# Radiation Oncology/Liver/HCC

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Hepatocellular carcinoma

## Epidemiology

* 6th most common cancer in the world. 14.7 per 100,000 men and 4.9 per 100,000 women. 3 to 1 ratio male to female. Highest risk areas are East and Southeast Asia and Sub-Saharan Africa.
* In North America, only 1-3 per 100,000 people. Incidence is increasing due to hepatitis virus.
* Death rate equal to (or exceeds!) the incidence. There are more deaths than new cases because of the poor outcome and because metastatic disease to the liver is mistakenly attributed to liver cancer in statistics.

## Risk

* Roughly 80% of HCC is attributable to either HBV or HCV, of which HBV accounts for ~55% and HCV 25%
* Persistent HBV infection: 100x-250x risk
* Chronic HCV and cirrhosis: 100x
* Ethanol is carcinogenic. Higher risk of HCC than in non-alcohol-drinkers with HCV.
* Other chemicals: alfatoxin B, nitrites, hydrocarbons, solvents, organochlorine pesticides, primary metals, polychlorinated biphenyls

## Prevention

* Treatment of HCV with interferon alpha decreases risk of developing HCC

## Clinical presentation

Asymptomatic in early stages. Detected with AFP and ultrasound in patients with liver disease. Many patients are asymptomatic even in advanced stages. The majority of symptoms are from liver disease itself. Tumor-related symptoms are palpable mass in abdomen, acute onset pain from hemorrhage, dull pain, abdominal fullness, low grade fever, obstructive jaundice, and splenomegaly.

## Biology

* Rapid doubling time of 41 days

## Workup

* Triphasic CT scan is most sensitive imaging modality (more than MRI). Since AFP has a 10-15% false positive rate and may be elevated in HCC, intrahepatic cholangiocarcinoma (ICC), or some colon metastases, since 2005, the AASLD has recommended the triphasic CT scan as the distinguishing test of choice for radiologic diagnosis of HCC.
* Metastases are rare at presentation
* Indocyanine green (IDG) 15-minute retention rate for determining eligibility for resection
Child Pugh Score Table
| Points | 1 | 2 | 3 |
| Bilirubin | <2 mg/dL | 2-3 | >3 |
| Albumin | >3.5 | 2.8-3.5 | <2.8 |
| PT (secs) | 1-4 | 4-6 | >6 |
| Hepatic encephalopathy | None | 1-2 | 3-4 |
| Ascites | None | Mild (detectable) | Severe (tense) |
Child Pugh Class Designation
| Class | Points | One-year survival | Two-year survival |
| A | 5-6 | 100% | 85% |
| B | 7-9 | 81% | |
| C | 10-15 | 45% | |

## Staging
### Current staging

AJCC 7th Edition (2009)
Note: Staging applies only to hepatocellular carcinoma (no longer includes intrahepatic bile ducts)
Primary Tumor:
* T1 - Solitary tumor without vascular invasion
* T2 - Solitary tumor with vascular invasion or multiple tumors none more than 5 cm
* T3
** T3a - Multiple tumors more than 5 cm
** T3b - Tumor of any size involving a major branch of the portal vein or hepatic vein
* T4 - Tumor with direct invasion of adjacent organs, other than the gallbladder, or with perforation of visceral periteonum
Regional Lymph Nodes:
* N0 - no
* N1 - yes
    Regional nodes include: hepatic artery, portal vein, hilar, hepatoduodenal ligament, inferior phrenic, caval lymph nodes
Distant Metastases:
* M0 - none
* M1 - yes
Stage Grouping:
* Stage I: T1 N0 M0
* Stage II: T2 N0 M0
* Stage IIIA: T3a N0 M0
* Stage IIIB: T3b N0 M0
* Stage IIIC: T4 N0 M0
* Stage IVA: N1
* Stage IVB: M1

### Older staging editions

AJCC 6th Edition (2002)
Note: staging was also used for intrahepatic bile ducts
* T1 - Solitary, <= 2cm, without vascular invasion
* T2 - Solitary <= 2cm with vascular invasion; multiple, limited to one lobe, <= 2cm, without vascular invasion; solitary, >2 cm, without vascular invasion
* T3 - Solitary, >2cm, with vascular invasion; multiple, one lobe, <= 2cm, with vascular invasion; multiple, one lobe, any more than 2cm
* T4 - Multiple tumors, involving more than one lobe; invasion of a major branch of portal or hepatic veins; invasion of adjacent organs other than gallbladder; perforation of visceral peritoneum
* Stage I: T1 N0 M0
* Stage II: T2 N0 M0
* Stage IIIA: T3 N0 M0
* Stage IIIB: T1-3 N0 M0
* Stage IVA: T4
* Stage IVB: M1

## Prognosis

* Fibrolamellar variant has a better prognosis

## Treatment

Most studies include both mets and primary liver cancer; for now they are kept together. Please see the main Liver page.
* HCC (hepatocellular carcinoma) tumors can be classified as resectable (can be removed by an operation) and unresectable (cannot be removed by an operation). Only 10-15% of cases can be effectively treated with surgical resection.
* Surgical resection with 2-cm margin of liver for T1-3 N0. Minimum of 1-cm is recommended but literature is mixed on the exact margin required.
* For unresectable, chemoembolization, intraarterial infusional chemo, cryosurgery, ethanol injection, radioimmunotherapy, conformal radiotherapy, radiofrequency ablation.
* For stage IV, chemotherapy, but low response rates.
* The radionuclide 131-Lipiodol treatment is believed to offer a significant reduction in recurrence rate for resectable HCC. A 1999 Lancet study by WY Lau et al (PMID 10459961) report an improvement in the 3-year survival rate from 46.3% (control group) to 86.4% (treatment group). This treatment is not yet approved in the United States, but it is in Phase III clinical trials in Singapore and can be administered in Hong Kong.

### SBRT

* Princess Margaret (2003-2006)
** Phase I. 41 patients, unresectable HCC (n=31) or IHC (n=10). SBRT 6 fractions; dose dependent on NTCP calculations. Toxicity risk escalated from 5% to 10% and 20%. Median tumor size 173 mL (9-1913 mL); had to have >=800 mL uninvolved liver; Child-Pugh A liver function. Median dose 36.0 Gy (24.0 - 54.0 Gy). CTV=GTV+8mm, PTV=CTV+5mm or more
** 2008 PMID 18172187 -- "Phase I Study of Individualized Stereotactic Body Radiotherapy for Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma." (Tse RV, J Clin Oncol. 2008 Jan 2 [Epub ahead of print]). Medium F/U 1.5 years
*** 3 month toxicity: No dose-limiting toxicity or RILD; 24% Grade 3 liver enzymes, no Grade 4/5; 23% experienced progression to Child-Pugh B liver function. Late toxicity 2 patients (6%): 1 patient dead from GI bleed from tumor-duodenal connection, 1 patient SBO requiring surgery.
*** Outcome: median OS HCC 11.7 months, IHC 15.0 months
*** Conclusion: Individualized 6-fraction SBRT safe
** 2006 PMID 16982550 -- "Individualized image guided iso-NTCP based liver cancer SBRT." (Dawson LA, Acta Oncol. 2006;45(7):856-64.)
*** Phase I/II. 79 patients with HCC (33), IHC (12) or liver mets (34).
*** RT: prescription based on NTCP to maintain given risk of RILD to max 60/6 (median dose 36.6/6)
* Hokkaido; 2007 (2001-2004) PMID 17869660 -- "Intercepting radiotherapy using a real-time tumor-tracking radiotherapy system for highly selected patients with hepatocellular carcinoma unresectable with other modalities." (Taguchi H, Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):376-80.)
** Retrospective. 18 HCC tumors, 15 patients. Real-time tumor tracking with implanted 2.0 mm fiducial marker. Median dose 48/8 (median BED 76.8 Gy). Mean F/U 1.7 years
** Outcome: 2-year OS 39%, LC 83% (92% with re-irradiation)
** Toxicity: 1 Grade 3 transient gastric ulcer, 2 transient LFT elevation
** Conclusion: Fiducial marker-guided RT effective at delivering focal high dose

### TACE and RT

* Meta-analysis; 2008 PMID 19042048 -- "Transcatheter arterial chemoembolization in combination with radiotherapy for unresectable hepatocellular carcinoma: A systematic review and meta-analysis." (Meng MB, Radiother Oncol. 2008 Nov 28. [Epub ahead of print])
** Meta-analysis. 17 trials and 1476 patients, 5 RCT.
** Conclusion: TACE + RT is more therapeutically beneficial than TACE alone

## Survival

* Unresectable: less than 10% 5-year survival
* Resectable: 5-year survival 50-73% stage I, 30-56% stage II, 10-29% stage III, 10% stage IV.

## Radioemobolization

* SIRveNIB; 2018 (2010 - 2016) PMID 29498924 -- "SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma." (Chow PKH, J Clin Oncol. 2018 Jul 1;36(19):1913-1921. doi: 10.1200/JCO.2017.76.0892. Epub 2018 Mar 2.
** Randomized, 11 countries. 360 patients, locally advanced HCC. Arm 1) Radioemolization Y90 (mean activity 1.8 GBq); 29% did not receive assigned therapy vs Arm 2) sorafenib; 9% did not receive assigned therapy
** Outcome: Median OS RE 8.8 months vs sorafenib 10.0 months (NS). Median PFS 5.8 month vs 5.1 months (NS)
** Toxicity: Grade 3+ RE 28% vs sorafenib 51% (SS). Most common G3 toxicity ascites ~3%. Radiation hepatitis 1.5%
** Conclusion: No difference in OS, but improved toxicity profile of radioembolization

## Patterns of failure

* Local tumor recurrence and intrahepatic recurrence are the predominant sites of failure.

## Fibrolamellar Carcinoma

* Considered a variant of HCC comprising < 1%; however, evidence suggests it is uniquely distinct in both epidemiology and better prognosis
* Associated with cirrhosis in <10% patients, typically presents in a background of normal liver function and histologic architecture
* 50-60% solitary, rest satellite lesions next to primary mass; rarely diffuse involvement
* Surgery (hepatic resection/transplant) is primary treatment alternative
* Radiotherapy
** Hopkins 1985-90 PMID 10025374 -- Metastatic nonresectable fibrolamellar hepatoma: prognostic features and natural history. (1999 Epstein BE, Am J Clin Oncol. 1999 Feb;22(1):22-8.)
*** Retrospective. 17 patients with met disease. Matched control analysis with HCC patients
*** Median survival: 14 months vs. 7.7 months (p<0.001)