- Email: [email protected]
A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma
A Randomized Placebo-Controlled Study of Long-Acting Octreotide for the Treatment of Advanced Hepatocellular Carcinoma Man-Fung Yuen,1 Ronnie Tung-Ping Poon,2 Ching-Lung Lai,1 Sheung-Tat Fan,2 Chung-Mau Lo,2 Ka-Wah Wong,1 Wai Man Wong,1 and Benjamin Chun-Yu Wong1 Although various types of treatment of hepatocellular carcinoma (HCC) have been tried, the prognosis remains dismal, especially in patients with advanced stage of the disease. Somatostatin analogues exert antitumor effects. HCC have been shown to exhibit somatostatin receptors. The present randomized placebo-controlled study aimed at examining the efficacy of long-acting octreotide (Sandostatin LAR) for the treatment of advanced HCC. Seventy patients were randomized to receive a 2-week course of 250 g short-acting octreotide twice daily followed by Sandostatin LAR 30 mg injection once every 4 weeks for 6 doses (n ⴝ 35) or placebo (control group) (n ⴝ 35). The clinical and laboratory parameters were monitored. There was no difference in the cumulative survival between the Sandostatin LAR-treated group compared with the control group [median survival 1.93 months vs. 1.97 months, respectively, P ⴝ NS (log-rank test)]. There was no tumor regression and no reduction of ␣-fetoprotein (AFP) levels in patients receiving Sandostatin LAR treatment. There was no improvement of quality of life assessed by Karnofsky performance score. In conclusion, Sandostatin LAR monotherapy did not have survival benefit in our selected group of patients with advanced HCC. Further studies should be performed in patients with less advanced disease and/or different etiology to evaluate its benefit. (HEPATOLOGY 2002;36:687-691.)
H
epatocellular carcinoma (HCC) is responsible for nearly a quarter of a million deaths per year in the world.1 It is of particular importance in endemic areas such as Asia where there is a high prevalence of chronic hepatitis B virus (HBV) infection. Although a screening program increases the chance of receiving more curative treatment,2,3 many patients still present at a relatively late stage with advanced disease. Surgical resection is the first choice of treatment in patients without portal vein involvement and distant metastasis. However, it requires a relatively good liver funcAbbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; TACE, transcatheter arterial chemoembolization; AFP, ␣-fetoprotein; PT, prothrombin time; CT, computed tomography. From the 1Department of Medicine and 2Department of Surgery, Center for the Study of Liver Disease, The University of Hong Kong, Queen Mary Hospital, Hong Kong. Received March 4, 2002; accepted June 4, 2002. Supported by the Gastrointestinal Research Fund, Department of Medicine, University of Hong Kong, Hong Kong. Address reprint requests to: Benjamin Chun-Yu Wong, M.D., Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. E-mail: [email protected]; fax: (852) 287-25828. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3603-0021$35.00/0 doi:10.1053/jhep.2002.35071
tion reserve.4 Only less than 30% of patients are eligible for resection because of the high prevalence of underlying cirrhosis secondary to HBV infection.2 For patients with unresectable HCC, there are few options. Transcatheter arterial chemoembolization (TACE) requires a reasonable liver reserve because of the risk of hepatic decompensation after TACE.5,6 Liver transplantation, another option for small HCC with poor liver reserve, is limited by the scarcity of organ donation. Other modalities of treatment include percutaneous alcohol injection, which is only applicable for tumors less than 3 cm.7 Thermal ablation for small tumors using heating effect by radiofrequency or microwave has also been tried.8 These local ablative therapies are not suitable for patients with large HCC or advanced HCC with portal vein thrombosis with or without distant metastasis. Despite the extensive efforts in exploring the treatment of HCC, the prognosis remains dismal. The prognosis is even worse in patients with advanced unresectable HCC and with poor liver reserve. Somatostatin analogues exert regulatory or suppressive effects in various tumors.9 Different mechanisms of action including stimulation of Kupffer cells and antimitotic effect through inhibition of insulin-like growth factor I and engagement of receptors expressed by tumor 687
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YUEN ET AL.
cells have been postulated.10,11 Forty-one percent of HCC express somatostatin receptors according to one study.12 HCC predominantly expresses somatostatin-receptor subtype 2.12,13 Octreotide, one of the somatostatin analogues, has a high affinity to somatostatin-receptor subtype 2 and subtype 5.14 In a recent clinical study involving 58 patients, those receiving octreotide treatment (250 g subcutaneously, twice daily) had significant improvement in survival compared with the untreated patients (13 months vs. 4 months, respectively, P ⫽ .002).15 In addition, the use of octreotide did not have significant side effects. The need to give octreotide subcutaneously and at least twice daily was associated with significant treatment morbidity. The recently introduced long-acting preparation of octreotide, Sandostatin LAR, can be given once every month. It can be used as an effective treatment for various endocrine tumors, e.g., malignant carcinoid syndrome, acromegaly, and thyrotropin-stimulating hormone-secreting pituitary adenoma.16-18 Long-acting octreotide preparation has also been used in short bowel syndrome, resulting in satisfactory prolongation of small bowel transit time.19 A recent preliminary study shows promising clinical improvement in patients with rheumatoid arthritis treated with long-acting octreotide.20 So far, only 1 clinical study using octreotide as monotherapy for treatment of HCC has been published. The aim of the present study was to evaluate the efficacy of the long-acting octreotide formulation, Sandostatin LAR, for the treatment of advanced HCC with respect to the overall survival and tumor response.
Patients and Methods Patients with HCC admitted to the Department of Medicine and Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, from July, 1999, to April, 2001, were first assessed for the surgical resection that would be performed if the patients had unilobar HCC, adequate liver reserve as indicated by the indocyanine green clearance less than 14% at 15 minutes, and absence of portal vein thrombosis or distant metastasis. If surgical resection was not possible, TACE would be considered if the patients fulfilled the following criteria: bilirubin levels less than 50 mol/L, prothrombin time (PT) less than 5 seconds above the control value, serum creatinine level less than 200 mol/L, patent portal vein, no evidence of metastatic lesions, and no extensive arteriovenous shunting. If TACE was not possible, patients would be assessed for enrollment into the present study if they fulfilled the following criteria: between 18 to 80 years of age, histological proven HCC or serum ␣-fetoprotein (AFP) of more than 400 ng/mL with typical imaging
HEPATOLOGY, September 2002
findings of HCC by computed tomography (CT) or hepatic angiogram, serum bilirubin less than 100 mol/L, and PT less than 18 seconds. Patients were excluded if they had one of the following: previous antitumor treatment, somatostatin treatment given for other reasons, inability to perform injections by patients or relatives, and pregnancy or breast feeding. Patients were randomized to receive either Sandostatin LAR treatment or no antitumor treatment in a 1:1 ratio. Randomization was performed by drawing a sealed envelope that contained a preassigned randomized treatment generated by computer on entry to the study. No stratification according to the tumor size, portal vein thrombosis, presence of cirrhosis, and AFP level was performed during the randomization procedure. For patients randomized into the Sandostatin LAR group, 250 g short-acting octreotide was given subcutaneously twice a day for the first 2 weeks followed by Sandostatin LAR 30 mg injection once every 4 weeks for 6 doses. The study was approved by the Ethics Committee of the University of Hong Kong, Hong Kong. Written informed consents were obtained from each enrolled patient. The baseline assessments included complete physical examination and laboratory tests. The laboratory tests are composed of liver biochemistry, PT, AFP, renal function test, and complete blood count. The patients were followed up biweekly until week 6 and every four weeks until week 26. During each follow-up, all laboratory tests were repeated, and any adverse events were monitored. The tumor response was assessed by comparing the tumor dimensions measured by CT performed at baseline, at week 14, and at week 26, if possible. The performance status was assessed by the Karnofsky performance status scale in every visit. Survival and Tumor Response. The survival was calculated from the date of randomization to the date of last follow-up or death. Complete tumor response was defined as disappearance of all clinical evidence of tumor. Partial response was defined as 50% or greater reduction in the sum of the products of diameters of measurable lesions, no simultaneous increase in the size of any lesion, and no new extrahepatic lesions. Statistical Analysis. Using the available survival data from the previous study,15 the effect size was calculated to be 0.43. Inputting this effect size into a sample size software (PASS2000; NCSS, Kayswille, UT) for a comparison between 2 groups, it was estimated that the total sample size required would be approximately 60, i.e., 30 in each group, to achieve 0.9 power at 0.05 ␣ level. Therefore, the present study targeting 70 patients had more than 90% power to detect any difference in the survival between 2 groups. The statistics were performed by inten-
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Table 1. Demographic Data, Baseline Laboratory Data, and Child Pugh Score of Sandostatin LAR-Treated Group and Control Group Sandostatin LARTreated Group
Number of patients Median age, years (range) Sex ratio M:F Etiology Median follow-up, months (range) Albumin, g/L (range) Bilirubin, mol/L (range) ALT, U/L (range) Prothrombin time, sec (range) Platelet count, ⫻109/L (range) Child Pugh grading A:B:C (%)
Control
35 35 54.8 (26.6-78.8) 61.7 (36-78.4) 32:3 33:2 HBV, 30 HBV, 23; HCV, 2 Unknown, 5 Alcohol, 1; unknown, 9 1.93 (0.53-15.6) 1.97 (0.37-10.6) 34 (22-46) 32 (26-41) 29 (9-92) 24 (9-99) 67 (31-305) 61 (13-236) 14.1 (11.1-18.1) 13.6 (10.9-17.8) 203 (36-411) 188 (55-432) 18:14:3 12:22:1 (51.4:40:8.6) (34.3:62.9:2.9)
NOTE. The values of the laboratory data are expressed in median. Abbreviation: ALT, alanine aminotransferase.
tion-to-treat analysis. The data was analyzed by the Mann-Whitney test for the continuous ordinal data, 2 test with Yates’ correction, and Fisher exact test for the association between 2 qualitative variables. The comparison of cumulative survival between Sandostatin LARtreated group and control group was performed by Kaplan-Meier analysis. P values of less than .05 were considered as statistically significant.
Results A total of 70 patients (35 received Sandostatin LAR treatment and 35 acted as control) were recruited. The demographic data, baseline laboratory data, and Child Pugh score are listed in Table 1. There were no differences in any of the parameters between the 2 groups of patients (all P ⫽ NS). Clinical and biochemical evidence of cirrhosis was present in 25 (71.4%) and 30 (85.7%) patients of Sandostatin LAR-treated group and control group, respectively. Two patients from octreotide-treated group died before receiving a full 2-week course of short-acting octreotide and had not received the Sandostatin LAR. Eleven patients received a full 2-week course of shortacting octreotide but died before receiving Sandostatin LAR. Twenty-two Sandostatin LAR-treated patients received a full course of short-acting octreotide and received various doses of Sandostatin LAR (4 patients received the full 6 doses, 18 patients died before receiving the full 6 doses: 3 received 4 doses, 4 received 3 doses, 3 received 2 doses, and 8 received 1 dose). The characteristics of the tumors of both the Sandostatin LAR-treated patients and control patients are described in Table 2. There were no significant differences in various parameters of HCC between the 2 groups ex-
689
Table 2. Characteristics of the Tumors of Sandostatin LAR-Treated Group and Control Group
Solitary:multifocal:diffuse Lobar involvement (1 lobe: bilobar) Portal vein thrombosis (%) Distant metastasis (%) CLIP score Median score (range) Patient with score ⬎4 (%) Okuda stage (I:II:III) (%) Median AFP, ng/mL (range)
Sandostatin LARTreated Group
Control
26:3:6
19:8:8
26:9 17 (48.6) 7 (20)
19:16 21 (60) 5 (14.3)
4 (1-5) 19/35 (54.3) 6:23:6 (17.1:65.7:17.1) 19,177* (2-864,030)
4 (2-6) 23/35 (65.7) 3:26:6 (8.6:74.3:17.1) 721* (1-475,270)
Abbreviation: CLIP, The Cancer of the Liver Italian Program. *P ⫽ .021.
cept that patients receiving Sandostatin LAR had a significantly higher median AFP level on presentation compared with that of controls [19,177 ng/mL (range 2-864,030 ng/mL) vs. 721 ng/mL (range 1-475,270 ng/ mL), P ⫽ .021]. There was no difference in the cumulative survival between the Sandostatin LAR-treated patients and control patients (Fig. 1) (P ⫽ NS). The median survivals were 1.93 months and 1.97 months for Sandostatin LARtreated patients and control patients, respectively. Three patients from the Sandostatin LAR-treated group (duration of follow-up, 6.4, 11.8, 12.4 months) and 2 patients from the control group (duration of follow-up, 5.6 and 10.6 months) are still alive at the time of writing. Fiftyseven patients (28 Sandostatin LAR-treated patients and 29 control patients) died of tumor progression, and 8 patients (4 Sandostatin LAR-treated patients and 4 control patients) died of progressive liver decompensation. Because 48.6% of the Sandostatin LAR-treated patients and 60% of the control patients had portal vein
Fig. 1. The cumulative survival for the Sandostatin LAR-treated group (solid line) and the control group (dotted line) (P ⫽ NS).
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YUEN ET AL.
thrombosis indicating a more advanced HCC, the cumulative survival for patients with relatively less advanced HCC was calculated by excluding patients with portal vein thrombosis. There was no significant difference in the cumulative survival for Sandostatin LAR-treated patients (n ⫽ 18) and control patients (n ⫽ 14) without portal vein thrombosis (median survival 1.43 months vs. 2.5 months, respectively, P ⫽ NS). Fifteen patients (7 Sandostatin LAR-treated and 8 control) and 7 patients (3 Sandostatin LAR-treated and 4 control) had a second CT and third CT at week 14 and week 26, respectively, to assess the tumor response. Among the 7 Sandostatin LAR-treated patients, 1 patient had static disease, whereas the other 6 patients had tumor progression. Among the 8 control patients, 1 had spontaneous tumor regression of 32.9%, 2 had static disease, and 5 had tumor progression. The median AFP at the last follow-up was significantly higher than that of pretreatment AFP in the Sandostatin LAR-treated patients [41,897 ng/mL (range 3-73,707 ng/ mL) vs. 19,177 ng/mL (range 2-864,030 ng/mL), P ⬍ .0001]. Among the 32 Sandostatin LAR-treated patients with elevated pretreatment AFP, only 4 patients (12.5%) had a decrease of the AFP levels ranging from 2% to 18% reduction. Seven of 27 control patients (26.0%) with elevated baseline AFP also had a spontaneous decrease of AFP levels ranging from 29% to 97% reduction. However, only 2 control patients (7.4%) had normalization of AFP levels. The remaining 5 patients still had abnormal AFP levels of more than 200 ng/mL. There was no significant difference in the percentage of patients with AFP reduction between Sandostatin LAR-treated patients and control patients (P ⫽ NS). No patients in either group had improvement in Karnofsky performance status. Eight of 35 Sandostatin LAR-treated (22.9%) patients and 6 of 35 (17.1%) control patients had same Karnofsky performance status at baseline and at the last follow-up. There were no significant side effects observed for the Sandostatin LAR-treated patients.
Discussion The present study showed that Sandostatin LAR treatment was not effective in prolonging survival or inducing tumor regression in a selected subgroup of HCC patients in which surgical resection and TACE were not suitable. Therefore, patients with advanced HCC probably do not have survival benefit from octreotide treatment alone. Our findings support the comment of Jenkins et al.21 that the use of the presently available somatostatin analogue therapy in advanced malignancies is disappointing.21 Whether there are any added beneficial effects by com-
HEPATOLOGY, September 2002
bining somatostatin analogues with other established cytotoxic agents or hormones in advanced malignancies would require further investigation. Recently, Kouroumalis et al.15 demonstrated an improvement in survival for patients with HCC treated with octreotide. There are 3 differences in the study population between our study and Kouroumalis’s study. First, compared with the previous study, our study had fewer patients with advanced HCC with Okuda stage III (46% vs. 17.1%, respectively). On the other hand, nearly half of the patients in the present study had portal vein thrombosis, which is not a staging criterion for the Okuda classification but is a definite indicator of advanced HCC (proportion of patients with portal vein thrombosis was not mentioned in Kouroumalis’s study). This was supported by the fact that the median Cancer of the Liver Italian Program (CLIP) score (portal vein thrombosis is one of the scoring parameters) was 4, and more than 50% of our study population had a CLIP score more than 4 (Table 2). The short median survival time of 1.9 months was compatible with the median survival time of 2.5 and 1 month for patients with CLIP scores of 4 and greater than 5, respectively.22 The high percentage of patients (37.1%, 13 of 35) dying before receiving the first injection of Sandostatin LAR, and the fact that 14% to 20% of patients had distant metastasis might also indicate more aggressive diseases in our study population. Second, our patients had a relatively better liver function/reserve compared with those of Kouroumalis’s study as indicated by the higher percentage of patients with Child’s A cirrhosis (51.4% vs. 4%, respectively). The third difference between the present study and Kouroumalis’s study is the causative agents for HCC. More than 80% of the HCC in this study was due to chronic HBV infection compared with only 21% in the latter study [majority (54%) was due to chronic hepatitis C virus infection]. We cannot exclude the possibility that the poorer survival in our study might be due to the difference in the causative agents for HCC. Future studies are required to determine whether there are any differences in the expression of somatostatin receptor subtypes between hepatitis B- and hepatitis C-related HCC. Finally, whether the use of long-acting octreotide (Sandostatin LAR) instead of shorting-acting octreotide as used in Kouroumalis’s study can explain the discrepancy in terms of survival remains to be determined. It will be interesting to explore in the future whether short-acting octreotide has any pharmacological advantages over long-acting octreotide in treating HCC. In this study, Sandostatin LAR monotherapy did not have survival benefit in patients with advanced HCC, particularly with portal vein thrombosis or metastasis.
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However, further studies should be performed in patients with less advanced disease and/or different etiology to evaluate its benefit. Acknowledgment: The authors thank Novartis Hong Kong for supplying the Sandostatin LAR drugs and YukKit Mak for data collection for the study.
References 1. Kew MC. Hepatocellular carcinoma. A century of progress. Clin Liver Dis 2000;4:257-268. 2. Yuen MF, Cheng CC, Lauder IJ, Lam SK, Ooi CGC, Lai CL. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. HEPATOLOGY 2000;31:330-335. 3. McMahon BJ, Bulkow L, Harpster A, Snowball M, Lanier A, Sacco R, Dunaway E, et al. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. HEPATOLOGY 2000;32:842-846. 4. Fan ST, Lai EC, Lo CM, Ng IO, Wong J. Hospital mortality of major hepatectomy for hepatocellular carcinoma associated with cirrhosis. Arch Surg 1995;130:198-203. 5. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med 1995;332:1256-1261. 6. Poon RTP, Ngan H, Lo CM, Liu CL, Fan ST, Wong J. Transarterial chemoembolization for inoperable hepatocellular carcinoma and postresection intrahepatic recurrence. J Surg Oncol 2000;73:109-114. 7. Yamamoto J, Okada S, Shimada K, Okusaka T, Yamaski S, Ueno H, Kosuge T. Treatment strategy for small hepatocellular carcinoma: comparison of long-term results after percutaneous ethanol injection therapy and surgical resection. HEPATOLOGY 2001;34:707-713. 8. McGahan JP, Dodd GD III. Radiofrequency ablation of the liver: current status. Am J Roentgenol 2001;176:3-16. 9. Weckbecker G, Raulf F, Stolz B, Bruns C. Somatostatin analogs for diagnosis and treatment of cancer. Pharmacol Ther 1993;60:245-264. 10. Kouroumalis EA. Octreotide for cancer of the liver and biliary tree. Chemotherapy 2001;47:150-161.
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11. Shouval D. Octreotide in hepatocellular carcinoma. Gut 1998;42:316318. 12. Reubi JC, Zimmermann A, Jonas S, Waser B, Neuhaus P, La¨derach U, Wiedenmann B. Regulatory peptide receptors in human hepatocellular carcinoma. Gut 1999;45:766-774. 13. Reubi JC, Waser B, Schaer JC, Laissue JA. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 2001;28:836846. 14. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996;334:246-254. 15. Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 1998;42:442-447. 16. Rubin J, Ajani J, Shirmer W, Venook AP, Bukowski R, Pommier R, Saltz L, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 1999;17:600-606. 17. Lancranjan I, Bruns C, Grass P, Jaquet P, Jervell J, Kendall-Taylor P, Lamberts SWJ, et al. Sandostatin LAR: a promising therapeutic tool in the management of acromegalic patients. Metabolism 1996;45:6771. 18. Caron P, Arlot S, Bauters C, Chanson P, Kuhn JM, Pugeat M, Marech R, et al. Efficacy of the long-acting octreotide formulation (octreotide-LAR) in patients with thyrotropin-secreting pituitary adenomas. J Clin Endocrinol Metab 2001;86:2849-2853. 19. Nehra V, Camilleri M, Burton D, Oenning L, Kelly DG. An open trial of octreotide long-acting release in the management of short bowel syndrome. Am J Gastroenterol 2001;96:1494-1498. 20. Paran D, Elkayam O, Mayo A, Paran H, Amit M, Yaron M, Caspi D. A pilot study of a long-acting somatostatin analogue for the treatment of refractory rheumatoid arthritis. Ann Rheum Dis 2001;60:888-891. 21. Jenkins SA, Kynaston HG, Davis ND, Baxter JN, Nott DM. Somatostatin analogs in oncology: a look to the future. Chemotherapy 2001;47:162196. 22. The Cancer of the Liver Italian Program (CLIP) Investigators. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients. HEPATOLOGY 1998;28:751-755.
H
epatocellular carcinoma (HCC) is responsible for nearly a quarter of a million deaths per year in the world.1 It is of particular importance in endemic areas such as Asia where there is a high prevalence of chronic hepatitis B virus (HBV) infection. Although a screening program increases the chance of receiving more curative treatment,2,3 many patients still present at a relatively late stage with advanced disease. Surgical resection is the first choice of treatment in patients without portal vein involvement and distant metastasis. However, it requires a relatively good liver funcAbbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; TACE, transcatheter arterial chemoembolization; AFP, ␣-fetoprotein; PT, prothrombin time; CT, computed tomography. From the 1Department of Medicine and 2Department of Surgery, Center for the Study of Liver Disease, The University of Hong Kong, Queen Mary Hospital, Hong Kong. Received March 4, 2002; accepted June 4, 2002. Supported by the Gastrointestinal Research Fund, Department of Medicine, University of Hong Kong, Hong Kong. Address reprint requests to: Benjamin Chun-Yu Wong, M.D., Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. E-mail: [email protected]; fax: (852) 287-25828. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3603-0021$35.00/0 doi:10.1053/jhep.2002.35071
tion reserve.4 Only less than 30% of patients are eligible for resection because of the high prevalence of underlying cirrhosis secondary to HBV infection.2 For patients with unresectable HCC, there are few options. Transcatheter arterial chemoembolization (TACE) requires a reasonable liver reserve because of the risk of hepatic decompensation after TACE.5,6 Liver transplantation, another option for small HCC with poor liver reserve, is limited by the scarcity of organ donation. Other modalities of treatment include percutaneous alcohol injection, which is only applicable for tumors less than 3 cm.7 Thermal ablation for small tumors using heating effect by radiofrequency or microwave has also been tried.8 These local ablative therapies are not suitable for patients with large HCC or advanced HCC with portal vein thrombosis with or without distant metastasis. Despite the extensive efforts in exploring the treatment of HCC, the prognosis remains dismal. The prognosis is even worse in patients with advanced unresectable HCC and with poor liver reserve. Somatostatin analogues exert regulatory or suppressive effects in various tumors.9 Different mechanisms of action including stimulation of Kupffer cells and antimitotic effect through inhibition of insulin-like growth factor I and engagement of receptors expressed by tumor 687
688
YUEN ET AL.
cells have been postulated.10,11 Forty-one percent of HCC express somatostatin receptors according to one study.12 HCC predominantly expresses somatostatin-receptor subtype 2.12,13 Octreotide, one of the somatostatin analogues, has a high affinity to somatostatin-receptor subtype 2 and subtype 5.14 In a recent clinical study involving 58 patients, those receiving octreotide treatment (250 g subcutaneously, twice daily) had significant improvement in survival compared with the untreated patients (13 months vs. 4 months, respectively, P ⫽ .002).15 In addition, the use of octreotide did not have significant side effects. The need to give octreotide subcutaneously and at least twice daily was associated with significant treatment morbidity. The recently introduced long-acting preparation of octreotide, Sandostatin LAR, can be given once every month. It can be used as an effective treatment for various endocrine tumors, e.g., malignant carcinoid syndrome, acromegaly, and thyrotropin-stimulating hormone-secreting pituitary adenoma.16-18 Long-acting octreotide preparation has also been used in short bowel syndrome, resulting in satisfactory prolongation of small bowel transit time.19 A recent preliminary study shows promising clinical improvement in patients with rheumatoid arthritis treated with long-acting octreotide.20 So far, only 1 clinical study using octreotide as monotherapy for treatment of HCC has been published. The aim of the present study was to evaluate the efficacy of the long-acting octreotide formulation, Sandostatin LAR, for the treatment of advanced HCC with respect to the overall survival and tumor response.
Patients and Methods Patients with HCC admitted to the Department of Medicine and Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, from July, 1999, to April, 2001, were first assessed for the surgical resection that would be performed if the patients had unilobar HCC, adequate liver reserve as indicated by the indocyanine green clearance less than 14% at 15 minutes, and absence of portal vein thrombosis or distant metastasis. If surgical resection was not possible, TACE would be considered if the patients fulfilled the following criteria: bilirubin levels less than 50 mol/L, prothrombin time (PT) less than 5 seconds above the control value, serum creatinine level less than 200 mol/L, patent portal vein, no evidence of metastatic lesions, and no extensive arteriovenous shunting. If TACE was not possible, patients would be assessed for enrollment into the present study if they fulfilled the following criteria: between 18 to 80 years of age, histological proven HCC or serum ␣-fetoprotein (AFP) of more than 400 ng/mL with typical imaging
HEPATOLOGY, September 2002
findings of HCC by computed tomography (CT) or hepatic angiogram, serum bilirubin less than 100 mol/L, and PT less than 18 seconds. Patients were excluded if they had one of the following: previous antitumor treatment, somatostatin treatment given for other reasons, inability to perform injections by patients or relatives, and pregnancy or breast feeding. Patients were randomized to receive either Sandostatin LAR treatment or no antitumor treatment in a 1:1 ratio. Randomization was performed by drawing a sealed envelope that contained a preassigned randomized treatment generated by computer on entry to the study. No stratification according to the tumor size, portal vein thrombosis, presence of cirrhosis, and AFP level was performed during the randomization procedure. For patients randomized into the Sandostatin LAR group, 250 g short-acting octreotide was given subcutaneously twice a day for the first 2 weeks followed by Sandostatin LAR 30 mg injection once every 4 weeks for 6 doses. The study was approved by the Ethics Committee of the University of Hong Kong, Hong Kong. Written informed consents were obtained from each enrolled patient. The baseline assessments included complete physical examination and laboratory tests. The laboratory tests are composed of liver biochemistry, PT, AFP, renal function test, and complete blood count. The patients were followed up biweekly until week 6 and every four weeks until week 26. During each follow-up, all laboratory tests were repeated, and any adverse events were monitored. The tumor response was assessed by comparing the tumor dimensions measured by CT performed at baseline, at week 14, and at week 26, if possible. The performance status was assessed by the Karnofsky performance status scale in every visit. Survival and Tumor Response. The survival was calculated from the date of randomization to the date of last follow-up or death. Complete tumor response was defined as disappearance of all clinical evidence of tumor. Partial response was defined as 50% or greater reduction in the sum of the products of diameters of measurable lesions, no simultaneous increase in the size of any lesion, and no new extrahepatic lesions. Statistical Analysis. Using the available survival data from the previous study,15 the effect size was calculated to be 0.43. Inputting this effect size into a sample size software (PASS2000; NCSS, Kayswille, UT) for a comparison between 2 groups, it was estimated that the total sample size required would be approximately 60, i.e., 30 in each group, to achieve 0.9 power at 0.05 ␣ level. Therefore, the present study targeting 70 patients had more than 90% power to detect any difference in the survival between 2 groups. The statistics were performed by inten-
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Table 1. Demographic Data, Baseline Laboratory Data, and Child Pugh Score of Sandostatin LAR-Treated Group and Control Group Sandostatin LARTreated Group
Number of patients Median age, years (range) Sex ratio M:F Etiology Median follow-up, months (range) Albumin, g/L (range) Bilirubin, mol/L (range) ALT, U/L (range) Prothrombin time, sec (range) Platelet count, ⫻109/L (range) Child Pugh grading A:B:C (%)
Control
35 35 54.8 (26.6-78.8) 61.7 (36-78.4) 32:3 33:2 HBV, 30 HBV, 23; HCV, 2 Unknown, 5 Alcohol, 1; unknown, 9 1.93 (0.53-15.6) 1.97 (0.37-10.6) 34 (22-46) 32 (26-41) 29 (9-92) 24 (9-99) 67 (31-305) 61 (13-236) 14.1 (11.1-18.1) 13.6 (10.9-17.8) 203 (36-411) 188 (55-432) 18:14:3 12:22:1 (51.4:40:8.6) (34.3:62.9:2.9)
NOTE. The values of the laboratory data are expressed in median. Abbreviation: ALT, alanine aminotransferase.
tion-to-treat analysis. The data was analyzed by the Mann-Whitney test for the continuous ordinal data, 2 test with Yates’ correction, and Fisher exact test for the association between 2 qualitative variables. The comparison of cumulative survival between Sandostatin LARtreated group and control group was performed by Kaplan-Meier analysis. P values of less than .05 were considered as statistically significant.
Results A total of 70 patients (35 received Sandostatin LAR treatment and 35 acted as control) were recruited. The demographic data, baseline laboratory data, and Child Pugh score are listed in Table 1. There were no differences in any of the parameters between the 2 groups of patients (all P ⫽ NS). Clinical and biochemical evidence of cirrhosis was present in 25 (71.4%) and 30 (85.7%) patients of Sandostatin LAR-treated group and control group, respectively. Two patients from octreotide-treated group died before receiving a full 2-week course of short-acting octreotide and had not received the Sandostatin LAR. Eleven patients received a full 2-week course of shortacting octreotide but died before receiving Sandostatin LAR. Twenty-two Sandostatin LAR-treated patients received a full course of short-acting octreotide and received various doses of Sandostatin LAR (4 patients received the full 6 doses, 18 patients died before receiving the full 6 doses: 3 received 4 doses, 4 received 3 doses, 3 received 2 doses, and 8 received 1 dose). The characteristics of the tumors of both the Sandostatin LAR-treated patients and control patients are described in Table 2. There were no significant differences in various parameters of HCC between the 2 groups ex-
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Table 2. Characteristics of the Tumors of Sandostatin LAR-Treated Group and Control Group
Solitary:multifocal:diffuse Lobar involvement (1 lobe: bilobar) Portal vein thrombosis (%) Distant metastasis (%) CLIP score Median score (range) Patient with score ⬎4 (%) Okuda stage (I:II:III) (%) Median AFP, ng/mL (range)
Sandostatin LARTreated Group
Control
26:3:6
19:8:8
26:9 17 (48.6) 7 (20)
19:16 21 (60) 5 (14.3)
4 (1-5) 19/35 (54.3) 6:23:6 (17.1:65.7:17.1) 19,177* (2-864,030)
4 (2-6) 23/35 (65.7) 3:26:6 (8.6:74.3:17.1) 721* (1-475,270)
Abbreviation: CLIP, The Cancer of the Liver Italian Program. *P ⫽ .021.
cept that patients receiving Sandostatin LAR had a significantly higher median AFP level on presentation compared with that of controls [19,177 ng/mL (range 2-864,030 ng/mL) vs. 721 ng/mL (range 1-475,270 ng/ mL), P ⫽ .021]. There was no difference in the cumulative survival between the Sandostatin LAR-treated patients and control patients (Fig. 1) (P ⫽ NS). The median survivals were 1.93 months and 1.97 months for Sandostatin LARtreated patients and control patients, respectively. Three patients from the Sandostatin LAR-treated group (duration of follow-up, 6.4, 11.8, 12.4 months) and 2 patients from the control group (duration of follow-up, 5.6 and 10.6 months) are still alive at the time of writing. Fiftyseven patients (28 Sandostatin LAR-treated patients and 29 control patients) died of tumor progression, and 8 patients (4 Sandostatin LAR-treated patients and 4 control patients) died of progressive liver decompensation. Because 48.6% of the Sandostatin LAR-treated patients and 60% of the control patients had portal vein
Fig. 1. The cumulative survival for the Sandostatin LAR-treated group (solid line) and the control group (dotted line) (P ⫽ NS).
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thrombosis indicating a more advanced HCC, the cumulative survival for patients with relatively less advanced HCC was calculated by excluding patients with portal vein thrombosis. There was no significant difference in the cumulative survival for Sandostatin LAR-treated patients (n ⫽ 18) and control patients (n ⫽ 14) without portal vein thrombosis (median survival 1.43 months vs. 2.5 months, respectively, P ⫽ NS). Fifteen patients (7 Sandostatin LAR-treated and 8 control) and 7 patients (3 Sandostatin LAR-treated and 4 control) had a second CT and third CT at week 14 and week 26, respectively, to assess the tumor response. Among the 7 Sandostatin LAR-treated patients, 1 patient had static disease, whereas the other 6 patients had tumor progression. Among the 8 control patients, 1 had spontaneous tumor regression of 32.9%, 2 had static disease, and 5 had tumor progression. The median AFP at the last follow-up was significantly higher than that of pretreatment AFP in the Sandostatin LAR-treated patients [41,897 ng/mL (range 3-73,707 ng/ mL) vs. 19,177 ng/mL (range 2-864,030 ng/mL), P ⬍ .0001]. Among the 32 Sandostatin LAR-treated patients with elevated pretreatment AFP, only 4 patients (12.5%) had a decrease of the AFP levels ranging from 2% to 18% reduction. Seven of 27 control patients (26.0%) with elevated baseline AFP also had a spontaneous decrease of AFP levels ranging from 29% to 97% reduction. However, only 2 control patients (7.4%) had normalization of AFP levels. The remaining 5 patients still had abnormal AFP levels of more than 200 ng/mL. There was no significant difference in the percentage of patients with AFP reduction between Sandostatin LAR-treated patients and control patients (P ⫽ NS). No patients in either group had improvement in Karnofsky performance status. Eight of 35 Sandostatin LAR-treated (22.9%) patients and 6 of 35 (17.1%) control patients had same Karnofsky performance status at baseline and at the last follow-up. There were no significant side effects observed for the Sandostatin LAR-treated patients.
Discussion The present study showed that Sandostatin LAR treatment was not effective in prolonging survival or inducing tumor regression in a selected subgroup of HCC patients in which surgical resection and TACE were not suitable. Therefore, patients with advanced HCC probably do not have survival benefit from octreotide treatment alone. Our findings support the comment of Jenkins et al.21 that the use of the presently available somatostatin analogue therapy in advanced malignancies is disappointing.21 Whether there are any added beneficial effects by com-
HEPATOLOGY, September 2002
bining somatostatin analogues with other established cytotoxic agents or hormones in advanced malignancies would require further investigation. Recently, Kouroumalis et al.15 demonstrated an improvement in survival for patients with HCC treated with octreotide. There are 3 differences in the study population between our study and Kouroumalis’s study. First, compared with the previous study, our study had fewer patients with advanced HCC with Okuda stage III (46% vs. 17.1%, respectively). On the other hand, nearly half of the patients in the present study had portal vein thrombosis, which is not a staging criterion for the Okuda classification but is a definite indicator of advanced HCC (proportion of patients with portal vein thrombosis was not mentioned in Kouroumalis’s study). This was supported by the fact that the median Cancer of the Liver Italian Program (CLIP) score (portal vein thrombosis is one of the scoring parameters) was 4, and more than 50% of our study population had a CLIP score more than 4 (Table 2). The short median survival time of 1.9 months was compatible with the median survival time of 2.5 and 1 month for patients with CLIP scores of 4 and greater than 5, respectively.22 The high percentage of patients (37.1%, 13 of 35) dying before receiving the first injection of Sandostatin LAR, and the fact that 14% to 20% of patients had distant metastasis might also indicate more aggressive diseases in our study population. Second, our patients had a relatively better liver function/reserve compared with those of Kouroumalis’s study as indicated by the higher percentage of patients with Child’s A cirrhosis (51.4% vs. 4%, respectively). The third difference between the present study and Kouroumalis’s study is the causative agents for HCC. More than 80% of the HCC in this study was due to chronic HBV infection compared with only 21% in the latter study [majority (54%) was due to chronic hepatitis C virus infection]. We cannot exclude the possibility that the poorer survival in our study might be due to the difference in the causative agents for HCC. Future studies are required to determine whether there are any differences in the expression of somatostatin receptor subtypes between hepatitis B- and hepatitis C-related HCC. Finally, whether the use of long-acting octreotide (Sandostatin LAR) instead of shorting-acting octreotide as used in Kouroumalis’s study can explain the discrepancy in terms of survival remains to be determined. It will be interesting to explore in the future whether short-acting octreotide has any pharmacological advantages over long-acting octreotide in treating HCC. In this study, Sandostatin LAR monotherapy did not have survival benefit in patients with advanced HCC, particularly with portal vein thrombosis or metastasis.
HEPATOLOGY, Vol. 36, No. 3, 2002
However, further studies should be performed in patients with less advanced disease and/or different etiology to evaluate its benefit. Acknowledgment: The authors thank Novartis Hong Kong for supplying the Sandostatin LAR drugs and YukKit Mak for data collection for the study.
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