Pocket Oncology (Pocket Notebook Series), 1st Ed.

GASTROINTESTINAL STROMAL TUMOR

James J. Harding and William D. Tap

Epidemiology

• Incidence: ∼5000 new cases/y in US, underreported for many y

• 1–3% all GI malignancies; most common gut mesenchymal tumor

• No clear RFs, median dx age ∼60, more common in men

• Rare hereditary syndrome

Germline Mt c-KIT or PDGDR-a = GIST + skin hyperpigmentation + urticaria pigmentosa

Carney–Stratakis syndrome; germline Mt in SDH = GIST + paraganglioma

Neurofibromatosis type 1NF1 Mts; ↑ incidence GIST

Pathology

• Cell of origin, related to interstitial cells of Cajal (located in the myenteric plexus & control gut peristalsis)

• c-KIT oncogene encodes the cell-surface receptor TK, KIT (CD117); Nl pathway: Stem cell factor, the ligand for KIT → KIT dimerization & phosphorylation → activation of multiple signaling cascades → cell growth

• c-KIT is mutated & activated in ∼90% of GISTs

• Mts on: Exon 11 (intracellular juxtamembrane domain, ∼70% cases), 9 (extracellular domain, up to 20% cases, >intestinal GIST), 13 & 17 (rare <5%)

• ∼5–10% GIST do not have ↑ KIT expression or activity, AKA “KIT negative GISTs;” in these cases somatic Mts in PDGFR-α, BRAF, & SDH have been observed

Carney’s Triad: GIST + paraganglioma + pulmonary chondroma, a/w somatic SDH Mts

• Anatomic Sites: Stomach (∼60%), small intestine (∼30%), less common sites include large bowel, esophagus, & mesentery

Clinical Manifestations

• Sx: Incidentally found or after the evaluation of nonspecific sx; Abd pain, N/V, gastric outlet obstruction, early satiety, anorexia, wt loss, upper GIB (occult or acute hemorrhage), intraperitoneal hemorrhage

• In late-stage GIST dissemination through IP cavity; lung, LN, bone mets are rare

• Exam: Palpable abdominal mass

• Labs: Microcytic anemia

Diagnostic Evaluations and Staging

• EGD or EUS w/FNA to establish dx

• Friable tumor, can hemorrhage, therefore, EUS–FNA is preferred to CT-guided percutaneous bx

• Pathology review:

IHC CD117 (+), diagnostic molecular pathology for c-KIT or PDGFR-α Mt

DOG1, a receptor chloride channel, is expressed on both KIT ± GISTs, can make dx in difficult cases

• EOD w/CT-CAP or MRI

• FDG-PET scan; GIST have high levels of avidity, early marker of response to TKIs

• Prognostic staging depends upon: Size of 1°, location of 1° & mitotic index; Gold Nomogram (Lancet Onc 2009;10:1045)

Treatment of Resectable and Locally Advanced Disease

• 1º tx modality is surgical resection

Complete resection w/negative margins is goal

Lymphadenectomy not required

Tumor is friable, forms pseudocapsule, surgery is optimized to prevent rupture (peritoneal dissemination)

Complete resection possible in 80% of cases

1° resected GIST 5-y disease-specific survival ∼50% (Ann Surg 2002;231:51)

Resectable but high morbidity OR not resectable → preoperative Rx w/imatinib

• Neoadj Rx; prospective trials indicate safety of imatinib in preop setting; difficult to ascertain if preop Rx ↑ OS as most trials gave postresection Rx; preferred strategy in rectal GIST to improve surgical outcome

• Adjuvant Rx: Imatinib ↑ OS w/longer duration of dosing; key clinical trials:

ACOSOG Z9001 → Phase III RCT of 1° localized GIST (>3 cm) to y of placebo vs. imatinib, ↑ RFS, no ΔOS, subset analysis ↑ OS in intermediate risk (6–10 cm) or high-risk (>10 cm) GIST (Lancet2009;373:1097)

Scandinavian Sarcoma Group → Phase III RCT of 1-y vs. 3-y imatinib in high-risk GIST, ↑ RFS/OS w/3 y of Rx. ∼10% absolute ↑ in 5-y OS (JAMA 2012;307:1265)

Trials w/longer duration of Rx are ongoing; current evidence suggests adjuvant imatinib is cytostatic, ie, may need long-term or indefinite Rx

• Surveillance: CT-CAP or MRI q3–6mos for 3–5 y

Treatment of Unresectable and Metastatic Disease

• Imatinib Mesylate

Selective inhibitor of KIT receptor TK; blocks ATP-binding domain

Multiple Phase II/III clinical trials shown benefit

Benefit in exon 11 > exon 9 > exon 13 or 17 Mts

Key trials of imatinib in adv GIST

RCT of 400 mg QD vs. 600 mg QD imatinib; ORR in all pts >50%, no ΔPFS/OS (NEJM 2002;347:472)

RCT of 400 mg QD (low dose) vs. 400 mg BID (high dose) imatinib; ORR & OS equivalent; ↑ tox but ↑ PFS w/high dose (Lancet 2004;364:1127)

RCT of low-dose vs. high-dose imatinib; median OS 51–55 mos; no ΔORR/PFS/OS between groups; after POD, pts who cross over to high dose had 33% ORR or SD (JCO 2008;26:626)

STANDARD therefore is imatinib 400 mg QD for adv GIST; consider ↑ to high dose in exon 9 Mts

• Resistance to imatinib/POD: 1° = POD <6 mos (more common in exon 9 Mt), 2° = >6 mos (typically develop 2° Mts in exon 11); Treat w/sunitinib

• Sunitinib

Multi-targeted TKI

RCT sunitinib vs. placebo in imatinib resistant GIST, sunitinib ↑ PFS/OS, RR ~10% (Lancet 2006;368:1329)

Higher RR, ↑ PFs/OS in exon 9 Mts

• Second gen. TKIs such as regorafenib, sorafenib, nilotinib, dasatinib, pazopanib can be used after POD after imatinib & sunitinib

GRID trial → Phase III RCT of GIST pts w/failure to imatinib/sunitinib to regorafenib vs. placebo; regorafenib w/↑ PFS compared to placebo (∼5 mos vs. 1 mo) (Lancet 2013;381:295)

• Prior to TKI, GIST considered not sensitive to chemotherapy & RT