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Radiation-Induced Enteritis: Incidence, Mechanisms, and Management

Radiation-Induced Enteritis: Incidence, Mechanisms, and Management

Diarrhea is a common problem in patients receiving pelvic
irradiation with concurrent chemotherapy. Virtually all patients develop
diarrhea of varying severity during the course of the treatment. The incidence
and severity of diarrhea vary with the chemotherapy type and dose, radiotherapy
field size, daily fraction size, and total dose of radiation given. Diarrhea
(any grade) occurs in 30% to 87% of patients receiving chemotherapy and in 20%
to 49% of patients receiving pelvic radiotherapy. The incidence of severe and
life-threatening (grade 3/4) diarrhea ranges from 20% to 40% in patients
receiving combined chemoradiotherapy.

Radiation-induced diarrhea can be severe and life
threatening. It is obvious that by reducing the chemoradiation-induced bowel
symptoms, the patient’s quality of life during (and following) therapy can be
enhanced. Additionally, minimizing the severity of radiation-induced enteritis
may increase the probability of completing the planned treatment without
interruption and improve the outcome. It is also expected that effective
management/prevention of severe diarrhea would avoid hospitalization for
complications such as dehydration, fluid and electrolyte imbalance, or
nutritional decline. Incidence of diarrhea may increase as more aggressive
therapeutic regimens are developed and employed.

The pathophysiology of radiation enteritis is not well
understood. Radiation-induced mucosal damage results in decreased absorption of
water and electrolytes, causing diarrhea. Another possible mechanism is
decreased bile acid absorption in the ileum (due to mucosal damage).[1] When passing through the bowel, the excess
bile acid irritates and damages the protective mucosal cap of the intestine.
This results in transudation of fluid and electrolytes into the lumen and causes
diarrhea.

Octreotide (Sandostatin), a somatostatin analog, is very
effective in controlling grade 3 diarrhea associated with chemotherapy.[2]
Octreotide seems to control diarrhea by decreasing intestinal motility and
increasing absorption of water and electrolytes. It also reduces bile secretion.
Petrelli et al treated 16 patients with colorectal carcinoma who received
fluorouracil (5-FU) and high-dose leucovorin and who had National Cancer
Institute (NCI) grade 3/4 diarrhea that did not respond to the maximum dose of
diphenoxylate.[3] Patients were treated with continuous octreotide infusion 50
to 150 µg/h, and complete resolution of diarrhea was seen in 94% of
patients.[3]

Cascinu et al conducted a randomized comparison of
subcutaneous octreotide to loperamide in patients having grade 3 diarrhea
secondary to therapy with
5-FU.[4] Complete resolution of diarrhea occurred in 90% of patients who
received octreotide compared with 15% of patients who received loperamide.[4]
Gebbia et al also showed 80% complete response of 5-FU-induced grade 3
diarrhea in patients treated with octreotide compared with 30% response in the
loperamide arm.[5] Octreotide has also been shown to be effective in controlling
severe radiation-induced diarrhea not responding to loperamide.[6] In a randomized study of octreotide vs
diphenoxylate for patients receiving pelvic radiation, octreotide was found to
be significantly more effective in controlling diarrhea.[7] Conventional
antidiarrheal agents fail to prevent the onset of grade 3/4 diarrhea.

The role of octreotide in the prevention of grade 3 diarrhea
has not been studied in patients receiving radiation therapy. Currently we are
developing a randomized, placebo-controlled, phase III study through the
Radiation Therapy Oncology Group (RTOG) using octreotide LAR depot for
prevention or reduction in the incidence of severe diarrhea in patients
receiving combined chemoradiotherapy for rectal/anal cancer. In this study,
patients will be given a test dose of subcutaneous octreotide and then
randomized to receive either octreotide LAR depot 30 mg (arm 1) or placebo (arm
2). The first dose will be given within 7 days of initiation of radiotherapy.
The second dose will be given on day 22 of radiotherapy concurrent with
chemotherapy. All patients will receive a minimum of 5,000 cGy to the pelvis,
using a field size greater than 10 × 10 cm. Radiotherapy will be given once a
day. Diarrhea will be graded weekly using the NCI Common Toxicity Criteria score
during the course of therapy and every 3 months during follow-up for 12 months.

The primary objective of the study is to show a 50% reduction
in the incidence of grade 3 diarrhea using octreotide LAR depot. We anticipate
that octreotide LAR depot will be cost-effective in terms of antdiarrheal
medication use and hospitalizations secondary to complications of diarrhea. Use
of octreotide LAR depot might reduce treatment delays and interruptions
secondary to diarrhea. Tools for assessment of diarrhea and change in quality of
life of patients treated with octreotide LAR depot will also be validated.

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