Modified FOLFIRINOX in pancreatic cancer patients Age 75 or older.

BACKGROUND: Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population. METHODS: We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT). RESULTS: 24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0-5.7) with a median OS of 11.6 months (95% CI: 6.14-15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0-12.8) and 12.2 months (95% CI: 4.8-30.8), respectively. CONCLUSIONS: In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.

Signet ring cell colorectal cancer: genomic insights into a rare subpopulation of colorectal adenocarcinoma.

BACKGROUND: Signet ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer (CRC). The aim of this study was to characterise the genomic alterations and outcomes of SRCC. METHODS: Medical records of metastatic CRC (mCRC) patients whose tumours were evaluated by NGS analysis were reviewed. SC-mCRC were classified into two groups: SRCC (>50% signet ring cells) and adenocarcinoma (AC) with SC component (≤50% signet ring cells). RESULTS: Six hundred and sixty-five mCRC patients were included. Of the 93 mCRC cases with SC features, 63 had slides for review. Of those 63 cases, 35 were confirmed SRCC, and 28 were AC with SC component. Compared with AC group, KRAS and PIK3CA mutations (mts) were found in only 11% (OR: 0.13) and 3% (OR: 0.15) of SRCC cases, respectively. In contrast to the 44% rate of APC mts in AC group, only 3% of SRCC patients had APC mts (OR = 0.04). CONCLUSIONS: SRCC has distinct molecular features, including low rates of KRAS, PIK3CA and APC mts. Further study to identify activation pathways and potential therapeutic targets are needed.

Physical activity and exercise during preoperative pancreatic cancer treatment.

PURPOSE: Guidelines recommend exercise to cancer survivors, but limited data exists regarding exercise among patients undergoing preoperative cancer treatment. We examined differences in weekly self-reported exercise and accelerometer-measured physical activity among participants in a home-based exercise program administered during preoperative treatment for pancreatic cancer. METHODS: Participants were encouraged to perform at least 60 min/week of moderate-intensity aerobic exercise and at least 60 min/week of full-body strengthening exercises concurrent with chemotherapy, chemoradiation therapy or both sequentially and received resistance equipment, program instruction, and biweekly follow-up calls to encourage adherence. Self-reported aerobic and strengthening exercise minutes were measured using daily logs, and physical activity was measured objectively using accelerometers. RESULTS: Fifty participants (48% female, mean age 66 ± 8 years) participated for an average of 16 ± 9 preoperative weeks. Participants reported overall means of 126 ± 83 weekly minutes of aerobic exercise and 39 ± 33 weekly minutes of strengthening exercise in daily logs. Participants performed 158.7 ± 146.7 weekly minutes of accelerometer-measured moderate-to-vigorous physical activity. There were no significant differences in exercise or physical activity between treatment phases. CONCLUSIONS: These findings suggest that it is feasible to target the entire preoperative course for exercise prescription. Although participants exceeded aerobic exercise recommendations on average, we observed low strengthening exercise adherence and wide variability in self-reported exercise and accelerometer physical activity variables. These findings suggest that additional support, including program adaptations, may be necessary to overcome barriers to exercise or improve motivation when prescribing exercise in this clinical scenario.

A predictive model of inflammatory markers and patient-reported symptoms for cachexia in newly diagnosed pancreatic cancer patients.

BACKGROUND: Cachexia is a frequent manifestation of pancreatic cancer, can limit a patient's ability to take chemotherapy, and is associated with shortened survival. We developed a model to predict the early onset of cachexia in advanced pancreatic cancer patients. METHODS: Patients with newly diagnosed, untreated metastatic or locally advanced pancreatic cancer were included. Serum cytokines were drawn prior to therapy. Patient symptoms were recorded using the M.D. Anderson Symptom Inventory (MDASI). Our primary endpoint was either 10% weight loss or death within 60 days of the start of therapy. RESULTS: Twenty-seven of 89 patients met the primary endpoint (either having lost 10% of body weight or having died within 60 days of the start of treatment). In a univariate analysis, smoking, history symptoms of pain and difficulty swallowing, high levels of MK, CXCL-16, IL-6, TNF-a, and low IL-1b all correlated with this endpoint. We used recursive partition to fit a regression tree model, selecting four of 26 variables (CXCL-16, IL-1b, pain, swallowing difficulty) as important in predicting cachexia. From these, a model of two cytokines (CXCL-16 > 5.135 ng/ml and IL-1b < 0.08 ng/ml) demonstrated a better sensitivity and specificity for this outcome (0.70 and 0.86, respectively) than any individual cytokine or tumor marker. CONCLUSIONS: Cachexia is frequent in pancreatic cancer; one in three patients met our endpoint of 10% weight loss or death within 60 days. Inflammatory cytokines are better than conventional tumor markers at predicting this outcome. Recursive partitioning analysis suggests that a model of CXCL-16 and IL-1B may offer a better ability than individual cytokines to predict this outcome.

Prechemotherapy Touch Sensation Deficits Predict Oxaliplatin-Induced Neuropathy in Patients with Colorectal Cancer.

OBJECTIVE: We examined the emergence of chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting toxicity of oxaliplatin, over the course of oxaliplatin-based chemotherapy for colorectal cancer (CRC). Predicting which patients will likely develop CIPN is an ongoing clinical challenge. METHODS: Oxaliplatin-naïve patients with CRC underwent quantitative sensory testing (QST) before beginning oxaliplatin-based chemotherapy and then rated CIPN-related symptoms via the MD Anderson Symptom Inventory (MDASI) weekly for 26 weeks. Mixed modeling examined the value of QST for predicting higher CIPN (MDASI numbness/tingling) during treatment. Trajectory analysis identified a patient subgroup with consistently higher CIPN symptoms. RESULTS: Numbness/tingling was the most frequent, most severe symptom, with 51% of patients clustering into a high CIPN subgroup. Touch sensation deficits (Bumps Detection test) significantly predicted the development of more severe numbness/tingling [estimate (est) = 0.106, p = 0.0003]. The high CIPN subgroup reported increased pain (est = 0.472, p < 0.0001) and interference with walking (est = 0.840, p < 0.0001). In the high CIPN subgroup, patient-reported numbness/tingling worsened rapidly in weeks 0-5 (est = 0.57, p < 0.0001) and then more gradually in weeks 6-26 (est = 0.07, p < 0.0001). CONCLUSION: Prechemotherapy screening with a simple, easily administered objective measure of touch sensation deficits (Bumps Detection test) and monitoring of patient-reported numbness/tingling during the first 2-3 chemotherapy cycles may support improved personalized care of CRC patients with oxaliplatin-induced CIPN.

Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study.

BACKGROUND: Treatment options for advanced, well-differentiated neuroendocrine tumours (NETs) remain scarce. Pazopanib is an orally bioavailable, small molecule, multitargeted kinase inhibitor that inhibits VEGF receptors 1, 2, and 3. We did a study of the efficacy of pazopanib with depot octreotide in patients with advanced NETs. METHODS: We did a parallel cohort study of patients with metastatic or locally advanced grade 1-2 carcinoid tumours or pancreatic NETs, by use of a single-group, two-stage design. Patients received pazopanib 800 mg orally once per day and octreotide at their preprotocol dosage. The primary endpoint was the proportion of patients achieving an objective response, as assessed by investigators, by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00454363, and was completed in March, 2014. FINDINGS: Between April 12, 2007, and July 2, 2009, we enrolled 52 patients, including 32 individuals with pancreatic NETs and 20 individuals with carcinoid tumours. Seven (21·9%, 95% CI 11·0-38·8) of 32 patients with pancreatic NETs achieved an objective response. We detected no responses in the first stage of the cohort with carcinoid tumours, and we terminated accrual at 20 patients. Toxic effects included one patient with grade 4 hypertriglyceridaemia and one with grade 4 thrombosis, with the most common grade three events being aminotransferase increases and neutropenia, each of which happened in 3 patients. In all 52 patients, the most frequently observed toxic effects were fatigue (39 [75%]), nausea (33 [63%]), diarrhoea (33 [63%]), and hypertension (28 [54%]). INTERPRETATION: Treatment with pazopanib is associated with tumour response for patients with pancreatic NETs, but not for carcinoid tumours; a randomised controlled phase 3 study to assess pazopanib in advanced pancreatic NETs is warranted. FUNDING: US National Cancer Institute of the National Institutes of Health.

Joint prognostic effect of obesity and chronic systemic inflammation in patients with metastatic colorectal cancer.

BACKGROUND: Obesity is strongly linked with chronic systemic inflammation, and each has been linked with disease progression and survival in patients with colorectal cancer (CRC). The authors investigated the joint prognostic effects of obesity and circulating cytokines in patients with metastatic CRC (mCRC), an understudied patient group. METHODS: In 242 chemotherapy-naive patients with mCRC, the authors measured a multiplex cytokine panel and abstracted clinicopathological features, height, and weight from medical records. Overall survival (OS) was calculated from the date of mCRC diagnosis until the date of death from any cause and evaluated by Kaplan-Meier analysis and multivariable Cox proportional hazards regression models. Cut points for cytokines were determined by restricted cubic spline regression. RESULTS: In multivariable models, elevated interleukin (IL)-8, IL-2 receptor alpha, and lactate dehydrogenase (LDH) emerged as significant predictors of poor OS (hazard ratio [HR] and 95% confidence interval [95% CI] for above vs below the (referent) knot point: 2.5 [95% CI, 1.7-3.7], 1.9 [95% CI, 1.3-2.7], and 2.2 [95% CI, 1.6-3.1], respectively; all P<.001). Obesity (body mass index ≥30 kg/m(2) ) was not found to be associated with OS, but appeared to modify the relationships observed with IL-8 and LDH, which were associated with a significant 4-fold and 5-fold risk of death, respectively, in obese patients compared with a 2-fold risk of death in nonobese patients (P for interaction of .06 and .04, respectively). Similar results emerged from joint effects analysis, in which obese patients with high IL-8 (or LDH) experienced the highest risk of death. CONCLUSIONS: Although obesity itself was not found to be independently associated with survival in patients with mCRC, the adverse prognostic significance of LDH and IL-8 was found to be enhanced in obese patients.

The addition of erlotinib to gemcitabine and cisplatin does not appear to improve median survival in metastatic pancreatic cancer.

Metastatic pancreatic cancer carries a poor prognosis, with median survival on the order of several months. There is evidence that combining gemcitabine with either erlotinib or cisplatin may be superior to single agent gemcitabine in patients with good performance (PS 0-1). We retrospectively compared outcomes of patients treated with either the three drug regimen of gemcitabine, cisplatin, and erlotinib (GCE) or the doublet of gemcitabine and cisplatin (GC) in order to assess the potential benefit of erlotinib. We also evaluated the role of erlotinib among smokers and non-smokers. We retrospectively analyzed 145 patients who presented between 2006 and 2009 with previously untreated metastatic pancreatic cancer initially treated at the M.D. Anderson cancer center with either GC or GCE. Information on tumor characteristics and overall survival time (OS) was collected by medical record review. Kaplan-Meier curves were used to estimate OS. Log rank tests were used to compare OS between groups. The Cox proportional hazards regression model was used to evaluate the ability of patient prognostic variables or treatment group to predict OS. A total of 71 patients were treated with GC, while 74 were treated with GCE. Cox analyses found no significant difference in overall survival (median 5.5 vs. 8.0 months, respectively, p-value=0.1). Small sampling numbers may have contributed to this result. One year survival was 23 % in the GCE group and 13 % in the GC group. Patients with poor performance status (PS=2-3) had worse survival as compared to patients with better performance status (PS=0-1, p=0.001). As in earlier studies, patients treated with more lines of therapy tended to have better survival (p <0.0001), and CA19-9 was found to be a significant predictor for OS (p=0.001). No statistical evidence of a survival difference was found between smokers and non-smokers in both treatment groups (p=0.72). In conclusion, though there was a trend towards improved survival with the addition of erlotinib to gemcitabine and cisplatin, this does not reach statistical significance.

Defined clinical classifications are associated with outcome of patients with anatomically resectable pancreatic adenocarcinoma treated with neoadjuvant therapy.

BACKGROUND: We previously introduced a classification system for patients with localized pancreatic adenocarcinoma that integrates assessments of tumor anatomy, cancer biology, and patient physiology. By means of this system, we sought to analyze outcomes of patients with resectable anatomy but heterogeneous biology and physiology who were treated with neoadjuvant therapy. METHODS: We evaluated consecutive patients (2002-2007) with anatomically potentially resectable cancers treated with chemotherapy or chemoradiation before potential pancreatectomy. We compared clinical factors and outcomes of patients classified as having disease that was clinically resectable (CR; no extrapancreatic disease, preserved performance status); suspicion for extrapancreatic disease (BR-B); or marginal performance status or significant comorbidity (BR-C). Patients with borderline resectable anatomy (BR-A) were excluded. RESULTS: Resection rates for 138 CR, 41 BR-B, and 38 BR-C patients were 75, 46, and 37%, respectively (P < 0.001). Metastases, detected during treatment in 23% of patients, were the most common contraindication to resection among CR (15%) and BR-B (46%) patients. Performance status rarely precluded surgery except among BR-C (32%) patients. Factors associated with selection against surgery were older age, poor performance status, pain, and therapeutic complications (P < 0.05). The median overall survival of all patients was 21 months. Resected and unresected BR-B and BR-C patients had median overall survival durations similar to those of resected and unresected CR patients, respectively (P > 0.22). CONCLUSIONS: This system describes discrete clinical subgroups of patients with pancreatic cancer who have similar, potentially resectable tumor anatomy but heterogeneous physiology and cancer biology. It may be used with neoadjuvant therapy to predict outcomes, individualize treatment algorithms, and optimize survival.

Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distributions of TIL populations. The CD8+ TIL contained a putative transitional GZMK+ population based on T-cell receptor clonotype sharing, and cell-state trajectory analysis showed similarity to a GZMB+PRF1+ cytotoxic and a CXCL13+ dysfunctional population. Statistical analysis suggested that certain TIL states, such as dysfunctional and inhibitory populations, often occurred together. Finally, analysis of cultured TIL revealed that high-frequency clones from effector populations were preferentially expanded. These data provide a framework for understanding the PDAC TIL landscape for future TIL use in immunotherapy for PDAC. SIGNIFICANCE: To improve the efficacy of immunotherapy in PDAC, there is a great need to understand the PDAC TIL landscape. This study represents a reference of PDAC TIL subpopulations and their relationships and provides a foundation upon which to base future immunotherapeutic efforts. This article is highlighted in the In This Issue feature, p. 2221.

Antibiotic use influences outcomes in advanced pancreatic adenocarcinoma patients.

Recent studies defined a potentially important role of the microbiome in modulating pancreatic ductal adenocarcinoma (PDAC) and responses to therapies. We hypothesized that antibiotic usage may predict outcomes in patients with PDAC. We retrospectively analyzed clinical data of patients with resectable or metastatic PDAC seen at MD Anderson Cancer from 2003 to 2017. Demographic, chemotherapy regimen and antibiotic use, duration, type, and reason for indication were recorded. A total of 580 patients with PDAC were studied, 342 resected and 238 metastatic patients, selected retrospectively from our database. Antibiotic use, for longer than 48 hrs, was detected in 209 resected patients (61%) and 195 metastatic ones (62%). On resectable patients, we did not find differences in overall survival (OS) or progression-free survival (PFS), based on antibiotic intake. However, in the metastatic cohort, antibiotic consumption was associated with a significantly longer OS (13.3 months vs. 9.0 months, HR 0.48, 95% CI 0.34-0.7, p = 0.0001) and PFS (4.4 months vs. 2 months, HR 0.48, 95% CI 0.34-0.68, p = <0.0001). In multivariate analysis, the impact of ATB remained significant for PFS (HR 0.59, p = 0.005) and borderline statistically significant for OS (HR 0.69, p = 0.06). When we analyzed by chemotherapy regimen, we found that patients who received gemcitabine-based chemotherapy as first-line therapy (n = 118) had significantly prolonged OS (HR 0.4, p 0.0013) and PFS (HR 0.55, p 0.02) if they received antibiotics, while those receiving 5FU-based chemotherapy (n = 98) had only prolonged PFS (HR 0.54, p = 0.03). Antibiotics-associated modulation of the microbiome is associated with better outcomes in patients with metastatic PDAC.

A Randomized, Placebo-Controlled, Double-Blind Study of Minocycline for Reducing the Symptom Burden Experienced by Patients With Advanced Pancreatic Cancer.

CONTEXT: Although it is well known that patients with advanced pancreatic cancer (PC) experience significant symptom burden, few strategies for effective symptom intervention are available for them. OBJECTIVES: To investigate the efficacy of minocycline, an anti-inflammatory agent, for symptom reduction in patients with advanced PC. METHODS: We conducted Phase II, randomized, and placebo-controlled trial to obtain preliminary estimates of the effects on symptom reduction with 100 mg of minocycline or placebo given twice a day. Eligible patients had diagnosed advanced PC and were scheduled for standard chemotherapy. Patient-reported symptoms were measured weekly during the eight-week trial using the MD Anderson Symptom Inventory (MDASI) module in patients with gastrointestinal cancer. The primary outcome measure was the area under the curve values of the five most severe symptoms in the two arms. RESULTS: Of the 44 patients recruited, 31 (71%) were evaluable for the primary efficacy analysis, with 18 received minocycline and 13 placebo. Fatigue, pain, disturbed sleep, lack of appetite, and drowsiness were the most severe symptoms reported by both groups. No significant differences in area under the curve values over time between the study arms were found for the composite MDASI score or single-item scores of the five most severe MDASI items. No treatment-related deaths were reported, and no Grade 3-4 toxicities were observed. CONCLUSION: Minocycline is safe for use in patients receiving treatment for PC. There is no observed symptom reduction with minocycline on the major symptom burden associated with advanced PC compared with placebo. Attrition because of rapid disease progression impacted the study significantly.

Germline DNA Sequencing Reveals Novel Mutations Predictive of Overall Survival in a Cohort of Patients with Pancreatic Cancer.

PURPOSE: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer. EXPERIMENTAL DESIGN: Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records. RESULTS: Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P = NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival. CONCLUSIONS: We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.

Trial Sponsorship and Time to Reporting for Phase 3 Randomized Cancer Clinical Trials.

The pace of clinical trial data generation and publication is an area of interest within clinical oncology; however, little is known about the dynamics and covariates of time to reporting (TTR) of trial results. To assess these, ClinicalTrials.gov was queried for phase three clinical trials for patients with metastatic solid tumors, and the factors associated with TTR from enrollment completion to publication were analyzed. Based on the 319 included trials, cooperative-group-sponsored trials were reported at a slower rate than non-cooperative-group trials (median 37.5 vs. 31.0 months; p < 0.001), while industry-funded studies were reported at a faster rate than non-industry-supported trials (31.0 vs. 40.0 months; p = 0.005). Furthermore, successful trials (those meeting their primary endpoint) were reported at a faster rate than unsuccessful studies (27.5 vs. 36.0 months; p < 0.001). Multivariable analysis confirmed that industry funding was independently associated with a shorter TTR (p = 0.006), while cooperative group sponsorship was not associated with a statistically significant difference in TTR (p = 0.18). These data underscore an opportunity to improve cooperative group trial efficiency by reducing TTR.

Modified gemcitabine plus nab-paclitaxel regimen in advanced pancreatic ductal adenocarcinoma.

BACKGROUND: Gemcitabine (GEM) plus nab-paclitaxel (NabP) (GEM 1000 mg/m2 IV over 30 minutes + NabP 125 mg/m2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM-NabP given every two-weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen. METHODS: Metastatic PDAC patients (pts) who initiated front-line or second-line GEM-NabP during 2013-2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression-free survival, and the incidence of dose delays and/or adjustments. RESULTS: From a total of 235 patients, 140 pts received GEM-NabP front-line while 95 pts received GEM-NabP second-line. Median dosing was 600 mg/m2 at fixed-dose rate for GEM and 125 mg/m2 for NabP given predominantly (~90%) every two-weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front-line OS of 12.7 and 9.6 months and when given second-line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front-line progression-free survival (PFS) of 5.3 months and 2.8 months and second-line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications. CONCLUSION: Our analysis revealed safety with every two-week low dose GEM-NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two-week GEM-NabP particularly in patients desiring a modified schedule.

Cell-free Circulating Tumor DNA Variant Allele Frequency Associates with Survival in Metastatic Cancer.

PURPOSE: Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis. EXPERIMENTAL DESIGN: We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival. RESULTS: cfDNA mutations were detected in 240 patients (80.5%). Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types, being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3; P < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, P = 0.0069; VAF Q4 HR = 3.8, P < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level <3.5 g/dL, number of nonvisceral metastatic sites >0 and number of prior therapies >4 were independent predictors of worse OS. CONCLUSIONS: Higher levels of cfDNA VAF and a higher number of NSMs were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision making and the utility of cfDNA VAF as a prognostic marker in different tumor types.

An open-label, single-arm pilot study of EUS-guided brachytherapy with phosphorus-32 microparticles in combination with gemcitabine +/- nab-paclitaxel in unresectable locally advanced pancreatic cancer (OncoPaC-1): Technical details and study protocol.

Current treatment options for patients with unresectable locally advanced pancreatic cancer (LAPC) include chemotherapy alone or followed by chemoradiation or stereotactic body radiotherapy. However, the prognosis for these patients remains poor, with a median overall survival <12 months. Therefore, novel treatment options are needed. Currently, there is no brachytherapy device approved for pancreatic cancer treatment. Hereby, we present the protocol of a prospective, multicenter, interventional, open-label, single-arm pilot study (OncoPac-1, Clinicaltrial.gov-NCT03076216) aiming to determine the safety and efficacy of Phosphorus-32 when implanted directly into pancreatic tumors using EUS guidance, for patients with unresectable LAPC undergoing chemotherapy (gemcitabine ± nab-paclitaxel).

Portal hypertension associated with oxaliplatin administration: clinical manifestations of hepatic sinusoidal injury.

Oxaliplatin-based chemotherapy regimens are currently a standard of care for the treatment of colorectal cancer (CRC) in both the adjuvant treatment and metastatic disease settings. Significant improvements in outcomes have been achieved with oxaliplatin-based combinations in these settings when compared with administration of 5-fluorouracil alone. Pathologic evaluation of normal liver from patients undergoing neoadjuvant oxaliplatin treatment has identified histologic evidence of sinusoidal injury, although the effect of this finding on patient outcomes after hepatic resection appears to be minimal. This article describes the use of oxaliplatin-based chemotherapy in 6 patients with stage III or IV CRC who developed evidence of noncirrhotic portal hypertension. These patients developed complications of portal hypertension including esophageal or hemorrhoidal varices with bleeding, splenomegaly with associated thrombocytopenia, and ascites. In each case, oxaliplatin-induced hepatic sinusoidal injury was identified as the most likely factor contributing to the development of noncirrhotic portal hypertension. The literature on hepatic sinusoidal injury after oxaliplatin is reviewed and the proposed pathophysiology is discussed.

Benefit of Gemcitabine/Nab-Paclitaxel Rescue of Patients With Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma After Early Failure of FOLFIRINOX.

OBJECTIVES: Neoadjuvant therapy (NT) is used for advanced pancreatic ductal adenocarcinoma (PDAC). No clear guidelines exist for switching therapies when patients do not respond to initial NT. We sought to characterize patients who underwent early switch from FOLFIRINOX to gemcitabine/nab-paclitaxel (GA) as NT for PDAC. METHODS: We identified patients at a single institution switched from FOLFIRINOX to GA within the first 4 months of NT for PDAC during 2012-2017. We compared clinicopathologic data and oncologic outcomes. RESULTS: Of 25 patients who met the criteria, 21 showed a serologic or radiographic response to GA; 11 (52%) reached resection. Responders had decreased carbohydrate antigen (CA) 19-9 levels from pretreatment to post-GA (P = 0.036). Resected responders had significantly decreased CA 19-9 comparing preswitch to post-GA (P = 0.048). The only predictor of GA response was prechemotherapy CA 19-9 of less than1000 U/mL (P = 0.021). Predictors of reaching resection were head/uncinate tumor (P = 0.010) and presenting stage lower than locally advanced (P = 0.041). CONCLUSIONS: When patients do not respond to neoadjuvant FOLFIRINOX, early switch to GA should be considered. Future efforts should be directed toward identifying markers that will allow correct choice of initial therapy rather than attempting to rescue patients who respond poorly to first-line therapy.

The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis.

PURPOSE: We developed a laboratory based regimen called GTX which induces synergistic apoptosis in human pancreatic cancer cells. This retrospective review summarizes our clinical experience with GTX in an initial group of 35 patients; 66% untreated and 34% failed prior therapies. METHODS: All patients treated with GTX for metastatic pancreatic cancer, prior to initiation of a prospective phase II trial of GTX were assessed and followed until death. GTX consisted of capecitabine (X), 750 mg/m(2) p.o. BID on days 1-14, gemcitabine (G) (750 mg/m(2)) over 75 min and docetaxel (T) (30 mg/m(2)) on days 4 and 11. Thus one cycle of GTX was 14 days with 7 days off for a 21 day cycle. Tumor assessments were repeated every 3 cycles. RESULTS: All 35 patients had metastatic pancreatic cancer (94% liver, 6% lung sites). Grade 3-4 hematological toxicities were: leukopenia and thrombocytopenia-both 14%, and anemia 9%, respectively. The overall response rate of all 35 patients treated with GTX (from 0.5 cycles onward) was 29% (CR/PR) by WHO criteria, and 31% had a minor response or stable disease (MR, SD). At the metastatic sites for the 35 patients, there were 9% complete (CR) and 31% partial (PR) responses (total 40%). For the 31 patients who had their primary tumor (4 patients had a prior Whipple resection), there were 13% CR and 19% PR for a response rate of 32% at the primary tumor site. Overall median progression free survival of responders was 6.3 months (95% C.I. 4.4-10.4 months) and median survival was 11.2 months (95% C.I. 8.1-15.1 months). Survival after initiation of GTX at 12, 18, 24 and 30 months was 43, 29, 20, and 11%, respectively. CONCLUSION: Our retrospective review suggests that GTX has potential as a regimen for untreated and treated metastatic pancreatic cancer.