1 point
2 points
3 points
Total bilirubin (mg/dl)a
<3.4
3.4–5.0
>5.0
INR
<1.7
1.7–2.3
>2.3
Albumin (g/dl)
>3.5
2.8–3.5
<2.8
Ascites
None
Mild
Moderate–severe
Hepatic encephalopathy
None
Medically controlled
Refractory
Initially developed as a predictor of perioperative mortality in patients with esophageal varices [20, 21]
Table 9.1
Hepatic function classification systems
Child-Pugh (CP) score | MELD score | ALBI grade | |
|---|---|---|---|
Prognostic factors included in model | Total bilirubin (mg/dL) INR Albumin (g/dL) Ascites Hepatic encephalopathy | Total bilirubin (mg/dL) INR Creatinine (mg/dL) Hemodialysis twice during prior week Serum sodium (mEq/L) | Total bilirubin (μmol/L) Albumin (g/L) |
Additional factors contributing to overall score | Diagnosis of HCC tumor(s) within Milan criteria Time on transplant list | ||
Score calculation | See Table 9.1 B | MELD = 10 × [0.957 × ln(creatinine)] + [0.378 × ln(bilirubin)] + [1.12 × ln(INR)] +6.43.a | Linear predictor (ALBI grade) = (log10 bilirubin × 0.66) + (albumin × −0.085) |
Risk categories | CP A: 5–6 points CP B: 7–9 points CP C: 10–15 points | MELD ≤10 MELD 11–18 MELD 19–24 MELD ≥25 | ALBI grade 1: ≤−2.60 ALBI grade 2: >−2.60 – ≤−1.39 ALBI grade 3: >−1.39 |
Model of end-stage liver disease (MELD)
Based on serum bilirubin, serum INR, and serum creatinine.
Developed as a predictor of survival after elective transjugular intrahepatic portosystemic shunt (TIPS) placement [22].
In 2002, the MELD score replaced the Child-Turcotte-Pugh score as the system employed by the United Network for Organ Sharing (UNOS) to assign priority for liver transplantation in the United States.
Albumin-bilirubin (ALBI) grade [25] employs only albumin and bilirubin levels to divide patients into three grades (A1, A2, and A3) to predict survival in HCC patients.
Developed using data from patients with HCC from Japan and validated using international databases and data from two randomized trials of sorafenib for unresectable HCC
Divided patients with Child-Pugh A cirrhosis into two prognostically distinct cohorts, with a 6-month difference in overall survival between ALBI grade 1 and ALBI grade 2 patients
9.7 Molecular Biology
9.7.1 HCC
While HCC often develops in the setting of progression from cirrhosis to dysplastic nodules to invasive carcinoma, the mechanisms underlying this process are not yet fully elucidated.
Altered expression of mTOR, inactivation of p53, loss of heterozygosity in IGF2 receptor, and disruption of the Ras/MAPK pathway, the Rb pathway, the PI3-kinase/Akt pathway, and the Wnt/beta-catenin pathway have all been demonstrated in HCC [26].
Studies have also attempted to classify mutation expression by cirrhosis etiology. A study of exome sequencing of 243 liver tumors identified mutations associated with alcohol use (CTNNB1) or HBV (TP53) [27].
9.7.2 ICC
9.8 Multidisciplinary Treatment
9.8.1 HCC
Management of HCC depends not only on the size and extent of the hepatic lesion but also on a patient’s hepatic function and performance status.
Early-stage HCC: Early-stage HCC includes patients with smaller tumors with adequate underlying hepatic function, a sufficient volume of uninvolved liver, and no evidence of vascular invasion or extrahepatic disease. Curative treatment options for early-stage HCC include surgical resection, orthotopic liver transplantation, and radio-frequency ablation for small tumors.
Surgical resection: preferred in patients with solitary tumors without vascular invasion without underlying cirrhosis and with a sufficient volume of uninvolved hepatic parenchyma
In patients with solitary tumors < 5 cm without vascular invasion, 5-year overall survival (OS) rates range from 60 % to 83 % [30]. Survival declines in patients with larger tumors, multiple tumors, and/ or vascular invasion [31].
There is a significant risk of recurrence, with predictors of recurrence after resection that include tumor size, number of tumors, margin status, vascular invasion, histologic grade, and underlying cirrhosis [31].
The role of adjuvant treatment after resection is not well defined. The randomized phase III STORM trial did not demonstrate an improvement in outcomes with the use of sorafenib after resection or ablation [32].
Randomized 1114 patients with HCC who had undergone surgical resection (n=900) or ablation (n=214) with a complete radiographic response to adjuvant sorafenib versus placebo.
There was no difference in median recurrence-free survival between the two arms (33.3 months with sorafenib vs. 33.7 months with placebo, HR 0.94, 95 % CI 0.78–1.13, one-sided P=0.26).
There is suggestion that antiviral therapy after resection in patients with HBV-related HCC may improve outcomes [33], but further study is needed.
Orthotopic liver transplantation (OLT).
Preferred treatment option in patients with unresectable HCC with underlying cirrhosis or compromised hepatic function.
Criteria for OLT: UNOS defines eligibility for organ transplantation as patients who fit with the Milan criteria on radiographic assessment, with no evidence of vascular invasion or extrahepatic disease.
MELD points are assigned based on underlying hepatic and renal function, with additional points included for the presence of HCC and time spent on the OLT waiting list.
Milan criteria: one tumor < 5 cm or three tumors all < 3 cm.
Based on a trial of 48 patients with HCC in the setting of HCV/HBV cirrhosis who underwent OLT between 1991 and 1994
In patients whose explanted tumors met the above criteria, 4-year OS was 75 %, and 4-year DFS was 83 %, while in patients whose tumors exceeded this criteria, 4-year OS was 50 %, and 4-year DFS was 59 % [34].
Beyond Milan criteria
UCSF criteria: one tumor < 6.5 cm or maximum of three tumors all < 4.5 cm with cumulative size < 8 cm
Based on UCSF review of 467 patients who underwent OLT for HCC between 1984 and 2006 [35].
There was no significant difference in 5-year OS for patients who met Milan criteria versus those patients who exceeded Milan criteria but met UCSF criteria by explant pathology (86 % vs. 81 %, P=0.057).
“Up-to-seven” criteria: sum of the size of the largest tumor (cm) + the number of tumors ≤ 7 [36]
Retrospective review of 1556 HCC patients undergoing liver transplantation suggested that microinvasion and accounting for the size and number of tumors could potentially identify patients outside Milan criteria who were candidates for OLT.
Included 1112 patients exceeding Milan criteria, with reduced 5-year OS of 53.6 % compared with 77.7 % in patients meeting Milan criteria.
However a subgroup of 238 patients who exceeded Milan criteria but did not have microinvasion and were within “up-to-seven” criteria had 5-year OS of 71.2 %.
Due to long waiting times, 12–38 % of patients will drop off the transplant list within 1 year due to tumor progression or functional decline [37]. Whether patients should proceed with resection instead is a topic of debate and varies based on the patient’s overall performance status and underlying hepatic function.
Intention-to-treat analysis of resection versus transplantation found that the survival of patients listed for transplantation declined as the wait list times for transplant increased (84 % from 1989 to 1995 versus 54 % from 1996 to 1997), likely due to increased numbers of patients who dropped off the transplant wait list during the latter era [38].
There are limited data on transplantation after surgical resection, with some studies suggesting that there was not a significant increase in toxicity [39]. Of note, “salvage transplantation” or transplant in the setting of recurrence after resection may be associated with increased toxicity.
Retrospective comparison of patients receiving primary liver transplantation versus transplantation in the setting of recurrence (“secondary” transplantation) after resection demonstrated that secondary OLT was associated with increased operative mortality, increased recurrence, and decreased disease-free and OS [40].
Ablative therapies include radio-frequency ablation (RFA), microwave ablation (MWA), and chemical ablation (percutaneous ethanol injection).
Effective therapy in the treatment of smaller tumors (< 4 cm) and as a bridge to transplantation.
Potential curative therapy in tumors < 2 cm.
Local control declines in tumors which are close to large blood vessels and larger lesions.
Randomized trials of resection versus RFA conducted in China between 1999 and 2008 randomized patients showed mixed results. One trial of 230 patients with tumors that fit within the Milan criteria demonstrated an improvement in OS and recurrence-free survival (RFS) with resection compared with RFA (OS, 82.6 % vs. 66.1 %; RFS, 60.9 % vs. 46.1 %) [41]. Two additional trials did not demonstrate an improvement in OS or RFS with resection over RFA [42, 43].
A meta-analysis of resection versus RFA did not show an improvement in recurrence but did demonstrate an improvement in survival with resection [44].
Advanced HCC: For patients with unresectable HCC who are not candidates for transplant, treatment options include ablation (described above), arterially directed therapies, radiotherapy, and systemic therapy.
There are no randomized data directly comparing these techniques.
Selecting an optimal treatment for a given patient depends on multiple factors including:
Hepatic function
Performance status
Tumor characteristics
Size and number of tumors
Tumor location
Vascular invasion
Arterially directed therapies include bland embolization, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE).
Arterially directed therapies exploit the blood supply of HCC, which is primarily supplied by the hepatic artery as compared to normal hepatic parenchyma which is primarily supplied by the portal vein.
Arterially directed therapies, including TACE, have been shown to improve palliation and survival when compared with supportive care [45–47], but there are no randomized trials of arterially directed therapies versus ablative techniques or radiotherapy.
Arterially directed therapies are also often not possible in patients with tumor vein thrombosis due to the risk of treatment-related ischemic injury and hepatic failure.
Although TARE or selective internal radiotherapy (SIRT) is thought to function via microvascular rather than primarily macrovascular occlusion, outcomes still decline in patients with thrombosis or compromised hepatic function [48].
Combination of arterially directed therapies with systemic and other locoregional therapies is an ongoing topic of research.
The SPACE (Sorafenib or Placebo plus TACE with doxorubicin-eluting beads for Intermediate Stage HCC) trial [49] showed that the combination of TACE with sorafenib was technically feasible but did not demonstrate an improvement in time to progression with the addition of sorafenib to TACE in patients with intermediate-stage HCC without macrovascular invasion or extrahepatic disease. Phase III trials are ongoing.
Multiple series have explored the use of arterially directed therapies in conjunction with RT. RT is discussed in further detail below.
Radiotherapy
Radiotherapy was historically relegated to the palliative setting; however, the development of modern RT techniques, including intensity-modulated radiotherapy (IMRT) and stereotactic body radiotherapy (SBRT), has enabled safe and effective delivery of ablative doses of radiotherapy to tumors while sparing uninvolved hepatic parenchyma.
RT has been safely used to treatment numerous patients with HCC, ranging from patients with small tumors who are not operative candidates to patients with large tumors or tumor venous thrombosis. Much of the original data of RT included patients who previously failed arterially directed therapies [50].
A series of dose-escalation protocols of hyperfractionated conformal RT with concurrent arterial chemotherapy at the University of Michigan demonstrated the feasibility of liver-directed RT and provided a framework for assessing the optimal RT dose while minimizing the risk of hepatotoxicity.
The series included 128 patients (47 with liver metastases, 35 patients with HCC, and 46 patients with cholangiocarcinoma). Median OS was 15.2 months in patients with HCC and 13.3 months in patients with cholangiocarcinoma.
Tumor dose ≥ 75 Gy was predictive of improved overall survival on multivariate analysis (23.9 months vs. 14.9 months, p<0.01) [51].
Multiple phase I and II prospective single-arm trials and retrospective series have shown impressive local control and survival outcomes, particularly with SBRT and hypofractionated RT, with 1-year OS rates of 48–100 % and 1-year local control rates of 64–100 % [52].
Prospective phase I and II trials of 102 HCC patients treated at Princess Margaret Hospital with SBRT reported an overall response rate of 54 %, 1-year local control rate of 87 %, and 1-year OS rate of 55 % [53].
Prospective phase II trial of 92 patients with HCC or ICC treated at Massachusetts General Hospital and MD Anderson Cancer Center with hypofractionated proton therapy reported a 2-year local control rate of 94.8 % and 2-year OS rate of 63.2 % for patients with HCC [54].
There were low rates of toxicity, with four patients (4.8 %) experiencing grade ≥3 toxicity and only three patients (3.6 %) experiencing a decline in Child-Pugh score from CP A to CP B cirrhosis.
The University of Tsukuba reported the largest series of liver-directed proton therapy, consisting of 318 patients with HCC and primarily CP A cirrhosis (73.6 % of patients had CP A cirrhosis, 24.2 % had CP B cirrhosis, and 2.2 % had CP C cirrhosis) [55].
For the overall cohort, 1-year OS was 89.5 %, 3-year OS was 64.7 %, and 5-year OS was 44.6 %.
Survival was improved in patients with CP A cirrhosis compared with patients with CP B cirrhosis, with 5-year OS of 55.9 % in CP A cirrhosis and 44.5 % in CP B cirrhosis.
There were five cases of grade ≥ 3 toxicities.
63 patients in the cohort received more than one course of proton therapy, with 5-year OS of 50.5 %.
In patients with smaller tumors (≤ 5 cm) who were not candidates for ablative therapies or resection, outcomes with RT have been particularly impressive, with two series reporting 1-year local control rates of 95–100 % and 1-year OS of 99–100 % [56, 57].
Prospective phase II multi-institutional trial demonstrated the safety of 3D-CRT following incomplete TACE, with an overall response rate of 64.5 % [58].
RT in conjunction with TACE has also been safely employed in patients with large tumors (> 10 cm), with one series of 72 patients reporting an overall response rate of 76.1 % and a median survival of 12.2 months, without any cases of grade ≥3 toxicity [59].
Patients with tumor vein thrombosis have particularly poor outcomes, with median survival of 2–4 months. These patients are often not candidates for arterially directed therapies due to the risk of ischemic injury and hepatic failure. Many patients with TVT have been successfully treated with RT with response rates range from 50 to 79 % and overall survival of 3.8–22 months [52, 53].
Prospective phase I and II trials of 102 patients treated with SBRT at Princess Margaret Hospital included 56 patients with TVT, who had a 1-year OS of 44 % [53]. TVT was a strong adverse prognostic factor on multivariate analysis (AHR 2.47, 95 % CI 1.25–4.88, P=0.01).
Systemic therapy: Sorafenib is the first-line therapy for patients with advanced and metastatic HCC, with randomized data demonstrating a small but significant improvement in overall survival.
The Sorafenib HCC Assessment Randomized Protocol (SHARP) Trial [60]
Randomized 602 patients with advanced HCC and Child-Pugh A cirrhosis to sorafenib versus placebo. 28 % of patients had HCV-related cirrhosis, 26 % had EtOH-related cirrhosis, and 12 % had HBV-related cirrhosis.
Trial was stopped after the second planned interim analysis demonstrated improvement in OS with sorafenib (10.7 months vs. 7.9 months, HR 0.59, 95 % CI 0.55 to 0.87, P<0.001).
There were no complete responses. The partial response rate was 2 % in the sorafenib arm vs. 1 % in the placebo arm (P=0.05).
Unplanned subgroup analyses [61] by cirrhosis etiology showed increased OS with sorafenib in both HCV-related and HBV-related cirrhosis; however there was no improvement in time to progression in patients with HBV-related cirrhosis. Analysis was limited by small numbers and lack of stratification by viral status.
Asia-Pacific Trial [62]
Randomized 226 patients with advanced HCC and Child-Pugh A cirrhosis to sorafenib versus placebo. 73 % had HBV-related cirrhosis, and 8.4 % had HCV-related cirrhosis.
Median OS was 6.5 months in patients treated with sorafenib vs. 4.2 months in the placebo arm (HR 0.68, 95 % CI 0.5 to 0.93, P=0.014).Related posts:
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