PTC CLINIC
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Primary Hepatocellular Carcinoma (HCC) – Justification of Indicating Proton Therapy

Radiation Therapy Strategy

No standard is available for radiotherapy dosage. A natural dependence of higher dose and greater effect is obvious, even at doses above 70 Gy. Despite current minimal usage, radiation therapy of HCC represents an effective tool for what is still believed to be palliative therapy. The development of application techniques moves radiotherapy to the level of radiosurgery, naturally not to the extent of radical resection, such as lobectomy or segmentectomy, but only to the extent of the resection of individual foci.

Advantages and Results of Proton Therapy

Proton irradiation is applied in the treatment of HCC for over 20 years. Maximum experience to a greater extent comes from Japan followed by the USA. The number of treated patients has already reached thousands. Number of printed publications is more than one hundred. Published experience is at the level of references on routine therapy, phase III or phase II studies in specific HCC variants (e.g. thrombosis of the vena cava). Proton radiotherapy has been used as an effective means of radiosurgery. References can be characterized by:

• Proton therapy is used in HCC as an effective variant of targeted irradiation of one or more tumor foci, i.e. as a variant of radiosurgery.
• Proton irradiation allows for safe application of doses up to 70-80 Gy in the tumor site.
• Proton radiation can be safely administered in various fractionation regimes from normal fractionation 2 Gy/day following a single 24 Gy irradiation. Most commonly used fractions were within the range of 3-6 Gy.
• The effects of therapy or toxicity are not dependent on the fractionation scheme.
• Proton radiation can even be applied in various specific situations (thrombosis of the inferior vena cava, localization in the porta hepatis, the presence of refractory ascites, advanced cirrhosis, elderly patients, etc.).
• Proton irradiation can be safely repeated for recurrences in the liver without influencing liver function (Child-Pugh A).
• The effectiveness of proton irradiation is the only alternative to surgery – 5 year survival of 56%, recurrence-free survival at 5 years over 80%. But there can be no comparisons with the surgical procedure, as it is a selection bias. Indications for the procedure are limited by small and specifically localized findings, while this limitation is not present in proton radiotherapy.
• The effectiveness of proton irradiation is superior to the photon radiation (also confirmed by meta-analysis). Validation by a randomized study is lacking and a randomized comparative study is unlikely to ever be performed.
• The efficacy criteria are indicators of survival and progression-free or relapse-free survival. Evaluation of the effect in accordance with the RECIST criteria has not been commonly reported in routine practice, as it is not beneficial.
• The toxicity of proton radiation is minimal. Acute toxicity rarely reaches grade 3; the dominant types of toxicity are gastrointestinal toxicity (incl. treatable ulcerations) and bleeding. As concerns chronic toxicity, RILD has not been reported in relation to proton radiation therapy.
• The risk of toxicity increases when exceeding the usual “dose constraint” V30Gy<25%. In proton radiation therapy, this limit is easily observed.

The expected effect of proton therapy is relevant to the references from the literature and availability of radiotherapy in the Czech Republic:

• the effectiveness is relevant to the surgical procedure, to the extent of survival parameters, i.e. it is the second most effective modality after transplantation,
• a very favorable toxicity profile,
• variability of fractionation regimens, which can be adapted to different needs,
• availability of radiotherapy for patients with HCC; photon radiation has been used sporadically to date.

Limitations of Current Radiation Therapy – Technical and Biological Aspects

The main toxicity risk of HCC radiotherapy is Radiation Induced Liver Disease (RILD). This is a limiting factor for the radiation dose and the extent of irradiated volume. Given the risk of side effects, in particular the development of RILD, a simple model was created based on the proportion of retained undamaged liver tissue and also on a functional indocyanine green (ICG) retention test to indicate irradiation of HCC and dose (40 to 60 Gy).

The limitation of HCC radiotherapy is based on the ratio of irradiated and non-irradiated liver tissue (liver tissue tolerance is only up to 30 Gy), i.e. it depends on the mode of application and the type of radiation. The achieved difference in doses delivered to the tumor versus liver tissue must be significant, i.e. 70 Gy vs. 30 Gy.

Efficacy of Current HCC Therapy

• Resection procedures in HCC result in a five-year survival rate of 30-70%. However, the 5-year recurrence rate reaches 70%.
• Liver transplantation, if indicated according to Milanese criteria (always in the Czech Republic) results in a 4-year survival rate of 85% and a recurrence-free survival rate of 95%.
• Combined local ablation techniques (chemoembolization, RFA) can be used to achieve a five-year survival rate of more than 40% (at the cost of significant toxicity); nevertheless, the reported populations were highly non-homogeneous and difficult to compare.
• Systemic biological therapy achieves a median survival of up to 1 year (in the SHARP trial, which served as a basis for authorization of sorafenib, the median survival rate was 10.7 months).
• When using radiotherapy with focal administration of doses up to 60-70 Gy, 50% of patients achieved regression of the tumor bed, and an additional 40% of patients achieved stabilization of the disease. The efficacy of local therapy is reflected in the survival parameter, with a median survival rate after radiotherapy close to 24 months.

Toxicity and Risks of Current Therapy

• Adverse effects of surgical and conservative modalities are described in the literature and are not limiting. In chemoembolization, the limiting factor is the risk of chemical hepatitis, depending on the material used and the extent of embolization. It has been reported to exceed 50% in extensive procedures.
• Other limiting factors are toxicity of biological therapy and its manifestations (hypertension, diarrhea, skin changes). Treatment of HCC is associated with the risk of liver toxicity in the form of drug-induced hepatitis, which exceeds 50%.
• Acute toxicity of HCC radiotherapy is of little importance and appears with symptoms of acute radiation-induced gastritis and enteritis.
• Chronic toxicity includes in particular RILD. (RILD is not a typical “late effect”, as it falls into the “consequential late effects” based on its development).
  The interval of RILD development is about 2 weeks to 4 months after irradiation. The high-risk factor for RILD is a previous infection with hepatitis B or antigen-positivity, preexisting cirrhosis of Child-Pugh stage B, and portal vein thrombosis. The risk of developing RILD is proportional to the irradiated volume, i.e. it is proportional to the extent of liver damage. At the same time, it is proportional to the amount of healthy liver tissue exposed to a dose higher than 30 Gy.

Benefits of Proton Therapy Applied in the Proposed PTC Protocol

As part of the proposed protocol for HCC therapy, at PTC we propose:

• Apply proton irradiation to localized forms of HCC in the form of radiosurgery, i.e. in a single irradiation, e.g. 24 Gy/1 fraction. tool.
• Use proton irradiation in parallel with other modalities, e.g. for relapse after surgery.
• Use fractionation in the range of 3-6 Gy/d as the most proven so far and achieve a total dose >70Gy.
• Monitor the safety parameters of therapy (acute and chronic side effects).