Capecitabine and temozolomide combination for treatment of high-grade, well-differentiated neuroendocrine tumour and poorly-differentiated neuroendocrine carcinoma — retrospective analysis
Abstract
Introduction: Many retrospective studies have confirmed that capecitabine combined with temozolomide is effective in neuroendocrine neoplasms. Most of the studies focused on grade 1 and grade 2 neuroendocrine tumours, mainly of pancreatic origin. There are limited data regarding the efficacy capecitabine with temozolomide in grade 3 neuroendocrine tumours. The new World Health Organisation 2017 classification distinguished well-differentiated grade 3 neuroendocrine tumours from poorly differentiated grade 3 neuroendocrine carcinomas. Treatment options for grade 3 neuroendocrine neoplasms are limited, and the overall prognosis is better in the subgroup of patients with grade 3 neuroendocrine tumours.
Material and methods: It was a retrospective study in the population of patients with diagnosed grade 3 neuroendocrine neoplasms of different origin treated with capecitabine and temozolomide. Data on clinical and demographic characteristics of the population were collected from four Polish clinical centres. This study aimed to evaluate response and survival parameters and compare outcomes of treatment of neuroendocrine tumours and carcinomas.
Results: The study included 32 patients with grade 3 neuroendocrine tumours treated with capecitabine and temozolomide. The disease control rate was twice as high in the group of patient with neuroendocrine tumours in comparison to carcinomas (70 vs. 30%). The progression-free survival for patients with neuroendocrine tumours was 15.3 months (95% CI: 3.9–30.4), and for patients with neuroendocrine carcinomas it was 3.3 months (95% CI: 2.5–7.1). Median overall survival was 22 months (95% CI: 11.8–22.0) and 4.6 months (95% CI: 2.2–5.9) for patients with tumours and carcinomas, respectively. The treatment regimen was generally well tolerated.
Conclusions: The combination of capecitabine and temozolomide is an effective treatment for patients with grade 3 neuroendocrine tumours with Ki-67 index ranging between 20 and 54%. The treatment did not overcome the aggressive character of neuroendocrine carcinomas and resulted in low response and survival outcomes in comparison to those achieved in tumour therapy.
Keywords: capecitabinegrade 3 neuroendocrine neoplasmsneuroendocrine carcinomaneuroendocrine tumourtemozolomide
References
- Klöppel G, Couvelard A, Hruban RH. Neoplasms of the neuroendocrine pancreas. WHO Classification of Tumours of Endocrine Organs. 4th ed. International Agency for Research on Cancer, Lyon 2017: 210–239.
- Kos-Kudła B, Blicharz-Dorniak J, Strzelczyk J, et al. Consensus Conference, Polish Network of Neuroendocrine Tumours. Diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours). Endokrynol Pol. 2013; 64(6): 418–443.
- Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, et al. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol. 2010; 21(9): 1794–1803.
- Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015; 39(5): 683–690.
- Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013; 24(1): 152–160.
- Garcia-Carbonero R, Sorbye H, Baudin E, et al. Vienna Consensus Conference participants. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. Neuroendocrinology. 2016; 103(2): 186–194.
- Rinke A, Gress TM. Neuroendocrine Cancer, Therapeutic Strategies in G3 Cancers. Digestion. 2017; 95(2): 109–114.
- Crespo G, Jiménez-Fonseca P, Custodio A, et al. Capecitabine and temozolomide in grade 1/2 neuroendocrine tumors: a Spanish multicenter experience. Future Oncol. 2017; 13(7): 615–624.
- Cives M, Ghayouri M, Morse B, et al. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016; 23(9): 759–767.
- Chauhan A, Farooqui Z, Murray LeA, et al. Capecitabine and Temozolomide in Neuroendocrine Tumor of Unknown Primary. J Oncol. 2018; 2018: 3519247.
- Owen DH, Alexander AJ, Konda B, et al. Combination therapy with capecitabine and temozolomide in patients with low and high grade neuroendocrine tumors, with an exploratory analysis of O-methylguanine DNA methyltransferase as a biomarker for response. Oncotarget. 2017; 8(61): 104046–104056.
- Ramirez RA, Beyer DT, Chauhan A, et al. The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors. Oncologist. 2016; 21(6): 671–675.
- Mizuno Y, Kudo A, Akashi T, et al. Sunitinib shrinks NET-G3 pancreatic neuroendocrine neoplasms. J Cancer Res Clin Oncol. 2018; 144(6): 1155–1163.
- National Cancer Institute: Protocol Development | Adverse Events/CTCAE. National Cancer Institute at the National Institutes of Health; c2018. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. 2010 Jun 14. Nhttps://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_4.03.xlsx (2019 Jan 29).
- Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2): 228–247.
- Moertel CG, Kvols LK, O'Connell MJ, et al. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer. 1991; 68(2): 227–232.
- Mitry E, Baudin E, Ducreux M, et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer. 1999; 81(8): 1351–1355.
- Fjällskog ML, Granberg DP, Welin SL, et al. Treatment with cisplatin and etoposide in patients with neuroendocrine tumors. Cancer. 2001; 92(5): 1101–1107.
- Hainsworth JD, Spigel DR, Litchy S, et al. Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. J Clin Oncol. 2006; 24(22): 3548–3554.
- Pavel M, Baudin E, Couvelard A, et al. Barcelona Consensus Conference participants. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012; 95(2): 157–176.
- Delle Fave G, O'Toole D, Sundin A, et al. Vienna Consensus Conference participants. ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms. Neuroendocrinology. 2016; 103(2): 119–124.
- Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992; 326(8): 519–523.
- Okusaka T, Ueno H, Morizane C, et al. Cytotoxic chemotherapy for pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci. 2015; 22(8): 628–633.
- U.S. National Library of Medicine. NCT01824875. Temozolomide With or Without Capecitabine in Treating Patients With Advanced Pancreatic Neuroendocrine Tumours. https://clinicaltrials.gov/ (2019 Feb 03).
- Kunz P, Catalano P, Nimeiri H, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN Cancer Research Group (E2211). J Clin Oncol. 2018; 36(15(suppl)): 4004–4004.
- 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(2): 268–275.
- Peixoto RD, Noonan KL, Pavlovich P, et al. Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs. J Gastrointest Oncol. 2014; 5(4): 247–252.
- Quinn AM, Chaturvedi A, Nonaka D. High-grade Neuroendocrine Carcinoma of the Lung With Carcinoid Morphology: A Study of 12 Cases. Am J Surg Pathol. 2017; 41(2): 263–270.
- Lu Y, Zhao Z, Wang Ji, et al. Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: A meta-analysis. Medicine (Baltimore). 2018; 97(41): e12784.
- Mizuno Y, Kudo A, Akashi T, et al. Sunitinib shrinks NET-G3 pancreatic neuroendocrine neoplasms. J Cancer Res Clin Oncol. 2018; 144(6): 1155–1163.
- Heetfeld M, Chougnet CN, Olsen IH, et al. other Knowledge Network members. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015; 22(4): 657–664.
