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A National Phase II Study of Proton Therapy in Hepatocellular Carcinoma

Primary Purpose

Hepatocellular Carcinoma

Status

Recruiting

Phase

Not Applicable

Locations

Denmark

Study Type

Interventional

Intervention

Proton therapy

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Herlev HospitalRecruiting
Aarhus University HospitalRecruiting
Odense University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Proton Arm

Arm Description

All patients in the study will receive proton therapy with 67.5 Gray/15 fractions(fx) /5fx per week .

Outcomes

Primary Outcome Measures

Number of deaths of any cause

Death of any cause

Number of participants with Radiation-induced liver disease (RILD)

Worsening of the Child- Pugh score ≥2 or alanin-aminotransferase (ALAT) ≥5 upper normal limit (ULN)

Secondary Outcome Measures

Number of participants with RILD within 6 months of start of radiotherapy

Worsening of the Child- Pugh score ≥2 or ALAT ≥5 ULN

Acute toxicity

Number of participants with Acute radiation-related toxicity grade 3 or higher measured by CTCAE v5.0

Late toxicity

Number of participants with Late radiation-related toxicity grade 3 or higher measured by CTCAE v5.0

Radiation-induced hospitalization

Number of days spend in the hospital due to radiotherapy toxicity

Health-related Quality of Life C30

Health-related Quality of life measured by the EORTC QoL questionnaires C30

Quality of Life HCC-18

Health-related Quality of life measured by the EORTC QoL questionnaires HCC18

Local control

1- and 3-year local control

Progression-free survival

1- and 3-year progression-free survival

Overall survival

1- and 3-year overall survival

Pattern of failure

Pattern of failure will be reported as number of patients with in-field failures in the clinical target volumen (CTV), in-field failures in the planning target volume (PTV), and out-of-field failures.

Technical feasibility

the proportion of patients where it was possible to adhere to the guidelines of CTV dose coverage and tolerable normal tissue dose

Reduction in mean liver dose

calculated on a per patient basis, and median (and inter-quartile ranged) will be reported for the study population.

Full Information

NCT ID

NCT05203120

First Posted

December 13, 2021

Last Updated

May 10, 2023

Sponsor

University of Aarhus

Collaborators

Herlev Hospital, Rigshospitalet, Denmark, Odense University Hospital, University of Leeds, Aarhus University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT05203120

Brief Title

A National Phase II Study of Proton Therapy in Hepatocellular Carcinoma

Official Title

A National Phase II Study of Proton Therapy in Hepatocellular Carcinoma

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 1, 2022 (Actual)

Primary Completion Date

December 31, 2025 (Anticipated)

Study Completion Date

January 1, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Aarhus

Collaborators

Herlev Hospital, Rigshospitalet, Denmark, Odense University Hospital, University of Leeds, Aarhus University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

350 new cases of hepatocellular carcinoma (HCC) are diagnosed in Denmark each year, but the overall prognosis is poor with a 1-year survival rate of less than 40% and a 5-year survival rate of 10% for the entire patient group. This national phase II non-randomized single-arm study of proton therapy in HCC is conducted with the aim to offer a safe and efficient radiation treatment to fragile patients with reduced dose to the normal liver compared to conventional photon-based radiotherapy.

Detailed Description

Each year, approximately 350 new cases of hepatocellular carcinoma (HCC) are diagnosed in Denmark, but the overall prognosis is poor with a 1-year survival rate of less than 40% and a 5-year survival rate of 10% for the entire patient group. This national phase II non-randomized single-arm study of proton therapy in HCC is conducted with the aim to offer a safe and efficient radiation treatment to fragile patients with reduced dose to the normal liver compared to conventional photon-based radiotherapy. The study aims to offer curative treatment to a larger group of patients and thus better prognosis for these patients. The study will include 50 patients enrolled within 3 years. Patients cannot be guaranteed any direct personal benefits of participating in the trial. Participating in the study can help with new knowledge that can benefit future patients with similar illness. The treatment will be given at the Danish Center for Particle Therapy. During radiotherapy, additional CT scans will be performed weekly as part of quality assurance until it can be documented that there is no such need. Participation in the study will also mean additional examinations and questionnaires at the start of treatment, below treatment and at follow-up. All patients will be asked to supply blood samples to analyze for circulating tumor DNA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatocellular Carcinoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Model Description

National phase II non-randomized single-arm study of proton therapy in patients with hepatocellular carcinoma.

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Proton Arm

Arm Type

Experimental

Arm Description

All patients in the study will receive proton therapy with 67.5 Gray/15 fractions(fx) /5fx per week .

Intervention Type

Radiation

Intervention Name(s)

Proton therapy

Intervention Description

All patients will receive proton therapy 67.5Gy/15fx

Primary Outcome Measure Information:

Title

Number of deaths of any cause

Description

Death of any cause

Time Frame

4 months after start of radiotherapy

Title

Number of participants with Radiation-induced liver disease (RILD)

Description

Worsening of the Child- Pugh score ≥2 or alanin-aminotransferase (ALAT) ≥5 upper normal limit (ULN)

Time Frame

4 months after start of radiotherapy

Secondary Outcome Measure Information:

Title

Number of participants with RILD within 6 months of start of radiotherapy

Description

Worsening of the Child- Pugh score ≥2 or ALAT ≥5 ULN

Time Frame

6 months after start of radiotherapy

Title

Acute toxicity

Description

Number of participants with Acute radiation-related toxicity grade 3 or higher measured by CTCAE v5.0

Time Frame

4 months after start of radiotherapy

Title

Late toxicity

Description

Number of participants with Late radiation-related toxicity grade 3 or higher measured by CTCAE v5.0

Time Frame

from 4 months until 60 months after start of radiotherapy

Title

Radiation-induced hospitalization

Description

Number of days spend in the hospital due to radiotherapy toxicity

Time Frame

within 4 months after start of radiotherapy

Title

Health-related Quality of Life C30

Description

Health-related Quality of life measured by the EORTC QoL questionnaires C30

Time Frame

Until 60 months after start of radiotherapy

Title

Quality of Life HCC-18

Description

Health-related Quality of life measured by the EORTC QoL questionnaires HCC18

Time Frame

Until 60 months after start of radiotherapy

Title

Local control

Description

1- and 3-year local control

Time Frame

3 years after start of radiotherapy

Title

Progression-free survival

Description

1- and 3-year progression-free survival

Time Frame

3 years after start of radiotherapy

Title

Overall survival

Description

1- and 3-year overall survival

Time Frame

3 years after start of radiotherapy

Title

Pattern of failure

Description

Time Frame

Until 5 years after start of radiotherapy

Title

Technical feasibility

Description

the proportion of patients where it was possible to adhere to the guidelines of CTV dose coverage and tolerable normal tissue dose

Time Frame

up to 5 years

Title

Reduction in mean liver dose

Description

calculated on a per patient basis, and median (and inter-quartile ranged) will be reported for the study population.

Time Frame

up to 5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Britta Weber, MD PhD

Phone

+4526236694

britta.weber@auh.rm.dk

First Name & Middle Initial & Last Name or Official Title & Degree

Hanna R Mortensen, MD PhD

Phone

+45 92432382

hanna.mortensen@auh.rm.dk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Britta Weber, MD PhD

Organizational Affiliation

Danish Center of Particle Therapy

Official's Role

Principal Investigator

Facility Information:

Facility Name

Herlev Hospital

City

Herlev

State/Province

Hovedstaden

ZIP/Postal Code

2730

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Mette van Overeem Felter, MD

mette.van.overeem.felter@regionh.dk

First Name & Middle Initial & Last Name & Degree

Kirsten Vistisen, MD

Kirsten.Vistisen@regionh.dk

Facility Name

Aarhus University Hospital

City

Aarhus

State/Province

Midtjylland

ZIP/Postal Code

8200

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Britta Weber, MD PhD

Phone

+45 26236694

britta.weber@auh.rm.dk

First Name & Middle Initial & Last Name & Degree

Hanna R Mortensen, Md PhD

Phone

+45 92432382

hanna.mortensen@auh.rm.dk

First Name & Middle Initial & Last Name & Degree

Hanna R Mortensen, MD

First Name & Middle Initial & Last Name & Degree

Britta Weber, MD

First Name & Middle Initial & Last Name & Degree

Morten Høyer, MD

First Name & Middle Initial & Last Name & Degree

Gerda E Villadsen, MD

First Name & Middle Initial & Last Name & Degree

Peter Jepsen, MD

First Name & Middle Initial & Last Name & Degree

Esben Worm

First Name & Middle Initial & Last Name & Degree

Elizaveta Tabeksblat, MD

Facility Name

Odense University Hospital

City

Odense

State/Province

Syd

ZIP/Postal Code

5000

Country

Denmark

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Merete Krogh

Merete.Krogh@rsyd.dk

First Name & Middle Initial & Last Name & Degree

Annette Fialla

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

A National Phase II Study of Proton Therapy in Hepatocellular Carcinoma

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