Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide

J Cebon, M Findlay, C Hargreaves, M Stockler, P Thompson, M Boyer, S Roberts, A Poon, A M Scott, V Kalff, G Garas, A Dowling, D Crawford, J Ring, R Basser, A Strickland, G Macdonald, M Green, A Nowak, B Dickman, H Dhillon, V Gebski, Australasian Gastro-Intestinal Trials Group (AGITG) Ag0001H Investigators, J Cebon, M Findlay, C Hargreaves, M Stockler, P Thompson, M Boyer, S Roberts, A Poon, A M Scott, V Kalff, G Garas, A Dowling, D Crawford, J Ring, R Basser, A Strickland, G Macdonald, M Green, A Nowak, B Dickman, H Dhillon, V Gebski, Australasian Gastro-Intestinal Trials Group (AGITG) Ag0001H Investigators

Abstract

Octreotide may extend survival in hepatocellular carcinoma (HCC). Forty-one per cent of HCCs have high-affinity somatostatin receptors. We aimed to determine the feasibility, safety, and activity of long-acting octreotide in advanced HCC; to identify the best method for assessing somatostatin receptor expression; to relate receptor expression to clinical outcomes; and to evaluate toxicity. Sixty-three patients with advanced HCC received intramuscular long-acting octreotide 20 mg monthly until progression or toxicity. Median age was 67 years (range 28-81 years), male 81%, Child-Pugh A 83%, and B 17%. The aetiologies of chronic liver disease were alcohol (22%), viral hepatitis (44%), and haemochromatosis (6%). Prior treatments for HCC included surgery (8%), chemotherapy (2%), local ablation (11%), and chemoembolisation (6%). One patient had an objective partial tumour response (2%, 95% CI 0-9%). Serum alpha-fetoprotein levels decreased more than 50% in four (6%). Median survival was 8 months. Thirty four of 61 patients (56%) had receptor expression detected by scintigraphy; no clear relationship with clinical outcomes was identified. There were few grade 3 or 4 toxicities: hyperglycaemia (8%), hypoglycaemia (2%), diarrhoea (5%), and anorexia (2%). Patients reported improvements in some symptoms, but no major changes in quality of life were detected. Long-acting octreotide is safe in advanced HCC. We found little evidence of anticancer activity. A definitive randomised trial would identify whether patients benefit from this treatment in other ways.

Figures

Figure 1
Figure 1
Overall survival.
Figure 2
Figure 2
Survival, by baseline octreotide scintigraphy status. The small graph shows the hazard ratio of the negative group (−) compared with the positive group (+).
Figure 3
Figure 3
(A) Octreotide scintigraphy (4-h image) showing uptake in an HCC in the dome of the right lobe of the liver (arrow): anterior image; (B) posterior image; normal octreotide uptake in spleen and kidneys; (C) SPECT transaxial section through the upper abdomen showing increased uptake in the HCC (arrow); and (D) the hepatoma in a corresponding CT scan slice (arrow).
Figure 4
Figure 4
(A) Octreotide scintigraphy (4-h image) showing no evidence of uptake in an HCC in the right lobe of the liver: anterior image; (B) posterior image; (C) SPECT transaxial section through the upper abdomen showing reduced uptake in the HCC (arrows) compared with normal liver; and (D) the HCC in a corresponding CT scan slice (arrows).
Figure 5
Figure 5
Chromogranin A levels over time in each patient.
Figure 6
Figure 6
Subjective HRQL status reported on the PBF after 1 month of treatment. *P<0.05.

References

    1. Akanuma M, Yoshida H, Okamoto M, Ogura K, Maeda S, Hata Y Sato S, Shiina S, Kawabe T, Shiratori Y, Omata M (2002) Risk factors for esophageal variceal bleeding in patients with hepatocellular carcinoma. Hepatogastroenterology 49(46): 1039–1044
    1. Cella D (1997) Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system (Version 4). Evanston: Northwestern Healthcare and Northwestern University, 1997
    1. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J, Eckberg K, Lloyd S, Purl S, Blendowski C, Goodman M, Barnicle M, Stewart I, Mchale M, Bonomi P, Kaplan E, Taylor S, Thomas CR, Harris J (1993) The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 11: 570–579
    1. Chow PK, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, Soo KC (2002) High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology 36(5): 1221–1226
    1. CLIP Group (1998) Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. CLIP Group (Cancer of the Liver Italian Programme). Lancet 352(9121): 17–20
    1. de Herder WW, Lamberts SW (2002) Somatostatin and somatostatin analogues: diagnostic and therapeutic uses. Curr Opin Oncol 14(1): 53–57
    1. Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, Zisimopoulos A, Andriotis E, Markidou S, Panagiotakos D, Chrysohoou C, Bazinis A, Paraskevas E (2002) The role of sandostatin LAR in treating patients with advanced hepatocellular cancer. Hepatogastroenterology 49(47): 1245–1250
    1. Florio T, Morini M, Villa V, Arena S, Corsaro A, Thellung S, Culler MD, Pfeffer U, Noonan DM, Schettini G, Albini A (2003) Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities. Endocrinology 144(4): 1574–1584
    1. Freda PU (2002) Somatostatin analogs in acromegaly. J Clin Endocrinol Metab 87(7): 3013–3018
    1. Heffernan N, Cella D, Webster K, Odom L, Martone M, Passik S, Bookbinder M, Fong Y, Jarnagin W, Blumgart L (2002) Measuring health-related quality of life in patients with hepatobiliary cancers: the functional assessment of cancer therapy-hepatobiliary questionnaire. J Clin Oncol 20(9): 2229–2239
    1. Jenkins SA, Baxter JN, Critchley M, Kingsnorth AN, Makin CA, Ellenbogen S, Grime JS, Love JG, Sutton R (1997) Randomised trial of octreotide for long term management of cirrhosis after variceal haemorrhage. BMJ 315(7119): 1338–1341
    1. Jenkins SA, Nott DM, Baxter JN (1998) Pharmacokinetics of octreotide in patients with cirrhosis and portal hypertension; relationship between the plasma levels of the analogue and the magnitude and duration of the reduction in corrected wedged hepatic venous pressure. HPB Surg 11(1): 13–21
    1. Johnson PJ (1996) The epidemiology of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 8(9): 845–849
    1. Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON (1998) Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 42(3): 442–447
    1. Lamberts SW, Krenning EP, Klijn JG, Reubi JC (1990) The clinical use of somatostatin analogues in the treatment of cancer. Baillieres Clin Endocrinol Metab 4(1): 29–49
    1. Lambrecht BN (2001) Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation. Respir Res 2(3): 133–138
    1. Leone N, Pellicano R, Brunello F, Rizzetto M, Ponzetto A (2002) Elevated serum chromogranin A in patients with hepatocellular carcinoma. Clin Exp Med 2(3): 119–123
    1. Leung TW, Johnson PJ (2001) Systemic therapy for hepatocellular carcinoma. Semin Oncol 28(5): 514–520
    1. Leung TW, Patt YZ, Lau WY, Ho SK, Yu SC, Chan AT, Mok TS, Yeo W, Liew CT, Leung NW, Tang AM, Johnson PJ (1999) Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 5(7): 1676–1681
    1. Raderer M, Hejna MH, Muller C, Kornek GV, Kurtaran A, Virgolini I, Fiebieger W, Hamilton G, Scheithauer W (2000) Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide in vitro and in vivo. Int J Oncol 16(6): 1197–1201
    1. Reubi JC, Zimmermann A, Jonas S, Waser B, Neuhaus P, Laderach U, Wiedenmann B (1999) Regulatory peptide receptors in human hepatocellular carcinomas. Gut 45(5): 766–774
    1. Samonakis DN, Moschandreas J, Arnaoutis T, Skordilis P, Leontidis C, Vafiades I, Kouroumalis E (2002) Treatment of hepatocellular carcinoma with long acting somatostatin analogues. Oncol Rep 9(4): 903–907
    1. Stewart PM, Kane KF, Stewart SE, Lancranjan I, Sheppard MC (1995) Depot long-acting somatostatin analog (Sandostatin-LAR) is an effective treatment for acromegaly. J Clin Endocrinol Metab 80: 3267–3272
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3): 205–216
    1. Yuen MF, Poon RT, Lai CL, Fan ST, Lo CM, Wong KW, Wong WM, Wong BC (2002) A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology 36(3): 687–691

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