Treatment/Prognosis

Question 1

What 3 features of the HCC pt and the pt’s tumors define the appropriate Tx paradigm?

Answer 1

The 3 features that define the Tx options for a pt with HCC are whether the pt (a) has metastatic Dz, (b) has resectable localized tumor, and (c) is medically fit for major Sg.

Question 2

What are the only 2 curative Tx options for HCC?

Answer 2

The only 2 established curative Tx options for HCC are partial hepatectomy to –margins and liver transplantation, with 5-yr OS for pts within Milan criteria around 50%–65% and 65% for each Tx, respectively. Potentially curative RT Tx with hypofractionated photons and proton therapy are being explored.

Question 3

Partial hepatectomy is an option in which HCC pts?

Answer 3

Partial hepatectomy is a potentially curative option in HCC pts who are medically fit for Sg, have a solitary mass without major vascular involvement, are Child–Turcotte–Pugh class A with mild or moderate portal hypertension, and have adequate future liver remnant (if no cirrhosis, require >20% of liver; if Child–Pugh A cirrhosis, require >30% of liver). Attempt at curative resection in HCC pts with multifocal tumors and major vascular invasion is controversial.

Question 4

What % of HCC pts will have an LR after partial hepatectomy after 5 yrs?

Answer 4

∼75% of pts with HCC will have an LR after 5 yrs (new primary or local spread). (Mathurin P et al., Aliment Pharmacal Ther 2003)

Question 5

What criteria are used to determine if liver transplant is an option for a pt with HCC?

Answer 5

The United Network for Organ Sharing (UNOS) criteria are used to determine if liver transplantation is appropriate in a pt with HCC. Per the UNOS criteria, transplantation is an option for medically fit pts with a single tumor ≤5 cm or 2–3 tumors ≤3 cm.

Question 6

What are the Tx options for an HCC pt with localized Dz who is medically unfit for major Sg?

Answer 6

Tx options for an HCC pt with localized Dz but who is unfit for major Sg include:

1. Sorafenib for Child–Pugh A and some B pts
2. Tumor ablation procedure (radio frequency, cryoablation, microwave, percutaneous alcohol injection)
3. Tumor embolization procedure (chemoembolization [aka transarterial chemoembolization, or TACE], drug-eluting bead trans-arterial chemoembolization (DEB-TACE), bland embolization, radioembolization)
4. EBRT, including stereotactic body radiation therapy (SBRT) and proton techniques

Question 7

In the United States, what radioembolization isotope is most commonly used for HCC?

Answer 7

In the United States, the most commonly used isotope for radioembolization in HCC pts is yttrium-90, a pure β emitter.

Question 8

What are the 2 forms of microspheres used for radioembolization in HCC pts, and what is the difference b/t them?

Answer 8

Microspheres used for radioembolization in HCC pts:

1. TheraSphere (glass microspheres)
2. Selective internal radiation (SIR)-Spheres (resin microspheres)

Question 9

Estimate the response rate of HCC to yttrium-90–labeled microspheres.

Answer 9

The response rate of HCC to yttrium-90–labeled microspheres varies from 50%–80% depending on the definition of response used.

Question 10

Is portal vein thrombosis a contraindication to catheter-based therapies?

Answer 10

Portal vein thrombosis is a relative contraindication to TACE, but not radioembolization.

Question 11

What are the EBRT options with either medically inoperable or technically unresectable HCC?

Answer 11

A number of EBRT options have been used for unresectable or medically inoperable HCC pts:

1. Whole liver RT for palliation (21 Gy in 7 fx, Borgelt et al., IJROBP 1981)
2. High-dose RT (>50 Gy) with standard fractionation
3. Hyperfractionated RT with chemosensitization
4. Hypofractionated SBRT
5. Hypofractionated proton therapy

Question 12

What are the Tx options for an HCC pt with metastatic Dz?

Answer 12

The only standard active Tx option for metastatic HCC is sorafenib, a small molecule TKI that acts against c-raf and platelet-derived growth factor-alpha (PDGF-α). HCC typically does not respond to traditional cytotoxic chemo.

Question 13

What is the MS in metastatic or inoperable HCC pts treated with sorafenib alone?

Answer 13

The MS of metastatic or inoperable HCC pts treated with sorafenib alone is 10.7 mos vs. 7.9 mos (p = 0.0058) in pts treated with placebo. No significant difference in time to symptomatic progression (4.1 mos vs. 4.9 mos). (Llovet JM et al., NEJM 2008)

Question 14

What are the dose and results of SBRT for HCC?

Answer 14

In a sequential phases I–II trial of SBRT for HCC, 102 pts with Child–Pugh class A Dz with at least 700 cc of non-HCC liver were treated with SBRT (24–54 Gy in 6 fx; median 36 Gy). Median OS was 17 mos with 87% LC at 1 yr. 30% experienced grade ≥3 toxicity. (Bujold A et al., JCO 2013)

Another single institutional experience utilized 12.5 Gy × 3 (<4 cm and no cirrhosis) or 5 Gy × 5 or 10 Gy × 3 (≥4 cm with cirrhosis) with LC rates of 94% and 82% in 1 and 2 yrs, respectively. (Mendez Romero A et al., Acta Oncol 2006)

Question 15

For HCC, what is the normal volume of liver (liver minus GTV) required to be eligible for stereotactic ablative radiotherapy (SABR)?

Answer 15

For HCC, the normal volume of liver (liver minus GTV) required to be eligible for SABR is ≥700 ccs (RTOG 1112).

Question 16

Is there a role for sorafenib with radiotherapy?

Answer 16

Phase I data exist regarding the safety and tolerability of sorafenib with RT and suggests that sorafenib exacerbates RT toxicity (Brade AM et al., IJROBP 2016). RTOG 1112 is a phase III study currently randomizing pts with Child–Turcotte–Pugh class A and BCLC b/c HCC to sorafenib alone vs. sequential SBRT f/b sorafenib.

Question 17

What is the role for proton beam in the management of unresectable HCC?

Answer 17

Potentially delivering high hypofractionated RT dose safely with excellent safety and tumor control outcomes

A Japanese prospective study enrolled 51 pts with tumors >2 cm from the porta hepatis and GI tract and treated them with 66 CGEs in 10 fx. LC was 94.5% at 3 yrs and 87.8% at 5 yrs. There were minor grade 1 acute adverse events, and only 3 pts were rated higher than grade 2. (Fukumitsu N et al., IJROBP 2009)

A phase II single arm multi-institutional study in 92 pts with HCC or intrahepatic cholangiocarcinoma (ICC), with Child–Pugh A or B, rcvd median dose 58 CGE/15 fx. Median size 5.0 cm (1.9–12 cm) for HCC and 6.0 cm (2.2–10.9 cm) for ICC. LC at 2 yrs 95% HCC and 94% ICC, and OS 63.2% HCC and 46.5% ICC. (Hong TS et al., JCO 2016)

Question 18

What studies have compared RT to other modalities for unresectable HCC?

Answer 18

An RCT conducted at Loma Linda compared 70.2 CGEs of proton beam radiotherapy in 15 fx to TACE in pts with HCC meeting transplantation criteria. Interim results of 69 pts revealed equivalent survival, with a 2-yr OS of 59%. There was a trend toward improved LC (88% vs. 45%, p = 0.06) and PFS (48% vs. 31%, p = 0.06) with protons. (Bush DA et al., IJROBP 2016)

A meta-analysis of 25 trials comparing TACE alone to TACE plus radiotherapy showed significantly improved 1-yr OS in the TACE plus radiotherapy group (OR 1.36, 95% CI, 1.19–1.54). The OS benefit of radiotherapy was persistent at 5 yrs (OR 3.98, 95% CI, 1.86–8.51). (Huo YR et al., JAMA Onc 2015)

Retrospective analysis of 224 pts at the University of Michigan compared SBRT and radiofrequency ablation (RFA). Those receiving SBRT had improved LC at 12 mos (97.4% vs. 83.6%) and 2 yrs (83.8% vs. 80.2%). For tumors ≥2 cm, RFA was associated with decreased LC (HR 3.35, p = 0.02). (Wahl DR et al., JCO 2016)

Question 19

Is there a QOL benefit to palliative radiotherapy for HCC?

Answer 19

A phase II study assessed the benefit of 8 Gy × 1 for pts with HCC or liver mets unsuitable for or refractory to standard therapies. Pts were premedicated with granisetron 1 mg and dex 2 mg ˜1 hr before RT. At 1 mo, 48% were noted to have an improvement in Sx (FACT-Hep 29%, EORTC QLQ-C30 functional 11%–21%, Sx 11%–50%). (Soliman H et al., JCO 2013)