Systemic therapy of hepatocellular carcinoma:Current status and future perspectives

The management of hepatocellular carcinoma(HCC)has substantially changed in the past few decades,the introduction of novel therapies(such as sorafenib)have improved patient survival.Nevertheless,HCC remains the third most common cause of cancer-related deaths worldwide.Decision-making largely relies on evidencebased criteria,as showed in the US and European clinical practice guidelines,which endorse five therapeutic recommendations:resection;transplantation;radiofrequency ablation;chemoembolization;and sorafenib.Many molecularly targeted agents that inhibit angiogenesis,epidermal growth factor receptor,and mammalian target of rapamycin are at different stages of clinical development in advanced HCC.Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention.Identification and validation of potential surrogate and predictive biomarkers hold promise to individualize patient’s treatment to maximize clinical benefit and minimize the toxicity and cost of targeted agents.

Is human hepatocellular carcinoma a hormone-responsive tumor?

Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib,there was no standard systemic treatment for patients with advanced hepatocellular carcinoma(HCC).Sex hormones receptors are expressed in a significant proportion of HCC samples.Following preclinical and epidemiological studies supporting a relationship between sex hormones and HCC tumorigenesis,several randomized controlled trials (RCTs)tested the efficacy of the anti-estrogen tamoxifen as systemic treatment.Largest among these trials showed no survival advantage from the administration of tamoxifen,and the recent Cochrane systematic review produced a completely negative result.This questions the relevance of estrogen receptor-mediated pathways in HCC.However,a possible explanation for these disappointing results is the lack of proper patients selection according to sex hormones receptors expression,but unfortunately the interaction between this expression and efficacy of tamoxifen has not been studied adequately.It has been also proposed that negative results might be explained if tamoxifen acts in HCC via an estrogen receptor-independent pathway,that requires higher doses than those usually administered, but an Asian RCT conducted to assess dose-response effect was completely negative.Interesting,preliminaryresults have been obtained when hormonal treatment (tamoxifen or megestrol)has been selected according to the presence of wild-type or variant estrogen receptors respectively,but no large RCTs are available to support this strategy.Negative results have been obtained also with anti-androgen therapy.In conclusion,there is no robust evidence to consider HCC a hormone-responsive tumor.Hormonal treatments should not be part of the current management of HCC.

Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma(HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Case Report: Long-Term Survival in Patient with Cirrhosis of the Liver and Colon Cancer K-ras Wild-Type

K-ras wild-type carcinoma is a tumour that is sensitive to treatment with anti-cancer and anti-EGFR drugs: the combination of Cetuximab and Panitumumab with chemotherapy (Cetuximab) or as a single therapy (Panitumumab). Case Report: The clinical case presented here refers to a 68-year-old patient who had been diagnosed with adenocarcinoma of the recto sigmoid with pelvic recurrence three years after surgery. The patient had a severe co-morbidity: correlated B-type liver cirrhosis. First-line chemotherapy was begun with Oxaliplatin plus Capecitabine (CAPOXI) following a relapse, and this continued for six months (six cycles), when the treatment was interrupted because of the disease’s progression and hematological and gastrointestinal toxicity. Following an assessment of the K-ras, diagnosed as wild type, the patient was excluded from second-line chemotherapy treatment because of decompensated cirrhosis and the persistence of thrombocytopenia and leukopenia. The patient was put forward for biological treatment with an anti-EGFR monoclonal antibody (Panitumumab). Panitumumab was administered at a dosage of 6 mg/kg every 2 weeks for 17 months;the treatment was well tolerated, despite the cirrhosis, and the main toxicity was the skin rash. Conclusion: In patients with severe comorbidities such as cirrhosis of the liver and K-ras wild-type carcinomas, therapy with a monoclonal antibody such as Panitumumab is a treatment that is well tolerated, with few serious toxic side-effects;it also offers advantages in terms of survival and clinical benefits.