Prediction of therapeutic outcome and survival in a transgenic mouse model of pancreatic ductal adenocarcinoma treated with dendritic cell vaccination or CDK inhibitor using MRI texture: a feasibility study.

There is a lack of a well-established approach for assessment of early treatment outcomes for modern therapies for pancreatic ductal adenocarcinoma (PDAC) e.g. dinaciclib or dendritic cell (DC) vaccination. Here, we developed multivariate models using MRI texture features to detect treatment effects following dinaciclib drug or DC vaccine therapy in a transgenic mouse model of PDAC including 21 LSL-KrasG12D ; LSL-Trp53R172H ; Pdx-1-Cre (KPC) mice used as untreated control subjects (n=8) or treated with dinaciclib (n=7) or DC vaccine (n=6). Support vector machines (SVM) technique was performed to build a linear classifier with three variables for detection of tumor tissue changes following drug or vaccine treatments. Besides, multivariate regression models were generated with five variables to predict survival behavior and histopathological tumor markers (Fibrosis, CK19, and Ki67). The diagnostic performance was evaluated using accuracy, area under the receiver operating characteristic curve (AUC) and decision curve analyses. The regression models were evaluated with adjusted r-squared (Radj 2). SVM classifier successfully distinguished changes in tumor tissue with an accuracy of 95.24% and AUC of 0.93. The multivariate models generated with five variables were strongly associated with histopathological tumor markers, fibrosis (Radj 2=0.82, P<0.001), CK19 (Radj 2=0.92, P<0.001) and Ki67 (Radj 2=0.97, P<0.001). Furthermore, the multivariate regression model successfully predicted survival of KPC mice by interpreting tumor characteristics from MRI data (Radj 2=0.91, P<0.001). The results demonstrated that MRI texture features had great potential to generate diagnosis and prognosis models for monitoring early treatment response following dinaciclib drug or DC vaccine treatment and also predicting histopathological tumor markers and long-term clinical outcomes.

Dinaciclib prolongs survival in the LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx-1-Cre (KPC) transgenic murine models of pancreatic ductal adenocarcinoma.

Dinaciclib is a small molecule cyclin-dependent kinase inhibitor with the potential to treat multiple cancers. To better understand its cytotoxic action in pancreatic ductal adenocarcinoma (PDAC), we evaluated dinaciclib therapeutic effects in the transgenic mouse model (LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx-1-Cre mice; KPC mice). Tumor growth and microenvironment were dynamically monitored by magnetic resonance imaging (MRI). Dinaciclib therapy significantly delayed tumor progression (P < 0.001) and prolonged survival (P = 0.007) in KPC mice. In vitro assays showed that dinaciclib exerted antiproliferative effects on PDAC cells by increasing surface calreticulin expression and release of ATP. Dinaciclib treatment inhibited proliferation and induced apoptosis in KPC tumor as assessed by Ki67 and cleaved caspase 3, respectively. Particularly, the tumor infiltrating CD8+ T cells were increased after dinaciclib treatment in KPC mice. Additionally, the mean apparent diffusion coefficient values of KPC tumor calculated from diffusion weighted MR images were significantly lower after dinaciclib treatment (P = 0.033). These finding suggest that dinaciclib as a single agent can inhibit tumor growth and improve the overall survival in KPC mice.

TheraSphere Yttrium-90 Glass Microspheres Combined With Chemotherapy Versus Chemotherapy Alone in Second-Line Treatment of Patients With Metastatic Colorectal Carcinoma of the Liver: Protocol for the EPOCH Phase 3 Randomized Clinical Trial.

BACKGROUND: Colorectal cancer is one of the most common cancers and causes of cancer-related death. Up to approximately 70% of patients with metastatic colorectal cancer (mCRC) have metastases to the liver at initial diagnosis. Second-line systemic treatment in mCRC can prolong survival after development of disease progression during or after first-line treatment and in those who are intolerant to first-line treatment. OBJECTIVE: The objective of this study is to evaluate the efficacy and safety of transarterial radioembolization (TARE) with TheraSphere yttrium-90 (90Y) glass microspheres combined with second-line therapy in patients with mCRC of the liver who had disease progression during or after first-line chemotherapy. METHODS: EPOCH is an open-label, prospective, multicenter, randomized, phase 3 trial being conducted at up to 100 sites in the United States, Canada, Europe, and Asia. Eligible patients have mCRC of the liver and disease progression after first-line chemotherapy with either an oxaliplatin-based or irinotecan-based regimen and are eligible for second-line chemotherapy with the alternate regimen. Patients were randomized 1:1 to the TARE group (chemotherapy with TARE in place of the second chemotherapy infusion and subsequent resumption of chemotherapy) or the control group (chemotherapy alone). The addition of targeted agents is permitted. The primary end points are progression-free survival and hepatic progression-free survival. The study objective will be considered achieved if at least one primary end point is statistically significant. Secondary end points are overall survival, time to symptomatic progression defined as Eastern Cooperative Oncology Group Performance Status score of 2 or higher, objective response rate, disease control rate, quality-of-life assessment by the Functional Assessment of Cancer Therapy-Colorectal Cancer questionnaire, and adverse events. The study is an adaptive trial, comprising a group sequential design with 2 interim analyses with a planned maximum of 420 patients. The study is designed to detect a 2.5-month increase in median progression-free survival, from 6 months in the control group to 8.5 months in the TARE group (hazard ratio [HR] 0.71), and a 3.5-month increase in median hepatic progression-free survival time, from 6.5 months in the control group to 10 months in the TARE group (HR 0.65). On the basis of simulations, the power to detect the target difference in either progression-free survival or hepatic progression-free survival is >90%, and the power to detect the target difference in each end point alone is >80%. RESULTS: Patient enrollment ended in October 2018. The first interim analysis in June 2018 resulted in continuation of the study without any changes. CONCLUSIONS: The EPOCH study may contribute toward the establishment of the role of combination therapy with TARE and oxaliplatin- or irinotecan-based chemotherapy in the second-line treatment of mCRC of the liver. TRIAL REGISTRATION: ClinicalTrials.gov NCT01483027; https://clinicaltrials.gov/ct2/show/NCT01483027 (Archived by WebCite at http://www.webcitation.org/734A6PAYW). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/11545.

Treatment adherence, healthcare resource utilization, and costs in patients with lung neuroendocrine tumors (lung NETs) in the USA.

OBJECTIVE: To assess first-line treatment adherence, healthcare resource utilization, and costs in lung NET patients initiating pharmacologic treatments. METHODS: In two US claims databases, patients aged ≥18 years with ≥1 inpatient or ≥2 outpatient lung NET claims within 12 months were identified. The first claim for pharmacologic treatments (e.g. somatostatin analogs [SSAs], cytotoxic chemotherapy [CC], targeted therapy [TT]) following diagnosis, between July 1, 2009-December 31, 2014, was defined as the index date. A 6-month pre-index period without any NET treatment, and ≥1-year post-index enrollment were required. Proportion of days covered (PDC) was calculated during follow-up. Descriptive statistics, including means, standard deviations, and frequencies/percentages for continuous and categorical data, respectively, were reported. RESULTS: Of 354 patients with 1-year of follow-up, 252 initiated CC, 89 SSA, 3 TT, and 10 various combinations. Due to sample sizes, the remaining results focus only on CC and SSAs. Mean PDC (SD) was 0.320 (0.176) for CC and 0.673 (0.322) for SSAs; CC users had a mean (SD) of 33.3 (23.8) office visits and 0.79 (1.39) hospitalizations; SSA users had 23.1 (12.4) visits and 0.48 (1.07) hospitalizations. Mean total (SD) annual cost for CC users was $124,383 (135,836) and $98,713 (81,495) for SSA users. Among 163 patients with 2 years of follow-up, the annual mean cost in the second-year was $43,026 lower and $8110 higher than the first-year for CC and SSAs, respectively. CONCLUSIONS: The majority of patients with lung NETs initiated CC; only about one quarter initiated SSA in the first-line. This descriptive study updates the utilization and costs of pharmacologically-treated lung NETs.

Single- versus Triple-Drug Chemoembolization for Hepatocellular Carcinoma: Comparing Outcomes by Toxicity, Imaging Response, and Survival.

PURPOSE: To determine the efficacy of single- versus triple-drug chemoembolization for the treatment of hepatocellular carcinoma, as measured by toxicity, tumor response, time to progression (TTP), and overall survival (OS). MATERIALS AND METHODS: A single-center retrospective review was performed on 337 patients who underwent chemoembolization over a 14-year period; 172 patients underwent triple-drug conventional transarterial chemoembolization, and 165 patients underwent single-agent doxorubicin chemoembolization. Imaging characteristics and clinical follow-up after conventional transarterial chemoembolization were evaluated to determine TTP. Imaging response was determined per World Health Organization and European Association for the Study of Liver criteria. OS from time of first chemoembolization was calculated. RESULTS: Median TTP was similar between groups: 7.9 months (95% confidence interval [CI], 7.1-9.4) and 6.8 months (95% CI, 4.6-8.6) for triple- and single-drug regimens, respectively (P > .05). For single-agent conventional transarterial chemoembolization, median OS varied significantly by Barcelona Clinic for Liver Cancer (BCLC) stage: A, 40.8 months; B, 36.4 months; C, 10.9 months (P < .01). Median OS for triple-drug therapy also varied significantly by BCLC: A, 28.9 months; B, 18.1 months; C, 9.0 months (P < .01). Single-drug conventional transarterial chemoembolization demonstrated longer median OS compared with triple-drug therapy (P < .05) for BCLC A/B patients. CONCLUSIONS: Single-agent chemoembolization with doxorubicin and ethiodized oil demonstrates acceptable efficacy as measured by TTP and OS. Results compare favorably with traditional triple-drug therapy.

Independent Analysis of Albumin-Bilirubin Grade in a 765-Patient Cohort Treated with Transarterial Locoregional Therapy for Hepatocellular Carcinoma.

PURPOSE: To assess validity of albumin-bilirubin (ALBI) grade as a predictor of survival in patients undergoing transarterial embolization for hepatocellular carcinoma. MATERIALS AND METHODS: Baseline albumin and bilirubin values of 765 consecutive patients treated with conventional transarterial chemoembolization or yttrium-90 ((90)Y) radioembolization at a single institution were used to determine liver function according to ALBI grade. Survival outcomes were stratified by ALBI grade using Kaplan-Meier and stratified by Child-Pugh (C-P) class and Barcelona Clinic Liver Cancer (BCLC) stage. Discriminatory ability was assessed by C-index. RESULTS: For 428 patients receiving (90)Y radioembolization, ALBI grade yielded distinct survival curves (P < .001). When stratified by C-P class and BCLC stage, ALBI grade revealed different survival outcomes for C-P B (P = .001), BCLC A (P < .001), BCLC B (P = .001), and BCLC C (P < .001). When substratified by BCLC stage, ALBI grade was a better discriminator of survival than C-P class (C-index 0.792, 0.763, respectively). For 337 patients receiving transarterial chemoembolization, ALBI grade yielded distinct survival curves (P < .001). When stratified by C-P class and BCLC stage, ALBI grade provided distinct survival curves for C-P B (P = .02), BCLC B (P = .001), and BCLC C (P = .02). When substratified by BCLC stage, ALBI grade was a better discriminator of survival than C-P class (C-index 0.739, 0.735, respectively). CONCLUSIONS: ALBI grade outperforms C-P class at discriminating survival in patients receiving transarterial chemoembolization or (90)Y radioembolization. ALBI grade is also valuable in patients with moderate liver dysfunction and BCLC B disease.

Comparative clinical benefits of systemic adjuvant therapy for paradigm solid tumors.

Adjuvant therapy employing cytotoxic chemotherapy, molecularly targeted agents, immunologic, and hormonal agents has shown a significant impact upon a variety of solid tumors. The principles that guide adjuvant therapy differ among various tumor types and specific modalities, but generally indicate a greater impact of therapy in the postsurgical setting of micrometastatic disease, for which adjuvant therapy is commonly pursued, vs. the setting of gross unresectable disease. This review of adjuvant therapies in current use for five major solid tumors highlights the rationale for current effective adjuvant therapy, and draws comparisons between the adjuvant regimens that have found application in solid tumors.

A phase I study of docetaxel, Cisplatin, 5-Fluorouracil and leucovorin.

OBJECTIVES: Cisplatin, 5-fluorouracil (5-FU) and docetaxel are active agents in the treatment of upper gastrointestinal malignancies. This phase I study was undertaken to determine the maximally tolerated dose and dose-limiting toxicities of a combination of these drugs given in an ambulatory setting using a bolus schedule of 5-FU. METHODS: Twenty patients with gastrointestinal malignancies were treated with docetaxel on day 1, cisplatin on day 2 and bolus 5-FU with leucovorin each day for 5 days, without prophylactic antibiotics or colony-stimulating factors. The cycle was repeated at 21-day intervals. A dose-escalating phase I design was used. RESULTS: There were two treatment-related deaths as a result of neutropenia and sepsis. The maximally tolerated dose was docetaxel at 60 mg/m2 on day 1, cisplatin at 75 mg/m2 on day 2 and 5-FU at 200 mg/m2 with leucovorin at 20 mg/m2 daily from day 1 to day 5. At this dose, neutropenia was occurring in 4 of 6 patients treated. There were three partial responses, 1 patient with esophagogastric cancer and 2 with gastric cancer. CONCLUSIONS: This regimen demonstrates efficacy in upper gastrointestinal malignancies. Strategies to improve the tolerance of these agents in combination should be pursued.