A Case Series of Choroidal and Orbital Neuroendocrine Tumors: Metastasis: Two Patients Treated With Peptide Radionuclide Therapy.

ABSTRACT: Neuroendocrine tumors (NETs) are rare cancers with heterogeneous histologies, response to treatments, and prognoses. Majority of these cancers originate in the gastrointestinal tract and metastasize to the liver. We report the cases of 5 patients with low-grade NET disease with rare metastases to the choroids. Two of the patients were treated with peptide receptor radionuclide therapy (lutetium 177 [ 177 Lu]). This is the first report confirming peptide radionuclide therapy safety in patients with low-grade NET with ocular metastases.

Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer.

BACKGROUND: Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study. METHODS: Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0-1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry. RESULTS: A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50-67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475). CONCLUSIONS: Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.

Phase II randomised, double-blind study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients (HCRN GI14-198).

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR)-mediated signalling contributes to andgiogenesis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Ramucirumab (RAM) is a VEGFR2 monoclonal antibody. We conducted a randomised phase II trial to compare progression-free survival (PFS) between mFOLFIRINOX with or without RAM in first line therapy of metastatic PDAC. METHODS: This phase II randomised, multi-centre, placebo controlled, double-blinded, trial randomly assigned to recurrent/metastatic PDAC patients to either mFOLFIRINOX/RAM (Arm A) or mFOLFIRINOX/placebo (Arm B). The primary endpoint is PFS at 9 months, and the secondary endpoints include overall survival (OS), response rate and toxicity evaluation. RESULTS: A total of 86 subjects enrolled, 82 eligible (42 in Arm A versus 40 in Arm B). The mean age was comparable (61.7 versus 63.0, respectively). Majority were White (N = 69) and males (N = 43). The median PFS was 5.6 compared to 6.7 months, for Arm A and B, respectively. At 9 months, the PFS rates were 25.1% and 35.0% for Arms A and B, respectively (p = 0.322). The median OS in Arm A was 10.3 compared to 9.7 months for Arm B (p = 0.094). The disease response rate for Arm A was 17.7% compared to Arm B of 22.6%. FOLFIRINOX/RAM combination was well tolerated. CONCLUSIONS: The addition of RAM to FOLFIRINOX did not significantly impact PFS or OS. The combination was well tolerated (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02581215).

Survival and Prognostic Factors in Patients With Pancreatic Colloid Carcinoma Compared With Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Colloid carcinoma (CC) is a rare subtype of pancreatic carcinoma. The aims of the study are to characterize the clinicopathological features and to evaluate the overall survival (OS) of patients with CC. METHODS: Patients diagnosed with pancreatic CC and pancreatic ductal adenocarcinoma (PDAC) between 2004 and 2016 were identified from the National Cancer Database using International Classification of Disease-O-3 morphology (8480/3 and 8140/3) and topography (C25) codes. Kaplan-Meier analysis and Cox proportional hazards models were used to analyze OS. RESULTS: Fifty-six thousand eight hundred forty-six patients were identified. A total of 2430 patients (4.3%) were diagnosed with pancreatic CC. Males constituted 52.8% of CC and 52.2% of PDAC. Colloid carcinoma presented with pathological stage I disease more often (16.7% vs 5.9%) and stage IV disease less often (42.1% vs 52.4%) than PDAC (P < 0.001). Stage I CC received chemotherapy (36.0% vs 59.4%) and neoadjuvant chemotherapy (4.4% vs 14.2%) less often compared with PDAC (P < 0.001). Statistically significant improved OS was seen among stage I, II, and IV CC compared with PDAC. CONCLUSIONS: Pancreatic CC presented as stage I disease more often compared with PDAC. Neoadjuvant chemotherapy was administered more often in stage I PDAC compared with CC. Colloid carcinoma had improved OS compared with PDAC among all stages except stage III.

FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review.

BACKGROUND: Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC. METHODS: We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based. RESULTS: A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC. CONCLUSIONS: In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

Role of local therapy in the management of patients with metastatic anal squamous cell carcinoma: a National Cancer Database study.

Background: About 10-20% of patients with anal squamous cell carcinoma (SCCa) present with metastatic disease and are usually treated with systemic chemotherapy. However, primary tumor control is crucial as local failure is associated with significant morbidity. Using the largest cohort to date, we report the impact of local therapy on survival among patients with metastatic anal SCCa. Methods: Data were collected from US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2015. Patients who did not receive palliative systemic chemotherapy were excluded from analysis. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to evaluate the association between tumor/patient characteristics and overall survival (OS). Results: A total of 1,160 patients were identified over the 12 years of study. Median age was 57 years. Majority were female (64.9%), non-Hispanic Whites (79.1%) and had Charlson-Deyo Score of 0 (83.6%). Most common metastatic sites were liver (25.9%), lung (11.6%) and bone (8.5%). More than 79% of the patients had received radiation to the primary site, and 10.4% underwent surgical resection for local control. Use of local therapy correlated closely with OS on MVA (HR 0.66; 0.55-0.79; P<0.001), with a 12-month and 5-year OS rates of 72.8% and 25.7% respectively, compared with 61.1% and 14.6% for patients treated with chemotherapy only. Poor prognostic factors included male gender (HR 1.44; 1.24-1.67; P<0.001), age >70 years (HR 1.28; 1.02-1.62; P=0.034), lack of health insurance (HR 1.32; 1.02-1.71; P=0.034), and cloacogenic zone location (HR 4.02; 1.43-11.30; P=0.008). There was no benefit from abdominoperineal resection (mOS =19.7 months; HR 1.05; 0.48-2.29; P=0.909), but both local resection of the primary (mOS =24.8 months, HR 0.48; 0.29-0.80; P=0.005) and palliative radiation (mOS =22.6 months; HR 0.66; 0.55-0.79; P<0.001) were associated with improved OS. Conclusions: In addition to systemic therapy, resection of the primary tumor or palliative radiation improved OS in patients with anal SCCa. Patients unlikely to benefit from local control were those >70 years of age, male, lack of health insurance and cloacogenic carcinoma.

A randomized phase 2 trial of nivolumab, gemcitabine, and cisplatin or nivolumab and ipilimumab in previously untreated advanced biliary cancer: BilT-01.

BACKGROUND: Gemcitabine and cisplatin has limited benefit as treatment for advanced biliary tract cancer (BTC). The addition of an anti-programmed death receptor (PD-1)/PD-ligand (L1) antibody to either systemic chemotherapy or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody has shown benefit in multiple solid tumors. METHODS: In this phase 2 trial, patients 18 years or older with advanced BTC without prior systemic therapy and Eastern Cooperative Oncology Group Performance Status 0-1 were randomized across six academic centers. Patients in Arm A received nivolumab (360 mg) on day 1 along with gemcitabine and cisplatin on days 1 and 8 every 3 weeks for 6 months followed by nivolumab (240 mg) every 2 weeks. Patients in Arm B received nivolumab (240 mg) every 2 weeks and ipilimumab (1 mg/kg) every 6 weeks. RESULTS: Of 75 randomized patients, 68 received therapy (Arm A = 35, Arm B = 33); 51.5% women with a median age of 62.5 years. The observed primary outcome of 6-month progression-free survival (PFS) rates in the evaluable population was 59.4% in Arm A and 21.2% in Arm B. The median PFS and overall survival (OS) in Arm A were 6.6 and 10.6 months, and in Arm B 3.9 and 8.2 months, respectively, in patients who received any treatment. The most common treatment-related grade 3 or higher hematologic adverse event was neutropenia in 34.3% (Arm A) and nonhematologic adverse events were fatigue (8.6% Arm A) and elevated transaminases (9.1% Arm B). CONCLUSIONS: The addition of nivolumab to chemotherapy or ipilimumab did not improve 6-month PFS. Although median OS was less than 12 months in both arms, the high OS rate at 2 years in Arm A suggests benefit in a small cohort of patients.

Survival Outcomes of Adjuvant Chemotherapy in Elderly Patients with Stage III Colon Cancer.

BACKGROUND: The survival impact of multi-agent (MAC) compared with single-agent (SAC) adjuvant chemotherapy (AC) in elderly patients with stage III colon cancer (CC) remains controversial. The aim of this study was to compare survival outcomes of MAC and SAC in this population utilizing the National Cancer Database (NCDB). PATIENTS AND METHODS: Patients aged ≥70 years with pathological stage III CC diagnosed in 2004-2015 were identified in the NCDB. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazard models were used to identify associations between MAC vs. SAC and overall survival (OS). RESULTS: Among 41 707 elderly patients (≥70 years old) with stage III CC, about half (n = 20 257; 48.5%) received AC; the majority (n = 12 923, 63.8%) received MAC. The median age was 79 (range 70-90). The majority were female (n = 11 201, 55.3%), Caucasians (88%) and had moderately differentiated tumor grade (n = 12 619, 62.3%), tumor size >4 cm (11 785, 58.2%), and negative surgical margins (18 496, 91.3%). Low-risk stage III CC constituted 50.6% (n = 10 264) of the study population. High-risk stage III CC was associated with worse OS compared with low-risk disease (HR 0.35, 0.34-0.36, P < .001). Multi-agent chemotherapy was associated with a better 5-year OS compared with SAC (P < .001). High-risk stage III patients who received MAC vs. SAC had an OS of 4.2 vs. 3.4 years, respectively (P < .001). Low-risk stage III patients who received MAC vs. SAC had a median OS of 8.5 vs. 7 years (P < .001). In univariate and multivariable analyses, male sex, positive surgical margin, insurance and facility types, age, year of diagnosis, tumor size, and Charlson-Deyo score of >2 were associated with worse OS (P < .05). CONCLUSIONS: Any adjuvant chemotherapy has a trend of survival benefits. Multi-agent chemotherapy seems to have an enhanced benefit in the 70-75 age group. Multi-agent chemotherapy seemed to have similar efficacy as SAC in those aged >76 years.

Comparing Somatostatin Analogs in the Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: The 2 approved somatostatin analogs (SSAs) in the first-line treatment of advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are octreotide long-acting release (Sandostatin LAR) and somatuline depot (Lanreotide). The study's objective was to compare progression-free survival (PFS) and overall survival (OS) of patients (pts) with GEP-NETs treated with somatuline or octreotide LAR. Pts and Methods: Pts with advanced well-differentiated GEP-NET who received either SSA at Emory University between 1995 and 2019 were included after institutional review board approval. The primary end point was PFS, defined as time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.1, or clinical progression) or death. The secondary end point was OS. Kaplan-Meier curves were generated, and log-rank tests were conducted to compare the survival outcomes. RESULTS: A total of 105 pts were identified. The mean age was 62.1 years (SD ± 11.8). The male-to-female ratio was 51:54. The majority (N = 69, 65.7%) were white. Most pts had grade 2 (G2) disease (N = 44, 41.9%). Primary location was small bowel in 58 (55.2%), pancreas in 27 (25.7%), and other in 20 (19.0%). Functional tumors were defined in 32 pts distributed equally between the 2 groups. Distribution of treatment was similar in the 2 groups, with 54 receiving octreotide LAR and 51 receiving somatuline depot. The median PFS for the octreotide LAR and somatuline depot groups was 12 months (95% CI, 6-18 months) and 10.8 months (95% CI, 6-15.6 months), respectively, and the difference was not statistically significant (p = 0.2665). For pts with G1 disease, the median PFS for the octreotide LAR and somatuline depot was 8.4 versus 32.4 months, respectively, and the difference was not statistically significant (p = 0.159). For G2 disease, the difference in median PFS between octreotide LAR and somutaline depot groups was statistically significant (12 vs. 7.2 months, respectively; p = 0.0372). The mean follow-up time for octreotide LAR was 21.6 months versus 11.3 months for somatuline depot. CONCLUSIONS: Overall, there was no difference in PFS between octreotide LAR and somatuline depot for pts with well-differentiated, metastatic GEP-NETs. A prospective study is worth designing selecting for G.

Predictive and Prognostic Effects of Primary Tumor Size on Colorectal Cancer Survival.

BACKGROUND: Pathologic staging is crucial in colorectal cancer (CRC). Unlike the majority of solid tumors, the current staging model does not use tumor size as a criterion. We evaluated the predictive and prognostic impact of primary tumor size on all stages of CRC. METHODS: Using the National Cancer Database (NCDB), we conducted an analysis of CRC patients diagnosed between 2010 and 2015 who underwent resection of their primary cancer. Univariate and multivariate analyses were used to identify predictive and prognostic factors, Kaplan-Meier analysis and Cox proportional hazards models for association between tumor size and survival. RESULTS: About 61,000 patients met the inclusion criteria. Median age was 63 years and majority of the tumors were colon primary (82.7%). AJCC stage distribution was: I - 20.1%; II - 32.1%; III - 34.7% and IV - 13.1%. The prognostic impact of tumor size was strongly associated with survival in stage III disease. Compared to patients with tumors <2cm; those with 2-5cm (HR 1.33; 1.19-1.49; p<0.001), 5-10cm (HR 1.51 (1.34-1.70; p<0.001) and >10cm (HR 1.95 (1.65-2.31; p<0.001) had worse survival independent of other variables. Stage II treated without adjuvant chemotherapy had comparable survival outcomes (HR 1.09; 0.97-1.523; p=0.148) with stage III patients who did, while Stage II patients who received adjuvant chemotherapy did much better than both groups (HR 0.76; 0.67-0.86; p<0.001). Stage III patients who did not receive adjuvant chemotherapy had the worst outcomes among the non-metastatic disease subgroups (HR 2.66; 2.48-2.86; p<0.001). Larger tumors were associated with advanced stage, MSI high, non-rectal primary and positive resection margins. CONCLUSIONS: Further studies are needed to clarify the role of tumor size in prognostic staging models, and how to incorporate it into therapy decisions.

High-Risk Features Are Prognostic in dMMR/MSI-H Stage II Colon Cancer.

BACKGROUND: High-risk features, such as T4 disease, bowel obstruction, poorly/undifferentiated histology, lymphovascular, perineural invasion, and <12 lymph nodes sampled, indicate poor prognosis and define high-risk stage II disease in proficient mismatch repair stage II colon cancer (CC). The prognostic role of high-risk features in dMMR/MSI-H stage II CC is unknown. Similarly, the role of adjuvant therapy in high-risk stage II CC with dMMR/MSI-H (≥1 high-risk feature) has not been studied in prospective trials. The aim of this analysis of the National Cancer Database is to evaluate the prognostic value of high-risk features in stage II dMMR/MSI-H CC. METHODS: Univariate (UVA) and multivariate (MVA) Cox proportional hazards (Cox-PH) models were built to assess the association between clinical and demographic characteristics and overall survival. Kaplan-Meier survival curves were generated with log-rank tests to evaluate the association between adjuvant chemotherapy in high-risk and low-risk cohorts separately. RESULTS: A total of 2,293 stage II CC patients have dMMR/MSI-H; of those, 29.5% (n = 676) had high-risk features. The high-risk dMMR/MSI-H patients had worse overall survival [5-year survival and 95%CI, 73.2% (67.3-78.1%) vs. 80.3% (76.7-83.5%), p = 0.0001]. In patients with stage II dMMR/MSI-H CC, the high-risk features were associated with shorter overall survival (OS) along with male sex, positive carcinoembryonic antigen, Charlson-Deyo score >1, and older age. Adjuvant chemotherapy administration was associated with better OS, regardless of the high-risk features in dMMR/MSI-H (log-rank test, p = 0.001) or not (p = 0.0006). When stratified by age, the benefit of chemotherapy was evident only in patients age ≥65 with high-risk features. CONCLUSION: High-risk features are prognostic in the setting of dMMR/MSI-H stage II CC. Adjuvant chemotherapy may improve survival specifically in patients ≥65 years and with high-risk features.

A multi-center, single-arm, phase Ib study of pembrolizumab (MK-3475) in combination with chemotherapy for patients with advanced colorectal cancer: HCRN GI14-186.

Modified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression-free survival (mPFS), with secondary objectives including median overall survival, safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients, respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.

Evaluating the impact of the Patient Preference Assessment Tool on clinicians' recommendations for phase I oncology clinical trials.

OBJECTIVE: Many groups recommend assessment of patient preferences particularly for patients with advanced, incurable cancer. We, therefore, developed the Patient Preference Assessment Tool (PPAT) to ascertain patient preferences in order to inform clinician recommendations and improve shared decision-making. The aim of this study is to assess the PPAT's impact on clinicians' strength of recommendations for phase I oncology clinical trials. METHODS: Clinicians recorded the strength of their recommendation on a Likert scale before viewing the patient's PPAT. After viewing the PPAT, the clinician discussed the clinical trial with the patient and then recorded the strength of recommendation again. If there was a change, the clinician noted the reason for the change: clinical findings or patient preference. Clinicians were interviewed about the acceptability of the tool. Our threshold for determining if a change in recommendation due to the PPAT was significant was 20%, given the multiple factors influencing a clinician's recommendation. We also noted the type of phase I conversation observed based on classifications defined in prior work-priming, treatment-options, trial logistics, consent. RESULTS: N = 29. The strength of the clinicians' recommendations changed due to patient preferences in 7 of 29 (24%) of the conversations. The seven changes due to preferences were all in the 23 treatment-options conversations, for an impact rate of 30% in this type of conversation. 82% of clinicians found the PPAT useful. CONCLUSION: The PPAT was impactful in an academic setting, exceeding our 20% impact threshold. This tool helps achieve the important goal of incorporating patient preferences into shared decision-making about clinical trials.

Multicenter, Open-Label, Phase I Study of DSP-7888 Dosing Emulsion in Patients with Advanced Malignancies.

BACKGROUND: Wilms' tumor 1 (WT1) is overexpressed in various malignancies. DSP-7888 Dosing Emulsion, also known as ombipepimut-S (United States Adopted Name; International Nonproprietary Name: adegramotide/nelatimotide), is an investigational therapeutic cancer vaccine comprising two synthetic peptides derived from WT1 to promote both cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte-mediated immune responses against WT1-expressing tumors. OBJECTIVE: The aim of this study was to report the results from a phase I dose-escalation study (NCT02498665) that evaluated DSP-7888, administered either intradermally (ID) or subcutaneously (SC), in patients with recurrent or advanced malignancies associated with overexpression of WT1. PATIENTS AND METHODS: In this phase I dose-escalation study, patients with recurrent or advanced malignancies associated with overexpression of WT1 who progressed on, were intolerant to, or not a candidate for standard therapy or who presented with a malignancy that had no definite standard therapy received escalating doses of ID or SC DSP-7888 in a rolling-six study design. DSP-7888 3.5, 10.5, or 17.5 (ID only) mg was administered until disease progression or other discontinuation event. Primary objectives were safety, tolerability, and identification of the recommended phase II dose (RP2D). Overall survival (OS) and WT1-specific CTL induction were included as secondary and exploratory objectives, respectively. RESULTS: Twenty-four patients received either ID (3.5 mg, n = 4; 10.5 mg, n = 3; 17.5 mg, n = 3) or SC DSP-7888 (3.5 mg, n = 9; 10.5 mg, n = 5). No dose-limiting toxicity was observed. The most frequent treatment-emergent adverse event was injection site reactions (ID, 100% [10/10]; SC, 35.7% [5/14]); all were grade 1 or 2. Four patients (ID 17.5 mg, n = 1; SC 3.5 mg, n = 1; SC 10.5 mg, n = 2) had stable disease, 16 had progressive disease, and four were not evaluable. Median (95% confidence interval) OS duration was 180.0 (136.0-494.0) days. Among evaluable patients, WT1-specific CTL induction was observed in 66.7% (6/9) and 41.7% (5/12) of those administered ID and SC DSP-7888, respectively. CONCLUSIONS: DSP-7888 Dosing Emulsion was well tolerated, with no dose-limiting toxicities, in patients with recurrent or advanced malignancies. Higher WT1-specific CTL induction activity was noted with ID compared with SC administration; because of this, the ID route was selected for further evaluation in the clinical program. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02498665.

Survival Outcomes of Acinar Cell Pancreatic Cancer: A National Cancer Database Analysis.

OBJECTIVES: Acinar cell pancreatic carcinomas (ACPCs) are rare neoplasms accounting for 1% to 2% of pancreatic tumors in adults. The objective of this study is to evaluate the benefit of chemotherapy in the adjuvant setting in resected ACPC and in the palliative setting for metastatic ACPC. METHODS: Data were obtained from all US hospitals that contributed to the National Cancer Database between 2004 and 2014. Cases were identified using the histology code 8550. RESULTS: A total of 593 patients with ACPC were identified. The mean age was 64.4 years (range, 18-90 years), with a male preponderance (72.8%, n = 432). Localized stage disease comprised 52.3% (n = 310) of patients. Among localized ACPC patients, 88.0% (n = 191) underwent surgery and 50.6% (n = 91) received adjuvant chemotherapy. The 5-year overall survival in those who received adjuvant treatment was slightly higher than those who did not receive adjuvant treatment (46.7% vs 44.8%, P = 0.3271). Among advanced-stage ACPC patients, 67.6% received chemotherapy, which translated into improved 5-year overall survival compared with no chemotherapy (8.1% vs 0%, P < 0.0001). CONCLUSIONS: Chemotherapy in the palliative setting for advanced-stage ACPC patients was associated with improved survival. Adjuvant therapy did not translate into significant survival benefit.

Impact of Tumor Side on Clinical Outcomes in Stage II and III Colon Cancer With Known Microsatellite Instability Status.

BACKGROUND: Tumor sidedness as a prognostic factor in advanced stage colon cancer (CC) is well established. The impact of tumor sidedness on the clinical outcomes of stage II and III CC has not been well studied. METHODS: The National Cancer Database (NCDB) was utilized to identify patients with pathological stage II and III primary adenocarcinoma of the colon from 2010 to 2015 using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490 and C18.0, 18.2,18.3, 18.5,18.6, 18.7. Univariate (UVA) and multivariable (MVA) survival analyses and Kaplan-Meier Curves with Log-rank test were utilized to compare overall survival (OS) based on tumor location and treatment received. RESULTS: A total of 35,071 patients with stage II (n = 17,629) and III (n = 17,442) CC were identified. 51.3% female; 81.5% Caucasian; median age 66 (range, 18-90). Majority of stage II and III tumors were right sided, 61.2% (n = 10,794) and 56.0% (n = 9,763). Microsatellite instability high (MSI-H) was more common in stage II compared to III, 23.3% (n = 4,115) vs 18.2% (n = 3,171) (p < 0.0001). In stage II MSI-H CC right was more common than left, 78.3% (n = 3223) vs 21.7% (n = 892). There was no significant difference in survival between stage II MSI-H left vs right (5-year OS 76.2 vs 74.7%, p = 0.1578). Stage II MSS CC right was more common than left, 56.0% (n = 7571) vs 44.0% (n = 5943), and survival was better in the left vs right (5-year OS 73.2 vs 70.8%, p = 0.0029). Stage III MSI-H CC was more common in the right than in the left, 75.6% (n = 2,397) vs 24.4% (n = 774) and survival was better in the left (5-year OS 62.5 vs 56.5%, p = 0.0026). Stage III MSS CC was more common in the right than in the left, 51.6% (n = 7,366) vs 48.4% (n = 6,905), and survival was better in the left vs right (5-year OS 67.0 vs 54.4%, p < 0.001). CONCLUSION: Survival was better in left sided tumors compared to right in stage II MSS, stage III MSS, and stage III MSI-H CC.

Safety and Efficacy of 7 Days on/7 Days off Versus 14 Days on/7 Days off Schedules of Capecitabine in Patients with Metastatic Colorectal Cancer: A Retrospective Review.

INTRODUCTION/BACKGROUND: The administration schedule of capecitabine for the treatment of metastatic colorectal cancer (mCRC) in clinical trials has been 14 days of drug with 7 days off in a 21 day cycle (14/7). In an effort to improve tolerability, an alternative every other week treatment (7/7) is often administered. The purpose of this study was to determine the safety and efficacy of administering 7/7 compared with 14/7 capecitabine dosing. MATERIALS AND METHODS: In this retrospective study, mCRC patients received capecitabine on a 7/7 or 14/7 schedule. The primary objective was to determine the tolerability of the respective dosing schedules, defined according to frequency of dose reductions and treatment delays. Secondary objectives included comparisons of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of dosing strategies. RESULTS: Of 175 included patients, 73 (41.7%) received the capecitabine 7/7 schedule and 102 (58.3%) received the 14/7 schedule. There was a statistically significant difference between the 7/7 and 14/7 groups with regard to dose reductions (4% vs. 29%; P < .001) and treatment delays (22% vs. 43%; P = .004). The incidence of any adverse effects (45% vs. 72%; P < .001) and specifically, palmar-plantar erythrodysesthesia (18% vs. 45%; P < .001), were significantly higher in the 14/7 group. No significant difference was seen with regard to ORR, PFS, or OS. CONCLUSION: Patients with mCRC who received the 7/7 schedule had significantly fewer dose reductions and treatment delays compared with patients who received the 14/7 schedule. Although no difference in efficacy outcomes were observed, prospective studies are needed to confirm these findings.

Impact of high-risk features for stage II adenocarcinoma of the appendix.

BACKGROUND: Clinico-pathological high-risk features are frequently utilized in adjuvant chemotherapy (AC) decisions in stage II colorectal cancer and their utility in stage II appendiceal adenocarcinoma (AA) is not established. The aim of this study is to determine the impact of high-risk features in clinical outcomes and whether high risk features are predictive of AC benefit in stage II AA. METHODS: Patients with pathological stage II AA between 2010 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8140, 8480 and C18.1. High risk stage II AA was defined as having at least one of the following clinicopathological features: T4 tumor, <12 lymph nodes examined, poorly differentiated histology, positive margins, or lymphovascular invasion. Patients with none of these features were defined as low-risk. RESULTS: A total of 1040 patients with pathological stage II AA were identified. 51.0% males, 84.5% Caucasian; median age 61 (range, 19-90). 46.4% were determined to have high-risk stage II AA. High-risk status was associated with worse OS compared to low-risk in univariate (HR 1.55; 95% CI 1.18-2.02; p = 0.001) and multivariable analyses (HR 1.36; 95% CI 1.03-1.79; p = 0.028). High-risk stage II AA patients had significantly worse 5-year OS compared to low-risk patients (67.1% vs. 74.5%, p = 0.0013). AC was administered in 34.4% (n = 166) of high-risk patients and in 36.5% (n = 203) of low-risk patients. Among high-risk patients, AC was not associated with better OS in univariate (HR 0.86; 95% CI 0.59-1.26; p = 0.448) and multivariable analyses (HR 1.35; 95% CI 0.90-2.04; p = 0.151) compared to no AC. Similarly, among low-risk patients, AC was not associated with better OS in univariate (HR 0.92; 95% CI 0.60-1.39; p = 0.679) and multivariable analyses (HR 1.27; 95% CI 0.81-2.02; p = 0.299) compared to no AC. For high-risk patients, 5-year OS was 68.3% in patients that received AC vs. 66.5% in patients that did not (p = 0.722). For low-risk patients, 5-year OS was 74.0% in patients that received AC vs. 76.3% in patients that did not (p = 0.813). CONCLUSION: High-risk stage II AA patients had significantly worse 5-year OS compared to low-risk patients. AC did not improve survival regardless of high-risk features in stage II AA in this retrospective study. A prospective randomized clinical trial would be required to determine the impact of high-risk features on AC in stage II AA.