Therapy of Patients with Neuroendocrine Neoplasia—Evidence-Based Approaches and New Horizons

Bundschuh, Ralph A.; Habacha, Bilêl; Lütje, Susanne; Essler, Markus

doi:10.3390/jcm8091474

Cited by 8 publications

(6 citation statements)

References 46 publications

(49 reference statements)

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“…5,6 Other potential therapies for metastatic NETs include systemic chemotherapy, liverdirected therapy, surgical treatment, and peptide receptor radionuclide therapy (PRRT). 4,[7][8][9] In PRRT, a radionuclide linked to a somatostatin analogue is used, allowing for targeted delivery of radiotherapy to somatostatin receptor-expressing NETs, which represent most NETs. 10,11 The first randomized clinical trial assessing the efficacy of PRRT for treatment of NETs was the Neuroendocrine Tumors Therapy (NETTER-1) trial, which included patients with metastatic, welldifferentiated (ie, World Health Organization [WHO] grade 1 or 2) midgut NETs who had progressed on somatostatin analogue therapy.…”

Section: Introductionmentioning

confidence: 99%

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Laboratory, Clinical, and Survival Outcomes Associated With Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors

et al. 2021

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IMPORTANCE Peptide receptor radionuclide therapy (PRRT) is approved in the US for treatment of gastroenteropancreatic neuroendocrine tumors (NETs), but data on PRRT outcomes within US populations remain scarce. OBJECTIVE To analyze the first 2 years of PRRT implementation at a US-based NET referral center. DESIGN, SETTING, AND PARTICIPANTS This cohort study was conducted using medical records of patients with metastatic NET receiving PRRT from 2018 through 2020 in a NET program at a tertiary referral center. Included patients were those at the center with metastatic NETs who received at least 1 dose of PRRT over the study period. Laboratory toxic effects were assessed using Common Terminology Criteria for Adverse Events version 5.0. Tumor response was determined using Response Evaluation Criteria in Solid Tumors 1.1. Survival analysis was conducted to identify factors associated with progression-free survival (PFS) and overall survival. Data were analyzed from August 2018 through August 2020. EXPOSURES Receiving 4 cycles of lutetium-177-dotatate infusion, separated by 8-week intervals targeted to 7.4 GBq (200 mCi) per dose. MAIN OUTCOMES AND MEASURES Data were compared from before and after PRRT to determine hematologic, liver, and kidney toxic effects and to assess tumor progression and patient survival. RESULTS Among 78 patients receiving at least 1 dose of PRRT, median (interquartile range) age at PRRT initiation was 59.8 (53.5-69.2) years and 39 (50.0%) were men. The most common primary NET sites included small bowel, occurring in 34 patients (43.6%), and pancreas, occurring in 22 patients (28.2%). World Health Organization grade 1 or 2 tumors occurred in 62 patients (79.5%). Among all patients, 56 patients underwent pretreatment with tumor resection (71.8%), 49 patients received nonsomatostatin analogue systemic therapy (62.8%), and 49 patients received liverdirected therapy (62.8%). At least 1 grade 2 or greater toxic effect was found in 47 patients (60.3%). Median PFS was 21.6 months for the study group, was not reached by 22 months for patients with small bowel primary tumors, and was 13.3 months for patients with pancreatic primary tumors. Having a small bowel primary tumor was associated with a lower rate of progression compared with having a pancreatic primary tumor (hazard ratio, 0.19; 95% CI, 0.07-0.55; P = .01). Median overall survival was not reached. CONCLUSIONS AND RELEVANCE This cohort study of patients with metastatic NETs found that PRRT was associated with laboratory-measured toxic effects during treatment for most patients and (continued) Key Points Question What are the clinical outcomes for patients who receive peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs) in US-based populations? Findings In this cohort study of 78 patients who underwent PRRT, the treatment was associated with transient laboratory-measured toxic effects in most patients. Median progression-free survival was significantly increased for patients with small bowel primary tumors compared with p...

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Section: Introductionmentioning

confidence: 99%

“… 5 , 6 Other potential therapies for metastatic NETs include systemic chemotherapy, liver-directed therapy, surgical treatment, and peptide receptor radionuclide therapy (PRRT). 4 , 7 , 8 , 9 …”

Section: Introductionmentioning

confidence: 99%

Laboratory, Clinical, and Survival Outcomes Associated With Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors

et al. 2021

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“…Neuroendocrine tumors (NETs) are rare cancers derived from enterochromaffin cells of the diffuse neuroendocrine system. They are most frequently observed in the gastrointestinal tract and bronchopulmonary system [ 1 , 2 , 3 ]. Surgery is a curative option for localized NETs, but for the majority of the patients, a delayed diagnosis associated with distant metastases necessitates systemic treatment.…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy-Induced Upregulation of Somatostatin Receptor-2 Increases the Uptake and Efficacy of 177Lu-DOTA-Octreotate in Neuroendocrine Tumor Cells

Shah

Merlin

Adant

et al. 2021

Cancers

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The peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for different types of neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination with chemotherapy improves objective response to LuTate in NET patients and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. The NET cell lines with low (BON-1) or relatively high (NCI-H727) SSTR2-expression levels, and non-NET cancer and normal cells were treated with chemotherapeutic drugs and assessed for upregulation of SSTR2. We report that an exposure to low or high doses of drugs, such as temozolomide for 24 h or 5 day results in upregulation of SSTR2 between 3–7 days, increased LuTate uptake and decreased rate of cell proliferation. This effect is at the level of SSTR2-mRNA and is more pronounced in low SSTR2 expressing BON-1 than in high SSTR2 expressing NCI-H727 or non-NET cancer or normal cells. Thus, a properly timed pre-treatment with low-dose chemotherapy could not only improve therapeutic efficacy of LuTate in NET patients who are presently eligible for PRRT, but also allow PRRT to be administered to patients with low SSTR-expressing NETs, who would otherwise not respond to this modality because of insufficient radiation delivery.

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“…Radiotherapy, namely PRRT, has emerged as the next-generation treatment for GEP-NET patients [44,45]. Here, we tested the hypothesis that combination of a PI3K/mTOR inhibitor with radiotherapy may enhance therapeutic effects in GEP-NETs.…”

Section: Enhanced Radiosensitization Of Gep-net Cells Via Schedule Dementioning

confidence: 99%

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors

Chow

Johnson

Chauhan

et al. 2021

Cells

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Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)). Better treatment options are needed to improve disease regression and patient survival. The purpose of this study was to examine a new treatment strategy by combining PI3K/mTOR dual inhibition and radiotherapy. First, we assessed the efficacy of two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, to inhibit pAkt and increase apoptosis in NET cell lines (BON and QGP-1) and patient-derived tumor spheroids as single agents or combined with radiotherapy (XRT). Treatment with PF-04691502 decreased pAkt (Ser473) expression for up to 72 h compared with the control; in contrast, decreased pAkt expression was noted for less than 24 h with PKI-402. Simultaneous treatment with PF-04691502 and XRT did not induce apoptosis in NET cells; however, the addition of PF-04691502 48 h after XRT significantly increased apoptosis compared to PF-04691502 or XRT treatment alone. Our results demonstrate that schedule-dependent administration of a PI3K/mTOR inhibitor, combined with XRT, can enhance cytotoxicity by promoting the radiosensitivity of NET cells. Moreover, our findings suggest that radiotherapy, in combination with timed PI3K/mTOR inhibition, may be a promising therapeutic regimen for patients with GEP-NET.

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Therapy of Patients with Neuroendocrine Neoplasia—Evidence-Based Approaches and New Horizons

Cited by 8 publications

References 46 publications

Laboratory, Clinical, and Survival Outcomes Associated With Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors

Laboratory, Clinical, and Survival Outcomes Associated With Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors

Chemotherapy-Induced Upregulation of Somatostatin Receptor-2 Increases the Uptake and Efficacy of 177Lu-DOTA-Octreotate in Neuroendocrine Tumor Cells

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors

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