-

tailored treatment paradigms based on medical operability, we can potentially improve

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clinical outcomes in locally-advanced NSCLC.

Funding: This research did not receive any specific grant from funding agencies in the

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public, commercial, or not-for-profit sectors.

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Chemoradiotherapy vesus Chemotherapy alone Followed by Surgery for Resectable Stage III Non-Small-Cell Lung Cancer: a Meta-Analysis. Nat Publ Gr. 2016;2016(December 2010):7. doi:10.1038/srep34388. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative

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nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373(17):1627–

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1639. http://dx.doi.org/10.1056/NEJMoa1507643.

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Figure Legends Figure 1. Flow diagram depicting the mediastinal nodal clearance (MNC) and pathologic

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complete response (pCR) rates in the patient cohort. Of the 111 patients who underwent repeat nodal assessment, 107 pathology reports were available for review. Eighty-eight patients underwent surgical resection, with 85 of them having pathology reports

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accessible for this study. Eight patients with positive nodes underwent trimodality therapy, three patients had N1 disease at time of resection.

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Figure 2. Five-year (A) OS (HR: 0.455, 95% CI: 0.272 – 0.763, P = 0.004) and (B) FFR (HR: 0.455, 95% CI: 0.272 – 0.763, P = 0.004) in patients who achieved MNC (gray dashed line) and in those with residual disease in the mediastinum (dark solid line) after definitive neoadjuvant CRT.

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Figure 3. Five-year (A) OS (HR: 1.032, 95% CI: 0.566 – 1.881, P = 0.918) and (B) FFR (HR: 1.287, 95% CI: 0.645 – 2.569, P = 0.474) in patients who did (gray dashed line) and did not (dark solid line) achieve a complete pathologic response (pCR) at the primary site

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following definitive, neoadjuvant CRT and surgical resection.

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Table 1: Baseline demographic, disease, and treatment characteristics of patients undergoing repeat mediastinoscopy after chemoradiation (n = 111) Characteristic No. Patients (%) Age (years) Median/range 61/30-87 ≥ 60 46 (41.4) Sex Men 60 (54.1) Women 51 (45.9) Race White 81 (73.0) Black 28 (25.2) Other 2 (1.8) Above Median Income ≥ 43, 723 68 (61.3) Eastern Cooperative Oncology Group performance status 0 78 (70.3) ≥1 32 (28.8) Unknown 1 (0.9) Marital status Married 75 (67.6) Single 36 (32.4) Smoking (pack-years) Median/Range 40/0-212 Chronic obstructive pulmonary disease diagnosis Yes 20 (18.3) Charlson comorbidity score ≤6 72 (64.9) >6 38 (34.2) Unknown 1 (0.9) Histology Adenocarcinoma 41 (37.0) Squamous Cell 27 (24.3) NSCLC 35 (31.5) (not otherwise specified) Other 8 (7.2) a T stage TX 1 (0.9) ≤ T2 63 (56.8) ≥ T3 47 (42.3) N stagea NX 1 (0.9) ≤ N1 17 (15.3) N2 77 (69.4) N3 16 (14.4) b Superior Sulcus Tumors Yes 4 (3.6) Mediastinal staging at time of diagnosis

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Mediastinoscopy 10 (9.0) EBUS 70 (63.0) PET/CT alone 21 (18.7) CT alone 7 (6.6) Unknown 3 (2.7) Overall stagea IIIA 78 (70.3) IIIB 33 (29.7) Treatment Trimodality 88 (79.3) Bimodality 23 (20.7) Type of chemoradiation Concurrent 109 (98.2) Sequential 2 (1.8) Radiation dose delivered (Gy) Median/Range 63.9/39.6 – 70.2 ≥ 60 104 (93.7) Radiation techniquec 3D-confromal 93 (83.8) IMRT 11 (9.9) Time to nodal assessment after chemoradiation (days)d Median/Range 52 (28-178) Adjuvant chemotherapye Yes 83 (74.8) a American Joint Committee on Cancer (AJCC) 7th edition staging. b Of the 88 patients who went to surgery, 3 were pancoast tumors. c Data not available for 7 patients. d Data not available for 18 patients. e Data not available for 8 patients.

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Table 2. Factors associated with overall survival (OS) and freedomfrom-recurrence (FFR) on univariate analysis a Characteristic Hazard 95% confidence p-value Ratio interval OS MNC achieved 0.455 0.272 – 0. 763 p = 0.004 ECOG PS (0 vs. ≥ 1) 0.519 0.321 – 0.840 p = 0.008 Trimodality vs. 0.498 0.297 – 0.837 p = 0.008 Bimodality Age 0.213 0.087 – 0.522 p = 0.001 Histology 0.792 0.632 – 0.992 p = 0.021 Medium Income 1.648 1.008 – 2.692 p = 0.046 FFR MNC achieved 0.426 0.250 – 0.726 p = 0.002 Trimodality vs. 0.457 0.265 – 0.788 p = 0.005 Bimodality Diagnosis Era 0.731 0.551 – 0.970 p = 0.030 a Abbreviations: MNC = mediastinal nodal clearance, ECOG PS = Eastern

Cooperative Oncology Group performance status

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Table 3. Factors associated with overall survival (OS) and freedomfrom-recurrence (FFR) in the cox regression model a,b Characteristic Hazard 95% confidence p-value Ratio interval OS MNC achieved 0.460 0.239 – 0. 699 p = 0.001 ECOG PS (0 vs. ≥ 1) 0.423 0.250 – 0.718 p = 0.001 Medium Income 1.728 1.030 – 2.898 p = 0.038 FFR MNC achieved 0.455 0.266 – 0.778 p = 0.004 a Cox regression with forward model selection was used for MVA (entry criteria P = 0.10, exit criteria P > 0.05). b Abbreviations: MNC = mediastinal nodal clearance, ECOG PS = Eastern

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Cooperative Oncology Group performance status

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Table 4. Patterns of failure between patients who achieved MNC or a pCRa, e. Sites of first recurrence MNCb pCRc Achieved Not Achieved p-value Achieved Not Achieved 43 (53.1) 1 (4.2) 22 (61.1) 18 (47.4) None 0.001 9 (11.1) 6 (25) 4 (11.1) 3 (7.9) Locoregional 24 (29.6) 14 (58.3) 8 (22.2) 14 (36.8) Distant 5 (6.2) 3 (12.5) 2 (5.6) 3 (7.9) Combinationd a Number of patients (%) b MNC – failure status unknown for 2 patients c pCR – failure status unknown for 1 patient d Locoregional + distant metastatic disease e Abbreviations: MNC = mediastinal nodal clearance, pCR = complete pathologic response in mediastinum + primary

p-value 0.527

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Mediastinal Evaluation for Surgery n = 111 M AN U

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Pathology missing n=2 ypN0 = 73 pCR = 48% ypT0 = 37

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77 to surgery

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MNC = 74%

ypN+ = 2 ypT+ = 38

25 med positive 8 to surgery

ypN0 = 0 ypT0 = 1

ypN+ = 8 ypT+ = 7

Pathology missing n=4 n=3

MNC + MNC -

Overall survival (%)

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No. At Risk: 25 82

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No. At Risk: 25 82

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No. At Risk: 36 37

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Summary Mediastinal nodal clearance (MNC) is associated with improved outcomes in patients with stage III NSCLC, however, the benefit of a complete pathologic response (pCR) after high-dose

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(≥60Gy), neoadjuvant chemoradiation is unclear. A retrospective analysis on stage III NSCLC patients treated at our center with curative intent from 2000-2013 was performed. We found that

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pCR did not further improve overall survival.

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MNC remains prognostic for oncological outcomes in stage III NSCLC, however, obtaining a