Ramucirumab for Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha Fetoprotein Following Non-Sorafenib Systemic Therapy: An Expansion Cohort of REACH-2.

BACKGROUND: Ramucirumab is indicated for patients with advanced hepatocellular carcinoma (HCC) and α-fetoprotein (AFP) ≥400 ng/mL following sorafenib. Here, we prospectively studied ramucirumab following non-sorafenib systemic therapies. MATERIALS AND METHODS: This open-label, non-comparative cohort of REACH-2 enrolled patients with advanced HCC, Child-Pugh class-A liver disease, and AFP ≥400 ng/mL who had received 1-2 lines of therapy, excluding sorafenib or chemotherapy. Ramucirumab was administered 8 mg/kg intravenously Q2W. The primary endpoint was safety. Secondary endpoints were overall survival, progression-free survival, objective response rate (RECIST v1.1), time to progression, pharmacokinetics, and patient-reported outcomes. Final analysis occurred after all enrolled patients completed ≥3 treatment cycles or discontinued treatment. RESULTS: Between April 27, 2018, and March 29, 2021, 47 patients were treated at 21 investigative sites in Asia, Europe, and USA. The most frequently reported grade ≥3 adverse events, regardless of causality, were hypertension (11%), proteinuria (6%), hyponatremia (6%), and AST increased (6%). Two patients died from adverse events (myocardial infarction and upper gastrointestinal hemorrhage), deemed related to treatment. Median progression-free survival, time to progression, and overall survival were 1.7 months, 2.8 months, and 8.7 months, respectively. The objective response rate was 10.6% with a median duration response of 8.3 months. Median time to deterioration in FHSI-8 total score was 4.4 months. CONCLUSION: Ramucirumab demonstrated consistent and meaningful clinical activity with no new safety signals following non-sorafenib therapies in patients with advanced HCC and AFP ≥400 ng/mL. This represents one of the first sequencing studies for patients with advanced HCC not treated with sorafenib.

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. FINDINGS: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. INTERPRETATION: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

The Outcomes of Systemic Treatment in Recurrent Hepatocellular Carcinomas Following Liver Transplants.

BACKGROUND: Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant (LT) is challenging. Most clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. We aimed to assess the outcomes in using various systemic therapies in patients with post-LT recurrence. METHODS: Consecutive patients with HCC and recurrences following LT at a large tertiary centre from 2005 to 2018 were reviewed. Overall survival (OS), response rates and adverse events (AEs) were analysed. RESULTS: Forty-three consecutive patients with a recurrence of HCC following LT were identified from 2005 to 2018. Median OS from diagnosis of recurrence was 17 months (CI 11.3, 22.7). Early recurrence within 12 months of transplant was associated with a significantly worse median survival of 10 months (CI 8.5, 11.4) compared to 26 months (CI 18.8, 33.2) when recurrences occurred after 12 months from transplant (p < 0.001) with a hazard ratio of 0.104 (log-rank test, p < 0.001). A total of 41 patients had received systemic therapies and 79.1% of them were on sorafenib as the first-line treatment. Among these patients treated with sorafenib, median OS from recurrence was 14 months (CI 7.3, 20.7). Hand-foot syndrome (34.7%) was most common among AEs followed by diarrhoea (26.7%). Overall, AEs led to dose interruptions in 8.8% of patients. Notably, 47.1% of patients received subsequent lines of systemic therapies after sorafenib. CONCLUSIONS: Early recurrence within 1 year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.

Nivolumab + Ipilimumab for patients with hepatocellular carcinoma previously treated with Sorafenib.

INTRODUCTION: The systemic treatment of advanced, unresectable hepatocellular carcinoma (HCC) has undergone an evolution in recent years. In March 2020, a combination of nivolumab and ipilimumab was approved by the FDA for treatment of patients with advanced HCC who received prior sorafenib. This was based on the results of the phase I/II CheckMate-040 cohort 4 trials, which showed a promising overall response rate and encouraging overall survival with a manageable safety profile. AREAS COVERED: This article reviews the pharmacology, efficacy and safety of nivolumab-ipilimumab in advanced HCC with prior sorafenib. Other existing systemic treatment options for advanced HCC will be described and compared to nivolumab-ipilimumab. Impact of different dose regimes, ongoing research and future developments of nivolumab-ipilimumab will be discussed. We focus on the analysis from the aforementioned CheckMate-040 cohort 4 registration trial. EXPERT OPINION: The approval of nivolumab-ipilimumab in the second-line treatment of advanced HCC by the FDA is an important development for treatment of advanced HCC. However, further investigations are needed to optimize dosing regimens and explore the use of nivolumab-ipilimumab in other combinations and settings.

Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial.

OBJECTIVE: In the phase 3 CELESTIAL trial, cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). This subgroup analysis evaluated cabozantinib in patients who had received sorafenib as the only prior systemic therapy. METHODS: CELESTIAL randomised (2:1) patients with advanced HCC and Child-Pugh class A liver function to treatment with cabozantinib (60 mg daily) or placebo. Eligibility required prior treatment with sorafenib, and patients could have received ≤2 prior systemic regimens. The primary endpoint was OS. Outcomes in patients who had received sorafenib as the only prior therapy were analysed by duration of prior sorafenib (<3 months, 3 to <6 months and ≥6 months). RESULTS: Of patients who had received only prior sorafenib, 331 were randomised to cabozantinib and 164 to placebo; 136 patients had received sorafenib for <3 months, 141 for 3 to <6 months and 217 for ≥6 months. Cabozantinib improved OS relative to placebo in the overall second-line population who had received only prior sorafenib (median 11.3 vs 7.2 months; HR=0.70, 95% CI 0.55 to 0.88). This improvement was maintained in analyses by prior sorafenib duration with longer duration generally corresponding to longer median OS-median OS 8.9 vs 6.9 months (HR=0.72, 95% CI 0.47 to 1.10) for prior sorafenib <3 months, 11.5 vs 6.5 months (HR=0.65, 95% CI 0.43 to 1.00) for 3 to <6 months and 12.3 vs 9.2 months (HR=0.82, 95% CI 0.58 to 1.16) for ≥6 months. Cabozantinib also improved PFS in all duration subgroups. Safety data were consistent with the overall study population. CONCLUSION: Cabozantinib improved efficacy outcomes versus placebo in the second-line population who had received only prior sorafenib irrespective of duration of prior sorafenib treatment, further supporting the utility of cabozantinib in the evolving treatment landscape of HCC. CLINICAL TRIAL NUMBER: NCT01908426.

Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design.

Cabozantinib is an oral tyrosine kinase inhibitor that targets VEGFR, MET and the TAM (TYRO3, AXL, MER) family of kinase receptors. In addition to their role in tumor growth and angiogenesis, cabozantinib targets promote an immune-suppressive microenvironment. Cabozantinib is approved as single-agent therapy for patients with advanced hepatocellular carcinoma who received prior sorafenib. Owing to its antitumor and immunomodulatory properties, cabozantinib is being developed in combination with immune checkpoint inhibitors. Early studies of these combinations have shown promising antitumor activity and tolerability in patients with solid tumors. Here, we describe the rationale and design of COSMIC-312, a Phase III study evaluating the safety and efficacy of cabozantinib in combination with atezolizumab (anti-PD-L1 monoclonal antibody) versus sorafenib for treatment-naive patients with advanced hepatocellular carcinoma. ClinicalTrial.gov Registration: NCT03755791.

Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis.

BACKGROUND & AIMS: Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. METHODS: CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. RESULTS: There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. CONCLUSION: Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. LAY SUMMARY: The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878.

Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma.

BACKGROUND: In colorectal carcinoma (CRC), activation of the Raf/MEK/ERK signaling pathway is commonly observed. In addition, the commonly used 5FU-based chemotherapy in patients with metastatic CRC was found to enrich a subpopulation of CD26(+) cancer stem cells (CSCs). As activation of the Raf/MEK/ERK signaling pathway was also found in the CD26(+) CSCs and therefore, we hypothesized that an ATP-competitive pan-Raf inhibitor, Raf265, is effective in eliminating the cancer cells and the CD26(+) CSCs in CRC patients. METHODS: HT29 and HCT116 cells were treated with various concentrations of Raf265 to study the anti-proliferative and apoptotic effects of Raf265. Anti-tumor effect was also demonstrated using a xenograft model. Cells were also treated with Raf265 in combination with 5FU to demonstrate the anti-migratory and invasive effects by targeting on the CD26(+) CSCs and the anti-metastatic effect of the combined treatment was shown in an orthotopic CRC model. RESULTS: Raf265 was found to be highly effective in inhibiting cell proliferation and tumor growth through the inhibition of the RAF/MEK/ERK signaling pathway. In addition, anti-migratory and invasive effect was found with Raf265 treatment in combination with 5FU by targeting on the CD26(+) cells. Finally, the anti-tumor and anti-metastatic effect of Raf265 in combination with 5FU was also demonstrated. CONCLUSIONS: This preclinical study demonstrates the anti-tumor and anti-metastatic activity of Raf265 in CRC, providing the basis for exploiting its potential use and combination therapy with 5FU in the clinical treatment of CRC.

Efficacy and tolerability of adjuvant oral capecitabine plus intravenous oxaliplatin (XELOX) in Asian patients with colorectal cancer: 4-year analysis.

BACKGROUND: Although FOLFOX (infusional fluorouracil/leucovorin plus oxaliplatin) is established as a standard chemotherapeutic regimen, the long term efficacy of adjuvant XELOX (oral capecitabine plus intravenous oxaliplatin) in Asian colorectal cancer (CRC) patients remains anecdotal. Moreover, uncertainties persist as to whether pharmacogenetic differences in Asian populations preclude equally tolerable and effective administration of these drugs. METHOD: One hundred consecutive patients with resected colorectal cancer received adjuvant XELOX (oxaliplatin 130 mg/m2 on day 1 plus capecitabine 900 mg/m2 twice daily on day 1 to 14 every 3 weeks for 8 cycles) at Queen Mary Hospital, Hong Kong. Endpoints monitored during follow-up were disease-free survival (DFS) and disease recurrence, overall survival (OS) and adverse events (AEs). RESULTS: The median patient age was 56 years, 56% were diagnosed with rectal cancer and 44% with colonic cancer. After a median follow-up of 4.3 years (95% confidence interval, 3.2-4.7), 24 recurrences were confirmed including 13 patients who died due to progressive disease. Four-year DFS was 81% in colon cancer patients and 67% in rectal cancer patients (p=0.06 by log-rank test). For the cohort as a whole, OS was 90% at 3 years and 84% at 5 years. Treatment-related AEs led to early withdrawal in four patients. The commonest non-hematological AEs were neuropathy (91%), hand-foot syndrome (49%) and diarrhea (46%), while the commonest grade 3/4 AEs were neutropenia (11%) and diarrhea (10%). CONCLUSION: These results confirm the favourable long term survival benefit with good tolerability in using adjuvant XELOX in treating East Asian colorectal cancer patients.

Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the only therapy shown to improve overall survival in advanced hepatocellular carcinoma (HCC). Combination therapy targeting multiple signaling pathways may improve outcomes. This phase I study was designed to determine the maximum tolerated dose (MTD) of everolimus given with sorafenib 400mg twice daily in patients with advanced HCC of Child-Pugh class A liver function who were naive to systemic therapy. METHODS: Everolimus was initiated at 2.5mg once daily and increased per a Bayesian sequential dose-escalation scheme based on the dose-limiting toxicities experienced within the first 28 days of treatment. Adverse events were assessed continuously. Efficacy was evaluated using the best overall response rate per RECIST. RESULTS: Thirty patients were enrolled; 25 were evaluable for MTD determination. One out of 12 patients treated with everolimus 2.5mg once daily and 6 out of 13 patients treated with everolimus 5.0mg once daily experienced a dose-limiting toxicity, most commonly thrombocytopenia (n=5). All patients experienced 1 adverse event, most commonly diarrhea (66.7%), hand-foot skin reaction (66.7%), and thrombocytopenia (50.0%). Best overall response was stable disease (62.5% and 42.9% in the 2.5-mg and 5.0-mg cohorts, respectively). Median time to progression and overall survival in the 2.5-mg cohort were 4.5 months and 7.4 months, respectively, and 1.8 months and 11.7 months, respectively, in the 5.0-mg cohort. CONCLUSIONS: In patients with advanced HCC, the everolimus MTD in combination with standard-dose sorafenib was 2.5mg once daily. The inability to achieve a biologically effective everolimus concentration at the MTD precluded phase II study of this combination.

The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits.

BACKGROUND: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis. METHODS: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups. RESULTS: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups (P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P = .01), gastrointestinal bleeding (P = .02), and hepatic encephalopathy (P = .02). CONCLUSIONS: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed.

Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease.

BACKGROUND: The combination of bevacizumab (B) and erlotinib (E) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients. We aimed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment. METHODS: Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited. All patients received bevacizumab(B) at 10 mg/kg every 2 weeks with erlotinib(E) at 150 mg daily for a maximum of 6 cycles. Response assessments using both RECIST and modified RECIST criteria were performed after every 6 weeks. The primary endpoint was clinical benefit (CB) rate and a Simon two-stage design was employed. RESULTS: The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited. The median age was 47 years (range, 28-61) and all patients were in ECOG performance status 1. Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis. Among these 10 patients, none of the enrolled patients achieved response or stable disease. The median time-to-progression was 1.81 months (95 % confidence interval [C.I.], 1.08-1.74 months) and overall survival was 4.37 months (95 % C.I., 1.08-11.66 months). Rash (70 %), diarrhea (50 %) and malaise (40 %) were the most commonly encountered toxicities. CONCLUSION: The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population. Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population.

The outcomes and safety of single-agent sorafenib in the treatment of elderly patients with advanced hepatocellular carcinoma (HCC).

BACKGROUND: With the aging population, hepatocellular carcinoma (HCC) in the elderly represents a significant health burden. We aimed to evaluate and compare the efficacy and tolerability of single-agent sorafenib in treating elderly patients with advanced HCC versus the younger population. METHODS: We retrospectively analyzed a consecutive cohort of advanced HCC patients with Child-Pugh A or B liver function and an Eastern Cooperative Oncology Group performance status score of 0-2 treated with sorafenib. The patients were categorized into older (age ≥70 years) and younger (age <70 years) groups. Treatment outcomes and related adverse events (AEs) were compared. RESULTS: In total, 172 patients, 35 in the older (median age, 73 years) and 137 in the younger (median age, 55 years) group, were analyzed. The median progression-free survival time was similar in the older and younger groups (2.99 months versus 3.09 months; p = .275), as was the overall survival time (5.32 months versus 5.16 months; p = .310). Grade 3 or 4 AEs were observed in 68.6% of older and 62.7% of younger patients (p = .560), with neutropenia (11.4% versus 0.7%; p = .007), malaise (11.4% versus 2.2%; p = .033), and mucositis (5.7% versus 0.0%; p = .041) being more frequently reported in the elderly cohort. CONCLUSIONS: The survival benefits and overall treatment-related AEs of sorafenib are comparable in elderly and younger advanced HCC patients. Nevertheless, more vigilant monitoring in the elderly is warranted because they are more susceptible to develop neutropenia, malaise, and mucositis.

The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib.

BACKGROUND: he role of serum alpha-fetoprotein (AFP) changes in predicting the treatment outcomes of advanced hepatocellular carcinoma (HCC) patients to sorafenib remains unknown. METHODS: Serum AFP was collected prospectively at baseline and subsequent follow-up visits in parallel with clinical and survival outcomes. AFP response was defined as a relative drop of AFP >20% of the baseline level after 6 weeks of sorafenib. The relationship between AFP response and the treatment outcomes was first explored in patients who received sorafenib in a phase II study. Subsequently, an independent validation set of patients were obtained to validate the association of AFP response to clinical outcomes. RESULTS: Included in the exploration and validation sets for analysis were 41 and 53 patients, respectively, with baseline AFP level >20 µg/L. In the exploration cohort, AFP response was significantly associated with clinical benefit (CB) rate (relative chance 3.4, 95% confidence interval [CI], 1.1-11.1), and multivariate analysis indicated that AFP response was associated with significantly better progression-free survival (PFS) (hazard ratio [HR], 0.31; 95% CI, 0.13-0.76) and marginally better overall survival (OS) (HR, 0.30; 95% CI, 0.09-1.02). When applying AFP changes in the validation set, significant associations were again found between AFP response with CB rate (relative chance, 5.5; 95% CI, 2.3-13.6) and PFS (HR, 0.12; 95% CI, 0.04-0.30) but not OS (HR, 0.61; 95% CI, 0.27-1.26). CONCLUSION: Drop in AFP level at 6 weeks is an exploratory early surrogate for both CB and PFS in advanced HCC patients receiving sorafenib.

Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib.

IMPORTANCE OF THE FIELD: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC. AREAS COVERED IN THIS REVIEW: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early-phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor. WHAT THE READER WILL GAIN: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC. TAKE HOME MESSAGE: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention.

A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer.

Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer metastasis is unclear. Here, we identified a subpopulation of CD26(+) cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26(+) cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26(+) cells, but not CD26(-) cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26(+) cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy.

Longitudinal assessment of quality of life in rectal cancer patients with or without stomas following primary resection.

PURPOSE: The purpose of this study was to assess the longitudinal impact of stoma formation on the health-related quality of life of rectal cancer patients treated with adjuvant chemotherapy. METHODS: Health-related quality of life data was prospectively collected in a randomized trial designed to compare 24 weeks of bolus 5-fluorouracil/leucovorin with 12 weeks of continuous 5-fluorouracil in patients with resected Dukes B and C colorectal cancer. Health-related quality of life data was collected at baseline, during adjuvant treatment, and at one and three years after completion of chemotherapy. RESULTS: Between 1993 and 2003, 186 rectal cancer patients were enrolled. One hundred thirty-nine patients had anterior resection, of whom 46 had a temporary defunctioning colostomy. Forty-seven patients had abdominoperineal resection with formation of a permanent colostomy. There was no significant difference in global health-related quality of life between patients with and patients without a stoma at any time point. However, during adjuvant treatment, role (P = 0.04) and social (P = 0.005) functioning were significantly worse in stoma patients than in nonstoma patients. Moreover, the impairment in social functioning persisted at one (P = 0.03) and three years (P = 0.04) after adjuvant chemotherapy. CONCLUSION: Our results demonstrate important adverse effects of either temporary or permanent stoma formation on subsequent health-related quality of life in patients with rectal cancer.

Management of advanced hepatocellular carcinoma in the era of targeted therapy.

Systemic chemotherapy has had a disappointing track record in the management of advanced hepatocellular carcinoma (HCC). Single-agent doxorubicin produces a response rate of 10-15%, but without any survival benefit, and combination chemotherapy has also yielded unimpressive results. With recent advances in the knowledge of hepato-carcinogenesis, there has been encouraging development in the systemic therapy of advanced HCC patients, and particularly in the targeted therapy of advanced HCC. Among the newly identified targets, exciting results have been shown in targeting the anti-angiogenic pathway and the Raf/mitogen-activated protein kinase pathways. Bevacizumab, both as a single agent and in combination with other agents, has shown initial encouraging activity in treating advanced HCC. More recently, single-agent sorafenib, a putative multitargeted kinase inhibitor, has shown to prolong the overall survival of patients with advanced HCC in the pivotal phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Oriental study. Currently, sorafenib is the only approved targeted therapy for patients with advanced HCC. In addition, however, promising early results have been reported for other molecular-targeted drugs including erlotinib and sunitinib. Future progress seems likely to depend on using controlled clinical trials to optimize synergistic combination treatments.

Complications of traditional Chinese/herbal medicines (TCM)--a guide for perplexed oncologists and other cancer caregivers.

INTRODUCTION: Cancer patients often seek complementary or alternative medicines to supplement or replace treatments prescribed by licensed medical practitioners. Traditional Chinese/herbal medicine (TCM) is a popular complementary intervention among cancer patients of Asian ethnicity, many of whom take it during their conventional treatment. Few of these patients inform their doctors, however, creating a risk of unexpected sequelae arising from either pharmacologic toxicity, unsuitable dosing, interactions with anti-cancer drugs or other medications, adulteration, or idiosyncratic reactions. If unrecognized, these problems may be misattributed to conventional treatment toxicity or disease progression, and remedial action may be inappropriate or delayed. GOALS OF WORK: The purpose of this review is to help oncologists recognize the common presentations of TCM-related problems in cancer patients-such as abnormal liver function tests, unexpectedly severe myelosuppression, hemostatic defects, renal functional impairment, or suspected drug interactions-and to teach strategies by which these problems can be anticipated, prevented, or managed. CONCLUSION: Through sensitive understanding of the reasons favoring TCM usage, oncologists can gain the trust and respect of their TCM-using patients while ensuring the safety and efficacy of conventional anticancer treatments.

Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response.

BACKGROUND: The current study was a phase 2 open-label study to evaluate the efficacy and tolerability of single-agent sorafenib in the treatment of advanced HCC patients in a hepatitis B-endemic Asian population. METHODS: Patients with advanced hepatocellular carcinoma (HCC) received sorafenib at a dose of 400 mg twice daily in 4-week cycles. Tumor response was assessed every 3 cycles using Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Fifty-one patients were enrolled in the study and were treated with sorafenib for at least 12 weeks. The median age was 56 years (range, 28-79 years). Approximately 90% had hepatitis B virus-related HCC. Thirty-six (71%) patients had underlying Child-Pugh A cirrhosis, 13 (26%) Child-Pugh B, and 2 (3%) Child-Pugh C. Four (8%) patients achieved partial responses, and 9 (18%) patients had stable disease for at least 12 weeks. The median overall survival was 5 months (range, 4-17 months). Patients without extrahepatic spread, particularly without lung metastasis (P<.01), are more likely to benefit from sorafenib treatment. The most common toxicities were diarrhea (67%), malaise (55%), and hand-foot-skin reaction (54%). The majority of patients had transient liver function derangement. Patients with and without underlying portal vein thrombosis had similar therapeutic benefits and likewise shared a similar treatment-related toxicity profile with sorafenib treatment. CONCLUSIONS: Single-agent sorafenib demonstrates good efficacy and acceptable tolerability in treating an advanced HCC patient population in a hepatitis B-endemic area. The presence of lung metastasis predicts poor response to sorafenib in advanced HCC patients.