Hepatocelullar Carcinoma
About Lesson

The treatment is based on the staging- The most common classification used is the  BCLC staging system,  created in 1999 and frequently updated, and takes into account number, size, vascular invasion, extrahepatic involvement and patient ECOG (Performance status) and liver function (Cirrhosis stage)

Very early stage (BCLC 0)

Solitary HCC ≤2 cm without vascular invasion or extrahepatic spread in a patient with preserved liver function and no cancer-related symptoms.

Early stage (BCLC-A)

This is defined as solitary HCC irrespective of size or as a multifocal HCC up to 3 nodules (none of them >3 cm, in keeping with Milan Criteria )

Intermediate stage (BCLC-B)

Multifocal HCC (exceeding BCLC-A criteria) with preserved liver function, no cancer-related symptoms (PS 0) and no vascular invasion or extrahepatic spread

Advanced stage (BCLC-C)

Vascular invasion or extrahepatic spread who are still relatively fit, as reflected by a PS ≤2 at staging work-up, and who have preserved liver function.

End-stage (BCLC-D)

Patients with major cancer-related symptoms (PS >2) and/or impaired liver function without the option of LT due to HCC burden or non–HCC–related factors present poor short-term survival and belong to the BCLC stage D.

 

TREATMENT:

Surgical resection/ Transplant

Surgery is the core of potentially curative treatment for HCC. Surgical resection and liver transplantation achieve the best results in appropriately selected candidates (5-year survival 60% and higher).  In general, surgical resection is preferred in non cirrhotic HCC (odd in Western only 5%; but in Asia can make up 40%) but depends on accesibility , segment involved, predicted adequate functional liver remnant (at least 40%) and absence of portal hypertension and collaterals that worsen intra and post-surgical risk and morbidity.

Liver transplant is prefered in cirrhotic patients which are fit surgical candidates. More so if they have decompenated cirrhosis which is by itself a criteria for transplant. 

Patient with multifocal disease are prefered due that it is usually not possible to resect different lesions in different locations.   Milan Criteria (Or expanded Milan: up to 5 lesions <3cm, or stable up to 7cm lesions, AFP <1000ng/ml) – seems to have similar outcomes) . In appropriate candidates, liver tranplant associates a fully restoration of liver function, resolution of any portal hypertension and complete cure of HCC.  Overall 4-year survival 74%, HCC recurrence only 8%. However, waiting times are long and 20% of the patients are de-listed from transplant list in the interim. 

Resection may be preferred if patient has one solitary lesion which is easily accesible and no contraindications with impaired liver function or  portal pressure, especially in those whose are more erdlerly in which a transplant seems like too risky a process but they are still fit to undergo surgery.  The problem with resection is that despite 5-year survival rates of 60%, tumor recurrence occurs in 70% within 5 years. Using adjuvancy with antitumoral medication appears to have very promising results in reducing recurrence. AASLD recommends adjuvant immune checkpoint inhibitor-based systemic therapy for 1 year if high risk (>5cm ,>3 lesions, poorly differenciated, vascular invasion) 

Local ablative treatment

Thermal Ablation

These include radiofrequency ablation (RFA) or microwave ablation (MWA). cryotherapy is an non thermal alternative which will not be discussed in this topic.   In very early or early  (BCLC 0 o A) ablation is in general an alternative  treatment modality to surgery and associates the same effectivenes and survival if <3cm . Ethanol injection, very used in the past, has been proved to be less effective than RFA therefore it is no longer recommended as a standard.

RFA  consists in a high-energy electric current (>60 ºC) causing tumoral necrosis. They usually use a thin needle electrode percutaneously and guided by CT scan. MWA uses microwave energy which achieves higher energy than RFA, with shorter ablation times, higher ablation temperatures, larger ablation zones and a lower heat-sink effect (the undesirable cooling of the area due to vessels nearby) than RFA . Overall, MWA achieves more extensive tumour necrosis than RFA, especially near vessels or liquid structures where RFA does not propagate that well, whereas RFA is safe and can be more precise in smaller lesions, both are similar in efficacy. Thermal ablation is first-line treatment in patients not suitable for surgery, with up to three HCC tumours <3 cm in size

Stereotactic ablative radiotherapy (SABR)

Focal administration of a high dose of radiation with the ability to spare the healthy liver parenchyma, and by this limiting the risk of radiation-induced liver disease.  SABR could be a potential local ablative treatment for patients in whom thermal ablation is not appropriate, for example those tumours who are inaccesible percutaneously or are close to the liver capsule, lung or heart with risk of damaging near structures.

Radiation segmentectomy

This is using high ablative radiation dose in one or two segments with the view of causing complete atrophy, which woud be  analogous in anatomic precision to surgery but are minimally invasive. 

INTRAARTERIAL THERAPY

In general, this therapies are the first-line treatment for intermediate (BCLC B) stage HCC (multinodular HCC beyond liver transplant criteria, with preserved liver function and performance status), and the most common treatment for unresectable HCC due the capacity of treating a big area, based on the arterial supply of the tumor compared to the portal vein supply of the surrounding parenchyma. 

Transarterial radioembolization (TARE) also called  Selective internal radiation therapy (SIRT)

TARE or SIRT  is a liver-directed therapy in which the  radioactive microspheres become lodged in arterioles in or on the periphery of the tumor, which is then irradiated by Yttrium-90 (90Y) inducing DNA damage by Beta rays emitted from radioactive microspheres.

 Transarterial chemoembolisation (TACE) 

This is an embolic therapy by embolisation of the HCC arterial supply. The most common technique is cTACE using lipiodol (conventional TACE) or drug-eluting beads (DEB-TACE).  By selective catheterization of segmental or distal branches, (with c-arm CT when possible to ensure localization) in an attempt to delivery of therapy to the tumor(s) to maximize chance of response and minimizes ischemic injury to noncancerous background liver. Note that patient with a high tumoral burden > 50% liver involvement, main vascular invasion,  or hepatic disfunction are at high risk of hepatic decompensation or ischemic complications and it is not worth the risks. 

Original.01515467 202312000 00027.F9 1
BCLC treatment algorythm, adapted from reig et al. https://journals.lww.com/hep/fulltext/2023/12000/aasld_practice_guidance_on_prevention,_diagnosis,.27.aspx

Follow up

Patients treated with TACE should have a CT or contrast-enhanced MRI approximately 6 weeks after treatment, whereas those treated with ablation, TARE or EBRT should undergo imaging to assess response approximately 12 weeks (3 months) after treatment

 

SYSTEMIC THERAPY

In the last decade, Sorafenib which is a tirosin kinase inhibitor, was the first choice for systemic therapy. In the last years, numerous clinical trials have proved superior outcomes with atients with atezolizumab  (immune checkpoint inhibitor–> monoclonal antibody that works by binding to the protein PD-L1 on the surface of some cancer cells)  and bevacizumab (monoclonal antibody that targets VEGF, inhibits angiogenesis and tumor growth) . The 12 month survival compared to Sorafenib 67%vs 54%.  Most studies are done with Child A and good performance status (PS), therefore the reccommendation to start this are 

  • Preserved liver function (Child-Turcotte-Pugh A or well-selected Child-Turcotte-Pugh B cirrhosis),
  • ECOG PS 0-1
  • BCLC Stage C
  • BCLC Stage B not amenable to or progressing after locoregional therapy 
  • Check Oesophageal varices with an EGD and band them (or carvedilol if not possible) due to the high risk of variceal bleeding. 

durvalumab plus tremelimumab is an appropriate first line as well, but approved in USA but not in the UK as per 2024.  The risk of variceal bleeding seems lower with this.  Both are monoclonal antibodies of checkpoint inhibitors class.

Second line, Sorafenib appears a good choice, and specially because can be given to performance status 2, contrary to lenvatinib which is another tirosin kinase option (Only up to PS 1)

 

PALLIATIVE CARE

In our clinical practice, it is not uncommon to find advanced HCC with BCLC D especially in patients with advanced cirrhosis (for example, CHILD high B or C unfit for consideration for liver transplant) or on the contrary, patients that despite having preserved liver function (In example, Child A or early B) they have limited performance status (PS 3 or 4) . In those patients, consideration of systemic therapy is contraindicated and also it is not in their best interest, as either the liver impairtment or the performance status reduces the overall survival and it is likely that the systemic therapy will, if anything may cause severe adverse events or being even fatal without significantly improving the survival time.

In those case, the earlier we refer to palliative care, the better quality of life the patient will have, best multidisciplinar care and approaching all the needs (pain, physical, psychological needs, oher problems such as ascites or oedema…etc) as well as preparing a plan for when progression of he disease occurs. 

 

 

 

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Excellent summary of therapy- Suddle et al, https://gut.bmj.com/content/73/8/1235-   EHS, extrahepatic disease spread; LT, liver transplantation; MVI, macrovascular tumour infiltration; PS, performance status; SABR, stereotactic ablative radiotherapy; SIRT, selective internal radiation therapy; TACE, transarterial chemoembolisation. *Sorafenib can be considered in PS=2. **Turnour <3 cm. ***Disease confined to one lobe. ****Solitary tumour, branch portal vein thrombosis, no EHS. *****No ascites, PS=0.

 

Bibliography

BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update Reig, Maria et al. Journal of Hepatology, Volume 76, Issue 3, 681 – 693
 
Suddle AReeves HHubner R, et al British Society of Gastroenterology guidelines for the management of hepatocellular carcinoma in adults
 
 
 
 
 
 
Mikell JK, Dewaraja YK, Owen D. Transarterial Radioembolization for Hepatocellular Carcinoma and Hepatic Metastases: Clinical Aspects and Dosimetry Models. Semin Radiat Oncol. 2020 Jan;30(1):68-76
 
Cunha GM, Hosseini M, Furlan A, Fowler KJ. Hepatocellular Carcinoma Staging: Differences Between Radiologic and Pathologic Systems and Relevance to Patient Selection and Outcomes in Liver Transplantation. AJR Am J Roentgenol. 2022 Jan;218(1):77-86.