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Concomitant 177Lu-DOTATATE and capecitabine therapy in malignant paragangliomas.

ABSTRACT: BACKGROUND:The role of concomitant peptide receptor radionuclide therapy (PRRT) and capecitabine therapy has shown benefit in gastroenteropancreatic neuroendocrine tumors. However, data reporting its role in paraganglioma (PGL) patients is lacking. The aim of this study was to evaluate the role of combined capecitabine and 177Lu-DOTATATE in malignant PGL patients. METHODS:In this retrospective, single-institutional, single-arm, observational study, data of consecutive advanced stage PGL patients treated with concomitant 177Lu-DOTATATE-capecitabine therapy, between July 2009 and March 2017, were collected and analyzed. RESULTS:Twenty-five PGL patients received an average dose of 22.86?±?9.54 (14.43-50) GBq 177Lu-DOTATATE and 1250?mg/m2 capecitabine from days 0 to 14, commencing on the morning of PRRT. The median overall survival (OS) was not attained in this patient cohort; however, the median PFS was 32?months. Morphological response according to RECIST 1.1 criteria was achieved in 28% (7/25) patients. Biochemical response with >?50% reduction in chromogranin A levels was observed in 28% of the patients. CONCLUSIONS:Our data confirm that 177Lu-DOTATATE-capecitabine therapy is effective in achieving an objective response in 28% and symptomatic response in 43% patients. In comparison to published PRRT monotherapy outcomes in PGL, we did not observe any great advantage of concomitant therapy; however, it could be due to under-powered study. We recommend a large randomized trial to prove or disprove the utility of capecitabine as a radiosensitizer for PRRT in PGL patients.

SUBMITTER: Yadav MP

PROVIDER: S-EPMC6365580 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Concomitant <sup>177</sup>Lu-DOTATATE and capecitabine therapy in malignant paragangliomas.

Yadav Madhav Prasad MP Ballal Sanjana S Bal Chandrasekhar C

EJNMMI research 20190206 1

<h4>Background</h4>The role of concomitant peptide receptor radionuclide therapy (PRRT) and capecitabine therapy has shown benefit in gastroenteropancreatic neuroendocrine tumors. However, data reporting its role in paraganglioma (PGL) patients is lacking. The aim of this study was to evaluate the role of combined capecitabine and <sup>177</sup>Lu-DOTATATE in malignant PGL patients.<h4>Methods</h4>In this retrospective, single-institutional, single-arm, observational study, data of consecutive a ...[more]

PMID: 30725219

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Project description:177Lu‑DOTATATE was recently approved for the treatment of somatostatin receptor (SSTR)‑positive neuroendocrine tumors (NETs). However, despite impressive response rates, complete responses are rare. Heat shock protein 90 (HSP90) inhibitors have been suggested as suitable therapeutic agents for NETs, as well as a potential radiosensitizers. Consequently, the aim of this study was to investigate whether the HSP90‑inhibitor onalespib could reduce NET cell growth and act as a radiosensitizer when used in combination with 177Lu‑DOTATATE. The NET cell lines BON, NCI‑H727 and NCI‑H460, were first characterized with regards to 177Lu‑DOTATATE uptake and sensitivity to onalespib treatment in monolayer cell assays. The growth inhibitory effects of the monotherapies and combination treatments were then examined in three‑dimensional multicellular tumor spheroids. Lastly, the molecular effects of the treatments were assessed. 177Lu‑DOTATATE uptake was observed in the BON and NCI‑H727 cells, while the NCI‑H460 cells exhibited no detectable uptake. Accordingly, 177Lu‑DOTATATE reduced the growth of BON and NCI‑H727 spheroids, while no effect was observed in the NCI‑H460 spheroids. Onalespib reduced cell viability and spheroid growth in all three cell lines. Furthermore, the combination of onalespib and 177Lu‑DOTATATE exerted synergistic therapeutic effects on the BON and NCI‑H727 spheroids. Western blot analysis of BON spheroids revealed the downregulation of epidermal growth factor receptor (EGFR) and the upregulation of γ H2A histone family member X (γH2AX) following combined treatment with onalespib and 177Lu‑DOTATATE. Moreover, flow cytometric analyses revealed a two‑fold increase in caspase 3/7 activity in the combination group. In conclusion, the findings of this study demonstrate that onalespib exerts antitumorigenic effects on NET cells and may thus be a feasible treatment option for NETs. Furthermore, onalespib was able to synergistically potentiate 177Lu‑DOTATATE treatment in a SSTR‑specific manner. The radiosensitizing mechanisms of onalespib involved the downregulation of EGFR expression and the induction of apoptosis. Consequently, the combination of onalespib and 177Lu‑DOTATATE may prove to be a promising strategy with which to improve therapeutic responses in patients with NETs. Further studies investigating this strategy in vivo regarding the therapeutic effects and potential toxicities are warranted to expand these promising findings.

Project description:BACKGROUND:Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS:We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS:At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS:Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Project description:PurposeIn this study, we aim to evaluate the efficacy and safety of 225AC-DOTATATE targeted alpha therapy in advanced-stage paragangliomas (PGLs).MethodsNine (6 males and 3 females) consecutive patients with histologically proven PGLs were treated with 225Ac-DOTATATE targeted alpha therapy (TAT) and concomitant radiosensitizer, capecitabine, at 8-weekly intervals up to a cumulative activity of ~ 74 MBq. The primary endpoint included evaluating therapy response and disease control rate (DCR) using the RECIST 1.1 criteria. Additional secondary endpoints comprised clinical response assessment using EORTC QLQ-H&N35 questionnaire, Karnofsky Performance Scale (KPS), Eastern Cooperative Oncology Group performance status (ECOG), analgesic score (AS), dose alterations of anti-hypertensive drugs (anti-HTN), and the safety and side-effect profile evaluation as per CTCAE criteria version 5.0.ResultsFollowing 225Ac-DOTATATE treatment, morphological response revealed partial response in 50%, stable disease in 37.5%, and disease progression in 12.5%, with a DCR of 87.5%. Similarly, the symptomatic response was remarkable, and anti-HTN drugs were stopped in 25% and reduced in 37.5%. Another significant finding in our study revealed a morphologic DCR of 66.6% (2/3) in patients who failed previous lutetium-177 peptide receptor radionuclide therapy (177Lu-PRRT). Regarding the KPS, ECOG, and AS performance scores, a notable improvement was observed post-225Ac-DOTATATE treatment. The QLQ-H&N35 symptom scores evaluated in seven H&N PGL patients showed significant improvement in all aspects. No improvement in sexual function was noted (P = 0.3559). Despite the significant reduction in the analgesic score post-treatment (P = 0.0031), the QLQ-H&N35 revealed only marginal significance concerning the intake of pain killers (P = 0.1723). No grade III/IV hematological, renal, and hepatological toxicities were noted.ConclusionThe evidence from this study suggests 225Ac-DOTATATE therapy is effective and safe in the treatment of advanced-stage PGLs and also reports a clear benefit even in patient's refractory to the previous 177Lu-PRRT.

Dataset Information

Concomitant 177Lu-DOTATATE and capecitabine therapy in malignant paragangliomas.

Publications

Concomitant <sup>177</sup>Lu-DOTATATE and capecitabine therapy in malignant paragangliomas.

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