Can Cytokines Predict the Severity of Acute Mucositis and the Need for PEG During Chemo-Radiation Treatment to Head and Neck Cancer?
Mucositis has a significant detrimental effect on patient's quality of life in terms of
pain, ability to eat, to swallow and talk. It may be so severe that an interruption of
therapy is required, consequently influencing tumor response and overall patient outcome.
The degree of mucositis varies between different patients: some patients may develop a
limited condition, confined to patches of mildly sore erythematous mucosa, while others may
experience diffuse areas of painful ulceration.
In the more severe cases, pain may be so overwhelming that it prevents patients from
swallowing food and fluids. The patient is therefore at a risk to develop malnutrition, and
must be treated vigorously. In this respect, the use of gastrostomy tubes (PEG) has been
shown to be beneficial.
Another aspect of radiation induced mucositis is its health-care costs. Patients with more
severe mucositis have statistically greater outpatient support costs; these include
maintenance of appropriate nutritional and hydration support, such as placement of
gastrostomy tubes. In the U.S, the mucositis overall medical costs are in the order of
approximately $3000±$1000, per treatment.
Completion of the full course of irradiation, without interruption, is important for
achieving best possible results in cancer of the H&N. It is therefore essential to identify
and refer patients at risk to receive effective and timely nutritional intervention.
Since mucositis represents a clinical continuum which differs between patients, it is
difficult to assess before-hand which patients will be at risk to develop severe mucositis
during the course of radiotherapy. In today's practice, patients undergoing radiation
therapy of the H&N will undergo feeding gastrostomy by the treating physician prior to the
treatment if he will anticipate severe mucositis, based on the radiation fields, the
chemotherapy used, and his prior experience. Some of these procedures were eventually
unnecessary. In cases where gastrostomy was not placed a priory, the common practice is
monitoring the patients during treatment. If their weight loss exceeds 10% of their initial
body weight, a feeding gastrostomy is recommended (at this time point, the mucositis is
usually severe, and many patients need admission for fluid administration and semi-urgent
Unfortunately, there is no simple laboratory tool available, which could predict which
patients are susceptible to develop severe mucositis and dysphagia, and eventually will
require a feeding gastrostomy.
Mucositis develops in four successive phases: an inflammation phase, an epithelial phase, an
ulceration phase and lastly, a healing phase.
The first phase, inflammation, is also entitled "the initial tissue injury phase", and it
results in the production of pro-inflammatory cytokines such as IL-1 and TNF-α .
In general, the inflammatory cytokines IL-1, IL-6 and TNF-α are elevated in inflammatory
conditions and are found in increased levels in blood and tissue fluid during inflammation,
while anti-inflammatory cytokines are produced in a decreased manner.
In breast cancer patients, it has been shown that changes in cytokines levels, Including
IL-1β and IL-6, also correspond with the response of the malignant tissue to treatment. In
this case, a good clinical response to therapy has been associated with decreases in IL-1β
and IL-6 levels, versus increases in their levels which have been associated with the
progression of the disease. Furthermore, tumor markers such as the cytokeratin TPS, have
been shown to be sensitive in assessing the tumor's response to therapy and the patient's
It should be emphasized though, that the findings cited above reflect the response of tumor
cells to therapy, while the proposed project deals with radiation effects on both normal
tissues and tumor.
The main purpose of this study is to find the best indicators and prognosticators of
mucositis occurring in the healthy oral tissues of H&N cancer patients receiving treatment,
and to understand the cytokines balance mechanism of action.
Assuming there is a correlation between high cytokines levels during inflammation and the
severity of radiation induced mucositis, finding these prognostic factors may help us
predict during the first part of the treatment the need for PEG, placing it prior to the
complications associated with severe mucositis on one hand, and avoiding unnecessary
procedures on the other hand. This study may also lead to a new strategy of assessing
severity of mucositis by laboratory tests, a tool that can be used as an objective
assessment in developing strategies that aim to reduce the mucositis. The understanding of
the cytokines balance in this condition can also be translated to the use of anti-cytokine
treatment for this condition, similar to other immune related diseases such as RA, Crohn's
Disease and MS.
Secondary aims of this study are to measure recently available tumor markers SCC and TPS,
and to correlate them with tumor response. Genetic markers will be assessed for extreme
alteration in radiation reactions such as severe skin reaction, early and unexpectedly
severe mucositis, and on the other hand - lack of response. The blood for these tasks will
be collected prospectively, but evaluated at the end of the study.
The study will comprise of at least 14 and up to 35 patients with H&N epithelial cancer.
Patients will be clinically evaluated during the week before treatment, and during the
treatment period weekly.
Blood samples will be drown for cytokines prior to treatment, at week 2, 4 and at the end of
the treatment. The serum collected will be separated for the following factors:
1. Inflammatory Cytokines: IL-1, IL-6, IL-8, IL-18 and TNF α.
2. Anti inflammatory cytokines: IL-10 and TGF β.
3. Tumor markers: SCC and TPS.
4. Genetic assessment of genes that may be involved in extreme treatment reaction. At each
weekly follow up, patients will be assessed for mucositis by physician using the WHO
common toxicity criteria, and will answer a mucositis questionnaire (based on the
RTOG/EORTC questionnaire). Patient's weight will also be recorded.
The primary aims:
1. To investigate the relationship between cytokine level and the clinically suggested PEG
at the end of the H&N chemo-irradiation.
2. To investigate whether a correlation exists between blood cytokines (inflammatory
versus anti-inflammatory cytokines) levels and the severity of radiation induced
mucositis in patients receiving chemo-radiotherapy for cancer of the H&N.
3. To investigate whether blood cytokines levels could serve as a simple laboratory tool,
to predict the severity of mucositis and dysphagia occurring during H&N
The secondary aims:
1. To study the clinical usefulness of the Tumor Markers SCC and TPS in this setting,
namely, to evaluate the correlation between their blood levels and response to therapy.
2. To compare the associated mucositis between two commonly used radiation treatment
strategies - IMRT 5 field plan and classic two dimensional plan for the subgroup of
patients with advanced glottic and supraglottic cancer.
3. To assess whether cytokine levels during treatment can predict long term treatment
Observational Model: Defined Population, Observational Model: Natural History, Time Perspective: Longitudinal, Time Perspective: Prospective
Amichay Meirovitz, MD
Hadassah Medical Organization
Israel: Israeli Health Ministry Pharmaceutical Administration