Adjuvant Pancreatic Cancer Management: Towards New Perspectives in 2021.

Adjuvant chemotherapy is currently used in all patients with resected pancreatic cancer who are able to begin treatment within 3 months after surgery. Since the recent publication of the PRODIGE 24 trial results, modified FOLFIRINOX has become the standard-of-care in the non-Asian population with localized pancreatic adenocarcinoma following surgery. Nevertheless, there is still a risk of toxicity, and feasibility may be limited in heavily pre-treated patients. In more frail patients, gemcitabine-based chemotherapy remains a suitable option, for example gemcitabine or 5FU in monotherapy. In Asia, although S1-based chemotherapy is the standard of care it is not readily available outside Asia and data are lacking in non-Asiatic patients. In patients in whom resection is not initially possible, intensified schemes such as FOLFIRINOX or gemcitabine-nabpaclitaxel have been confirmed as options to enhance the response rate and resectability, promoting research in adjuvant therapy. In particular, should oncologists prescribe adjuvant treatment after a long sequence of chemotherapy +/- chemoradiotherapy and surgery? Should oncologists consider the response rate, the R0 resection rate alone, or the initial chemotherapy regimen? And finally, should they take into consideration the duration of the entire sequence, or the presence of limited toxicities of induction treatment? The aim of this review is to summarize adjuvant management of resected pancreatic cancer and to raise current and future concerns, especially the need for biomarkers and the best holistic care for patients.

Adjuvant chemotherapy in pancreatic cancer: state of the art and future perspectives.

PURPOSE OF REVIEW: The modalities of management of resectable pancreatic ductal adenocarcinoma (PDAC) have evolved in recent years with new practice guidelines on adjuvant chemotherapy and results of randomized phase III trials. The aim of this review is to describe the state of the art in this setting and to highlight future possible perspectives. RECENT FINDINGS: Resectable PDAC is the tumor without vascular contact or a limited venous contact without vein irregularity. Several pathologic and biologic robust prognostic factors such as an R0 resection defined by a margin at least 1 mm have been validated. In phase III trials, the doublet gemcitabine-capecitabine provided a statistically significant, albeit modest overall survival benefit, but failed to show an improvement in relapse-free survival. Similarly, gemcitabine plus nab-paclitaxel did not increase disease-free survival. Modified FOLFIRINOX led to improved disease-free survival, overall survival, and metastasis-free survival, with acceptable toxicity. In the future, prognostic and/or predictive biomarkers could lead the optimization of therapeutic strategies and neoadjuvant treatment could become a standard of care in PDAC. SUMMARY: After curative intent resection, modified FOLFIRINOX is the standard of care in adjuvant in fit patients with PDAC. Others regimens (monotherapy or gemcitabine-based) are an option in unfit patients.

Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study).

BACKGROUND: At time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC. METHODS: PANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence. DISCUSSION: The "ideal" cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02959879 . Trial registration date: November 9, 2016.

Is there an oncological interest in the combination of CRS/HIPEC for peritoneal carcinomatosis of HCC? Results of a multicenter international study.

INTRODUCTION: Peritoneal metastasis (PM) of hepatocellular carcinoma (HCC) without distant spread are rare. The related prognosis is poor without standard treatment available. The role of cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is poorly documented. METHODS: An international multicentric cohort was constituted by retrospective analysis of 21 patients undergoing CRS/HIPEC for PM of HCC between 1992 and 2016 from 10 reference centers of PSOGI. Data on clinical features, treatment strategies, and survival outcomes were analyzed. RESULTS: The median time interval from the diagnosis of PM to the procedure was 4.5 months. The median peritoneal cancer index was 14. Sixteen patients had complete cytoreduction (CCR0-1). Ten patients had grades 3 to 4 complications. The median duration of follow-up was 52.2 months. The median OS was 46.7 months. The projected 3y-OS and 5y-OS were 88.9 and 49.4% respectively. The median OS for patients with CCR0-1 resection was not reached whereas it was 5.9 months for those with CCR2-3 resection after CRS (p = 0.0005). The median RFS was 26.3 months and projected RFS at 3 years of 36.5 months Three prognostic factors were associated with improved RFS in the univariate analysis: preoperative chemotherapy (p = 0.0156), PCI >15 (p = 0.009), Number of chemotherapy agents used for HIPEC (p = 0.005). CONCLUSION: CRS/HIPEC is a safe and effective approach in selected patients with PM of HCC. CRS/HIPEC gives the patient a chance for a good relapse free and overall survival and should be considered as an option.

Does Intraoperative Systematic Bacterial Sampling During Complete Cytoreductive Surgery (CRS) with Hyperthermic Intraoperative Peritoneal Chemotherapy (HIPEC) Influence Postoperative Treatment? A New Predictive Factor for Postoperative Abdominal Infectious Complications.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an emerging curative treatment option for patients with peritoneal carcinomatosis. It has a long-term survival benefit but is associated with high rates of morbidity, ranging from 12 % to 65 %, mainly due to infectious complications. We sought to evaluate the clinical relevance of routine intraoperative bacteriological sampling following CRS/HIPEC. STUDY DESIGN: Between November 2010 and December 2014, every patients receiving CRS/HIPEC were included. Three samples were routinely collected from standardized locations for intraperitoneal rinsing liquid bacteriological analysis (RLBA) after completion of HIPEC. The clinical and surgical features, bacteriological results, and short-term outcomes were retrospectively reviewed. RESULTS: The overall mortality and morbidity rates were 5 and 45 %, respectively. Among the 75 included patients, 40 % (n = 30) had at least one positive bacterial culture. Risk factors for a positive culture were colorectal resection (adjusted hazard ratio [HR] = 3.072, 95 % CI 1.843-8.004; p = 0.009) and blood loss >1000 mL (HR = 4.272, 95 % CI 1.080-18.141; p = 0.031). Among 26 (35 %) patients with abdominal infectious complications, 13 (17 %) experienced isolated complications. A positive RLBA result was independently associated with abdominal infectious complications (HR = 5.108, 95 % CI 1.220-16.336; p = 0.024) and isolated abdominal infectious complications (HR = 4.199, 95 % CI 1.064-15.961; p = 0.04). CONCLUSIONS: Forty percent of the RLBA samples obtained following CRS/HIPEC tested positive for bacteria. Bacterial sampling of rinsing liquid should be systematically performed. An aggressive and immediate antibiotic strategy needs to be evaluated.

Adjuvant I-131 Lipiodol After Resection or Radiofrequency Ablation for Hepatocellular Carcinoma.

BACKGROUND AND OBJECTIVES: High rates of recurrence have been observed after curative treatment for hepatocellular carcinoma (HCC). The main aim of this study was to establish the influence of adjuvant transarterial radioembolization-based I-131 lipiodol on survival and recurrence. METHODS: Between 2004 and 2010, 38 patients were treated with adjuvant I-131 lipiodol therapy, at a dosage of 2220 MBq, within 4 months after surgery. This treated cohort was compared to a control cohort consisting of 42 consecutive patients operated prior to the time the I-131 lipiodol treatment became available. RESULTS: Recurrence-free survival in the control and in the I-131 lipiodol cohort was 12.6 and 18.7 months, respectively (HR = 1.871, p = 0.025). At 2 and 5 years, the cumulative incidence of a first recurrence or death was, respectively, 50 % and 61 % in the treated cohort versus 69 % and 74 % in the control cohort. Median overall survival was 55 and 29 months, respectively (p = 0.051). Among patients with a recurrence at 2 years, more patients had already experienced such recurrence at 1 year in the control cohort (70 % vs 33 %, p = 0.014). CONCLUSIONS: Adjuvant I-131 lipiodol improves disease-free survival in patients with HCC.

Is the Combination of Distal Pancreatectomy and Cytoreductive Surgery With HIPEC Reasonable?: Results of an International Multicenter Study.

OBJECTIVE: To report the morbidity and risk factors for overall complications and for pancreatic fistula (PF) after distal pancreatic resection (DP) during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). SUMMARY BACKGROUND DATA: The safety of DP in patients with peritoneal surface malignancies treated by CRS and HIPEC has been debated. The risk of PF and its impact on surgical outcomes are not well defined. METHODS: Between 2001 and 2012, 118 patients with peritoneal surface malignancy undergoing CRS/HIPEC required DP at 7 oncological surgical centers. The incidence, clinical impact, and risk factors of PF were analyzed. RESULTS: The indications for DP were tumoral invasion of the pancreatic gland with (n = 24; 20%) or without splenic extension (n = 76; 64%), invasion of the pancreatic capsule (n = 10; 9%), or iatrogenic lesions during CRS (n = 8; 7%). The rate of 90 days postoperative mortality was 7.6%, and the rate of severe morbidity (Clavien-Dindo ≥III) was 44%. Pancreatic fistula was observed in 39 cases (33%), with the majority grade B (48.7%) or C (28.2%). In multivariate analysis, the risk factors for PF were a peritoneal cancer index more than 20 (risk ratio: 3.01; P = 0.022) and an operative time more than 550 min (risk ratio: 2.74; P = 0.038). The occurrence of PF was not associated with a higher risk of 90-day mortality (5.1% vs 8.8%, not significant). CONCLUSIONS: With regard to reported morbi-mortality rates, DP associated with CRS/HIPEC may be a reasonable procedure in highly selected patients when done in high-volume centers. Therefore, distal pancreatic involvement should not be considered as a definitive contraindication for CRS/HIPEC in patients with resectable peritoneal surface disease.

Hemophagocytic syndrome: an unusual and underestimated complication of cytoreduction surgery with heated intraperitoneal oxaliplatin.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) improves the survival of select patients with peritoneal carcinomatosis. Hemophagocytic syndrome (HS) is a rare and potentially fatal disease. We describe our experience with five patients who developed HS following oxaliplatin HIPEC and propose a management procedure. METHODS: Hyperthermic intraperitoneal chemotherapy was performed using the open-abdomen technique (43 °C) with oxaliplatin (460 mg/m (2) ) for 30 min. If thrombocytopenia occurred from days 5 to 14, heparin-induced thrombocytopenia was evaluated. For thrombocytopenia with unknown etiology, we performed a bone marrow analysis (BMA). A BMA indicating HS stimulated an extensive infectious disease workup. Herein, we describe "reactive septic HS" and HS of unknown origin. RESULTS: We documented five patients with HS as a result of severe thrombocytopenia. Underlying infections were present in two patients who were treated with antibiotics and survived. For the remaining three patients, we found no underlying etiology of HS; multidisciplinary staff adapted the clinical management daily. Two patients died on postoperative days 40 and 29. The third patient survived after several operations and treatment with the VAC abdominal dressing system. CONCLUSIONS: We present these cases to ensure that physicians are aware of the symptoms of HS after HIPEC, which are important for initiating immediate life-saving therapy. This condition is a diagnostic and therapeutic emergency. When HS complicates HIPEC, aggressive, early medical, and surgical management is required. However, the optimal management has not been defined.