Study on Effectiveness and Safety of Hepatocellular Carcinoma Patients Treated With CyberKnife

An Open-Label, Multi-Center, Single-Arm Study on Effectiveness and Safety of Stereotactic Body Radiotherapy (SBRT) Treating Hepatocellular Carcinoma Patients With CyberKnife

Study Phase: multi-institutional Phase II study Primary Objective(s): To determine overall survival for HCC patients treated with CyberKnife SBRT at 2 years.

Secondary Objective(s): 1) To determine overall survival for HCC patients treated with CyberKnife SBRT at 1 year 2) To determine local control using RECIST and EASL criteria at 1 and 2 years 3) To assess progression-free survival at 1 and 2 years 4) To assess acute and late toxicities following CyberKnife SBRT.

Hypothesis: Overall survival rate of HCC patients at one year after SBRT treatment is not less than 65%.

Study Design: Single arm study. Patients will undergo a CT scan with and without contrast and MRI scan for radiation treatment planning and target delineation.SBRT will be delivered on the CyberKnife with Synchrony Respiratory Tracking capabilities. The tumor will be tracked with 3 implanted fiducial seeds for targeting. Treatment will be delivered in 3 fractions within a 7 day window at the discretion of the investigator.

Sample size: The sample size required is 93 with a power of 90%, p=0.05, 50% response rate is considered not effective (p0) and 65% overall survival rate at 1 year (p1) is considered effectiveness of the treatment. The estimated drop-out rate is 20%, so the total sample size would be 117.

Statistical Considerations: The set of Intention-To-Treat (ITT) will be analyzed. All patients will be censored at their last visit, including the patients lost to follow-up. All patients will be followed and counted in the therapy to which they were assigned, even if they decline that therapy. Only those patients who refuse (in writing) to have their outcomes count in the study's conclusions will not be included in the analyses from that time forward; however, the follow-up data for such patients will be included up until the time they withdraw consent. Such patients will be replaced.

Baseline characteristics of patients will be presented with summary statistics. Time-to-event survival rates for OS and DFS will be estimated using the Kaplan-Meier method and presented at one and/or two years. The incidence of acute and late toxicities will be presented in tabular form on both a per-patient and per-event basis.

Indication: Hepatocellular carcinoma (HCC) is the third most deadly cancer in the world. It is primarily seen in areas where hepatitis is endemic, such as Asia, but other risk factors include alcoholic cirrhosis.

Surgical resection and/or transplantation remain the only curative options. However, more than 80% of patients present with unresectable disease. For these patients with unresectable tumors, a variety of treatment options are available, including transarterial chemoembolization (TACE), radiofrequency ablation (RFA), radioactive microspheres, microwave coagulation, laser-induced thermotherapy, and percutaneous alcohol injection, all of which have similar survival rates. Stereotactic body radiotherapy (SBRT) for unresectable HCC is a relatively new treatment option made available because of significant improvements in diagnostic imaging and radiation delivery techniques. Although follow-up is limited, results show encouraging local control rates.

The investigators propose to conduct a Phase II study assessing the efficacy and safety of CyberKnife SBRT for the treatment of HCC.

Summary of Subject Eligibility Criteria:

Inclusion Criteria

1. Confirmed hepatocellular carcinoma according to one of three EASL criteria:

   • Histopathology
   • Two radiographic techniques (out of US, MRI, CT, Angiography) that confirm a lesion >2 cm with arterial hypervascularization
   • One radiographic technique that confirms a lesion >2 cm with arterial hypervascularization and an AFP>400 ng/mL

2. Unifocal liver tumors not to exceed 5 cm in greatest axial dimension. Multifocal lesions will be restricted to a maximum of 3 lesions with a maximum lesion size of 3 cm for each lesion, that can be treated within a single target volume within the same liver segment as long as the dose constraints to normal tissue can be met.

3. Volumn of uninvolved liver >750 cc

4. Hepatic lesion in patients for whom surgical resection is not possible or patients who refuse surgery.

5. Eastern Clinical Oncology Group (ECOG) performance status 0, 1 or 2 (Appendix I)

6. Patients with liver disease classified as Child Pugh class A

7. Life expectancy >6 months

8. Age > 18 years old

9. Albumin > 2.5 g/dL

10. Total Bilirubin < 3 mg/dL

11. INR <1.5

12. Transaminases (SGOT and SGPT) no more than 3 times the upper limit of normal

13. Creatinine < 2.0 mg/dL

14. Both men and women and members of all races and ethnic groups are eligible for this study

15. Ability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document Exclusion Criteria

1. Prior surgery, chemotherapy or radiation for the liver tumor 2. Prior radiotherapy to the upper abdomen 3. Prior RFA or liver transplant 4. Tumors greater than 5 cm in greatest axial dimension 5. Child B status 6. Contraindication to receiving radiotherapy 7. Active gastrointestinal bleed within 2 weeks of study enrollment 8. Clinically significant ascites refractory to medical therapy 9. Women who are pregnant 10. Administration of any systemic chemotherapy within the last 6 months 11. Presence of multifocal lesions located in different lobes of the liver or extrahepatic metastases 12. Portal vein thrombus 13. Participation in another concurrent treatment protocol Intervention and Mode of Delivery: CyberKnife SBRT - External photon radiation. Procedure is outpatient. Synchrony Respiratory Tracking System Duration of Intervention and Evaluation: The duration of treatment will be 1 week.. The follow-up period will be for 3 years following completion of therapy.

Inclusion Criteria:

1. Confirmed hepatocellular carcinoma according to one of three EASL criteria:

   • Histopathology
   • Two radiographic techniques (out of US, MRI, CT, Angiography) that confirm a lesion >2 cm with arterial hypervascularization
   • One radiographic technique that confirms a lesion >2 cm with arterial hypervascularization and an AFP>400 ng/mL

2. Unifocal liver tumors not to exceed 5 cm in greatest axial dimension. Multifocal lesions will be restricted to a maximum of 3 lesions with a maximum lesion size of 3 cm for each lesion, that can be treated within a single target volume within the same liver segment as long as the dose constraints to normal tissue can be met.

3. Volumn of uninvolved liver >750 cc

4. Hepatic lesion in patients for whom surgical resection is not possible or patients who refuse surgery.

5. Eastern Clinical Oncology Group (ECOG) performance status 0, 1 or 2 (Appendix I)

6. Patients with liver disease classified as Child Pugh class A

7. Life expectancy >6 months

8. Age > 18 years old

9. Albumin > 2.5 g/dL

10. Total Bilirubin < 3 mg/dL

11. INR <1.5

12. Transaminases (SGOT and SGPT) no more than 3 times the upper limit of normal

13. Creatinine < 2.0 mg/dL

14. Both men and women and members of all races and ethnic groups are eligible for this study

15. Ability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

1. Prior surgery, chemotherapy or radiation for the liver tumor
2. Prior radiotherapy to the upper abdomen
3. Prior RFA or liver transplant
4. Tumors greater than 5 cm in greatest axial dimension
5. Child B status
6. Contraindication to receiving radiotherapy
7. Active gastrointestinal bleed within 2 weeks of study enrollment
8. Clinically significant ascites refractory to medical therapy
9. Women who are pregnant
10. Administration of any systemic chemotherapy within the last 6 months
11. Presence of multifocal lesions located in different lobes of the liver or extrahepatic metastases
12. Portal vein thrombus
13. Participation in another concurrent treatment protocol