Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients.
BACKGROUND
Mammalian target of rapamycin (mTOR) inhibitors may have efficacy as an intervention for advanced malignancies. Oral ulceration (OU), reported as mucositis, has been a dose-limiting toxicity for this new class of agents. An analysis of the appearance, course, and toxicity associations of mTOR inhibitor-associated stomatitis (mIAS) demonstrated that the condition is distinct from conventional mucositis (CM) and more closely resembles aphthous stomatitis.


METHODS
Safety data from 78 solid tumor patients enrolled in 2 Phase 1, multicenter trials of the mTOR inhibitor deforolimus (AP23573, MK-8669) were evaluated. Adverse events (AEs) based on National Cancer Institute Common Toxicity Criteria for National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) criteria were coded, consolidated, and stratified according to the presence or absence and duration of concordant OU. The relation between OU and other AEs was analyzed.


RESULTS
Treatment-emergent AEs were reported in 91% of 78 study participants. OUs were reported in 66%, appeared within 5 days of deforolimus administration, and were discrete, ovoid, superficial, well demarcated, and surrounded by an erythematous halo. Their clinical appearance and distribution were similar to that of aphthous stomatitis but inconsistent with CM. Patients with OU were more likely to have nonspecific rashes and acneiform dermatitis but not gastrointestinal AEs.


CONCLUSIONS
OU associated with mTOR inhibitor therapy differed from CM. Lesions more closely resembled those of aphthous stomatitis. The lack of other gastrointestinal involvement but the presence of a higher incidence of concomitant cutaneous AEs provided additional evidence to suggest a distinction between mIAS and CM. Treatment strategies for aphthous stomatitis may be a rational approach for the prevention and control of mIAS.
Division of Oral Medicine and Dentistry, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA02115, USA. ssonis@partners.org
Stephen
S
Sonis
Nathaniel
N
Treister
Sant
S
Chawla
George
G
Demetri
Frank
F
Haluska
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced*; D009369:Neoplasms / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives*; D013280:Stomatitis / Q000139:chemically induced; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; C515074:ridaforolimus; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus