The Management of Mucositis in 2005
Dorothy M K Keefe Chairman, Mucositis Study Group, Multinational Association for Supportive Care in Cancer (MASCC)
Introduction
Mucositis is defined as the damage that occurs to the
tissues of the alimentary canal following
chemotherapy and/or radiotherapy. For many years,
the literature concentrated on the damage done to
the oral mucosa, namely the erythema, mouth ulcers
and pain. However, other more distal parts of the
alimentary canal are affected, particularly the
oesophagus and small intestine, but also the colon
and rectum. In each area, pain is a manifestation, and
in distal damage diarrhea, abdominal bloating and
rectal bleeding can also occur. High dose
chemotherapy, prior to stem cell or bone marrow
transplantation and head and neck radiotherapy, have
the highest frequency of severe mucositis for the
number of patients treated (50% to 90%). However,
the enormous numbers of patients receiving multicycle
standard dose chemotherapy mean that
standard dose chemotherapy actually causes the bulk
of the problem even though the frequencies are
much lower (10% to 30%). Up until very recently,
treatment of mucositis was merely palliative, with the
use of analgesics, mouth washes and treatment
reductions or delays. In 2004, the US Food and Drug
Administration (FDA) approved the first agent
(Palifermin) for the reduction of mucositis in
transplant patients with haematological malignancies.
However, there is still no licensing of any agents for
use in solid tumours and multi-cycle chemotherapy
or radiotherapy.
Measuring Mucositis
There are many scales available for assessing oral
mucositis, and only a few for the assessment of the
rest of the alimentary canal. The discrepancy is partly
to do with the inaccessibility of the distal parts of the
gastrointestinal tract and partly to do with the greater
incidence of oral compared with more distal
mucositis. The scales range from those that are easy
to use in the clinic on a daily basis, such as the World
Health Organization (WHO) and National Cancer
Institute Common Toxicity Criteria (NCI/CTC)
scores, and those that are suited more to intensive
research where highly trained investigators are
performing the assessments. The FDA has recognised the utility of the WHO score in registration trials for
oral anti-mucotoxics, and the NCI/CTC are used
for the rest of the gastrointestinal tract (see Table 1).
Epidemiology and Impact on
Healthcare System
Measuring the exact incidence and severity of
alimentary mucositis is very difficult. These particular
toxicities are often only reported as a secondary endpoint
in clinical trials, and this can lead to underpowering
to detect the true incidence. Well designed,
prospective trials, particularly of the newer anti-cancer
agents, are required to determine the total burden of
this problem. However, in its recent review of the
literature, the Mucositis Study Group of
Multinational Association of Supportive Care in
Cancer (MASCC) did report the incidence of grade 3
or 4 mucositis for various common regimens. The
incidences of grade 1 to 2 mucositis were not felt to
be reliably reported. While the incidence of
gastrointestinal (GI) mucositis was generally lower
than that of oral mucositis (OM) there were
exceptions, such as Irinotecan, where GI mucositis is
much more common than OM. Risks of grade 3 to 4
mucositis ranged from <10% with the anthracyclines
to >15% with 5-Fluorouracil (5-FU). 5-FU and
Irinotecan combined had GI mucositis rates >30%. If
total body irradiation was used with high dose
chemotherapy, the rates of OM exceeded 60%.
While these rates for standard dose chemotherapy
may seem low, the implications for healthcare costs
are enormous. In the presence of Grade 3 to 4
mucositis, 35% of patients will have a dose delay,
60% will have a dose reduction and 30% will have
the treatment stopped all together. More than 50%
will also need feeding tubes and/or admission to
hospital. The incidence of fever is approximately
60%. Opioid analgesic requirements also rise, and the
costs per cycle rise by approximately US$5,500.
Risk Factors
It would be a great advantage to be able to accurately
predict those at the highest risk of developing any form
of mucositis. The risk factors, as currently understood, can be divided into treatment- or patient-related. The
former are the type and dose of chemotherapy, the
location of radiotherapy (increased if alimentary canal is
in the treatment field) and particularly the combined
use of chemotherapy and radiotherapy. The latter are
much harder to define. It was previously believed that
children were at a higher risk than adults. However,
this is not borne out in the incidences reported in
clinical trials. The risks for the elderly are unknown
because they have not been specifically studied. There
is a possibility that gender has an impact, and there is
an increased risk in the obese compared with those of
normal weight. However, this last risk may be due to
inadvertently using larger doses of chemotherapy in the
obese due to body surface area dose calculations.
Overall, risk prediction is currently unsatisfactory.
There is, however, work being done on genetic risk
prediction, and this is an exciting area of research.
