Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with very poor prognosis. Genome-wide, high-throughput technologies have made major advances in understanding the molecular basis of ...this disease, although important mechanisms are still unclear. Recent data have revealed specific genetic mutations (for example, KRAS, IDH1 and IDH2), epigenetic silencing, aberrant signaling pathway activation (for example, interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), tyrosine kinase receptor-related pathways) and molecular subclasses with unique alterations (for example, proliferation and inflammation subclasses). In addition, some ICCs share common genomic traits with hepatocellular carcinoma. All this information provides the basis to explore novel targeted therapies. Currently, surgery at early stage is the only effective therapy. At more advanced stages, chemotherapy regimens are emerging (that is, cisplatin plus gemcitabine), along with molecular targeted agents tested in several ongoing clinical trials. Nonetheless, a first-line conclusive treatment remains an unmet need. Similarly, there are no studies assessing tumor response related with genetic alterations. This review explores the recent advancements in the knowledge of the molecular alterations underlying ICC and the future prospects in terms of therapeutic strategies leading towards a more personalized treatment of this neoplasm.
Liver transplantation is proposed as the best therapy for early hepatocellular carcinoma in cirrhotic patients. However, the confrontation with the results obtained by surgical resection has never ...been done on an intention‐to‐treat basis. Between 1989 and 1997, 164 out of 1,265 patients with hepatocellular carcinoma were evaluated for surgery. Seventy‐seven (48 men, mean 61 years of age, 74 Child‐Pugh class A, size 33 ± 18 mm) were resected (first line option) and 87 (65 men, mean 55 years of age, 50 Child‐Pugh class B/C, size 24 ± 14 mm) were selected for transplantation. The 1‐, 3‐, and 5‐year “intention‐to‐treat” survival was 85%, 62%, and 51% for resection and 84%, 69%, and 69% for transplantation (8 drop‐outs on waiting list). Bilirubin and clinically relevant portal hypertension were independent survival predictors after resection. Thereby, the 5‐year survival of the best candidates (absence of clinically relevant portal hypertension, n = 35) was 74%, whereas it was 25% for the worst candidates (portal hypertension and bilirubin ≥1 mg/dL, n = 27) (P < .00001). The variable “drop‐out on waiting list” was the sole survival predictor after transplantation. The 2‐year survival rate of patients evaluated for transplantation was 84% in the 1989 to 1995 period (mean waiting time, 62 days; no drop‐outs) and 54% during 1996 to 1997 (mean waiting time, 162 days; 8 drop‐outs)(P < .003). This outcome was significantly lower than that of the best candidates for resection (P = .002). In conclusion, a proper selection of candidates for resection promotes better results than transplantation, in which the results are significantly hampered by the growing incidence of drop‐outs because of the increasing waiting time.
Summary
The treatment strategy of hepatocellular carcinoma applied following scientific guidelines is only supported by 77 randomized controlled trials published so far, a figure that clearly ...pinpoints hepatocellular carcinoma as an ‘orphan’ cancer in terms of clinical research when compared with other high‐prevalent cancers worldwide.
A systematic review analysing 61 randomized controlled trials (1978–2002) showed a modest survival benefit from chemoembolization in patients with intermediate tumours, and the lack of an effective first‐line treatment option for patients with advanced disease. These conclusions have been endorsed by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases.
The present updated evidence‐based approach includes 16 randomized controlled trials published from 2002 to 2005 assessing percutaneous ablation (seven), other loco‐regional therapies (three) and systemic therapies (six). Eight showed high‐quality methodological profiles.
Four randomized controlled trials demonstrated a better local hepatocellular carcinoma control in tumours larger than 2 cm treated by radiofrequency ablation compared with ethanol injection. No survival advantages were obtained from systemic treatments in patients with advanced hepatocellular carcinoma, an area that is an unmet need. Therefore, there is an urgent request to conduct well‐designed phase III investigations in hepatocellular carcinoma patients.
Radiofrequency (RF) ablation is an alternative to percutaneous ethanol injection (PEI) for single nonsurgical hepatocellular carcinoma (HCC) and is currently used as adjuvant therapy before liver ...transplantation. This phase II study assesses the treatment-related complications and response rate of RF for the treatment of single HCC ≤5 cm. Percutaneous RF was performed under conscious sedation and ultrasound (US) guidance with an electrical generator connected to a single cooled-tip electrode. Neoplastic cells in peripheral blood (reverse transcription-polymerase chain reaction for alpha fetoprotein AFP messenger RNA) were analyzed before and after RF. Treatment response was assessed by spiral computed tomography (CT) at 1 month and every 3 months by US or spiral CT thereafter. Thirty-two patients (20 men; age 67 ± 4 years; 78% hepatitis C virus; 24 Child-Pugh A) with a mean tumor size of 2.8 cm (25 patients ≤3 cm) were treated by RF (1.25 sessions; mean time, 22.1 ± 2 minutes). Adjuvant PEI was performed in 9 cases. Complete response was achieved in 21 patients (65%), being significantly higher for HCC ≤3 cm (76% vs. 29%, P = .03). After a median follow-up of 10 months, 8 patients showed treatment-related morbidity. Four of them (12.5%) showed biopsy-proven needle-track seeding detected between 4 to 18 months. Neoplastic seeding was related to subcapsular location (P = .009), poor differentiation degree (P = .02), and baseline AFP levels (P = .02). Thus, RF ablation with cooled-tip needle for HCC is associated with a high risk of neoplastic seeding. Iatrogenic dissemination was related to subcapsular location or an invasive tumoral pattern, and has to be considered when selecting curative treatments for HCC or adjuvant therapies before liver transplantation. (HEPATOLOGY 2001;33:1124-1129.)
Hepatocellular carcinoma LLOVET, Josep M; BURROUGHS, Andrew; BRUIX, Jordi
The Lancet (British edition),
12/2003, Letnik:
362, Številka:
9399
Journal Article
Recenzirano
Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer, and its incidence is increasing worldwide because of the dissemination of hepatitis B and C virus infection. Patients with ...cirrhosis are at the highest risk and should be monitored every 6 months. Surveillance can lead to diagnosis at early stages, when the tumour might be curable by resection, liver transplantation, or percutaneous treatment. In the West and Japan, these treatments can be applied to 30% of patients, and result in 5-year survival rates higher than 50%. Resection is indicated among patients who have one tumour and well-preserved liver function. Liver transplantation benefits patients who have decompensated cirrhosis and one tumour smaller than 5 cm or three nodules smaller than 3 cm, but donor shortage greatly limits its applicability. This difficulty might be overcome by living donation. Most HCC patients are diagnosed at advanced stages and receive palliative treatments, which have been assessed in the setting of 63 randomised controlled trials during the past 25 years. Meta-analysis shows that only chemoembolisation improves survival in well-selected patients with unresectable HCC.
This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in ...Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.
•The incidence of HCC will continue to rise.•HCC is curable at an early stage.•New locoregional treatments such as radioembolisation are showing impressive results.•A combination of immunotherapy is the gold standard of first-line treatment for advanced hepatocellular cancer.•There are more and more active systemic treatment options.
Background: Survival after liver transplantation for early hepatocellular carcinoma (HCC) is worsened by the increasing dropout rate while waiting for a donor. Aims: To assess the cost effectiveness ...of adjuvant therapy while waiting for liver transplantation in HCC patients. Method: Using a Markov model, a hypothetical cohort of cirrhotic patients with early HCC was considered for: (1) adjuvant treatment—resection was limited to Child-Pugh's A patients with single tumours, and percutaneous treatment was considered for Child-Pugh's A and B patients with single tumours unsuitable for resection or with up to three nodules < 3 cm; and (2) standard management. Length of waiting time ranged from six to 24 months. Results: Surgical resection increased the transplantation rate (>10%) and provided gains in life expectancy of 4.8–6.1 months with an acceptable cost ($40 000/ year of life gained) for waiting lists ≥1 year whereas it was not cost effective ($74 000/life of year gained) for shorter waiting times or high dropout rate scenarios. Percutaneous treatment increased life expectancy by 5.2–6.7 months with a marginal cost of approximately $20 000/year of life gained in all cases, remaining cost effective for all waiting times. Conclusions: Adjuvant therapies for HCC while waiting for liver transplantation provide moderate gains in life expectancy and are cost effective for waiting lists of one year or more. For shorter waiting times, only percutaneous treatment confers a relevant survival advantage.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and its incidence will further increase, to reach a plateau in 2015-2020. The natural history of the disease is quite well ...known, except for its early stages, because the majority of patients at this stage are treated with radical approaches. Staging systems are key to predict the prognostics of patients with cancer, to stratify the patients according to prognostic variables in the setting of clinical trials, and to guide the therapeutic approach. The current knowledge of the disease, however, is not sufficient for recommending a staging system to be used worldwide. The conventional staging systems-Okuda stage, and TNM stage-have shown important limitations for classifying patients. Several new systems have been recently proposed, but only three of them have been validated. The Barcelona Clinic Liver Cancer (BCLC) staging classification links the stage of the disease to a specific treatment strategy. The Japan Integrated Staging (JIS) score has been proposed and used in Japan, although it needs Western validation. The Cancer of the Liver Italian Program (CLIP) score is mainly proposed for patients with advanced tumors. Early detection of HCC through surveillance programs allows the application of potentially curative therapies, such as resection, liver transplantation, and percutaneous ablation in patients with early tumors. The applicability of these treatments varies according to geographical distribution: from 50% to 70% of cases in Japan; 25% to 40% of cases in Europe and the United States; and fewer than 10% in Africa. There are no randomized controlled trials (RCTs) comparing any of the three major therapies. These studies are not feasible in the West. Therefore, there is no firm evidence to establish the optimal first-line treatment for small single HCC in patients with well-preserved liver function. Resection and transplantation achieve the best outcomes in well-selected candidates (5-year survival of 60%-70%), and compete as the first option from an intention-to-treat perspective. If surgery is precluded, local, nonsurgical therapies are applied. Percutaneous treatments provide good results (5-year survival of 40%-50%), but are unable to achieve response rates and outcomes comparable to those for surgical treatments, even when applied as the first option. Radiofrequency thermal ablation provides slightly better objective response rates than ethanol injection, but no survival advantages have been fully demonstrated. The remaining treatments have been assessed in the setting of around 70 RCTs conducted during the past 25 years. Chemoembolization has been shown to provide modest survival advantages in two RCTs and a metaanalysis, and is currently the mainstay of treatment in 10% of the whole HCC population. The ideal candidates for this option are patients with well-preserved liver function (Child-Pugh class A) and multinodular asymptomatic tumors without vascular invasion. Further RCTs are needed to assess the best chemotherapeutic agent and the ideal re-treatment schedule. There is no firstline option for patients with advanced HCC (vascular invasion, extrahepatic spread, or cancer-related symptoms). Systemic doxorubicin provides partial responses in 10% of cases, without proven survival advantages, and well-known treatment-related complications. Several other treatments, such as immunotherapy, internal radiation, tamoxifen, or anti-androgen agents, have not shown any relevant anti-tumoral effect or survival benefit. New drugs, such as tyrosine kinase inhibitors and anti-angiogenic agents, are currently being tested in the setting of clinical trials.
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