Safety, Efficacy, and Dosing of Stereotactic Radiosurgery for Hepato-cellular Carc/Colo-rectal Liver Metastases

• Sponsor: UNC Lineberger Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01528878
• Collaborator: (none)
• Enrollment: 30
• Locations: 2
• Arms: 2
• Duration (Months): 81.9
• Patients Per Site: 15
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine a tolerable dose of radiation delivered by the CyberKnife system in two groups of patients with hepatocellular carcinoma (HCC).

Condition or Disease	Intervention/Treatment	Phase
Liver Neoplasms; Colonic Neoplasms; Metastatic Cancer to Liver	Radiation: Stereotactic Radiosurgery using the CyberKnife System.	N/A

Detailed Description

The CyberKnife system has been cleared by the U.S. Food and Drug Administration (FDA) to treat lesions, tumors and conditions anywhere in the body when radiation treatment is indicated. In order to treat tumors during the respiratory cycle (vs. increasing the margin of treatment around the tumor to compensate for movement or requiring the patient to breath hold during the delivery of each beam), the Synchrony™ option, a system option that enables dynamic radiosurgery during respiration, will be used. The purpose of this study is to determine a tolerable dose of radiation delivered by the CyberKnife in two groups of patients with hepatocellular carcinoma (HCC).Group 1: Patients with HCC and Childs A cirrhosis, and patients with colorectal liver metastases. Group 2: Patients with Childs B cirrhosis. Patients will be irradiated with radiation doses using the CyberKnife system in 3-5 radiation fractions using guidance from fiducials placed by interventional radiology. Treatments will be delivered with standard CyberKnife procedures to account for respiratory motion and set up variations. The fiducial location will be the prime determinant of the delivery site and respiratory motion and fiducial markers will be placed via percutaneous approach by interventional radiology.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Dose-finding, Safety and Preliminary Efficacy Study of Stereotactic Radiosurgery for Hepato-cellular Carcinoma and Metastatic Disease to the Liver.
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Aug 18, 2014
• Actual Study Completion Date: Jan 28, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Good liver function. Patients with good liver function as defined by no more than Child-Pugh Class A.	Radiation: Stereotactic Radiosurgery using the CyberKnife System.; Radiation: Stereotactic Radiosurgery using the CyberKnife System. The CyberKnife system has been cleared by the U.S. Food and Drug Administration (FDA) to treat lesions, tumors and conditions, anywhere in the body when radiation treatment is indicated. To address movement of target lesion during the respiratory cycle, the Synchrony™ option will be used. The Synchrony option precisely tracks tumors in or near the target organ as they move, enabling the highly focused beams of radiation to destroy the tumors with minimal injury to adjacent normal tissue. The Synchrony option records the breathing movements of a patient's chest and combines that information with sequential x-ray pictures of tiny markers inserted inside or in the proximity of the tumor to enable precise delivery of radiation during any point in the respiration cycle. The CyberKnife system with the Synchrony option enables reduced normal tissue exposure by using smaller treatment margins and increased accuracy.; Other Names: Radiotherapy CyberKnife Stereotactic Radiosurgery
Experimental: Compromised liver function. Patients with compromised liver function as defined by patients with Child-Pugh Class B.	Radiation: Stereotactic Radiosurgery using the CyberKnife System.; Radiation: Stereotactic Radiosurgery using the CyberKnife System. The CyberKnife system has been cleared by the U.S. Food and Drug Administration (FDA) to treat lesions, tumors and conditions, anywhere in the body when radiation treatment is indicated. To address movement of target lesion during the respiratory cycle, the Synchrony™ option will be used. The Synchrony option precisely tracks tumors in or near the target organ as they move, enabling the highly focused beams of radiation to destroy the tumors with minimal injury to adjacent normal tissue. The Synchrony option records the breathing movements of a patient's chest and combines that information with sequential x-ray pictures of tiny markers inserted inside or in the proximity of the tumor to enable precise delivery of radiation during any point in the respiration cycle. The CyberKnife system with the Synchrony option enables reduced normal tissue exposure by using smaller treatment margins and increased accuracy.; Other Names: Radiotherapy CyberKnife Stereotactic Radiosurgery

Outcome Measures

Primary Outcome Measures

1. Tolerability of Stereotactic Body Radiotherapy (SBRT) Based on Number of Cumulative Acute Toxicities Occurring Within 90 Days of Treatment and Related to SBRT. [90 days]

   To determine a tolerable dose, cumulative acute toxicity was collected (defined as toxicity occurring within 90 days of treatment initiation). Adverse events were graded by the Common Terminology Criteria for Adverse Events version 3.0. Tolerability was based on hepatic toxicity. A grading (severity) scale is provided for each adverse event (AE) term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

Secondary Outcome Measures

1. Local Tumor Control to Doses of Radiation in Patients With Liver Cancer or Metastases to the Liver [12.7 months]

   1 year local control defined as percentage of patients with freedom from local progression at a median follow-up time of 12.7 months. Progressive disease is defined as increase by >= 50% of product of the two perpendicular diameters of an irradiated lesion.

2. Percentage of Local Response to Doses of Radiation in Patients With Liver Cancer or Metastases to the Liver [6 months]

   Complete response (CR) is defined as disappearance of the target lesion, partial response (PR) as regression of measureable disease, progressive disease (PD) as increase by >= 50% in product of the two perpendicular diameters of an irradiated lesion, and stable disease (SD) as all others not meeting criteria for CR, PR, or PD.

3. Overall Survival of Patients With Liver Cancer or Metastases to the Liver [1 year]

   Overall survival is defined as percentage of patients remaining alive from start of study treatment to 1 year.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Hepatocellular carcinoma (as defined by biopsy or alpha-fetoprotein (AFP) greater than 1000ng/dL with appropriate imaging) or liver metastases from colorectal cancer or other tumor (as defined by biopsy or elevated Carcinoembryonic antigen (CEA) or a positive positron emission tomography (PET) scan in conjunction with a mass on CT or MRI in a patient with previously resected cancer). Patients with at least one measurable liver lesion and no more than 3 are eligible if they meet all other eligibility criteria including the dose constraints on the composite plan.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

3. Patients are not candidates for definitive surgical resection because of tumor location, hepatic function, or other medical or personal reasons.

4. Patients with HCC who are being considered for liver transplant may be entered as a bridge to transplant if it is considered by the transplant team that an ablative therapy would be of value while awaiting transplant.

5. If cirrhosis is present, patients will have Child-Pugh score of A or B (see Appendix A in the Master Protocol).

6. Patients will have tumors not optimally treated with radio-frequency ablation by interventional radiology, or by GI/transplant surgery. This could be for reasons of size, tumor location, or other reasons.

7. Ability to place fiducial markers in the vicinity of the tumor to allow for radiographic tracking of respiratory motion and tumor localization. Fiducial placement will generally be done by interventional radiology.

8. Estimates of hepatic tolerance must meet the criteria as defined in Section III. This eligibility will not be able to made definitively until the patient has agreed to participate. in the study and the appropriate scan analyses and dosimetry have been performed. No more than one decrement in dose from the planned dose level will be allowed for an individual patient because of exceeding the maximal liver doses before the patient is declared ineligible for study.

9. Adequate bone marrow and renal function as assessed by the following:

• Absolute neutrophil count (ANC) > 1000/mm3

• Platelet count > 80,000/mm3

• Creatinine < 2.0 mg/dL OR Creatinine clearance > 45 mL/min based on Cockcroft-Gault formula).

1. Patients with extra hepatic metastatic disease are eligible if it is the opinion of the treating physician that local therapy to the liver may produce worthwhile clinical benefits

2. Patient is able to understand fully the potential risks and benefits of this approach and signs an appropriate informed consent.

3. Male and female of >18 years of age. Male or female patients capable of reproduction must agree to use medically acceptable methods of contraception, such as an intrauterine device, diaphragm, with spermicide, condom with spermicide or abstinence. Inclusion of females of childbearing potential requires a negative pregnancy test within 14 days prior to study initiation.

Exclusion Criteria:

1. Child-Pugh Class C cirrhosis

2. Patients with clinically apparent central nervous system (CNS) disease.

3. Medical or psychiatric illness that would not allow the patient to tolerate the proposed treatment including inability to lie flat for an extended period of time, severe claustrophobia or other reasons.

4. Uncontrolled or significant cardiovascular disease including: myocardial infarction within 6 months, uncontrolled angina within 6 months, Class III-IV New York Heart Association (NYHA) congestive heart failure, grade 3 cardiac valve dysfunction

5. Evidence of decompensated liver disease as evidenced by: clinically significant ascites refractory to diuretic therapy) evidence of hepatic encephalopathy, coagulopathy not corrected by conservative measures.

6. A history of CTCAE Grade 3 bleeding esophageal or gastric varices within the past 2 months. Prior variceal bleed permitted if patient has undergone banding or sclerotherapy and there has been no evidence of bleeding for 2 months. Patients at risk for varices (based on the following: known history of esophageal or gastric varices; evidence of hepatic cirrhosis and/or portal hypertension including biopsy-proven cirrhosis, hypersplenism, or radiographic findings of varices) will be screened for esophageal varices. If varices are identified that require intervention (banding), patient will not be eligible until varices adequately treated.

7. Prisoners or patients who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.

8. Uncontrolled intercurrent illness.

9. Inability to comply with study and/or follow-up procedures.

10. A patient with Child-Pugh Class A will not be eligible for study if the liver dose constraint described in Section 3.2 cannot be met after two decrements in dose per fraction as described above.

11. A patient with Child-Pugh Class B will not be eligible for study if the liver dose constraint described in Section 3.2 cannot be met after two decrements in dose per fraction as described above.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
2	East Carolina Medical School	Greenville	North Carolina	United States	27858

Sponsors and Collaborators

• UNC Lineberger Comprehensive Cancer Center

Investigators

• Principal Investigator: Joel Tepper, MD, University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 6, 2011

More Information

Additional Information:

• Website for University of North Carolina Lineberger Comprehensive Cancer Center

Publications

None provided.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01528878
• Other Study ID Numbers: LCCC 0809
• First Posted: Feb 8, 2012
• Last Update Posted: Jul 26, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by UNC Lineberger Comprehensive Cancer Center: Liver Cancer; Hepatocellular Carcinoma; HCC; Metastatic Cancer to Liver; Metastatic Colon Cancer; Metastatic Colo-rectal Cancer; mCRC; Liver Function; Child-Pugh
• Additional relevant MeSH terms: Neoplasms; Neoplasm Metastasis; Liver Neoplasms; Colonic Neoplasms

Study Results

Participant Flow

Recruitment Details	Patients were enrolled from June, 2009 to March, 2014 at two institutions.
Pre-assignment Detail	39 participants were consented and 9 were found ineligible and were not treated.

Arm/Group Title	Single Arm Patients With HCC or Liver Metastases
Arm/Group Description	Patients with hepatocellular carcinoma (HCC) who are not appropriate for surgical resection or radiofrequency ablation (RFA) as a bridge to transplant. The original cohort was not analyzed between good vs compromised liver function because there were only 2 patients with Child-Pugh Class B and secondary outcomes measured are thought to be more influenced by disease rather than liver function (which may be more relevant for toxicity).
Period Title: Overall Study
STARTED	30
COMPLETED	30
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Single Arm Patients With HCC or Liver Metastases
Arm/Group Description	Patients with hepatocellular carcinoma (HCC) who are not appropriate for surgical resection or radiofrequency ablation (RFA) as a bridge to transplant. The original cohort was not analyzed between good vs compromised liver function because there were only 2 patients with Child-Pugh Class B and secondary outcomes measured are thought to be more influenced by disease rather than liver function (which may be more relevant for toxicity).
Overall Participants	30
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65.5
Sex: Female, Male (Count of Participants)
Female	11 36.7%
Male	19 63.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 3.3%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	9 30%
White	18 60%
More than one race	0 0%
Unknown or Not Reported	2 6.7%
Region of Enrollment (Count of Participants)
United States	30 100%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0	17 56.7%
1	13 43.3%
Child Pugh Score (Count of Participants)
5 (Class A)	22 73.3%
6 (Class A)	6 20%
>=7 (Class B)	2 6.7%
Primary Disease (Count of Participants)
Hepatocellular carcinoma	11 36.7%
Metastatic cancer	19 63.3%
Prior liver-directed therapies (Count of Participants)
Any local therapy	14 46.7%
Liver resection	9 30%
Trans-arterial chemoembolization (TACE)	7 23.3%
Radiofrequency ablation (RFA)	6 20%
> 1 prior local therapy	9 30%
Resection + RFA	3 10%
Resection + TACE	2 6.7%
Resection x2 + RFA	1 3.3%
TACE + RFA x3	1 3.3%
TACE x 2 + RFA	1 3.3%
TACE x 2	1 3.3%
Prior systemic therapy (Count of Participants)
Count of Participants [Participants]	16 53.3%
Number of lesions treated (Count of Participants)
1	26 86.7%
2	3 10%
3	1 3.3%
Lesion size (cm) (Count of Participants)
<2	1 3.3%
2-2.9	10 33.3%
3-3.9	9 30%
4-4.9	2 6.7%
5-5.9	5 16.7%
>6	3 10%
Lesion size (cm) median (range) (cm) [Median (Full Range) ]
Median (Full Range) [cm]	3.5
Gross tumor volume (cc) median (range) (cc) [Median (Full Range) ]
Median (Full Range) [cc]	22.5
Planning target volume (cc) median (range) (cc) [Median (Full Range) ]
Median (Full Range) [cc]	65.5
Fractionation (Count of Participants)
5.5 Gy x 5 = 27.5 Gy	1 3.3%
7 Gy x 5 = 35 Gy	2 6.7%
10 Gy x 3 = 30 Gy	1 3.3%
12.5 Gy x 3 = 37.5 Gy	4 13.3%
13.33 Gy x 3 = 40 Gy	1 3.3%
15 Gy x 3 = 45 Gy	21 70%
Dose of Radiation Therapy (Gy) (Gray (Gy)) [Median (Full Range) ]
Median (Full Range) [Gray (Gy)]	45
Mean liver dose (Gy) ) (Gy) [Median (Full Range) ]
Median (Full Range) [Gy]	10.3
Volume of liver receiving <15 Gy (cc) (cc) [Median (Full Range) ]
Median (Full Range) [cc]	1239

Outcome Measures

1. Primary Outcome

Title	Tolerability of Stereotactic Body Radiotherapy (SBRT) Based on Number of Cumulative Acute Toxicities Occurring Within 90 Days of Treatment and Related to SBRT.
Description	To determine a tolerable dose, cumulative acute toxicity was collected (defined as toxicity occurring within 90 days of treatment initiation). Adverse events were graded by the Common Terminology Criteria for Adverse Events version 3.0. Tolerability was based on hepatic toxicity. A grading (severity) scale is provided for each adverse event (AE) term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Grade 2 Adverse Events	Grade 3 Adverse Events
Arm/Group Description	Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL)	Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL.
Measure Participants	30	30
Elevated Aspartate Aminotransferase	5 16.7%	1 NaN
Elevated Bilirubin	4 13.3%	0 NaN
Low Hemoglobin	4 13.3%	0 NaN
Fatigue	4 13.3%	0 NaN
Increased Alanine Aminotransferase	3 10%	0 NaN
Decreased Leukocyte	2 6.7%	1 NaN
Nausea	2 6.7%	0 NaN
Abdominal pain	2 6.7%	0 NaN
Increased alkaline phosphatase	2 6.7%	0 NaN
international normalized ratio increased	2 6.7%	0 NaN
Decreased Platelets	2 6.7%	0 NaN
Dyspnea	1 3.3%	0 NaN
Acute total	14 46.7%	2 NaN

2. Secondary Outcome

Title	Local Tumor Control to Doses of Radiation in Patients With Liver Cancer or Metastases to the Liver
Description	1 year local control defined as percentage of patients with freedom from local progression at a median follow-up time of 12.7 months. Progressive disease is defined as increase by >= 50% of product of the two perpendicular diameters of an irradiated lesion.
Time Frame	12.7 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm Patients With HCC or Liver Metastases
Arm/Group Description	Patients with hepatocellular carcinoma (HCC) who are not appropriate for surgical resection or radiofrequency ablation (RFA) as a bridge to transplant. The original cohort was not analyzed between good vs compromised liver function because there were only 2 patients with Child-Pugh Class B and secondary outcomes measured are thought to be more influenced by disease rather than liver function (which may be more relevant for toxicity).
Measure Participants	30
Number [percentage of participants]	81 270%

3. Secondary Outcome

Title	Percentage of Local Response to Doses of Radiation in Patients With Liver Cancer or Metastases to the Liver
Description	Complete response (CR) is defined as disappearance of the target lesion, partial response (PR) as regression of measureable disease, progressive disease (PD) as increase by >= 50% in product of the two perpendicular diameters of an irradiated lesion, and stable disease (SD) as all others not meeting criteria for CR, PR, or PD.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm Patients With HCC or Liver Metastases
Arm/Group Description	Patients with hepatocellular carcinoma (HCC) who are not appropriate for surgical resection or radiofrequency ablation (RFA) as a bridge to transplant. The original cohort was not analyzed between good vs compromised liver function because there were only 2 patients with Child-Pugh Class B and secondary outcomes measured are thought to be more influenced by disease rather than liver function (which may be more relevant for toxicity).
Measure Participants	30
Complete Response	7 23.3%
Partial Response	13 43.3%
Stable Disease	80 266.7%

4. Secondary Outcome

Title	Overall Survival of Patients With Liver Cancer or Metastases to the Liver
Description	Overall survival is defined as percentage of patients remaining alive from start of study treatment to 1 year.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm Patients With HCC or Liver Metastases
Arm/Group Description	Patients with hepatocellular carcinoma (HCC) who are not appropriate for surgical resection or radiofrequency ablation (RFA) as a bridge to transplant. The original cohort was not analyzed between good vs compromised liver function because there were only 2 patients with Child-Pugh Class B and secondary outcomes measured are thought to be more influenced by disease rather than liver function (which may be more relevant for toxicity).
Measure Participants	30
Number [percentage of participants]	62 206.7%

Adverse Events

Time Frame	44 weeks
Arm/Group Title	Single Arm Patients With HCC or Liver Metastases
Arm/Group Description	Patients with hepatocellular carcinoma (HCC) who are not appropriate for surgical resection or radiofrequency ablation (RFA) as a bridge to transplant. The original cohort was not analyzed between good vs compromised liver function because there were only 2 patients with Child-Pugh Class B and secondary outcomes measured are thought to be more influenced by disease rather than liver function (which may be more relevant for toxicity).
All Cause Mortality
	Single Arm Patients With HCC or Liver Metastases
	Affected / at Risk (%)	# Events
Total	15/30 (50%)
Serious Adverse Events
	Single Arm Patients With HCC or Liver Metastases
	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)
Musculoskeletal and connective tissue disorders
Pain- chest wall	1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	Single Arm Patients With HCC or Liver Metastases
	Affected / at Risk (%)	# Events
Total	27/30 (90%)
Blood and lymphatic system disorders
Hemoglobin	7/30 (23.3%)
Gastrointestinal disorders
Constipation	3/30 (10%)
Diarrhea	3/30 (10%)
Nausea	5/30 (16.7%)
Pain - Abdomen NOS	7/30 (23.3%)
General disorders
Edema: limb	2/30 (6.7%)
Fatigue (asthenia, lethargy, malaise)	16/30 (53.3%)
Investigations
Alkaline phosphatase	13/30 (43.3%)
ALT, SGPT (serum glutamic pyruvic transaminase)	9/30 (30%)
AST, SGOT(serum glutamic oxaloacetic transaminase)	14/30 (46.7%)
Bilirubin (hyperbilirubinemia)	7/30 (23.3%)
GGT (gamma-Glutamyl transpeptidase)	2/30 (6.7%)
INR (International Normalized Ratio of prothrombin time)	3/30 (10%)
Leukocytes (total WBC)	7/30 (23.3%)
Lymphopenia	14/30 (46.7%)
Neutrophils/granulocytes (ANC/AGC)	4/30 (13.3%)
Platelets	11/30 (36.7%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	7/30 (23.3%)
Glucose, serum-high (hyperglycemia)	4/30 (13.3%)
Sodium, serum-low (hyponatremia)	2/30 (6.7%)
Musculoskeletal and connective tissue disorders
Pain - Back	4/30 (13.3%)
Pain - Chest wall	3/30 (10%)
Pain - Extremity-limb	2/30 (6.7%)
Nervous system disorders
Dizziness	3/30 (10%)
Psychiatric disorders
Confusion	2/30 (6.7%)
Mood alteration - Anxiety	2/30 (6.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	2/30 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.