Abstract
Background
Streptozocin (STZ) administration with or without other cytotoxic drugs remains a crucial chemotherapy for patients with advanced pancreatic neuroendocrine neoplasms (Pan-NENs). However, the therapeutic effects of combination treatment with weekly STZ and oral S-1 therapy (STS1) remain unknown. Therefore, the aim of this study was to evaluate the safety and clinical feasibility of STS1.
Methods
Twenty of 243 Pan-NEN patients were included in this retrospective study, all of whom had received STS1 for unresectable or distant metastatic diseases from November 2015 to January 2019. The maximum tumor shrinkage rate, time course of the tumor shrinkage rate, prognosis (progression-free survival and overall survival), and adverse events were evaluated.
Results
The median age of the patients was 61.5 years and the median tumor size was 35 mm. The number of NET-G1, NET-G2, NET-G3, and NEC-G3 patients was 3, 13, 3, and 1, respectively. The median Ki-67 index and mitoses were 10.2% and 2/10 high-power fields, respectively. The overall objective response rate and disease control rate were 30% and 90%, respectively. The median maximum tumor reduction rate was 19%. The Ki-67 index and tumor size did not influence the tumor shrinkage rate. Progression-free survival after STS1 treatment was 19 months with no significant difference between NET-G1/G2 and NET-G3/NEC-G3 patients (p = 0.4). There was one case each of grade 3/4 toxicity, including general fatigue, hyperglycemia, and renal dysfunction. No serious myelosuppressive events are manifested.
Conclusions
STS1 treatment is an effective and safe therapeutic option for patients with advanced Pan-NEN.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Antonodimitrakis PC, Sundin A, Wassberg C, Granberg D, Skogseid B, Eriksson B (2016) Streptozocin and 5-fluorouracil for the treatment of pancreatic neuroendocrine tumors: efficacy, prognostic factors and toxicity. Neuroendocrinology 103:345–353. https://doi.org/10.1159/000439086
Boku N et al (2009) Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study Lancet Oncol 10:1063–1069. https://doi.org/10.1016/S1470-2045(09)70259-1
Bolzan AD, Bianchi MS (2002) Genotoxicity of streptozotocin. Mutat Res 512:121–134
Dilz LM et al (2015) Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours Eur J Cancer 51:1253–1262. https://doi.org/10.1016/j.ejca.2015.04.005
Frilling A et al (2014) Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol 15:e8–21. https://doi.org/10.1016/S1470-2045(13)70362-0
Frilling A, Clift AK (2015) Therapeutic strategies for neuroendocrine liver metastases. Cancer 121:1172–1186. https://doi.org/10.1002/cncr.28760
Halfdanarson TR, Rabe KG, Rubin J, Petersen GM (2008) Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol 19:1727–1733. https://doi.org/10.1093/annonc/mdn351
Hauso O, Gustafsson BI, Kidd M, Waldum HL, Drozdov I, Chan AK et al (2008) Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer 113:2655–2664. https://doi.org/10.1002/cncr.23883
Ito T et al (2010) Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan. J Gastroenterol 45:234–243. https://doi.org/10.1007/s00535-009-0194-8
Koizumi W et al. (2008) S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9:215–221. https://doi.org/10.1016/S1470-2045(08)70035-4
Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC (2004) Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22:4762–4771. https://doi.org/10.1200/JCO.2004.04.024
Krug S et al (2015) Streptozocin-based chemotherapy in patients with advanced neuroendocrine neoplasms-predictive and prognostic markers for treatment stratification. PLoS One 10:e0143822. https://doi.org/10.1371/journal.pone.0143822
Mizuno Y et al (2018) Sunitinib shrinks NET-G3 pancreatic neuroendocrine neoplasms. J Cancer Res Clin Oncol 144:1155–1163. https://doi.org/10.1007/s00432-018-2636-2
Moertel CG, Hanley JA, Johnson LA (1980) Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 303:1189–1194. https://doi.org/10.1056/NEJM198011203032101
Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D (1992) Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 326:519–523. https://doi.org/10.1056/NEJM199202203260804
Muro K et al (2010) Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol 11:853–860. https://doi.org/10.1016/S1470-2045(10)70181-9
Panzuto F et al (2011) Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol 29:2372–2377. https://doi.org/10.1200/JCO.2010.33.0688
Pavel M et al (2016) ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 103:172–185. https://doi.org/10.1159/000443167
Raymond E et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513. https://doi.org/10.1056/NEJMoa1003825
Shibuya H et al (2018) Multi-center clinical evaluation of streptozocin-based chemotherapy for advanced pancreatic neuroendocrine tumors in Japan: focus on weekly regimens and monotherapy. Cancer Chemother Pharmacol 82:661–668. https://doi.org/10.1007/s00280-018-3656-y
Shirasaka T et al (1996) Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 56:2602–2606
Turner NC et al (2010) Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours. Br J Cancer 102:1106–1112. https://doi.org/10.1038/sj.bjc.6605618
Yamada Y et al (2013) Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol 14:1278–1286. https://doi.org/10.1016/S1470-2045(13)70490-X
Yao JC et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523. https://doi.org/10.1056/NEJMoa1009290
Yao JC et al (2008) One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063–3072. https://doi.org/10.1200/JCO.2007.15.4377
Acknowledgements
This work was supported by Grant-in-Aid for Scientific Research (C); Grant Number 19K09041.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
None of the authors have personal conflicts of interest associated with the publication of this article.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Ono, H., Kudo, A., Akahoshi, K. et al. Combination of weekly streptozocin and oral S-1 treatment for patients of unresectable or metastatic pancreatic neuroendocrine neoplasms. J Cancer Res Clin Oncol 146, 793–799 (2020). https://doi.org/10.1007/s00432-019-03109-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-019-03109-5