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

Liver Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02363218
• Other study ID #: Ping Wang
• Status: Recruiting
• Phase: Phase 2
• First received: February 9, 2015
• Last updated: October 5, 2016
• Start date: May 2014
• Est. completion date: December 2017

Study information

• Verified date: February 2015
• Source: Tianjin Medical University Cancer Institute and Hospital
• Contact: YONGCHUN SONG, MD
• Phone: 8613512208919
• Email: sych1977[@]qq.com
• Is FDA regulated: No
• Health authority: China: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 117
• Est. completion date: December 2017
• Est. primary completion date: May 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Hepatocellular
• Liver Neoplasms

Intervention

Radiation:
• CyberKnife
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.

Locations

Country	Name	City	State
China	Tianjin Medical University Cancer Institute & Hospital	Tianjin	Tianjin

Sponsors (1)

Lead Sponsor	Collaborator
Tianjin Medical University Cancer Institute and Hospital

Country where clinical trial is conducted

China, 

References & Publications (16)

Blomgren H, Lax I, Näslund I, Svanström R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol. 1995;34(6):861-70. — View Citation

Bruix J, Hessheimer AJ, Forner A, Boix L, Vilana R, Llovet JM. New aspects of diagnosis and therapy of hepatocellular carcinoma. Oncogene. 2006 Jun 26;25(27):3848-56. Review. — View Citation

Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005 Nov;42(5):1208-36. — View Citation

Cárdenes HR, Price TR, Perkins SM, Maluccio M, Kwo P, Breen TE, Henderson MA, Schefter TE, Tudor K, Deluca J, Johnstone PA. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol. 2010 Mar;12(3):218-25. doi: 10.1007/s12094-010-0492-x. — View Citation

Fuss M, Salter BJ, Herman TS, Thomas CR Jr. External beam radiation therapy for hepatocellular carcinoma: potential of intensity-modulated and image-guided radiation therapy. Gastroenterology. 2004 Nov;127(5 Suppl 1):S206-17. Review. — View Citation

Herfarth KK, Debus J, Lohr F, Bahner ML, Rhein B, Fritz P, Höss A, Schlegel W, Wannenmacher MF. Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol. 2001 Jan 1;19(1):164-70. — View Citation

Herfarth KK, Hof H, Bahner ML, Lohr F, Höss A, van Kaick G, Wannenmacher M, Debus J. Assessment of focal liver reaction by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors. Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):444-51. — View Citation

Katz AW, Carey-Sampson M, Muhs AG, Milano MT, Schell MC, Okunieff P. Hypofractionated stereotactic body radiation therapy (SBRT) for limited hepatic metastases. Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):793-8. Epub 2006 Dec 29. — View Citation

Kavanagh BD, Scheftera TE, Wersäll PJ. Liver, renal, and retroperitoneal tumors: stereotactic radiotherapy. Front Radiat Ther Oncol. 2007;40:415-26. Review. — View Citation

Lax I, Blomgren H, Näslund I, Svanström R. Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects. Acta Oncol. 1994;33(6):677-83. — View Citation

Méndez Romero A, Wunderink W, Hussain SM, De Pooter JA, Heijmen BJ, Nowak PC, Nuyttens JJ, Brandwijk RP, Verhoef C, Ijzermans JN, Levendag PC. Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study. Acta Oncol. 2006;45(7):831-7. — View Citation

Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001 Oct 15;94(2):153-6. — View Citation

Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE. A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1371-8. — View Citation

Takeda A, Takahashi M, Kunieda E, Takeda T, Sanuki N, Koike Y, Atsukawa K, Ohashi T, Saito H, Shigematsu N, Kubo A. Hypofractionated stereotactic radiotherapy with and without transarterial chemoembolization for small hepatocellular carcinoma not eligible for other ablation therapies: Preliminary results for efficacy and toxicity. Hepatol Res. 2008 Jan;38(1):60-9. Epub 2007 May 15. — View Citation

Tse RV, Hawkins M, Lockwood G, Kim JJ, Cummings B, Knox J, Sherman M, Dawson LA. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2008 Feb 1;26(4):657-64. doi: 10.1200/JCO.2007.14.3529. Epub 2008 Jan 2. Erratum in: J Clin Oncol. 2008 Aug 10;26(23):3911-2. — View Citation

Wada H, Takai Y, Nemoto K, Yamada S. Univariate analysis of factors correlated with tumor control probability of three-dimensional conformal hypofractionated high-dose radiotherapy for small pulmonary or hepatic tumors. Int J Radiat Oncol Biol Phys. 2004 Mar 15;58(4):1114-20. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival rate		Two years	Yes
Secondary	Overall survival rate		One year	Yes
Secondary	Local Control rate		Two years	Yes
Secondary	Progression-free survival		One-Two Years	Yes