Long-Acting Sandostatin Not Therapeutic for Liver Cancer

FREIBURG, Germany, Jan. 3 -- Long-acting release Sandostatin (octreotide) appears to have no benefit for hepatocellular carcinoma either in clinical outcomes or quality of life, according to German researchers.

Six-month survival was no different with Sandostatin LAR Depot than with placebo (41% versus 42%), said Hubert E. Blum, M.D., of the University Hospital Freiburg here, and colleagues, in the January issue of Hepatology.

Sandostatin, a synthetic form of somatostatin that has shown antimitotic activity in endocrine and nonendocrine tumors, had positive results in some previous, non-placebo controlled studies of hepatocellular carcinoma but has been controversial for use in the disease. It is FDA-approved for acromegaly, carcinoid syndrome, and vasoactive intestinal peptide tumors (VIPomas).

The researchers randomized 119 German and Swiss patients with histologically confirmed hepatocellular carcinoma but no indication for surgery or local treatment to receive either monthly intramuscular injections of 30 mg of Sandostatin LAR or placebo.

Patients were excluded from the study if they had a second malignancy, any local or systemic pretreatment including chemotherapy or tamoxifen, first diagnosis of hepatocellular carcinoma six months or more prior to the study, tumor stage Okuda III, symptomatic cholelithiasis, contraindications for intramuscular injection, or a known allergy to Sandostatin.

Both groups had comparable clinical characteristics at baseline. Advanced tumor stage was present in 7.5% of patients by Okuda stage III and about 30% by CLIP (Cancer of the Liver Italian Program) score of 4 or more.

Portal vein infiltration or thrombosis and compensated liver function (CPT class A or B), both important negative predictors of survival, were common at 49% and about 90%, respectively. About half of the patients had alcohol-induced chronic liver disease.

After a mean of about 32 months, 54 patients in the treatment group and 52 patients in the control group had died (median survival 4.7 versus 5.3 months).

The researchers reported that the raw relative mortality risk was no different between groups (1.11, 95% confidence interval 0.76 to 1.63, P=0.59). Neither was the relative risk adjusted for Okuda, CTP, and CLIP score (1.05, 95% CI 0.71 to 1.55, P=0.83).

Patients' target lesions, measured by ultrasonography at baseline, were followed at follow-up visits at months 1, 3, 6 and every six months subsequently. None of the patients had even a partial response, defined as at least 50% decrease in the longest diameter of the lesion. There were no significant differences between groups in stable disease (less than 50% decrease in lesion diameter or less than 25% decrease and no new lesions) or progressive disease (25% or more increase in diameter or at least one new lesion).

Quality of life was measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at baseline and then at month 1, 3, and every three months thereafter. However, there were no significant differences in any of the 15 subdomains at any time.

Routine follow-ups also included clinical examination, Karnofsky score determination, serum alpha-fetoprotein and HbA1c determination, and abdominal ultrasonographic examination.

The investigators found a similar rate of adverse events overall (169 placebo versus 161 Sandostatin) and concluded that Sandostatin was well tolerated by most patients.

The most common side effect was diarrhea, a known effect of Sandostatin. It was more common, though not significantly so, in the treatment group (13 of 60 patients versus seven of 59, P=0.220). Serious adverse events occurred among 16 and 25 patients, respectively, but only three were potentially related to Sandostatin (one hypoglycemia, one hyperglycemia, and one death from sudden bradycardia resulting in asystolia).

Sandostatin was an attractive therapy for liver cancer because liver transplantation and resection are the only potentially curative therapies, which 70% to 80% of patients are ineligible for at diagnosis.

Local ablation with transarterial chemoembolization, percutaneous ethanol injection, and radiofrequency thermal ablation have been used but they are not suitable for patients with advanced, large or multicentric hepatocellular carcinoma, Dr. Blum and colleagues said. Trials of systemic therapy including intravenous chemotherapy or estrogen suppression have been disappointing, they added.

"Although numerous treatment modalities have been explored in patients with advanced hepatocellular carcinoma, the therapeutic options are still limited," they wrote.