Objective: To determine the efficacy of long acting octreotide (LAR) in the treatment of inoperable hepatocellular carcinoma; as well as to estimate the improvement in the quality of life.
Methods: This study was carried out at the Shifa International Hospital, Islamabad between February and September 2003. Patients were recruited after an informed consent. There were 22 patients who decided to take the medication whereas 20 patients refused due to socio-economic issues. They served as controls.The patients agreeable for treatment were administered octreotide 100 mcg subcutaneously thrice daily for two weeks. This was followed by monthly administration of 20 mg intramuscular octreotide. The patients were followed up for 6 months. Tumor size, alpha-fetoprotein levels, and improvement in quality of life (QOL) were monitored during therapy.
Results: Out of 22 patients, 19 patients completed the treatment. All were males. Mean age at presentation was 55 years. Tumor size regression was seen in 10 out of 22 patients (45.5%). Mean alpha-fetoprotein levels decreased in 11 out of 22 (50%) patients. An improvement in the quality of life was seen in 10 out of 22 (45.5%) patients after treatment with long acting octreotide. In the treatment arm, 14 out of 22 (64%) patients were alive at the end of six months as compared to 10 out of 20 (50%) in the control group.
Conclusion: LAR causes tumor size regression, decreases AFP levels and improves quality of life in patients with inoperable hepatocellular carcinoma (JPMA 55:135;2005).
Hepatocellular carcinoma (HCC) is widely distributed in different geographical areas. There is a high prevalence in Asia and Africa1 whereas the prevalence is very low in Western societies.2 In Pakistan its incidence is 8/100,000 per annum3, Viral hepatitis has been found to account for most of the HCC cases.4
Treatment of inoperable HCC remains unsatisfactory and different therapeutic regimes have been tested. Recently trials with tamoxifen5, flutamide6 and chemoembolisation with lipiodol7-10 have been reported.
Somatostatin, a hormone with well proven efficacy for the treatment of hormone producing tumors,11 has been tested for efficacy in non-hormone producing tumors.Somatostatin receptors have been identified in various Adenocarcinomas including breast, kidney, large bowel, and ovary.12,13 Significant decrease in the tumor size and AFP levels were first reported by Kouroumalis and colleagues using long acting octrotide (LAR).14 Since HCC in Pakistan presents with an advanced stage in a high proportion of patients15,16, it is important to determine optimal treatment strategy for our patients with HCC. With this background, we decided to determine the efficacy and safety profile of long acting octreotide in advanced stage HCC.
Patients and Methods
This observational study was carried out at the Department of Gastroenterology, Shifa International Hospital, Islamabad. The study was conducted after approval by the institutional review board and hospital ethical committee.
We enrolled 42 patients in the study between February 2003 and September 2003. All patients had a detailed history and physical examination by the consultant gastroenterologist. The diagnosis was made by ultrasound (US) or Computed Tomography (CT) guided biopsy, and measurement of alpha-fetoprotein (AFP). After establishing the diagnosis, the prognosis of the disease was also explained to the patient and family members.
We staged patients using Okuda staging system, which takes into account tumor size, presence of ascites, bilirubin and mean albumin levels. Since we were interested in patients with advanced hepatocellular carcinoma, we included patients only with Okuda stage III.
After establishing the diagnosis and staging the disease extent, the prognosis was explained. These patients were referred to a consultant surgeon for possible resection of the lesion. Only if surgical resection was not possible or considered not to have any possible benefit to the patient, remaining treatment options were discussed with the patient. Out of the 42 patients, 20 refused to undertake the treatment due to financial issues. Therefore we divided the patients into two groups; 22 patients undergoing treatment served as cases whereas 20 who could not afford the treatment served as controls. It was discussed that administering octreotide was only a palliative measure. After obtaining informed consent, the treatment regimen was initiated. First 100µcg of octreotide was administered subcutaneously three times a day for two weeks. Thereafter, 20 mg of LAR was given intramuscularly every month for 6 months.
In order to assess the improvement in QOL measures, Likert scale values between 1-5 were assigned to four variables including pain control, appetite, energy level and over-all well being.
Symptoms were rated as, "excellent" (total resolution), "good" (substantial improvement), "fair" (minor improvement), "poor" (no change) and "very poor" (worse outcome). Tumor size regression was assessed by repeated ultrasound every 2 months whereas decrease in alpha-fetoprotein levels was documented by doing AFP every 3 months. We used a paired t-test to compare the treatment efficacy in this subgroup.
The mean age of the study group was 52.5 years (45-60 years). All patients were males and 15 (68%) under treatment had hepatitis C as a cause of HCC, 5 (23%) hepatitis B and in 2 (9%) patients the cause of HCC was unknown. The treatment was stopped in three because of side effects. Nineteen patients continued the treatment for 6 months.
Since our study was based on multi-focal tumors, we measured the size of the lesion biggest in size; designated as the index tumor. Amongst patients undergoing treatment, mean tumor size at the initial presentation was 5.0+1.0 cm whereas mean AFP levels at the time of initial presentation were 15000+1000 IU/L. However, index tumor size and AFP levels in patients serving, as controls were 4.5+ 1.5 and 14500+750 IU/L respectively.
|Table 1. Tumor size and AFP levels before and after treatment with LAR in HCC (n=22). |
| ||Before treament ||After treament (mean score) ||p-value|
|Tumor size (cms) ||5.00 + 1.00 ||3.0 + 1.00 ||0.05 |
|AFP levels (IU/L) ||15000 + 1000 ||8000 + 1000 ||0.04 |
A drop in tumor size greater than 25% was seen in 10 out of 22 (45.5%) patients undergoing treatment. Mean tumor size in these patients was 3.5 cm at the end of
|Table 2. Likert Scale for assessing quality of life pre-treatment and post -treatment (n=22). |
| ||Before treament (mean score) ||After treament (mean score) ||p-value|
|Pain control ||2 ||4 ||0.04 |
|AFP levels (IU/L) ||2 ||4 ||0.03 |
|Energy level ||2 ||4 ||0.03 |
|Overall wellbeing ||2 ||4 ||0.01 |
treatment. AFP levels decreased in 11 out of 22 (50%) patients under treatment. In this subgroup, mean AFP levels at the end of treatment, were 8000 IU/L. (Table 1)
QOL indices for pain control, appetite, energy level, and over all well being improved in 10 out of 22 (45.5%) patients from a mean score of 2 to a mean score of 4. (Table 2)
Out of 22 patients, 14 (64%) were alive at the end of the 6 months follow-up whereas 10 out of 20 (50%) patients in the control arm died at the end of follow up for 6 months (Figure).
Figure. Survival analysis at the end of 6 months.
No serious side effects were seen in any patients who continued the treatment. However two patients developed diarrhea and discontinued the treatment.
The most common etiology for HCC in our patient population was Hepatitis C. This has also been validated by other studies from Pakistan.15-19
In our observation, long acting octreotide caused a decrease in the tumor size and decrease in AFP levels at three and six months after treatment amongst patients with inoperable hepatocellular carcinoma.
Since we do not currently have long term follow up of these patients, it is not possible to determine the efficacy of the regimen in terms of increasing median survival. However, it is important to take into account the fact that 64% patients were alive at the end of 6 months of treatment where the median survival for patients with advanced disease has been reported between 2 to 4 months in untreated patients.14,18,20,21
The improvement in quality of life was considered an important variable to be assessed in the study population. The Likert Scale was used to assess the quality of life in patients undergoing treatment. Around 45% of the patients showed an improvement in the quality of life index.
There have been conflicting reports about the efficacy of long acting octreotide in hepatocellular carcinoma. In a cohort of 63 patients from Germany, a partial remission in tumor size was achieved in only two patients (3.17%) after three months of treatment but without any difference in median survival of these patients.20 Likewise, investigators from Hong Kong found no differences in the cumulative survival, tumor size regression, drop in AFP and quality of life between the LAR treated and untreated groups.21
On the contrary, Greek investigators have shown a significant difference in the median survival time and a substantial improvement in the quality of life. However, no reduction in the AFP levels or a decrease in the tumor mass was observed.22
In one study from Pakistan, high dose octreotide was shown to cause a significant decrease in AFP levels and improvement in the quality of life of the treated patients.23
Although we do not have enough evidence if LAR increases the long-term survival of patients with HCC, the significant improvement in the quality of life is an important variable to be taken into consideration. This certainly refers to the palliative care measures in terminally ill patients.
Some of the pertinent limitations of the study include being a non-randomized trial. Also the lack of long-term follow up at this stage and the fact that this study was based at a single center are other factors to be considered.
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