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Octreotide Acetate in the Treatment of Fluorouracil-Induced Diarrhea

^a E.N.T. Department, ^b Department of Medicine/Oncology, ^c Gastroenterology, University Hospital of Patras, Patras, Greece

Correspondence: Panos D. Goumas, M.D., University of Patras, Medical School, Department of Otolaryngology, Rio, Patras 26 500, Greece. Telephone: 30-61-999-265; Fax: 30-61-993-986

	ABSTRACT

Top Abstract Introduction Patients and Methods Results Discussion References

 
Cytotoxic chemotherapy, particularly the regimens that contain 5-fluorouracil (5-FU), can produce diarrhea. Octreotide acetate appears to have a major therapeutic effect in the management of 5-FU-induced diarrhea. A prospective study was conducted to investigate the efficacy of two different doses of octreotide acetate, 100 µg and 500 µg three times daily, for the treatment of severe 5-FU-induced diarrhea refractory to loperamide, and also to evaluate whether the higher dose is more effective in the management of this complication. Fifty-nine patients with tissue-documented colorectal and head and neck carcinoma were enrolled in this study, 28 in the 100 µg arm and 31 in the 500 µg arm of octreotide acetate which was administered s.c. three times daily. Patients were required to have National Cancer Institute Common Toxicity Criteria grade 3 diarrhea secondary to treatment with the 5-FU regimen. Octreotide acetate was well tolerated by all patients. Complete resolution of diarrhea was achieved in 17 of 28 (60.71%) patients treated with 100 µg, and in 28 of 31 (90.32%) patients treated with 500 µg of octreotide (p < 0.05). This study suggests a significant benefit in the treatment of 5-FU-induced diarrhea in favor of the 500 µg versus the 100 µg arm. These results support the dose-response effect of octreotide acetate. Even though higher doses of octreotide are more expensive, the cost saved in reduced hospitalization makes the higher dose more cost-effective.

Key Words. Octreotide acetate • 5-fluorouracil • Diarrhea

	Introduction

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Diarrhea is a dose-limiting toxicity of 5-fluorouracil (5-FU) in patients with malignancies and is sometimes associated with profuse loss of water and electrolytes [1]. A combination of chemotherapeutic agents, notably those containing 5-FU and analogs, such as folinic acid, cisplatin, or methotrexate, can also produce diarrhea [2-4]. The incidence of diarrhea for patients taking cisplatin in moderate or high-dose schedules appears to be at least 20%-25% [4]. Refractory diarrhea following chemotherapy can produce severe protein loss, and effective medical treatment is needed to control symptoms and minimize the associated risks. In most cases, the diarrhea induced by 5-FU resolves simply by withdrawal of therapy, but in other cases requires symptomatic relief with loperamide or diphenoxylate atropine as well as bowel rest and i.v. hydration [1, 2]. However, quite often these therapies are ineffective and can result in prolonged hospitalization or development of infections or metabolic complications.

Somatostatin belongs to the family of regulatory peptides that is characterized by a variety of actions in different organ systems throughout the body [5, 6]. Somatostatin modulates neurotransmission in the central nervous system and regulates the release of growth hormone and thyrotropin. It also has a regulatory role in the gastrointestinal tract as well as in the exocrine and endocrine pancreas. Somatostatin decreases the gastrointestinal transit time and the endogenous fluid secretion in the jejunum, and stimulates the intestinal absorption of water and electrolytes [5, 6]. However, the half-life of somatostatin in plasma is estimated to be 1.1-3.0 min in humans; this presents difficulties for its clinical use [7]. Octreotide acetate (Sandostatin; Sandoz-Novartis) is a synthetic polypeptide analog of somatostatin with a longer half-life (90 min) and a duration of action of about eight hours after s.c. administration [8]. Octreotide has been useful in the treatment of secretory diarrhea associated with carcinoid syndrome, Verner-Morrison syndrome, graft-versus-host disease, AIDS-related diarrhea, and radiation-induced colitis [1, 9]. Furthermore, preliminary data suggest that octreotide is useful in the management of 5-FU-induced diarrhea, but it is unclear what is the optimum dose for the treatment of this syndrome [10, 11].

This study was conducted to investigate the efficacy of two different doses of octreotide for the treatment of severe refractory diarrhea induced by chemotherapy with 5-FU and to address the question of whether there is a dose-response effect.

	Patients and Methods

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All enrolled patients developed diarrhea that resulted from chemotherapy with 5-FU-containing regimens at a level grade 3 (more than seven to nine stools per day, incontinence, or severe cramping) according to the National Cancer Institute Common Toxicity Criteria [12]. Patients with grossly bloody diarrhea were excluded from the trial. All 59 patients enrolled in this trial were initially treated as outpatients, and all had failed a 48-h treatment with 4 mg three times daily of loperamide (Imodium) with no improvement of the diarrhea. The 5-FU was discontinued when diarrhea grade 3 occurred. Patients had a performance status according to ECOG 2, age 70 years, and absence of fever. All patients were given oral hydration and dietary advice. Patients were treated with octreotide acetate, 100 µg or 500 µg three times per day s.c. Each patient was interviewed before and during the course of treatment, and compliance with the daily s.c. injection routine was checked.

Duration of diarrhea therapy was recorded starting from the first day of administration of octreotide acetate until complete disappearance of loose bowel movements was achieved.

However, if after five days of therapy with octreotide no improvement was observed, patients were considered nonresponsive and were consequently hospitalized. This outcome was characterized as therapeutic failure. If progressive improvement was seen, therapy was continued until complete resolution was obtained. This outcome was characterized as therapeutic success. Partial response was not considered a response because of potential bias.

On each treatment day, the response was measured by a reduction in the number of bowel movements, or in the case of patients with a colostomy, the total volume of fluid excreted in a 24-h period.

None of the patients had a history of diarrhea in the three months before chemotherapy. None were previously treated with other antidiarrheal drugs, nor did they require medications that could interfere with the antidiarrheal effects of loperamide or octreotide.

All patients had histologically confirmed cancer. Fourteen patients had tissue-documented metastatic colorectal carcinoma, and 36 patients were treated adjuvantly. Furthermore, nine patients had head and neck cancer. Pretreatment liver function tests were comparable in both groups.

Chemotherapeutic regimens were as follows: in 22 patients with colorectal cancer, 5-FU 425 mg/m² i.v. days 1 to 5 and leucovorin 20 mg/m² i.v. days 1 to 5, every 28 days; in 28 patients with colorectal cancer, 5-FU 600 mg/m² i.v. weekly and leucovorin 100 mg/m² i.v. weekly; in nine patients with head and neck cancer, cisplatin 100 mg/m² i.v., day 1 and 5-FU 1 g/m² i.v. continuous infusion days 1 to 5, every 28 days. The main demographic and clinical characteristics of enrolled patients are depicted in Table 1.

For statistical analysis, the chi-square test, the chi-square test with Yate's correction, and the Student's t-test were used. The differences were considered statistically significant when p < 0.05.

	Results

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Fifty-nine patients entered the study, 28 in the 100 µg arm and 31 in the 500 µg arm. All patients included in this study were assessable. The two groups of patients were comparable in terms of demographic and clinical characteristics (Table 1.). The difference between the efficacy of the two octreotide doses is depicted in Table 2.

In 28 of 31 patients (90.32%) treated with 500 µg of octreotide, complete resolution of diarrhea was observed, while complete response was achieved in 17 of 28 patients (60.71%) treated with 100 µg of octreotide. For statistical analysis between the two groups, chi-square test with Yate's correction was used. The results represent a statistically significant difference at a significant level p < 0.05 (x² = 5.58; p = 0.018).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Chemotherapeutic regimens containing 5-FU may produce diarrhea, and octreotide acetate appears to have an important therapeutic effect in the management of this complication. In this study, we considered two prospective doses of octreotide acetate, 100 µg and 500 µg, administered s.c. three times daily, to evaluate whether the higher dose is more effective for reversing the 5-FU-induced refractory diarrhea. There is evidence that the higher doses of octreotide acetate reverse the 5-FU-induced diarrhea [10, 13]. The results from this study suggest that 500 µg administered s.c. has a significantly better result than the lower dose (100 µg), supporting the correlation between response to therapy and octreotide dose.

The precise mechanism of the antidiarrheal effect of octreotide was not evaluated. However, possible mechanisms include inhibition of gastrointestinal hormones, prolongation of intestinal transit time, and regulation of intestinal water and electrolyte transport [9, 14]. In addition, control of chemotherapy-induced diarrhea may involve an anti-inflammatory effect of octreotide observed in an in vivo model [15]. Opiates are believed to exert their antidiarrheal effect only by means of a delay in intestinal transit time. The antisecretory effect of somatostatin, using an in vitro model, suggests that higher doses of the drug are more effective [16]. Furthermore, a dose-response effect was observed when octreotide acetate was used in increasing doses in a patient to control the effects of carcinoid syndrome [17].

The s.c. administration of relatively low doses of octreotide acetate, 50 µg and 100 µg three times daily, has been reported in an early trial to be successful in the management of 5-FU-induced severe diarrhea [18]. Furthermore, in a randomized trial, Cascinu et al. have demonstrated a statistically significant benefit in favor of a low dose of octreotide (100 µg) administered s.c. twice per day for three days versus loperamide [19]. Diarrhea resolved in 90% of the patients treated with octreotide versus only 15% in the loperamide arm (p < 0.05). In another trial, Gebbia et al. [11] demonstrated the superiority of octreotide in a series of 40 patients who were randomly allocated to treatment with either 500 µg of octreotide administered s.c. three times per day, or with loperamide. Response was observed in 80% of those treated with octreotide, within four days of therapy, versus 30% of those treated with loperamide, and the difference was significant (p < 0.001). In addition, in the group of responding patients treated with loperamide, the mean duration of antidiarrheal therapy necessary to achieve complete remission was 6.1 days (range 2-10), while those treated with octreotide required a mean of 3.4 days of therapy (p < 0.001) [11]. Both trials report high response rates and comment on the absence of side effects of octreotide treatment in their series.

In another prospective trial [10], a high-dose continuous infusion of octreotide acetate (100-150 µg/h) was used by Petrelli et al. in 16 patients with colorectal carcinoma and 5-FU-induced severe diarrhea who had failed to respond to conventional therapy with diphenoxylate atropine. Complete resolution of diarrhea was observed in 15 of 16 patients (94%). However, recurrence of diarrhea was seen in two patients after a complete cycle of octreotide. The authors also reported an absence of toxicity and no adverse effects of the treatment.

In a phase I trial by Wadler et al. [13], octreotide was administered in 35 patients with 5-FU-induced diarrhea to determine the maximum tolerated dose. The doses of octreotide studied were 50 to 2,500 µg administered s.c. three times daily for five days. The authors reported that the efficacy of the treatment correlated significantly (p < 0.01) with the dose of octreotide administered. Furthermore, patients experienced significant toxicities, including hypoglycemia and allergic reaction, which argued against the administration of higher doses.

The current trial has demonstrated a statistically significant benefit in the management of 5-FU-induced diarrhea in favor of the 500 µg regimen versus 100 µg octreotide administered s.c. three times per day. These results are in support of the dose-response effect of octreotide acetate. Even though higher doses of administered octreotide are substantially more expensive, the cost saved in reduced hospitalization and the improved palliation suggest that the higher dose is more cost-effective. However, since earlier studies have demonstrated a high response rate of 5-FU-induced diarrhea with low doses of octreotide acetate, and considering the cost of this treatment, additional comparative trials are warranted. It is reasonable to perform further double-blind, prospective randomized trials to compare the efficacy of this treatment at conventional dose over a wide range of higher doses.

	References

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