Reference No: Author(s) Approval date: 12/05/16. Committee. June Operational Date: Review:

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1 Reference No: Title: Author(s) Systemic Anti-Cancer Therapy (SACT) Guidelines for Biliary Tract Cancer (BTC) Dr Colin Purcell, Consultant Medical Oncologist on behalf of the GI Oncologists Group, Cancer Centre Belfast City Hospital Ownership: Approval by: Operational Date: NICaN NICaN Drugs & Therapeutics Committee June 2016 Version No. 1.1 Supercedes 1.0 Links to other policies Version control for drafts: NICaN Biliary Tract SACT protocols Approval date: Next Review: 12/05/16 June 2018 Date Version Author Comments May Dr C Purcell Final version issued February Dr C Purcell Reviewed. No change SACT for Biliary Tract Cancer version1.1 Page 1 of 8

2 Authorisation of Systemic Anti-Cancer therapy (SACT) Guidelines for Biliary Tract Cancer These SACT guidelines are being submitted by the author on behalf of the GI oncologists group. SACT for Biliary Tract Cancer version1.1 Page 2 of 8

3 1.0 INTRODUCTION / PURPOSE OF POLICY 1.1 Background Systemic anti-cancer therapy (SACT) is an important modality in the management of patients with a diagnosis of BTC. This guideline describes the agreed management for these patients. 1.2 Purpose To ensure consistent use of SACT for patients with BTC 2.0 SCOPE OF THE POLICY This document is aimed at all clinical staff involved in the management of patients receiving SACT for BTC. 3.0 ROLES/RESPONSIBILITIES It is the responsibility of all clinical staff involved in the management of patients receiving SACT for BTC to familiarise themselves with these guidelines. 4.0 KEY POLICY PRINCIPLES Adjuvant therapy following resection of BTC Background Patients with resectable biliary tract cancers should be considered for surgical resection of their disease. Surgical resection is the only potentially curative treatment for BTC. However, the resectability rate has been reported to range between 30% and 70%, with large variability based on tumor location (70% for ampullary cancer, 40%-50% for gallbladder, intrahepatic and distal extrahepatic cancer and 30% for hilar BTC) (1, 2). The type of resection and prognosis vary with anatomical location with a 5-year overall survival (OS) rate of 20%-40% for intrahepatic adenocarcinoma, 50%-70% for ampullary cancer, 25%-50% for distal cholangiocarcinoma and for gallbladder cancer and 15%-35% for hilar BTC (3). The role for adjuvant SACT following resection of biliary tract cancers is not proven and prospective randomised clinical trials are addressing this issue. Patients with resected periampullary adenocarcinoma were eligible for recruitment into the ESPAC-3 trial and results for this group of patients treated within the ESPAC-3 trial have been reported (4). Overall the trial did not meet its endpoint as adjuvant chemotherapy did not significantly improve survival in resected periampullary cancer. There was a trend toward better 5-year overall survival but the P value was not significant. In the subset of patients who had undergone an R0 resection, improved survival was seen when using multiple regression. SACT for Biliary Tract Cancer version1.1 Page 3 of 8

4 Patient selection Adjuvant SACT following resection of biliary tract cancer cannot be recommended routinely due to lack of evidence of benefit. In the subset of patients who have undergone R0 resection of a periampullary adenocarcinoma and who have good performance status and adequate hepatic and bone marrow function, adjuvant SACT may be considered based on the results of the ESPAC-3 trial. Treatment Regimens The oral fluoropyrimidine capecitabine is preferred to the 5FU regimen used in the ESPAC-3 study. Capecitabine 1250mg/m 2 PO BD D1-14 q21d x 8 cycles For patients where fluoropyrimidine is contraindicated gemcitabine can be considered. Gemcitabine 1000mg/m 2 IV D1, 8, 15 q28d x 6 cycles Follow up Repeat CT scanning should be considered following surgery and any adjuvant treatment to ensure absence of residual / metastatic disease and provide a baseline for comparative purposes if future imaging is required. Subsequent follow up will be clinically based with further imaging reserved for situations where there is clinical concern. 4.2 Advanced (Unresectable or Metastatic) Disease Background Patients presenting with locally advanced unresectable or metastatic BTC, including those who have previously undergone resection of their primary tumour and develop recurrent disease, can be considered for SACT. Treatment in this setting is given with palliative intent. Combination chemotherapy can be associated with symptomatic benefit and an improvement in survival when compared to best supportive care or single agent chemotherapy regimens. SACT for Biliary Tract Cancer version1.1 Page 4 of 8

5 4.2.1 First Line Therapy in Advanced Disease Patient selection Patients with locally advanced unresectable or metastatic disease should be considered for systemic therapy providing they demonstrate: ECOG performance status of 0-2 Adequate liver and bone marrow function Treatment Regimens The ABC02 trial compared cisplatin plus gemcitabine with gemcitabine alone in advanced BTC (5). This study included patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer. The median overall survival was 11.7 months among the 204 patients in the cisplatin gemcitabine group and 8.1 months among the 206 patients in the gemcitabine group. Adverse events were similar in the two groups. The combination of gemcitabine plus a platinum agent has become the standard of care for these patients. In the Northern Ireland setting, the combination of gemcitabine and carboplatin is usually considered for these patients. Carboplatin is generally accepted as a suitable alternative to cisplatin in a palliative treatment setting and may be associated with less toxicity than cisplatin regimens. Single agent gemcitabine did demonstrate antitumour activity in the ABC02 trial and may be considered in patients who are not considered suitable for combination chemotherapy treatment. Gemcitabine Carboplatin (Gem/carbo) Gemcitabine 1000mg/m 2 IV D1, 8 Carboplatin AUC5 IV D1 21 day cycle for up to 8 cycles Imaging after 3-4 cycles to evaluate response. Gemcitabine 1000mg/m 2 IV D1, 8, 15 q28d Imaging after 3-4 cycles to evaluate response. Continue for up to 8 cycles Second Line Therapy There is no standard of care for the second line treatment of advanced BTC. This is due, in part, to the paucity of trials in this patient population. This is due, in part, to the paucity of trials in this patient population. In addition, only a proportion of patients who fail first-line treatment will be fit enough to consider second line therapy. SACT for Biliary Tract Cancer version1.1 Page 5 of 8

6 Three groups of agents have broadly shown activity in biliary tract cancer in retrospective and prospective trials: gemcitabine, fluoropyrimidines and platinum agents (6). After progressing on a first line gemcitabine-based chemotherapy, switching to a fluoropyrimidine-based schedule could be considered appropriate. A previous pooled analysis suggests that patients receiving doublet-chemotherapy have a greater benefit vs. monotherapy (6). The third-generation platinum analogue oxaliplatin is known for its activity in several gastrointestinal tumours and a synergistic activity with a favourable toxicity profile seems to exist with its combination with 5FU. Studies using Oxaliplatin/ 5FU based regimens for biliary tract tumours are available, with good results and acceptable toxicity (7-10). Patient selection Patients with locally advanced unresectable or metastatic disease that has progressed following first line treatment could be considered for second line systemic therapy providing they demonstrate ECOG performance status of 0-2 Adequate liver and bone marrow function Treatment Regimens OMDG Oxaliplatin 85mg/m 2 IV D1 Folinic acid 400mg/m 2 IV D1 Fluorouracil 400mg/m 2 IV D1 Fluorourcil 2400mg/m 2 IVI over 48hr D1 14 day cycle for up to 12 cycles CT scan at baseline, three months and 6 months Capecitabine 1250mg/m 2 PO BD D1-14 q21d CT scan at baseline, three months and 6 months Treatment continued for up to 8 cycles 5.0 IMPLEMENTATION OF POLICY 5.1 Dissemination This policy will be agreed by all consultant oncologists treating patients with SACT for upper GI malignancies. The guideline will form the basis for development of the SACT regimen specific protocols. It will be available on SACT for Biliary Tract Cancer version1.1 Page 6 of 8

7 the intranet for use by all doctors, nurses and pharmacists involved in all stages of SACT assessment and delivery in patients with BTC. 6.0 MONITORING Use of these guidelines will be monitored using audit. 7.0 EVIDENCE BASE / REFERENCES 1) Talamini MA, Moesinger RC, Pitt HA, et al. Adenocarcinoma of the ampulla of Vater. A 28-year experience. Ann Surg. 1997;225: ) Nagakawa T, Kayahara M, Ikeda S, et al. Biliary tract cancer treatment: results from the Biliary Tract Cancer Statistics Registry in Japan. J Hepatobiliary Pancreat Surg. 2002;9: ) Heron DE, Stein DE, Eschelman DJ, et al. Cholangiocarcinoma: the impact of tumor location and treatment strategy on outcome. Am J Clin Oncol. 2003;26: ) Neoptolemos JP, Moore MJ, Cox TF, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA Jul 11;308(2): ) Valle J1, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med Apr 8;362(14): ) Eckel F, Schmid RM, et al. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007; 96(6): ) Nehls O, Oettle H, Hartmann JT, et al. Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer 2008; 98(2): ) Novarino AM, Satolli MA, Chiappino I, et al. FOLFOX-4 Regimen or Single-agent Gemcitabine as First-line Chemotherapy in Advanced Biliary Tract Cancer. Am J Clin Oncol Oct;36(5): ) Mane J, Iruarrizaga E, Rubio I, et al. Second-line chemotherapy with capecitabine (CAP) and oxaliplatin (OX) in patients with pancreatic or biliary tree adenocarcinoma (ADC) Gastrointestinal Cancers Symposium. J Clin Oncol 2011; 29(Suppl. 4):Abstract ) Lim JY, Jeung HC, Mun HS, et al. Phase II trial of oxaliplatin combined with leucovorin and fluorouracil for recurrent/metastatic biliary tract carcinoma. Anticancer Drugs Jul;19(6): CONSULTATION PROCESS GI oncologists group. SACT for Biliary Tract Cancer version1.1 Page 7 of 8

8 10.0 EQUALITY STATEMENT In line with duties under the equality legislation (Section 75 of the Northern Ireland Act 1998), Targeting Social Need Initiative, Disability discrimination and the Human Rights Act 1998, an initial screening exercise to ascertain if this policy should be subject to a full impact assessment has been carried out. The outcome of the Equality screening for this policy is: Major impact Minor impact No impact. SACT for Biliary Tract Cancer version1.1 Page 8 of 8