Oncologic management of ampullary cancer: International survey among surgical and medical oncologists.

BACKGROUND: Ampullary adenocarcinoma (AAC) is a rare neoplasm which as a result is lacking specific treatment guidelines. This international survey study was performed to gain insight in the current daily practice of AAC. METHODS: Surgeons and medical oncologists, whom were members of the Dutch Pancreatic Cancer Group, International Study Group on Ampullary Cancer, International Hepato-Pancreato-Biliary Association, European and International Consortium on Minimally Invasive Pancreatic Surgery, or contributed to (peri)ampullary cancer research, were invited through email and newsletters between January and October 2021. RESULTS: Overall, 217 surgeons and medical oncologists completed the survey. Most of the respondents work in Europe (60%), and in a pancreatic expertise center (86%). The majority of respondents (87%) stated that the histological AAC subtype (e.g. intestinal vs. pancreatobiliary) was determined in the resection specimen. Neoadjuvant treatment for resectable disease was considered by 24% and adjuvant therapy by 90% of the respondents, with 80% of them choosing adjuvant chemotherapy alone. The formation of multidisciplinary teams, improvement in resection procedures, increased availability of chemotherapy regimens, and increased knowledge on tumor biology were considered as the most important developments in the last five years. The necessity for randomized controlled trials was mentioned by 50% of the respondents. CONCLUSIONS: This international survey highlights the existing variation in the management of patients with AAC, especially regarding the use of (neo)adjuvant therapy. More data from trials and international registries are needed to develop evidence-based guidelines on surgical and oncological management with the ultimate aim to improve outcomes for patients with AAC.

Patterns of recurrence following definitive chemoradiation for patients with proximal esophageal cancer.

INTRODUCTION: The aim of this retrospective study was to determine the patterns of recurrence and overall survival (OS) in patients achieving clinical complete response after treatment with definitive chemoradiation (CRT) for proximal esophageal cancer. MATERIALS AND METHODS: Patients with proximal esophageal cancer treated with CRT between 2004 and 2014 in 11 centers in the Netherlands were included. OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Cumulative incidence of first recurrence (locoregional or distant) and locoregional recurrence (LRR) were assessed using competing risk analyses. RESULTS: In 197 of the 200 identified patients, response was evaluated, 133 (68%) showed a complete response. In complete responders, median OS, three-year OS, and PFS were 45.0 months (95% CI 34.8-61.5 months), 58% (95% CI 48-66), and 49% (95% CI 40-57), respectively. Three- and five-year risk of recurrence were respectively 40% (95% CI 31-48), and 45% (95% CI 36-54). Three- and five-year risk of LRR were 26% (95% CI 19-33), and 30% (95% CI 22-38). Eight of 32 patients with an isolated LRR underwent salvage surgery, with a median OS of 32.0 months (95% CI 6.8-not reached). CONCLUSION: In patients with a complete response after definitive CRT for proximal esophageal cancer, most recurrences were locoregional and developed within the first three years after CRT. These findings suggest to shorten locoregional follow-up from five to three years.

Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study.

BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.

Isolated hepatic perfusion with oxaliplatin combined with 100 mg melphalan in patients with metastases confined to the liver: A phase I study.

AIM: To improve isolated hepatic perfusion (IHP), we performed a phase I dose-escalation study to determine the optimal oxaliplatin dose in combination with a fixed melphalan dose. METHODS: Between June 2007 and July 2008, 11 patients, comprising of 8 colorectal cancer and 3 uveal melanoma patients and all with isolated liver metastases, were treated with a one hour IHP with escalating doses of oxaliplatin combined with 100 mg melphalan. Samples of blood and perfusate were taken during IHP treatment for pharmacokinetic analysis of both drugs and patients were monitored for toxicity, response and survival. RESULTS: Dose limiting sinusoidal obstruction syndrome (SOS) occurred at 150 mg oxaliplatin. The areas under the concentration-time curves (AUC) of oxaliplatin at the maximal tolerated dose (MTD) of 100 mg oxaliplatin ranged from 11.9 mg/L h to 16.5 mg/L h. All 4 patients treated at the MTD showed progressive disease 3 months after IHP. CONCLUSIONS: In view of similar and even higher doses of oxaliplatin applied in both systemic treatment and hepatic artery infusion (HAI), applying this dose in IHP is not expected to improve treatment results in patients with isolated hepatic metastases.

Management of isolated nonresectable liver metastases in colorectal cancer patients: a case-control study of isolated hepatic perfusion with melphalan versus systemic chemotherapy.

BACKGROUND: To compare the median overall survival of patients with isolated nonresectable liver metastases in comparable groups of patients treated with either isolated hepatic perfusion (IHP) with melphalan or systemic chemotherapy. PATIENTS AND METHODS: Colorectal cancer patients with isolated liver metastases, who underwent IHP, were included in this study. The control group consisted of a subgroup of colorectal cancer patients with liver metastases only, who were enrolled in the randomized CApecitabine, IRinotecan, Oxaliplatin (CAIRO) phase III study. RESULTS: Ninety-nine patients were treated with IHP, and 111 patients were included in the control group. All patient characteristics were comparable except for age. Median follow-up was 78.1 months for IHP versus 54.7 months in the control group. Median overall survival was 25.0 [95% confidence interval (CI) 19.4-30.6] months for IHP and 21.7 (95% CI 19.6-23.8) months for systemic treatment and did not differ significantly (P = 0.29). Treatment-related mortality was 2% for the systemic treatment and 6% for IHP (P = 0.11). CONCLUSION: Compared with a patient group with comparable characteristics treated with systemic chemotherapy, IHP does not provide a benefit in overall survival in patients with isolated nonresectable colorectal liver metastases. Currently, the use of IHP cannot be advocated outside the scope of clinical studies.

Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients.

BACKGROUND: The aim of this study was to identify prognostic factors for local and systemic failure after isolated hepatic perfusion (IHP) with 200 mg melphalan in patients with colorectal liver metastases. PATIENTS AND METHODS: Hundred and fifty-four patients were selected for IHP and underwent laparotomy. Patients were monitored for response, toxicity and survival. Univariate and multivariate analyses were carried out to identify prognostic factors for hepatic response and progression-free and overall survival. RESULTS: Hepatic response rate was 50% with a median progression-free and overall survival of, respectively, 7.4 and 24.8 months. In multivariate analyses, absence of ability to perfuse through the hepatic artery (P = 0.003), severe postoperative complications (P = 0.048) and >10 liver metastases (P = 0.006) adversely influenced overall survival and no adjuvant chemotherapy adversely influenced progression-free survival. CONCLUSION: This is the first study to report prognostic factors for survival after IHP. Possibly, overall and disease-free survival can increase if preoperative screening is improved. In future studies on IHP, adjuvant chemotherapy should be considered.

Hepatic artery infusion of high-dose melphalan at reduced flow during isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: a clinical and pharmacologic evaluation.

Isolated hepatic perfusion (IHP) offers the advantage of high local drug exposure with limited systemic toxicity. To increase local drug exposure, we administered melphalan at a reduced flow in the hepatic artery during IHP (hepatic artery infusion, hepatic artery-portal vein perfusion, HI-HPP). Between December 2001 and December 2004, 30 patients with colorectal cancer liver metastases underwent HI-HPP with 200mg melphalan. Samples of the perfusate were taken for pharmacokinetic analysis. Patients were monitored for response, toxicity and survival. Perfusion was aborted prematurely in 2 patients due to leakage. During melphalan administration in the hepatic inflow cannula a mean flow rate of 121.3 mL/min and mean pressure of 62.5mm Hg were achieved. One patient died within 30 days after HI-HPP. Four patients developed veno-occlusive disease (VOD), while 2 patients showed signs of VOD. Twelve patients showed hepatic response, with a median duration of response of 11.5 months, according to WHO criteria. Although HI-HPP results in high perfusate melphalan concentration levels, it is associated with a relatively high level of hepatotoxicity and a limited response rate. We believe that the low flow and pressure rates found in this study can result in reduced drug penetration of the tumour and thus limited tumour response.