Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer.

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1-57.8) months with pembrolizumab and 43.9 (range 36.6-55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months-NR) with pembrolizumab versus 10.4 (95% CI 6.3-22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26-1.20). Median OS was NR (range 13.8 months-NR) versus 30.0 (14.7-NR) months (HR 0.65, 95% CI 0.27-1.55) and ORR was 50% (95% CI 28-72) versus 46% (95% CI 27-67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.

KEYSTEP-008: phase II trial of pembrolizumab-based combination in MSI-H/dMMR metastatic colorectal cancer.

Robust clinical activity has been observed with the immune checkpoint inhibitor pembrolizumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). However, given the response rate of 45% and a median progression-free survival of 16.5 months with first-line pembrolizumab demonstrated in KEYNOTE-177, there is room for improvement. Targeting a second immune receptor, such as CTLA-4, LAG-3, TIGIT, or ILT-4 may improve efficacy of PD-1 inhibition. Here we describe the design and rationale for the open-label, randomized, phase II KEYSTEP-008 trial, which will evaluate the efficacy and safety of pembrolizumab-based combination therapy compared with pembrolizumab monotherapy in chemotherapy-refractory (cohort A) or previously untreated (cohort B) MSI-H/dMMR mCRC. Clinical Trial Registration: NCT04895722 (ClinicalTrials.gov).

Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study.

BACKGROUND: Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study. METHODS: This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2) or intravenous FOLFIRI (irinotecan 180 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m2, then 250 mg/m2 for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients. FINDINGS: Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7-49·8]), median overall survival was not reached (NR; 95% CI 49·2-NR) with pembrolizumab vs 36·7 months (27·6-NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53-1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4-38·1) with pembrolizumab versus 8·2 months (6·1-10·2) with chemotherapy (HR 0·59, 95% CI 0·45-0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy. INTERPRETATION: In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. FUNDING: MSD.

Radiographic and Serologic Predictors of Pathologic Major Response to Preoperative Therapy for Pancreatic Cancer.

OBJECTIVE: We sought to identify potential radiologic and serologic markers of pancreatic tumor response to therapy, using pathologic major response (pMR) as the objective endpoint. BACKGROUND: We previously demonstrated that a pMR to preoperative therapy, defined as detection of <5% viable cancer cells in the surgical specimen on histopathological analysis, is an important prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Pretreatment and posttreatment computed tomography scans of consecutive patients who received preoperative chemotherapy and/or (chemo)radiation before pancreatectomy for PDAC between January 2010 and December 2018 were rereviewed. Response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, other radiographic changes in tumor size and anatomic extent, and posttreatment CA 19-9 levels were compared between patients who did and did not have a pMR on final histopathologic analysis of their surgical specimens. RESULTS: A total of 290 patients with localized PDAC underwent pancreatectomy between 2010 and 2018 after receiving preoperative chemotherapy (n = 36; 12%), (chemo)radiation (n = 87; 30%), or both (n = 167; 58%). Among them, 28 (10%) experienced pMR, including 9 (3.1%) who experienced pathologic complete response. On multivariable logistic regression, low posttreatment CA 19-9 level, RECIST partial response, and reduction in tumor volume were confirmed to be independently associated with pMR (P < 0.01). CONCLUSIONS: We identified serologic and radiographic indicators of pMR that could help inform the delivery of preoperative therapy to patients with PDAC.

Postoperative Chemotherapy Benefits Patients Who Received Preoperative Therapy and Pancreatectomy for Pancreatic Adenocarcinoma.

OBJECTIVE: We sought to determine whether postoperative chemotherapy after preoperative therapy and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) prolongs survival. BACKGROUND: Data to support administering postoperative chemotherapy to patients who received preoperative therapy are lacking. METHODS: All patients with PDAC who underwent pancreatectomy after preoperative therapy between 2010 and July 2017 at The University of Texas MD Anderson Cancer Center were identified. To control for selection bias, patients who received postoperative therapy and patients who did not were matched by propensity scores based on factors associated with the use of postoperative chemotherapy. RESULTS: Among 245 patients treated with a median of 4 cycles of preoperative treatment and pancreatectomy, 155 (63%) initiated postoperative chemotherapy and 90 (37%) did not. Patients who received postoperative therapy had a higher median cancer antigen 19-9 level before surgery, larger median tumor diameter, higher rate of extrapancreatic invasion, and lower rate of pathologic major response. The propensity-matched cohort comprised 122 patients: 61 who received postoperative chemotherapy and 61 who did not. The median overall survival (OS) and recurrence free survival (RFS) for patients who received postoperative therapy were 42 and 17 months, respectively, versus 32 and 12 months for patients who did not (OS: P = 0.06; RFS: P = 0.04). Postoperative therapy was marginally associated with a longer OS (hazard ratio 0.55, 95% confidence interval 0.29-1.01; P = 0.05) and significantly associated with a longer RFS (hazard ratio 0.55, 95% confidence interval 0.29-0.96; P = 0.04). CONCLUSIONS: Despite being administered more frequently to patients with poor prognostic factors, postoperative chemotherapy after preoperative therapy and pancreatectomy for PDAC was of clinical benefit.

The Sequential Radiographic Effects of Preoperative Chemotherapy and (Chemo)Radiation on Tumor Anatomy in Patients with Localized Pancreatic Cancer.

BACKGROUND: The incidence and magnitude of indicators of radiographic response of pancreatic cancer to systemic chemotherapy and (chemo)radiation administered prior to anticipated pancreatectomy are unclear. METHODS: Sequential computed tomography scans of 226 patients with localized pancreatic cancer who received chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) or gemcitabine and nanoparticle albumin-bound paclitaxel (GA) with or without (chemo)radiation and who subsequently underwent surgery with curative intent from January 2010 to December 2018 at The University of Texas MD Anderson Cancer Center and Verona University Hospital were re-reviewed and compared. RESULTS: Overall, 141 patients (62%) received FOLFIRINOX, 70 (31%) received GA, and 15 (7%) received both; 164 patients (73%) received preoperative (chemo)radiation following chemotherapy and prior to surgery; and 151 (67%), 70 (31%), and 5 (2%) patients had Response Evaluation Criteria in Solid Tumors (RECIST) stable disease, partial response, and progressive disease, respectively. The tumors of 29% of patients with borderline resectable or locally advanced cancer were downstaged after preoperative therapy. Radiographic downstaging was more common with chemotherapy than with (chemo)radiation (24% vs. 6%; p = 0.04), and the median tumor volume loss after chemotherapy was significantly greater than that after (chemo)radiation (28% vs. 17%; p < 0.01). CONCLUSIONS: Less than one-third of patients treated with FOLFIRINOX or GA with or without (chemo)radiation experienced either RECIST partial response or radiographic downstaging prior to surgery. The incidence of tumor downstaging was higher and the magnitude of tumor volume loss was greater following chemotherapy than after (chemo)radiation.

Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low Cmax and improved tolerability, in patients with solid tumors.

5-fluorouracil (5-FU) and 5-FU derivatives, such as capecitabine, UFT, and S-1, are the mainstay of chemotherapy treatment for gastrointestinal cancers, and other solid tumors. Compared with other cytotoxic chemotherapies, these drugs generally have a favorable safety profile, but hematologic and gastrointestinal toxicities remain common. DFP-11207 is a novel oral cytotoxic agent that combines a 5-FU pro-drug with a reversible DPD inhibitor and a potent inhibitor of OPRT, resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicities. In this Phase I study (NCT02171221), DFP-11207 was administered orally daily, in doses escalating from 40 mg/m2/day to 400 mg/m2/day in patients with esophageal, colorectal, gastric, pancreatic or gallbladder cancer (n = 23). It was determined that DFP-11207 at the dose of 330 mg/m2/day administered every 12 hours was well-tolerated with mild myelosuppressive and gastrointestinal toxicities. The pharmacokinetic analysis determined that the 5-FU levels were in the therapeutic range at this dose. In addition, fasted or fed states had no influence on the 5-FU levels (patients serving as their own controls). Among 21 efficacy evaluable patients, 7 patients had stable disease (33.3%), of which two had prolonged stable disease of >6 months duration. DFP-11207 can be explored as monotherapy or easily substitute 5-FU, capecitabine, or S-1 in combination regimens.

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.

First-Line Gemcitabine and Nab-Paclitaxel Chemotherapy for Localized Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Preoperative chemotherapy provides early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy for localized pancreatic ductal adenocarcinoma (PDAC). For locally advanced (LA) PDAC, induction chemotherapy is the standard of care. This study evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy for localized PDAC. METHODS: Clinicopathologic features, treatment, and outcomes were evaluated for 99 patients with localized PDAC. The patients were staged using previously published criteria as follows: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR-C (comorbidities requiring medical optimization), and LA. RESULTS: The 99 patients (PR/BR/LA: 45/14/40) were treated with Gem/nab-P. Clinical staging showed that 20 patients had PR or BR-A disease, whereas 39 patients had BR-B or BR-C disease. The BR-B+C cases included one or more of the following: age of 80 years or older (13%), Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more (13%), moderate to severe comorbidities (55%), CA19-9 of 1000 or higher (28%), and suspicion for metastases (21%). The majority of the patients received biweekly Gem/nab-P dosing, which was well tolerated. Pancreatectomy was performed for 12 (60%) of 20 patients with PR+BR-A, 2 (5%) of 39 patients with BR-B+C, and 1 (3%) of 40 patients with LA disease. During a median follow-up period of 26 months, the median overall survival (OS) period was 18 months (95% confidence interval [CI], 15.6-20.5 months) for all the patients, 17 months (95% CI, 14.6-19.5 months) for the unresected patients, and not reached for the resected patients (p = 0.028 for resected vs unresected patients). CONCLUSIONS: A significant number of patients with radiographically resectable PDAC albeit aggressive biology (BR-B), medically inoperable conditions (BR-C), or both received biweekly first-line Gem/nab-P. The resection rates were lower for the BR-B/BR-C patients than for the PR/BR-A patients (hazard ratio [HR], 0.43; 95% CI, 0.19-1.00; p = 0.05).

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.

Portomesenteric Venous Stenting for Palliation of Ascites and Variceal Bleeding Caused by Prehepatic Portal Hypertension.

BACKGROUND: The purpose of this study was to evaluate percutaneous transhepatic portal vein stenting (PVS) for palliation of refractory ascites and/or variceal bleeding caused by extrahepatic portomesenteric venous stenosis in patients with pancreaticobiliary cancer. MATERIALS AND METHODS: A single-institution, retrospective review of patients who underwent PVS between January 2007 and July 2015 was performed. A total of 38 patients were identified, of whom 28 met the inclusion criterion of PVS performed primarily for refractory ascites or variceal bleeding. In addition to technical success and overall survival, clinical success was measured by fraction of remaining life palliated. The palliative effect of PVS was also quantified by measuring changes in liver and ascites volumes after the procedure. RESULTS: Technical success was 93% (26/28). Stent deployment involved more than one portomesenteric vessel in most patients (20/26). The cumulative probability of symptom recurrence at 6, 12, 18, and 24 months was 12%, 16%, 26%, and 40%, respectively. There was a significant difference (p < .001) in the probability of symptom recurrence, recurrence of abdominal ascites, and increase in liver volume between patients whose stents remained patent and those whose stents demonstrated partial or complete occlusion. The mean fraction of remaining life palliated was 87%. All but two patients were found to have improvement in clinical symptoms for the majority of their lives after the procedure. There were no major or minor complications. CONCLUSION: As a low-risk procedure with a high clinical success rate, PVS can play a substantial role in improving quality of life in patients with portomesenteric stenoses. IMPLICATIONS FOR PRACTICE: Portomesenteric venous stenosis is a challenging complication of pancreaticobiliary malignancy. Portomesenteric stenoses can lead to esophageal, gastric, and mesenteric variceal bleeding, as well as abdominal ascites. The purpose of this study was to evaluate the safety and efficacy of portal vein stenting (PVS) in patients with cancer who have symptomatic portal hypertension caused by portomesenteric venous compression. As a low-risk procedure with a high clinical success rate, PVS can play a substantial role in improving quality of life in patients with portomesenteric stenoses.

Influence of Preoperative Therapy on Short- and Long-Term Outcomes of Patients with Adenocarcinoma of the Ampulla of Vater.

INTRODUCTION: Although preoperative therapy is increasingly administered to patients with pancreatic adenocarcinoma, the role of preoperative therapy for patients with adenocarcinoma of the ampulla of Vater is undefined. METHODS: All patients with ampullary cancer who were evaluated between 1999 and 2014 were retrospectively reviewed. Differences in clinicopathologic characteristics, perioperative complications, and overall survival were compared between patients who underwent surgery de novo and those who received preoperative therapy before pancreatoduodenectomy. RESULTS: A total of 142 patients underwent pancreatoduodenectomy: 43 (30.3%) who received preoperative therapy and 99 (69.7%) who did not. Preoperative therapy consisted of chemoradiation (65%), chemotherapy (7%), or both (28%). Patients who underwent surgery first had a lower comorbidity index (p < 0.05) and were more likely to receive postoperative chemotherapy (p < 0.01) and chemoradiation (p < 0.0001). Tumors resected de novo were larger (p < 0.01) and had a different histopathologic subtype distribution (p < 0.01) on final pathology than those resected following preoperative therapy. Six (14.0%) patients demonstrated a complete pathologic response. There were no differences in rates of postoperative complications, mortality, readmission, LR (9.1 vs. 7.0%), median survival (107 vs. 146 months), or 5-year overall survival (60.6 vs. 70.4%). On multivariate cox regression analysis, the receipt of preoperative therapy was not associated with improved survival (odds ratio 1.14, 95% confidence interval (CI) 0.56-2.31). CONCLUSIONS: Although these data do not support the routine administration of preoperative therapy to all patients with ampullary cancer, the delivery of preoperative therapy represents an alternative strategy that is associated with excellent short- and long-term outcomes and appears appropriate for a subset of patients.

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.

Home-based exercise during preoperative therapy for pancreatic cancer.

PURPOSE: Exercise concurrent with neoadjuvant chemotherapy and/or chemoradiation for pancreatic adenocarcinoma (PDAC) may mitigate the decline in function that may occur as a result of the disease or its treatment in the preoperative period. The primary objective of this single-arm prospective trial was to determine adherence to a home-based exercise program administered during preoperative therapy. METHODS: Twenty patients from a quaternary cancer center with potentially resectable PDAC were enrolled. Patients were prescribed a minimum of 120 min of moderate-intensity exercise weekly: at least 60 min of aerobic exercise and 60 min of resistance exercise. Self-reported exercise was recorded in daily logs. Functional and survey measures were collected upon enrollment, following preoperative therapy, and 1 month after surgery. RESULTS: Fifteen out of 20 patients participated in the program. They reported a mean (standard deviation (SD)) of 98.6 (69.8) min of aerobic exercise weekly and 57.4 (36.0) min of strengthening exercise weekly over a median of 17 weeks (range, 5-35 weeks) of preoperative therapy, for a mean (SD) of 156.0 (64.5) min of total exercise weekly. Eighty percent reported a mean of least 120 min of total exercise weekly during preoperative therapy. Patients with low baseline physical activity based on the International Physical Activity Questionnaire significantly increased their preoperative physical activity (p = .01). There were no adverse events associated with the exercise program. CONCLUSIONS: Patients with PDAC will participate in a home-based exercise program of aerobic and strengthening exercise and will increase physical activity, concurrent with preoperative chemotherapy and/or chemoradiation.

Impact of hypofractionated and standard fractionated chemoradiation before pancreatoduodenectomy for pancreatic ductal adenocarcinoma.

BACKGROUND: Previous studies have suggested that preoperative chemoradiation (CRT) is associated with an improved margin-negative resection rate among patients who undergo pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, the optimal preoperative regimen has not been established. METHODS: All patients with PDAC who received chemotherapy and/or CRT followed by PD between 1999 and 2014 were retrospectively reviewed. The effects of 2 external-beam radiation regimens-a standard course of 50.4 Gy in 28 fractions and a hypofractionated course of 30 Gy in 10 fractions-were compared. Differences in clinicopathologic characteristics, locoregional recurrence (LR), and overall survival (OS) were assessed. RESULTS: Among 472 patients who received preoperative therapy, 224 (47.5%) received 30 Gy, 221 (46.8%) received 50.4 Gy, and 27 (5.7%) received chemotherapy alone. Patients who received 50.4 Gy were more likely to have advanced-stage disease and to have received induction and postoperative chemotherapy, but there was no difference in the R1 margin status, treatment effect, LR, or OS between the 2 radiation groups (all P values > .05). Patients who received preoperative CRT had a lower rate of LR than patients who received preoperative chemotherapy alone (P < .01). In a multivariate Cox proportional hazards analysis, 50.4 Gy was associated with OS and LR similar to those associated with 30 Gy, whereas the absence of preoperative radiation was associated with a higher rate of LR (odds ratio, 2.21; 95% confidence interval, 1.04-4.70) and similar OS. CONCLUSIONS: Preoperative hypofractionated CRT was associated with similar local control and OS in comparison with standard CRT in patients undergoing PD for PDAC. The use of chemotherapy alone without CRT was associated with poorer local control but similar survival. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2671-2679. © 2016 American Cancer Society.

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.

Cutaneous Metastasis of a Mucoepidermoid Carcinoma of the Pancreas: First Reported Case.

BACKGROUND: Mucoepidermoid pancreatic cancer is a rare entity with only 8 cases reported in the literature. On review of the literature, the authors found that cutaneous metastases in pancreatic cancer are rare and have not been associated with the mucoepidermoid subtype. The authors present the first reported case of cutaneous metastasis in a patient with mucoepidermoid carcinoma of the pancreas. CASE PRESENTATION: A 50-year old white male with a metastatic invasive poorly differentiated mucoepidermoid carcinoma of the pancreas was found to have a slow growing lesion in the skin over his left upper quadrant while undergoing active therapy. The lesion was biopsied and the pathology was consistent with pancreatic origin sharing similar morphologic features when compared with the primary pancreactectomy specimen. CONCLUSIONS: Mucoepidermoid pancreatic cancer is an exceedingly rare subtype of pancreatic cancer, with very little information regarding its diagnosis, treatment, and patterns of metastases. Here, the authors present the first reported case of cutaneous metastases of mucoepidermoid pancreatic cancer.

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.