What is the incidence and mechanism of cisplatin-induced diarrhea? How should cisplatin-induced diarrhea be treated?

Comment by InpharmD Researcher

Cisplatin-induced diarrhea, reported in up to 67% of patients in one study, is linked to increased serotonin release in the gut, which drives motility and secretion. Additionally, elevated serotonin levels may contribute to an inflammatory response and increased gut permeability, further worsening the condition. Management begins with loperamide at 4 mg, followed by 2 mg after each episode, up to 16 mg daily. If diarrhea persists, high-dose loperamide may be necessary. For refractory cases, octreotide at 100 to 150 mcg subcutaneously three times daily has been shown to be effective. Hospitalized patients should receive intravenous fluids, electrolyte correction, and antibiotics as needed.

Background

Cisplatin is known for causing significant gastrointestinal toxicity, including severe diarrhea, which impacts patients' quality of life. Notably, up to 67% of patients suffer from diarrhea during their treatment course. Serotonin (5-hydroxytryptamine, 5HT) emerges as a critical player in the mechanism of cisplatin-induced diarrhea. Cisplatin tends to increase the release of serotonin from the enterochromaffin cells in the gut, which can then bind to 5-HT3 receptors on the afferent nerves, leading to enhanced gut motility and secretion, culminating in diarrhea. Moreover, increased serotonin levels may contribute to the inflammatory response and aggravate gut permeability, further intensifying diarrhea symptoms. While the study discussed the use of ondansetron to inhibit the cisplatin-induced release of 5-HT from the gut and prevent emesis, it did not address any treatments specific to diarrhea. [1]

Though not specific to cisplatin, a consensus statement by the Canadian Working Group on chemotherapy-induced diarrhea provides recommendations on the prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer. Effective management of chemotherapy-induced diarrhea involves prompt intervention with bowel rest, hydration, and electrolyte replacement. Patients should be hospitalized if they show dehydration, fever, neutropenia, or severe nausea and vomiting. Dietary modifications are crucial, including the avoidance of dairy, high-fat foods, caffeine, and alcohol, while increasing oral fluid intake. First-line treatment typically involves loperamide or diphenoxylate. The recommended dose of loperamide is 4 mg initially, followed by 2 mg after each episode of diarrhea, up to a maximum of 16 mg daily. For intractable grade 1 or 2 diarrhea or de novo grade 3 or 4 diarrhea, octreotide is recommended, starting at 100 to 150 mcg subcutaneously three times daily, with the possibility of dose escalation in 50 mcg increments. Octreotide should be discontinued 24 hours after diarrhea resolves. Hospitalized patients should receive intravenous fluids, electrolyte correction, and antibiotics as needed. [2]

Similar to the recommendation provided in the Canadian consensus statement, review articles also refer to loperamide as the first line of defense for the management of chemotherapy-induced diarrhea. If diarrhea continues for more than 24 hours, high-dose loperamide (2 mg every 2 hours) is a recognized treatment option along with starting oral antibiotics to prevent infectious complications. If diarrhea persists beyond 48 hours despite high-dose loperamide, the medication should be discontinued, and second-line treatments such as subcutaneous octreotide (100-150 mcg), tincture of 10 mg/mL opium (10-15 drops in water orally every 3-4 hrs), or oral budesonide (9 mg by mouth daily, or 3 mg by mouth 3 times daily) should be considered. It was also highlighted that while the exact cause of chemotherapy-induced diarrhea is not fully understood, it is thought to involve a complex process that disrupts the balance between fluid absorption and secretion in the gastrointestinal tract. Other factors such as diet, medications, and infections may also contribute to diarrhea in cancer patients. [2], [3], [4]

References:

[1] Shahid F, Farooqui Z, Khan F. Cisplatin-induced gastrointestinal toxicity: An update on possible mechanisms and on available gastroprotective strategies. Eur J Pharmacol. 2018;827:49-57. doi:10.1016/j.ejphar.2018.03.009
[2] Maroun JA, Anthony LB, Blais N, et al. Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea. Curr Oncol. 2007;14(1):13-20. doi:10.3747/co.2007.96
[3] Bcop SKP. Chemotherapy-Induced diarrhea: Options for treatment and prevention. The Journal of Hematology Oncology Pharmacy. https://jhoponline.com/issue-archive/2012-issues/december-2012-vol-3-no-4/15408:chemotherapy-unduced-diarrhea-options
[4] Andreyev J, Ross P, Donnellan C, et al. Guidance on the management of diarrhoea during cancer chemotherapy. Lancet Oncol. 2014;15(10):e447-e460. doi:10.1016/S1470-2045(14)70006-3

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the incidence and mechanism of cisplatin-induced diarrhea? How should cisplatin-induced diarrhea be treated?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Table 1 for your response.


 

Control of Chemotherapy-Induced Diarrhea with Octreotide

Design

Prospective, randomized, double-blind controlled trial

N= 43

Objective

To compare octreotide with placebo in patients receiving cisplatin (CDDP) who had developed diarrhea (three or more loose bowel movements) during a previous course of cisplatin

Study Groups

Octreotide (n= 23)

Placebo (n= 20)

Inclusion Criteria

Previously experienced diarrhea (≥3 loose bowel movements) in the 24-h period after a course of CDDP; white blood cell (WBC) count >3,000/mm3

Exclusion Criteria

Not disclosed

Methods

Patients were randomized to either octreotide 0.1 mg or placebo saline (1 cm3 saline solution) for two subcutaneous doses 15 minutes and 6 hours after CDDP therapy. All patients received intravenous CDDP at doses of 60-120 mg/m2 of body surface area over 20 minutes. Each patient received the same antiemetic treatment of alizapride or ondansetron and CDDP regimen in the therapeutic cycle in which antidiarrheal effects were assessed.

Duration

Observation period: 24 hours

Outcome Measures

Diarrhea during 24 h following chemotherapy

Baseline Characteristics

 

Octreotide (n= 23)

Placebo (n= 20)

 

Age, years (range)

61 (38-70)  60 (43-68)  

Female

10 (43.4%) 10 (50%)  

Chemotherapy

CDDP (60 mg/m2)

ADR + CDDP (60 mg/m2)

VP16 + CDDP (60 mg/m2)

CTX + CDDP (60 mg/m2)

MTX + VLB + CDDP (60 mg/m2)

MitC + VLB + CDDP (120 mg/m2)

 

2

7

6

2

4

2

 

3

6

4

2

3

2

 

Median number of loose bowel movements in previous CDDP course

5 4  

Abbreviations: ADR= doxorubicin; CTX= cyclophosphamide; MitC= mitomycin; MTX= methotrexate; VLB= vinblastine; VP16= etoposide

No patient had a history of diarrhea before chemotherapy, or had received radiation therapy to the abdomen. Additionally, no patient was previously treated with other antidiarrheals, nor were antibiotics or other medications required that may interfere with the antidiarrheal effects of the study drugs.

Results

Endpoint

Octreotide (n= 23)

Placebo (n= 20)

p-value

No loose bowel movement

95% 25% 0.01

Diarrhea (>2 loose bowel movements)

5% 75%

Median number of loose bowel movements (range)

0 (0-4) 4 (3-10) -

No patients presented recurrence of diarrhea upon study completion after 24 h.

Adverse Events

No differences in incidence and severity of vomiting and nausea; no definite side effects related specifically to use were observed.

Study Author Conclusions

In conclusion, the results of this trial show that octreotide is an effective and safe antidiarrheal drug that is superior to placebo. For this reason, we think that its use can be recommended to reduce patients' discomfort and to increase compliance to chemotherapy in patients who developed diarrhea during a previous course of CDDP.

InpharmD Researcher Critique

Data were derived from adult patients, and thus applicability regarding octreotide to pediatric patients experiencing diarrhea is uncertain. Additionally, the small sample size, variability in cisplatin-containing chemotherapy regimens, and short-term follow-up limit strength of the findings.

References:

Cascinu S, Fedeli A, Fedeli SL, Catalano G. Control of chemotherapy-induced diarrhea with octreotide. A randomized trial with placebo in patients receiving cisplatin. Oncology. 1994;51(1):70-73. doi:10.1159/000227313