Gastrointestinal neuroendocrine tumors treated with high dose octreotide-LAR: A systematic literature review

Table 1 Description of included studies

Ref. (OCEBM)	Country, timeframe	Study design	Study subjects	Doses of SLAR administered (number of patients or number of doses)	Reasons for high dose SLAR2	Relevant outcomes reported
Strosberg et al[2] 2013 (5)	United States	Modified delphi process	404 patient scenarios of patients with unresectable metastatic well-differentiated carcinoid tumors	Subset of patient scenarios treated with SLAR (frequency: every 2 wk, 3 wk, 4 wk; dosing 30 mg, 40 mg, 60 mg, 90 mg, 120 mg)	NA/NR	Expert clinical opinion
Colao et al[8] 2010 (5)	Italy	Literature review	Pituitary tumors and NETs	NA/NR	NA/NR	Expert clinical opinion
Oberg et al[9] 2004 (5)	Europe, United States	Literature review	Relating to pts. with GEPNETs	NA/NR	NA/NR	Expert clinical opinion
Yao et al[10] 2008 (5)	United States	Letter to editor	Relating to pts. with NETs	NA/NR	NA/NR	Expert clinical opinion
Anthony et al[11] 2011 (3b)	United States, 2000-2006	Retrospective multicenter medical chart review	392 pts. with functioning NETs (with or without CS), treated with SLAR ≥ 4 mo	10 mg (22 doses), 20 mg (224), 30 mg (316), 40 mg (78), 50 mg (16), 60 mg (42)	Lack of efficacy	Efficacy, safety
Chadha et al[12] 2009 (2b)	United States, 2002-2007	Retrospective single-center medical chart review	54 pts. with GEPNETs treated with SLAR 20-30 mg	Median high dose of SLAR 40 mg, ranging 40-90 mg/mo (30 pts.)	Control of symptoms, treatment of tumor	Efficacy, safety, Expert clinical opinion
Costa et al[13] 20061 (4)	2005	Retrospective case series	9 pts. with progressive metastatic NETs treated with SLAR 20 mg/mo	20 mg/mo (9 pts.); 30 mg/mo, 40 mg/mo (3 pts.)	Treatment of tumor	Efficacy, Expert clinical opinion
Ferolla et al[14] 2012 (2b)	Italy	Multicenter open-label non-randomized prospective clinical trial	28 pts. with well-differentiated NETs, progressing at standard dose SLAR ≥ 6 mo	30 mg/28 d initially for 6-32 mo (28 pts.); 30 mg/21 d (28 pts.) for 4-48 mo	Control of symptoms, treatment of tumor, other	Efficacy, safety
Koumarianou et al[15] 20101(4)	2008-2009	Retrospective case series	13 pts. with pretreated progressive metastatic GEPNETs	30 mg/3 wk (12 pts.)	Treatment of tumor	Efficacy, safety
Markovich et al[16] 20121 (4)		Retrospective clinical trial	31 pts. with pretreated progressing disseminated NETs	20 mg/mo initially (29 pts.); 30 mg/mo (18); 40 mg/mo (13) long acting octreotide	Control of symptoms, treatment of tumor, other	Efficacy, safety
Valle et al[17] 20011 (4)		Retrospective single-center case series	8 pts. with metastatic carcinoid syndrome	Initially 20 mg/mo (5 pts), 15 mg/mo, 60/mo, 20/2 wk (all 1); escalated to 20 mg/3 wk, 30 mg/3 wk, 50 mg/4 wk, 120 mg/4 wk (4 pts.)	Control of symptoms	Efficacy, safety
Weber et al[18] 20121 (4)	United States, 2000-2010	Retrospective single-center medical chart review	337 pts. with metastatic small-bowel carcinoid tumors, treated with SLAR	27% (99 pts.) with increased high dose; common max doses were 40 mg/4 wk (37 pts.), 60 mg/mo (34), 30 mg/3 wk (17)	Control of symptoms, tumor progression, other	Efficacy
Wolin et al[19] 20131 (2b)		Multicenter randomized phase III clinical trial	110 pts. with unresponsive NET symptoms to standard dose SLAR	40 mg/28 d (57 pts.)	Control of symptoms	Efficacy, safety
Woltering et al[20] 2006 (3)	United States	Non-randomized prospective clinical trial	40 pts. with carcinoid syndrome on stable doses of SLAR for ≥ 3 mo	20 mg (8 pts.), 30 mg (19), 60 mg (13) SLAR/mo	Control of symptoms	Efficacy
Ludlam et al[21] 2011 (3a)	1965-2010	Systematic literature review	Relating to pts. with NETs	NA/NR	Control of symptoms	Safety
Strosberg et al[22] 20131 (2b)	United States, 2004-2010	Retrospective multicenter medical chart review	271 pts. with carcinoid and pancreatic NETs, treated with octreotide-LAR	40% (n = 82) of carcinoid pts had high dose: common max doses of 40 mg/mo (39%), 40 mg/3 wk (18%), 30 mg/2 wk (17%); and 23% (15) of pNET pts: 40 mg/mo (33%), 30 mg/2 wk (27%), 60 mg/mo (27%)	Control of symptoms, treatment of tumor, other	Expert clinical opinion
Xu et al[23] 20121 (3b)	United States, 1999-2007	Retrospective analysis of SEER-Medicare claims	355 pts. with NETs	26 pts. (7.3%) with ≤ 10 mg initially, of which 3.9% increased to > 40 mg; 91 (25.6%) with 11-20 mg initially, 5.5% increased to 31-40 mg and 4.4% to > 40 mg; 147 (41.4%) with 21-30 mg initially, 11.6% increased to 31-40 mg and 10.9% to > 40 mg; 65 (18.3%) with 31-40 mg initially, 86.2% increased to 31-40 mg and 13.9% to > 40 mg; 26 (7.3%) with > 40 mg initially, 100% increased to > 40 mg; 134 pts. (37.7%) escalated to > 30 mg/mo during 1st year of therapy	NA/NR	Expert clinical opinion

¹Conference abstract;

²Control of symptoms (flushing, diarrhea, and etc.); treatment of tumor (tumor progression); other (biochemical markers). NA/NR: Not applicable/not reported; OCEBM: Oxford’s Centre for Evidence-Based Medicine Levels Of Evidence; CS: Carcinoid syndrome; NETs: Neuroendocrine tumors; GEPNETs: Gastroenteropancreatic neuroendocrine tumors; SLAR: Octreotide long-acting repeatable; pts.: Patients.

Table 2 Efficacy of octreotide long-acting repeatable > 30 mg/mo

Ref.	Symptoms	Disease markers2	Tumor response/Disease progression
Anthony et al[11] 2011	NA/NR	NA/NR	Complete response rates: 2% (20 mg), 1% (30 mg), 0% (40 mg), 2% (60 mg); partial response: 6% (20mg), 8% (30 mg), 4% (40 mg), 10% (60 mg); stable disease: 57% (20 mg), 57% (30 mg), 55% (40 mg), 50% (60 mg); progression: 21% (20 mg), 25% (30 mg), 18% (40 mg), 29% (60 mg)
Chadha et al[12] 2009	NA/NR	NA/NR	Median time to intervention was 2.9 mo (conventional dose group) vs 17.7 mo (high-dose) (P = 0.12)
Costa et al[13] 20061	NA/NR	NA/NR	After evidence of progressive disease in liver, disease stabilization was achieved with increase to 30 mg and to 40 mg/mo
Ferolla et al[14] 2012	Complete normalization: 40%; partial symptom control: 60%; flushing (normalized in 71.4%, improved in 28.6%), diarrhea (70%, 30%); pain (disappeared in 33%; improved in 67%); bronchospasm improved in 100%; hypoglycemia improved in 100%; weakness/well-being improved in all pts	30% of pts. with elevated markers responded to higher dose; significant response to high dose SLAR was in 30% of pts. with high CgA, 57.1% of pts. with high 5-HIAA, and 100% of pts. with high gastrin; median time-to-biochemical progression was 30 mo (SLAR 30 mg/21 d) vs 14 mo (standard dose) (P < 0.01)	Partial response in 7.2%, stable disease in 92.8%; median time to progression was 30 mo. (SLAR 30 mg/21 d) vs 9 mo. (standard dose) (P < 0.0001);
Koumarianou et al[15] 20101	NA/NR	NA/NR	75% (9/12) with > 50% tumor size reduction, and 25% had stable disease; median PFS was 24.6 wk
Markovich et al[16] 20121	NA/NR	NA/NR	Partial response in 3.2%, stable disease in 80.7%, progressed in 16.1%; tumor growth control in 83.9%, pts. had biochemical response and symptom relief (results not broken down by dose)
Valle et al[17] 20011	Improvement in flushing, diarrhea, and bronchospasm (results not broken down by dose)	pts. with dose-escalation of SLAR had increased 5-HIAA, suggesting increased disease activity
Weber et al[18] 20121	In pts., with increased doses of SLAR for refractory CS, 62% had improvement in diarrhea and 56% had improvement in flushing	NA/NR	NA/NR
Wolin et al[19] 20131	At month 6, symptom response was 21% (9/43) in pasireotide-LAR vs 27% (12/45) in ocrteotide-LAR arms (OR = 0.73; 95%CI: 0.27-1.97; P = 0.53); 36.5% ± 29.1% had a reduction in diarrhea/d and a 49.4% ± 36.7% in flushing/2 wk	NA/NR	Median PFS was 6.8 mo in octreotide-LAR vs 11.8 mo pasireotide-LAR arms (HR = 0.46; P = 0.045)
Woltering et al[20] 2006	Flushing not controlled in 0% (20 mg), 11.1% (30 mg), vs 7.1% (60 mg) SLAR groups (P = 1.0); diarrhea not controlled in 0% of pts. (20 mg), 27.8% (30 mg), vs 30.8% (60 mg) groups (P = 0.3182)	Mean absolute serum CgA: 53.1 (20 mg SLAR), 65.8 (30 mg), 70.7 (60 mg) (P = 0.9847); mean absolute plasma CgA: 56.6 (20 mg), 66.2 (30 mg), 65.2 (60 mg) (P = 0.9092)	NA/NR

¹Conference abstract;

²Disease makers: 5-hydroxyindoleacetic acid (5-HIAA), chromogranin A (CgA), gastrin, and insulin. NA/NR: Not applicable/not reported; CS: Carcinoid syndrome; SLAR: Octreotide long-acting repeatable; PFS: Progression free survival.

Table 3 Safety of octreotide long-acting repeatable > 30 mg/mo

Ref.	Safety
Anthony et al[11] 2011	NA/NR (adverse events not broken down by SLAR dose); of 392 pts., 8.7% had hyperglycemia, 6.4% had cholelithiasis, 2.8% had cholecystitis, 2.3% had steatorrhea, and 1.5% had hypoglycemia, and 22% had ≥ 1 adverse event during SLAR use
Chadha et al[12] 2009	p 4129: “No treatment related toxicities were reported.”
Ferolla et al[14] 2012	p 329: “No additional toxicity was recorded for the schedule treatment with LAR 30 mg every 21 d when compared with standard LAR dose and no treatment discontinuation or dose modification was required. Adverse events observed in patients in treatment with LAR 30 mg every 21 d were diarrhea in 1, abdominal pain in 1, cholelithiasis in 2, pyrexia in 1 patient. No constipation, dizziness, arterial hypertension or any other adverse event was observed.”
Koumarianou et al[15] 20101	“Patients reported no significant symptoms related to treatment adverse events. Two patients experienced a grade I neutropenia and one patient a grade II thrombocytopenia. One patient did not receive treatment due to persistent nausea and vomiting resistant to metoclopramide.”
Ludlam et al[21] 2011	p 838: “A trial designed to compare two dose levels of octreotide LAR (30 and 40 mg/mo) highlighted the ability of octreotide LAR to control diarrhea in patients with active or prior chemotherapy-induced diarrhea. Fewer patients in the 40 mg/mo group compared with those in the 30 mg/mo group experienced severe diarrhea (62% vs 48%; P = 0.14), required intravenous fluid (32% vs 19%; P = 0.10), or had diarrhea-related unscheduled healthcare visits (42% vs 28%; P = 0.11). Most importantly, adverse events were balanced between the two groups.”
Markovich et al[16] 20121	"Tolerability of long-acting octreotide in a dose of 30-40 mg was satisfactory for all pts.”
Valle et al[17] 20011	"All patients found the long-acting analogue acceptable and none requested a change back to conventional daily octreotide. Sandostatin LAR is an alternative somatostatin analogue that is highly acceptable to patients; doses may be safely escalated if required.”
Wolin et al[19] 20131	“Hyperglycemia (11% vs 0%), diarrhea (9% vs 7%), and abdominal pain (2% vs 9%) were the most common grade 3/4 AEs in the pasireotide-LAR (P) vs octreotide-LAR (O) arms in the core phase, and 7 (13%) and 4 (7%) patients discontinued due to AE. P and O showed a similar safety profile except for the higher frequency of hyperglycemia in P.”

¹Conference abstract. NA/NR: Not applicable/not reported.

Table 4 Expert clinical opinion statements on use of octreotide long-acting repeatable > 30 mg/mo

Ref.	Quoted expert clinical opinion
Chadha et al[12] 2009	p 4130: "Our experience and those of others have shown that S-LAR can provide disease control to prolong time needed for liver- directed therapies and systemic therapies. Dose escalation provides an opportunity to spare patients from morbidities associated with these procedures and systemic therapy."
Colao et al[8] 2010	p 290: “The dosages of SSAs currently used are probably insufficient to determine control of hormone secretion and tumor growth both in acromegaly and NETs.”
Costa et al[13] 20061	"Dose increase with octreotide LAR should be offered to those patients who progress after achieving a first objective response with SS analogues."
Oberg et al[9] 2004	p 970: "As a general rule, if the total IR dose is 200-600 μg/d, LAR 20 mg should be tried, and if total IR dose is 750-1500 μg/d, LAR 30 mg should be tried. The LAR doses range from 20 to 60 mg/28 d. Supplementary administration with the IR form of octreotide in patients escaping anti-secretory response is often required during long-term treatment with LAR. If it is necessary to give the patient rescue doses of IR octreotide three or four times per week, increase the LAR dose to 30 mg/4 wk, or reduce the interval between administrations of the depot formulation (e.g., 20 mg/3 wk). Furthermore, the temporal occurrence of hypersecretion during the 4-week dosing interval should be considered. For example, if the rescue s.c. therapy is required during the week before the next injection of LAR, then a reduction of the dosing interval by 1 wk is advisable. On the other hand, if the need for rescue medication occurs sporadically throughout the month then increasing the dose stepwise by 10 mg/mo up to 60 mg/mo should be tried. Doses of LAR > 60 mg/mo are rarely of added value."
Strosberg et al[2] 2013	p 5: "In patients with uncontrolled secretory symptoms, increasing the dose/frequency of SSAs is appropriate (median rating, 8), particularly among patients who had previously responded to a lower dose. The panel considered dose escalations of octreotide LAR up to 60 mg/4 wk (median rating, 7) or up to 40 mg/3 wk (median rating, 7) to be reasonable adjustments for refractory carcinoid syndrome. Increasing the dose/frequency of SSAs may be considered in patients with radiographic progression, particularly those whose disease was previously stabilized at a lower dose. The panel considered an increase in dose/frequency up to 40 mg/3 or 4 wk to be reasonable (median rating: 4-5.5). There is a lack of evidence that increasing the dose/frequency of SSAs slows radiographic progression."
Strosberg et al[22] 20131	“Above label dosing of octreotide LAR is common in NCCN institutions. The primary indication is refractory carcinoid syndrome.”
Xu et al[23] 20121	"Our analyses showed that patients frequently required the escalation of octreotide LAR dose during their course of illness. A substantial number of patients required doses greater than the FDA approved dose of 30 mg/mo."
Yao et al[10] 2008	p 338: "Although octreotide has proven to be a safe and efficacious drug for carcinoid syndrome, it nonetheless can cause adverse events including steatorrhea, cholelithiasis, and hyperglycemia. Until conclusive data from randomized studies are available to show that octreotide has a disease-stabilizing effect and at what does this effect occurs in humans, we advocate titrating the octreotide LAR dose according to symptoms rather than to an arbitrary blood level."

¹Conference abstract. NCCN: National Comprehensive Cancer Network; NETs: Neuroendocrine tumors; S-LAR: Octreotide long-acting repeatable; FDA: Food and Drug Administration; SSAs: Somatostatin analogues.