LWBK1006-20 LWW-Govindan-Review December 12, 2011 19:4
Chapter 20•Cancer of the Gastrointestinal Tract 265ANSWERS
Answer 20.4.1. The answer is E.
In the majority of malignant GISTs, a gain-of-function mutation results
in the constitutive activation of the KIT proto-oncogene. Approximately
80% of GISTs harbor mutations in the KIT receptor, whereas another 5%
to 7% have activating PDGFRA mutations. The most common muta-
tion is identified in the KIT juxtamembrane domain, exon 11. Other
mutations in exon 9, 13, 17, and 18 have been described. In the Inter-
group US-Finland study, higher response rates and better outcomes were
observed among patients with GIST with the exon 11 mutation compared
with those with exon 9 mutation. Objective responses to imatinib ther-
apy among patients with GIST with exon 11 and exon 9 mutations are
approximately 70% and 40%, respectively. Patients with wild-type GIST
have a response rate of approximately 30%. Median time to progression
also is longer for those with exon 11 compared with other genotypes. The
higher prevalence of a specific exon 9 mutation among GISTs originating
in the small intestine may explain in part the observation of worse progno-
sis of these tumors compared with gastric GISTs. Although tumor size and
mitotic index carry prognostic significance for patients with GIST, both
have not been associated with response to tyrosine kinase inhibition.Answer 20.4.2. The answer is B.
Current data on adjuvant therapy for patients with resected GIST are
derived from the American College of Surgeons Oncology Group studies,
which demonstrated a 1-year relapse-free survival rate of 97% among
patients who received imatinib at 400 mg PO daily for 1 year, compared
with 83% for those who received placebo, with a hazard ratio of 0.325
(DeMatteo, J Clin Oncol. 25:18S, abstract 10079). Although no survival
benefit was demonstrated, those with tumors greater than 10 cm derived
the most benefit from adjuvant imatinib. A Phase II study on adjuvant ima-
tinib in resected high-risk GIST (tumor size≥10 cm, tumor rupture, or≤ 5
peritoneal metastases) demonstrated improved overall survival compared
with historical controls (DeMatteo, Proc 2008 Gastrointestinal Cancers
Symposium, abstract 8). Three-year recurrence-free survival and overall
survival rates were 61% and 97%, respectively. Current studies are eval-
uating longer duration of adjuvant therapy, but there are no data on the
benefit of adjuvant therapy beyond 1 to 2 years or on the use of sunitinib
in the adjuvant setting.Answer 20.4.3. The answer is A.
No dose adjustment is necessary for patients with mild-to-moderate renal
dysfunction receiving imatinib therapy based on the National Cancer
Institute Organ Dysfunction Working Group Study published by Gib-
bons et al. (Gibbons J, Egorin MJ, Ramanathan RK, et al. Phase I and
pharmacokinetic study of imatinib mesylate in patients with advanced
malignancies and varying degrees of renal dysfunction: a study by the