Role of Octreotide in Pancreatic Cancer

September 1, 2002

Cancer of the pancreas is the fourth leading cause of cancer death in the United States. Of the 28,000 patients diagnosed each year, more than 95% will die of pancreatic cancer. Therefore, the focus of therapy for most patients is palliative care. In fact, the most active single-agent therapy for advanced disease-gemcitabine (Gemzar)-was first compared to fluorouracil (5-FU) with relief of disease symptoms as a primary end point. However, the survival with gemcitabine remains approximately 6 months for advanced disease, and no new agent, either alone or in combination, has exceeded this time frame in phase III study.

Cancer of the pancreas is the fourth leading cause of cancerdeath in the United States. Of the 28,000 patients diagnosed each year, morethan 95% will die of pancreatic cancer. Therefore, the focus of therapy for mostpatients is palliative care. In fact, the most active single-agent therapy foradvanced disease—gemcitabine (Gemzar)—was first compared to fluorouracil(5-FU) with relief of disease symptoms as a primary end point. However, thesurvival with gemcitabine remains approximately 6 months for advanced disease,and no new agent, either alone or in combination, has exceeded this time framein phase III study.

Octreotide (Sandostatin) is a synthetic analog of the hormonesomatostatin. In vitro, it appears to inhibit cellular proliferation, largelymediated through somatostatin receptors (types 2 and 5).[1] Data with MIA PaCa-2and other pancreatic cancer cell lines or human tumors suggest that there is anantiproliferative effect mediated by octreotide in tumors that express the type2 receptor.[2,3] The exact mechanism for this antiproliferative effect is notknown, but octreotide has been shown to decrease lipid peroxidation, andinhibition of tumor growth by octreotide is accompanied by increased glutathionereductase and superoxide dismutase activity.[4] Octreotide has been shown in thelaboratory to inhibit insulin-like growth factor I, epidermal growth factor, andtransforming growth factor-beta. In addition, administration of octreotideappears to decrease vascular endothelial growth factor (VEGF) levels, which maylead to inhibition of angiogenesis.

The above in vitro studies provided the rationale forassessing the efficacy of octreotide in clinical trials. One of the most pivotaltrials of octreotide in pancreatic cancer was a randomized trial of low-doseshort-acting octreotide vs best supportive care. In that trial, although noresponses were seen, there were some patients with stable disease, and survivalwas improved for the octreotide arm. Unfortunately, a subsequent trial comparing5-FU vs 5-FU plus leucovorin vs octreotide was closed early due to a lack ofefficacy in the octreotide arm. Patients were treated with reasonable doses ofshort-acting octreotide at 200 to 500 mg tid. Other phase II trialsadministering doses of octreotide as high as 2,000 mg have shown limitedactivity in pancreatic cancer with median survival times of 4 to 6 months.[5-7]Thus, the single-agent trials suggest that octreotide may have some limitedefficacy against pancreatic cancer, but this is inferior to 5-FU-basedchemotherapy.

Octreotide may have additive or synergistic effects whengiven with chemotherapeutic agents. In AR24J pancreatic cancer cell lines,octreotide appears to have synergy with paclitaxel, doxorubicin, and mitomycin (Mutamycin),and additive effects when combined with 5-FU.[8] Gemcitabine, the standard agentfor treatment of pancreatic cancer, was not assessed. However, a clinical trialcombining gemcitabine with octreotide LAR depot is under way.

Finally, several other hormonal agents have also been testedin pancreatic cancer. Preclinical models suggest that luteinizinghormone-releasing hormone (LHRH) agonists may inhibit growth of pancreaticcancers. In the Syrian golden hamster (BOP-induced) model for pancreatic cancer,the combination of octreotide and RC-160 (an LHRH agonist) resulted in at leastadditive growth inhibition.[9] Phase II trials with a variety of agents haveresulted in median survival times of 4 to 6 months.[10,11]

Thus far, octreotide has shown limited efficacy in patientswith pancreatic cancer. While results of the phase II trial of gemcitabine plusoctreotide are still pending, none of the prior regimens produced resultswarranting further investigation. Unless octreotide has relevant interactionswith newer biologic agents, further investigation of this agent in pancreaticcancer patients should probably focus on symptom management.

References:

1. Buscail L, Esteve JP, Saint-Laurent N, et al: Inhibitionof cell proliferation by the somatostatin analogue RC-160 is mediated bysomatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. ProcNatl Acad Sci USA 92:1580-1584, 1995.

2. Radulovic S, Comaru-Schally AM, Milovanovic S, et al:Somatostatin analogue RC-160 and LH-RH antagonist SB-75 inhibit growth of MIAPaCa-2 human pancreatic cancer xenografts in nude mice. Pancreas 8:88-97,1993.

3. Fisher WE, Muscarella P, O’Dorisio TM, et al: Expressionof the somatostatin receptor subtype-2 gene predicts response of humanpancreatic cancer to octreotide. Surgery 120:234-240, 1996.

4. Wenger FA, Kilian M, Mautsch I, et al: Influence ofoctreotide on liver metastasis and hepatic lipid peroxidation in BOP-inducedpancreatic cancer in Syrian hamsters. Pancreas 23:266-272, 2001.

5. Friess H, Buchler M, Beglinger C, et al: Low-doseoctreotide treatment is not effective in patients with advanced pancreaticcancer. Pancreas 8:540-545, 1993.

6. Sulkowski U, Buchler M, Pederzoli P, et al: A phase IIstudy of high-dose octreotide in patients with unresectable pancreaticcarcinoma. Eur J Cancer 35:1805-1808, 1999.

7. Klijn JG, Hoff AM, Planting AS, et al: Treatment ofpatients with metastatic pancreatic and gastrointestinal tumours with thesomatostatin analogue Sandostatin: A phase II study including endocrine effects.Br J Cancer 62:627-630, 1990.

8. Weckbecker G, Raulf F, Tolcsvai L, et al: Potentiation ofthe anti-proliferative effects of anti-cancer drugs by octreotide in vitro andin vivo. Digestion 57(suppl 1):22-28, 1996.

9. Zalatnai A, Schally AV: Treatment ofN-nitrosobis(2-oxopropyl)amine-induced pancreatic cancer in Syrian goldenhamsters with D-Trp-6-LH-RH and somatostatin analogue RC-160 microcapsules. CancerRes 49:1810-1815, 1989.

10. Fazeny B, Baur M, Prohaska M, et al: Octreotide combinedwith goserelin in the therapy of advanced pancreatic cancer—Results of a pilotstudy and review of the literature. J Cancer Res Clin Oncol 123:45-52,1997.

11. Huguier M, Samama G, Testart J, et al: Treatment of adenocarcinoma of thepancreas with somatostatin and gonadoliberin (luteinizing hormone-releasinghormone). The French Associations for Surgical Research. Am J Surg164:348-353, 1992.