Impact of Radiation Dose on Postoperative Complications in Esophageal and Gastroesophageal Junction Cancers.

Introduction: The impact of radiation prescription dose on postoperative complications during standard of care trimodality therapy for operable stage II-III esophageal and gastroesophageal junction cancers has not been established. Methods: We retrospectively reviewed 82 patients with esophageal or gastroesophageal junction cancers treated between 2004 and 2016 with neoadjuvant chemoradiation followed by resection at a single institution. Post-operative complications within 30 days were reviewed and scored using the Comprehensive Complication Index (CCI). Results were compared between patients treated with <50 Gy and ≥ 50 Gy, as well as to published CROSS study neoadjuvant chemoradiation group data (41.4 Gy). Results: Twenty-nine patients were treated with <50 Gy (range 39.6-46.8 Gy) and 53 patients were treated with ≥ 50 Gy (range 50.0-52.5 Gy) delivered using IMRT/VMAT (41%), 3D-CRT (46%), or tomotherapy IMRT (12%). Complication rates and CCI scores between our <50 Gy and ≥ 50 Gy groups were not significantly different. Assuming a normal distribution of the CROSS data, there was no significant difference in CCI scores between the CROSS study neoadjuvant chemoradiation, <50 Gy, or ≥ 50 Gy groups. Rates of pulmonary complications were greater in the CROSS group (50%) than our <50 Gy (38%) or ≥ 50 Gy (30%) groups. Conclusions: In selected esophageal and gastroesophageal junction cancer patients, radiation doses ≥ 50 Gy do not appear to increase 30 day post-operative complication rates. These findings suggest that the use of definitive doses of radiotherapy (50-50.4 Gy) in the neoadjuvant setting may not increase post-operative complications.

Namodenoson in Advanced Hepatocellular Carcinoma and Child-Pugh B Cirrhosis: Randomized Placebo-Controlled Clinical Trial.

Namodenoson, an A3 adenosine-receptor agonist, showed promising results in advanced hepatocellular carcinoma (HCC) and moderate hepatic dysfunction (Child-Pugh B; CPB) in a phase I/II clinical study. This phase II study investigated namodenoson as second-line therapy in such patients. Patients were randomized 2:1 to twice a day (BID) namodenoson (25 mg; n = 50) or placebo (n = 28). The primary endpoint (overall survival [OS]) was not met. Median OS was 4.1/4.3 months for namodenoson/placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI] 0.49-1.38; p = 0.46). Pre-planned subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed a nonsignificant improvement in OS/progression-free survival (PFS). OS: 6.9 versus 4.3 months; HR, 0.81; 95% CI: 0.45-1.43, p = 0.46. PFS: 3.5 versus 1.9 months; HR, 0.89; 95% CI: 0.51-1.55, p = 0.67 (log-rank test). The difference in 12-month OS was significant (44% versus 18%, p = 0.028). Response rates were determined in patients for whom ≥ 1 assessment post-baseline was available (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3/34 (8.8%) and 0/21 (0%) patients, respectively. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported; no patients withdrew due to toxicity. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in HCC CPB.

Cecal Volvulus as a Rare Complication of Osimertinib Dosed at 160 mg in Patients With EGFR-Mutant Non-small Cell Lung Cancer.

Background: Osimertinib is a 3rd-generation tyrosine kinase inhibitor (TKI) that blocks the epidermal growth factor receptor (EGFR) in non-small lung cancer (NSCLC) and has dramatically improved outcomes for patients with EGFR mutations. While gastrointestinal complications such as diarrhea have been reported with EGFR inhibitors (due to off-target interactions with EGFR receptors within the gut lining), cecal volvulus is an extremely rare complication in advanced malignancy. To date, there are no reported cases associating cecal volvulus with any EGFR TKIs. Case Presentation: In this case series, we present three cases of cecal volvulus among patients with EGFR-positive NSCLC patients treated with osimertinib dosed at double the standard 80 mg dose (160 mg daily). No patient was receiving concurrent chemotherapy or bevacizumab at the time of this described complication. In two cases where pathology was available for review, peritoneal carcinomatosis or intra-abdominal spread was not observed. In a retrospective evaluation of 101 patients treated with osimertinib in our institution, there was a statistically significant difference in the incidence of cecal volvulus among patients receiving osimertinib at 160 mg vs. patients receiving the 80 mg dose (27 vs. 0%; p < 0.001). Conclusions: To our knowledge, these are the first cases to highlight a potentially important and serious gastrointestinal complication associated with the 160 mg dose of osimertinib.

Clinicopathologic Characteristics, Treatment Outcomes, and Acquired Resistance Patterns of Atypical EGFR Mutations and HER2 Alterations in Stage IV Non-Small-Cell Lung Cancer.

BACKGROUND: The clinicopathologic characteristics, acquired resistance patterns, and outcomes among patients with atypical EGFR mutations and HER2 alterations remain underexplored. PATIENTS AND METHODS: A single-center retrospective review was conducted. Oncogenes assessed include typical EGFR (t-EGFR; exon 19 del and L858R), atypical EGFR (a-EGFR; G719X, exon 20, L861Q), HER2 (exon 19, exon 20, amplifications), gene fusions (ALK, ROS1, RET), RAS (KRAS, NRAS), and RAF (BRAF V600E). Progression-free survival (PFS), overall survival (OS), disease control rate, and objective response rate (Response Evaluation Criteria in Solid Tumors 1.1) were collected. RESULTS: Among 570 patients, we found 55 a-EGFR mutations (13 G719X, 38 exon 20, 4 L861Q) and 31 HER2 alterations (2 exon 19 mutations, 27 exon 20 insertions, 2 amplifications). Patients with EGFR and HER2 alterations had increased lung and bone metastases relative to patients with gene fusions, RAS/RAF mutations, and no identified driver oncogenes (P < .001). Patients with EGFR exon 20 insertions had a median PFS to EGFR tyrosine kinase inhibitors (TKIs) of 5 months and an OS of 16 months-significantly worse than exon 19 del and L858R (Bonferroni correction; P < .001), but not G719X or L861Q. Relative to t-EGFR mutations, T790M and MET amplification occurred less frequently as acquired resistance mechanisms among a-EGFR samples (P < .001). Ten patients with a-EGFR mutations and HER2 alterations received single-agent immune checkpoint inhibitors (ICIs) with no radiographic responses and a median PFS of 2 months. CONCLUSION: EGFR and HER2-mutated NSCLC have a high rate of synchronous lung and bone metastases. Patients with a-EGFR mutations have inferior responses to EGFR-directed therapies with lower rates of acquired T790M and MET amplification. Responses to ICIs are uniformly poor. Novel therapeutic approaches are needed.

Pilot Prehabilitation Program for Patients With Esophageal Cancer During Neoadjuvant Therapy and Surgery.

BACKGROUND: Locally advanced esophageal cancer is often treated with neoadjuvant therapy followed by surgery. Many patients present with or experience clinical deconditioning during neoadjuvant therapy. Prehabilitation programs in other areas of surgery have demonstrated improved postoperative outcomes. The aims of this study were to evaluate the feasibility of a pilot prehabilitation program and determine preliminary effects on surgical and cancer-related outcomes. METHODS: A retrospective review of patients treated at a single institution with resectable esophageal cancer was performed (n = 22). Patients in the prehabilitation group received protocol-structured intervention in several clinical domains including nutrition, psychosocial support, and physical exercise. RESULTS: Clinical stage and comorbidities were well matched between groups. The structured prehabilitation program was feasible and well received by participants. Fewer patients required admission during neoadjuvant therapy in the prehabilitation group (27.3% versus 54.5%). Percentage weight loss during treatment was 3.0% in the prehabilitation group versus 4.3% in the control group. Compared with the control group, the prehabilitation group demonstrated 0.0% versus 18.2% 30-d postoperative readmission rate and 18.2% versus 27.3% 90-d postoperative readmission rate. There were no statistically significant differences between groups in regard to complications or mortality. CONCLUSIONS: The pilot prehabilitation program demonstrated feasibility of implementing a structured program for patients receiving neoadjuvant therapy for esophageal cancer. Although the small population limits evaluation of statistical significance, trends in the data suggest a potential benefit of the prehabilitation program on neoadjuvant hospital admission rates, postsurgical readmission rates, and nutritional status.

The Incidence of Brain Metastases in Stage IV ROS1-Rearranged Non-Small Cell Lung Cancer and Rate of Central Nervous System Progression on Crizotinib.

INTRODUCTION: Central nervous system (CNS) metastases in lung cancer are a frequent cause of morbidity and mortality. There are conflicting data on the incidence of CNS metastases in stage IV ROS1-positive NSCLC and the rate of CNS progression during crizotinib therapy. METHODS: A retrospective review of 579 patients with stage IV NSCLC between June 2008 and December 2017 was performed. Brain metastases and oncogene status (ROS1, ALK receptor tyrosine kinase gene [ALK], EGFR, KRAS, BRAF, and others) were recorded. We measured progression-free survival and time to CNS progression in ROS1-positive and ALK-positive patients who were taking crizotinib. RESULTS: We identified 33 ROS1-positive and 115 ALK-positive patients with stage IV NSCLC. The incidences of brain metastases for treatment-naive, stage IV ROS1-positive and ALK-positive NSCLC were 36% (12 of 33) and 34% (39 of 115), respectively. There were no statistically significant differences in incidence of brain metastases across ROS1, ALK, EGFR, KRAS, BRAF, or other mutations. Complete survival data were available for 19 ROS1-positive and 83 ALK-positive patients. The median progression-free survival times for ROS1-positive and ALK-positive patients were 11 and 8 months, respectively (p = 0.304). The CNS was the first and sole site of progression in 47% of ROS1-positive (nine of 19) and 33% of ALK-positive (28 of 83) patients, with no statistically significant differences between these groups (p = 0.610). CONCLUSIONS: Brain metastases are common in treatment-naive stage IV ROS1-positive NSCLC, though the incidence does not differ from that in other oncogene cohorts. The CNS is a common first site of progression in ROS1-positive patients who are taking crizotinib. This study reinforces the importance of developing CNS-penetrant tyrosine kinase inhibitors for patients with ROS1-positive NSCLC.

Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non-Small Cell Lung Cancer.

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a noninvasive way to identify ALK fusions and actionable resistance mechanisms without an invasive biopsy.Patients and Methods: The Guardant360 (G360; Guardant Health) deidentified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma.Results: Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ, KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK-positive patients had no history of targeted therapy (cohort 1), with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, and 11 tissue insufficient). Follow-up of 3 of the 5 tissue-negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 to 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR-activating mutations, an ALK fusion was identified on progression (cohort 4; 4 STRN, 1 EML4; one both STRN and EML4); five harbored EGFR T790M.Conclusions: In this cohort of cfDNA-detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a noninvasive means of detecting targetable alterations and characterizing resistance mechanisms on progression. Clin Cancer Res; 24(12); 2758-70. ©2018 AACR.

Perioperative Mortality in Nonelderly Adult Patients With Cancer: A Population-based Study Evaluating Health Care Disparities in the United States According to Insurance Status.

OBJECTIVES: The purpose of this study was to evaluate whether insurance status predicts for perioperative mortality (death within 30 d of cancer-directed surgery) for the 20 most common surgically treated cancers. METHODS: The SEER database was examined for the 20 most common surgically resected cancers and included nonelderly adults, aged 18 to 64 years. The database was queried from 2007 to 2011, with a total of 506,722 patients included in the analysis. RESULTS: Insurance status for all patients were the following: non-Medicaid insurance (83%), any Medicaid (10%), uninsured (4%), and unknown (3%). In univariate analyses, predictors for perioperative mortality included insurance status (P<0.001), age (P=0.015), race (P<0.001), marital status (P<0.001), residence (P=0.002), percent of county below the federal poverty level (P<0.001), and median county-level income (P<0.001). Perioperative mortality was also associated with advanced disease (P<0.001). Under multivariate analysis, patients with either Medicaid (Cochran-Mantel-Haenszel odds ratio [CMH OR], 1.21; 95% confidence interval [CI], 1.14-1.29; P<0.001) or uninsured status (CMH OR, 1.56; 95% CI, 1.44-1.70; P<0.001) were more likely to die within 30 days of surgery compared with patients with non-Medicaid insurance. When comparing Medicaid with the uninsured, Medicaid patients had significantly lower rates of perioperative mortality when compared with the uninsured (CMH OR, 0.80; 95% CI, 0.73-0.89, P<0.001). CONCLUSIONS AND RELEVANCE: In the largest reported analysis of perioperative mortality evaluating the 20 most common surgically treated malignancies, patients with Medicaid coverage or without health insurance were more likely to die within 30 days of surgery, with the uninsured having the worst outcomes.

Patterns of Care for Locally Advanced Pancreatic Adenocarcinoma Using the National Cancer Database.

OBJECTIVES: The role of radiotherapy (RT) in locally advanced pancreatic cancer (LAPC) is uncertain. This study examines patterns of care and survival outcomes of LAPC undergoing chemotherapy alone versus chemotherapy plus RT (C + RT). METHODS: The National Cancer Database was queried for nonmetastatic LAPC patients who received chemotherapy alone or C + RT. RESULTS: Of the 13,695 patients included, 5306 underwent chemotherapy alone and 4971, C + RT. Use of C + RT declined from 2003 to 2011 (73%-53%), whereas chemotherapy alone increased. Of those receiving RT, rates of intensity-modulated radiotherapy (IMRT) increased (27%-72%), whereas 3-dimensional (3D) RT decreased (73%-28%). Unadjusted 1-year overall survival (OS) was longer for versus chemotherapy (45.6% vs 38.7%), as was 2-year OS (12.9% vs 11.9%) (hazard ratio, 0.88; 0.85-0.91; P < 0.001). Under multivariate analysis, C + RT was associated with improved OS (hazard ratio, 0.84; 0.81-0.87; P < 0.001). On subgroup analysis comparing C + IMRT, C + 3D RT, and chemotherapy alone, 1-year OS was 49.1%, 45.1%, and 38.7%, and 2-year OS was 13.1%, 11.6%, and 11.9% accordingly. CONCLUSIONS: Utilization of RT in LAPC is decreasing, whereas chemotherapy alone is increasing. Of patients undergoing RT, rates of IMRT are increasing. Whereas C + IMRT appeared to be associated with improved OS compared with chemotherapy alone, 3D RT was not.

Malignant pleural disease is highly associated with subsequent peritoneal metastasis in patients with stage IV non-small cell lung cancer independent of oncogene status.

INTRODUCTION: Peritoneal metastasis from lung cancer is an uncommon clinical event and there are limited data on what factors predict peritoneal progression. This study retrospectively investigated whether patterns of metastatic spread and oncogene status in patients with advanced non-small cell lung cancer (NSCLC) are associated with peritoneal metastasis. METHODS: Patients with metastatic non-squamous NSCLC (n=410) were identified at the University of Colorado Cancer Center. Sites of metastatic disease and baseline oncogene status (EGFR, ALK, KRAS, or triple negative) were documented via a retrospective chart review. In patients with EGFR mutations who developed peritoneal disease, we documented the presence of known resistance mechanisms. Median time to peritoneal metastasis, time from peritoneal disease to death, and overall survival were collected. RESULTS: Eight percent (33/410) patients in this study developed peritoneal metastasis. Malignant pleural disease at baseline was significantly associated with subsequent peritoneal spread. There was no association between oncogene status and peritoneal metastasis. Three patients with EGFR mutations who developed peritoneal metastasis had documented resistance to tyrosine kinase inhibitors (TKIs) in the ascitic fluid. Median time from stage IV disease to peritoneal metastasis was 16.5 months (range 0.6-108 months). There were no differences in overall survival between patients who developed peritoneal metastasis and those who did not. CONCLUSIONS: Malignant pleural disease is highly associated with peritoneal metastasis in patients with advanced NSCLC. The underlying mechanism is not clear. The presence of resistance mutations in ascitic fluid implies that poor drug penetration is unlikely to be the dominant mechanism. Despite being a late clinical finding, there were no differences in overall survival between patients who developed peritoneal metastasis and those who did not. Additional studies exploring treatment related factors in patients with malignant pleural disease that can reduce risk of peritoneal metastasis are warranted.