Faculty Bibliography

Despite the established efficacy of sorafenib in advanced hepatocellular carcinoma (HCC), a significant number of sorafenib-treated patients experience disease progression. Current guidelines recommend either best supportive care or clinical trial enrollment for this population. As such, there remains an unmet need for tolerable, life-prolonging strategies in the second-line setting. New information regarding the molecular pathogenesis of resistance to antiangiogenic therapy and positive post-progression experience with antiangiogenics in other tumor types has led to trials investigating the effect of continued use of sorafenib, alone or combined with other agents. Trials investigating the effect of switching from sorafenib to alternate antiangiogenic agents, phosphatidylinositol 3 kinase/AKT/mammalian target of rapamycin inhibitors, or cMet inhibitors are also underway. As these data emerge, clinicians may consider a new paradigm for managing advanced HCC. This article briefly reviews the mechanisms of disease resistance to antiangiogenic therapy as a vehicle for discussing clinical strategies to prolong survival in patients with advanced HCC that are currently employed at our institutions or are under investigation. Key ongoing trials investigating the use of molecularly targeted therapies in patients with progressive disease are also highlighted.

Background: GIDEON is a global, prospective, noninterventional study of patients (pts) treated with sorafenib (SOR) for unresectable hepatocellular carcinoma (uHCC). Regions evaluated included US, Europe, Japan, Asia Pacific, and Latin America. Using data from the second interim analysis, we compare safety and efficacy of sorafenib in US pts with the entire (global) study population. Methods: Eligible pts had uHCC and were treated with SOR. Demographics, disease etiology, treatment history, and SOR dosing were compared in a descriptive, preplanned subgroup analysis. Results: The safety population comprised 1571 pts. In the 313 US pts, hepatitis B was less common (18% vs 37% global), but hepatitis C was more frequent (53% vs 32% global) (Table). Rate of alcoholic liver disease was higher in US pts (41% vs 29% global). At start of SOR, fewer US pts had BCLC stage C-D disease (49% vs 60% global), but more US pts were Child-Pugh (CP) B or C status (38% vs 25% global) (Table). Rates of prior surgery and locoregional treatment (LRT) were similar in US (11% and 49%, respectively) and global pts (19% and 55%, respectively). US pts received fewer TACE procedures (3 treatments: 13.8% vs 38.9% global); most (59%) TACE-treated pts in the US received 1 treatment. In US vs global pts, median time from prior surgery to start of SOR was 10 months (range 1-61) vs 14 months (range 1-181) and median time from last TACE to start of SOR was 3.2 months vs 3.1 months. Conclusions: Disease characteristics and treatment patterns differ in the US and global GIDEON populations. Although its limitations as an observational study must be considered, GIDEON is a valuable repository of data reflecting real-world practices in a variety of regions and pt types. (Table presented)

Background/Rationale: Sorafenib improves overall survival in patients with advanced hepatocellular carcinoma (HCC). GIDEON is a global, prospective, noninterventional study of sorafenib-treated patients with unresectable HCC to evaluate safety in clinical practice. Objective: To present results from the second interim analysis of sorafenib dosing in US patients. Methods: From 1/2009 to 11/2010, 1650 patients were enrolled globally. 92 US centers enrolled 326 (20%) patients; 313 were evaluable. Demographics, initial dose, treatment duration (TD), dose interruptions/ modifications, and adverse events (AEs) were analyzed in patients with complete data. Results: Initially, 106 patients (34%) received sorafenib 400mg/d and 177 patients (57%) received sorafenib 800mg/d. Thirty (10%) patients received alternate doses or lacked data. Age distribution was similar (400mg/d: <65 yr, 59%; >65 yr, 41%; 800mg/d: <65 yr, 64%; >65 yr, 36%). In 400mg/d and 800mg/d groups, ECOG performance status 0/1/ 2 was 19%/49%/16% and 34%/35%/12%; Child- Pugh A/B/C status was 32%/35%/7% (26% unevaluable) and 42%/29%/6% (21% unevaluable), respectively. Among patients who received an initial 400mg/d dose, median TD was 9.8 weeks. Dose modifications occurred in 57% (36% AEs) and treatment interruptions in 38%. Among patients who received an initial 800mg/d dose, median TD was 13.2 weeks. Dose modifications occurred in 49% (37% AEs) and treatment interruptions in 35%. Conclusions: Performance status or Child-Pugh status may influence initial sorafenib dose selection, but statistical comparisons were not conducted. Other characteristics did not affect this decision. Despite differences in initial dose, rates of dose modifications, interruptions, and AEs were similar. Clinical judgment is important in initial sorafenib dose selection

Background: Sorafenib (SOR) is the first systemic therapy to improve survival in patients (pts) with advanced hepatocellular carcinoma (HCC). GIDEON is a global, prospective, noninterventional study to evaluate SOR safety in pts with unresectable HCC in real-life practice. We present results from the second interim analysis, describing SOR dosing in US pts. Methods: From Jan 2009 - Nov 2010, 326 pts were enrolled in 92 US centers and followed 4 months, with 313 pts evaluable for safety. Demographics, initial dose, treatment duration (TD), dose modifications (mods), treatment interruptions (TIs), and adverse events (AEs) were analyzed in pts with complete data available. Results: Initial SOR dose was 400 mg/d in 106 pts (34%) and 800 mg/d in 177 pts (57%). Thirty (10%) pts received alternate doses or had incomplete data. Most pts were male (400 mg/d: 75%; 800 mg/d: 80%). Age distribution was similar between groups (400 mg/d: 59% <65 yr and 41% >65 yr; 800 mg/d: 64% <65 yr and 36% >65 yr). In 400 mg/d vs 800 mg/d groups respectively, ECOG PS was 0/1/2 in 19%/49%/16% vs 34%/35%/12%, and Child-Pugh (CP) status was A/B/C in 32%/35%/7% (26% unevaluable) vs 42%/29%/6% (21% unevaluable). Median TD was 9.8 wks (<4 wks in 22%, >4-12 wks in 40%, and >12 wks in 39%) in the 400 mg/d group and 13.2 wks (<4 wks in 17%, >4-12 wks in 29%, and >12 wks in 53%) in the 800 mg/d group. Dose mods and TIs occurred in 49% (37% due to AE) and 35%, and 57% (36% due to AE) and 38% of 400 mg/d vs 800 mg/d pts, respectively. See table for safety data. Conclusions: While statistical comparisons were not made, PS or CP status may impact initial SOR dose selection. Other baseline characteristics did not affect this decision. Frequencies of dose mods, TIs, and AEs were similar between dosing groups. Limitations of an observational study must be considered. Clinical judgment remains important in choosing initial SOR dose. (Table Presented)

<p>Purpose: SOR is the first systemic therapy to improve overall survival in patients (pts) with advanced hepatocellular carcinoma (HCC). GIDEON is a global, prospective, noninterventional study of SOR-treated patients with unresectable HCC designed to further evaluate safety and treatment in routine clinical practice. In this analysis, we present results from the second interim analysis (IA) of SOR dosing in US pts. <p>Methods: From Jan 2009-Nov 2010, 1650 pts were enrolled globally and followed >=4 months; 1571 pts were evaluable for safety. In the US, 92 centers enrolled 326 (20%) pts with 313 pts evaluable for safety. Demographics, initial dose, treatment duration (TD), dose interruptions/modifications (mods), and adverse events (AEs) were analyzed in a descriptive fashion. This analysis included only pts for whom complete data were available. <p>Results: Initially, 106 pts (34%) received SOR 400mg/d and 177 pts (57%) received SOR 800mg/d. Thirty (10%) pts received alternate doses or had incomplete data. Most US pts were male (400mg/d: 75%; 800mg/d: 80%). Age distribution was similar between groups (400mg/d: <65 yr [59%], >65 yr [41%]; 800mg/d: <65 yr [64%], >65 yr [36%]. In 400mg/d and 800mg/d initial dose groups, ECOG PS 0/1/2 was 19%/49%/16% and 34%/35%/12%, while Child Pugh (CP) A/B/C were 32%/35%/7% (26% unevaluable) and 42%/29%/6% (21% unevaluable), respectively. Among pts who received an initial dose of 400mg/d, median TD was 9.8 wks. TD was <4 wks in 22%, >4-12 wks in 40% and >12 wks in 39%. Dose mods occurred in 57% (36% due to AE) and treatment interruptions in 38%. Among pts who received an initial dose of 800mg/d, median TD was 13.2 wks and <4 wks (17%), >4-12 wks (29%), and >12 wks (53%). Dose mods occurred in 49% (37% due to AE) and treatment interruptions in 35%. See table for interim safety data. <p>Conclusions: In this second IA of GIDEON data, it is possible that PS or CP status could have influenced initial SOR dose selection, but statistical comparisons were not conducted. However, other baseline characteristics did not appear to affect this decision. Despite differences in initial dose, frequencies of dose mods, interruptions, and AEs were similar between groups. Limitations of an observational study must be considered. Clinical judgment remains an important factor in choosing an initial SOR dose. Results (Table presented) 30 (10%) pts received alternate doses or had incomplete data

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is rare but is one of the most aggressive and lethal human malignancies. Cytologically, ATC has a variable morphologic appearance, including squamoid, giant, spindled and pleomorphic cells. The coexistence of ATC and differentiated or poorly differentiated thyroid carcinoma has been described and usually is diagnosed when the disease is locally advanced. CASE: We describe a case of surgically resectable, encapsulated, well-circumscribed ATC occurring in association with a better differentiated follicular carcinoma diagnosed by fine needle aspiration in a patient exposed to external ionizing radiation. CONCLUSION: Encapsulated variants of anaplastic carcinoma can be seen in association with lower grade thyroid carcinoma such as follicular carcinoma. Accurate diagnosis is dependent on adequate sampling