CYTOREDUCTION SURGERY WITH HIPEC IN PERITONEAL CARCINOMATOSIS OF GASTRIC ORIGIN: A HOPEFUL TREATMENT?

INTRODUCTION The incidence of peritoneal metastases in gastric cancer are frequent and are associated with very poor median survival rates. The multimodal treatment of cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) could offer a better prognosis in selected cases although it is not currently contemplated in clinical practice guidelines. MATERIAL AND METHODS Of the 100 patients operated on for peritoneal carcinomatosis in our centre between May 2014 and December 2020, we selected those of gastric origin. Multidisciplinary CRS treatment with HIPEC was indicated in those patients with positive cytology and/or preoperative PCI <7. RESULTS Four men and one woman with a mean age of 63 years underwent surgery. The mean preoperative PCI was 2 and complete cytoreduction was achieved in all cases (CC-0). Complications included a biliary leak, a postoperative collection and a bronchoaspirative pneumonia. One patient died at 34 months. The other four are still alive: one with recurrence at 18 months and the rest without disease with a mean follow-up of 25 months. In one of the cases CRS surgery with HIPEC was performed as surgical salvage after initial surgery and in the rest as the only treatment. CONCLUSIONS Palliative systemic chemotherapy is considered the treatment of gastric cancer with peritoneal involvement, however, treatment based on CRS and HIPEC in selected cases could improve survival rates, disease-free interval and even be considered as salvage treatment in resectable oligometastatic recurrences.

Opportunity Costs of Receiving Palliative Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma

PURPOSE: The median overall survival (OS) for metastatic pancreatic ductal adenocarcinoma (mPDAC) is < 1 year. Factors that contribute to quality of life during treatment are critical to quantify. One factor—time spent obtaining clinical services—is understudied. We quantified total outpatient time among patients with mPDAC receiving palliative systemic chemotherapy. METHODS: We conducted a retrospective analysis using four patient-level time measures calculated from the medical record of patients with mPDAC receiving 5-fluorouracil infusion, leucovorin, oxaliplatin, and irinotecan; gemcitabine/nab-paclitaxel; or gemcitabine within the University of Pennsylvania Health System between January 1, 2011 and January 15, 2019. These included the total number of health care encounter days (any day with at least one visit) and total visit time. Total visit time represented the time spent receiving care (care time) plus time spent commuting and waiting for care (noncare time). We performed descriptive statistics on these outpatient time metrics and compared the number of encounter days to OS. RESULTS: A total of 362 patients were identified (median age, 65 years; 52% male; 78% white; 62% received gemcitabine plus nab-paclitaxel). Median OS was 230.5 days (7.6 months), with 79% of patients deceased at the end of follow-up. On average, patients had 22 health care encounter days, accounting for 10% of their total days survived. Median visit time was 4.6 hours, of which 2.5 hours was spent commuting or waiting for care. CONCLUSION: On average, patients receiving palliative chemotherapy for mPDAC spend 10% of survival time on outpatient health care. More than half of this time is spent commuting and waiting for care. These findings provide an important snapshot of the patient experience during ambulatory care, and efforts to enhance efficiency of care delivery may be warranted.

Palliative systemic chemotherapy with or without pressurized intraperitoneal aerosol chemotherapy with cisplatin and doxorubicin (PIPAC C/D) for gastric cancer with peritoneal metastasis: A propensity score analysis.

380 Background: Gastric cancer (GC) with peritoneal metastasis (PM) has a dismal prognosis. Palliative systemic chemotherapy (SC), usually doublet combinations of platinum and fluoropyrimidines, is the standard of care. Pressurized IntraPeritoneal Aerosol Chemotherapy with Cisplatin and Doxorubicin (PIPAC C/D) yields promising results. Here we aimed to compare overall survival (OS) between SC + PIPAC C/D vs. SC alone in patients with PM from GC. Methods: Prospective cohort of 95 consecutive patients with PM from GC treated in palliative intent at our institution from 2010 to 2018. Of these patients, 69 received SC + PIPAC C/D („PIPAC“), 26 SC alone („control“). Choice of treatment was not dictated by medical criteria, but by (non-) availability of the single-use medical devices needed for PIPAC in Russia. All patients received doublet or triplet chemotherapy with platinum together with fluoropyrimidines or capecitabin. A Cox proportional hazard model based on propensity score (PS) was used to assess the effect of PIPAC on OS and account for confounding factors. Results: The HR adjusted for PS for PIPAC vs. control was 0.396 (CI 5- 95% = 0.224-0.700, p-value 0.001). In the simple (unadjusted) Kaplan-Meier, median survival in the control group was 7.0 months (CI: 4.51 - 9.49) and in the PIPAC group 14.0 months (CI: 11.46-16.54). In the control group, all 26 patients died after 1-25 months. In the PIPAC group, 36 of 69 patients died after 4 to 20 months. The longest observed survival time in the PIPAC group was 27 months. Significance for the log-rank test after Mantel-Cox (not adjusted) was p < 0.0001. Conclusions: Compared with SC alone, intensified chemotherapy combining PIPAC C/D and SC doubled OS. These promising results need to be confirmed in a randomized trial.

Palliative chemotherapy in carcinoma nasopharynx

Introduction: Nasopharyngeal carcinoma is a rare malignancy. We conducted an audit of systemic therapies received in palliative setting in carcinoma nasopharynx and studied their outcomes. Methods: Patients who underwent first-line palliative systemic chemotherapy between January 2014 and April 2017 for carcinoma nasopharynx at the department of medical oncology at authors' institute were selected for this analysis. Toxicities, responses, progression-free survival (PFS), and overall survival (OS) were analyzed. In addition, a Quality-Adjusted Time without Symptoms or Toxicity analysis with threshold utility analysis was performed. Results: Fifty-one patients were included in this analysis. The indication of palliative chemotherapy was locoregionally recurrent disease in 25 (49.0%) patients and metastatic disease in 26 (51.0%) patients. The overall response rate was 62.0% (n = 33). The median PFS was 225 days (95% confidence interval [CI]: 164–274 days) and median OS was 513 days (95% CI: 286–931 days). The restricted mean TOX state duration was 2.6 days (95% CI: 0.3–4.9), restricted mean TWiST duration was 219.2 days (95% CI: 184.0–254.4), and restricted mean REL duration was 74.3 days (95% CI: 38.1–110.4). Conclusion: Systemic cytotoxic therapy in nasopharyngeal cancers is associated with high response rates and clinically meaningful PFS; with low duration of time spent in adverse events.

Circulating Biomarkers for Prediction of Objective Response to Chemotherapy in Pancreatic Cancer Patients

Pancreatic cancer is a lethal disease with increasing incidence. Most patients present with advanced disease, for which palliative systemic chemotherapy is the only therapeutic option. Despite improved median survival rates with FOLFIRINOX or gemcitabine chemotherapy compared to the best supportive care, many individual patients may not benefit from chemotherapy. Biomarkers are needed to predict who will benefit from chemotherapy and to monitor a patient’s response to chemotherapy. This review summarizes current research and future perspectives on circulating biomarkers for systemic chemotherapy response.

Downstaging of unresectable intrahepatic or hilar cholangiocellular carcinoma by selective intra-arterial floxuridine and systemic cisplatin and gemcitabine. A dose finding single center phase IIa study.

478 Background: Patients with unresectable cholangiocarcinomas (CCC) have a poor prognosis even if palliative systemic chemotherapy is offered. A combined approach of systemic and intrahepatic chemotherapy may improve local control rates and allow downstaging. The aim of the study was to determine the maximum tolerated dose (MTD) of systemic intravenous gemcitabine in combination with intravenous cisplatin and hepatic arterial infusion with floxuridine in patients with unresectable intrahepatic or hilar CCC. Safety, toxicity, response rates and resectability rates after 3 months of combination treatment are reported. Methods: 12 patients were treated within a 3+3 dose escalation algorithm with 600, 800 or 1000 mg/m2 gemcitabine and a fixed dose of cisplatin 25 mg/m2 systemic chemotherapy on day 1, 8 every 3 weeks for 4 cycles and floxuridine 0,2 mg/kg on day 1-14 continous hepatic intra-arterial chemotherapy every 4 weeks for 3 cycles. PET/CT and/or CT scan was performed after 12 weeks. Results: The MTD of gemcitabine was 800 mg/m2 in this setting. Dose-limiting toxicities were recurrent biliary tract infections (n = 1) and neutropenic fever (n = 1). Response rates were: 27% partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, 3-year-overall survival (OS) was 33%, median OS 21,9 months (1-49) and median progression-free survival 10,5 months (2-40). Conclusions: Combination of systemic gemcitabine and cisplatin plus intraarterial floxuridine is feasible and appears effective in disease control, but achievement of resectability seems challenging. Randomized trials comparing this combination to gemcitabine/cisplatin alone are warranted. Clinical trial information: NCT01692704.

Phase I study of hepatic arterial infusion (HAI) therapy with floxuridine (FUDR) combined with systemic gemcitabine and oxaliplatin in patients with locally advanced intrahepatic cholangiocarcinoma (ICC).

417 Background: The standard of care for unresectable ICC is palliative systemic chemotherapy with cisplatin and gemcitabine. HAI therapy with FUDR in ICC resulted in high response rates [Kemeny 2011]. The use of HAI FUDR with systemic chemotherapy may improve outcomes. We conducted a phase 1 study of HAI FUDR with systemic gemcitabine and oxaliplatin. Methods: We enrolled patients in 3 cohorts: FUDR 0.16mg/kg/day x 14 days (Cohort 1), FUDR 0.12 mg/kg/day x 14 days with gemcitabine 1000mg/m2 on days 1, 8, 15 (Cohort 2), and FUDR 0.10 mg/kg/day x 14 days with gemcitabine 800mg/m2 days 1, 15 and oxaliplatin 85mg/m2 days 1, 15 (Cohort 3). The primary endpoint was the recommended phase 2 dose (RP2D) for Cohort 3. DLTs were assessed during cycle 1. Secondary objectives were response rate and survival. Results: We enrolled 24 patients, 6 male, age range 42-81 years (median 64). No DLTs were observed in Cohort 1 (FUDR). In Cohort 2 (FUDR + Gem), the addition of gemcitabine at 1000mg/m2 days 1, 8, 15 resulted in grade 3 LFT elevation in 2 patients; for subsequent patients, the gemcitabine dose was reduced to 800mg/m2, and no further DLT were noted. No DLT were observed in Cohort 3 (FUDR + GemOx). 10 patients experienced partial responses and conversion to resectable disease occurred in all cohorts. No other significant toxicities occurred. Conclusions: FUDR via HAI with systemic gemcitabine and oxaliplatin is well-tolerated in patients with unresectable cholangiocarcinoma, with a high rate of response and disease control, allowing for resection in some patients. Our RP2D is FUDR 0.10 mg/kg/day x 14 days, with gemcitabine 800mg/m2 days 1, 15 and oxaliplatin 85mg/m2 days 1, 15. Collaboration with MSKCC is ongoing. Clinical trial information: NCT01525069. [Table: see text]

Electrostatic precipitation Pressurized IntraPeritoneal Aerosol Chemotherapy (ePIPAC): first in-human application

Background: Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a drug delivery technique with superior pharmacological properties for treating peritoneal metastasis (PM). Adding electrostatic loading (ePIPAC) as an adjunct to aerosol and artificial hydrostatic pressure improved tissue uptake in a preclinical model.Methods: We report the first ePIPAC use in 3 patients with PM of hepatobiliary-pancreatic (HBP) origin. All 3 patients received concomitant palliative systemic chemotherapy that was discontinued in two patients. PIPAC with cisplatin 7.5 mg/m2 and doxorubicin 1.5 mg/m2 was applied intraperitoneally at a pressure of 12 mmHg and a temperature of 37% °C for 30 min. Additionally, a voltage 7,500–9,500 V and a current≤10 µA were applied over a stainless steel brush electrode emitting a stream of electrons.Results: ePIPAC was technically feasible. No intraoperative complication was noted. The procedures were well tolerated with no adverse event CTCAE > 2. Patient 1 with PM of unknown origin (CUP with HBP phenotype) showed an objective histological and radiological response and survived 11 months. Patient 2 with ductal pancreatic cancer underwent secondary resection after ePIPAC with no residual PM; however, tumor recurred 5 months later. Patient 3 with adenocarcinoma of the gallbladder showed a radiological regression of liver infiltration and is alive after 22 months without histological evidence of PM.Conclusion: ePIPAC is technically feasible, is well tolerated and can induce tumor regression of PM in HBP cancers with and without concomitant systemic chemotherapy. These preliminary results justify prospective clinical studies with ePIPAC.