Long-Term Outcomes and Patterns of Failure After Surgical Resection of Small-Cell Lung Cancer

Accepted Manuscript Long-term Outcomes and Patterns of Failure Following Surgical Resection of Small Cell Lung Cancer Bradley J. Stish, MD, Christopher L. Hallemeier, MD, Kenneth R. Olivier, MD, William S. Harmsen, MS, Mark S. Allen, MD, Yolanda I. Garces, MD PII:

S1525-7304(15)00057-1

DOI:

10.1016/j.cllc.2015.02.004

Reference:

CLLC 357

To appear in:

Clinical Lung Cancer

Received Date: 29 December 2014 Revised Date:

12 February 2015

Accepted Date: 17 February 2015

Please cite this article as: Stish BJ, Hallemeier CL, Olivier KR, Harmsen WS, Allen MS, Garces YI, Long-term Outcomes and Patterns of Failure Following Surgical Resection of Small Cell Lung Cancer, Clinical Lung Cancer (2015), doi: 10.1016/j.cllc.2015.02.004. 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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[Category: Original Study] Revised Ms No. CLC-D-14-00420

Bradley J. Stish, MD Christopher L. Hallemeier, MD Kenneth R. Olivier, MD

Mark S. Allen, MD

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William S. Harmsen, MS

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Lung Cancer

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Long-term Outcomes and Patterns of Failure Following Surgical Resection of Small Cell

Yolanda I. Garces, MD

Author Affiliations: Department of Radiation Oncology (Drs Stish, Hallemeier, Olivier,

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and Garces), Division of Biomedical Statistics and Informatics (Mr Harmsen), and Department of General Thoracic Surgery (Dr Allen), Mayo Clinic, Rochester, Minnesota. Reprints: Yolanda I. Garces, MD, Department of Radiation Oncology, Mayo Clinic, 200

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First St SW, Rochester MN 55905 ([email protected]) Phone: 507-284-3261 Fax: 507-284-0079.

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Conflicts of Interest and Source of Funding: None declared.

Text word count: 2,772 Abstract word count: 231 No. of tables: 2

No. of figures: 4 Running title: Surgery for Small Cell Lung Cancer Publisher: To expedite proof approval, send proof via e-mail to [email protected]. ©2015Mayo Foundation for Medical Education and Research

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Abstract Background: The role of surgical resection as a treatment option for early-stage small

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cell lung cancer is controversial, and little data exist regarding patterns of treatment failure in these patients.

Patients and Methods: The records of all patients receiving definitive surgical

management of small cell lung cancer at Mayo Clinic, Rochester, Minnesota, between

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January 1, 1985, and December 31, 2012, were reviewed. Estimates of survival and risk of recurrence were recorded using the Kaplan-Meier method, and comparative analyses

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were performed with Cox regression.

Results: A total of 54 patients were identified. The median follow-up was 5.9 years. At 5 years, overall survival was 37% and recurrence-free survival was 44%. Intrathoracic recurrence, the most frequent treatment failure, occurred in 14 patients, with an estimated intrathoracic recurrence-free survival at 3 years of 64.4%. Patients undergoing wedge

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resection or segmentectomy rather than lobectomy or pneumonectomy had an increased risk of intrathoracic recurrence (hazard ratio, 3.5; P=.01). Overall survival was improved at 5 years after lobectomy or pneumonectomy compared with wedge resection or

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segmentectomy (48% vs 15%, respectively; P=.03). Conclusions: Surgical resection of small cell lung cancer achieves reasonable treatment

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outcomes and can be considered for well-selected patients with clinical early-stage disease. Intrathoracic recurrence is the most common site of treatment failure. Caution should be taken with patients who are unable to tolerate at least lobectomy, as they are at high risk for local recurrence.

Keywords: adjuvant/neoadjuvant therapy; lobectomy, segmentectomy, wedge resection; lung cancer surgery

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Microabstract We reviewed the outcomes and patterns of failure for patients with small cell

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lung cancer who underwent definitive surgical resection. Our data revealed that intrathoracic recurrences were the most common site of failure, especially in those

undergoing limited resections. Careful patient selection and consideration of aggressive

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adjuvant treatments for those at high risk of recurrence may help improve outcomes.

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Abbreviations CI, confidence interval

IR, intrathoracic recurrence L/P, lobectomy or pneumonectomy NSCLC, non–small cell lung cancer OS, overall survival

RFS, recurrence-free survival SCLC, small cell lung cancer TRT, thoracic radiation therapy

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PET, positron emission tomographic

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W/S, wedge resection or segmentectomy

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HR, hazard ratio

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CT, computed tomographic

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Introduction Small cell lung cancer (SCLC) accounts for approximately 15% (30,000

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cases) of the primary lung cancer diagnoses in the United States each year (1). Due to SCLC’s aggressive clinical behavior and propensity for distant dissemination, the

prognosis for patients with SCLC is poor. Median survival times have been reported as 15 to 20 months in patients with limited-stage disease and as 8 to 13 months in those with

after aggressive treatment of localized SCLC (3).

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extensive-stage disease (2). Despite these dismal outcomes, long-term survival can occur

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The majority of patients with limited-stage disease are not considered surgical candidates because of preexisting comorbid conditions, the presence of lymph node metastases at diagnosis, or both. However, the current National Comprehensive Cancer Network guidelines recommend surgical resection as the preferred first-line treatment for patients with early-stage, node-negative disease (4). These patients

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represent less than 5% of all patients with SCLC (5), and limited data have been published to guide recommendations for adjuvant therapy after surgery. Adjuvant chemotherapy is recommended after complete surgical resection, but data assessing the

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role of adjuvant thoracic radiation therapy (TRT) in these patients are lacking. Given the relative infrequency of surgery for SCLC, additional studies are

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needed to help guide recommendations for adjuvant therapy. The purpose of this study was to evaluate clinical outcomes and patterns of recurrence in a single-institution series of patients undergoing curative resection of SCLC. We hypothesized that there are subsets of patients at high risk for local recurrence after surgery. Thorough analyses were performed to identify risk factors for intrathoracic recurrence (IR) and to determine whether there are patients who may benefit from adjuvant TRT.

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Patients and Methods Patient Selection

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Databases from the Department of Thoracic Surgery and the Mayo Clinic Cancer Registry were searched to identify patients undergoing surgical resection for SCLC between January 1, 1985, and December 31, 2012. Patients were included in the final analysis if complete records of staging, operative notes, surgical pathology, adjuvant

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treatment, and follow-up were available for review. Exclusion criteria were incomplete resection of all known disease, histology other than SCLC, death within 3 months of

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surgery, and incomplete records of adjuvant treatment or follow-up. This retrospective medical record review was approved by the Mayo Clinic Institutional Review Board. Disease Staging, Treatment, and Follow-up

All patients included in this analysis had computed tomographic (CT) imaging of the chest performed before surgery. Any radiographically suspicious lymph

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nodes amenable to bronchoscopy were biopsied before surgery. Patients with biopsyproven lymph node metastases were excluded from surgery and treated with definitive chemoradiation. Systemic staging, including brain imaging, was performed within 2

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months of the date of surgery. Positron emission tomographic (PET) imaging was performed on all patients treated after 2000. Final staging was assigned in accordance

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with the American Joint Committee on Cancer’s AJCC Cancer Staging Manual, seventh edition (6). The method and extent of surgical resection were determined for each patient individually by the thoracic surgeon according to tumor extent and location and the patient’s pulmonary function. Use of adjuvant chemotherapy, radiation therapy, and follow-up imaging was determined on a case-by-case basis at the discretion of the treating oncologists. Patient follow-up information was reviewed through April 30, 2013.

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Patterns of Recurrence and Study End Points Date of recurrence was defined by biopsy-proven SCLC or radiographic

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evidence of new disease. Overall survival (OS) and recurrence-free survival (RFS) were determined from the date of surgery to the date of last clinical follow-up. If recurrences were synchronous in 2 separate sites (eg, intrathoracic and distant) at the time of first recurrence, each was recorded. Locations of IR were recorded from physician review of

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the radiographic images. Local failures were defined as recurrence involving the

bronchial stump or staple line. Although subsequent recurrences were recorded, patients

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were censored for all statistical analyses at the time of first recurrence. Statistical Analysis

Descriptive statistics are reported as number (percentage) or median (range) as appropriate. RFS, IR, and OS were estimated using Kaplan-Meier survival methods. Results are reported as an estimate (at 3 years for RFS and IR and at 5 years for OS) and

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as a 95% confidence interval (CI). The univariable association of each variable with each of the 3 outcomes of interest was assessed using Cox proportional hazards regression, reported as hazard ratios (HRs) and 95% CIs. In addition, models were examined for the

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outcome of RFS for each variable of interest, and included extent of surgery in each of the models. All analyses were done using SAS software version 9.2. The α level was set

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at .05 for statistical significance. Results

Patient and Treatment Characteristics A total of 56 patients who underwent definitive resection for SCLC were

identified; however, 2 patients who died in the immediate perioperative period were excluded from subsequent analyses. Patient and treatment characteristics are listed in Table 1. Of the 54 evaluable patients, a preoperative diagnosis of SCLC was made for 10 patients (19%), whereas an additional 34 patients (63%) received an intraoperative

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diagnosis of SCLC based on frozen pathology as noted in the operative note. Median age at the time of surgery was 69.3 years (range, 53-84 years). Open thoracotomy was

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performed in 42 patients (78%), with the remainder having a thorascopic procedure. Formal mediastinal lymph node assessment was performed in 50 patients (93%), and the median number of lymph nodes assessed on final pathologic analysis was 17 (range, 197). Use of PET imaging improved the sensitivity of preoperative staging compared with

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CT staging alone (86% vs 14%; P=.03). This increased sensitivity was primarily related to preoperative identification of involved regional lymph nodes. Pathologic nodal

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upstaging occurred in only 1 of 27 patients staged with PET/CT, compared with 11 of 27 patients staged with CT imaging alone. Thirty patients (56%) had pathologic stage I disease, and overall pathologic upstaging occurred in 22 patients (41%). Forty-seven patients (87%) received adjuvant chemotherapy, most commonly platinum doublets, and of these, 40 (74%) received at least 4 cycles. Chemotherapy was not administered to the

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other 7 patients because of poor performance status or significant medical comorbidity. Nine of the 54 patients received adjuvant TRT. Median TRT dose was 50 Gy, which was initiated an average of 3.6 months after the date of surgery and in all patients followed

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up-front chemotherapy. Concurrent chemoradiation was not used for any patient. Prophylactic cranial irradiation was administered to 10 patients.

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OS, RFS, and Patterns of Recurrence Median length of follow-up was 5.9 years. Figure 1 shows the Kaplan-Meier

estimates of OS and RFS for the 54 patients in this study. Median OS was 3.1 years, with 1-year and 5-year estimates of OS of 89% and 37%, respectively. Median OS was significantly longer for patients with clinical stage I disease compared to those with preoperative stage II or III disease (4.5 vs 1.6 years; P=.04). A total of 24 patients experienced recurrence of SCLC, and RFS at 3 years was 50% (median RFS, 2.4 years). Patients who had PET staging had no improvement in 3-year RFS (49%) compared to

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less modern imaging modalities. The majority of all recurrences were within 18 months of surgery, with only 3 recurrences (12%) recorded beyond that period. Initial sites of

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recurrence were intrathoracic alone in 8 patients, distant in 10 patients, and intrathoracic and distant in 6 patients. All patients experiencing disease recurrence died of SCLC. RFS was significantly better in patients who had a lobectomy or pneumonectomy (L/P) than in patients who had a wedge resection or a segmentectomy (W/S) (Figure 2A; 3-year RFS,

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70% vs 16%). The HR for any recurrence with W/S compared with L/P was 3.7

(P=.003). No other statistically significant risk factors for recurrence of SCLC were

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identified. Limited surgical resection with W/S was also associated with a decrement in OS at 5 years compared to L/P (Figure 2B; 15% vs 48%, respectively). HR for death in the W/S patients relative to L/P patients was 2.3 (P=.03). Risk Factors for IR

Initial IR occurred in 14 patients, survival free of IR at 3 years of 64.4%. Of

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these 14 IRs, 8 were isolated recurrences (ie, no other site of concurrent failure). Three additional patients experienced IR after initial distant recurrence; however, these were not included in statistical analyses. The Venn diagram in Figure 3 demonstrates the pattern of

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IR by anatomical subsite. Although local parenchymal recurrences were the most common site of isolated IR, the majority of patients had some component of nodal

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recurrence. Table 2 shows HRs of various risk factors for IR as determined by univariate analysis. Patients undergoing less extensive surgery for the primary tumor (W/S) had a significantly increased risk of IR (HR, 3.5; P=.01) compared with those who had L/P. Traditional pathologic indicators of more advanced disease, such as tumor size, lymph node status, and increasing stage, were not significantly associated with increased risk of IR.

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Impact of Adjuvant Treatment on Outcomes Receipt of adjuvant chemotherapy was associated with an improvement in

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OS (HR, 0.49; P=.11) and IR-free survival (HR, 0.5; P=.31) on univariate analysis. Adjuvant TRT was given to 50% of patients with pathologic stage III disease compared with just 5% of stage I/II patients (P=.01). Initial IR occurred in 2 of 9 patients receiving TRT and in 12 of 45 not receiving TRT. Of the 2 patients that experienced IR in the

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adjuvant TRT group, 1 treatment failure was within the radiation field. IR-free survival was improved in patients receiving adjuvant TRT (Figure 4), although this value was not

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statistically significant (P=.31). Median OS was higher in patients given adjuvant TRT (4.3 years vs 2.4 years), and they had a nonsignificant reduced risk of death (HR, 0.6; P=.42). In a multiple-variable model including extent of surgery, use of adjuvant TRT was associated with a reduced risk of any recurrence (HR, 0.5 [95% CI, 0.2-1.5]; P=.23). Comment

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In this retrospective study, we analyzed the clinical outcomes in patients with SCLC who had complete resection of all known disease. The 3-year RFS rate was 50%, with the majority (56%) of patients having pathologic stage I disease. Patterns of failure

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analysis revealed that IR was the most common for initial recurrence. Less extensive surgical resection (W/S vs P/L) was strongly associated with inferior intrathoracic control

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and OS.

Whether surgery is beneficial in patients with SCLC remains unclear (7).

Two randomized trials showed no benefit to surgery compared to radiation for limited stage SCLC; however, these studies were conducted more than 20 years ago and it is unclear whether the outcomes would be different in the modern era (8,9). A 2012 analysis of the National Cancer Database showed that patients undergoing surgery alone or surgery plus adjuvant therapy for SCLC had improved HRs for OS (0.73 and 0.59, respectively) compared with those who had chemoradiation (10). Turrisi et al (11)

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reported a 5-year OS rate of 26% in a randomized study that established twice-daily thoracic radiation with concurrent chemotherapy as the standard treatment for limited-

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stage SCLC. Our analysis found a 5-year OS of 37% in all patients. However, the patients in this series likely represent a more favorable cohort, as indicated by the percentage with mediastinal disease compared with the patients in the study by Turrisi et al (15% vs 60%, respectively). Currently, there is no convincing evidence that the addition of surgery to

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chemotherapy and radiation therapy improves patient outcomes, but the data reported herein suggest that further investigation of the role of surgery in well-selected patients

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with SCLC is warranted. However, the relative infrequency of surgical candidates with SCLC makes prospective, randomized research difficult.

Current National Comprehensive Cancer Network guidelines do not recommend surgical resection for clinically node-positive SCLC patients. Our data support this conclusion, because median OS was significantly decreased in patients with

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clinical stage II/III disease. However, many patients (22%) who were clinically node negative following preoperative staging were found to have nodal metastases on final pathology. Previously, a report from our institution showed a significant decrease in OS

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for patients undergoing surgical resection for stage III/IV SCLC compared with those with stage I/II disease (12). A number of small institutional studies have demonstrated 5-

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year OS rates of 19% to 43% in stage III patients having surgery as a component of multimodality therapy for treatment of SCLC (13-16). Interestingly, our data revealed no significant difference in RFS (data not shown) or OS between pathologically nodenegative and node-positive patients. While this somewhat paradoxical finding is likely due to the limited size of this study, it may be the result of unrecognized nodal spread due to insufficient preoperative or intraoperative staging. The majority of our patients did have formal mediastinal lymph node sampling, with a median of 17 lymph nodes assessed. Interestingly, the extent of lymph node sampling did not differ significantly

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based on the extent of primary tumor resection. However, it is possible that inadequate sampling of the hilar or mediastinal lymph nodes led to unidentified nodal disease.

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Finally, it is possible that adjuvant TRT, which was more frequently used in stage III patients, improved outcomes in these patients by sterilizing residual disease.

Thorough preoperative staging is imperative for proper selection of

appropriate surgical candidates with SCLC. The importance of clinical staging is further

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reinforced by the International Association for the Study of Lung Cancer staging project that demonstrated that clinical TNM staging correlated with survival (5). Previous reports

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have shown PET/CT imaging to be an improved clinical staging tool compared with CT alone in patients with SCLC (17-19), and our series found that PET/CT staging had a significantly improved sensitivity for detecting lymph node metastases. Although modern staging tools, such as PET/CT and endotracheal ultrasonography (20), can improve selection of truly node-negative patients for surgical resection, our data do not

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demonstrate improved outcomes in PET/CT-staged patients. This observation is likely related to the early, systemic nature of SCLC and our limitations in detecting occult metastatic disease during routine staging. At this time, there are no compelling data

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showing that patients with known nodal involvement from SCLC benefit from surgical resection, and they are likely best served with definitive chemoradiation.

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Our data show that the extent of surgical resection for the primary tumor was

the factor most strongly associated with IR. Patients undergoing less extensive surgery (W/S) were significantly more likely to experience IR than those undergoing L/P (HR, 3.5; P=.01). This impact on local recurrence also correlated with an improvement in OS at 5 years (48% vs 15%). These data are consistent with Surveillance, Epidemiology, and End Results analyses that have shown improvements in median survival after lobectomy compared with wedge resection in stage I and II SCLC patients (21-24). Similar findings have been observed in non–small cell lung cancer (NSCLC), with a randomized study

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demonstrating a 3-fold increase in local failure and a corresponding decrement in OS (25). Given the lack of effective salvage treatments for recurrent disease, these data

considered to improve local control rates in operable SCLC.

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suggest that more extensive surgical resection or adjuvant TRT should strongly be

Forty-seven patients (87%) in our study received adjuvant chemotherapy; however only 9 patients (17%) received adjuvant TRT. This small number of patients

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limited our ability to determine if adjuvant TRT provided significant improvements in local control or OS. Our data suggest that there may be gains in RFS and OS with the

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addition of adjuvant TRT, despite these patients having more advanced disease. Little data are present in the literature addressing the question of the optimal adjuvant therapy strategy for patients undergoing surgery for SCLC; however, studies have demonstrated that adjuvant chemotherapy improves patient survival (26-28). In NSCLC, a metaanalysis has shown that adjuvant TRT may be beneficial for patients with N2 disease

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(29). Extrapolation of this observation likely explains the relatively high rate of adjuvant TRT in patients with N2 disease. Our data on patterns of failure reveal that both the surgical margin and the regional lymph nodes are sites of significant risk of IR. This

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finding supports consideration of comprehensive radiation volumes when using adjuvant TRT; however, this must be balanced with potential increases in treatment-related side

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effects.

This study had several limitations. The retrospective nature of the analysis

leaves it open to potentially unappreciated confounding factors or biases. Second, the relatively low number of patients limits statistical power and the conclusions that can be drawn from the analysis. Specifically, only 9 patients received TRT, which limits interpretation of the effect of this treatment. Patients were also treated over the course of more than 25 years, and coinciding advances in medical imaging, radiation technique, and surgical practices lead to heterogeneity among the treatments received by patients. In

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spite of these limitations, this study provides important information to help guide treatment recommendations for patients with SCLC.

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Clinical Practice Points The role of surgical resection for small cell lung cancer (SCLC) remains controversial, and limited data exist regarding patterns of failure in these patients.

Our study reports the outcomes of patients undergoing surgical management

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of SCLC and provides detailed patterns of failure analysis. Intrathoracic

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recurrences were the most common site of failure in our series, and patients undergoing limited resections (ie, wedge or segmentectomy) had a significantly increased risk of intrathoracic recurrence. •

From these data, we recommend that patients with clinically node-positive disease be treated with chemoradiation rather than surgery. Adjuvant

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chemotherapy should be used in all patients after surgery, and postoperative radiation therapy should be strongly considered for those who underwent limited resection or had evidence of pathologic nodal metastases.

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Acknowledgments and Disclosures

No internal or external funding sources were used for this study. No technologies

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were tested in the completion of this research. All listed authors had full control of the study design, methods used, outcome parameters, analysis of data, and production of the written report.

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Table 1. Patient Characteristics (N=54) Valuea

Characteristic

69.3 (53-84)

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Age, median (range), y Sex Male

23 (43)

Female

31 (57)

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PET staging Yes

27 (50) 27 (50)

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No Extent of resection Wedge

16 (30)

Segmentectomy

5 (9)

Lobectomy

31 (57)

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Pneumonectomy

2 (4)

Preoperative (clinical) stage IA

IIA

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IIB

EP

IB

IIIA

32 (59) 9 (17) 6 (11) 3 (6) 4 (7)

Pathologic T stage 0

1 (2)

I

28 (55)

II

17 (31)

III

6 (11)

IV

2 (4)

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Table 1 (continued) Valuea

Characteristic

RI PT

Pathologic N stage 32 (59)

I

13 (24)

II

8 (15)

Not documented

1 (2)

SC

0

Overall pathologic stage

20 (37)

M AN U

IA IB

10 (19)

IIA

9 (17)

IIB

1 (2)

IIIB

13 (24)

TE D

IIIA

1 (2)

Yes No

EP

Adjuvant chemotherapy

47 (87) 7 (13)

Adjuvant thoracic radiation therapy

AC C

Yes No

9 (17) 45 (83)

Prophylactic cranial irradiation Yes

10 (18)

No

44 (82)

Abbreviation: PET, positron emission tomography. a

Values are number (percentage) unless indicated otherwise.

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Kaplan-Meier Survival,

No.

Recurrences

(95% CI)

54

17

64.4 (49.5-79.8)

≤70

30

8

>70

24

9

Characteristic Overall

HR

P

Overall

(95% CI)

Value

P Value

71.7 (53.7-90.4)

1.0 (Reference)

.37

55.5 (32.4-82.7)

1.6 (0.6-4.0)

29

8

II

17

8

III or IV

8

1

0

32

I or II

21

1.0 (Reference)

.13

51.8 (30.4-82.7)

2.1 (0.8-5.7)

.41

85.7 (57.4-100)

0.4 (0.1-3.3)

8

70.5 (51.7-90.4)

1.0 (Reference)

8

60.4 (39.1-86.3)

1.3 (0.5-3.4)

AC C

Pathologic N stage

.15

66.5 (45.9-88.8)

EP

0 or I

TE D

Age, y

Pathologic T stage

Cox Proportional Hazards Model

SC

3-Year Estimate, %

M AN U

No. of

RI PT

Table 2. Univariate Associations of Risk Factors With the Risk of Intrathoracic Recurrence

.65

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Kaplan-Meier Survival, 3-Year Estimate, %

No.

Recurrences

(95% CI)

I

30

8

II

10

III

Cox Proportional Hazards Model HR

P

Overall

(95% CI)

Value

P Value

69.0 (50.2-89.9)

1.0 (Reference)

.19

5

42.2 (16.6-94.5)

2.1 (0.7-6.5)

.75

14

4

70.7 (45.4-99.6)

0.8 (0.2-2.7)

L/P

33

6

W/S

21

11

No

27

9

Yes

27

Characteristic

PET staging

TE D

1.0 (Reference)

37.2 (15.1-70.5)

3.5 (1.3-9.6)

64.8 (46.1-86.4)

1.0 (Reference)

8

63.9 (41.8-88.3)

1.0 (0.4-2.7)

10

67.5 (50.0-86.5)

1.0 (Reference)

AC C

Lymph nodes

80.3 (64.7-95.8)

EP

Extent of surgery

M AN U

Pathologic stage

SC

No. of

RI PT

Table 2 (continued)

.01

.93

sampled, No. ≥10

34

.69

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No. of

3-Year Estimate, %

Cox Proportional Hazards Model HR

P

Overall

(95% CI)

Value

P Value

SC

Kaplan-Meier Survival,

RI PT

Table 2 (continued)

No.

Recurrences

(95% CI)

<10

19

6

63.0 (39.4-92.6)

3

57.1 (20.7-100)

1.0 (Reference)

47

14

65.7 (50.3-82.3)

0.5 (0.2-1.8)

No

45

15

Yes

9

2

M AN U

Characteristic

Adjuvant

Yes Adjuvant thoracic

AC C

radiation therapy

EP

No

TE D

chemotherapy

1.2 (0.4-3.4)

61.7 (45.3-79.4)

1.0 (Reference)

77.8 (50.0-100)

0.5 (0.1-2.1)

.31

.32

Abbreviations: CI, confidence interval; HR, hazard ratio; L/P, lobectomy or pneumonectomy; PET, positron emission tomography; W/S, wedge resection or segmentectomy.

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Legends Figure 1. Kaplan-Meier Estimates of Outcomes in 54 Patients After Definitive Surgical

RI PT

Resection for Small Cell Lung Cancer. A, Overall survival. B, Recurrence-free survival. Figure 2. Impact of Extent of Resection in Patients With Small Cell Lung Cancer.

Patients underwent lobectomy or pneumonectomy, or they underwent wedge resection or segmentectomy. A, Recurrence-free survival. B, Overall survival.

SC

Figure 3. Venn Diagram With Locations of Intrathoracic Recurrence. Detailed overview shows locations of the 14 intrathoracic recurrences. Local indicates recurrence involving

M AN U

the bronchial stump or staple line; hilum, recurrence within the ipsilateral hilar lymph node(s); mediastinum, recurrence within any mediastinal lymph node(s). Figure 4. Impact of Adjuvant Thoracic Radiation Therapy (XRT) on Intrathoracic Recurrence (IR)-Free Survival. Kaplan-Meier estimates of IR-free survival for patients

AC C

EP

XRT (solid line).

TE D

who received adjuvant thoracic XRT (dashed line) or did not receive adjuvant thoracic

AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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