Current treatment strategies and future perspectives for gastrointestinal stromal tumors

Table 1 Various laparoscopic and endoscopic cooperative surgery procedures for gastrointestinal stromal tumors

Procedure	Yr	Author	Indication	Non-exposure	First approach	Preferred type and location	Extraction site	Suturing
Classical LECS	2008	Hiki	< 5 cm ulcer (-)	No	Endoscopic	Intraluminal > extraluminal; Anterior wall	Trans abdominal	Hand or mechanical
Inverted LECS	2012	Nunobe	< 5 cm ulcer (±)	No	Endoscopic	Intraluminal > extraluminal; Anterior wall	Either site	Hand or mechanical
Closed-LECS	2017	Kikuchi	< 3 cm ulcer (+)	Yes1	Endoscopic	Intraluminal < extraluminal; Anterior wall	Trans oral	Hand
NEWS	2011	Goto	< 3 cm ulcer (+)	Yes	Laparoscopic	Intraluminal < extraluminal; Anterior wall	Trans oral	Hand
CLEAN-NET	2012	Inoue	< 3 cm ulcer (+)	Yes	Laparoscopic	Intraluminal < extraluminal; Anterior wall	Trans abdominal	Mechanical
PEIGS	1995	Ohashi	< 3 cm ulcer (+)	No	Laparoscopic	Intraluminal > extraluminal; Posterior wall	Either site	Hand or mechanical

¹Open the gastric wall.

LECS: Laparoscopic endoscopic cooperative surgery; NEWS: Non-exposed endoscopic wall-inversion surgery; CLEAN-NET: Combination of laparoscopic and endoscopic approaches to neoplasia with a non-exposure technique; PEIGS: Percutaneous endoscopic intragastric surgery.

Table 2 Studies on neoadjuvant imatinib therapy for gastrointestinal stromal tumors

Ref.	Clinical trial	Yr	Design	Endpoint	Cases	Agent/Dose	Patients	Duration	RR	R0 rate	Adjuvant imatinib	PFS	OS
Prospective study
Eisenberg et al[39]	RTOG0132 trial	2009	Phase II	RFS	30 (all; 52)	Imatinib/600 mg	GIST (> 5 cm)	8-12 wk	7%	77%	24 mo	2-yr PFS; 83%	2-yr OS; 93%
Wang et al[40]	RTOG0132 (long follow up)	2012			31 (all; 53)							5-yr PFS; 57%	5-yr OS; 77%
Doyon et al[41]		2012	Phase II	RR	14	Imatinib/400 mg	Locally advanced GIST	6 mo	43%	79%	12 mo	4-yr DFS; 64%	4-yr OS; 100%
Kurokawa et al[42]	Asia	2017	Phase II	PFS	53	Imatinib/400 mg	Gastric GIST (> 10 cm)	6-9 mo	62%	91%	36 mo	2-yr PFS; 89%	2-yr OS; 98%
Retrospective study
Blesius et al[35]	BFR14 trial	2011	Subset phase III	-	25	Imatinib/400 mg	Locally advanced GIST	4.2 mo (median)	60%	32%	13-24 mo	3-yr PFS; 67%	3-yr OS; 89%
Rutkowski et al[36]	EORTC	2012	Database	-	161	Imatinib/400 mg	Locally advanced GIST	40 wk (median)	80%	83%	At least 1 yr (56%)	5-yr DFS; 65%	5-yr DSS; 95%
Tielen et al[37]		2013	Database	PFS/OS	57	Imatinib/400 mg	GIST (> 5 cm) and/or ill-located for surgery	8 mo (median)	83%	84%	1, 2 yr or lifelong (58%)	5-yr PFS; 77%	5-yr OS; 88%

RFS: Relapse-free survival; RR: Response rate; PFS: Progression-free survival; OS: Overall survival; DSS: Disease-specific survival.

Table 3 Clinical studies on adjuvant imatinib

Trial	ACOSOG Z9001	SSG XVIII/AIO	EORTC 62024	PERSIST-5
Study/yr	Phase III/2009	Phase III/2012, 2020	Phase III/2015	Phase II/2018
Number	359 (total: 713)	397 (199 vs 198)	454 (total: 908)	91
Eligible criteria	Tumor size ≥ 3 cm	High risk group	Intermediate and high-risk group	Intermediate and high-risk group
Treatment dose	400 mg/d	400 mg/d	400 mg/d	400 mg/d
Duration	1 yr vs placebo	1 yr vs 3 yr	2 yr vs placebo	5 yr
Risk classification
High risk	NA	178 (89%)	266 (58.6%)	67 (74%)
Intermediate risk		15 (8%)	186 (41%)	24 (26%)
Etc.		6 (3%)	2 (0.4%)
Residual tumor
R0	325 (90.5%)	169 (85%)	381 (83.9%)	90 (99%)
R1,2	34 (9.5%)	30 (15%)	73 (16.1%)	0 (0%) 1; unknown
Tumor rupture
No	NA	164 (82%)	404 (89%)	NA
Yes		35 (18%)	50 (11%)
End point
Primary endpoint	RFS	RFS	IFFS	RFS
Secondary endpoint		OS, safety	RFS, OS, safety	OS
Results	1-yr RFS; 98% vs 83% (HR = 0.35, P < 0.0001); OS: Not significant	5-yr RFS; 71% vs 53% (HR = 0.66, P = 0.003); 5-yr OS; 92% vs 86%; 10-yr OS; 79% vs 65%	5-yr IFFS; 87% vs 84% (HR = 0.79, P = 0.21); 3-yr RFS; 84% vs 66%; 5-yr RFS; 69% vs 63%	5-yr RFS; 90%; 5-yr OS; 95%; 45 (49%) pts early discontinuation of imatinib

NA: Not associated; RFS: Relapse-free survival; OS: Overall survival; IFFS: Imatinib failure-free survival.

Table 4 Clinical features of various molecular subtypes of gastrointestinal stromal tumors

Gene mutation	Exon	Proportion	Common mutation	Treatment	Characteristics
KIT	11	70%	Del-inc557/558	Sensitive to imatinib, secondary mutation resistant to sunitinib, some effect for regorafenib	High risk of recurrence
			p.W557_K558 del		Adverse prognosis effect in stomach
			SNSs and Dup		Relatively good prognosis
	9	10%	A502-'503 Dup	Need high dose of imatinib, effective for sunitinib	Mainly in small intestinal, worse prognosis
	13	1%	Lys642Glu	Secondary mutation resistant to imatinib	Mainly in small intestinal
	17	1%	Asn822Lys	Secondary mutation resistant to imatinib and sunitinib, but responding to regorafenib	Mainly in small intestinal
	8	0.30%	Del-Asp419	Sensitive to imatinib	Extragastric, metastatic prone nature
PDGFRA	18	5%	Asp842Val (D842V)	Responds to avapritinib, resistance to imatinib	Mainly in gastric and favorable prognosis
	14	1%	Apn659Lys	Sensitive to imatinib	Relatively good prognosis
	12		V561D	Sensitive to imatinib	Relatively good prognosis
Wild-type GIST		10%-15%	SDH-deficient	Not sensitive to imatinib, response to sunitinib, regorafenib	Overall indolent disease
			NF1	Not sensitive to imatinib, response to sunitinib	Mainly in the small intestine and good prognosis
	15	1%	BRAF	Not sensitive to imatinib, response to dabrafenib	Relatively good prognosis
			K-RAS	Not sensitive to imatinib

PDGFRA: Platelet derived growth factor receptor; SNSs: Single-nucleotide substitutions; Dup: Duplication; SDH: Succinate dehydrogenase; NF1: Neurofibromatosis type 1.