A National Phase II Study of Proton Therapy in Hepatocellular Carcinoma

Inclusion Criteria:

* Patients with HCC based on classical radiologic findings as defined by the American Association for the Study of Liver Diseases (AASLD) criteria or verified by biopsy
* No extra-hepatic disease
* Deemed ineligible for resection or Radiofrequency Ablation (RFA), or the patients should refuse RFA or surgery
* Age ≥ 18 years
* Performance status ≤ 2
* Total diameter of tumor(s) ≤ 12 cm and a maximum of 3 tumors
* Adequate liver function as measured by Child-Pugh score (Child-Pugh score ≤ 8), or absence of cirrhosis
* Has recovered adequately from toxicity and/or complications from any previous local interventions
* Patients with past or ongoing hepatitis C infection are allowed, but treatment for hepatitis C must have been completed one month before study entry
* Patients with hepatitis B infection is allowed if antiviral therapy have been given for at least 4 weeks and Hepatitis B Virus (HBV) viral load is less than 100 IU/ml. The active therapy must continue throughout the radiation therapy. Patients who are Total hepatitis B core antibody (anti-HBc)(+), negative for Hepatitis B surface antigen (HbsAg) and negative or positive for Hepatitis B surface antibody (anti-HBs) with a HBV viral load under 100 IU/mL do not require HBV anti-viral prophylaxis
* Adequate organ function

  * hematological: hemoglobin ≥ 6 mmol/l, absolute neutrophil count (ANC) ≥ 1,5 x 109/L, platelets ≥ 50 x 109/L
  * hepatic: bilirubin ≤ 1.5 x ULN, alanin-aminotransferase (ALAT) ≤ 1.5 x ULN
  * renal: creatinine ≤ 1.5 x ULN
* Ability to adhere to procedures for study and follow-up
* Signed informed consent to participate
* Final decisions on inclusion and treatment with proton therapy are at the discretion of the investigator

Exclusion Criteria:

* Previous x-ray-based radiotherapy in the liver
* Child Pugh score \>8
* Tumor less than 1 cm from any critical organs at risk (OAR) (duodenum, kidney, stomach, intestines).
* Previous Selective internal radiation therapy (SIRT)
* Episode of hepatic encephalopathy within the last 6 months
* Uncontrolled ascites with need for drainage \> 1 per month
* Episode of bleeding esophageal varices within the past month. If active bleeding from esophageal varices has occurred, a gastroscopy should be performed 4 weeks after the bleeding episode to ensure maximum grade 1 varices.
* Patients with metal implants where beam entrance through the metal implants cannot be avoided (not applicable for fiducial markers implanted for radiotherapy use)
* Patients for whom it is not possible to produce a robust treatment plan following the technical guidelines (Appendix A)
* Patients for whom it is not possible to implant fiducial markers e.g. due to insufficient coagulation of the blood.