Dana Backlund Cardin

Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101

IMPORTANCE Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. OBJECTIVE To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. DESIGN, SETTING, AND PARTICIPANTS A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. INTERVENTIONS Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy. MAIN OUTCOMES AND MEASURES Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. RESULTS The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. CONCLUSIONS AND RELEVANCE The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trials completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01821612.

Pancreatic adenocarcinoma, version 2.2017: Clinical practice guidelines in Oncology

Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

Thymidylate synthase genotype-directed chemotherapy for patients with gastric and gastroesophageal junction cancers

Background Retrospective studies indicate associations between TSER (thymidylate synthase enhancer region) genotypes and clinical outcomes in patients receiving 5-FU based chemotherapy, but well-controlled prospective validation has been lacking. Methods In this phase II study (NCT00515216 registered through ClinicalTrials.gov, http://clinicaltrials.gov/show/NCT00515216), patients with “good risk” TSER genotypes (at least one TSER*2 allele) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates (ORR) in patients with gastric and gastroesophageal junction (GEJ) cancers, compared with historical outcomes in unselected patients (estimated 43%). Results The ORR in genotype-selected patients was 39.1% (9 partial responses out of 23 evaluable patients, 95% CI, 22.2 to 59.2), not achieving the primary objective of improving ORR. An encouraging disease control rate (DCR, consisting of partial responses and stable diseases) of 95.7% was noted and patients with homozygous TSER*2 genotype showed better tumor response. Conclusions In this first prospective, multi-institutional study in patients with gastric or GEJ cancers, selecting patients with at least one TSER*2 allele did not improve the ORR but led to an encouraging DCR. Further studies are needed to investigate the utility of selecting patients homozygous for the TSER*2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers. Trial Registration ClinicalTrials.gov NCT00515216

Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial

Importance KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer. Objective To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. Design, Setting, and Participants SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. Interventions Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. Main Outcomes and Measures The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. Results There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients). Conclusions and Relevance Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX. Trial Registration clinicaltrials.gov Identifier: NCT01658943

Current treatment options for pancreatic carcinoma.

Pancreas cancer is a significant cause of cancer mortality; therefore, the development of early diagnostic strategies and effective treatment is essential. Improvements in imaging technology, as well as use of biomarkers such as CA 19–9, are changing the way that pancreas cancer is diagnosed and staged. Although progress in treatment for pancreas cancer has been incremental, development of combination therapies involving both chemotherapeutic and biologic agents is ongoing. This article reviews current strategies in the diagnosis and treatment of resectable and advanced pancreas cancer.

Phase II trial of sorafenib and erlotinib in advanced pancreatic cancer

This trial was designed to assess efficacy and safety of erlotinib with sorafenib in the treatment of patients with advanced pancreatic adenocarcinoma. An exploratory correlative study analyzing pretreatment serum samples using a multivariate protein mass spectrometry‐based test (VeriStrat®), previously shown to correlate with outcomes in lung cancer patients treated with erlotinib, was performed. Patients received sorafenib 400 mg daily along with erlotinib 150 mg daily with a primary endpoint of 8‐week progression free survival (PFS) rate. Pretreatment serum sample analysis by VeriStrat was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups (by VeriStrat classification) was assessed using log‐rank P values; hazard ratios (HR) were obtained from Cox proportional hazards model. Thirty‐six patients received study drug and were included in the survival analysis. Eight‐week PFS rate of 46% (95% confidence interval (CI): 0.32–0.67) did not meet the primary endpoint of a rate ≥70%. Thirty‐two patients were included in the correlative analysis, and VeriStrat “Good” patients had superior PFS (HR = 0.18, 95% CI: 0.06–0.57; P = 0.001) and OS (HR = 0.31 95% CI: 0.13–0.77, P = 0.008) compared to VeriStrat “Poor” patients. Grade 3 toxicities of this regimen included fever, anemia, diarrhea, dehydration, rash, and altered liver function. This study did not meet the primary endpoint, and this combination will not be further pursued. In this small retrospective analysis, the proteomic classification was significantly associated with clinical outcomes and is being further evaluated in ongoing studies.

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer

BACKGROUND AND PURPOSE This single institution phase I trial determined the maximum tolerated dose (MTD) of concurrent vorinostat and capecitabine with radiation in non-metastatic pancreatic cancer. MATERIAL AND METHODS Twenty-one patients received escalating doses of vorinostat (100-400mg daily) during radiation. Capecitabine was given 1000mg q12 on the days of radiation. Radiation consisted of 30Gy in 10 fractions. Vorinostat dose escalation followed the standard 3+3 design. No dose escalation beyond 400mg vorinostat was planned. Diffusion-weighted (DW)-MRI pre- and post-treatment was used to evaluate in vivo tumor cellularity. RESULTS The MTD of vorinostat was 400mg. Dose limiting toxicities occurred in one patient each at dose levels 100mg, 300mg, and 400mg: 2 gastrointestinal toxicities and one thrombocytopenia. The most common adverse events were lymphopenia (76%) and nausea (14%). The apparent diffusion coefficient (ADC) increased in most tumors. Nineteen (90%) patients had stable disease, and two (10%) had progressive disease at time of surgery. Eleven patients underwent surgical exploration with four R0 resections and one R1 resection. Median overall survival was 1.1years (95% confidence interval 0.78-1.35). CONCLUSIONS The combination of vorinostat 400mg daily M-F and capecitabine 1000mg q12 M-F with radiation (30Gy in 10 fractions) was well tolerated with encouraging median overall survival.

Could the PD-1 Pathway Be a Potential Target for Treating Small Intestinal Adenocarcinoma?

Objectives The programmed death 1 (PD-1) pathway is upregulated in the immune microenvironment of many cancers. In this study, we examined the PD-1 pathway and the immune microenvironment of small intestinal adenocarcinomas by immunohistochemistry. Methods From our department pathology archives we identified 42 small intestinal adenocarcinomas from between 2000 and 2015, with blocks available for IHC studies. Tumors were immunohistochemically stained for CD3, CD4, CD8, CD20, PD-1, and programmed death ligand 1 (PD-L1) expression. Results PD-1 was expressed by intratumoral and peritumoral lymphocytes in 35 of 42 (83%) cases. PD-L1 expression on tumor cells and immune cells was observed in seven of 42 (17%), and 18 of 42 (43%) cases, respectively. PD-L1 was mainly expressed by histiocytes capping cancerous glands/nests at the invasive front or by most tumor cells in medullary carcinomas. All the PD-L1+ tumors also expressed PD-1. The tumors expressing PD-L1 contained more CD3+, CD4+, and CD8+ T cells, but showed a lower CD4+/CD8+ ratio than those without expression of PD-L1. Conclusions PD-1 and PD-L1 are highly expressed by most small intestinal adenocarcinomas. Blockage of the PD-1 pathway should be evaluated in the treatment of small intestinal adenocarcinomas.

Harnessing the Immune System in Pancreatic Cancer

Opinion statementManaging patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab’s tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy’s general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.

Tu1953 Nab-Paclitaxel Plus Gemcitabine vs Gemcitabine Alone for Resected Pancreatic Cancer in a Phase III Trial (APACT)

INTRODUCTION: Treatment of pancreatic cancer depends on the stage of disease. For patients with tumors deemed resectable, the best chance for prolonged survival is with early curative resection. However, it is not clear that this is the best general approach because of the high morbidity and mortality of pancreatic resection, and because tumors often are found to be unresectable at the time of surgery. The aim of this study was to compare survivals of patients who had early curative resection of their pancreatic tumors with those who did not. METHODS: We reviewed medical records of all patients diagnosed with pancreatic cancer at our VA Medical Center from 2005 through 2010, and gathered data on multiple demographic and clinical variables. Survivals of patients with and without tumor resection were compared using Kaplan Meier analysis. RESULTS: We identified 116 patients with pancreatic cancer (all men, 66% white, 29% black, 90% adenocarcinoma, 8% neuroendocrine tumor). Tumor location was head (66%), body (10%), tail (16%) and body/tail of pancreas (4%). Stage at presentation was: I (3%); II (22%); III (12%); IV (63%). 28 patients had tumors deemed resectable (group R) (mean age 64±1.7 years [SEM], 64% white, 81% adenocarcinoma), and 88 had non-resectable (group NR) tumors (mean age 67.1±9.7 years, 66% white, 92% adenocarcinoma). Ultimate treatments overall included surgery (21%), neoadjuvant therapy (4%), adjuvant therapy (10%) and palliative chemotherapy (35%). Kaplan-Meier analysis demonstrated an overall median survival of 153 days (95% CI 93195) for the total group of patients with pancreatic cancer. A total of 17 (14.7%) patients underwent surgery with curative intent (group R+) including 13 Whipple procedures and 4 pancreatic tail resections. 11 patients initially deemed resectable did not undergo tumor resection (group R-) because they were later deemed unfit for surgery (n=4), declined surgery (n=1) or were found to have unresectable disease with intraoperative metastases during surgery (n=6). Both groups (R+ and R-) had similar mean ages (63.6±2.2 vs. 64.5±2.7 years, p=0.80), weight at diagnosis (85.7±5.4 vs. 81.2±3.9, p=0.56), race, stage, tumor size, Ca 19-9 and serum albumin levels. Median survival of the R+ group (401±95 days) was significantly longer than that of the Rgroup (162±70, p =0.03) and the NR group (112±33, p=0.0009). Survival for the 6 patients who had surgery revealing unresectable tumors was poorer than that for the 17 patients who had tumor resections with curative intent (R+), but did not reach significance (246.5 days vs. 401 days, p=0.18). CONCLUSIONS: Early surgery for patients with resectable pancreatic cancer is associated with improved survival. The finding of unresectable disease at surgery is a poor prognostic sign, but the surgery itself does not appear to be the factor influencing the shortened survival.