Putnam, Joe B.

7524 Background: A multicenter study (Z4032) compared sublobar resection (SR) to sublobar resection with brachytherapy (SRB) for stage I NSCLC. Local recurrence (LR) and overall survival (OS) rates at 3-years (3-yr) were similar between arms (see abstract 113613). This analysis combines arms, and evaluates the effect of factors previously reported to impact oncological outcomes after SR. Methods: 213 patients (pts) were evaluable for analysis. LR was defined as recurrence at the staple line (local progression), same lobe away from the staple line, or within hilar nodes. Factors assessed for impact on 3-yr outcomes were: resection type (wedge/segmentectomy), margin size (<1cm /≥1cm), margin:tumor ratio (<1/ ≥1), tumor size (≤2cm/>2cm) and staple line cytology (+/-). Results: LR occurred in 27/213 (12.6%) pts and included local progression in 12/213 (5.6%). OS rate at 3-yr was 152/213 (71.4%). Trends favored the use of segmentectomy, margin:tumor ratio≥1, tumor size ≤2cm and negative staple line cytology; no factor reached statistical significance at 3-yr. The only factor significantly (p=0.02) associated with decreased 3-yr LR was margin size ≥1cm (8.3%) compared to margin<1cm (19.3%). Conclusions: SR is a good option for high-risk pts with NSCLC. The 3-yr OS rate of 71.4% and local progression rate of 5.6% are useful benchmarks to compare to other therapies. A resection margin of at least 1 cm is desirable. Clinical trial information: NCT00107172. [Table: see text]

7502 Background: Prior studies suggest that adjuvant brachytherapy reduces local recurrence (LR) after sublobar resection (SR) for NSCLC. A multicenter randomized study was undertaken in patients (pts) with stage I NSCLC ≤3cm comparing SR to SR with brachytherapy (SRB). Methods: High-risk operable patients with NSCLC were randomized to SR or SRB. Brachytherapy involved placement of I125 seeds incorporated into Vicryl sutures or into Vicryl mesh placed over the staple line. Wedge or segmental resection was allowed. The primary endpoint was time to local recurrence (LR) defined as recurrence within the primary tumor lobe at the staple line (local progression), away from the staple line or within hilar nodes. The trial was designed to have 90% power to detect a hazard ratio (HR) of 0.315 in favor of the SRB arm using a one-sided α of 0.05 with a sample size of 100 eligible pts per arm. Follow-up CT scans were obtained serially for 36 months. Results: 224 pts were randomized; 213 (109 SR,104 SRB) were eligible. Median (range) age was 71 (49-87) yrs; 94 (44%) were male. No differences were found in baseline characteristics. Adverse events, previously reported, were not different between arms. Median (range) follow-up was 4.06 (0.04, 5.0) yrs. There was no difference between arms in time to LR (HR = 0.87; 5% CI: 0.41, 1.86, p=0.72) or to LR or death (LRD) (HR = 0.81, 95% CI: 0.50, 1.32, p=0.40). There was no difference between arms in pattern of LR (table). In subgroups of pts with potentially compromised surgical margin (margin < 1cm; margin:tumor ratio <1; positive staple line cytology) SRB did not reduce LR or LRD at 3-yrs. Overall 3-yr survival was similar for SR (71%) and SRB (72%) (p=0.81). Conclusions: LR remains a concern after sublobar resection. However, local progression at the staple line was low. This trial demonstrated that adjuvant brachytherapy does not impact oncologic outcomes. Clinical trial information: NCT00107172. [Table: see text]

7008 Background: Fluoro-deoxyglucose positron emission tomography (FDG-PET) is recommended for diagnosis and staging of known or suspected NSCLC. Meta-analyses examining the accuracy of FDG-PET to diagnose lung cancer demonstrated high sensitivity 94% and specificity 83% but were performed in select centers. The purpose of this study is to evaluate the accuracy of FDG-PET to diagnose NSCLC and examine enrolling site differences in the national prospective ACOSOG Z4031 trial. Methods: 1,074 patients with clinical stage I (cT1-2N0M0) known or suspected NSCLC were enrolled between 2004 and 2006 in the Z4031 study and underwent surgical resection. The final diagnosis was determined by pathological examination. FDG-PET results were abstracted from radiology interpretations included in the case report forms. FDG-PET avidity was categorized based on either radiologist description or reported maximum standard uptake value (SUV). The four categories were: not avid and not cancerous (SUV=0), low avidity and likely not cancerous (SUV>0 and <2.5), avid and probably cancerous (SUV>2.5 and <5) and highly avid and likely cancerous (SUV>5). Sensitivity analysis of FDG-PET diagnostic accuracy was performed for varying levels of avidity and by preoperative lesion size. Differences in accuracy by enrolling site were examined. Results: There were 51 enrolling sites in 39 cities with 969 eligible participants. Preoperative FDG-PET results were available for 682 participants. Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% (95% CI: 79-85), and specificity was 31% (95% CI: 23-40). Positive and negative predictive values were 85% and 26%, respectively and accuracy improved with lesion size. There were 80 false positive scans and 69% were granulomas. False negative scans occurred in 101 patients (11were ≤10mm) with adenocarcinoma, squamous, bronchoalveolar cell and neuroendocrine tumors responsible for 64%, 12%, 10% and 8% of false negative results, respectively. Specificity did not differ between the 8 sites with >25 patients (p=0.74). Conclusions: In a national surgical population with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed poorly compared to published studies. Reasons for poor test performance should be explored.

4062 Background: Multiple clinical trials have incorporated preoperative chemotherapy and radiation (RT) in an attempt to improve local tumor control, distant disease failure and overall survival rates for locally advanced but resectable adenocarcinoma of the distal esophagus and gastroesophageal junction (GEJ). This multicenter, cooperative group study combined active chemotherapy agents cisplatin (C), docetaxel (D) and the targeted EGFR agent panitumumab (P) in the induction phase followed by concurrent chemotherapy (CDP) and radiation. Pathologic complete response (pCR), a surrogate for improved survival, was the primary endpoint. Methods: From 01/15/09 to 07/22/11, 70 patients (pts) with Siewert I or II adenocarcinomas and clinical stages T3N0M0, T2-3N1M0 or T2-3N0-1M1a (celiac LN ≤ 2 cm) were accrued. Patients received cisplatin (40 mg/m2), docetaxel (40 mg/m2) and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, 9 with RT (5040 cGy, 180 cGy/day x 28d) beginning week 5. The decision rule had a 90% power with a 0.10 significance level to detect a pCR rate of at least 35%. Secondary objectives included near-pathologic complete response (near-pCR), toxicity, and overall and disease-free survival rates. Results: Five pts were ineligible. Of the remaining 65 pts (59 M, 6 F; median age 61), 12 pts did not undergo surgery (5 progressed, 4 refused, 3 other). Of the 58 evaluable pts, the pCR rate was 32.8% (90% CI: 22.6% -42.9%) and near-pCR 22.4% (90% CI: 13.4%-31.4%). Total doses of C, D, and P were achieved in 76%, 80%, and 73%, respectively (n = 70). 66 pts (94%) received the total RT dose. Sixteen pts (23%) had a grade 4+ non-heme adverse event possibly related to treatment. Venous thrombosis (5 pts) was most common. Conclusions: The CDP regimen in the neoadjuvant setting in patients with esophageal adenocarcinomas is active (pCR + near-pCR = 55.2%) and feasible. The toxicity though tolerable is substantial.

7555 Background: Lymph node status is a major determinant of stage and survival in patients with lung cancer; however, little information is available about the yield of a mediastinal lymphadenectomy done at the time of pulmonary resection. Methods: The ACOSOG Z0030 trial is a prospective, randomized trial of mediastinal lymph node sampling versus complete mediastinal lymphadenectomy during an operation for early stage lung cancer. Total enrollment from July 1999 to February 2004 was 1,111 patients, of which 1,023 were eligible and/or evaluable. There were 524 patients who underwent complete mediastinal lymph node resection after randomization to this arm that were declared eligible and/or evaluable with lymph node data available. The number of lymph nodes examined from each station was collected beginning in January 2002. Prospectively collected data from these patients was analyzed to determine the number of lymph nodes obtained. Results: Median age was 67 (range 37–87) and 267 (52%) were men. Histology was squamous cell in 141 (27%), adenocarcinoma in 227 (44%), large cell in 22 (4%), bronchoavelolar in 32 (6%) and other non-small cell in 99 (19%). There were 317 right sided cancers and 207 left sided cancers. For lymphadenectomy for cancers in the right lung the yield from station 2R was a median of 2 lymph nodes (range 1 to 15), station 4R was 2 (1 –17), station 7 was 2 (1–24), station 8 was 1 (1–5), station 9 was 1 (1–6) and station 10R was 1 (1–10). For lymphadenectomy for cancers on the left side the yield from station 2L was 2 (1–4), station 4L was 1 (1–12), station 5 was 2 (1–18), station 6 was 2 (1–11), station 7 was 2 (1–16), station 8 was 1 (1–3), station 9 was 1 (1–8) and 10L was 2 (1–12). The total number of lymph nodes or fragments obtained for right sided cancers was a median of 13.5 (range 1 to 56) and for left sided tumors 15 (range 4 to 81). Conclusions: Although high variability exists in the actual number of lymph nodes obtained from various nodal stations, a complete mediastinal lymphadenectomy should obtain one or more lymph nodes from each mediastinal station. Adequate mediastinal lymphadenectomy should include exploration and remove of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right sided cancers and stations 4L, 5, 6, 7, 8 and 9 for left sided cancers. No significant financial relationships to disclose.

BACKGROUNDThis study evaluated the 2‐year overall survival rate, adverse event rate, local control rate, and impact on pulmonary function tests for medically inoperable patients with stage IA non–small cell lung cancer (NSCLC) undergoing computed tomography (CT)–guided radiofrequency ablation (RFA) in a prospective, multicenter trial.METHODSFifty‐four patients (25 men and 29 women) with a median age of 76 years (range, 60‐89 years) were enrolled from 16 US centers; 51 patients were eligible for evaluation (they had biopsy‐proven stage IA NSCLC and were deemed medically inoperable by a board‐certified thoracic surgeon). Pulmonary function tests were performed within the 60 days before RFA and 3 and 24 months after RFA. Adverse events were recorded and categorized. Patients were followed with CT and fludeoxyglucose positron emission tomography. Local control rate and recurrence patterns were analyzed.RESULTSThe overall survival rate was 86.3% at 1 year and 69.8% at 2 years. The local tumor recurrence–free rate was 68.9% at 1 year and 59.8% at 2 years and was worse for tumors > 2 cm. In the 19 patients with local recurrence, 11 were re‐treated with RFA, 9 underwent radiation, and 3 underwent chemotherapy. There were 21 grade 3 adverse events, 2 grade 4 adverse events, and 1 grade 5 adverse event in 12 patients within the first 90 days after RFA. None of the grade 4 or 5 adverse events were attributable to RFA. There was no significant change in the forced expiratory volume in the first second of expiration or the diffusing capacity of lung for carbon monoxide after RFA. A tumor size less than 2.0 cm and a performance status of 0 or 1 were associated with statistically significant improved survival of 83% and 78%, respectively, at 2 years.CONCLUSIONSRFA is a single, minimally invasive procedure that is well tolerated in medically inoperable patients, does not adversely affect pulmonary function tests, and provides a 2‐year overall survival rate that is comparable to the rate reported after stereotactic body radiotherapy in similar patients. Cancer 2015;121:3435–43. © 2015 American Cancer Society.

Abstract Background: Fluoro-deoxyglucose positron emission tomography (FDG-PET) scans are used for diagnosis and staging of known or suspected non-small cell lung cancer (NSCLC). Single institution studies examining the impact of avidity on survival have reported mixed results. The purpose of this study is to evaluate the association between FDG-PET avidity and survival in the national prospective ACOSOG Z4031 trial in patients with pathological Stage I NSCLC. Methods: Between 2004 and 2006, 1074 patients with known or suspected clinical stage I (cT1-2N0M0) NSCLC were enrolled in the ACOSOG Z4031 trial and underwent surgical resection. FDG-PET results were abstracted from radiology interpretations included in the case report forms. FDG-PET avidity was categorized based on either radiologist description or reported maximum standard uptake value (SUV). The four categories were: 1) not avid and not cancerous (SUV=0), 2) low avidity and likely not cancerous (SUV&gt;0 and &lt;2.5), 3) avid and probably cancerous (SUV≥2.5 and &lt;5) and 4) highly avid and likely cancerous (SUV≥5). The lesion was classified as avid if in categories 3 or 4. The final diagnosis was determined by pathological examination and all cause mortality was reported. Cox proportional hazard regression was used to assess the impact of FDG-PET avidity on survival. The covariates used in the model included pStage, gender, age, race, and preoperative lesion size. Kaplan-Meier survival curves were calculated and the log-rank test was used to determine differences in survival based on FDG-PET avidity. Results: There were 51 enrolling sites in 39 cities with 969 eligible participants. Preoperative FDG-PET results were available for 540 participants with NSCLC and 81% had FDG-PET avid or highly avid lesions. 400 patients had pStage I NSCLC and the 5 year survival was 70% with 95%CI (65%, 75%). FDG-PET avidity, male gender, age, and lesion size negatively impacted survival. FDG-PET avidity in pStage I disease still negatively impacted survival (p=0.03) when controlling for lesion size. The 5 year survival for Stage I disease was 80% with 95%CI (68%, 88%) in FDG-PET negative patients and 67% with 95% CI (61%, 72%) in FDG-PET positive patients (p=0.02). Conclusions: In a national surgical population with pathological stage I NSCLC, FDG-PET avidity negatively impacted five year survival, independently of lesion size. Further work should be done to determine if chemotherapy would be beneficial in patients with PET avid lesions and pStage I NSCLC. Citation Format: Eric L. Grogan, Stephen A. Deppen, Heidi Chen, Karla V. Ballman, Francys C. Verdial, Melinda C. Aldrich, Paul A. Decker, David H. Harpole, Robert J. Cerfolio, Robert J. Keenan, David R. Jones, Thomas A. D'Amico, Joseph B. Shrager, Bryan F. Meyers, Joe B. Putnam. FDG-PET avidity negatively impacts survival in pStage I NSCLC in the ACOSOG Z4031 trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-296. doi:10.1158/1538-7445.AM2013-LB-296

Purpose A major concern with sublobar resection (SR) for non–small-cell lung cancer (NSCLC) is high local recurrence (LR). Adjuvant brachytherapy may reduce LR This multicenter randomized trial compares SR to SR with brachytherapy (SRB). Patients and Methods High-risk operable patients with NSCLC ≤ 3 cm were randomly assigned to SR or SRB. The primary end point was time to LR, where LR included recurrence at the staple line (local progression), in the primary tumor lobe away from the staple line, and in ipsilateral hilar nodes. The trial was designed to have a 90% power to detect a hazard ratio (HR) of 0.315 in favor of SRB, using a one-sided type I error rate of 0.05 with a sample size of 100 eligible patients in each arm. Results Two hundred twenty-four patients were randomly assigned; 222 patients were evaluable for intent-to-treat analysis. Median age was 71 years (range, 49 to 87 years). No differences were found in baseline characteristics. Median follow-up time was 4.38 years (range, 0.04 to 5.59 years). There was no difference in time to LR (HR, 1.01; 95% CI, 0.51 to 1.98; log-rank P = .98) or in the types of LR. Local progression occurred in only 17 (7.7%) of 222 patients. In patients with potentially compromised margins (margin < 1 cm, margin-to-tumor ratio < 1, positive staple line cytology, wedge resection, nodule size > 2.0 cm), SRB did not reduce LR, although trends favored the SRB arm. This was most marked in 14 patients with positive staple line cytology (HR, 0.22; P = .24). Three-year overall survival rates were similar for patients in the SR (71%) and SRB (71%) arms (P = .97). Conclusion Brachytherapy did not reduce LR after SR. This finding may have been related to closer attention to parenchymal margins by surgeons participating in this study.

Abstract Background: Current management of lung nodules is complicated by nontherapeutic resections and missed chances for cure. We hypothesized that a serum proteomic signature may add diagnostic information beyond that provided by combined clinical and radiographic data. Methods: Cohort A included 265 and cohort B 114 patients. Using multivariable logistic regression analysis we calculated the area under the receiver operating characteristic curve (AUC) and quantified the added value of a previously described serum proteomic signature beyond clinical and radiographic risk factors for predicting lung cancer using the integration discrimination improvement (IDI) index. Results: The average computed tomography (CT) measured nodule size in cohorts A and B was 37.83 versus 23.15 mm among patients with lung cancer and 15.82 versus 17.18 mm among those without, respectively. In cohort A, the AUC increased from 0.68 to 0.86 after adding chest CT imaging variables to the clinical results, but the proteomic signature did not provide meaningful added value. In contrast, in cohort B, the AUC improved from 0.46 with clinical data alone to 0.61 when combined with chest CT imaging data and to 0.69 after adding the proteomic signature (IDI of 20% P = 0.0003). In addition, in a subgroup of 100 nodules between 5 and 20 mm in diameter, the proteomic signature added value with an IDI of 15% (P ≤ 0.0001). Conclusions: The results show that this serum proteomic biomarker signature may add value to the clinical and chest CT evaluation of indeterminate lung nodules. Impact: This study suggests a possible role of a blood biomarker in the evaluation of indeterminate lung nodules. Cancer Epidemiol Biomarkers Prev; 21(5); 786–92. ©2012 AACR.