Nichols, Francis C.

239 Background: After trastuzumab (T) approval for advanced HER2-positive E/GEJ-AC, HER2 testing has increased in patients (pts) with resectable disease. Neoadjuvant carboplatin/paclitaxel chemoradiation (nCP-CRT) is a common therapy approach. We performed the largest evaluation, to our knowledge, of the prognostic impact of HER2 in E/GEJ-AC pts treated with nCP-CRT. Methods: We retrospectively reviewed medical records of all trimodality-eligible (T2+ or N+) pts with E/GEJ-AC who started nCP-CRT (usually 50.4 Gy) with planned surgery at Mayo Clinic (2014-2019). HER2 was tested using standard criteria for HER2 positivity (ie, immunohistochemistry 3+ or amplification by in situ hybridization). Clinicopathologic data and time to recurrence (TTR), disease free survival (DFS), overall survival (OS), survival after recurrence (SAR), and pathologic complete response (pCR – ie, no residual tumor in primary or nodes) were collected. Kaplan Meier and multivariate Cox analysis were used. Results: Of 161 consecutive eligible pts, HER2 status was available in 107 pts (HER2-positive n=26, HER2-negative n=81) of whom n=82 had surgery and n=19 had pCR. Most tumors were clinical T3 (80%) or N+ (81%), histologic grade 3 of 3 (62%). HER2 positivity was significantly associated with lower grade, but not with age, clinical T or N, or ECOG performance status (PS). A similar proportion of HER2-positive ( vs negative) pts had surgery. Among pts who had surgery, pCR rates were lower in HER2-positive ( vs negative) pts (11% [2/19] vs 27% [17/63]). After a median follow up of 23 mo, DFS and TTR were significantly shorter in HER2 positive ( vs negative) pts, independent of other pretreatment covariables (Table). Yet OS was comparable. Lung recurrence was enriched in HER2 positive ( vs negative) pts. Among pts with recurrence, SAR was longer in HER2-positive vs -negative pts. A total of 53% (10/19) of previously HER2-positive pts received T-based therapy after recurrence, and these pts were the drivers of favorable SAR (median 22 mo in n=10 HER2-positive pts who received T vs 11 mo in n=9 HER2-positive pts who did not receive T vs 11 mo in n=40 HER2-negative pts; P log-rank=.01). Conclusions: HER2 positivity ( vs negativity) is independently associated with shorter TTR and DFS, but more comparable OS. The adverse association of HER2 on tumor response and TTR may have been largely overcome through enhanced survival after recurrence, although OS data are maturing. These data may have implications for the design of endpoints in future curative-intent anti-HER2 trials. [Table: see text]

e19013 Background: Mutation profiling to assess for potentially druggable mutations in NSCLC is being offered at an increasing number of cancer centers throughout North America and internationally. Although data continue to accumulate for the potential value of mutation testing in designing chemotherapeutic regimens, the treatment impact of obtaining information beyond assessment of EGFR and ALK status remains unclear. How best to obtain and clinically utilize these data, including information from exome and whole genome sequencing, also remains unclear. Methods: Patients were reviewed electronically in a multidisciplinary conference regarding indications for testing and results of mutation profiling from various methods, including the mass-spec based LungCarta test, targeted NexGen sequencing, exome, and whole genome sequencing. Outcomes of the multidisciplinary review were communicated back to treating physicians. Results: Mutation testing was performed on 200 patients using a variety of approaches. The majority (>150) were surgically resected stage I and II tumors. Mutations in at least 1 major cancer driver gene, including EGFR, KRAS, MET, BRAF and PIK3CA, were found in 47% of all patients tested. EGFR mutations were present in 14.8% of patients tested, KRAS 21.3%, BRAF 2.6%, PIK3CA 3.2%, and MET 4.5%. A total of 8 patients underwent either exome or whole genome sequencing. A limited number of patients (<10) had mutation results that impacted treatment decisions from this cohort. Conclusions: Mutation profiling can influence treatment decisions in NSCLC, but at a low frequency. The role of exome and or whole genome sequencing for patients with NSCLC is evolving and remains undefined.

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]

Abstract Background Pneumatosis intestinalis has long been a marker of advanced bowel ischemia and prompts urgent laparotomy. In post-operative settings, the presence of pneumatosis represents a significant management dilemma. We share a case-series of post-esophagectomy patients with pneumatosis intestinalis and no corollary intra-abdominal pathologic findings on re-exploration. Methods January 2000 to December 2017, 1760 patients underwent Ivor-Lewis esophagectomy or gastrectomy with jejunostomy-tube placement. Charts were reviewed retrospectively to identify patients with pneumatosis intestinalis discovered in the post-operative period. Demographic data, operative details and postoperative course were reviewed including incidence and details of re-exploration. Results Eleven patients met inclusion criteria. Nine were male (81.8%) and mean age was 69 years. All patients had radiographic confirmation of pneumatosis intestinalis and in many cases portal venous gas (Figure 1). Clinical course was variable without discernable trends in vitals or laboratory values. Development of significant postoperative ileus along with delivery of enteral tube feeds through a jejunostomy tube preceded development of the pneumatosis in all patients. Nine patients were re-explored and none had evidence of bowel ischemia. Conclusion The finding of pneumatosis intestinalis in the post-operative setting can be alarming and pose a management dilemma. With the advent of improved and readily available imaging, there has been an increase in findings that have no corollary physical symptomatology. In this series of patients, despite dramatic radiographic findings, none had ischemic bowel. Pneumatosis intestinalis alone in patients who have undergone esophagectomy should not be considered an indication for emergency re-exploration. Disclosure All authors have declared no conflicts of interest.

Abstract Background The purpose of this study was to evaluate the survival difference in clinical T2N0 esophageal cancer patients receiving neoadjuvant chemoradiotherapy (CRT) vs. upfront surgery. Methods Between 1/1/1995 to 12/31/2012, a prospectively maintained database was used to identify patients with cT2N0 esophageal adeno- and squamous cell carcinoma. Exclusion criteria included: lack of endoscopic esophageal ultrasonographic (EUS) staging, incomplete resection, and prior treatment with endoscopic mucosal or submucosal resection. Cox-proportional hazard ratios were used to compare the primary outcomes of overall (OS) and disease-free survival (DFS). Secondary outcomes included: rate of postoperative complications, rate of pathologic upstaging/response, and induction/adjuvant treatment completion rate. Pre-hoc subgroup analysis compared pathologically upstaged patients receiving upfront surgery followed by adjuvant chemotherapy to those treated with neoadjuvant CRT. Results A total of 161 cT2N0 esophageal cancer patients were identified based on EUS staging. Upfront surgery was offered to 134 patients (83%), with 27 patients (17%) receiving induction CRT. Univariate analysis did not demonstrate any significant baseline differences between the two groups. In the upfront surgery group, 53 (39.6%), 28 (20.9%) and 53 (39.6%) patients were pathologically down-staged, accurately staged and upstaged respectively. Upstaging was higher in the upfront surgery group (53/134, 39.6% vs. 4/27, 14.8%; P = 0.02), while 11/27 (40.7%) patients receiving neoadjuvant CRT demonstrated complete pathologic response. Of those eligible for adjuvant chemotherapy, only 21/55 (38.2%) received treatment. In the neoadjuvant CRT group, 51.9% completed all planned therapy, compared to 23.6% of patients treated with upfront surgery followed by adjuvant chemotherapy (P = 0.01). Cox proportional hazard ratio did not demonstrate an advantage to induction CRT in terms of OS (HR = 1.64, P = 0.43) or DFS (HR = 1.36, P = 0.69). In general, patients with pathologic upstaging had worse OS (HR = 2.73, P = 0.001) and DFS (HR = 4.18, P = 0.003). Conclusion EUS was only accurate in staging T2N0 patients in 20.9% of cases. While neoadjuvant CRT did not confer a survival advantage, these results likely reflect the low number of patients being referred for induction therapy. Neoadjuvant CRT was however associated with lower rates of pathologic upstaging and higher rates of treatment completion. Further research should evaluate the survival outcomes in pathologically upstaged cT2N0 patients not receiving neoadjuvant therapy. Disclosure All authors have declared no conflicts of interest.

Abstract Background The objective of this study was to analyze the induction therapy regimens employed since publication of CROSS Trial in patients treated with locally advanced EGJ cancer in terms of toxicity, complications, survival and recurrence. Methods Retrospective chart review all patients in single institution prospective database who had neoadjuvant CRT→Surgery 2012–2015. Complications during CRT and after surgery graded using National Cancer Institute CTCAE. Cox-proportion hazard ratios were used to compare the primary outcomes of overall survival (OS) and disease-free survival (DFS). Results 288 patients, 237 men and 51 women were identified. 246 were adenocarcinoma, 38 squamous cell carcinoma, and 4 had other histologic types. 4 distinct neoadjuvant regimens were observed: 50.4 Gy radiation with 5-fluorouracil and cisplatin (N = 22), CROSS regimen (41.4 Gy with carboplatin & paclitaxel) (N = 44), 50.4 Gy with carboplatin and paclitaxel (N = 152), and ‘Other’ which include 27 distinct regimens (N = 70). There were no differences in treatment related complications or postoperative complications between regimens. There was no difference in pathologic complete response rate, OS, or DFS between regimens. Conclusion Since the publication of the CROSS Trial, there is a significant heterogenity in the neoadjuvant chemoradiation treatment regimen employed for patients with locally advanced EGJ tumors. Does not appear to be any differences in treatment related complications or postoperative complications between regimens. There was also no difference in pCR, overall survival or disease-free survival. Disclosure All authors have declared no conflicts of interest.

Purpose This brief report describes a planned, interim, 6-patient toxicity analysis that confirms the safety of pemetrexed, carboplatin, radiation with subsequent surgery, as prescribed in the North Central Cancer Treatment Group trial N044E, in patients with locally advanced esophageal cancer. Methods Six patients with locally advanced, potentially resectable esophageal cancer received pemetrexed 500 mg/m 2 and carboplatin AUC = 6 on days 1 and 22 with 5040 centigray of concomitant radiation in 28 fractions over 5.5 weeks followed by esophagectomy as a prelude to a phase II multi-institutional trial. Results Only 1 of the 6 patients experienced a grade 4 adverse event (neutropenia). This patient also experienced a grade 3 depression. Of the remaining 5 patients, three experienced at least one grade 3 adverse event (neutropenia, nausea/vomiting, and esophagitis). There were no deaths. Incidentally, one patient manifested a complete pathologic response, three a partial pathologic response, and one stable disease. Conclusion These preliminary observations on safety suggest that this regimen can be further studied in this clinical setting.