Palliative Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis: Is It Safe and Effective?

INTRODUCTION: Palliation is a controversial indication for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Patients with peritoneal carcinomatosis (PC) are living longer, and the roles of palliative CRS and HIPEC are increasingly challenged. The purpose of this study is to evaluate indications, morbidity, and symptom improvement from CRS/HIPEC in advanced PC. METHODS: A retrospective review of patients undergoing CRS and/or HIPEC with a palliative intent at a single institution from February 2008 to February 2018 was performed. Main end points included symptom improvement, symptom-free interval, and overall survival. RESULTS: Two hundred and seventy seven patients were referred for CRS/HIPEC during the study period and 17 underwent 20 palliative procedures. Appendiceal (n = 6) and colorectal cancers (n = 6) were the most common malignancies. Ascites (n = 8) and bowel obstruction (n = 8) were the most common indications for intervention. The postoperative complication rate was 50% and major complication rate was 20%. Partial symptom improvement or resolution of symptoms was achieved in 18 (90%) cases. A durable symptom control at 90 d was achieved in 13 (65%) cases. The median time to symptom recurrence was 5.1 mo (interquartile range: 2-11.4), and the median overall survival was 11.6 mo (interquartile range: 3.8-28.5). CONCLUSIONS: Palliative CRS and/or HIPEC achieve symptom improvement in patients with advanced PC. Risk assessment and expected time to recovery from surgery remain paramount for patient selection.

Ten-year experience in optimizing neoadjuvant therapy for localized pancreatic cancer-Medical college of Wisconsin perspective.

Treatment of localized pancreatic cancer has also evolved to prioritize preoperative (neoadjuvant) multimodality therapy over a surgery-first approach. Given the complexities of pancreatic cancer staging and the challenge of delivering multiple treatment modalities (chemotherapy, radiation therapy, and surgery), an experienced and highly integrated multidisciplinary team is necessary to achieve the best outcomes. In this review, we will discuss our institutional experience with neoadjuvant therapy, guiding principles for treatment, and outline the landscape for future investigations.

Radiographic patterns of first disease recurrence after neoadjuvant therapy and surgery for patients with resectable and borderline resectable pancreatic cancer.

BACKGROUND: More than 70% of patients with localized pancreatic cancer treated with upfront surgery develop disease recurrence. Herein we describe the radiographic patterns and timing of disease recurrence after neoadjuvant therapy and surgery in patients with pancreatic cancer. METHODS: Radiographic patterns of first disease recurrence were examined in patients with localized pancreatic cancer who completed neoadjuvant therapy and surgery. Disease recurrence was classified as local (pancreas, resection bed, or peripancreatic vasculature); regional (peritoneum or abdominal wall); or distant (liver, lung, bone). Progression-free survival was calculated from the date of diagnosis to the date of recurrence. RESULTS: Of 306 consecutive patients who completed neoadjuvant therapy and surgery, 149 (49%) had resectable pancreatic cancer and 157 (51%) had borderline resectable disease. Neoadjuvant therapy consisted of chemoradiation (32%), chemotherapy (14%), or both therapies (54%). Overall, primary therapy (including preoperative and postoperative therapy) consisted of chemoradiation alone in 29 (9%), chemotherapy alone in 14 (5%), and both therapies in 263 (86%) patients. At a median follow-up of 27 months, 186 (61%) of the 306 patients had recurrent pancreatic cancer. Sites of first recurrence were local-only in 29 (9%), regional-only in 19 (6%), distant-only in 87 (28%), and multisite in 51 (17%). The overall median progression-free survival for all patients was 24 months. Neoadjuvant chemoradiation reduced the odds of local-only recurrence (odds ratio: 0.21; 95% confidence interval: 0.06-0.77; P = .02). CONCLUSION: After neoadjuvant therapy and surgery, 9% of patients were found to have local-only recurrence. Treatment sequencing that incorporates neoadjuvant chemoradiation may improve local disease control.

RAS Mutation Status Confers Prognostic Relevance in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) with peritoneal carcinomatosis is an increasingly prevalent disease that carries significant mortality if left untreated. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in this patient population is associated with improved outcomes but high morbidity. We sought to study the prognostic significance of the known genomic driver, RAS, in patients with mCRC undergoing CRS/HIPEC to allow for improved assessment of risk-benefit ratio in this patient population. METHODS: Patients undergoing CRS/HIPEC for mCRC between 2010 and 2017 at our institution were identified. Patient demographics, RAS mutation status, perioperative morbidity, overall survival (OS), and relapse-free survival (RFS) were evaluated. RESULTS: Forty-seven patients met inclusion criteria. RAS mutant versus RAS wild-type groups were well matched with no difference in the clinicopathologic factors between groups. RAS mutation was associated with decreased RFS but no difference in OS. CONCLUSIONS: RAS mutation is an independent marker of early recurrence in patients undergoing CRS/HIPEC for mCRC and may identify patients who do not derive benefit from this high-risk procedure.

Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma.

HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH-), induces cytotoxicity and oxidative stress selectively in cancer cells by acting as a pro-drug for the delivery of hydrogen peroxide (H2O2); early clinical data suggest improved survival and inhibition of metastasis in patients being actively treated with P-AscH-. Previous studies have demonstrated that activation of HIF-1α is necessary for P-AscH- sensitivity. We hypothesized that pancreatic cancer (PDAC) progression and metastasis could be be targeted by P-AscH- via H2O2-mediated inhibition of HIF-1α stabilization. Our study demonstrates an oxygen- and prolyl hydroxylase-independent regulation of HIF-1α by P-AscH-. Additionally, P-AscH- decreased VEGF secretion in a dose-dependent manner that was reversible with catalase, consistent with an H2O2-mediated mechanism. Pharmacological and genetic manipulations of HIF-1α did not alter P-AscH--induced cytotoxicity. In vivo, P-AscH- inhibited tumor growth and VEGF expression. We conclude that P-AscH- suppresses the levels of HIF-1α protein in hypoxic conditions through a post-translational mechanism. These findings suggest potential new therapies specifically designed to inhibit the mechanisms that drive metastases as a part of PDAC treatment.

Multi-Phenotypic subtyping of circulating tumor cells using sequential fluorescent quenching and restaining.

In tissue biopsies formalin fixed paraffin embedded cancer blocks are micro-sectioned producing multiple semi-identical specimens which are analyzed and subtyped proteomically, and genomically, with numerous biomarkers. In blood based biopsies (BBBs), blood is purified for circulating tumor cells (CTCs) and clinical utility is typically limited to cell enumeration, as only 2-3 positive fluorescent markers and 1 negative marker can be used. As such, increasing the number of subtyping biomarkers on each individual CTC could dramatically enhance the clinical utility of BBBs, allowing in depth interrogation of clinically relevant CTCs. We describe a simple and inexpensive method for quenching the specific fluors of fluorescently stained CTCs followed by sequential restaining with additional biomarkers. As proof of principle a CTC panel, immunosuppression panel and stem cell panel were used to sequentially subtype individual fluorescently stained patient CTCs, suggesting a simple and universal technique to analyze multiple clinically applicable immunomarkers from BBBs.

Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling.

Patients with pancreatic ductal adenocarcinoma (PDAC) invariably succumb to metastatic disease, but the underlying mechanisms that regulate PDAC cell movement and metastasis remain little understood. In this study, we investigated the effects of the chemokine gene CXCL12, which is silenced in PDAC tumors, yet is sufficient to suppress growth and metastasis when re-expressed. Chemokines like CXCL12 regulate cell movement in a biphasic pattern, with peak migration typically in the low nanomolar concentration range. Herein, we tested the hypothesis that the biphasic cell migration pattern induced by CXCL12 reflected a biased agonist bioenergetic signaling that might be exploited to interfere with PDAC metastasis. In human and murine PDAC cell models, we observed that nonmigratory doses of CXCL12 were sufficient to decrease oxidative phosphorylation and glycolytic capacity and to increase levels of phosphorylated forms of the master metabolic kinase AMPK. Those same doses of CXCL12 locked myosin light chain into a phosphorylated state, thereby decreasing F-actin polymerization and preventing cell migration in a manner dependent upon AMPK and the calcium-dependent kinase CAMKII. Notably, at elevated concentrations of CXCL12 that were insufficient to trigger chemotaxis of PDAC cells, AMPK blockade resulted in increased cell movement. In two preclinical mouse models of PDAC, administration of CXCL12 decreased tumor dissemination, supporting our hypothesis that chemokine-biased agonist signaling may offer a useful therapeutic strategy. Our results offer a mechanistic rationale for further investigation of CXCL12 as a potential therapy to prevent or treat PDAC metastasis.

Neoadjuvant FOLFIRINOX for borderline resectable pancreas cancer: a new treatment paradigm?

BACKGROUND: Borderline resectable pancreatic cancer is best treated by multimodality therapy. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) tripled the response rate and significantly increased median survival for patients with advanced pancreatic cancer and shows promise for neoadjuvant use. Toxicity concerns prompted a careful analysis of our initial FOLFIRINOX experience. METHODS: All patients diagnosed with borderline resectable, biopsy-proven pancreatic adenocarcinoma treated with neoadjuvant FOLFIRINOX between July 2010 and December 2012 were reviewed. Primary outcome was surgical resectability. Secondary outcomes were treatment-related toxicities and survival. RESULTS: FOLFIRINOX followed by gemcitabine- or capecitabine-based chemoradiation was initiated in 18 patients. The most common grade 3 or 4 toxicities during chemotherapy were gastrointestinal, including nausea/emesis (n = 5), weight loss (n = 3) and diarrhea (n = 2), and hematologic (n = 2; neutropenia); five patients (36%) required a total of six admissions. Neoadjuvant therapy was completed in 15 of 18 patients (83%), and 12 (67%) underwent pancreatectomy (10 Whipple, 2 total pancreatectomy) including portal vein resection/reconstruction in 10 (83%). Disease progression precluded surgery in 6 of the 18 patients (33%). All 12 resected patients had negative (R0) margins. Only 2 of 12 (17%) were node positive (median node count: 26.5 [range: 15-39]). There were no in-hospital or 30-day mortalities and no clinical pancreatic leaks or reoperations. Of the 12 patients who completed all intended therapy, 7 (58.3%) are alive, including 5 who have no evidence of disease (median months from diagnosis: 22 months [range: 18-35 months). The six patients who did not complete all planned therapy are deceased (months from diagnosis: 6.9-17.5 months). CONCLUSION: FOLFIRINOX followed by chemoradiation as neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma is safe, and our initial experience suggests favorable resection rates compared with previous reports in this high-risk patient population.