Octreotide Treatment

Octreotide Treatment

PEP Topic 
Chemotherapy-Induced Diarrhea
Description 

Octreotide is a medication that has physiologic effects that inhibit glucagon, insulin, splanchnic blood flow, and vasoactive peptides in the gastrointestinal tract. It has been used for treatment of watery diarrhea from tumors that secrete vasoactive intestinal peptides. Octreotide has been studied for use in the management of chemotherapy- and radiation-therapy-induced diarrhea. Octreotide is given by IV or subcutaneous injection.

Likely to Be Effective

Systematic Review/Meta-Analysis

Bhattacharya, S., Vijayasekar, C., Worlding, J., & Mathew, G. (2009). Octreotide in chemotherapy induced diarrhoea in colorectal cancer: A review article. Acta Gastro-Enterologica Belgica, 72(3), 289–295.

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Purpose:

To assess the role of octreotide in the management of chemotherapy-induced diarrhea (CID) in patients with colorectal cancer

Search Strategy:

Databases searched were Pubmed, MEDLINE, and Cochrane Database (1984–2009).

Search keywords were ocreotide in chemotherapy-induced diarrhea, octerotide CID, colorectal cancer CID, and octreotide.

Studies were included in the review if they

  • Were published in the English language.
  • Reported on a sample that was all or primarily patients with colorectal cancer.

Studies were excluded if they

  • Involved the use of chemotherapy used solely for the treatment of cancers other than colorectal cancer.
  • Were solitary case reports.

Literature Evaluated:

The authors did not describe the literature review and evaluation process. The article did incorporate information on relevant clinical guidelines.

Sample Characteristics:

The authors reviewed two randomized trials; four nonrandomized, controlled studies; and two case series, involving a total of 169 patients.

Results:

  • The two randomized trials demonstrated that octreotide was superior to loperamide in controlling severe CID.
  • In one of the nonrandomized trials, patients with loperamide-resistant CID had complete (16%) or substantial (59%) resolution of CID.
  • In another nonrandomized trial, which included patients with other types of cancer, 94% achieved complete resolution of diarrhea with octreotide.
  • A prospective trial and two case series reported similar successful treatment of severe CID (grade 3 and above) with octreotide.
  • The Canadian Working Group on CID has recommended that patients with refractory CID at grade 3 or 4 receive 100–150 mg octreotide subcutaneously three times daily, with potential increased doses up to 500 mg three times per day.
  • For prophylaxis treatment, the group has recommended 30 mg octreotide long-acting release intramuscularly once every 28 days.
  • Adverse effects included short-term local pain at the injection site (38%), fatigue (48%), weakness (33%), and nausea (28%). Long-term use in acromegaly has been associated with vitamin B12 deficiency and risk of gallstone formation.
  • A review of economic issues identified a study that found that the mean expenditure for CID in Canada was $2,559 per patient for grade 3 or 4 diarrhea. The average expenditure with grade 4 was $5,776. The cost of octreotide was not reported.

Conclusions:

Octreotide has been shown to be effective and safe for short-term treatment of severe CID.

Limitations:

Few studies have been done with the long-acting formulation and for prophylactic use. Further studies in these areas would be useful.

Nursing Implications:

Nurses should be aware of potential side effects with long-term use as seen in other than cancer cases.

Guideline/Expert Opinion

Gibson, R.J., Keefe, D.M., Lalla, R.V., Bateman, E., Blijlevens, N., Fijlstra, M., … Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). (2013). Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Supportive Care in Cancer, 21(1), 313–326.

doi: 10.1007/s00520-012-1644-z
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Purpose & Patient Population:

To systematically review current evidence for prevention and treatment of gastrointestinal (GI) mucositis in adults and children receiving cancer treatment and to update relevant Multinational Association of Supportive Care in Cancer (MASCC) guidelines

Type of Resource/Evidence-Based Process:

This was an evidence-based guideline developed based on a systematic review of the literature with rating of levels of evidence and identification of study flaws.

Database searched was MEDLINE.

Search keywords were numerous and included all known possible interventions tested.

Inclusion and exclusion criteria were not stated in this article but provided elsewhere in the journal.

Phase of Care and Clinical Applications:

  • Patients were undergoing the active treatment phase of care.
  • The study has clinical applicability for pediatrics.

Results Provided in the Reference:

A total of 1,336 papers were initially retrieved; of these, 146 were reviewed for development of the guidelines.

Guidelines & Recommendations:

  • Probiotics with Lactobacillus spp. may be beneficial for prevention of chemotherapy- and radiotherapy-induced diarrhea in patients with pelvic malignancies. Two studies with positive results were cited.
  • Amifostine may reduce esophagitis because of concomitant radiation and chemotherapy. It is not recommended in other situations because of conflicting evidence.
  • Mesalazine, 5-aminosalicylic acid (5-ASA), and olsalazine are not recommended because they have been associated with increased diarrhea compared to placebo.
  • Sucralfate is not recommended for diarrhea prevention because it is associated with increased GI side effects, including rectal bleeding.
  • Oral sulfasalazine given at 500 mg twice daily is recommended to reduce incidence and severity of radiation-induced enteropathy.
  • No guideline was provided for glutamine, but three new studies were sited that showed promising results.
  • If loperamide has not resulted in diarrhea control with standard or high-dose chemotherapy in HCTY patients, 100 mcg or greater of subcutaneous octreotide twice daily is recommended.

Limitations:

This review had a limited search strategy, as only one database was searched. In addition, most of the suggestions and recommendations provided were based on low-level evidence by the rating system used.

Nursing Implications:

These guidelines provide some suggestions for management of oral mucositis and diarrhea in patients with cancer. They also provide information regarding evidence for mucositis in the entire GI tract.

Maroun, J.A., Anthony, L.B., Blais, N., Burkes, R., Dowden, S.D., Dranitsaris, G., . . . Wong, R. (2007). Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: A consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea. Current Oncology, 14, 12–20.   

doi: 10.3747/co.2007.96
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Purpose & Patient Population:

PURPOSE: To review the optimal approach for managing chemotherapy-induced diarrhea (CID) and expand on guidelines previously developed by Cancer Care Ontario
 
TYPES OF PATIENTS ADDRESSED: Patients receiving chemotherapy for colorectal cancer

Type of Resource/Evidence-Based Process:

RESOURCE TYPE: Consensus-based guideline  

PROCESS OF DEVELOPMENT: Review of selected literature and retrospective review of 63 patients hospitalized for CID

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment

Results Provided in the Reference:

No specific broad search and literature review were used. A few study findings are cited. No information was provided regarding the strength of evidence cited.

Guidelines & Recommendations:

  • Recommends CID severity grading using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)
  • Notes the lack of and need for information identifying risk factors and development of a predictive model for CID severity
  • Outlines methods for patient evaluation of possible causes of diarrhea and workup to include complete and differential blood count, blood chemistry, and stool analysis
  • Recommends dietary management eliminating caffeine, alcohol, lactose, and high-fat foods
  • Identifies loperamide or high-dose loperamide as first-line treatment, octreotide for intractable grade 1 or 2 diarrhea, and fluid/electrolyte replacement for grade 3 or 4 diarrhea
  • Recommends consideration of long-acting octreotide for patients who had grade 3 or 4 diarrhea in a previous chemotherapy cycle as prophylaxis

Limitations:

  • Mainly consensus-based guideline

Nursing Implications:

Algorithm and consensus recommendations are provided for management of CID. Although these guidelines are aimed specifically at colorectal cancer cases, principles are likely to apply to other tumor types. Whether the mechanisms of diarrhea, and, therefore, effective treatments, are the same with various chemotherapy agents is unclear, and research is limited in this area. Prophylactic use of octreotide is suggested for patients who had diarrhea in a previous cycle of treatment in order to attempt to avoid the need for dose reductions or treatment delays.

Research Evidence Summaries

Hoff, P.M., Saragiotto, D.F., Barrios, C.H., del Giglio, A., Coutinho, A.K., Andrade, A.C., . . . van Eyll, B. (2014). Randomized phase III trial exploring the use of long-acting release octreotide in the prevention of chemotherapy-induced diarrhea in patients with colorectal cancer: The LARCID trial. Journal of Clinical Oncology, 32(10), 1006–1011. 

doi: 10.1200/JCO.2013.50.8077
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Study Purpose:

To evaluate the efficacy and safety of long-acting release (LAR) octreotide for the prevention of chemotherapy-induced diarrhea (CID)

Intervention Characteristics/Basic Study Process:

This prospective, randomized clinical trial compared the administration of octreotide LAR 30 mg IM every four weeks beginning with first-cycle to the administration of a physician’s choice of medication in a group of patients with colorectal cancer starting adjuvant or first-line treatment. Patients received combination chemotherapy with fluorouracil, capecitabine, and/or irinotecan. Treatment with octreotide LAR was continued for six months or until chemotherapy discontinued or until the patient developed unacceptable toxicity related to the study drug (whichever occurred first). The choice for the treatment for diarrhea for both arms was at the physicians' discretion, but the control group could not receive octreotide LAR. Patients were stratified according to the use of irinotecan.

Sample Characteristics:

  • N = 139  
  • AGE RANGE = 22–78 years
  • MALES: Treatment group 45.6%; control group 42.3%, FEMALES: Treatment group 54.4%; control group 57.7%
  • KEY DISEASE CHARACTERISTICS: Patients with colorectal cancer starting adjuvant or first-line treatment with combination chemotherapy containing fluorouracil, capecitabine, and/or irinotecan.
  • OTHER KEY SAMPLE CHARACTERISTICS: Sites of metastatic disease, colostomy, and type of surgery

Setting:

  • SITE: Multi-site    
  • SETTING TYPE: Outpatient    
  • LOCATION: Brazil at multiple institutions

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Study Design:

Randomized, multi-centered, open-labeled, phase III trial

Measurement Instruments/Methods:

  • To evaluate the incidence and severity of diarrhea, a patient diary was given to patients at each visit, and the completed tool was collected at the next visit. The diary was used to record patient events. 
  • All adverse events (related to laboratory or dose reductions) were collected through medical records.
  • A Functional Assessment of Chronic Illness Therapy For Patients With Diarrhea (FACIT-D) scale was collected at each visit. 

Results:

139 patients were randomly assigned. Most received a fluorouracil (treatment  98.5%, control  98.6%) or oxaliplatin (treatment 76.5%, control 63.4%) containing regimen. The rate of diarrhea was 76.1% in the treatment group (n = 68) and 78.9% in the control group (n = 71). Treatment with octreotide LAR did not prevent or reduce the severity of chemotherapy-induced diarrhea.

Conclusions:

There was no benefit in using octreotide LAR prophylactic in patients with colorectal cancer starting adjuvant or first-line treatment with combination chemotherapy containing fluorouracil, capecitabine, and/or irinotecan.

Limitations:

  • Risk of bias (no blinding)
  • There was a small number of patients who received chemotherapy with other regimens containing irinotecan. There was also the smaller proportion of patients presenting with grade 3 or 4 diarrhea. 

Nursing Implications:

There was no benefit in using octreotide LAR prophylactic in patients with colorectal cancer starting adjuvant or first-line treatment with combination chemotherapy containing fluorouracil, capecitabine, and/or irinotecan. This has also been evaluated in other studies that have looked at octreotide LAR using escalation doses of 30 or 40 mg, and the results were similar. Per the authors of this study, the short-acting octreotide remains the formulation of choice in the treatment of CID.

Pai, V., Porter, K., & Ranalli, M. (2011). Octreotide acetate is efficacious and safe in children for treating diarrhea due to chemotherapy but not acute graft versus host disease. Pediatric Blood & Cancer, 56(1), 45–49.

doi: 10.1002/pbc.22838
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Study Purpose:

To evaluate the efficacy and safety of octreotide in the management of chemotherapy-induced diarrhea (CID) or acute graft-versus-host disease (aGVHD) in pediatric patients

Intervention Characteristics/Basic Study Process:

A total of 38 courses of octreotide were administered (27 courses for CID and 11 for aGVHD).

Sample Characteristics:

  • The study reported on 34 patients ranging in age from 5 months to 11 years.
  • The sample was 56% male and 44% female.
  • The majority of patients were diagnosed with leukemia.
  • The majority of patients were experiencing grade 3 diarrhea and were Caucasian.
  • Patients were eligible to participate if they had received at octreotide and had at least two days between the courses.
  • Response was measured in stool output as either complete response, partial response, or no response.

Setting:

This was a single-site study conducted in an inpatient setting in Columbus, OH.

Phase of Care and Clinical Applications:

  • Patients were undergoing the active treatment phase of care.
  • The study has clinical applicability for pediatrics.

Study Design:

This was a respective study of subjects that received octreotide acetate between 1994 and 2008.

Measurement Instruments/Methods:

Data was collected based on chart reviews.

Results:

A complete response was observed in 25 out of 27 (92%) courses of treatment in patients with CID; side effects were minimal. In patients with aGVHD, a complete response was observed in 5 out of 11 (45%) courses.

Conclusions:

Octreotide was effective in 92% of courses given to patients with CID and 45% of courses given to patients with aGVHD.

Limitations:

  • The sample size was small with fewer than 100 patients.
  • A larger number of patients in the aGVHD group died, which could affect applicability and validity of this trial.
  • This was a nonrandomized trial with a controlled group.

Nursing Implications:

Octreotide has been shown to have an impact on reducing CID; however, larger randomized control studies are needed to confirm the validity of these findings as well as to determine efficacy in patients with aGVHD.

Rosenoff, S.H., Gabrail, N.Y., Conklin, R., Hohneker, J.A., Berg, W.J., Ghulam, W., … Anthony, L. (2006). A multicenter, randomized trial of long-acting octreotide for the optimum prevention of chemotherapy-induced diarrhea: Results of the STOP trial. Journal of Supportive Oncology, 4(6), 289–294.

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Study Purpose:

To compare the efficacy of two dose levels of octreotide long-acting release (LAR) in preventing chemotherapy-induced diarrhea (CID) in patients with active or prior CID

Intervention Characteristics/Basic Study Process:

A sample of 124 evaluable patients were assigned randomly to either the 30-mg or 40-mg octreotide dose group. The first dose of ocreotide was given intramuscularly 7–14 days prior to day 1 of the patient's next chemotherapy cycle. The second dose coincided with the chemotherapy cycle. Subsequent cycles were given every 28 days up to a total of 6 doses on a schedule independent of the chemotherapy cycles. Prior to initiation of octreotide LAR, patients were given a 100-mcg test dose of octreotide subcutaneously to determine potential intolerance.

Sample Characteristics:

  • The two treatment groups were similar in current chemotherapy regimens, severity of most recent diarrhea episode, body weight, primary tumor type, and proportion of patients with colostomy prior to study entry.
  • More than half (57%) of patients were receiving regimens with 5-fluorouracil (5-FU) with or without irinotecan, leucovoran, or oxaliplatin; 25% were receiving irinotecan regimens with or without 5-FU, leucovoran, or oxaliplatin.
  • Primary tumor types were colorectal (75%), breast (7%), lung (6%), hematologic (1%), other (10%).

Study Design:

This was an open label, randomized, multicenter study with a parallel-group design.

Measurement Instruments/Methods:

  • Patient diaries were collected on a monthly basis to obtain data for diarrhea assessment, concomitant medications, adverse events, and use of healthcare resources.
  • Health-related quality of life (QOL) was assessed at baseline and at the end of each study visit using a modified Functional Assessment of Chronic Illness Therapy-Diarrhea (FACIT_D) scale.
  • Investigators collected data from the Treatment Satisfaction Questionnare for Medication for Chemotherapy Induced Diarrhea (TSQM-CID), a version of the previously validated TSQM, at baseline for loperamide and diphenoxylate and at the end of study visit for octreotide LAR.
  • The primary study endpoint was the proportion of patients experiencing severe diarrhea (National Cancer Institute [NCI] grade 3 or 4).
  • Secondary study endpoints were the proportion of patients requiring IV fluids, unscheduled provider visits, and changes in primary therapy because of diarrhea as well as treatment satisfaction and QOL.

Results:

  • The proportion of patients who experienced severe diarrhea (grade 3 or 4) during the study was 61.7% in the 30-mg group and 48.4% in the 40-mg group (p = 0.14).
  • Fewer patients in the 40-mg group experienced severe diarrhea, required IV fluid (p = 0.11), or had unscheduled diarrhea-related healthcare visits (p = 0.11).
  • The percentage of patients in the 30-mg group who had changes in their primary therapy as a result of diarrhea was 61.7%, and the percentage in the 40-mg group was 64.1% (p = 0.78).

Limitations:

  • No comparison was made between daily and three times per day octreotide and octreotide LAR.
  • The 30-mg group contained a significantly greater proportion of females because sensitivity analysis showed no need to adjust for gender.

Nursing Implications:

No specific recommendations regarding the superiority of 30 mg or 40 mg octreotide in the management of CID can be made based on this study.

Topkan, E., & Karaoglu, A. (2006). Octreotide in the management of chemoradiotherapy-induced diarrhea refractory to loperamide in patients with rectal carcinoma. Oncology, 71(5–6), 354–360.

doi: 10.1159/000108593
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Intervention Characteristics/Basic Study Process:

  • Patients received 150 mcg octreotide subcutaneously three times daily once they were unresponsive to oral loperamide administration (4 mg three times per day for 48 hours).
  • All patients received hydration and were advised to consume a low-fiber, low-lactose diet.

Sample Characteristics:

  • The study reported on 42 patients with rectal carcinoma who experienced grade 2-3 diarrhea associated with at least one course of 5-fluorouracil (5-FU) administration refractory to loperamide during whole pelvic radiation therapy (RT).
  • The maximum number of days of octreotide treatment was five. If patients had progressive improvement of chemoradiotherapy-induced diarrhea (CRTID) during the five days of treatment but not a complete response (CR), chemoradiotherapy (CRT) was discontinued and octreotide was extended for three days.

Study Design:

This study was prospectively designed.

Measurement Instruments/Methods:

The primary goal was complete resolution of CRTID. The secondary goal was prevention of treatment delays attributed to diarrhea.

Results:

  • The median duration of diarrhea prior to first dose of octreotide was 78 hours.
  • Most cases of diarrhea were diagnosed in the first four weeks.
  • The median time-to-first dose of octreotide acetate was 19 days.
  • All patients tolerated octreotide well.
  • Complete resolution of diarrhea was achieved in 34 of 42 patients during the planned treatment period (five days).
  • Average time to CR was 2.7 days.
  • No treatment delays were reported in 34 patients who responded to subcutaneous octreotide administration.
  • CRT was delayed an average of 7.7 days in the eight unresponsive patients.
  • Those with CR were able to be treated as outpatients; nonresponders required hospitalization.

Limitations:

  • The sample size was small.
  • The study looked at rectal carcinoma only so generalizing to other disease sites is difficult.
  • No statistical significance was reported.
  • Only descriptive results were provided.

Zidan, J., Haim, N., Beny, A., Stein, M., Gez, E., & Kuten, A. (2001). Octreotide in the treatment of severe chemotherapy-induced diarrhea. Annals of Oncology, 12(2), 227–229.

doi: 10.1023/A:1008372228462
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Intervention Characteristics/Basic Study Process:

Patients with chemotherapy-induced diarrhea (CID) refractory to loperamide received 100 mcg subcutaneous octreotide three times per day for three days followed by 50 mcg three times per day for three days. The median time between chemotherapy and starting octreotide was 8 days (range = 5–9 days).

Sample Characteristics:

  • The study reported on 32 patients from two cancer centers with grade 2–3 CID (according to World Health Organization [WHO] classification) refractory to loperamide.
  • Chemotherapy regimens were 5-fluorouracil (5-FU) and leucovorin (n = 19): irinotecan, 5-FU, and leucovorin (n = 4); 5-FU combination including one or more of cyclophosphamide, epirubicin, cisplatin, methotrexate, and cisplatin (n = 8); and 5-FU combination plus radiation therapy (n = 1).
  • Primary tumors were colorectal (23), gastric (3), and other (6).
  • Patients initially had received 4 mg loperamide followed by 2 mg every six hours for 48 hours.

Study Design:

This was a prospective study.

Measurement Instruments/Methods:

Patients recorded the number of bowel movements. Complete response (CR) was defined as no diarrheal stools per day; partial response (PR) was defined as 1–2 diarrheal stools per day; and no response was defined as three or more diarrheal stools per day. Progression was defined as an increase in the number of diarrheal stools.

Results:

  • The majority of patients (94%) experienced CR. Five patients experienced CR within 24 hours; 14 within 48 hours; and 11 within 72 hours.
  • Twelve of the patients who experienced CR discontinued treatment after three days because they reported feeling "very healthy."
  • No toxic side effects were documented.

Conclusions:

Octreotide was found to be highly effective as second-line therapy in managing patients with CID. 

Limitations:

The sample size was small.


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