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Predictive factors of antiproliferative activity of octreotide LAR as first-line therapy for advanced neuroendocrine tumours.

ABSTRACT: The antiproliferative activity of octreotide LAR in neuroendocrine tumours (NETs) has been demonstrated by small retrospective studies and confirmed by a prospective phase III trial (PROMID). However, there are limited data about the duration and predictors of response. The aim of our retrospective study was to determine the time to radiological progression (TTRP) of disease and the factors that were associated with better response.A total of 254 treatment naïve patients with advanced NETs and positive somatostatin receptor scintigraphy were included. Mean follow-up period was 42 months.The location of primary was in the small bowel in 204, pancreas in 22, lungs in 14, rectum in 7 and unknown in 7 patients. Most tumours were well-differentiated, G1 (58%) and G2 (23%). The majority of patients commenced octreotide LAR due to functional symptoms (57%), radiological progression (10%) or in the presence of asymptomatic and stable disease on the basis of data from the PROMID trial (18.5%). Partial response occurred in 5%. For all patients, the median TTRP was 37 months (95% confidence interval, CI: 32-52 months). There was a statistically significant shorter TTRP in patients with pancreatic tumours, liver metastases and intermediate grade tumours. Extremely raised (>10 times the upper limit of normal) baseline chromogranin A levels were associated with an unfavourable outcome. In contrast, male sex, carcinoid heart disease and initiation of treatment in the presence of stable disease were predictive of a better response. Age, extra-hepatic metastases, presence of mesenteric desmoplasia, previous resection and functional status of the primary tumour did not affect response.The duration of the antiproliferative effect of octreotide LAR seems to be longer than previously reported. This study has identified several predictors of response in a large cohort of patients with NETs on somatostatin analogue therapy.

SUBMITTER: Laskaratos FM

PROVIDER: S-EPMC5129835 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Predictive factors of antiproliferative activity of octreotide LAR as first-line therapy for advanced neuroendocrine tumours.

Laskaratos Faidon-Marios FM Walker Martin M Naik Keval K Maragkoudakis Emmanouil E Oikonomopoulos Nikolaos N Grant Lee L Meyer Tim T Caplin Martyn M Toumpanakis Christos C

British journal of cancer 20161103 11

<h4>Background</h4>The antiproliferative activity of octreotide LAR in neuroendocrine tumours (NETs) has been demonstrated by small retrospective studies and confirmed by a prospective phase III trial (PROMID). However, there are limited data about the duration and predictors of response. The aim of our retrospective study was to determine the time to radiological progression (TTRP) of disease and the factors that were associated with better response.<h4>Methods</h4>A total of 254 treatment naïv ...[more]

PMID: 27811856

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Project description:BACKGROUND:Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials. MATERIALS AND METHODS:This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointestinal NETs (GI-NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin-like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression). RESULTS:Forty-three patients were included in the intent-to-treat analyses. After 12 months of treatment, 62.3% (95% confidence interval [CI] 48%-77%) of patients had not progressed or died. The 24-month PFS rate was 43.6% (95% CI 29%-58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow-up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS. CONCLUSION:The everolimus-octreotide combination provided clinically relevant efficacy in nonfunctioning GI-NETs, similar to the results of RADIANT-2 in functioning setting. IMPLICATIONS FOR PRACTICE:The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting.

Project description:BackgroundIn the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2.Patients and methodsThe RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated.ResultsA total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm.ConclusionNo significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates.Clinical trial numberNCT00412061, www.clinicaltrials.gov.

Project description:This paper details the case of a 77-year-old male with refractory hypoglycaemia due to inoperable metastatic pancreatic neuroendocrine tumour (pNET) co-secreting insulin and gastrin. Multiple medical therapies were trialled with limited success, and we describe the complications experienced by our patient. Somatostatin analogues can ameliorate hypoglycaemia and may have tumour-stabilising effects; however, in our case resulted in paradoxical worsening of hypoglycaemia. This rendered our patient hospital dependent for glycaemic support including continuous dextrose infusion. Although this is a reported adverse effect with initiation of therapy, we describe successful initiation of short-acting octreotide as an inpatient followed by commencement of long-acting octreotide. Hypoglycaemic collapse occurred only after dose titration of long-acting octreotide. We outline the pitfalls of somatostatin analogue therapy and the mechanisms that may contribute to worsening hypoglycaemia. This rare side effect cannot be reliably predicted, necessitating close supervision and glucose monitoring during therapy. Our patient achieved disease stabilisation and gradual resolution of hypoglycaemia with peptide receptor radionuclide therapy (PRRT), an emerging therapeutic option for metastatic neuroendocrine tumours with high efficacy and low toxicity. We present a brief but comprehensive discussion of currently available and novel therapies for insulin secreting pNETs.Hypoglycaemia due to malignant insulin secreting pNET is frequently severe and may be life-threatening despite supportive therapies.Octreotide can ameliorate hypoglycaemia, and may have anti-proliferative and tumour-stabilising effects in malignant pNETs that are surgically unresectable.Paradoxical worsening of hypoglycaemia may occur with octreotide initiation and dose titration, necessitating close supervision and glucose monitoring.PRRT is emerging as a therapeutic option with high efficacy and low toxicity.

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Predictive factors of antiproliferative activity of octreotide LAR as first-line therapy for advanced neuroendocrine tumours.

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Predictive factors of antiproliferative activity of octreotide LAR as first-line therapy for advanced neuroendocrine tumours.

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