Groman, Adrienne

AbstractIn this phase I, dose‐escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c‐ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine‐based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab‐paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC‐MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c‐MET) and c‐Jun N‐terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty‐one patients were evaluable for dose‐limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression‐free survival was 4.8 months. Three out of five response‐evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c‐MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted.

Background: The incidence and prevalence of neuroendocrine neoplasms (NENs) are rapidly rising. Epidemiologic trends have been reported for common NENs, but specific data for lung NENs are lacking. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Associated population data were utilized to report the annual age-adjusted incidence and overall survival (OS) trends. Trends for large-cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC) were reported from 2000–2015, while those for typical carcinoid (TC) and small cell lung cancer (SCLC) were reported from 1988–2015. Results: We examined a total of 124,969 lung NENs [103,890—SCLC; 3303—LCNEC; 8146—TC; 656—AC; 8974—Other]. The age-adjusted incidence rate revealed a decline in SCLC from 8.6 in 1988 to 5.3 in 2015 per 100,000; while other NENs showed an increase: TC increased from 0.57 in 1988 to 0.77 in 2015, AC increased from 0.17 in 2001 to 0.22 in 2015, and LCNEC increased from 0.16 in 2000 to 0.41 in 2015. The 5-year OS rate among SCLC, LCNEC, AC, and TC patients was 5%, 17%, 64%, and 84%, respectively. On multivariable analyses, OS and disease-specific survival (DSS) varied significantly by stage, sex, histological type, insurance type, marital status, and race, with a better survival noted in earlier stages, females, married, insured, Hispanic and other races, and urban population. Similarly, TC and AC had better survival compared to SCLC and LCNEC. Conclusion: The incidence of lung NENs is rising, possibly in part because of advanced radiological techniques. However, the incidence of SCLCs is waning, likely because of declining smoking habits. Such population-based studies are essential for resource allocation and to prioritize future research directions.

A negative sentinel lymph node biopsy (SLNB) for stage IB (T1b/T2a N0) melanoma would predict an excellent long-term prognosis. Combined with the concept of conditional survival, an “abbreviated” cancer surveillance strategy was implemented to reduce the number of visits and total length of follow-up. Retrospective review of all pathologic stage IB melanoma patients (negative SLNB) at a single institution between 2006 and 2008 after implementation of an “abbreviated” cancer surveillance; clinic visits every six months for five years followed by one annual visit (total follow-up six years). Patient demographics, tumor characteristics, and information regarding recurrences were obtained. Recurrence-free, disease-specific, and overall survival were calculated. Eighty-seven patients underwent the “abbreviated” cancer surveillance. Median age was 55.4 years and 50.6 per cent were male. Median Breslow thickness was 1.1 mm (range 0.5–2.0 mm) and 1.1 per cent were ulcerated. Primary tumor site was 49 per cent extremities, 39 per cent trunk, and 12 per cent head/ neck. Median follow-up was 68.6 months. Five-year recurrence-free, disease-specific, and overall survivals were 89, 95, and 88 per cent, respectively. During surveillance, 10 patients had concerning symptoms or physical findings prompting subsequent workup, all of which were negative for recurrence/metastases. There were only three true melanoma recurrences; all were distant metastases and presented symptomatically between scheduled follow-up visits. In light of the excellent prognosis for pathologic (SLNB negative) stage IB melanoma, an “abbreviated” cancer surveillance schedule based on conditional survival would reduce both direct and indirect costs in this cohort. The few recurrences were symptomatic and unlikely to have changed with more intensive surveillance.

INTRODUCTION: Gastric cancer is one of the leading causes of cancer-related mortality worldwide, with a global burden of 5.7% new cases each year and 8.2% of cancer-related deaths. Area of residence has been found to affect survival in different cancers but their impact on gastric cancer remains largely unknown. The purpose of this study is to address the potential disparities between the rural and urban populations affected by gastric cancer. METHODS: We conducted a retrospective study, analyzing different socio-demographic factors associated with populations affected by gastric cancer between 1973 and 2015. Data was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses were performed to evaluate disease-specific survival (DSS) and overall survival (OS). Different socio-demographic factors including location of residence, that is urban area (UA) or rural area (RA), gender, race, insurance status and marital status were included in the analyses. RESULTS: A total of 68,959 [RA, N = 6,841; UA, N = 60,282] patients were included in the study. The incidence of gastric cancer was noted to have a steady decline during the studied time period, in both RA and UA. Majority of the study population was non-Hispanic white (N = 42,806, 62%) and male (N = 46,504, 67%). Univariate and multivariate analysis showed that RA had the worst DSS (univariate - HR = 1.15, P < 0.001; multivariate - HR = 1.13, P < 0.001) and OS (univariate - HR = 1.13, P < 0.001; multivariate HR = 1.11; P < 0.001) compared to UA. Similarly, DSS and OS was poor in uninsured and single patient population compared to insured patients and married couples respectively. Multivariate analysis further showed female patients had better DSS (HR = 0.91, P < 0.001) and OS (HR = 0.88, P < 0.001) in comparison to their male counterparts. CONCLUSION: This study identifies socio-demographic disparities in gastric cancer. Access to healthcare, variations in patient care, environmental and lifestyle factors as well as genomic differences are all potential factors that affect the OS. This is consistent with the available literature in gastric cancer, including studies demonstrating survival differences in different populations undergoing surgical treatment in the United States. Based on the above data, it is imperative for future health policy initiatives to address these disparities in an effort to improve OS.

Objectives: Vascular endothelial growth factor overexpression, seen in 42% to 76% of biliary tract cancers (BTCs), correlates with poor survival. We explored the safety/efficacy and potential biomarkers for bevacizumab in combination with gemcitabine-capecitabine in advanced BTCs. Patients and Methods: Inoperable stage III/IV BTC patients in our prospective study were given 1000 mg/m 2 of gemcitabine (on days 1, 8), 650 mg/m 2 of capecitabine (on days 1 to 14), and 15 mg/kg of bevacizumab (on day 1) in 21-day cycles. Circulating tumor cells and quality of life were assessed at baseline and before cycle 2 and 3. Results: In total, 50 patients with gallbladder cancer (22%), intrahepatic (58%), and extrahepatic (20%) cholangiocarcinoma, received a median of 8 treatment cycles for median treatment duration of 5.8 months. Common grade 3/4 toxicities were neutropenia (36%), thrombocytopenia (16%), fatigue (20%), infections (14%), and hand-foot syndrome (10%). There were 12 partial response (24%), 24 stable disease (48%) with clinical benefit rate of 72%. Median progression-free survival was 8.1 months (95% confidence interval, 5.3-9.9). Median overall survival was 10.2 months (95% confidence interval, 7.5-13.7). Circulating tumor cells were identified at baseline in 21/46 patients (46%), who had lower median overall survival compared with those without (9.4 vs. 13.7 mo; P =0.29). Patients with quality of life scores greater than the group median by the end of first cycle of treatment had improved survival compared with those who did not (13.3 vs. 9.4 mo; P =0.39). Conclusions: Addition of bevacizumab to gemcitabine/capecitabine did not improve outcome in an unselected group of patients with advanced BTC compared with historical controls. The selective benefit of vascular endothelial growth factor inhibition in BTC remains to be explored.