2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

New Frontiers in Mucositis
By Douglas E. Peterson, DMD, PhD, Dorothy M. Keefe, MD, and
Stephen T. Sonis, DMD, DMSc
Overview: Mucositis is among the most debilitating side
effects of radiotherapy, chemotherapy, and targeted anticancer
therapy. Research continues to escalate regarding key
issues such as etiopathology, incidence and severity across
different mucosae, relationships between mucosal and nonmucosal
toxicities, and risk factors. This approach is being
translated into enhanced management strategies. Recent
technology advances provide an important foundation for this
continuum. For example, evolution of applied genomics is
fostering development of new algorithms to rapidly screen
genomewide single-nucleotide polymorphisms (SNPs) for
patient-associated risk prediction. This modeling will permit
individual tailoring of the most effective, least toxic treatment
in the future. The evolution of novel cancer therapeutics is
changing the mucositis toxicity profile. These agents can be
associated with unique mechanisms of mucosal damage.
Additional research is needed to optimally manage toxicity
UCOSITIS” is an umbrella term covering cancer
“Mtreatment regimen-related damage to mucosal
surfaces. Although mucositis has been clinically observed for
several decades, comprehensive advances in pathobiology,
clinical impact, and molecularly targeted treatment have
chiefly occurred the past 15 years. As a result “mucositis”
was incorporated as a medical subject headings (MeSH)
term by the National Library of Medicine in 2006.
Although targeted anticancer therapies can cause mucosal
damage, the actual scope of injury is not identical to that
caused by conventional cancer therapies. While mucositis
is most often considered in relation to the oral cavity and
digestive tract, other mucosae such as respiratory and
genitourinary tract can be affected. The degree of damage is
not uniform, with oral mucositis typically most prominent
with systemic cancer treatments. Conjunctivae and vaginal
mucosa appear uniquely resistant to damage for reasons
that are not well delineated.
Incidence and severity of mucositis is related to the type of
treatment administered, the risk factors of the host, and the
tumor being treated. 1,2 Chemotherapy can cause mucositis
even in a limited number of doses if the agent is sufficiently
mucotoxic, whereas radiation tends to cause local toxicity,
only leading to distant toxicities if a sufficiently high dose is
used. 2 The various targeted agents cause mucositis depending
on cross-reactivity of receptors in the mucosa concerned,
or presence of their known target in mucosa. 3
Standard-dose chemotherapy causes oral mucositis in up
to 40% of patients, whereas high-dose chemotherapy related
to stem cell/bone marrow transplantation causes oral mucositis
in up to 80% of patients. 4,5 Radiotherapy for head
and neck cancer causes oral mucositis in virtually 100% of
patients. 6 Oral mucositis incidence secondary to mTOR
inhibitors is approximately 50%, and incidence of diarrhea
from targeted agents is approximately 40%, albeit of low
grade. 7,8 Chemotherapy causes diarrhea in up to 40% of
patients as well; it is also typically low-grade but can be
more frequent and severe in relation to irinotecan. 9
Given the clinical and economic importance of the toxicity,
there has been an escalating trajectory of basic and clinical
caused by agents such as mammalian target of rapamycin
(mTOR) inhibitors and tyrosine kinase inhibitors, without reducing
antitumor effect. There has similarly been heightened
attention across the health professions regarding clinical
practice guidelines for mucositis management in the years
following the first published guidelines in 2004. New opportunities
exist to more effectively interface this collective guideline
portfolio by capitalizing upon novel technologies such as
an Internet-based Wiki platform. Substantive progress thus
continues across many domains associated with mucosal
injury in oncology patients. In addition to enhancing oncology
patient care, these advances are being integrated into highimpact
educational and scientific venues including the National
Cancer Institute Physician Data Query (PDQ) portfolio as
well as a new Gordon Research Conference on mucosal health
and disease scheduled for June 2013.
research over the past 15 years. 10 This has in turn fostered
development of clinical practice guidelines. These have been
disseminated widely via publications and presentations at
scientific conferences. In addition, clinical management interventions
and their biologic basis have been incorporated
into electronic technologies such as the National Cancer
Institute PDQ website “Oral Complications of Chemotherapy
and Head/Neck Radiation.” 11 A comprehensive update
of this website, including oral mucositis pathobiology, prevention,
and treatment, was posted in March 2011. This
material was the fourth of 35 most frequently viewed Supportive
Care PDQ websites in the following 3 months (April
to June 2011), with continued high activity among health
professionals and patients into 2012.
Effect on Quality of Life (QoL)
Mucositis is but one of the toxicities typically associated
with cancer treatment. It rarely occurs alone; study of links
between toxicities provides information on shared pathobiology
and opportunities for intervention in multiple toxicities.
12,13 The importance of these toxicities lies in the effect
not only on patients’ QoL, but also on their ability to
withstand effective doses of treatment. 14 Dose reductions or
delays lead to reduction in efficacy and survival. Most
clinical trials of cancer treatment do not have toxicity as a
primary endpoint, making evaluation of true incidence difficult.
15 Health professionals’ estimates of incidence and
severity of toxicity may be lower than those reported by
patients themselves. 16
From the Department of Oral Health and Diagnostic Sciences, School of Dental Medicine,
Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington,
CT; University of Adelaide, Adelaide, Australia; Harvard School of Dental Medicine,
Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, and Biomodels,
LLC, Boston, MA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Douglas E. Peterson, DMD, PhD, Department of Oral Health
and Diagnostic Sciences, School of Dental Medicine, University of Connecticut Health
Center, 263 Farmington Ave., Farmington, CT 06030-1605; email: peterson@nso.uchc.edu
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1–10
545