NICaN Pancreatic Neuroendocrine Tumour SACT protocols. 1.0 Dr M Eatock Final version issued

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1 Reference No: Title: Author(s) Systemic Anti-Cancer Therapy (SACT) Guidelines for Pancreatic Neuro-endocrine Tumours Dr Martin Eatock, 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. 2.1 Supercedes 1.1 Links to other policies Version control for drafts: Approval date: Next Review: 12/05/16 June 2018 NICaN Pancreatic Neuroendocrine Tumour SACT protocols Date Version Author Comments January Dr M Eatock Final version issued 04/12/ Dr M Eatock Section 4.2 & 4.3 updated 22/6/ Dr M Eatock Section SACT for GIST version2.1 Page 1 of 10

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3 1.0 INTRODUCTION / PURPOSE OF POLICY 1.1 Background Systemic anti-cancer therapy (SACT) is a potential treatment modality in the management of patients with advanced pancreatic neuroendocrine tumours (NET). This guideline describes the agreed management for patients with this disease. 1.2 Purpose To ensure consistent use of SACT for patients with Pancreatic NET. 2.0 SCOPE OF THE POLICY This document is aimed at all clinical staff involved in the management of patients receiving SACT for Pancreatic NET. 3.0 ROLES/RESPONSIBILITIES It is the responsibility of all clinical staff involved in the management of patients receiving SACT for Pancreatic NET to familiarise themselves with these guidelines. 4.0 KEY POLICY PRINCIPLES 4.1 Pancreatic NET Background Pancreatic NET are uncommon tumours accounting for around 2% of all digestive tract neoplasms. They occur in approximately 4-12 patients per million population per year (1,2) accounting for between new cases per year in Northern Ireland. These tumours have a wide variety of clinical behaviours ranging from benign to highly aggressive malignant tumours and this guideline will be limited to discussing the management of malignant metastatic disease Classification of Pancreatic NET Pancreatic NET can be classified by function (hormone secreting Vs non functional) however the malignant potential of a pancretic NET is best described by its size, degree of differentiation and proliferation index (table 1). These features and the observed clinical behaviour of the tumour will help to determine the most appropriate approach to treatment. Most pancreatic NETS are well differentiated neuroendocrine carcinomas (WHO grade 2) and the survival rate 5 years from diagnosis is between 30 and 60% with a median suirvival of 72 months (3). Rapid progression of liver metastases (>25% increase over 6 months) and the presence of bone metastases confer a poor prognosis. SACT for GIST version2.1 Page 3 of 10

4 Biological Behaviour WHO Classification Metastases Histological Differentiation Tumour Size Ki67 index (%) Benign WHO Group 1 - Well Differentiated 2cm <2 Low grade malignant High grade malignant Table 1. WHO Group 2 + Well differentiated >2cm >2 WHO Group 3 + Poorly differentiated any > Management of Pancreatic NET For those with localised disease which is assessed by an appropriate MDT to be potentially resectable, the treatment of choice is surgical resection. There is no established role for the use of any adjuvant therapy following surgical resection for pancreatic NET. Follow up following surgery will be with a combination of clinical review, biochemical testing (for Chromogranin A and for specific hormones if elevated prior to surgery) and imaging with CT if recurrent disease is suspected and also with Somatostatin receptor scintigraphy and MIBG scanning if recurrence suspected on CT scan. For patients with a resectable pancreatic NET and liver only metastases which are deemed resectable by an appropriate MDT resection of the primary tumour and the liver metastases should be considered for those with well differentiated tumours. There is no evidence to suggest a role for adjuvant therapy following resection of a pancreatic NET or following metastatectomy. The European Neuroendocrine Tumour Society guidelines do suggest that adjuvant chemotherapy may be considered for selected patients following resection of a poorly differentiated NET (4). For those with disease recurrence following surgery or unresectable disease, treatment will depend on the presence or absence of a hormonal syndrome related to the neuro-endocrine tumour, the rate of disease progression and the histological features of the disease including proliferation index. There are a number of treatment options available for these patients including Transarterial chemo-embolisation (TACE), systemic chemotherapy, moleculary targeted therapies, radio-isotope treatments (such as PRRT and MIBG) and selective interna radiotherapy (SIRT). The sequence of treatment used will be based on individual patient characteristics as there is a paucity of randomised controlled trial (RCT) data to determine optimal treatment scheduling. SACT for GIST version2.1 Page 4 of 10

5 4.1.3 Staging of Pancreatic NET. Patients with low grade (WHO grade 1 or 2) pancreatic NET should be staged by CT scanning, somatostatin receptor scintigraphy and by MIBG scan. EUS may be recommended to assess local factors which may affect resectability if the disease appears to be localised to the pancreas. The majority of patients with high grade pancreatic NET do not have somatostatin receptor positive disease and it is acceptable to omit MIBG scanning and somatostatin receptor scintigraphy for this group of patients. 4.2 High Grade Pancreatic NET These are highly malignant chemosensitive tumours and patients with these should be offered first line systemic platinum based cytotoxic chemotherapy for 4-6 cycles (4). There is no universally accepted standard of care for second line treatment of high grade pancreatic NET. Choice of second line therapy will depend on the interval between completion of first line therapy and disease progression and on performance status and co-morbidity. It may be appropriate to offer re-challenge with further platinum based chemotherapy for p atients with a long (>6 month) progression free interval following first line platinum based chemotherapy. Other treatment options in second line therapy include; irinotecan based chemotherapy regimens, paclitaxel, docetaxel, topotecan and gemcitabine (NANETS guideline 2010) Patient Selection ECOG PS 0-2 Adequate hepatic and renal function Adequate bone marrow function Treatment Regimen First Line Cisplatin/Etoposide or Carboplatin/Etoposide or single agent carboplatin depending on patients age, renal function and performance status. Cisplatin/Etoposide Cisplatin 80mg/m 2 IV day 1 Etoposide 100mg/m 2 IV days 1 to 3 SACT for GIST version2.1 Page 5 of 10

6 Cycle repeated every 21 days Disease response monitored by CT after Cycle 3and after cycle 6 To be given for up to 6 cycles. Carboplatin/Etoposide Carboplatin AUC x 5 IV Day 1 Etoposide 100mg/m 2 IV Days 1 to 3 Cycle repeated every 21 days for up to 6 cycles Disease to be monitored by CT scan after cycles 3 and 6 Single agent Carboplatin Carboplatin AUC x 5 IV day 1 Cycle to be repeated every 21 days CT to assess response after cycles 3 and 6. Second Line There is no universally accepted standard of care for second line treatment of high grade pancreatic NET. In patients who are fit enough to consider second line treatment the choice of treatment will depend on progression free interval following first line chemotherapy, performance status and co-morbidity. The 2016 ENETS guidelines recommend the use of an iriontecan based regimen in patients where re-challenge with platinum etoposide is felt to be inappropriate. IMDG Irinotecan 180mg/m 2, IV day 1 fluorouracil 400 mg/m 2 and calcium folinate 200mg/m 2, IV day 1 fluorouracil 2400 mg/m 2 (48 hour infusion) on day 1 Cycle to be repeated every 14 days for up to 12 cycles SACT for GIST version2.1 Page 6 of 10

7 4.3 Systemic Therapy for Advanced Well Differentiated Pancreatic NET There is evidence to support the use of chemotherapy, biological therapy and hormone therapy in these patients. Patients with a low Ki67 labelling index, a syndrome related to tumour hormone production and indolent disease may be treated in the first instance with somatostatin analogue (SSA) therapy, particularly in those with functioning pancreatic NET and a syndrome related to hormone secretion. This approach has been confirmed in the CLARINET trial. The two recent RCTs, assessing the targeted agents sunitinib and everolimus, are the first and only published studies to documented an improvement in PFS compared with BSC/placebo. Both studies had a similar design: selection of a homogeneous patient subgroup (pathologically-confirmed well-differentiated pancreatic NET with evidence of disease progression), use of a double-blind placebo-controlled design using a robust oncological end-point (PFS, by RECIST) and ability of patients to cross over from placebo to active drug on disease progression. Sunitinib demonstrated an improved PFS of 11.4 vs. 5.5 months (vs. placebo, HR 0.42 ( ); p< vs. placebo) (ref) and everolimus also had a similar magnitude of effect with an improved PFS of 11.0 vs. 4.6 months (vs. placebo, HR 0.35 ( ); p<0.001) (ref). Although neither of the targeted agents reported a significantly improved OS compared with placebo (5,6), this endpoint could not be reliably assessed due to extensive crossover from placebo to active treatment (69% of patients in the sunitinib trial and 74% of patients in the everolimus trial) (5,6).. An exploratory analysis attempting to correct for such patient crossover suggests an improved OS for sunitinib compared with placebo (7). Those with disease progression despite SSA therapy whose tumours have a low Ki67 labelling index may be offered targeted therapy with either sunitinib (on a cost per case basis following positive SMC recommendation) or everolimus (on a cost per case basis following a positive SMC recommendation). For those with a higher Ki67 labelling index or with rapid disease progression despite a low Ki67 labelling index, treatment with systemic chemotherapy may be offered. For more than three decades, a combination of streptozotocin plus 5-FU or doxorubicin has been the gold standard for treatment of different types of endocrine pancreatic tumors. Early data indicated objective tumour responses in up to 60% of the patients (8). More recent studies using MRI/CT evaluation have reduced the objective tumor responses down to 16 30% (9-12). More recently, phase II trials of capecitabine and temozolomide have demonstrated a response rate in excess of 50% with a median time to progression of > 18 months in these patients (13). Systemic chemotherapy for patients with well differentiated pancreatic NET will be with either temolzolamide and SACT for GIST version2.1 Page 7 of 10

8 capecitabine or with streptozocin/5fu. In general the use of Temozolomide/Capecitabine is preferred in Northern Ireland as this is an oral chemotherapy regimen and more suited to patients who have a distance to travel to the Cancer Centre for treatment. Somatostatin Analogue Therapy Somatuline (Lanreotide) Autogel Lanreotide autogel 120 mg by S/C injection every 28 days. This is usually administered on a shared care basis with GPs Sandostatin LAR Sandostatin LAR 30 mg every 28 days by deep IM injection This is usually administered on a shared care basis with GPs Temozolomide/Capecitabine Capecitabine 750mg/m 2 orally bd on days 1 to 14 Temozolomide 200mg/m 2 orally once daily on days 10 to 14 Cycle repeated every 28 days. Follow Up Monitoring by CT scan every 12 weeks Tumour markers fasting gut hormone profile every 12 weeks (only if abnormal at start of treatment), Chromogranin A every 4 weeks. Sunitinib 37.5 mg/day orally for 6 weeks Cycle repeated every 6 weeks Clinical Review in first cycle after 3 weeks thereafter reviewed every 6 weeks. Follow Up CT scan every 12 weeks Fasting gut hormone profile every 12 weeks (only if abnormal at start of treatment, Chromogranin A every 6 weeks Monitoring of TFT prior to treatment and every 12 weeks on treatment. SACT for GIST version2.1 Page 8 of 10

9 Everolimus 10mg/day orally for 4 weeks Cycle repeated every 4 weeks Follow Up CT scan every 12 weeks Fasting gut hormone profile every 12 weeks (only if abnormal at start of treatment, Chromogranin A every 4 weeks) 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 the intranet for use by all doctors, nurses and pharmacists involved in all stages of SACT assessment and delivery in patients with Pancreatic NET. 6.0 MONITORING Use of these guidelines will be monitored using audit. 7.0 EVIDENCE BASE / REFERENCES 1) Eriksson B, Arnberg H, Lindgren PG et al. Neuroendocrine pancreatic tumors: clinical presentation, biochemical and histopathological findings in 84 patients. J Intern Med 1990; 228: ) Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97: ) Mignon M: Natural history of neuroendocrine enteropancreatic tumors. Digestion 2000; 62(suppl 1): ) Nilsson O, Van Cutsem E, Della Fave G, et al. Poorly Differentiated Carcinomas of the Foregut (Gastric, Duodenal and Pancreatic): ENETS guidelines. Neuroendocrinology 2006; 84: ) Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: ) Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: ) Faivre S, Niccoli P, Raoul JL et al... Updated Overall Survival (OS) Analysis From A Phase III Study Of Sunitinib Vs Placebo In Patients (Pts) SACT for GIST version2.1 Page 9 of 10

10 With Advanced, Unresectable Pancreatic Neuroendocrine Tumor (Net). ESMO; th September-2nd October; Vienna, Austria. 8) Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozotocinfluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992; 326: ) Ducreux M, Ruszniewski P, Chayvialle JA, et al. The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors. Am J Gastroenterol 2000; 95: ) Fjallskog ML, Granberg DP, Welin SL, et al. Treatment with cisplatin and etoposide in patients with neuroendocrine tumors. Cancer 2001; 92: ) Pavel ME, Baum U, Hahn EG, Hensen J. Doxorubicin and streptozotocin after failed biotherapy of neuroendocrine tumors. Int J Gastrointest Cancer 2005; 35: ) Sun W, Lipsitz S, Catalano P, et al. Phase II/III study of doxorubicin with fluorouracil compared with streptozotocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 2005; 23: ) Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011; 117: CONSULTATION PROCESS GI oncologists group 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 GIST version2.1 Page 10 of 10