Somatostatin analog therapy effectiveness on the progression of polycystic kidney and liver disease: A systematic review and meta-analysis of randomized clinical trials

Background Uncertainty underlies the effectiveness of somatostatin analogues for slowing the progression of polycystic kidney or liver disease. Methods Eligible studies included randomized controlled trials (RCTs) evaluating somatostatin analog as therapy for patients with polycystic kidney disease (PKD) or polycystic liver disease (PLD) compared to placebo or standard therapy. Two reviewers independently screened studies identified from databases (MEDLINE, EMBASE, Cochrane Database), clinical trial registries, and references from pertinent articles and clinical practice guidelines. Outcome measurements were changes in total liver volume (TLV), total kidney volume (TKV), and estimated glomerular filtration rate (eGFR). Results Of 264 nonduplicate studies screened, 10 RCTs met the inclusion criteria. The body of evidence provided estimates warranting moderate confidence. Meta-analysis of 7 RCTs including a total of 652 patients showed that somatostatin analogs are associated with a lower %TLV growth rate compared to control (mean difference, -6.37%; 95% CI -7.90 to -4.84, p<0.00001), and with a lower %TKV growth rate compared to control (mean difference, -3.66%; 95% CI -5.35 to -1.97, p<0.0001). However, it was not associated with a difference in eGFR decline (mean difference, -0.96 mL/min./1.73m2; 95% CI -2.38 to 0.46, p = 0.19). Conclusions Current body of evidence suggests that somatostatin analogs therapy slows the increase rate of TLV and TKV in patients with PKD or PLD compared to control within a 3-year follow-up period. It does not seem to have an effect on the change in eGFR. Somatostatin analogs therapy can be a promising treatment for ADPKD or ADPLD, and we need to continue to research its effectiveness for ADPKD or ADPLD.

Metastatic Malignant Paraganglioma Presenting as a Neck Mass Treated with Radiolabeled Somatostatin Analog

Paragangliomas are rare neuroendocrine tumors that arise from chromaffin-containing tissue. Surgical resection and/or radiation are used for locoregional disease, and reduction of tumor burden with systemic therapy is reserved for metastatic disease. Iobenguane I-131, somatostatin analog (octreotide), and Sunitinib are noncytotoxic options for treatment, while cyclophosphamide, vincristine, and dacarbazine (CVD) and temozolomide are often used as initial chemotherapy options as studies have shown that they offer some tumor response. However, there are no randomized clinical trials demonstrating prolonged survival with the use of chemotherapeutics in metastatic cases. Investigation of alternative therapies that provide survival benefit is thus necessary. We present a case of a 69-year-old female with metastatic malignant paraganglioma presenting as a left parapharyngeal neck mass, which metastasized after surgery, requiring radiation therapy for bony metastasis who was treated with a radioisotope somatostatin analog for disease progression.

The safety and efficacy of PEN-221 somatostatin analog (SSA)-DM1 conjugate in patients (PTS) with advanced GI mid-gut neuroendocrine tumor (NET): Phase 2 results.

4110 Background: PEN-221 is a small molecule drug conjugate composed of a SSTR2 binding somatostatin analog linked to the toxin DM1. PEN-221-001 was a study which assessed the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-221 in well differentiated neuroendocrine tumors (NETs) and small cell lung cancer. Here we present the efficacy outcomes for patients enrolled in the GI mid-gut cohort and the safety data for the entire study. Methods: Pts with advanced, SSTR2+ (by imaging) GI mid-gut NETs were enrolled in this cohort of the study. The primary objective was to determine the safety and efficacy of PEN-221 given intravenously, every (q) 3 weeks in patients with documented radiographic progression within the 6 months prior to enrollment. Patients previously treatment with cytotoxic chemotherapy were excluded. Preliminary efficacy was assessed using RECIST 1.1. A clinically meaningful efficacy result was defined as a Clinical Benefit Rate (CBR) > 75% and a median progression-free survival (mPFS) > 8 months. Results: 32 patients (17M/15F) were enrolled between January 2018 to June 2020 and the data cut-off for this report is July 31, 2020. The first nine patients were treated at the phase 1 determined Maximum Tolerated Dose of 18 mg. After review of the safety, tolerability, and PK data from these pts, the regimen was amended to 8.8 mg/m2 for all subsequent pts to achieve more uniform exposures (AUC) across all pts and reduce toxicity in pts with lower body-surface areas (BSA). The mean number of cycles received by pts in this cohort was 7 (range 1-18), with 5 pts still on treatment at time of data lock. PEN-221 was well tolerated in all pts at the dose of 8.8 mg/m2. The most frequent (≥20% pts) PEN-221 related adverse events of any grade were fatigue (39%), nausea (38%), diarrhea (35%), decreased appetite (30%), infusion reaction (24%), AST/ALT/Alk Phos increase (24%), and peripheral neuropathy (21%). Only 14 (10%) of these events were grade 3 or greater. Grade 3 PEN-221 related adverse events which were reported in 2 or more pts included fatigue (7.6%), ALT/AST/Alk Phos increase (7.6%), and peripheral neuropathy (3%). PEN-221 plasma median t1/2 was ̃4.5 h, with exposures uniform using BSA based dosing. Of the 26 pts who were evaluable for response, 23 (88.5%) had stable disease (SD) reported as their best response with a CBR of 88.5%. Target lesion shrinkage was observed in 10 (38%) patients. The median PFS for this cohort was 9 months (CI 5 – 16.5 months). Tumor marker data (Neuron Specific Enolase, Chromogranin A, 5-Hydroxyindoleacetic Acid, and Circulating Tumor Cells) will also be presented. Conclusions: PEN-221 appears well tolerated at 8.8 mg/m2 q 3 weeks and has demonstrated efficacy exceeding its clinical efficacy goals with a CBR of 88.5% and a mPFS of 9 months. A randomized trial of PEN-221 in GI mid-gut NET patients is now in development. Clinical trial information: NCT02936323.

Adherence to somatostatin analog therapy for acromegaly

The main goals of treatment for many diseases are to improve the prognosis of diseases and to enhance the quality of life. Among the barriers that restrict achieving these goals we have to mention adherence to treatment. Patients with chronic diseases, including acromegaly, are at increased risk of poor adherence to treatment. The duration of supervision of patients with acromegaly in most cases exceeds 25-30 years, which makes the issue of adherence to treatment extremely important.One of the main goals of the acromegaly treatment is to achieve the target values of STH and IGF-1, which ensures the regression of most clinical symptoms and restoration of life expectancy. For this purpose, a significant proportion of patients with acromegaly receive somatostatin analog treatment - as a second line of treatment after non-radical neurosurgical intervention, or as the first line of treatment if neurosurgical intervention could not be performed for any reason. Adherence to treatment is influenced by socio-economic factors, the characteristics of the drug, and the characteristics of the patient. Recent studies have shown that the easy administration of lanreotide provides better treatment adherence than octreotide. Factors that can reduce adherence to the treatment of acromegaly are old age, mental disorders, subjective opinion about the low quality of life, the need to visit medical institutions to administer the drug. On the contrary, the ability to perform subcutaneous injections (on their own or with the help of relatives) without visiting medical facilities, providing accessible information about the disease and the need for its treatment significantly increases adherence to treatment. It is necessary to continue research on the factors and methods of increasing adherence to drug treatment of acromegaly.

A Machine Learning Decision Support System (DSS) for Neuroendocrine Tumor Patients Treated with Somatostatin Analog (SSA) Therapy

The application of machine learning (ML) techniques could facilitate the identification of predictive biomarkers of somatostatin analog (SSA) efficacy in patients with neuroendocrine tumors (NETs). We collected data from 74 patients with a pancreatic or gastrointestinal NET who received SSA as first-line therapy. We developed three classification models to predict whether the patient would experience a progressive disease (PD) after 12 or 18 months based on clinic-pathological factors at the baseline. The dataset included 70 samples and 15 features. We initially developed three classification models with accuracy ranging from 55% to 70%. We then compared ten different ML algorithms. In all but one case, the performance of the Multinomial Naïve Bayes algorithm (80%) was the highest. The support vector machine classifier (SVC) had a higher performance for the recall metric of the progression-free outcome (97% vs. 94%). Overall, for the first time, we documented that the factors that mainly influenced progression-free survival (PFS) included age, the number of metastatic sites and the primary site. In addition, the following factors were also isolated as important: adverse events G3–G4, sex, Ki67, metastatic site (liver), functioning NET, the primary site and the stage. In patients with advanced NETs, ML provides a predictive model that could potentially be used to differentiate prognostic groups and to identify patients for whom SSA therapy as a single agent may not be sufficient to achieve a long-lasting PFS.