Quality of life in patients with gastroenteropancreatic tumours: A systematic literature review

Table 1 Extracted literature

Ref.	Intervention	Comparator(s)	Study design, “Open” Label / “Blinded” / “Double blinded”	Total sample size	Patient sub-group	Pt sub-group sample size	Sex (% female)	Average age (yr)	Mean/median	Total GI-NET, %	P-NET, %	Functioning /Non-functioning, “function”	Additional information about disease1: “Stage (TNM)” “progressive” “stable”, (“advanced” “metastatic/metastases” “spread”) (“grow” “grade” “differentiated”)
Zandee et al[58], 2019	177Lu-DOTATATE	NA	Retrospective study	34	NA	NA	50	59	Mean	NA	100	Functioning (100%)	Grade 1 or 2 tumours with metastases (stage IV). Metastatic disease sites: Liver (97%), bone (21%), lung (6%)
Ramage et al[54], 2019	Everolimus	NA	Phase IV, open	48	All Patients	46	30	64.3	Median	NR	100	NR	Advanced and/or metastatic, well-differentiated, grade 1 and 2
					Continuing treatment at month 6	30	NR	NR	NR	NR	NR
Ballal et al[8], 2019	225Ac-DOTATATE	NA	Prospective study, open	21	NA	NA	57	54	Median	38	57	NR	Metastatic GEP-NETs with stable disease after completing 177Lu-PRRT (57%) or progressive disease on 177Lu-PRRT (43%). Grades 1 (n = 9), 2 (n = 11), and 3 (n = 1). Metastatic disease sites: Liver (86%), lymph node (71%), bone (33%)
Marinova et al[61], 2019	177Lu-DOTATATE	NA	Retrospective study	70	NA	NA	44.3	64.2	Mean	100	NR	Functioning (83%), non-functioning (17%)	Metastatic. Grade 1 (50%), grade 2 (35.7%), unknown (14.3%). Morphological or clinical progression prior to 1st cycle PRRT (78.6%)
Rinke et al[16], 2019	Long-acting octreotide	Placebo (sodium chloride)	Clinical trial (RCT), Phase IIIb trial, double blind, placebo controlled	85	Long-acting octreotide	42	49.4	62.4	Mean	NR	NR	Functioning (39%), non-functioning (61%)	Metastatic, liver metastases (86%)
					Placebo	43		60.3	Mean	NR	NR
					NA	NA		NR	NA	NR	NR
Martini et al[59], 2018	DOTATATE or 90Y-DOTATOC	General population norms	Retrospective study	61	Small intestine NET patients	37	40.5	62.8	Mean	100	0	NR	No brain metastases; otherwise not defined
					P-NET patients	24	37.5	61.0	Mean	0	100
Lewis et al[3], 2018	Not defined	Patients with CS vs patients without CS	Prospective study	50	Without CS (CS)	25	48.0	62.0	Median	60.0	40.0	NR	Advanced, well-differentiated, with liver metastases
					With CS (CS)	25	36.0	67.0	Median	96.0	4.0	NR
Strosberg et al[17], 2018	177Lu-DOTATATE	High-dose octreotide	Clinical trial (RCT), phase III, open	231	177Lu-DOTATATE	117	NR	NR	NR	100	NR	NR	Advanced, progressive, low- or intermediate-grade
					octreotide LAR	114	NR	NR	NR	100	NR
Karppinen et al[46], 2018	NA	Control population	Cross-sectional	134	Impaired excretion	87	55	66.8	Mean	100	NR	Flushing (31%), diarrhoea (63%)	Locally advanced or metastatic disease (91%), grade 1 (54.1%), grade 2 (45.9%)
Cella et al[44], 2018	Telotristat ethyl	Placebo	Clinical trial (RCT), phase III trial, double blind	135	NA	135	48.1	63.6	Mean	NR	NR	NR	Well-differentiated, metastatic NETs and CS inadequately controlled by somatostatin analogues (for ≥ 3 mo)
					Durable responders (DR)	48	52.1	63.4	Mean	NR	NR
					Non-durable responders (DR)	87	46	63.6	Mean	NR	NR
Meng et al[28], 2017	Somatostatin analogue lanreotide	Placebo	Clinical trial (RCT), phase III trial, double blind	204	Lanreotide	101	48	62.1	Mean	NR	NR	Non-functioning	Advanced, well-differentiated or moderately differentiated, somatostatin receptor-positive NETs of grade 1 or 2
					Placebo	103				NR	NR
					Overall	204				NR	NR
Vinik et al[35], 2016	Sunitinib plus best supportive care	Placebo plus best supportive care	Clinical trial (RCT), phase III trial, double blind	171	NA	NA	NR	NR	NR	NA	100	NR	Advanced and/or metastatic, pathologically confirmed, well-differentiated P-NETs with disease progression as assessed by RECIST
Haugland et al[9], 2016	None	None	Cross-sectional	196	None	NA	50.5	65.0	Mean	100.0	0.0	NR	NR
Pavel et al[56], 2016	Everolimus	NA	Clinical trial, Phase IIIb, open, expanded access study	246	P-NET	126	46	61	Median	NR	100	Functioning (n = 38), non-functioning (n = 88)	Metastatic, well differentiated (n = 81), moderately differentiated (n = 26), poorly differentiated (n = 1), unknown (n = 16), missing (n = 2)
					Non P-NET	120	50.8	66	Median	NR	0	Functioning (n = 66), non-functioning (n = 55)	Metastatic, well differentiated (n = 65), moderately differentiated (n = 34), poorly differentiated (n = 2), unknown (n = 19)
Delpassand et al[66], 2014	177Lu-DOTATATE	NA	Clinical trial, phase II, open	37	Patients with available data participated in quality of life questionnaire	27	56.8	63.4	Mean	43.2	37.8	NR	Grade 1 and grade 2, disseminated, progressive, somatostatin receptor-positive. Multiple metastases in the liver: grade 2 (n = 4), grade 3 (n = 26), grade 4 (n = 7). Metastatic disease sites: Liver (n = 34), lymph nodes (n = 16), bone (n = 11), pancreas (n = 8), lung (n = 3)
Ducreux et al[41], 2014	Bevacizumab combined with 5-FU/ streptozocin (Mitry et al[40] 2014)	Capecitabine plus bevacizumab	Clinical trial, phase II, open	34	NA	NA	35	55	Median	NR	100	Functioning (n = 7): CS (n = 3), Zollinger–Ellison syndrome (n = 1), other (n = 3)	Progressive, metastatic disease. Metastatic disease sites: Liver (n = 33), lymph node (n = 14), peritoneum (n = 2), lung (n = 3), bone (n = 2), other (n = 2)
Mitry et al[40], 2014	Bevacizumab combined with 5-FU/ streptozocin (reported in a companion paper focusing on P-NET patients (Ducreux et al[41], 2014)	Capecitabine plus bevacizumab	Clinical trial, phase II, open	49	NA	NA	47	60	Median	100	NA	NR	Progressive, metastatic well-differentiated. Metastatic disease sites: Liver (n = 46), lymph node (n = 24), peritoneum (n = 23), lung (n = 7), bone (n = 7), other (n = 5)
Meyer et al[42], 2014	Capecitabine and streptozocin plus cisplatin (stratified)	Capecitabine and streptozocin (stratified)	Clinical trial (RCT), Phase II	86	Capecitabine and streptozocin	44	39	57	Median	21	46.0	Functioning (n = 31; 36%)	Advanced and/or metastatic. Metastatic disease sites: Local/regional (n = 2), distant (n = 42), liver (included in distant; n = 41)
					Capecitabine and streptozocin plus cisplatin	42	45	59	Median	19	50.0
Yadegarfar et al[33], 2013	Somatostatin analogues or interferon therapy (88 patients)	Peptide-receptor radiotherapy (102 patients), chemotherapy (23 patients), surgery (20 patients) or ablative/ other therapies (20 patients)	Phase IV, open	253	P-NET	70	NR	NR	NR	NR	NR	Functioning: Secreting 5-hydroxy-indoloacetic acid (n = 111), gastrin (n = 4), glucagon (n = 3), insulin (n = 5), vasoactive intestinal peptide (n = 1). Non-functioning (secreting only chromogranin-A; n = 124)	Any gut-primary with metastases, lung-primary with liver/abdominal metastases and pancreas with/without metastases
Casciano et al[36], 2012	Everolimus (Afinitor)	Sunitinib (Sutent)	Economic analysis of phase III studies	NA	NA	NA	NA	NA	NA	NA	NA	NR	Advanced, progressive
Kvols et al[29], 2012	Pasireotide	Octreotide	Prospective study, phase II, open	44	Pasireotide responders	12 (Baseline), 12 (Month 1), 10 (Month 2), 11 (Month 3)	44	61	Mean	NR	NR	NR	Advanced, metastatic (symptoms refractory or resistant to octreotide LAR therapy). Metastatic disease sites: Liver (87%), lymph node (n = 16), peritoneum (n = 8), lung (n = 5), bone (n = 3), abdomen (n = 3), pleura (n = 3), retroperitoneal (n = 2), pancreas (n = 2), kidney (n = 1)
					Pasireotide non responders	13 (Baseline), 13 (Month 1), 13 (Month 2), 13 (Month 3)				NR	NR
					Patients who discontinued treatment before 3 mo	19 (Baseline), 15 (Month 1), 8 (Month 2)				NR	NR
Raymond et al[34], 2011	Sunitinib plus Best Supportive Care	Placebo plus Best Supportive Care	Clinical trial (RCT), phase III, double blind	171	sunitinib	86	51	56	Median	NR	100	Sunitinib Arm: Functioning: Gastrinoma (n = 9), glucagonoma (n = 3), insulinoma (n = 2), somatostatinoma (n = 1), other, multisecretory, or unknown (n = 10). Non-functioning (n = 42)	Advanced and/or metastatic, progressive, well-differentiated
					Placebo	85	53	57	Median	NR	100	Placebo Arm: Functioning: Gastrinoma (n = 10), glucagonoma (n = 2), insulinoma (n = 2), vasoactive intestinal peptide–secreting tumour (n = 2), other, multisecretory, or unknown (n = 5). Non-functioning (n = 44)
Pezzilli et al[49], 2009	NA	NA	Prospective study	51	NA	NA	58.8	61	Mean	NR	100	NR	Advanced disease (lymph node involvement/liver metastases) (n = 22)
Rinke et al[27], 2009	Octreotide LAR	Placebo	Clinical trial (RCT), phase IIIb, double blind	85	Octreotide LAR	42	52.4	63.5	Median	100	NR	Octreotide LAR arm: Functioning: CS (n = 17) 40.5%	Well-differentiated, metastatic. Metastatic disease sites: Liver (n = 73), regional lymph node involvement (n = 6)
					Placebo	43	46.5	61	Median	100	NR	Placebo arm: Functioning: CS (n = 16) 37.2%
Korse et al[30], 2009	Long-acting sandostatin LAR	Short-acting Sandostatin	Clinical trial, phase II	39	NA	NA	51.3	61	Mean	51.3	NR	Functioning: CS (n = 39)	Metastatic: Liver metastases (n = 35)
van der Horst-Schrivers et al[67] , 2009	NA	NA	Prospective study	43	NA	NA	37.2	60.6	Mean	NR	NR	NR	Metastatic midgut carcinoid tumours: Liver metastases (n = 37)
Haugland et al[47], 2009	NA	NA	Cross-sectional	5341	NET patients	189	50	65	Mean	100	NR	NR	GI-NET patients (excluded radical surgery that may have been curative), otherwise undefined
					General population	5152	48.8	NR	NR	NA	NA
Larsson and Janson[50], 2008	Erythropoietin	None	Pilot study	18	None	NA	50.0	63.0	Mean	100	NR	NR	NR
Kulke et al[55], 2008	Sunitinib	NA	Clinical trial, phase II, open	107	NA	NA	40.2	Carcinoid tumour = 58, P-NET= 56	Median	37.3	61.7	P-NET: Functioning: Gastrinoma n = 5 (7.6%), insulinoma n = 3 (4.5%), VIPoma n = 2 (3.0%), glucagonoma n = 4 (6.1%), other n = 5 (7.6%). Non-functioning n = 46 (69.7%)	Advanced carcinoid or P-NET
Fröjd et al[37] , 2007	Various included	None	Longitudinal, prospective, comparative study	59	T1-T4 successful	36	47.0	60.0	Mean	NR	NR	NR	Metastatic (70% metastatic at start; 78% metastatic at end)
Davies et al[68], 2006	NA	NA	Cross-sectional, open	50	Patients	35	42.9	60	Mean	NR	NR	NR	Metastatic
					Healthcare workers	15	NR	NR	NR	NA	NA
Frilling et al[48], 2006	90Y-DOTATOC then 177Lu-DOTATOC	NA	Prospective study	20	Excluding pt (no 3) with Paraganglioma-neck	19	30	53.8	Median	NR	NR	NR	Advanced, progressive, and metastatic
Arnold et al[31], 2005	Octreotide plus interferon alpha	Octreotide monotherapy	Clinical trial (RCT), open	114	Octreotide monotherapy	51	47.1	58	Median	NR	NR	Octreotide: Functioning (n = 23), non-functioning (n = 28). Octreotide plus Interferon-alpha: functioning (n = 24), non-functioning (n = 30)	Metastatic or locally advanced disease without curative therapeutic option
					Octreotide plus interferon alpha	54	44.4	57	Median	NR	NR
					Nonrandomised	9	33.3	60	Median	NR	NR
Teunissen et al[62], 2004	177Lu-DOTATOC	None	Clinical trial	50	None	NA	56.0	58.3	Mean	NR	26.0	NR	Metastatic
Pasieka et al[43], 2004	I-MIBG	NA	Clinical trial, open	19	I-MIBG	10	40	59	Mean	90	10	NR	Progressive
					Octreotide	9	55.6	55.6	Mean	66.6	33.3
Kwekkeboom et al[60], 2003	Somatostatin analogue 177Lu-DOTATOC	NA	Clinical trial, open	35	None	NA	60	54	Mean	NR	NR	NR	Metastatic
Larsson et al[25], 2001	Interferon, somatostatin analogue, interferon, and a somatostatin	None	Prospective study	24	None	NA	42.0	62.0	Median	100	NR	NR	NR
O'Toole et al[32], 2000	Octreotide followed by lanreotide	Lanreotide followed by octreotide	Clinical trial (RTC), double blind	33	Patients received octreotide followed by Lanreotide	16	50	63	NR	62.5	0
					Patients received lanreotide followed by octreotide	17	53	64	NR	76	5.9	NR	NR
Wymenga et al[57], 1999	Lanreotide prolonged release	NA	Clinical trial, phase II, open	55	NA	NA	49.1	59.7	Mean	NR	5.5	NR	Advanced (Stage IV), metastatic. Metastatic disease sites: Lymph nodes (n = 39), distant organs (n = 44)
Larsson et al[26], 1999	Ongoing treatment: interferon and octreotide, other	NA	Cross-sectional	119	Patients with carcinoid tumours	64	43.7	64	Median	53.8	NA	NR	NR
					Patients with EPT	55	37.5	54	Median	NR	46.20
					Overall	119	43.7	61	Median	53.8	46.20
Larsson et al[38] , 1999	Interferon and/or a somatostatin analogue	NA	Clinical trial	99	NA	NA	39.4	59	Mean	NR	NR	NR	Stage = not terminal, no other status provided.
					HADS Anxiety (cases)	19	NR	NR	NR	NR	NR
					HADS Depression (cases)	13	NR	NR	NR	NR	NR
Larsson et al[69], 1998	Interferon and/or a somatostatin analogue	NA	Cross-sectional	17	NA	NA	47	58	Mean	NR	NR	NR	NR

¹Disease description provided in each reference. NA: Not available; P-NET: Pancreas-neuroendocrine tumours; CS: Carcinoid syndrome; NR: Not relevant; HADS: Hospital Anxiety and Depression Scale; PRRT: Peptide receptor radionuclide therapy.

Table 2 Literature reporting scores for health-related quality of life average global health score for gastroenteropancreatic neuroendocrine tumours patients using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30

Ref.	Intervention/comparator	Time point	Global health score	Statistical analysis and P values, as presented in the literature
Arnold et al[31], 2005	Octreotide plus interferon alpha	Baseline	57.9	0.04 (between treatment arms at 3 mo)
		3 mo	51.2
	Octreotide monotherapy	Baseline	63
		3 mo	74.4
Cella et al[44], 2018	Telotristat ethyl	-	Overall: 55.4; Durable responders: 40; Non-durable responders: 66	NR (NS)
Fröjd et al[37], 2007	Various (i.e. interferon, octreotide, chemotherapy and other)	Timepoint 1	58	NR
		Timepoint 2	61	NR
		Timepoint 3	58	NR
		Timepoint 4	58	NR
van der Horst-Schrivers et al[67], 2009	NA	-	61.8	NR
Korse et al[30], 2009	Long-acting sandostatin LAR	Baseline	70	0.275 (repeated measurement analysis using mixed linear models)
		3 mo	71
		6 mo	67
		9 mo	68
		12 mo	64
Larsson et al[50], 2008	Erythropoietin	Baseline	56	NR (NS)
		4 mo	55
		8 mo	66
		2 yr	70
Larsson et al[25], 2001	Interferon, somatostatin analogue, interferon, and a somatostatin.	Baseline	68	NR (NS)
		3 mo	59
		6 mo	58
		9 mo	50
		12 mo	63
Larsson et al[26], 1999	Interferon and/or a somatostatin analogue for at least 4 weeks - Five patients were treated with interferon, three with a somatostatin analogue, and nine with a combination	-	64.71	NR
Larsson et al[38], 1999	Interferon and/or a somatostatin analogue	-	Overall: 66.7; HADS Anxiety (cases): 46; HADS Anxiety (non-cases): 71.6; HADS Depression (cases): 43; HADS Depression (non-cases): 70.2	< 0.001 between HADS anxiety “cases” (n = 19) and “non-cases” (n = 80) and 0.001 between HADS depression “cases” (n = 13) and “non-cases” (n = 86)
Larsson et al[69], 1998	Interferon and/or a somatostatin analogue and/or a combination	-	64.71	NR
Lewis et al[3], 2018	NA	-	Without CS: 63.0; With CS: 61.7	0.04 (between subpopulations)
Marinova et al[61], 2019	177Lu-DOTATATE	Baseline	62.6
		3 mo	66.7	< 0.05 (compared to baseline using mixed longitudinal model)
		6 mo	69.6	< 0.01 (compared to baseline using mixed longitudinal model)
		9 mo	69.4	< 0.01 (compared to baseline using mixed longitudinal model)
Meyer et al[42], 2014	Capecitabine and streptozocin plus cisplatin.	Baseline	69.3
		≤ 9 wk - after 3 × 3 weekly cycles	52.2	0.052 (compared to baseline)
		6 mo	56	0.68 (compared to baseline)
	Capecitabine and streptozocin	Baseline	67
		≤ 9 wk - after 3 × 3 weekly cycles	62.2	0.5 (compared to baseline)
		6 mo	68.9	0.75 (compared to baseline)
Mitry et al[40], 2014	Bevacizumab plus capecitabine	Baseline	67
		6 mo	63	NR (NS)
		12 mo	71	NR (NS)
Pavel et al[56], 2016	Everolimus	End of treatment (compared to baseline)	P-NET: -3.9; non P-NET: -13	NR
Ramage et al[54], 2019	Everolimus	1 mo	FAS Population (paired scores baseline and 1 m): 58	NR (NS)
			Continuing tx at 6m (paired scores baseline and 1 m): 56.9	NR (NS)
		2 mo	FAS Population (paired scores baseline and 2 m): 57.6	NR (NS)
			Continuing tx at 6m (paired scores baseline and 2 m): 56.9	NR (NS)
		3 mo	FAS Population (paired scores baseline and 3 m): 56.7	NR (NS)
			Continuing tx at 6m (paired scores baseline and 3 m): 56.3	NR (NS)
		4 mo	FAS Population (paired scores baseline and 4 m): 56	NR (NS)
			Continuing tx at 6 m (paired scores baseline and 4 m): 56.8	NR (NS)
		5 mo	FAS Population (paired scores baseline and 5 m): 56.6	NR (NS)
			Continuing tx at 6 m (paired scores baseline and 5 m): 58.6	NR (NS)
		6 mo	FAS Population (paired scores baseline and 6 m): 56.9	NR (NS)
			Continuing tx at 6 m (paired scores baseline and 6 m): 56.9	NR (NS)
Raymond et al[34], 2011	Sunitinib	Baseline	67
		"post-baseline"	62.4	NR
	Placebo	Baseline	64
		"post-baseline"	61.3	NR
Rinke et al[16], 2019	Long-acting octreotide	Baseline	64
	Placebo	Baseline	65.7
		12 wk	+4.13 (difference in global health score compared to placebo)	NR
		24 wk	+5.05 (difference in global health score compared to placebo)	NR
		36 wk	+1.85 (difference in global health score compared to placebo)	NR
Strosberg et al[17], 2018	177Lu-DOTATATE	Baseline	67	NR
	High-dose octreotide	Baseline	64	NR
Teunissen et al[62], 2004	177Lu-DOTATOC	Baseline	69
		6 wk	78.2	< 0.01 (Analysis of variance (two-sided) compared to baseline)
Vinik et al[35], 2016	Sunitinib	Baseline	67	NR (NS difference between arms)
		Up to cycle 10 (about 9 mo)	60.4
	Placebo	Baseline	64	NR (NS difference between arms)
		Up to cycle 10 (about 9 mo)	61.3
Wymenga et al[57], 1999	Lanreotide prolonged release	Baseline	60.4
		1 mo	69.7	0.001 (compared to baseline using t tests or Wilcoxon signed rank)
		End of treatment	65.5	NR (NS)
Yadegarfar et al[33], 2013	Somatostatin analogues or interferon therapy	Baseline	61
		3 mo	67	NR
		6 mo	67	NR
Zandee et al[58], 2019	177Lu-DOTATATE	Baseline	61.7
		3 mo (after final PRRT cycle)	79.5	0.002 (compared to baseline using paired t test)

NA: Not available; NET: Neuroendocrine tumours; CS: Carcinoid syndrome; NR: Not relevant; PRRT: Peptide receptor radionuclide therapy; NS: Not significant.

Table 3 The specific domain scores reported in the literature for gastroenteropancreatic neuroendocrine tumours patients using QLQ-GI.NET21

Ref.	Intervention/ comparator	Time point	Endocrine Symptoms	Gastrointestinal Symptoms	Social function	Disease related worries	Muscle/bone pain symptom	Weight gain	Information/Communication function	Body Image	Sexual function	Treatment related symptoms scale
Ramage et al[54], 2019	Everolimus	Baseline (paired scores with 3 mo)	14.8	24.4	44.1	51.1	35.2	NR	1.9	25.9	37	NA
		3 mo	12.3	20.2	42.6	44.8	35.2	NR	4.6	24.1	42.6	22
		Baseline (paired scores with 6 mo)	14.4	25.8	44.8	50.9	33.3	NR	1.1	20	35.6	NA
		6 mo	12.6	21.8	34.4	43.7	30	NR	1.1	21.1	37.8	14.1
Lewis et al[3], 2018	NA	Single timepoint (patients without CS)	16.7	18.9	60.0	56.9	41.3	18.7	10.7	15.3	60.8	17.5
		Single timepoint (patients with CS)	28.4	24.0	68.4	38.7	46.7	13.3	16.0	13.3	68.4	10.1
Yadegarfar et al[33], 2013	Various	Baseline (P-NETs)	22	26	39	56	25	11	10	25	32	18
		3 mo (P-NETs)	16	18	33	44	31	9	4	21	31	22
		6 mo (P-NETs)	18	22	30	50	32	13	10	19	31	23
Ballal et al[8], 2019	225Ac-DOTATATE TAT	Baseline	21.4	40.2	64.3	61.2	38.8	25	NR	28.8	40	6.53
		End of assessment	3.57	22.8	72.9	84.2	26.8	27.8	NR	15.6	45	26.24
Strosberg et al[17], 2018	177Lu-DOTATATE	Baseline	NR	22.8	33.4	43.7	29	NR	5.4	20	30.6	11.6
	High-dose octreotide	Baseline	NR	23.8	37.1	43.8	34.6	NR	12.3	20.3	28.2	11.9
Cella et al[44], 2018	Telotristat ethyl	Baseline (Durable responders)	37.8	33.8	46.7	41.1	35	NR	5	29.1	47.2	18.1
		Baseline (Nondurable responders)	29.5	28.5	38.5	37.6	30.3	NR	7	26.9	32.6	12.8
		Difference in change from baseline between subpopulations	-1.9	-9.6	-2.8	1.9	-4.5	NR	3.9	1	-1.6	-3.4

NA: Not available; P-NET: Pancreas-neuroendocrine tumours; CS: Carcinoid syndrome; NR: Not relevant.