Systematic literature review of the antitumor effect of octreotide in neuroendocrine tumors

Table 1 Comparative studies (with no treatment/placebo, different doses, or monotherapy treatment as the comparator)

First author	Study design	No. of patients	Tumor type	Treatment and dose	Treatment duration/observation period	TTP, mo	SD, %	PR, %	OS, mo	5-yr survival	PFS, mo
Octreotide vs placebo or no treatment
Rinke et al[13] (2009) PROMID study	RCT	85	Well-differentiated, advanced NET with midgut or unknown origin. Functional and nonfunctional	LA OCT 30 mg every 28 d (n = 42) vs PBO (n = 43)	Patients enrolled between March 2001 and Jan 2008; followed until June 2008	Median OCT: 14.3 vs PBO: 6.0 HR: 0.34; 95%CI: 0.20-0.59; P = 0.000072	At 6 mo: OCT: 66.7 vs PBO: 37.2 (P = 0.0079)	At 6 mo: 1 in each group	Interim analysis: Median: OCT: Not reached (> 77.4) vs PBO: 73.7 HR: 0.81; 95%CI: 0.30-2.18; P = 0.77	-	-
Rinke et al[14] (2017) PROMID study	RCT	85	Well-differentiated, advanced NET with midgut or unknown origin. Functional and nonfunctional	LA OCT 30 mg every 28 d (n = 42) vs PBO (n = 43)	Patients enrolled between March 2001 and Jan 2008; followed until May 2014	-	-	-	Final analysis Median: OCT: 84.7 vs PBO: 83.7 HR: 0.83; 95%CI: 0.47-1.46; P = 0.51	-	-
Shen et al[15]1 (2014)	RWE	1291	Distant and local/regional disease; well, moderately, and unknown differentiated tumors with various origin Functional NETs	LA OCT (dose not defined) vs no LA OCT	Cohort entry: July 1999-Dec 2007 Follow-up through Dec 2009	-	-	-	Distant stage: OCT: 2.11 y vs no OCT: 1.25 y; P = 0.002 Local/regional stage: “no significant survival benefit”	Distant-stage: HR: 0.61; 95%CI: 0.47-0.79; P ≤ 0.001 Local/regional stage: HR: 0.88; 95%CI: 0.57-1.36; P = 0.563	-
Shen et al[16]2 (2015)	RWE	6940	Distant and local/regional disease; well, moderately, and unknown. differentiated tumors with various origin Functional and nonfunctional NETs	LA OCT and no LA OCT distant stage (n = 1176) local/regional stage (n = 5764)	Cohort entry: Jan 1999-Dec 2009 Follow-up through Dec 2011	-	-	-	Distant stage: OCT: 35.22 vs no OCT: 19.15 HR: 0.68; 95%CI: 0.554-0.840; P < 0.001 Local/regional stage: OCT: 64.85 vs no OCT: 104.97 HR: 1.253; 95%CI: 0.928-1.692; P = 0.1415	-	-
Anthony and Vinik[19] (2011)	RWE	392	Tumor pathology: NR. Localized/metastatic/ unknown disease with various origin	Without carcinoid syndrome (n = 106) With carcinoid syndrome (n = 260) Carcinoid syndrome after initiation of treatment (n = 24) Overall population initial dose: LA OCT 20 mg: 49% LA OCT 30 mg: 39%	NR	-	57 (any dose)	6 (any dose)	-	-	-
Chadha et al[20] (2009)	RWE	54	Tumor pathology: NR Metastatic disease with GEP origin	OCT conventional dose (20 or 30 mg every month; n = 24) OCT high dose (40-90 mg3; n = 30)	Median follow-up, mo: OCT conventional dose: 35.8 OCT high dose: 44.1	-	-	-	1 yr OS: 0.77 vs 0.88; P = 0.4777)	-	-
Ferolla et al[17] (2012)	CT	28	Well differentiated functional and nonfunctional NET with various origin	LA OCT 30 mg every 28 d (n = 28) LA OCT 30 mg every 21 d (n = 28)	NR	-	- vs 93	- vs 7	-	-	-
Jann et al[21] (2013)	RWE	43	G1/G2/Unknown KI-67 index Functional and nonfunctional metastatic tumors with pancreas origin	LA OCT 30 mg (n = 19) LA OCT ≤ 20 mg (n = 16) OCT (dose unknown(n = 8)	Median follow-up: 58 mo	-	37 (any dose)	5 (any dose)	Median, 98	-	-
Shen et al[18]2 (2016)	RWE	222	Well, moderately, or poorly differentiated Functional and nonfunctional distant-stage NETs with various origin	LA OCT every 28 d by dose: ≤ 20 mg (n = 81) 21-30 mg (n = 82) > 30 mg (n = 59)	Cohort entry: Jan 1999-Dec 2009 Follow-up through Dec 2011	-	-	-	≤ 20 mg: 20.8 21-30 mg: 32.6 > 30 mg: 36.3 ≤ 20 mg vs 21-30 mg: HR: 2.000; 95%CI: 1.318-3.035; P = 0.0011 > 30 mg vs 21-30 mg: HR: 1.094; 95%CI: 0.671-1.788; P = 0.7193	-	-
Octreotide monotherapy vs another monotherapy
Bongiovanni et al[23] (2017)	RWE	30	Well or moderately differentiated locally advanced/metastatic tumors with lung origin	LA OCT 30 mg every 28 d (n = 20) LAN 120 mg every 28 d (n = 10)	Median follow-up , 40 mo	-	-	-	-	65.6% vs 87.5% (P = 0.864)	11.1 vs 10.1 (P = 0.769)
Creutzfeldt et al[24] (1991)	CT	33	Tumor pathology: NR Metastatic gastrointestinal tumors	IFN-α2c (2 × 106 IU/m2 daily; n = 17) OCT (200 μg 3 times daily, 500 μg 3 times daily if tumor progressed; n = 16)	NR	-	85.7 vs 37.5 Comparison NR	-	-	-	-
Wolin et al[22] (2015)	RCT	110	Well, moderate, or poorly differentiated Locally advanced/metastatic tumors with various origin	PAS LAR 60 mg every 28 d (n = 53) LA OCT 40 mg every 28 d (n = 57)	NR	-	70.6 vs 73.1 Comparison NR	2.0 vs 1.9 Comparison NR	-	-	-

¹Sample restricted to patients who either never received treatment with long-acting octreotide or who received it within 6 mo of index date; ²Sample restricted to patients who either never received treatment with long-acting octreotide or who received it within 12 mo of index date; ³Median: 40 mg. “-“ indicates that data were not reported. CI: Confidence interval; CT: Controlled trial; GEP: Gastroenteropancreatic; HR: Hazard ratio; IFN: Interferon; LAN: Lanreotide; LA: Long-acting; NET: Neuroendocrine tumor; NR: Not reported; OCT: Octreotide; OS: Overall survival; PAS: Pasireotide; PBO: Placebo; PD: Progressive disease; PFS: Progression-free survival; PR: Partial response; PROMID: Placebo-Controlled, Double-Blind, Prospective, Randomized Study of the Effect of Octreotide LAR (long-acting release) in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors; RCT: Randomized controlled trial; RWE: Real-world evidence; SD: Stable disease; TTP: Time to tumor progression.