The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors

Ramirez, Robert A.; Beyer, David T.; Chauhan, Aman; Boudreaux, J. Philip; Wang, Yi-Zarn; Woltering, Eugene A.

doi:10.1634/theoncologist.2015-0470

Cited by 81 publications

(61 citation statements)

References 23 publications

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“…Recently Ramirez et al[51] reported the results of another study reviewing the CAPTEM regimen again but in a wide variety of metastatic NETs. Twenty nine patients were included, small bowel (31%), pancreas (52%), lung (10%), and rectum (7%)[51].…”

Section: Chemotherapy: Past Present and Futurementioning

confidence: 99%

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New therapeutic approaches to metastatic gastroenteropancreatic neuroendocrine tumors: A glimpse into the future

Cidon

2017

WJGO

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Neuroendocrine (NE) gastroenteropancreatic tumors are a heterogeneous group of neoplasias arising from neuroendocrine cells of the embryological gut. Their incidence have increased significantly over the past 3 decades probably due to the improvements in imaging and diagnosis. The recent advances in molecular biology have translated into an expansion of therapeutic approaches to these patients. Somatostatin analogs, which initially were approved for control of hormonal syndromes, have recently been proven to inhibit tumor growth. Several new drugs such as antiangiogenics and others targeting mammalian target of rapamycin pathways have been approved to treat progressive pancreatic neuroendocrine tumors (NETs) although their role in non-pancreatic is still controversial. The treatment of NETs requires a coordinated multidisciplinary approach. The management of localized NETs primarily involves surgical resection followed by surveillance. However, the treatment of unresectable and/or metastatic disease may involve a combination of surgical resection, systemic therapy, and liver-directed therapies with the goal of alleviating symptoms of peptide release and controlling tumor growth. This article will review the current therapeutic strategies for metastatic gastroenteropancreatic NETs and will take a glimpse into the future approaches.

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Section: Chemotherapy: Past Present and Futurementioning

confidence: 99%

“…Twenty nine patients were included, small bowel (31%), pancreas (52%), lung (10%), and rectum (7%)[51]. …”

Section: Chemotherapy: Past Present and Futurementioning

confidence: 99%

New therapeutic approaches to metastatic gastroenteropancreatic neuroendocrine tumors: A glimpse into the future

Cidon

2017

WJGO

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“…In fact, regression and control of the tumor are highly needed and very important in patients with large symptomatic tumors [16][17][18][19]. In recent years, the CAPTEM regimen (capecitabine and temozolomide) has emerged with exceptionally promising objective RR and overall survival duration [13,14].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies suggest that continuous antimetabolite (capecitabine) treatment with a lipophilic methylator (temozolomide) may lead to better control of tumor growth and may be efficacious for NETs [13][14][15][16]. Considering that S-1 is also a fluoropyrimidine antimetabolite agent, we treated metastatic NETs with the STEM regimen.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of the S-1/Temozolomide Regimen in Patients with Metastatic Neuroendocrine Tumors

Zhao

Chi

2017

Neuroendocrinology

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Purpose: Both capecitabine alone and capecitabine in combination with temozolomide have activities against neuroendocrine tumors (NETs). However, the role of S-1 in NETs is still unknown. We performed a study to evaluate the safety and efficacy of the S-1/temozolomide (STEM) regimen in patients with locally advanced or metastatic NETs. Methods: A retrospective review was conducted in 20 patients with locally advanced or metastatic NETs treated with the STEM regimen. Of the patients, 15 (75.00%) had failed 1 or more lines of treatment with somatostatin analogues, sunitinib, everolimus, anlotinib, or other chemotherapy regimens. The patients received S-1 at 40 mg/m² orally twice daily on days 1-14 and temozolomide 200 mg orally once daily on days 10-14 of a 21-day cycle. The patients were followed up for evidence of object response, toxicity, and progression-free survival. Results: Response to treatment was assessed using RECIST 1.1. Eight patients (40.00%) achieved a partial response (PR), and another 8 (40.00%) had stable disease (SD). The clinical benefit rate (PR and SD) was 80.00%. The median progression-free survival was not achieved. Only 1 patient (5.00%) had grade 3 adverse events. Among the patients with NETs of different origins, 4 (40.00%) and 5 (50.00%) with pancreatic NETs attained PR and SD, respectively. Four (40.00%) and 3 patients (30.00%) with nonpancreatic NETs attained PR and SD, respectively. Conclusions: The STEM regimen is exceptionally highly active and well tolerated in patients with locally advanced or metastatic NETs. Even in patients who showed disease progression with previous therapies, it is still highly active. In this 20-patient study, the regimen appeared to be similarly active in pancreatic endocrine tumors and nonpancreatic NETs.

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“…Even the alternative alkylating agent temozolomide, which has been explored clinically for treating NETs including in phase II trials, has resulted in limited therapeutic benefit in carcinoids specifically, as described in the above discussion 13–17 . Clinical challenges surrounding temozolomide and similar cytotoxic drugs are reflected by a study by Ramirez et al who although endorse survival benefits from temozolomide and capecitabine therapy in metastatic NET patients, add that adverse reactions forced dose reductions in 24% of patients 66 . Therefore, translating these treatments into effective and rational therapeutic regimens is challenging, particularly due to the long natural histories of carcinoids making formal treatment comparisons difficult to devise.…”

Section: Discussionmentioning

confidence: 99%

The PARP inhibitor ABT-888 potentiates dacarbazine-induced cell death in carcinoids

et al. 2016

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Monoagent DNA-alkylating chemotherapies like dacarbazine are among a paucity of medical treatments for advanced carcinoid tumors, but are limited by host toxicity and intrinsic chemoresistance through the base excision repair (BER) pathway via poly (ADP-ribose) polymerase (PARP). Hence, inhibitors of PARP may potentiate DNA-damaging agents by blocking BER and DNA restoration. We show that the PARP inhibitor ABT-888 (Veliparib) enhances the cytotoxic effects of dacarbazine in carcinoids. Two human carcinoid cell lines (BON and H727) treated with a combination of ABT-888 and dacarbazine resulted in synergistic growth inhibition signified by combination indices <1 on the Chou-Talalay scale. ABT-888 administered prior to varying dacarbazine doses promoted the suppression of neuroendocrine biomarkers of malignancy ASCL1 and CgA, shown by Western analysis. ATM phosphorylation and p21Waf1/Cip1 activation, indicative of DNA damage, were increased by ABT-888 when combined with dacarbazine treatment, suggesting BER pathway attenuation by ABT-888. PE Annexin V/7-AAD staining and sorting revealed a profound induction of apoptosis following combination treatment, which was further confirmed by increased PARP cleavage. These results demonstrate that ABT-888 synergizes dacarbazine treatment in carcinoids. Therefore, ABT-888 may help treat carcinoids unresponsive or refractory to mainstay therapies.

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The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors

Cited by 81 publications

References 23 publications

New therapeutic approaches to metastatic gastroenteropancreatic neuroendocrine tumors: A glimpse into the future

New therapeutic approaches to metastatic gastroenteropancreatic neuroendocrine tumors: A glimpse into the future

Safety and Efficacy of the S-1/Temozolomide Regimen in Patients with Metastatic Neuroendocrine Tumors

The PARP inhibitor ABT-888 potentiates dacarbazine-induced cell death in carcinoids

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