Molecular basis and management of gastrointestinal stromal tumors

Table 1 Risk stratification of primary GISTs

Tumor feature		Risk of tumor progression
Mitotic index	Size (cm)	Stomach	Small bowel1
< 5/50 HPF	≤ 2	Very low	Very low
	> 2 ≤ 5	Very low	Low
	> 5 ≤ 10	Low	Moderate
	> 10	Moderate	High
≥ 5/50 HPF	≤ 2	Very low	Moderate
	> 2 ≤ 5	Moderate	High
	> 5 ≤ 10	High	High
	> 10	High	High

Modified from Hornick et al[33] Copyrighted permission from Elsevier Inc.

¹GISTs arising from other sites should probably be stratified as small bowel tumors. GISTs: Gastrointestinal stromal tumors; HPF: High power fields.

Table 2 Adjuvant and neoadjuvant trials of imatinib in patients with GISTs

Trial	Accrual	Eligibility	Therapy (n)	End points
Phase II study of adjuvant imatinib mesylate in patients with completely resected high-risk primary GIST (ACOSOG-Z9000)	Closed	Diameter > 10 cm or tumor rupture or multifocal	Imatinib 400 mg daily for 1 year (107)	2-year OS: 97%, 2-year RFS: 73%[33]
Phase III randomized study of adjuvant imatinib mesylate in patients with resected primary GIST (ACOSOG-Z9001)	Closed	Diameter > 3 cm	Imatinib 400 mg daily for 1 year (359)	1-year RFS: 98%[36]
			Placebo (354)	1-year RFS: 83%
EORTC soft tissue and bone sarcoma group (EORTC-62024) randomized phase III trial	Closed	Diameter > 5 cm or mitotic rate > 5/50 HPF	Imatinib 400 mg daily for 2 years	Primary: OS
			Observation (Total projected 750)	Secondary: RFS and safety
Scandinavian sarcoma group trial SSGXVIII	Closed	Diameter > 10 cm or mitotic rate > 10/50 HPF or > 5 cm and > 5/50 HPF or tumor rupture	Imatinib 400 mg daily for 36 mo	Primary: RFS
			Imatinib 400 mg daily for 12 mo (Total projected 280)	Secondary: OS, safety
Phase II study of neoadjuvant and adjuvant imatinib mesylate in patients with primary or recurrent potentially resectable malignant GIST (RTOG-S0132)	Closed	Locally advanced or metastatic/recurrent	Imatinib 600 mg daily for 6-8 wk followed by debulking/resection (52)	2-year PFS: 80%, objective response rate: 6%, R0 resection in 65%[39]
Five year adjuvant imatinib mesylate in GIST (Phase II)	Open	Diameter > 2 cm and mitotic rate > 5/50 HPF or non-gastric GIST > 5 cm	Imatinib 400 mg daily for 5 years (Projected 133)	Primary: Time to recurrence
				Secondary: Safety
Phase II study of neoadjuvant imatinib mesylate in patients with locally advanced gastrointestinal stromal tumor (Germany/Austria)	Open	Locally advanced, KIT expressing, histologically confirmed GIST	Imatinib 400 mg daily/BID (Projected 40)	Primary: ORR Secondary: R0-resectability and organ-preserving resectability

OS: Overall survival; RFS: Relapse-free survival; PFS: Progression-free survival.

Table 3 Prevalence of c-kit and PDGFR-A mutations and clinical responses in advanced GISTs to imatinib and sunitinib correlated with mutational status

Genotype	Prevalence[59-61]	Clinical benefit from imatinib[15,58,59]	Clinical benefit from sunitinib[581
KIT exon 9 mutation (%)	5-14	74-81	60
KIT exon 11 mutation (%)	57-69	83-93	35
KIT exon 13 mutation (%)	< 5	60-100 (few cases)	65
KIT exon 17 mutation (%)	< 5	75-80 (few cases)
PDGFR-A mutations (%)	3-8	40-66	0 (few cases)
Both wild-type (%)	5-10	33-73	55

Clinical benefit is defined as complete, partial response or stable disease. ¹In imatinib-resistant GIST.

Table 4 Novel agents being developed for GIST therapy

Agent	Molecular target	Clinical benefit in pilot studies
Kinase inhibitors
Nilotinib	KIT, PDGFRs, bcr-abl	46%-77%[69,70]
Sorafenib	Raf, KIT, PDGFR-B, VEGFR, FLT3, RET	71%[71]
Dasatinib	Src, ABL, KIT, PDGFRs	Phase II ongoing in advanced sarcomas and accepting patients
AZD2171	VEGFR, KIT, PDGFRs	Phase II ongoing, not recruiting
OSI-930	VEGFR, KIT	Phase I ongoing, not recruiting
PTK787	VEGFR, KIT, PDGFRs	67%[74]
XL820	KIT, PDGFR-B, VEGFR	Phase II ongoing, not recruiting
AMG706	VEGFR, KIT, PDGFRs, RET	24%-27%[75,76]
mTOR and AKT inhibitors
Perifosine	AKT	Phase II ongoing in combination with imatinib
Everolimus	mTOR	26%[73]
Temsirolimus	mTOR	Phase II ongoing, closed recruitment
Others
IPI-504	Hsp90	78%[72], phase III ended due to safety concerns
Flavopiridol	Transcription inhibitor	Phase I ongoing in combination with doxorubicin

Clinical benefit is defined as complete or partial response or stable disease.