Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors: A Report From the PROMID Study Group

University of Freiburg, Freiburg, Baden-Württemberg, Germany
Journal of Clinical Oncology (Impact Factor: 18.43). 09/2009; 27(28):4656-63. DOI: 10.1200/JCO.2009.22.8510
Source: PubMed


Somatostatin analogs are indicated for symptom control in patients with gastroenteropancreatic neuroendocrine tumors (NETs). The ability of somatostatin analogs to control the growth of well-differentiated metastatic NETs is a matter of debate. We performed a placebo-controlled, double-blind, phase IIIB study in patients with well-differentiated metastatic midgut NETs. The hypothesis was that octreotide LAR prolongs time to tumor progression and survival.
Treatment-naive patients were randomly assigned to either placebo or octreotide LAR 30 mg intramuscularly in monthly intervals until tumor progression or death. The primary efficacy end point was time to tumor progression. Secondary end points were survival time and tumor response. This report is based on 67 tumor progressions and 16 observed deaths in 85 patients at the time of the planned interim analysis.
Median time to tumor progression in the octreotide LAR and placebo groups was 14.3 and 6 months, respectively (hazard ratio [HR] = 0.34; 95% CI, 0.20 to 0.59; P = .000072). After 6 months of treatment, stable disease was observed in 66.7% of patients in the octreotide LAR group and 37.2% of patients in the placebo group. Functionally active and inactive tumors responded similarly. The most favorable effect was observed in patients with low hepatic tumor load and resected primary tumor. Seven and nine deaths were observed in the octreotide LAR and placebo groups, respectively. The HR for overall survival was 0.81 (95% CI, 0.30 to 2.18).
Octreotide LAR significantly lengthens time to tumor progression compared with placebo in patients with functionally active and inactive metastatic midgut NETs. Because of the low number of observed deaths, survival analysis was not confirmatory.

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    • "Both octreotide and lanreotide, which have slightly different binding affinities to SSTR2 and SSTR5 (the most clinically relevant SSTR subtypes), can exert an in vivo anti-proliferative role. Results from a phase III randomised placebocontrolled trial have indicated that long-acting octreotide can significantly prolong the time to tumour progression in patients with a metastatic midgut NET (Rinke et al. 2009) and this has recently been confirmed for intestinal and pancreatic NET patients using lanreotide autogel in the CLARINET study (Caplin et al. 2014). New SSAs such as pasireotide, which binds four of the five SSTR subtypes with a high affinity, have been developed to optimise the activation of SSTRs expressed at GEP-NET cell membranes. "
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    • "Our assumption was that median PFS in the absence of treatment would be approximately 5 months (null hypothesis) whereas a median study PFS of longer than 9 months would indicate that pasireotide had significant activity. These assumptions were based on data sets from several clinical trials, including the placebo arms of the PROMID study (median PFS 6 months) (Rinke et al. 2009), and the RADIANT 3 trial in pNETs (median PFS 4.6 months on local review) (Yao et al. 2011). Also, we did not expect to achieve as long a median PFS as was seen in the treatment arm of the PROMID study (14.3 months) given the more aggressive tumor types eligible for our trial. "
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    • "Similarly, a phase III randomised study in 260 patients with advanced colorectal cancer did not identify a benefit in survival (neither in time to progression nor in overall survival (OS)) in the SSA arm (Goldberg et al. 1995). By contrast, an anti-tumour effect of SSA therapy has been demonstrated in advanced neuroendocrine tumours (NETs) in two large randomised studies both reporting significant and clinically relevant benefits: the PROMID (Rinke et al. 2009) and CLARINET (Caplin 2014) trials. Currently, advanced NETs are the only clinical setting where SSAs can be employed for tumour control outside a clinical trial. "
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