Effect of intraoperative secretin on operative outcomes in pancreatic resection: A randomized controlled trial.

BACKGROUND: Objectives: We performed a randomized, double-blind, placebo-controlled trial to determine if using Secretin intra-operatively to identify leaks and subsequently target operative intervention would decrease the frequency of clinically significant post-operative pancreatic fistula formation. METHODS: Patients undergoing pancreaticoduodenectomy or distal pancreatectomy were randomized to receive intra-operative Secretin or placebo intra-operatively following the completed pancreaticojejunostomy or closure of the cut remnant stump. If a potential leak was identified, targeted therapy with directed suture placement was performed. RESULTS: 170 patients were randomized; 83 receiving placebo and 87 receiving Secretin. The rate of clinically significant fistula formation was 3% (3/87) in the Secretin group and 6% (5/83) in the placebo group (p = 0.489). The rate of biochemical leak was 29% (25/87) in the Secretin group and 19% (16/83) in the placebo group (p = 0.157). There were no Grade C post-operative fistula in either group. Of the 9% of patients in the Secretin group who had a targeted intra-operative intervention, none developed a clinically significant fistula. Adverse events were similar between groups. CONCLUSIONS: Compared to placebo, intra-operative Secretin administration was not associated with an overall reduction in clinically significant pancreatic fistula formation. However, patients with an intra-operative leak identified by Secretin may benefit from intervention (clinicaltrials.gov: NCT02160808).

A Study of Thymidylate Synthase Expression as a Biomarker for Resectable Colon Cancer: Alliance (Cancer and Leukemia Group B) 9581 and 89803.

PURPOSE: Tumor levels of thymidylate synthase (TS), a target of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer, have been studied as a predictive or prognostic biomarker with mixed results. PATIENTS AND METHODS: Tumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer. TS expression was determined by standard immunohistochemistry and by automated quantitative analysis. Tumor mismatch repair deficiency (MMR-D) and BRAF c.1799T > A (p.V600E) mutation status were also examined. Relationships between tumor TS, MMR-D, and BRAF mutation status, overall survival (OS), and disease-free survival (DFS) were investigated in the subset of stage III patients. RESULTS: Patients whose tumors demonstrated high TS expression experienced better treatment outcomes, with DFS hazard ratio (HR) = 0.67, 95% confidence interval (CI) = 0.53, 0.84; and OS HR = 0.68, 95% CI = 0.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR = 0.94; OS: interaction HR = 0.94). Tumors with high TS expression were more likely to demonstrate MMR-D (22.2% vs. 12.8%; p = .0003). Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77%, compared with 58% for those whose tumors had low TS and were non-MMR-D (log-rank p = .0006). Tumor TS expression did not predict benefit of a particular therapeutic regimen. CONCLUSION: This large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer, although tumor TS expression did not predict benefit of 5-FU-based chemotherapy. The Oncologist 2017;22:107-114Implications for Practice: This study finds that measurement of tumor levels of thymidylate synthase is not helpful in assigning specific adjuvant treatment for colorectal cancer. It also highlights the importance of using prospective analyses within treatment clinical trials as the optimal method of determining biomarker utility.

Cost-effectiveness and clinical efficacy of biliary stents in patients undergoing neoadjuvant therapy for pancreatic adenocarcinoma in a randomized controlled trial.

BACKGROUND AND AIMS: The optimal type of stent for the palliation of malignant biliary obstruction in patients with pancreatic adenocarcinoma undergoing neoadjuvant chemoradiotherapy with curative intent is unknown. We performed a prospective trial comparing 3 types of biliary stents-fully covered self-expandable metal (fcSEMS), uncovered self-expandable metal (uSEMS), and plastic-to determine which best optimized cost-effectiveness and important clinical outcomes. METHODS: In this prospective randomized trial, consecutive patients with malignant biliary obstruction from newly diagnosed pancreatic adenocarcinoma who were to start neoadjuvant chemoradiotherapy were randomized to receive fcSEMSs, uSEMSs, or plastic stents during the index ERCP. The primary outcomes were time to stent occlusion, attempted surgical resection, or death after the initiation of neoadjuvant therapy, and the secondary outcomes were total patient costs associated with the stent, including the index ERCP cost, downstream hospitalization cost due to stent occlusion, and the cost associated with procedural adverse event. RESULTS: Fifty-four patients were randomized and reached the primary end point: 16 in the fcSEMS group, 17 in the uSEMS group, and 21 in the plastic stent group. No baseline demographic or tumor characteristic differences were noted among the groups. The fcSEMSs had a longer time to stent occlusion compared with uSEMSs and plastic stents (220 vs 74 and 76 days, P < .01), although the groups had equivalent rates of stent occlusion, attempted surgical resection, and death. Although SEMS placement cost more during the index ERCP (uSEMS = $24,874 and fcSEMS = $22,729 vs plastic = $18,701; P < .01), they resulted in higher procedural AE costs per patient (uSEMS = $5522 and fcSEMS = $12,701 vs plastic = $0; P < .01). Conversely, plastic stents resulted in an $11,458 hospitalization cost per patient due to stent occlusion compared with $2301 for uSEMSs and $0 for fcSEMSs (P < .01). CONCLUSIONS: In a prospective trial comparing fcSEMSs, uSEMSs, and plastic stents for malignant biliary obstruction in patients undergoing neoadjuvant therapy with curative intent for pancreatic adenocarcinoma, no stent type was superior in optimizing cost-effectiveness, although fcSEMSs resulted in fewer days of neoadjuvant treatment delay and a longer time to stent occlusion. (Clincial trial registration number: NCT01038713.).

Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites.

N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced phosphorylation of a marker of CDK9 activity (phospho-RNAPII CTD Ser2/5) and reduced viability/growth of explant cells derived from PDAC PDX models. Similarly, a CDK inhibitor reduced phospho-RNAPII CTD Ser2/5, increased apoptosis, and inhibited tumor growth in FNA-PDX and patient-matched metastatic-PDX models. In summary, PDX models can be constructed from FNA biopsies of PDAC which in turn can enable genomic characterization and identification of potential therapies.

The effect of neoadjuvant chemoradiation on pancreatic cancer-associated diabetes mellitus.

OBJECTIVES: Pancreatic cancer-associated diabetes mellitus (PaCDM) occurs in approximately 50% of patients. In patients with new-onset PaCDM undergoing neoadjuvant chemoradiation therapy before surgical resection, we hypothesized that pancreatic tumor destruction would lead to improvement in fasting glucose levels. METHODS: A retrospective chart review was performed on patients with newly diagnosed pancreatic adenocarcinoma without a history of DM treated with neoadjuvant therapy at our center. All patients underwent combined modality neoadjuvant chemoradiation therapy, followed by surgical excision of the primary tumor. RESULTS: Sixty-nine patients (31 with PaCDM) met inclusion criteria for the study; 18 had Evans grade II tumor kill response, 10 had grade III response, and 3 had grade IV response. In patients with grade IV response, the odds ratio (OR) for achieving a normal preoperative glucose was 5.0 (95% confidence interval [CI], 0.4-63.2), compared with grade III (OR, 0.5; 95% CI, 0.1-3.0) and grade II (OR, 1.1; 95% CI, 0.2-5.2). When adjusted for percent kilogram weight loss and tumor size in a multivariable regression model, the grade IV response became significant to an OR of 6.5 (95% CI, 1.2-77.3). CONCLUSIONS: In patients with new-onset PaCDM undergoing neoadjuvant chemoradiation therapy, fasting glucose response may mirror the extent of tumor destruction.

Molecular profiling of appendiceal epithelial tumors using massively parallel sequencing to identify somatic mutations.

BACKGROUND: Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2. METHODS: Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer. RESULTS: A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes. CONCLUSIONS: Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies.

Pancreatic cyst prevalence and the risk of mucin-producing adenocarcinoma in US adults.

OBJECTIVES: The presence of a pancreatic cyst often prompts concern, although the rate of malignant transformation to mucin-producing adenocarcinoma is not known. We aimed to determine the prevalence rate of mucin-producing adenocarcinoma in US adults with pancreatic cysts. METHODS: This retrospective, population-based cross-sectional study calculated the annual number of mucin-producing adenocarcinomas using the Surveillance Epidemiology and End Results (SEER 18) database and the 2010 US census. The overall prevalence rate of cysts in the population was found using data from large cross-sectional imaging studies of incidental cyst prevalence. Prevalence rates were then calculated by dividing the annual number of mucin-producing adenocarcinomas by the cyst prevalence rate. RESULTS: Between 2005 and 2009, 1,137 mucin-producing adenocarcinomas were estimated to be found annually in a US adult population of 137,154,960. The total number of pancreas cysts, given a cyst prevalence rate of 2.5%, was 3,428,874. Therefore, the prevalence rate of mucin-producing adenocarcinoma arising in patients with pancreatic cysts was 33.2 per 100,000 (95% confidence interval (CI): 21.9-44.5). The prevalence rate was 32.8 per 100,000 (95% CI: 21.6-44.0) in women and 33.5 per 100,000 (95% CI: 22.2-44.8) in men. As expected, the rate of malignant transformation increased linearly with advancing age (highest 38.6 per 100,000 in 80- to 84-year-old men). CONCLUSIONS: Malignant transformation of pancreatic cysts into mucin-producing adenocarcinoma in US adults is a very rare event. Current clinical guidelines and resource allocation for pancreatic cyst disease should be reconsidered given these findings.

Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581.

PURPOSE: We conducted a randomized trial comparing adjuvant treatment with edrecolomab versus observation in patients with resected, low-risk, stage II colon cancer. This study also prospectively studied patient- and tumor-specific markers of treatment outcome. PATIENTS AND METHODS: After surgical resection, patients with stage II colon cancer were randomly assigned to either five infusions of edrecolomab at 28-day intervals or observation without adjuvant therapy. RESULTS: Final accrual included 1,738 patients; 865 patients received edrecolomab, and 873 patients were observed without adjuvant treatment. Median follow-up time was 7.9 years. There were no significant outcome differences between study arms (overall survival [OS], P = .71; disease-free survival, P = .64). The combined 5-year all-cause OS was 0.86 (95% CI, 0.84 to 0.88), and the combined 5-year disease-specific OS was 0.93 (95% CI, 0.91 to 0.94). The relationships between demographic and histopathologic factors and survival differed for all-cause and disease-specific survival outcomes, but no combined prognostic factor model was found to adequately classify patients at higher risk of recurrence or death as a result of colon cancer. CONCLUSION: Edrecolomab did not prolong survival. Consequently, this large study with a long duration of follow-up provided unique data concerning the natural history of resected stage II colon cancer. Prognostic factors identified in previous retrospective and pooled analyses were associated with survival outcomes in this stage II patient cohort. Results from ongoing molecular marker studies may enhance our ability to determine the risk profile of these patients.

Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer--a study of CALGB 9581 and 89803.

PURPOSE: Colorectal cancer (CRC) develops as a result of a series of accumulated genomic changes that produce oncogene activation and tumor suppressor gene loss. These characteristics may classify CRC into subsets of distinct clinical behaviors. PATIENTS AND METHODS: We studied two of these genomic defects-mismatch repair deficiency (MMR-D) and loss of heterozygosity at chromosomal location 18q (18qLOH)-in patients enrolled onto two phase III cooperative group trials for treatment of potentially curable colon cancer. These trials included prospective secondary analyses to determine the relationship between these markers and treatment outcome. A total of 1,852 patients were tested for MMR status and 955 (excluding patients with MMR-D tumors) for 18qLOH. RESULTS: Compared with stage III, more stage II tumors were MMR-D (21.3% v 14.4%; P < .001) and were intact at 18q (24.2% v 15.1%; P = .001). For the combined cohort, patients with MMR-D tumors had better 5-year disease-free survival (DFS; 0.76 v 0.67; P < .001) and overall survival (OS; 0.81 v 0.78; P = .029) than those with MMR intact (MMR-I) tumors. Among patients with MMR-I tumors, the status of 18q did not affect outcome, with 5-year values for patients with 18q intact versus 18qLOH tumors of 0.74 versus 0.65 (P = .18) for DFS and 0.81 versus 0.77 (P = .18) for OS. CONCLUSION: We conclude that MMR-D tumor status, but not the presence of 18qLOH, has prognostic value for stages II and III colon cancer.

Effect of initiating a multidisciplinary care clinic on access and time to treatment in patients with pancreatic adenocarcinoma.

PURPOSE: Neoadjuvant therapy for pancreatic adenocarcinoma requires referral to multiple specialists before initiating therapy. We evaluated the effect of establishing a multidisciplinary clinic (MDC) for patients with newly diagnosed pancreatic adenocarcinoma on treatment access and time to therapy. METHODS: Patients with newly diagnosed pancreatic adenocarcinoma diagnosed and treated at our center were included. Two patient groups were defined: preclinic represented those patients diagnosed before 2008 and MDC represented those patients diagnosed since 2009 who were treated in the newly created MDC and were initially candidates for neoadjuvant therapy. The primary outcomes were days from diagnosis to first treatment (initiation of chemotherapy or external beam radiation), days to completion of all required consultations, and number of visits needed before initiation of therapy. RESULTS: Ninety-seven patients were diagnosed and treated at our medical center from 2003 to 2008; 22 were treated in 2009 after the implementation of the MDC. Compared with the preclinic group, patients treated in the MDC had shorter times from biopsy to treatment (7.7 days v 29.5 days, P < .001), shorter time to completion of all required pretreatment consultations (7.1 days v 13.9 days, P < .001), and fewer visits to complete all consultations (1.1 v 4.3, P < .001). Thirty-three percent of patients seen in the MDC enrolled onto clinical research trials. CONCLUSION: In patients with pancreatic adenocarcinoma undergoing neoadjuvant therapy, the establishment of a multidisciplinary pancreas tumor clinic led to improved patient access to consultations and shorter time to initial treatment.

Induction therapy for poor-prognosis anal canal carcinoma: a phase II study of the cancer and Leukemia Group B (CALGB 9281).

PURPOSE: Although most patients with anal canal cancer are cured with sphincter-preserving, nonsurgical, combined-modality therapy, those with large tumors and lymph node involvement have a poor prognosis. To establish the safety and efficacy of induction chemotherapy with infusional fluorouracil (FU) plus cisplatin followed by FU plus mitomycin C with concurrent radiation in patients with poor-prognosis squamous cell cancers of the anal canal. METHODS: Patients with previously untreated anal canal cancers with T3 or T4 tumors and/or extensive nodal involvement (bulky N2 or N3) received two 28-day cycles of induction treatment with infusional FU plus cisplatin followed by two 28-day cycles of FU plus mitomycin C with concurrent split-course radiation. A third cycle of FU and cisplatin with radiation boost was given to patients with persistent primary site disease or bulky N2 or N3 disease at presentation. RESULTS: Forty-five assessable patients received protocol therapy. Treatment was generally well tolerated, and gastrointestinal and hematologic toxicities were the most common. Induction chemotherapy resulted in eight complete and 21 partial responses. After induction, combined-modality, and boost therapy, 37 (82%) of 45 assessable high-risk patients achieved a complete response. After 4 years of follow-up, 68% of patients are alive, 61% are disease-free, and 50% are colostomy- and disease-free. CONCLUSION: A combined-modality approach that includes induction treatment with FU and cisplatin followed by combined-modality therapy with FU, mitomycin C, and concurrent radiation results in long-term disease control in the majority of patients with poor-prognosis anal canal cancer.

Effect of neoadjuvant therapy on local recurrence after resection of pancreatic adenocarcinoma.

BACKGROUND: It is unknown whether neoadjuvant chemoradiotherapy, compared with adjuvant chemoradiotherapy, decreases the rate of local recurrence after resection of pancreatic adenocarcinoma. STUDY DESIGN: This is a retrospective case review of 102 patients with pancreatic adenocarcinoma who underwent pancreatic resection between 1993 and 2005. RESULTS: Of 102 patients with pancreatic adenocarcinoma who underwent surgical resection, 19 (19%) had no additional treatment, 41 (40%) underwent adjuvant chemoradiotherapy, and 42 (41%) were treated preoperatively with neoadjuvant chemoradiotherapy. Patients selected to receive neoadjuvant therapy were more likely to have locally advanced tumors. Based on initial CT scan, the percentage of patients with unresectable or borderline resectable tumors in the neoadjuvant group was 67%, compared with 22% in the adjuvant group. Nevertheless, patients receiving neoadjuvant chemoradiotherapy were less likely to have a local recurrence develop than patients receiving adjuvant chemoradiotherapy (5% versus 34%, p = 0.02). For those patients with tumors determined to be resectable on initial CT scan, local recurrences were observed in 31% (10 of 32) of patients in the adjuvant therapy group, compared with only 7% (1 of 14) of the neoadjuvant group. Intraoperative radiation therapy, administered to 51% of patients, was not associated with a lower rate of local recurrence. CONCLUSIONS: Neoadjuvant chemoradiotherapy is associated with improved local tumor control in patients undergoing resection for pancreatic carcinoma.

Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma.

BACKGROUND: Pancreatic cancer remains highly lethal. Previous attempts with neoadjuvant therapy in this disease have been inconclusive, but a potential for benefit exists. We conducted a phase II trial of dose-intense docetaxel and gemcitabine followed by twice-weekly gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. METHODS: Patients with stage I to III disease were eligible. Docetaxel 65 mg/m(2) intravenously over 1 hour and gemcitabine 4000 mg/m(2) given intravenously over 30 minutes were given on days 1, 15, and 29. On day 43, radiotherapy was begun at 50.4 Gy with gemcitabine 50 mg/m(2) intravenously over 30 minutes twice weekly for 12 doses. After treatment, patients were considered for resection. RESULTS: Twenty-four assessable patients were recruited onto the trial. All but one patient completed a full 12 weeks of therapy. Grade 3 and 4 hematological and nonhematological toxicities were common but manageable, and neutropenic fever did not occur. No patient had local tumor progression. Twelve patients (50%) responded by Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria, including one radiographic complete response. Seventeen patients underwent resection after therapy. Margin-negative resections were performed in 13 patients, including 9 patients whose disease was borderline or unresectable before treatment. A treatment effect was seen in all resection specimens. There have been no local recurrences of tumor, and several patients remain alive without evidence of disease. CONCLUSIONS: Docetaxel/gemcitabine followed by gemcitabine/radiotherapy is active in the treatment of pancreatic adenocarcinoma, with manageable toxicity. Tumor downstaging occurs in some patients to allow complete resection. Further investigation of this regimen is warranted.