Edward Greeno

Neoadjuvant chemoradiotherapy for locally advanced pancreas cancer rarely leads to radiological evidence of tumour regression.

BACKGROUND Neo-adjuvant chemo-radiotherapy has been proposed to improve resectability of locally-advanced pancreatic cancer (LAPC). However, the ability of neo-adjuvant therapy to induce radiological tumour regression has not been reported. METHODS Pre- and post-treatment computed tomography (CT) scans of patients undergoing neo-adjuvant chemo-radiotherapy for LAPC were reviewed. LAPC was sub-classified into borderline resectable disease [≤ 180° involvement of the superior mesenteric artery (SMA); short-segment encasement/abutment of the common hepatic artery; or tumour-associated deformity, abutment or short-segment occlusion of the superior mesenteric vein (SMV)/ portal vein (PV) that was amenable to vascular resection and reconstruction] and locally advanced un-resectable pancreatic cancer (vascular involvement more than that described for borderline resectable pancreatic cancer). The radiological response and surgical resection rates were assessed. RESULTS Sixteen patients received neo-adjuvant therapy for LAPC during 2005-2008. Regression of major vascular involvement, i.e. un-encasement or regression of abutment of any involved vessels was not observed in any patient. Pre- and post-treatment tumour densities were not statistically different. Fifty per cent of patients with borderline resectable disease and none of the patients with locally advanced un-resectable pancreatic cancer eventually underwent surgical resection. CONCLUSION Neo-adjuvant treatment does not induce radiological tumour regression of LAPC with major vascular involvement. Patient selection for neo-adjuvant trial enrollment should remain focused on borderline disease which may have a potential for surgical resection.

Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT)

BACKGROUND In a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study. PATIENTS AND METHODS Patients with previously untreated MPC received nab-P/Gem or Gem. PN was evaluated using a broad-spectrum group of Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) and graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. A case report form was completed by physicians on day 1 of each cycle (also graded by NCI CTCAE version 3.0). RESULTS In the nab-P/Gem arm, 227/421 patients (54%) experienced any-grade PN and 70 (17%) experienced grade III PN. No grade IV PN was reported. Most early-onset PN events were grade I, and treatment-related grade III PN occurred in 7% of patients who received up to three cycles of nab-P. Of those who developed grade III PN with nab-P/Gem treatment, 30 (43%) improved to grade ≤ I (median time to improvement = 29 days) and 31 (44%) resumed therapy. Development of PN was associated with efficacy; median overall survival in patients with grade III versus 0 PN was 14.9 versus 5.9 months (hazard ratio, 0.33; P < .0001). CONCLUSIONS nab-P/Gem was associated with grade III PN in a small percentage of patients. PN development was associated with longer treatment duration and improved survival. Grade III PN was reversible to grade ≤ I in many patients (median ≈ 1 month) NCT00844649.

SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours

Background:Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.Methods:Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development.Results:The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m−2 min−1 and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP.Conclusion:Prolonged dFdCTP systemic exposures (⩾72 h) were commonly observed. Infusion rate <25 mg m−2 min−1 and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.

Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors.

AIM To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs) and provide consensus treatment recommendations. METHODS Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs, angiogenesis inhibitors, inhibitors of mammalian target of rapamycin and cytotoxic agents. At this time, there is little data to guide treatment selection and sequence. We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations. Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process. After studying the literature, a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale. Ratings were done both before and after an extended discussion of the evidence. Quantitative measurements of agreement were made and consensus statements developed from the second round ratings. RESULTS Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the face-to-face discussion of evidence to 1% (2) after. In the final ratings, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: (1) it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic; (2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors; and (3) beyond first line, these same agents can be used. In patients with uncontrolled secretory symptoms, octreotide LAR doses can be titrated up to 60 mg every 4 wk or up to 40 mg every 3 or 4 wk. CONCLUSION Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.

Neoadjuvant interferon-based chemoradiation for borderline resectable and locally advanced pancreas cancer: a Phase II pilot study.

OBJECTIVES Neoadjuvant chemoradiotherapy (CRT) is a viable treatment strategy for patients with pancreatic cancer. This study was conducted to evaluate the Virginia Mason Protocol (5-fluorouracil, cisplatin, interferon-α and radiation) given in the neoadjuvant setting for the treatment of locally advanced pancreatic cancer. METHODS A Phase II pilot study evaluating interferon-based neoadjuvant CRT in patients with locally advanced pancreatic cancer was performed. RESULTS A total of 23 patients were enrolled. The mean age of the patients was 58.6 years. Of the 23 patients, seven (30.4%) completed all treatments. In the remaining 16 (69.6%) patients, treatment was interrupted as a result of toxicity. The most commonly reported effects of toxicity were leucopoenia/cytopoenia (n = 19, 82.6%) and gastrointestinal effects (n = 19, 82.6%). Surgical resection was successful in seven (30.4%) patients. Margins were negative in six (85.7%) of these seven patients. Positive lymph nodes were identified in three (42.9%) of seven patients. Overall survival was 11.5 months. Surgery provided improved survival (22.6 months) compared with CRT alone (8.8 months). Disease-free survival in resected patients was 17.2 months. CONCLUSIONS Interferon-based neoadjuvant CRT may allow for resection of locally advanced pancreatic cancer, but with significant toxicity. In the absence of surgical resection, survival remains dismal.

RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long‐term survival and reveals a role for ANGPTL4

Pancreatic adenocarcinoma patients have low survival rates due to late‐stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care.

421. Evaluating the Efficacy of Combination Cancer Treatment: Oncolytic Adenovirus and 5FU Chemotherapy

Previous studies have shown that Interferon(IFN)-based chemoradiation therapy can improve survival after resection of pancreas cancer. However, its clinical utility to this point has been limited due to the severe toxicity related to its use systemically. Gene Therapy represents a promising approach to deliver localized treatments that are effective and minimally toxic. Our aim in this study is to evaluate our groups novel oncolytic adenovirus (OAd) which allows targeting IFN treatment to cancer cells while sparing healthy tissue. The OAd, 5/3Cox2DE3ADPIFN, is selectively replicative in Cox2 (+) cell lines, allowing for specificity in therapy. It has also been modified to with a 5/3 chimeric knob to facilitate transduction, an overexpression of the adenoviral death protein, and expresses our IFN gene of interest. This study was conducted to analyze the combination of 5FU chemotherapy and our OAd in vitro in order to assess the interaction of treatments and determine the optimum combined treatment regimen. Treatments were analyzed in pancreatic cancer and esophageal adenocarcinoma cell lines S2013 and OE19. Recombinant OAds expressing luciferase rather than IFN were used in this study to isolate the combination of 5FU and the virus. Two viral models were evaluated: our selective therapeutic virus (Cox2) and a nearly identical but universally replicative virus (wild type). Cells were treated with 0, 1 or 10 viral particles per cell and 0, 5, 10, or 20 uM 5FU. Three timing regimens were used: simultaneous administration, 5FU 4 hours before virus, and virus 48 hours before 5FU. Crystal Violet and MTS Assays were used to measure cell death. Viral Copy number was used to assess viral replication using qPCR with a viral E4 primer. Cell death analysis showed an earlier killing effect from the wild type virus but otherwise similar patterns. 5FU and each virus produced dose dependent cell death independently. There was a significant additive effect seen in cell death from combining treatments when using 5FU before virus in both S2013 and OE19. Simultaneous treatment showed an additive killing effect with the combination in S2013, but a reduced killing by the combination compared to virus alone in OE19. There was also reduced combination killing when using virus before 5FU in S2013. Viral copy experiments in S2013 using simultaneous treatment showed dose dependent inhibition of viral replication, with only the 20uM dose significantly limiting viral replication over time. Our Cox2 OAd shows a killing effect similar to wild type in multiple cancer cell lines. When combined with 5FU treatment the expected summation in overall cell death from the independent treatments varies by timing of administrations as well as by type of cancer cell line. The reduced killing of the combination treatment in the simultaneous and virus before 5FU regimens, as well as the replication inhibition shown by viral copy number, may suggest an inhibition of the virus by 5FU under certain conditions. This also suggests the possibility of a gene therapy treatment regimen with optimal therapeutic effect, which appears to be 5FU before virus based on the results collected. Further studies investigating different chemotherapeutic drugs and regimens should be conducted to examine these trends.

Abstract CT207: Phase I dose escalation and pharmokinetic study of 14-O-phosphonooxymethyltriptolide

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: We are conducting a phase I, first-in-human trial of 14-O-phosphonooxymethyltriptolide (Minnelide,) a water-soluble prodrug of triptolide, a diterpene derived from the thunder god vine (tripterygium wilfordii). Triptolide is a potent inhibitor of heat shock protein 70 (HSP70) and pancreatic ductal adenocarcinoma over-expresses HSP70 as a protective mechanism. We have previously shown Minnelide to be effective and well tolerated in preclinical models of pancreatic carcinoma. Methods: The study uses a 3+3 dose escalation scheme, enrolling subjects with gastrointestinal malignancies refractory to standard therapies. The drug is administered as a daily, brief IV infusion for 21 days out of a 28 day cycle. The primary endpoint is toxicity, with secondary endpoints of pharmokinetics and response. Results: To date we have enrolled 27 subjects (17 pancreas, 7 colorectal, 3 other GI) at doses from 0.16 to 0.8 mg/m2, with 24 evaluable for toxicity. The therapy has been generally well tolerated with the only common toxicity being hematologic, but one patient experienced reversible cerebellar dysfunction at the highest dose. Pharmokinetics (n = 21) indicate rapid conversion of Minnelide to triptolide, with all Minnelide cleared within 30 minutes and peak triptolide levels achieved within 5 minutes of completion of infusion. Triptolide was rapidly cleared with a half-life of less than 30 minutes, and complete clearance by 6 hours, except in the patient with cerebellar toxicity who demonstrated delayed clearance of the drug. All subjects, except those in the lowest dose cohort, have had a reduction in HSP70 levels. The 9 patients in the first 3 dose cohorts all progressed by the end of cycle two. Tumor response by PET after cycle 1 (n = 19), shows a partial metabolic response in 36%, and stable metabolic disease in 52%. Response after 2 cycles by RECIST criteria (n = 10) shows a 10% PR (gastric) and 60% SD (5 pancreas, 1 rectal) rate with disease control for up to 6 months. 5 patients remain on study, with ongoing enrollment planned. Conclusions: We have seen promising evidence of significant clinical activity in this group of heavily pretreated patients with refractory GI malignancies. The toxicity profile and optimal dosing of Minnelide are being defined. Citation Format: Edward Greeno, Erkut Borazanci, Jon Gockerman, Ronald Korn, Ashok Saluja, Daniel Von Hoff. Phase I dose escalation and pharmokinetic study of 14-O-phosphonooxymethyltriptolide. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT207. doi:10.1158/1538-7445.AM2015-CT207

Neoadjuvant interferon-based chemoradiation for locally advanced pancreas cancer: A phase II pilot study.

266 Background: Neoadjuvant chemoradiotherapy (CRT) is a viable treatment strategy for patients with locally advanced pancreas cancer. We evaluated the Virginia Mason Protocol (5-fluorouracil, cisplatin, interferon-α and radiation) given in the neoadjuvant setting for the treatment of locally advanced pancreatic cancer. METHODS We performed a phase II pilot study treating patients with locally advanced pancreas cancer, including borderline resectable and initially non-resectable cases. Patients with evidence of metastases, previous chemotherapy, ECOG performance status >1, or inadequate hematologic, renal or hepatic function were excluded. RESULTS We enrolled 23 patients between 1/2005 and 10/2010. Mean age at enrollment was 58.6 years. Males made up 73.4% of the cohort. Of 23 patients, 7 (30.4%) completed all treatments. The remaining 16 (69.6%) patients did not receive all scheduled treatments due to severe side effects (n=7, 30.4%), progressive disease (n=3, 13%), alternative treatment (n=3, 13%), patient withdrawal (n=1, 4.3%), other disease (n=1, 4.3%), and death on study (n=1, 4.3%). Hospitalization was required due to toxicity for 47.8% (n=11) of patients. The most commonly reported grade 3 or 4 toxicities were leucopenia/cytopenia (n=19, 82.6%) and gastrointestinal (n=19, 82.6%). Other toxicities were much less common (fatigue, weight loss, pain, skin rash, all n<3). Tumor regression was not seen in any patient. Surgical resection was ultimately successful in 7 (30.4%) cases. Surgical margins were negative in 6 of 7 cases (85.7%). The mean lymph node count was 11. Positive lymph nodes were identified in 3 of 7 cases (42.8%). Overall survival for all patients was 11.5 months. Surgical resection provided significantly improved survival (22.6 months) compared to CRT alone (8.8 months). Disease free survival in resected patients was 17.2 months. CONCLUSIONS Aggressive neoadjuvant CRT with immunotherapy may allow for resection of initially non-resectable, locally advanced pancreas cancer, but with significant toxicity. Overall survival was similar to other, less toxic regimens. In the absence of surgical resection, survival remains dismal.