Is There a Role for Octreotide in the Treatment of Hormone-Refractory Prostate Cancer?

September 1, 2002

Normal and hyperplastic prostate glandular epithelium does not express somatostatin receptors. Neuroendocrine prostatic cells contain bioactive secretory products such as chromogranin A, serotonin, and neuron-specific enolase. The stromal smooth muscle cells around glandular epithelium and ganglion cells of the prostatic plexus are positive for somatostatin subtype 2 receptors (sst 2).[1] In prostate cancer, however, there is nonhomogeneous distribution of sst 1. In the peritumoral veins of prostate cancer, sst 2 receptors were found by Reubi et al in 14 of 27 samples.[2]

Normal and hyperplastic prostate glandular epithelium doesnot express somatostatin receptors. Neuroendocrine prostatic cells containbioactive secretory products such as chromogranin A, serotonin, andneuron-specific enolase. The stromal smooth muscle cells around glandularepithelium and ganglion cells of the prostatic plexus are positive forsomatostatin subtype 2 receptors (sst 2).[1] In prostate cancer, however, thereis nonhomogeneous distribution of sst 1. In the peritumoral veins of prostatecancer, sst 2 receptorswere found by Reubi et al in 14 of 27 samples.[2]

Neuroendocrine differentiation is a common feature ofprostatic adenocarcinoma, although the prognostic value of neuroendocrinedifferentiation is controversial.[3] There are scattered clusters ofneuroendocrine differentiated cells among the non-neuroendocrine malignantcells. The neuroendocrine differentiation in prostate cancer results in anabnormal phenotype and an incomplete expression of neuroendocrine substances.This phenotypic shift generates cancer cells more adaptable to environmentalchanges. These cells tend to be androgen-independent rather thanandrogen-dependent.[3] Elevated chromogranin A and neuron-specific enolaselevels in the serum correlate with androgen independence, and distantmetastases, but not with locally progressive disease.[4] For prostate carcinomawith neuroendocrine differentiation, the serum markers of the chromograninfamily are of more promising prognostic value than neuroendocrine tissuecharacterization.[5,6]

Octreotide (Sandostatin) is a general inhibitor ofneuroendocrine secretion and may inhibit neuroendocrine tumor growth. Imaging inhormone-refractory prostate cancer using somatostatin receptor scintigraphy with111In-pentetreotide (OctreoScan, Mallinkrodt Imaging) will often be positive at the site of theprimary tumor as well as at sites of bone metastases.[7] The presence ofsomatostatin receptors in tumors, determined using radiolabeled octreotideimaging, has prompted clinical trials with octreotide.[8]

In one trial, by Logothetis et al, 20 of 24 patients withhormone-refractory prostate cancer were evaluable for efficacy.[9] Octreotidetreatment was administered at a dose of 100 µg subcutaneously three timesdaily. In this trial, 14 of 20 patients reported subjective improvement in theirpain. There was no evidence of objective tumor regression.

More recently, Acosta has treated 18 patients withprogressive hormone-refractory prostate cancer using octreotide LAR depot (SandostatinLAR Depot) at 30 mg/month.[10] Eleven of 18 patients had tumors positive forsomatostatin receptors demonstrated by somatostatin receptor scintigraphy. In 9of 18 patients, there was a greater than 50% decrease in prostate-specificantigen levels. In 8 of 18 patients, there was a 50% reduction in the number ofmetastases visualized by somatostatin receptor scintigraphy.[10]

In conclusion, there are conflicting clinical results whenoctreotide has been used for hormone-refractory prostate cancer. Furtherclinical studies are clearly needed in light of Acosta’s provocative findings.An intriguing question is whether other somatostatin receptors besides the sst 2receptor may be relevant. When analogs of somatostatin such as SOM 230, whichbinds to somatostatin receptor subtypes 1, 2, and 3, as well as 5, becomeclinically available, they deserve evaluation in this challenging diseasesetting.

References:

1. Reubi JC, Waser B, Schaer JC, et al: Somatostatinreceptors in human prostate and prostate cancer. J Clin Endocrinol Metab80:2806-2814, 1995.

2. Reubi JC, Waser B, Schaer JC, et al: Somatostatin receptorsst1-sst5 expression in normal and neoplastic human tissues using receptorautoradiography with subtype-selective ligands. Eur J Nucl Med28:836-846, 2001.

3. Abrahamsson PA: Neuroendocrine cells in tumour growth ofthe prostate. Endocr Relat Cancer 6:503-519, 1999.

4. Abrahamsson PA: Neuroendocrine differentiation inprostatic carcinoma. Prostate 39:135-148, 1999.

5. Yu DS, Hsieh DS, Chen HI, et al: The expression ofneuropeptides in hyperplastic and malignant prostate tissue and its possibleclinical implications. J Urol 166:871-875, 2001.

6. Ferrero-Pous M, Hersant AM, Pecking A, et al: Serumchromogranin-A in advanced prostate cancer. BJU Int 88:790-796, 2001.

7. Nilsson S, Reubi JC, Kalkner KM, et al: Metastatic hormon-refractoryprostatic adenocarcinoma expresses somatostatin receptors and is visualized invivo by [IIIIn]-labeled DTPA-D-[phe1]-octreotide scintigraphy. Cancer Res55(suppl 23):5805S-5810S, 1995.

8. Vainas IG: Octreotide in the management of hormon-refractoryprostate cancer. Chemotherapy 47(suppl 2):109-126, 2001.

9. Logothetis CJ, Hossan EA, Smith TL: SMS 201-995 in thetreatment of refractory prostate carcinoma. Anticancer Res 14:2731-2734,1994.

10. Acosta S: Somatostatin analogue treatment of patientswith hormone refractory prostate cancer: First clinical results. Presented atthe XVIth Congress of the European Associate of Urology, Geneva, April 7-10,2001.