Devita, Hellman, and Rosenberg's Cancer

LWBK1006-20 LWW-Govindan-Review December 12, 2011 19:4

266 DeVita, Hellman, and Rosenberg’s CANCER: Principles and Practice of Oncology Review

National Cancer Institute Organ Dysfunction Working Group. J Clin

Oncol. 2008;26:570–576). Although there was an increase in imatinib

drug exposure in patients with mild-to-moderate renal dysfunction, this

was not associated with any meaningful toxicities. Doses up to 600 to

800 mg daily were tolerable for those with moderate and mild renal dys-

function, respectively. In another study by Ramanathan et al. (Gibbons

J, Egorin MJ, Ramanathan RK, et al. Phase I and pharmacokinetic study

of imatinib mesylate in patients with advanced malignancies and vary-

ing degrees of liver dysfunction: a study by the National Cancer Institute

Organ Dysfunction Working Group. J Clin Oncol. 2008;26:563–569),

patients with mild hepatic dysfunction were able to tolerate imatinib doses

up to 500 mg daily. No relationship was found between imatinib pharma-

cokinetics and severity of hepatic dysfunction. The authors recommended

that for patients with moderate or severe hepatic dysfunction, patients can

be dosed at 400 mg daily with close monitoring for toxicity or to start at

300 mg daily and rapidly escalate the dose to 400 mg daily if tolerated.

Answer 20.4.4. The answer is D.

Primary resistance to imatinib, manifested by continued tumor growth

within the first 6 months of imatinib therapy, occurs in a minority of

GISTs. Secondary resistance generally occurs after a median of 24 months

of continued tyrosine kinase inhibition. Acquired mutations in KIT or

PDGFRA have been implicated in the development of drug resistance to

imatinib. The emergence of KIT-independent genotypes may also result

in imatinib resistance. Sunitinib was approved by the Food and Drug

Administration for the treatment of GIST after disease progression or

intolerance to imatinib. The pivotal Phase III study demonstrated a supe-

rior time to progression of 27.3 weeks for patients treated with sunitinib

compared with 6.4 weeks for patients treated with placebo. Six-month

survival rates also favor sunitinib at 79.4% compared with 56.9% for

placebo. With the crossover design, the advantage for survival benefit on

longer follow-up diminished. A subset analysis showed improvement in

response rates and outcomes for patients with GIST harboring exon 9

mutation compared with those harboring exon 11 mutations. Responses

were also observed among patients with wild-type genotype.

Answer 20.4.5. The answer is C.

Biochemical and clinical hypothyroidism has been associated with suni-

tinib therapy. Rini et al. reported an 85% rate of thyroid dysfunc-

tion associated with sunitinib use (Hypothyroidism in patients with

metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst.

2007;99:81). Routine monitoring of thyroid function test is warranted,

and thyroid hormone replacement therapy may alleviate symptoms. The

precise mechanism for sunitinib-associated hypothyroidism is unclear.

Destructive thyroiditis through follicular apoptosis has been postulated

for sunitinib-associated thyroid dysfunction based on the observation

of transient thyroid-stimulating hormone suppression and subsequent

absence of visualized thyroid tissue. Other causes of fatigue associated

with sunitinib include adrenal insufficiency or congestive heart failure.