Faculty Bibliography

Background: Preoperative chemoRT is a standardof- care as shown in the CROSS trial (N Engl J Med 2012;366:2074-2084), Surgery is sometimes deferred in pts with clinical CR (cCR) based on lack of overall survival benefit (J Clin Oncol 2005;23:2310-2317, J Clin Oncol2007;25:1160-1168). Nivolumab has activity in advanced ESCC (Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes.
Method(s): This phase I/II study was designed to assess the safety and tolerability and efficacy of nivolumab added to chemoRT (6 weekly carboplatin AUC 2, paclitaxel 50mg/m2, RT 50.4 Gy in 1.8 Gy fractions 5/7 days) for pts with TanyN1-3 or T3-4N0M0 ESCC. The phase I primary endpoint is 'unacceptable toxicity' at 28 days after the last dose of chemotherapy. The phase II primary endpoints are cCR (endoscopy + PET/CT) and pCR rates for pts undergoing surgery. Nivolumab is given q2W x2, then concurrent chemoRT with nivolumab q2W x3. If no cCR, pt proceeds to esophagectomy, then adjuvant nivolumab q2W x3; if cCR, pt has an option of no surgery but receives nivolumab q2W x3.
Result(s):From 7/20/17 to 12/27/18, 6 pts were enrolled. No unacceptable or grade 5 toxicities were observed. The most common grade 1/2 AEs in >1 pt were anorexia, myelosuppression, elevated AST and nausea. Grade 3/4 AEs in >1 pt were lymphopenia and leukocytopenia. 2 pts required hospitalizations (dyspnea 1, colitis 1). All pts completed therapy; 1 pt had dose delay due to grade 2 esophagitis; 2 pts progressed, 4 achieved cCR. Of 4 pts with cCR, 2 pts chose surgery and both achieved pCR. None of the 4 pts recurred.
Conclusion(s): ChemoRT with nivolumab is tolerable with manageable toxicities in locally advanced ESCC. Enrollment to the phase II portion ended because of slow accrual. Adverse Events. Grade 1 &2 in > 1 pt: 4/6: Anorexia & Anemia 3/6: Leukocytopenia Neutropenia Thrombocytopenia Nausea & Elevated AST 2/6: Hypomagnesemia Hypokalemia Grade 3 & 4 in > 1 pt: 5/6: Lymphopenia, 2/6: Leukocytopenia

Background: Malnutrition incidence in cancer approaches 85%, disproportionately burdening those with lung, GI, and advanced stage cancers. Malnourished patients have impaired chemotherapy response, shorter survival, longer hospital stays, and decreased QoL. Home delivered meals are nutritional interventions that improve patient well- being, nutrition, and lower healthcare costs in the elderly but have not been studied as an intervention in cancer patients. HDMTM are nutritionist prescribed home delivered meals tailored to patient's symptoms, co-morbidities, and health needs. Preliminary data in 211 cancer patients showed with HDMTM 87% ate more than half of meals, 91% lived more independently, 89% ate more nutritiously, and 70% had less fatigue. HDMTM may be a strategy to reduce financial toxicity and healthcare utilization and improve QoL in cancer patients, but no primary data exists evaluating its efficacy.
Method(s): We sought to develop the first RCT evaluating patientcentered QoL improvement from nutritional intervention with HDMTM in those with metastatic lung and non-colorectal GI cancer. We established a partnership with God's Love We Deliver, a 501c3 non-profit specializing in HDMTM.
Result(s): We developed a protocol for a single-institution RCT of standard of care (SoC) versus SoC and HDMTM in metastatic lung and non-colorectal GI cancer patients with primary aim comparing QoL between arms at 12 weeks using the FACT-G questionnaire. Sample size is 180. Secondary aims assess HDMTM's impact on nutritional status, weight, mood, survival, food security, financial toxicity, healthcare utilization, and cost effectiveness. Eligible patients tolerate oral alimentation, have PS 0-3, and newly diagnosed (< 6 weeks) metastatic cancer. All patients have pre-randomization nutritional evaluation by an oncologic dietician.
Conclusion(s):We present the first PRMC reviewed and IRB approved RCT evaluating the efficacy of HDMTM in metastatic cancer patients with primary endpoint of patient reported QoL. Investigating HDMTM expands our knowledge of nutrition as an effective arm of palliative oncology

BACKGROUND:Although outcomes for patients with squamous cell carcinoma of the anus (SCCA) have improved, the gains in benefit may not be shared uniformly among patients of disparate socioeconomic status. In the current study, the authors investigated whether area-based median household income (MHI) is predictive of survival among patients with SCCA. METHODS:Patients diagnosed with SCCA from 2004 through 2013 in the Surveillance, Epidemiology, and End Results registry were included. Socioeconomic status was defined by census-tract MHI level and divided into quintiles. Multivariable Cox proportional hazards models and logistic regression were used to study predictors of survival and radiotherapy receipt. RESULTS:A total of 9550 cases of SCCA were included. The median age of the patients was 58 years, 63% were female, 85% were white, and 38% were married. In multivariable analyses, patients living in areas with lower MHI were found to have worse overall survival and cancer-specific survival (CSS) compared with those in the highest income areas. Mortality hazard ratios for lowest to highest income were 1.32 (95% confidence interval [95% CI], 1.18-1.49), 1.31 (95% CI, 1.16-1.48), 1.19 (95% CI, 1.06-1.34), and 1.16 (95% CI, 1.03-1.30). The hazard ratios for CSS similarly ranged from 1.34 to 1.22 for lowest to highest income. Older age, black race, male sex, unmarried marital status, an earlier year of diagnosis, higher tumor grade, and later American Joint Committee on Cancer stage of disease also were associated with worse CSS. Income was not found to be associated with the odds of initiating radiotherapy in multivariable analysis (odds ratio of 0.87 for lowest to highest income level; 95% CI, 0.63-1.20). CONCLUSIONS:MHI appears to independently predict CSS and overall survival in patients with SCCA. Black race was found to remain a predictor of SCCA survival despite controlling for income. Further study is needed to understand the mechanisms by which socioeconomic inequalities affect cancer care and outcomes. Cancer 2018. © 2018 American Cancer Society.

PURPOSE/OBJECTIVE:Prior studies of timeliness of adjuvant chemotherapy (AC) initiation in stage III colon cancer have suggested longer time to AC at public compared with private hospitals. Few studies have explored differences in AC completion. We investigated whether timely initiation and completion of AC differed between a public and private hospital, affiliated with the same academic institution in a large, urban setting. METHODS:We conducted a retrospective cohort study of stage III colon cancer patients who had surgery and AC at the same medical center between 2008 and 2015, either at its affiliated public hospital (n = 43) or private hospital (n = 79). We defined timely initiation as receiving AC within 60 days postoperatively, and completion as receiving ≥ 75% of planned AC. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with AC delivery. RESULTS:Median number of days to AC was significantly greater among patients at the public (53, range 31-231) compared with the private hospital (43, range 25-105; p = 0.002). However, the percentage of patients with timely AC initiation did not differ substantially by hospital (74 vs 81%, p = 0.40). In multivariable analysis, age (OR 0.95/year, 95% CI 0.91-0.99) and laparoscopic versus open surgery (OR 5.65, 95% CI 1.92-16.62) were significant factors associated with timely AC initiation. Moreover, AC completion did not differ significantly between public (83.7%) and private (89.9%) hospital patients (p = 0.32). CONCLUSIONS:The proportions of patients with timely initiation and completion of AC were similar at a public and private hospital affiliated with a large, urban medical center. Future research should investigate how specific system-level factors help alleviate this expected difference in timely care delivery.

Background: ESCC comprises 80% of esophageal cancers worldwide. Preoperative chemoRT is a standard-of-care based on the CROSS trial (N Engl J Med 2012;366:2074-2084), which reported encouraging pathologic complete response (pCR) and overall survival (OS). Surgery is often deferred in patients with clinical CR (cCR) based on lack of overall survival (OS) benefit (J Clin Oncol 2005;23:2310-2317, J Clin Oncol 2007;25:1160-1168). Nivolumab has activity in advanced ESCC (Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes. ESCC has a high somatic mutation rate and treatment with chemoRT may augment the abscopal effect.
Method(s): Our trial aims to establish the safety and tolerability (phase I), as well as the efficacy (phase II) of nivolumab added to a standard chemoRT backbone for patients with Tany N1-3 or T3-4N0 M0 ESCC. Phase I will enroll up to 12 patients and phase II, up to 44, per an optimal two-stage design. The phase I primary endpoint is unacceptable toxicity at 28 days after the last dose of chemotherapy. Phase II primary endpoints are cCR (endoscopy + PET/CT), pCR for patients undergoing surgery, and median progression-free survival and OS, which will be estimated via Kaplan Meier curves. Extensive tumor and blood immune correlative studies are planned. (Table Presented)

Background: Although the optimal timing of adjuvant chemotherapy (AC) for stage III colon cancer patients has been debated, most studies recommend initiating AC within approximately 60 days of surgery. Significant disparities in timeliness of AC initiation in colon cancer have been reported in public versus private hospitals, with longer time to AC at public hospitals. We evaluated whether timeliness of AC differed between a public and a private hospital, both affiliated with the same major academic institution in New York City. Methods: We conducted a retrospective cohort study of Stage III colon cancer patients who underwent surgery and received AC at the same institution from 2008-2015 at NYU Langone Medical Center's affiliated public hospital (Bellevue) or its private hospital (Tisch). Patient data were obtained through review of hospital tumor registry and electronic medical records. Patient characteristics were compared by hospital. We defined timeliness as receipt of AC within 60 days postoperatively. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with timely AC. Results: Forty three patients at Bellevue Hospital and 79 patients at Tisch Hospital who underwent surgery and received AC at the same institution were included. Median number of days to AC was significantly greater among patients receiving care at Bellevue (53, range 31-231) compared to Tisch (43, range 25-105; p=0.002). However, the percentage of patients who received timely AC did not differ substantially at Bellevue and Tisch (74% vs 81%, p=0.40). Individual characteristics significantly associated with timely initiation of AC were non-Hispanic ethnicity (OR: 2.71, 95% CI: 1.06-6.95), married (OR: 2.89, 95%CI: 1.15-7.30), and laparoscopic (vs open) surgery (OR: 4.30, 95%CI: 1.64-11.25). The odds of receiving timely AC at Bellevue compared to Tisch was not significant (OR: 0.68, 95% CI: 0.28-1.65). When hospital and other factors were examined jointly, only age (OR: 0.95/year, 95% CI: 0.91-0.99) and laparoscopic (vs open) surgery (OR: 5.65, 95% CI: 1.92-16.62) remained as important factors associated with receiving timely AC (Likelihood Ratio Chi-Square=14.95, p=0.0019). When hospital was omitted from multivariable analysis, age and surgery type still remained the only significant factors associated with timely AC (OR's unchanged, Likelihood Ratio Chi-Square=14.81, p-value=0.0006). Conclusions: The proportion of patients receiving timely AC within 60 days of surgery was similar at both an affiliated public and private hospital at NYU Langone Medical Center. Age and type of surgery were significant predictors of timeliness in our population. Further research should be conducted to understand how system-level factors may promote timely receipt of care

Background: Mutant KRAS tumors show a dependency on WT-H/N-Ras for activation of ATR/Chk1-mediated G2 DNA damage response (Grabocka, Cell, 2015). We have shown in vitro that the Wee1 kinase inhibitor AZD1775, which acts to abrogate the G2 DNA damage checkpoint and induces replication stress during S-phase, selectively sensitizes RAS/RAF mutant cells to the DNA damaging agent irinotecan. Up to 65% of metastatic colorectal cancers harbor RAS or BRAF mutations and these patients have limited treatment options following first line therapy. Methods: This is an open label, single-arm, phase Ib study using a modified 3+3 dose-escalation schedule with expansion cohort. Primary objective is to determine the MTD of AZD1775 in combination with irinotecan as 2 -line therapy in patients with metastatic KRAS, NRAS or BRAF mutated colorectal cancer. Up to 18 patients will be enrolled in the dose escalation portion. Standard dose irinotecan is given on day 1 of every 2 week cycle. AZD1775 is administered PO twice daily for 3 to 5 days of each cycle, starting cycle 2. The maximum tolerated dose (MTD) is defined as the highest dose level at which <=1 of 6 patients experience a dose limiting toxicity. Once the MTD is reached and/or recommended dose for expansion is determined, a dose expansion cohort of 14 patients will be enrolled. Secondary endpoints include characterizing the safety profile at the MTD, obtaining a preliminary estimate of efficacy for the combination (measured by overall response rate, progressionfree and overall survival rates), and obtaining pharmacokinetic parameters. Pre- and on-treatment biopsies will be collected from the expansion cohort to determine: adequate target engagement of Wee1, changes in markers of DNA damage, TP53 mutation status, and changes in gene expression profiles in order to identify potential biomarkers of response. At February 2017, 2 patients have been enrolled on this study

Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States, with poor response to current standard of care, short progression-free and overall survival. Immunotherapies that target cytotoxic T lymphocyte antigen-4, programmed cell death protein-1, and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma, renal cell carcinoma, and non-small cell lung cancer due to high numbers of somatic mutations, combined with cytotoxic T-cell responses. However, single checkpoint blockade was ineffective in pancreatic cancer, highlighting the challenges including the poor antigenicity, a dense desmoplastic stroma, and a largely immunosuppressive microenvironment. In this review, we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy, radiotherapy, and targeted therapy. These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.