Octreotide

Octreotide

PEP Topic 
Radiation-Induced Diarrhea
Description 

Octreotide is a medication that has physicologic effects that inhibit glucagon, insulin, splanchic 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 management of chemotherapy- and radiation-therapy-induced diarrhea. Octreotide is given by IV or subcutaneous injection.

Effectiveness Unlikely

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.

Sun, J.X., & Yang, N. (2013). Role of octreotide in post chemotherapy and/or radiotherapy diarrhea: Prophylaxis or therapy? Asia-Pacific Journal of Clinical Oncology. Advance online publication.  doi:10.1111/ajco.12055

doi: 10.1111/ajco.12055
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Search Strategy:

Databases searched were MEDLINE, EMBASE, Cochrane Collaboration, and BIOSIS.

Search keywords were octreotide, somatostatin, and diarrhea.

Studies were included in the review if they were randomized clinical trials (RCTs) with with one group receiving octreotide.

Exclusion criteria was not specified.

Literature Evaluated:

  • A total of 37 references were retrieved.
  • Quality grading was done using the Jadad scale.  Odds ratio analysis was used.

Sample Characteristics:

  • Eight studies were included in the final review, representing 572 patients. The sample range across studies was 16–315.
  • Five studies involved chemotherapy, and three studies involved radiotherapy.

Phase of Care and Clinical Applications:

All patients were undergoing the active treatment phase of care.

Results:

  • Octreotide was effective compared to placebo (overall response [OR] = 4.9, 95% confidence interval [CI], 1.58–15.2).
  • With radiotherapy-induced diarrhea, octreotide OR = 1.64 (95% CI, 0.53–5.08) and the test for overall effect was not significant. 
  • For chemotherapy-induced diarrhea, OR =14.7 (95% CI,  4.06–53.26) and the test for overall effect was significant (p < 0.0001).
  • The radiotherapy data showed high heterogeneity.
  • The OR of octreotide was higher when used for treatment rather than prophylactically. However, only one trial evaluated prophylactic use.
  • Most studies compared octreotide to loperamide.

Conclusions:

Prophylactic use of octreotide did not show a statistically significant reduction in diarrhea. Octreotide did not reduce severity or incidence of diarrhea during pelvic radiotherapy, and some bowel functions appeared to be worse in the octreotide group. Octreotide showed significant benefit for the treatment of chemotherapy-induced diarrhea.

Limitations:

A limited number of studies were evaluated. No firm conclusions regarding prophylactic use can be made.

Nursing Implications:

Findings support the use of octreotide for management of chemotherapy-induced diarrhea. Prophylactic use and use in patients with diarrhea because of pelvic irradiation are not supported. Nurses can advocate for appropriate use of octreotide in the management of diarrhea.

Research Evidence Summaries

Martenson, J.A., Halyard, M.Y., Sloan, J.A., Proulx, G.M., Miller, R.C., Deming, R.L., … Atherton, P.J. (2008). Phase III, double-blind study of depot octreotide versus placebo in the prevention of acute diarrhea in patients receiving pelvic radiation therapy: Results of north central cancer treatment group N00CA. Journal of Clinical Oncology, 26, 5248-5253.

doi: 10.1200/JCO.2008.17.1546
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Study Purpose:

To determine the effectiveness of octreotide in reducing treatment-related diarrhea during radiation therapy to the pelvis

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive octreotide acetate or placebo. Patients in the treatment group were given 100 µg subcutaneous octreotide acetate on day 1 followed by 20 mg intramuscular octreotide acetate on days 2 and 29. Patients in the control group received placebo by the same routes on the same days.

Sample Characteristics:

  • The study reported on 125 patients.
  • Patients had histologic proof of cancer in the pelvis without distant metastases and were receiving radiation therapy, either as definitive treatment or adjuvantly.                           

Setting:

This was a multisite, collaborative trial of North Central Cancer Treatment Group.

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Study Design:

This was a double-blinded, randomized control trial.

Measurement Instruments/Methods:

A Bowel Function Questionnaire and a Uniscale Quality of Life (QOL) measure were used.

Results:

No statistically significant differences were found between groups. Octreotide did not reduce the severity or incidence of diarrhea during pelvic radiation therapy. Abdominal cramps were worse in patients on the octreotide arm, but the difference was not statistically significant (p = 0.053). Patients receiving octreotide experienced significantly more problems with nocturnal bowel movements (70% versus 45%, p = 0.004), clustering (90% versus 69%, p = 0.004), and blood with bowel movements (57% versus 35%, p = 0.01).

Conclusions:

Octreotide did not result in improvement in diarrhea in this population and was associated with more problems. Octreotide did not have an effect on the severity or incidence of diarrhea during pelvic radiation therapy. Some gastroinstestinal (GI) symptoms were worse in patients receiving octreotide compared to placebo.

Limitations:

  • The subjects in the treatment groups were different. More patients in the control group had histories of rectal surgery or primary rectal cancer.
  • Not all patients completed the day 29 dose of study medication. Only 49 (79%) of 62 of patients in the placebo arm and 43 (69%) of 62 of patients in the octreotide arm received a second dose.
  • No intention-to-treat analysis was conducted.

Nursing Implications:

More clinical research is needed to evaluate the effective prevention of diarrhea during pelvic radiation therapy. Long-acting octreotide (LAO) should not be used outside of a controlled clinical trial setting.

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.

Yavuz, M.N., Yavuz, A.A., Aydin, F., Can, G., & Kavgaci, H. (2002). The efficacy of octreotide in the therapy of acute radiation-induced diarrhea: A randomized controlled study. International Journal of Radiation Oncology, Biology, Physics, 54(1), 195–202.

doi: 10.1016/S0360-3016(02)02870-5
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Intervention Characteristics/Basic Study Process:

Patients were randomized to receive either 100 mcg subcutaneous octreotide three times per day or 2.5 mg oral diphenoxylate/atropine four times per day.

Sample Characteristics:

  • The study consisted of 61 patients with grade 2–3 diarrhea associated with pelvic external beam radiation therapy (XRT).
  • The octreotide group contained 33 patients, and the diphenoxylate group had 28 patients.
  • The sample was balanced for clinical characteristics, including radiation dose.
     

Measurement Instruments/Methods:

  • Investigators recorded the number of days to resolution of diarrhea and the number of days of interruption of radiation therapy.
  • Success was defined as a complete response within three days.

Results:

  • The octreotide group experienced diarrhea resolution in 3.3 days compared with 5.6 in the diphenoxylate group (p = 0.0001).
  • The octreotide group experienced 0.45 days of interrupted radiotherapy compared with 1.89 days in the diphenoxylate group (p = 0.003).
  • The octreotide group experienced a 61% success rate, while the diphenoxylate group experienced a 14% success rate (p = 0.002).

Limitations:

The sample size was small.

Zachariah, B., Gwede, C.K., James, J., Ajani, J., Chin, L.J., Donath, D., … Kachnic, L.A. (2010). Octreotide acetate in prevention of chemoradiation-induced diarrhea in anorectal cancer: Randomized RTOG trial 0315. Journal of the National Cancer Institute, 102(8), 547-556.

doi: 10.1093/jnci/djq063
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Study Purpose:

To assess the ability of long-acting octerotide (LAO) to prevent acute diarrhea in patients undergoing concurrent chemoradiation for rectal or anal cancer

Intervention Characteristics/Basic Study Process:

Patients were randomized to either receive two 30 mg intramuscular injections of LAO or placebo. A “test” dose of 100 µg LAO was administered. Patients who tolerated the test dose then received a 30-mg dose of study drug between days 4–7 before the start of radiation and a second dose on day 22 (+ 3 days) of radiation. Patients received concurrent chemotherapy and radiation therapy to the pelvis. Radiation and chemotherapy regimens varied by institution. The plan was for a minimal dose of 45 Gy with a portal of 10x10 cm to the whole pelvis and a boost to the tumor bed. Follow-up evaluations were performed 3, 6, 9, and 15 months from start of radiation therapy.

Sample Characteristics:

  • The study reported on 215 patients.
  • The mean age of patients in the LAO group was 61 years with a range of 27–83 years. The mean age of patients in the placebo group was 61 years with a range of 37–85 years.
  • The LAO sample was 38% female and 62% male. The placebo group was 36% female and 64% male.
  • The majority (80%) of patients had rectal cancer.

Setting:

The study was conducted at multiple outpatient settings in the United States.

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Study Design:

This was a randomized, double-blinded, placebo-controlled trial.

Measurement Instruments/Methods:

The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (version 3.0) (CTCAE), Qualify of Life–Radiation Therapy Instrument (QOL-RTI), 14-item Expanded Prostate Cancer Index (EPIC)–Bowel, 7-item Functional Alterations due to Changes in Elimination–Bowel (FACE-Bowel), and 4-item Diarrhea Assessment Scale (DAS) were used.

Results:

  • Prophylactic use of LAO is not beneficial in reducing the severity or preventing the incidence of diarrhea in patients receiving concurrent chemotherapy and radiation therapy for rectal or anal cancer.
  • Incidence of grade 2–4 acute diarrhea was similar in both groups (49% in the placebo group versus 44% in the LAO group).
  • LAO did not reduce the number of hospitalizations required (p = 0.55) or eliminate the need for additional standard antidiarrheal agents (p = 0.67).
  • LAO did not prevent modifications, delays, or interruptions in chemotherapy (p = 0.27) or radiation therapy (p = 0.95).

Conclusions:

LAO did not demonstrate a statistically significant reduction in the incidence or severity of diarrhea or change in patient-reported bowel function and QOL in patients with rectal or anal cancer undergoing chemotherapy and radiation therapy.

Limitations:

  • No intention-to-treat analysis was performed.
  • This study had a short follow-up timeframe with a median follow-up of only 9.64 months. Further long-term assessment should be conducted to evaluate QOL.

Nursing Implications:

More clinical research is needed to evaluate interventions for the prevention of diarrhea in patients receiving chemotherapy and radiation therapy concurrently for rectal or anal cancer. LAO does not appear to reduce the incidence or severity of diarrhea or change patient-reported bowel function or QOL. Other studies have reported similar results. LAO should not be used to prevent diarrhea in patients receiving combined chemotherapy and radiation therapy outside of a controlled clinical research setting.


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