Impact of Therapy Sequence with Alkylating Agents and MGMT Status in Patients with Advanced Neuroendocrine Tumors

Krug, Sebastian; Boch, Michael; Rexin, Peter; Gress, Thomas M.; Michl, Patrick; Rinke, Anja

doi:10.21873/anticanres.11590

Cited by 17 publications

(17 citation statements)

References 37 publications

(46 reference statements)

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“…Nevertheless, previous studies concerning the role of MGMT status in NENs reported contrasting results. In two previous studies [15,19,[29][30][31] no correlation was found between MGMT status and response to TEM. In three other studies [16,18,20], a predictive value was found only in the sub-group of pancreatic NENs.…”

Section: Discussionmentioning

confidence: 91%

Correlation between MGMT promoter methylation and response to temozolomide-based therapy in neuroendocrine neoplasms: an observational retrospective multicenter study

et al. 2017

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Section: Discussionmentioning

confidence: 91%

Correlation between MGMT promoter methylation and response to temozolomide-based therapy in neuroendocrine neoplasms: an observational retrospective multicenter study

et al. 2017

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“…It is important to note that these studies were heterogeneous and often small, with NET of various origins. Nevertheless, the efficacy of DTIC-based chemotherapy was higher in patients with pNET (36–50%) compared to NET from other sites [22, 24, 27, 28, 30]. …”

Section: Discussionmentioning

confidence: 98%

“…This study reported an ORR of 27%, but no results on survival. In addition, other studies exploring DTIC alone reported an ORR of 8–50% (pooled mean, 20%) with limited or no survival data [17-24]. More recently, 5 studies reported an increased efficacy of the 5FU-DTIC-epirubicin combination with an ORR ranging from 17 to 56% (pooled mean, 31%), and a median PFS varying from 5 to 21 months [25-29].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Temozolomide-Capecitabine to 5-Fluorouracile-Dacarbazine in 247 Patients with Advanced Digestive Neuroendocrine Tumors Using Propensity Score Analyses

et al. 2019

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Introduction: Although chemotherapy combining 5-fluorouracil (5FU)-dacarbazine (DTIC) or temozolomide (TEM)-capecitabine (CAP) is extensively used in patients with neuroendocrine tumors (NET), they were never compared. We compared their tolerance and efficacy in advanced NET. Methods: We evaluated the records of consecutive patients with pancreatic or small-intestine advanced NET who received 5FU-DTIC or TEM-CAP between July 2004 and December 2017 in 5 French centers. Tolerance, tumor response and progression-free survival (PFS) were compared. Factors associated with PFS were analyzed using Cox multivariate regression model. To reduce the confounding bias of the nonrandomized design, PFS was compared using propensity score analyses. Results: Ninety-four (5FU-DTIC) patients and 153 (TEM-CAP) patients were included. Pancreatic NET represented 82.3% of cases and 17.1, 61.8 and 10.9% of patients had G1, G2 or G3 NET respectively. Progression at baseline was reported in 92.7% of patients with available data. Grades 3–4 adverse events occurred in 24.7 and 8.5% of TEM-CAP and 5FU-DTIC patients respectively (p = 0.002). The overall response rate was 38.3 and 39.2% respectively (p = 0.596). Median PFS on raw analysis was similar to 5FU-DTIC and TEM-CAP (13.9 vs. 18.3 months, respectively p = 0.86). TEM-CAP was associated with an increased risk of progression on the raw multivariate analysis (hazard ratio [HR] 1.90, 95% CI [1.32–2.73], p = 0.001) and when adjusted on propensity score (HR 1.65, 95% CI [1.18–2.31], p = 0.004). Conclusion: PFS may be longer with 5FU-DTIC than TEM-CAP in patients with advanced NET. Although patients often prefer oral chemotherapy, 5FU-DTIC is a relevant alternative. A randomized comparison is needed to confirm these results.

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“…The following articles were excluded for the following reasons: NENs patients were not included (n = 11); undesired outcomes (n = 6); non-MGMT gene study (n = 4); reviews (n = 2); and study protocol (n = 1). Therefore, 11 studies were included in this meta-analysis [16,17,[19][20][21][22][23][24][25][26][27] (Figure 1 and Table 1). Abbreviations: GI, gastrointestinal; IHC, immunohistochemistry; MSP, methylation-specific polymerase chain reaction; NE, neuroendocrine tumours; NEN, neuroendocrine neoplasm; NOS, Newcastle-Ottawa Scale; PDEC, poorly differentiated endocrine carcinoma; PSQ, pyrosequencing.…”

Section: Resultsmentioning

confidence: 99%

Association between MGMT status and response to alkylating agents in patients with neuroendocrine neoplasms: a systematic review and meta-analysis

Tan

2020

Bioscience Reports

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Background: O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA damage reversal repair protein. The influence of MGMT status on alkylating agent sensitivity in patients with neuroendocrine neoplasms (NENs) is controversial. We conducted a meta-analysis to assess the influence of MGMT status on the therapeutic sensitivity of alkylating agents in patients with NENs. Methods: We searched PubMed, EmBase, and Cochrane library public databases through 3 July 2019. The objective response rate (ORR) was the outcome data of interest. Subgroup analysis was performed according based on MGMT methylation and expression of MGMT protein. Results: Eleven studies were included in the meta-analysis. The proportion of patients with NENs that achieved an ORR after alkylating agent treatment was higher in the MGMT-deficient group than the non-deficient group (OR: 5.00; 95% CI: 3.04–8.22; P < 0.001; I2: 3%). Similar results were noted in the MGMT methylation and MGMT protein expression subgroups. Conclusion: Patients with NENs and MGMT methylation or low protein expression had a higher ORR proportion than patients without MGMT methylation or high protein expression. The MGMT status can be used as a biological indicator of the response to alkylating agent treatment in patients with NENs.

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Impact of Therapy Sequence with Alkylating Agents and MGMT Status in Patients with Advanced Neuroendocrine Tumors

Abstract: Upfront chemotherapy with either STZ-based treatment or DTIC monotherapy showed similar efficacy and median TTP rates. In this study, MGMT protein expression assessed by immunohistochemistry did not play an important role as a predictive marker for alkylating agents.

Cited by 17 publications

References 37 publications

Correlation between MGMT promoter methylation and response to temozolomide-based therapy in neuroendocrine neoplasms: an observational retrospective multicenter study

Correlation between MGMT promoter methylation and response to temozolomide-based therapy in neuroendocrine neoplasms: an observational retrospective multicenter study

Comparison of Temozolomide-Capecitabine to 5-Fluorouracile-Dacarbazine in 247 Patients with Advanced Digestive Neuroendocrine Tumors Using Propensity Score Analyses

Association between MGMT status and response to alkylating agents in patients with neuroendocrine neoplasms: a systematic review and meta-analysis

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