2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

MUCOSAL INJURY CAUSED BY CANCER THERAPIES
Organization (Alphabetical Order) URL
The SNP algorithm follows a similar pattern with a couple
of caveats. First, the number of SNPs far exceeds 1,000, so
developing the “team” requires billions of computergenerated
calculations. Second, we have the ability to compare
predictive accuracy against a clinical observation
(almost like being able to see how each performed in the real
world). Third, we are not limited to only nine players being
on the team. Understanding that nongenetically controlled
factors (e.g., epigenetic pathways, concomitant disease) also
have potential to influence risk imposes an additional challenge,
but the analytic algorithms have the capacity to
overlay and integrate these elements into a risk-prediction
model.
This approach has been recently applied to the practical
clinical problem of predicting oral mucositis risk for patients
with hematologic malignancies receiving standard conditioning
regimens in preparation for hematopoietic stem cell
transplant (HSCT). These treatments typically result in
severe mucositis in almost 40% of treated patients. 4 Records
of approximately 500 patients who had received HSCT were
reviewed, and we identified groups of patients who had
developed significant mucositis and patients who had no
stomatotoxicity. With DNA extracted from the saliva of each
patient we ran genome-wide SNP arrays. Using a Bayesian
network framework in computer algorithms that were similar
to the recruitment of the Chicago ASCOs, we were able
to identify a subset of SNPs that predicted mucositis (unpublished
data; ST Sonis).
Applied genomics also provides a platform for the differentiation
of patients who respond to a particular drug from
those who do not. Using RNA obtained from subjects before
and after their participation in a clinical trial, a cluster of
genes was derived that was associated with drug response
as measured clinically by its ability to modify the course of
chemoradiation-associated oral mucositis. Knowing this information
in a phase II study could be transformative to
subsequent study design. Inclusion criteria could be specifically
adopted to reflect known responder genomics, resulting
in the need for fewer subjects to power the study such
that the trial was efficient, economical, and optimized for a
successful outcome. This application of personalized medicine
to determination of risk and selection of effective
therapies for mucosal toxicities is no longer hypothetical. Its
continued development represents a new frontier that will
continue to expand as new treatments become available. 38
Table 2. Examples of Mucositis Guidelines
ASCO http://jco.ascopubs.org/content/27/1/127.full
ESMO http://annonc.oxfordjournals.org/content/22/suppl_6/vi78.full
MASCC/ISOO http://www.mascc.org/mc/page.do?sitePageId�88037
NCCN http://www.nccn.org/JNCCN/PDF/mucositis_2008.pdf
ONS http://www.ons.org/Research/PEP/Mucositis
RTOG http://www.onlinecancereducationforum.com/OCEF/Oral%20mucositis%20in%20head%20and%20neck%20cancer.pdf
Atlantic Provinces Pediatric
Hematology Oncology Network
http://www.apphon-rohppa.com/en/guidelines/mucositis-guidelines
Meta-analysis: Cochrane review
(prevention)
http://summaries.cochrane.org/CD000978/interventions-for-preventing-oral-mucositis-for-patients-with-cancer-receiving-treatment
Meta-analysis: Cochrane review
(treatment)
http://summaries.cochrane.org/CD001973/interventions-for-treating-oral-mucositis-for-patients-with-cancer-receiving-treatment
Abbreviations: ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; MASCC/ISOO, Mucositis Study Group of Multinational
Association for Supportive Care in Cancer/International Society of Oral Oncology; NCCN, National Comprehensive Cancer Network; ONS, Oncology Nursing Society;
RTOG, Radiation Therapy Oncology Group.
New Frontier 3: New Types of Cancer Therapy
A number of targeted anticancer therapies are now in
regular use or on the cusp of being clinically available. Still
more are in development. With them come a new battery of
mucosal toxicities, some unique to particular agents and
others synergistic with other forms of conventional therapy.
27 The mucosa has not escaped as a tissue at risk and, in
fact is actually a common site for toxicities. 3
Toxicity data thus continue to accumulate at a rapid rate.
In general, the mechanism underlying the pathogenesis of
mucosal injury has not been well studied, although it likely
occurs through different pathways than those described for
cytotoxic drugs or radiation. Consequently, clinical course
may vary with respect to onset, duration, cycle-associated
risk, and clinical presentation. Diarrhea is common, as is
exacerbation of mouth ulcers.
The mTOR inhibitors illustrate the unique presentation
of targeted therapies. Of patients receiving this drug class,
approximately 40% will develop severe oral mucosal lesions.
39 These differ from conventional mucositis in time to
onset, duration, cycle-related dependence, and clinical
presentation. 39-41 Interestingly, concomitant toxicities typically
seen with oral mucositis (other gastrointestinal toxicity)
are uncommon, whereas rash is more frequent. 39-42
These differences are likely attributable to variations in
biologic pathways that contrast between the two types of
treatment.
As targeted therapies continue to evolve, more aggressive
investigation to understand their cellular etiologies will be
critical to develop effective interventions.
New Frontier 4: Studies Involving Nonalimentary Tract Mucosa
The mucosal surfaces share similarities of development
and structure, but have important differences relating to
their individual functions. Normal tissue has a limited
number of ways in which it can respond to insult, including
response to cancer therapy. The cancer community can learn
from other experts in mucosal health and disease such as
gastroenterologists, 43 and it is also likely that members of
the oncology community can provide key insights to the
modeling of nonalimentary tract mucosal lesions. For example,
and as noted previously, regimen-related mucosal injury
does not occur with equal frequency across other types of
mucosa. Why is it that patients receiving levels of chemo-
549