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 diseasegemcitabine (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.
Octreotide (Sandostatin) is a synthetic analog of the hormone
somatostatin. In vitro, it appears to inhibit cellular proliferation, largely
mediated through somatostatin receptors (types 2 and 5). Data with MIA PaCa-2
and other pancreatic cancer cell lines or human tumors suggest that there is an
antiproliferative effect mediated by octreotide in tumors that express the type
2 receptor.[2,3] The exact mechanism for this antiproliferative effect is not
known, but octreotide has been shown to decrease lipid peroxidation, and
inhibition of tumor growth by octreotide is accompanied by increased glutathione
reductase and superoxide dismutase activity. Octreotide has been shown in the
laboratory to inhibit insulin-like growth factor I, epidermal growth factor, and
transforming growth factor-beta. In addition, administration of octreotide
appears to decrease vascular endothelial growth factor (VEGF) levels, which may
lead to inhibition of angiogenesis.
The above in vitro studies provided the rationale for
assessing the efficacy of octreotide in clinical trials. One of the most pivotal
trials of octreotide in pancreatic cancer was a randomized trial of low-dose
short-acting octreotide vs best supportive care. In that trial, although no
responses were seen, there were some patients with stable disease, and survival
was improved for the octreotide arm. Unfortunately, a subsequent trial comparing
5-FU vs 5-FU plus leucovorin vs octreotide was closed early due to a lack of
efficacy in the octreotide arm. Patients were treated with reasonable doses of
short-acting octreotide at 200 to 500 mg tid. Other phase II trials
administering doses of octreotide as high as 2,000 mg have shown limited
activity 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 limited
efficacy against pancreatic cancer, but this is inferior to 5-FU-based
Octreotide may have additive or synergistic effects when
given 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. Gemcitabine, the standard agent
for treatment of pancreatic cancer, was not assessed. However, a clinical trial
combining gemcitabine with octreotide LAR depot is under way.
Finally, several other hormonal agents have also been tested
in pancreatic cancer. Preclinical models suggest that luteinizing
hormone-releasing hormone (LHRH) agonists may inhibit growth of pancreatic
cancers. In the Syrian golden hamster (BOP-induced) model for pancreatic cancer,
the combination of octreotide and RC-160 (an LHRH agonist) resulted in at least
additive growth inhibition. Phase II trials with a variety of agents have
resulted in median survival times of 4 to 6 months.[10,11]
Thus far, octreotide has shown limited efficacy in patients
with pancreatic cancer. While results of the phase II trial of gemcitabine plus
octreotide are still pending, none of the prior regimens produced results
warranting further investigation. Unless octreotide has relevant interactions
with newer biologic agents, further investigation of this agent in pancreatic
cancer patients should probably focus on symptom management.
1. Buscail L, Esteve JP, Saint-Laurent N, et al: Inhibition
of cell proliferation by the somatostatin analogue RC-160 is mediated by
somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. Proc
Natl 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 MIA
PaCa-2 human pancreatic cancer xenografts in nude mice. Pancreas 8:88-97,
3. Fisher WE, Muscarella P, O’Dorisio TM, et al: Expression
of the somatostatin receptor subtype-2 gene predicts response of human
pancreatic cancer to octreotide. Surgery 120:234-240, 1996.
4. Wenger FA, Kilian M, Mautsch I, et al: Influence of
octreotide on liver metastasis and hepatic lipid peroxidation in BOP-induced
pancreatic cancer in Syrian hamsters. Pancreas 23:266-272, 2001.
5. Friess H, Buchler M, Beglinger C, et al: Low-dose
octreotide treatment is not effective in patients with advanced pancreatic
cancer. Pancreas 8:540-545, 1993.
6. Sulkowski U, Buchler M, Pederzoli P, et al: A phase II
study of high-dose octreotide in patients with unresectable pancreatic
carcinoma. Eur J Cancer 35:1805-1808, 1999.
7. Klijn JG, Hoff AM, Planting AS, et al: Treatment of
patients with metastatic pancreatic and gastrointestinal tumours with the
somatostatin 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 of
the anti-proliferative effects of anti-cancer drugs by octreotide in vitro and
in vivo. Digestion 57(suppl 1):22-28, 1996.
9. Zalatnai A, Schally AV: Treatment of
N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancer in Syrian golden
hamsters with D-Trp-6-LH-RH and somatostatin analogue RC-160 microcapsules. Cancer
Res 49:1810-1815, 1989.
10. Fazeny B, Baur M, Prohaska M, et al: Octreotide combined
with goserelin in the therapy of advanced pancreatic cancerResults of a pilot
study and review of the literature. J Cancer Res Clin Oncol 123:45-52,
11. Huguier M, Samama G, Testart J, et al: Treatment of adenocarcinoma of the
pancreas with somatostatin and gonadoliberin (luteinizing hormone-releasing
hormone). The French Associations for Surgical Research. Am J Surg