Efficacy and safety of aranoza-based therapy in neuroendocrine neoplasms. Prognostic role of O6-methylguanine DNA methyltransferase expression in tumor tissue

Abstract

Aranoza (3-a-L-arabinopyranosyl-1-methyl-nitrosourea) is nitrosourea derivative, as streptozotocin STZ. O6-methylguanine DNA methyltransferase (MGMT) is an enzyme involved in chemotherapy resistance to alkalyting agents. Material and methods. There were observed 117patients with neuroendocrine neoplasms (NENs) received Aranoza-based therapy. They included 52 cases with pancreatic neuroendocrine tumors (P-NETs), 52 patients with non-pancreatic (notP-NETs, 13 NET patients with metastases without revealed primary tumor focus). There was investigated the radiologic response to the treatment according to Response Evaluation Criteria In Solid Tumors (RECIST) Score, version 1.0), biochemical response, median progression-free survival (PFS) by Kaplan-Meier estimator), toxicity (according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0) and the impact of MGMT expression (immunohistochemistry method) in tumor tissue on the efficacy of the treatment. Results. Objective response rate (ORR) in PNET cases accounted for 39% (20/52) whereas in nonP-NETpatients - 12% (6/52) (p = 0.0032). Median PFS accounted for 15.3 months in PNET patients and 16.6 months in non-PNET cases (p = 0.78). The most common types of the toxicity grade III-IV included thrombocytopenia (17from 871 courses) and neutropenia (11 from 871 courses). In samples of the tumor tissue the lack of MGMT expression was observed in 29 out of 35 P-NET cases, 12 out of 31 non-PNET cases (p = 0,0006). Objective response was recorded in 20 of 44 patients with MGMT-deficient tumors and in 1 out of 27patients with MGMT intact tumors (p = 0.0001). In the lack and presence of the MGMT expression in the tumor tissue median PFS accounted for 20.6 months and 14.4 months correspondingly (p = 0,022). Conclusion. Aranoza-based therapy demonstrated an antitumor activity and good safety profile in NENpatientss. MGMT deficiency in PNETs was more common than in non-PNETs and explained the susceptibility of some PNETs to treatment.

Full Text

Restricted Access

About the authors

Svetlana A. Polozkova

N.N. Blokhin Russian Cancer Research Center

Email: elevana@list.ru
MD, Clinical Postgraduate of the Department of Chemotherapy Moscow, 115478, Russian Federation

V. A Gorbunova

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

V. V Delektorskaya

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

N. F Orel

N.N. Blokhin Russian Cancer Research Center; Russian Medical Academy for Postgraduate Education

Moscow, 115478, Russian Federation

N. A Kozlov

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

A. E Kuzminov

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

A. A Markovich

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

A. S Odintsova

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

G. S Emelyanova

A.I. Evdokimov Moscow State University of Medicine and Dentistry

Moscow, 127473, Russian Federation

E. V Stepanova

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

A. A Kuznetsova

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

References

  1. Kulke M., Siu L., Tepper J., Fisher G., Jaffe D., Haller D. et al. Future directions in the treatment of neuroendocrine tumors: Consensus report of the National Cancer Institute, Neuroendocrine Tumor Clinical Trials Planning Meeting. J. Clin. Oncol. 2011; 29 (7): 934-43.
  2. Fjallskog M., Janson E., Falkmer U. et al. Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors. Neuroendocrinology. 2008; 88: 53-8.
  3. Kouvaraki M., Ajani J., Hoff P., Wolff R., Evans D., Lozano R. et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced metastatic pancreatic endocrine carcinomas. J. Clin. Oncol. 2004; 22(23): 4762-71.
  4. Sarker D., Williams M., Hochhauser D. et al. 5-Fluorouracil, cisplatin and streptozocin (FCiSt): an effective new regimen for advanced pancreatic neuroendocrine tumours. In: ASCO Gastroin-testinal Cancers Symposium. 2004: Abstr. 100.
  5. Turner N., Strauss S., Sarker D. Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumors. Br. J. Cancer. 2010; 102: 1106-12.
  6. Walter T., Bruneton D., Cassier P. et al. Evaluation of the combination 5-Fluorouracil, Dacarbazine, and Epirubicin in patients with advanced well-differentiated neuroendocrine tumors. Clin. Colorect. Cancer. 2010; 9(4): 248-54.
  7. Ekeblad S., Sundin A., Janson E. et al. Temozolomideas monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin. Cancer Res. 2007; 13: 2986-91.
  8. Saif M., Kaley K., Brennan M. et al. A retrospective study of capecitabine/temozolomide (CAPTEM) regimen in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs) after failing previous therapy. Journal of Pancreas. 2013; 14(5): 498-501.
  9. Crona J., Fanola I., Lindholm D. et al. Effect of temozolomide in patients with metastatic bronchial carcinoids. Neuroendocrinology. 2013; 98(2): 151-5.
  10. Fine R., Gulati A., Tsushima D. et al. Prospective phase II study of capecitabine and temozolomide (CAPTEM) for progressive, moderately, and well-differentiated metastatic neuroendocrine tumors. J. Clin. Oncol. 2014; 32: Abstr. 179.
  11. Chan J., Stuart K., Earle C. et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J. Clin. Oncol. 2012; 30(24): 2963-8.
  12. Mitry E., Baudin E., Ducreux M. et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br. J. Cancer. 1999; 81(8): 1351-5.
  13. Муханов В.И., Платонова Г.Н., Перетолчина Н.М. и др. Новый противоопухолевый препарат Араноза. Химиотерапия опухолей в СССР. 1980; 32: 133-9.
  14. Liu L., Gerson S. Targeted modulation of MGMT: clinical implications. Clin. Cancer Res. 2006; 12: 328-31.
  15. Степанова Е.В., Абрамов М.Е., Барышников А.Ю., Личиницер М.Р. Алкилгуаниналкилтрансфераза как фактор предсказания эффективности режима дакарбазин + цисплатин + нидран у больных метастатической меланомой кожи. Саркомы костей, мягких тканей и опухоли кожи. 2011; (1): 50-4.
  16. Olsen I., Sorensen J., Federspiel B. et al. Temozolomide as second or third line treatment of patients with neuroendocrine carcinomas. Scient. World J. 2012; 2012: 1-4.
  17. Welin S., Sorbye H., Sebjornsen S. et al. Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer. 2011; 117: 4617-22.
  18. Olsen I., Knigge U. et al. Topotecan monotherapy in heavily pretreated patients with progressive advanced stage neuroendocrine carcinomas. J. Canc. 2014; 5(8): 628-32.
  19. Kulke M., Hornick J., Frauenhoffer C. et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomidebased therapy in patients with neuroendocrine tumors. Clin. Cancer Res. 2009; 15(1): 338-45.
  20. Hentic O., Cros J. et al. Methylguanin DNA Methyl Transferase (MGMT) expression predicts response to temozolomide in patients with digestive Neuroendocrine Tumors (NETs). In: 9th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine TumorDise ase. 7-9 march 2012: Abstracts. Copenhagen; 2012.
  21. Muller D., Rinke A., Krug S., Majumder M., Konig A., Gress T. Dacarbazine chemotherapy in pancreatic NET. Pancreatology. 2013; Abstr. O-29.
  22. Eriksson B., Öberg K. Neuroendocrine tumours of the pancreas. Br. J. Surg. 2000; 87(2): 129-31.

Statistics

Views

Abstract: 94

PDF (Russian): 1

Article Metrics

Metrics Loading ...

Refbacks

  • There are currently no refbacks.

Copyright (c) 2016 Eco-Vector



This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies