2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

MUCOSAL INJURY CAUSED BY CANCER THERAPIES
Table 1. Selected Agents in Development for the Prevention/Treatment of Mucositis a
Stage of Trial Versus
Cancer Treatment Chemotherapy Radiotherapy
have emerged as poor predictors of risk. In contrast, and
based on the fact that virtually every mechanistically
important pathway in human biology is genetically controlled,
differences in gene expression are key risk determinants.
For example, oxidative stress and proinflammatory
cytokines have been implicated in development of mucositis.
30,31 Sharp increases in reactive oxygen species are noted
almost immediately after exposure to drug or radiation with
a resultant cascade of events that cause tissue destruction. 32
Based on this observation, studies directed at genes controlling
the metabolism of reactive oxygen species have identified
deletion-specific nucleotide polymorphisms that, when
present in a patient, are associated with increased risk of
mucositis induced by both chemotherapy 33 and radiation. 34
In addition, both systemic and tissue-associated increases
of proinflammatory cytokines (i.e., TNF-�) are associated
with regimen-related mucosal injury. 30,31 Genetically controlled
variability in pro-inflammatory cytokine production
and its association with disease status has been well established.
For example, the presence of SNPs associated with
Targeted Cancer
Therapy
Preclinical AMP-18/NX002 AMP-18/NX002
PMX-30063 CBLB502
TXA127 OralX
TZP-201 Transcutaneous electrical nerve stimulation
Phase I Elsiglutide Dexlansoprazole
Glucarpidase Glucarpidase
Oral selenium SGX201
Phase II AG013 ALD518 Doxycycline hyclate
Buprenorphine Camomilla recutita mouthwash
GelClair Clonidine lauriad
Lactobacillus CD 2 lozenges Dexpanthenol mouthwash
LED therapy GelClair
Omegaven Honey mouthwash
Oral impact IZN-6N4 (botanical extracts)
rhEGF LED therapy
rhGM-CSF L-lysine
Sargramostim (GM-CSF) rhGM-CSF
SCV-07 Sargramostim (GM-CSF)
Selenomethionine SCV-07
Selenomethionine
Phase III Amifostine trihydrate Amifostine trihydrate Caphosol
Caphosol Caphosol
Celecoxib Celecoxib
Fosaprepitant Doxepin hydrochloride rinse
Glutamine Fosaprepitant
Low-level laser light therapy Humidification
Palifermin Hyperbaric oxygen
Hyperimmune colostrum
Iseganan hydrochloride
Palifermin
Pilocarpine
rhEGF
Postmarketing Glutamine popsicles Impact enteral nutrition
Impact enteral nutrition Palifermin
Lenograstim
Morphine
MuGard
Palifermin
Epigallocatechin gallate
Abbreviation: LED, light-emitting diode.
a Source: ClinicalTrials.gov and industry websites.
TNF-� has a significant effect on severe toxicity risk (p �
0.005), including mucositis, in an allogeneic stem cell transplant
population. 35
Despite the importance of these lines of research, however,
the strategy of identifying “the” gene or SNP that
predicts toxicity is limited by the presumption that a single
genetic entity is controlling overall toxicity expression. Further,
although genetically controlled deficits in metabolic
enzymes have been consistently associated with toxicity
risk, the percentage of patients manifesting these genetic
alterations is minute compared with the numbers of patients
who develop mucositis.
Perhaps a more comprehensive assessment of genetically
based risk could thus be biologically valid. An alternative
approach has thus been recently validated. 36 The methodology
is based on a concept that recognizes that a phenotype is
at least as likely to be the consequence of a team of genes
working cooperatively as it is due to the expression of a
single master gene. The analysis employs Bayesian networks
derived from unsupervised and learned networks of
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