Long-acting Octreotide Treatment Research Articles

The effect of using long-acting octreotide as adjuvant therapy for patients with grade 2 pancreatic neuroendocrine tumors after radical resection

Abstract Objective: To investigate the effect of long-acting octreotide as adjuvant therapy in the prevention of tumor recurrence in patients with grade 2 pancreatic neuroendocrine tumors (pNETs) after radical resection. Methods: The postoperative follow-up data of 130 patients with resectable G2 pNET treated in the Changhai Hospital from 2008 to 2018 were retrospectively analyzed: 59 patients received long-acting octreotide as adjuvant therapy for 6 to 12 months (Oct group) and 71 patients received active follow-up (control group), both of which began after the radical resection, with the primary observation endpoint of disease-free survival (DFS) and the secondary study endpoint of overall survival. Results: The median age of the patients in the Oct group and control group was 52 and 54 years, respectively. There were 28 male cases (47.5%) and 33 male cases (46.5%) in the 2 groups. The median maximum tumor diameter was 3.5 and 3.0 cm, respectively; lymph node metastasis was positive in 13 cases (22.0%) and 9 cases (12.7%); there was peripancreatic nerve invasion in 11 cases (18.6%) and 6 cases (8.5%). Survival analysis revealed that there were significant differences in 2-year DFS% (98.3% vs 88.7%, P = .0371) and 3-year DFS% (96.6% vs 85.9%, P = .0498) between the Oct group and control group. Long-acting octreotide treatment was found to reduce the risk of 3-year recurrence of G2 pNET after radical resection (HR = 0.2, P = .044) with the application of inverse-probability-of-treatment weighted to balance the limited data bias. Conclusion: Using long-acting octreotide as adjuvant therapy for G2 pNET patients after radical surgery may improve the rate of 3y-DFS, but the benefit needs to be confirmed in a well-designed random control clinical trial.

P-254 An experience of two Croatian centers in the treatment of gastroenteropancreatic neuroendocrine neoplasms with long-acting octreotide treatment

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors whose incidence has increased steadily over the past decades. Octreotide is a somatostatin analogue which has traditionally been used for the relief of symptoms that result from the release of peptides and amines (carcinoid syndrome), although a substantial amount of evidence suggests that it has anti-proliferative effects and lengthens the time to progression of the disease. We’ve aimed to evaluate the relationship between octreotide use and progression-free survival (PFS) and overall survival (OS). Medical records of 76 patients with gastroenteropancreatic NENs treated with long-acting octreotide in the University Hospital Centre Zagreb and University Hospital Center Sisters of Charity were collected in the period from March 2011 to March 2019. A retrospective analysis was completed with the Kaplan-Meier method using the PFS and OS as a primary endpoint. Previous to octreotide treatment patients had confirmed high expression of somatostatin receptors (sst-rs) by tetroktyde scintigraphy. All patients were followed for a median of 38 months, all of them where grade 1 (27%) or grade 2 (73%). Median PFS for all patients was estimated at 12 ± 2,5 months (95% CI 9,62-14,38). Median PFS for patients with pancreatic NETs was estimated at 10 ± 0,5 months (95% CI 7,03-12,97; median Ki-67 10%), patients with NET of large intestine at 10 ± 3,67 months (95% CI 2,87-17,13; median Ki-67 14%), patients with NETs of unknown primary at 12 ± 2,6 months (95% CI 4,93-19,07; median Ki-67 6%) and for patients with NETs of small intestine at 30 ± 14,5 months (95% CI 1,57-58,48; median Ki-67 5%). Median OS was not reached in any subgroup of patients. Although overall median PFS is lower than in the PROMID study, the fact that the median OS was not reached renders long-acting octreotide as an effective treatment option with acceptable tolerability. This patient population was more heterogenous than in clinical trials and reflects the real-life setting of clinical practice.

Long-acting octreotide treatment has no impact on tumor uptake of 99mTc-HYNIC-TOC in patients with neuroendocrine tumors.

Our purpose is to investigate whether the tumor uptake of Tc-HYNIC-TOC in patients with neuroendocrine tumor would be influenced when the patients were treated with long-acting octreotide. Sixty G2 neuroendocrine tumor patients who underwent Tc-HYNIC-TOC single-photon emission computed tomography/computed tomography imaging were retrospectively analyzed. The ratios of target/muscle of normal organs and tumors were compared between the patients with (n = 30) and without octreotide treatment (n = 30). In addition, the octreotide treatment group was divided into two subgroups based on whether the time intervals were more than 14 days between the last time of octreotide administration and the day of imaging. There was no statistical significance in target/muscle of primary tumors (23.86 ± 4.49 vs. 20.72 ± 5.37, P = 0.070), metastases in the liver (20.74 ± 6.14 vs. 19.72 ± 6.54, P = 0.211), lymph nodes (16.29 ± 9.45 vs. 15.52 ± 7.67, P = 0.867), bone (9.18 ± 3.83 vs. 9.07 ± 3.61, P = 0.989) and lung (16.99 ± 6.06 vs. 12.40 ± 5.97, P = 0.133) between octreotide treated and untreated group. However, target/muscle of normal liver and bone were lower in the octreotide treated group than in untreated group (P = 0.003, and 0.0001, respectively). There was also no significant difference in target/muscle of normal organs, primary tumors and metastases between the two subgroups. Octreotide treatment had no impact on the results of Tc-HYNIC-TOC single-photon emission computed tomography/computed tomography to detect tumors and metastasis in patients with neuroendocrine tumor. However, the uptake in normal liver and bone can be reduced, which might increase the detection rate of lesions in corresponding organs.

Long-Acting Somatostatin Analog Therapy Differentially Alters 68Ga-DOTATATE Uptake in Normal Tissues Compared with Primary Tumors and Metastatic Lesions.

Synthetic somatostatin analogs have been posed as a potential source of error in somatostatin receptor imaging through interference with tumor detection; however, experimental models and clinical studies have shown a complex mechanism of the effect of octreotide on tumors. The aim of this study was to assess whether 68Ga-DOTATATE uptake before treatment with long-acting somatostatin analogs differs from that after treatment. Methods: Thirty patients (15 men; age [mean ± SD], 64.6 ± 13.4 y) who had intermediately differentiated to well-differentiated neuroendocrine tumors and who underwent 68Ga-DOTATATE PET/CT scanning before and after receiving long-acting repeatable octreotide (Sandostatin LAR) were included in the study. The SUVmax and SUVmean of healthy target organs, residual primary tumor, and up to 5 lesions with the highest SUVmax in each organ were compared before and after octreotide treatment. Results: The mean time interval between the 2 68Ga-DOTATATE studies was 9.6 ± 7.2 mo, and the mean time gap between the last Sandostatin LAR injection and the second 68Ga-DOTATATE study was 25.1 ± 14.8 d. The pretreatment mean SUVmax and SUVmean were both significantly higher in the thyroid, liver, and spleen (P < 0.05) than the values measured after the administration of Sandostatin LAR. No significant differences were found among the uptake indices for residual primary tumor or any metastatic lesions in the liver, bone, lung, or lymph nodes before and after Sandostatin LAR administration (P > 0.05). Conclusion: Long-acting octreotide treatment diminished 68Ga-DOTATATE uptake in the liver, spleen, and thyroid but did not compromise tracer uptake in residual primary tumor and metastatic lesions. These findings have a direct impact on the interpretation of 68Ga-DOTATATE PET/CT scans.

Preoperative long-acting octreotide treatment for invasive thyrotropin-secreting pituitary macroadenoma after previous radioiodine thyroid ablation

We report a 33-year-old woman with invasive thyrotropin-secreting pituitary adenoma after previous thyroid ablation with radioiodine who was successfully treated with transsphenoidal surgery after pre-treatment with octreotide-LAR for 10months. Since invasive and aggressive thyrotropin-secreting macroadenomas are more frequently observed in patients who have undergone thyroid ablation, we suggest preoperative treatment with somatostatin analogs should be considered in these patients to reduce serum thyrotropin and stabilize or reduce tumor size.

Night blindness in a haemodialysed ADPKD patient receiving octreotide.

A 62-year-old woman on chronic haemodialysis since November 2008 for end-stage renal disease (ESRD) due to autosomal dominant polycystic kidney disease (ADPKD) had developed a massive polycystic liver (10.647 mL), causing severe abdominal discomfort, early satiety, dyspepsia and dyspnoea (Figure 1). On the basis of the demonstrated effectiveness of somatostatin analogues in reducing the liver volume in ADPKD patients [1, 2] and taking into account her reluctance for any liver surgery, we offered her a trial treatment with octreotide. We administered a single-test dose of short-acting subcutaneous 100 μg octreotide and observed the patient over a 24-h period. Diarrhoea, vomiting and abdominal cramps occurred several hours after administration, but disappeared the day after. We then started long-acting octreotide treatment at a monthly dose of 20 mg. A few hours after the injection, the patient suffered from diarrhoea, nausea and vomiting. While nausea and vomiting rapidly resolved, diarrhoea persisted over the whole next month. Thus, the monthly dose of octreotide was reduced to 10 mg. After 3 months of treatment, diarrhoea persisted with fatty and discoloured stools. At the same time, the patient began to report loss of nocturnal peripheral vision. She explained that, in the dark, her visual field was restricted, giving her the feeling of seeing ‘like in a tunnel’.

Shortened interval of long-acting octreotide administration is effective in patients with well-differentiated neuroendocrine carcinomas in progression on standard doses.

In patients with well-differentiated (WD) neuroendocrine tumors (NET), long-acting octreotide (LAR), conventionally administered at a dose of 30 mg every 28 days, has well-documented anti-secretive but limited antiproliferative effects. The objective of this study was to evaluate a different schedule of LAR treatment consistent with a shorter interval between administrations (21 days) in WDNET patients with progressive disease at standard-dose interval. Twenty-eight patients followed for diagnosis and therapy of WDNET who had tumor progression during therapy with LAR 30 mg every 28 days were enrolled. Clinical, biological, and objective tumor response was evaluated after LAR 30 mg every 21 days. Time to progression was also evaluated after LAR 30 mg every 21 days and compared to LAR 30 mg every 28 days. The treatment with LAR 30 mg every 21 days resulted in complete and partial control of clinical symptoms in 40% and 60% of cases, respectively. Circulating neuroendocrine markers were significantly decreased in 30% of cases. A stabilization of disease was obtained in 93% and objective response in 7%. The median time to progression was significantly longer by using the shortened interval of LAR administration as compared to the standard one (30 vs 9 months, p<0.0001). The treatment was safe and well tolerated. The shortened schedule of LAR administration was able to re-institute control of clinical symptoms, to decrease level of circulating neuroendocrine markers and to increase time to progression in patients previously escaping from a standard schedule treatment.

Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: a prospective randomized study

Therapeutic effects of presurgical long-acting octreotide treatment on tumor shrinkage, and short- and long-term postoperative GH and IGF-1 levels of acromegaly patients with invasive pituitary macroadenomas were investigated prospectively in Huashan Hospital, Shanghai, China. Thirty-nine untreated acromegaly patients, all with invasive pituitary macroadenomas, were randomly divided into two groups: experimental group (n=19), and control group (n=20). Patients in the experimental group received a three-month course of long-acting octreotide treatment before transsphenoidal surgery; the control group underwent surgery directly. Tumor shrinkage after drug treatment and short- and long-term postoperative GH and IGF-1 levels were analyzed in the two groups. Long-acting octreotide treatment reduced tumor size from 7893 ± 6450 to 4794 ± 4682 mm(3). Mean shrinkage rate was 37.4 ± 30.9%. GH and IGF-1 levels of the experimental group were lower than the control group at 3 months, 6 months after surgery, and after long-term follow-up. Remission rate (both GH and IGF-1 normal) of the experimental group was higher at 3 and 6 months follow-up, but exhibited no advantage in long-term follow-up. In the experimental group, the total resection rate was higher in patients whose Hardy-Knosp grading decreased to ≤ 2 than those whose Hardy-Knosp grading is still ≥ 3 after drug pretreatment. In conclusion, presurgical long-acting octreotide treatment effectively reduces tumor size and invasion, which helps enhance early remission rates of invasive macroadenomas by transsphenoidal surgery, but does not appear to improve the long-term cure rate.

Long-acting octreotide treatment causes a sustained decrease in ghrelin concentrations but does not affect weight, behaviour and appetite in subjects with Prader–Willi syndrome

Ghrelin is secreted primarily by the stomach and circulates as both acylated and desacyl ghrelin. Acylated (but not desacyl) ghrelin stimulates appetite. Both concentrations are elevated in Prader-Willi syndrome (PWS), suggesting that ghrelin may contribute to hyperphagia and overweight in these subjects. We evaluated whether long-acting octreotide (Oct) decreases acylated and desacyl ghrelin concentrations, body mass, appetite and compulsive behaviour towards food in adolescents with PWS. A 56-week prospective, randomized, cross-over trial. Nine subjects with PWS (age 14.6 (10.8-18.9) years, body mass index (BMI) Z-score +1.9 (0.6-3.0)) received either Oct (30 mg) or saline i.m. every 4 weeks for 16 weeks and were switched over to the other treatment after a 24-week washout period. Eight subjects completed the study. Oct caused a decrease in both acylated (-53%) and desacyl (-54%) fasting ghrelin concentrations (P<0.05) but did not significantly affect BMI. Oct had no significant effect on peptide YY concentrations, appetite or compulsive behaviour towards food. Oct caused a decrease in insulin-like growth factor-I concentrations, an increase in HbA1c and transient elevation of blood glucose in two subjects. Three subjects developed gallstones. Oct treatment caused a prolonged decrease in ghrelin concentrations in adolescents with PWS but did not improve body mass or appetite. Future intervention studies aiming at clarifying the role of ghrelin in PWS should focus on the administration of specific inhibitors of ghrelin secretion or ghrelin receptor activity that do not interfere with other appetite-regulating peptides.