**2. Hormonal therapy**

Several HCCs express sex-hormone receptors such as estrogen (ER), progesterone (PR), and androgen receptors [9] as well as somatostatin receptors [10, 11]. Hence, hormonal therapies (hormone receptor blockers) can be initiated as practical therapeutic choices in patients with hormone receptor-positive HCC [5]. The most frequently employed hormonal agents for the management of HCC include tamoxifen, megestrol, octreotide, and lanreotide.

### **2.1. Tamoxifen**

Multiple studies including single-center and multicenter prospective randomized controlled trials, systematic reviews, and meta-analyses investigated the role of tamoxifen for the management of patients with advanced unresectable HCC [12-16]. These studies were unsatisfactory and failed to demonstrate improved survival advantages (disease-free survival [DFS] and overall survival [OS] rates) or enhanced quality of life (functional status).

One plausible explanation for absence of survival efficacy could be attributed to the existence of variant estrogen receptors (ERs) in a subset of these HCC lesions leading to more hostile biological behavior and insensitivity to tamoxifen therapy [17, 18].

Tamoxifen has been shown to function as a potential multidrug resistance (MDR)-reversing remedy in the chemoresistant HCC [19]. Subsequently, several clinical trials have been conducted exploring the clinical benefits of combining tamoxifen with diverse cytotoxic chemotherapeutics.

The cellular (molecular) potentiation of doxorubicin-induced apoptosis of HCC cells by tamoxifen has been confirmed in a bench laboratory work by Cheng et al. [20]. Subsequently, in 1998, a prospective phase II study by the same authors [21] enrolled 36 patients with advanced HCC. Patients received high-dose tamoxifen (120 mg/m2 per day) plus doxorubicin. Only 12 patients (33.3%) attained partial remission with a median PFS of roughly 7 months.

Another randomized controlled study by Melia et al. [22] enrolled around 60 advanced inoperable HCC patients who were then randomized to two groups: (1) doxorubicin alone (60 mg/m2 at 3-week intervals) and (2) combined doxorubicin plus tamoxifen (10 mg twice daily). Drug response happened only in 3 (11%) and 4 (16%) patients of the above-mentioned groups, respectively, without statistical significant difference.

Moreover, Lu et al. [23] studied the combination therapy of high-dose tamoxifen, doxorubicin, and interferon alpha [IFNα] in 25 patients with advanced unresectable HCC. Partial remission was achieved in five patients (20%) with median PFS of 7 months. Overall, median OS was 6 months, whereas the 1-year survival rate was roughly 16%. The study concluded that this triple combination (high-dose tamoxifen, doxorubicin plus IFNα) is effective but not superior to the double therapy (high-dose tamoxifen plus doxorubicin).

Furthermore, the combination of tamoxifen with oral etoposide [24] and epirubicin [25] have been conducted with only modest antitumor outcomes.

### **2.2. Megestrol**

such as autoimmune hepatitis, nonalcoholic steatohepatitis (NASH), hepatitis B, hepatitis C, alcohol-associated liver disease, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and other liver diseases [4]. Therefore, the patient population is varied, accounting for the intricacy of studying

Therapeutic modalities for management of HCC can be largely categorized into three main types: surgical and nonsurgical therapies [5, 6]. Surgical therapies include surgical resection, cryosurgery, and living/deceased donor liver transplantation. Nonsurgical therapies can be divided into liver-directed and systemic. Liver-directed therapies include percutaneous ethanol/acetic acid injection, percutaneous microwave coagulation therapy, radiofrequency ablation, microwave coagulation therapy, interstitial laser photo-coagulation, targeted cryoablation therapy, high-intensity focused ultrasound, transcatheter arterial therapy, and radiation therapy. Systemic therapy includes hormonal therapy, cytotoxic chemotherapy, and

At the time of clinical diagnosis, roughly 60%-70% of HCC patients present with primary advanced, inoperable, recurrent, or metastatic disease [7]. Moreover, tumor relapse (recur‐ rence) following curative surgical management continues to be a substantial dilemma and is documented as high as approximately 70% at 5 years postoperatively [8]. The standard of care

The management of primary locally advanced, inoperable, recurrent, or metastatic HCC is very challenging and continues to be a topic of controversy. Herein, we shed light on the past, present, and future perspectives on the systemic therapy (hormonal therapy, cytotoxic chemotherapy, and novel molecularly targeted therapy) for the management of patients with

Several HCCs express sex-hormone receptors such as estrogen (ER), progesterone (PR), and androgen receptors [9] as well as somatostatin receptors [10, 11]. Hence, hormonal therapies (hormone receptor blockers) can be initiated as practical therapeutic choices in patients with hormone receptor-positive HCC [5]. The most frequently employed hormonal agents for the

Multiple studies including single-center and multicenter prospective randomized controlled trials, systematic reviews, and meta-analyses investigated the role of tamoxifen for the management of patients with advanced unresectable HCC [12-16]. These studies were unsatisfactory and failed to demonstrate improved survival advantages (disease-free survival

[DFS] and overall survival [OS] rates) or enhanced quality of life (functional status).

management of HCC include tamoxifen, megestrol, octreotide, and lanreotide.

this neoplasm, and how to effectively manage it.

management for recurrent HCC remains undefined [8].

novel molecularly targeted therapy.

106 Recent Advances in Liver Diseases and Surgery

advanced HCC.

**2.1. Tamoxifen**

**2. Hormonal therapy**

In 1997, Chao et al. [26] (phase II study) explored the role of megestrol acetate (160 mg/day, orally) in 46 patients with advanced unresectable HCC. Thirty-two patients were included in the analysis. No single patient attained partial or complete response. Twenty patients (62%) experienced disease progression, and a similar percentage (62%) experienced improved symptoms/functional status. Twelve patients (38%) attained stable disease. Glucocorticoid receptor-positive HCC (*n* = 4/5) experienced stable disease, whereas glucocorticoid receptornegative HCC (*n* = 5/5) experienced disease progression. The study concluded that while megestrol acetate does not exhibit noteworthy anticancer activities against HCC, it is very beneficial as palliative treatment to improve quality of life. Also, the stable disease status may be attributed to glucocorticoid receptor-positive HCC. Further research is needed.

In 2001, Villa et al. [18] studied 45 patients with variant ER HCC. Twenty-one (*n* = 21) and twenty-four (*n* = 24) patients were randomized to receive megestrol 160 mg daily and only best supportive care (BSC), respectively. In comparison with the BSC group, the megestrol-treated group achieved higher statistically significant median survival (18 vs. 7 months; *P* = 0.0090) and decelerated tumor growth (*P* = 0.0212).

More recently in 2011, Chow et al. [27] studied 204 patients with therapy-naive advanced HCC across six Asia-Pacific countries. Patients were randomized to two groups: (1) treated group with megestrol acetate (320 mg daily) and (2) placebo group. Placebo group had higher (statistically insignificant) OS than the treated group (2.14 vs. 1.88 months, respectively). The treated group had lower frequencies of nausea, vomiting, and anorexia but experienced a worse (statistically insignificant) global health status. The study concluded that megestrol acetate does not extend OS in patients with advanced treatment-naive HCC.

Most importantly, the noticeably dissimilar OS intervals in the Chow et al. [27] placebo group versus the supportive care group in the Villa et al. [18] study (2.14 vs. 7 months, respectively) propose that therapeutic results may be largely dependent on different aspects, for example, baseline liver function (Child-Pugh score [CPS]) and performance status (Eastern Cooperative Oncology Group performance status).

### **2.3. Octreotide**

In 1998, Kouroumalis et al. [11] studied the role of octreotide in 58 patients with advanced unresectable HCC. Patients were randomized to two groups: (1) treated group with somatos‐ tatin analog, i.e., octreotide (250 mg twice daily subcutaneously) and (2) placebo-controlled group. Numerous quantities of somatostatin receptors were recognized in the liver tissue of all patients with HCC. The treated group achieved higher statistically significant median OS rates than the control group (13 vs. 4 months, respectively; *P* = 0.002), but without objective responses rates (ORR). Moreover, the treated group achieved higher cumulative survival rates than the placebo-controlled group at 6 and 12 months (75% vs. 37% and 56% vs. 13%, respec‐ tively). At 6 months post octreotide administration, the treated group had significantly decreased alpha-fetoprotein (AFP) levels. The study concluded that octreotide administration substantially offers survival advantages and is a plausible substitute in the management of advanced unresectable HCC.

However, the above-mentioned findings [11] could not be validated and reproduced in 2 successive randomized placebo-controlled trials employing sandostatin—a long-acting analog of octreotide [28, 29]. The two studies were conducted in 2002 and 2007.

In 2011, Ji et al. [30] conducted an updated systematic review and meta-analysis of 11 random‐ ized controlled trials (total of 802 patients) exploring the role of somatostatin analogs in advanced HCC. Only nine studies were incorporated into the meta-analysis and revealed higher statistically significant 6-month and 12-month survival rates in the treated octreotide group versus the control/placebo group. This meta-analysis concluded that octreotide administration could provide survival benefits in patients with advanced HCC.

### **2.4. Lanreotide**

Previous nonrandomized studies have shown inadequate antineoplastic effects of lanreotide for the management of patients with advanced inoperable HCC [10, 31].

In 2000, Raderer et al. [31] administered lanereotide (30 mg once intramuscularly every 2-week period) in 21 treatment-naive patients with advanced HCC. The object response rate (ORR) and the stable disease rates were 5% and 38%, respectively, whereas the median OS and the time to progression (TTP) were 4.2 months and 2.5 months, respectively.

In 2006, Cebon et al. [10] administered lanereotide (20 mg once intramuscularly every 4-week period) in 63 patients with advanced HCC. Only one patient (2%) experienced partial objective response and median OS was 8 months.

In 2009, Barbare et al. [32] conducted a multicenter, phase III, randomized, double-blind placebo-controlled study investigating the role of lanreotide in 272 patients with primary advanced or recurrent HCC. Patients were randomized to two groups: (1) treated group with lanreotide (intramuscular injection of 30 mg once every 4 weeks for up to 2-year interval) and (2) placebo-controlled group. The median OS and the disease-free survival (DFS) were comparable and did not differ significantly between both groups. Four and zero objective responses were achieved in the placebo and treated groups, respectively. Objective response and disease stabilization were achieved in 0% and 33% of the lanreotide-treated group, respectively. The treated group had faster global heath deterioration that the control group. The study concluded that lanreotide has fairly a well-tolerated toxicity profile, negative influence on functional status, and nonbeneficial OS outcomes.

#### **2.5. Conclusion**

group achieved higher statistically significant median survival (18 vs. 7 months; *P* = 0.0090)

More recently in 2011, Chow et al. [27] studied 204 patients with therapy-naive advanced HCC across six Asia-Pacific countries. Patients were randomized to two groups: (1) treated group with megestrol acetate (320 mg daily) and (2) placebo group. Placebo group had higher (statistically insignificant) OS than the treated group (2.14 vs. 1.88 months, respectively). The treated group had lower frequencies of nausea, vomiting, and anorexia but experienced a worse (statistically insignificant) global health status. The study concluded that megestrol

Most importantly, the noticeably dissimilar OS intervals in the Chow et al. [27] placebo group versus the supportive care group in the Villa et al. [18] study (2.14 vs. 7 months, respectively) propose that therapeutic results may be largely dependent on different aspects, for example, baseline liver function (Child-Pugh score [CPS]) and performance status (Eastern Cooperative

In 1998, Kouroumalis et al. [11] studied the role of octreotide in 58 patients with advanced unresectable HCC. Patients were randomized to two groups: (1) treated group with somatos‐ tatin analog, i.e., octreotide (250 mg twice daily subcutaneously) and (2) placebo-controlled group. Numerous quantities of somatostatin receptors were recognized in the liver tissue of all patients with HCC. The treated group achieved higher statistically significant median OS rates than the control group (13 vs. 4 months, respectively; *P* = 0.002), but without objective responses rates (ORR). Moreover, the treated group achieved higher cumulative survival rates than the placebo-controlled group at 6 and 12 months (75% vs. 37% and 56% vs. 13%, respec‐ tively). At 6 months post octreotide administration, the treated group had significantly decreased alpha-fetoprotein (AFP) levels. The study concluded that octreotide administration substantially offers survival advantages and is a plausible substitute in the management of

However, the above-mentioned findings [11] could not be validated and reproduced in 2 successive randomized placebo-controlled trials employing sandostatin—a long-acting analog

In 2011, Ji et al. [30] conducted an updated systematic review and meta-analysis of 11 random‐ ized controlled trials (total of 802 patients) exploring the role of somatostatin analogs in advanced HCC. Only nine studies were incorporated into the meta-analysis and revealed higher statistically significant 6-month and 12-month survival rates in the treated octreotide group versus the control/placebo group. This meta-analysis concluded that octreotide

Previous nonrandomized studies have shown inadequate antineoplastic effects of lanreotide

of octreotide [28, 29]. The two studies were conducted in 2002 and 2007.

administration could provide survival benefits in patients with advanced HCC.

for the management of patients with advanced inoperable HCC [10, 31].

acetate does not extend OS in patients with advanced treatment-naive HCC.

and decelerated tumor growth (*P* = 0.0212).

108 Recent Advances in Liver Diseases and Surgery

Oncology Group performance status).

advanced unresectable HCC.

**2.4. Lanreotide**

**2.3. Octreotide**

All studies examining the role of single-agent tamoxifen or in combination with diverse chemotherapeutic drugs were unsatisfactory and failed to yield substantial worthy survival advantages. Similar discouraging results occurred with megestrol administration as well as somatostatin analogs (octreotide and lanreotide). It can be concluded that the use of hormonal therapy for the management of advanced inoperable HCC is not recommended. Its use may be only recommended within the context of clinical trials. Further research is needed.
