Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.

BACKGROUND: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. METHODS: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. FINDINGS: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. INTERPRETATION: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. FUNDING: Bristol Myers Squibb and the US National Institutes of Health.

Neoadjuvant radiation therapy and its impact on complications after pancreaticoduodenectomy for pancreatic cancer: analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP).

OBJECTIVES: This study investigated the impact of neoadjuvant radiation therapy (XRT) on postoperative outcomes following pancreaticoduodenectomy for pancreatic cancer. METHODS: The American College of Surgeons National Quality Improvement Program database was queried for the period 2005-2010 to assess complication rates following pancreaticoduodenectomy for pancreatic cancer. Two groups of patients were identified, comprising those who received neoadjuvant XRT and those who did not (control group). RESULTS: A total of 4416 patients were identified, including 200 in the XRT group and 4216 in the control group. There were differences in patient characteristics between the groups, including in age, hypertension and bilirubin level. Despite the fact that weight loss was more common, median operative time was longer (423 min versus 368 min; P < 0.001), and vascular reconstruction was more commonly required (20.5% versus 8.4%; P < 0.001) in the XRT group. In addition, the XRT group had a shorter median hospital stay than the control group (9 days versus 10 days; P = 0.005). Mortality (3.0% versus 2.7%; P = 0.818) and morbidity (40.5% versus 37.6%; P = 0.404) rates were not influenced by neoadjuvant XRT. Blood transfusion rates were increased in the XRT group (13.0% versus 7.4%; P = 0.003). Severe complications were influenced by age >70 years, American Society of Anesthesiologists (ASA) class >2, preoperative sepsis, dyspnoea, weight loss, impaired functional status, peripheral vascular disease and operative time of >8 h. CONCLUSIONS: Neoadjuvant XRT is not associated with an increase in complications after pancreaticoduodenectomy.

The cost-effectiveness of neoadjuvant chemoradiation is superior to a surgery-first approach in the treatment of pancreatic head adenocarcinoma.

BACKGROUND: In treating pancreatic cancer, there is no clearly defined optimal sequence of chemotherapy, radiation therapy and surgery. Therefore, cost-effectiveness should be considered. The objective of this study was to compare cost and outcomes between a surgery-first approach versus neoadjuvant chemoradiation followed by surgery for resectable pancreatic head cancer. METHODS: A decision analytic model was constructed to compare the 2 approaches. Data from the National Cancer Database, National Surgical Quality Improvement Program, and literature populated the surgery-first arm. Data from our prospectively maintained institutional pancreatic cancer database populated the neoadjuvant arm. Costs were estimated by Medicare payment (2011 U.S. dollars). Survival was reported in quality-adjusted life-months (QALMs). RESULTS: The neoadjuvant chemoradiation arm consisted of 164 patients who completed preoperative therapy. Of these, 36 (22 %) did not proceed to surgery; 12 (7 %) underwent laparotomy but had unresectable disease; and 116 (71 %) underwent definitive resection. The surgery-first approach cost $46,830 and yielded survival of 8.7 QALMs; the neoadjuvant chemoradiation approach cost $36,583 and yielded survival of 18.8 QALMs. In the neoadjuvant arm, costs and survival times for patients not undergoing surgery, those with unresectable disease at laparotomy, and those completing surgery were $12,401 and 7.7 QALMs, $20,380 and 7.1 QALMs, and $45,673 and 23.4 QALMs, respectively. CONCLUSIONS: Neoadjuvant chemoradiation for pancreatic cancer identifies patients with early metastases or poor performance status, who can be spared an ineffective or prohibitively morbid operation, and is associated with improved survival at significantly lower cost than a surgery-first approach. Neoadjuvant chemoradiation followed by surgery is a strategy that provides more cost-effective care than a surgery-first approach.