Proton Beam Irradiation for the Treatment of Unresectable Hepatocellular Cancer and Cholangiocarcinoma

• ClinicalTrials.gov Identifier: NCT00976898
• Recruitment Status: Completed
• First Posted: September 15, 2009
• Results First Posted: January 31, 2018
• Last Update Posted: August 15, 2018
• Sponsor: Massachusetts General Hospital
• Collaborators: Dana-Farber Cancer Institute; Brigham and Women's Hospital; National Cancer Institute (NCI); M.D. Anderson Cancer Center; University of Pennsylvania
• Information provided by (Responsible Party): Theodore Sunki Hong, Massachusetts General Hospital

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Liver Cancer
• Intervention: Radiation: Proton Beam Irradiation
• Enrollment: 83

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Proton Beam Irradiation
Arm/Group Description	This is a single arm study. All study participants will receive proton radiation therapy. Proton Beam Irradiation: Given once a day, 5 days a week, for 3 weeks
Period Title: Overall Study
Started	83
Completed	78
Not Completed	5
Reason Not Completed
Protocol Violation	1
Adverse Event	1
Physician Decision	1
Liver Transplant	1
Progressive Disease	1

Baseline Characteristics

Arm/Group Title		Proton Beam Irradiation
Arm/Group Description		This is a single arm study. All study participants will receive proton radiation therapy. Proton Beam Irradiation: Given once a day, 5 days a week, for 3 weeks
Overall Number of Baseline Participants		83
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	83 participants
		67.6; (29.9 to 89.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	83 participants
	Female	32 38.6%
	Male	51 61.4%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	83 participants
White		76 91.6%
Black		4 4.8%
Asian		1 1.2%
Hispanic (white or black)		1 1.2%
Unknown		1 1.2%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	83 participants
		83
Underlying Liver Disease; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	83 participants
Hepatitis C Virus (HCV) (± Others)		28 33.7%
No HCV but Hepatitis B Virus (HBV) (± Others)		6 7.2%
No HCV/HBV but Ethyl Hepatocellularalcohol (EtOH)		8 9.6%
No HCV/HBV/EtOH but nonalcoholic steatohepatitis		3 3.6%
Other		2 2.4%
None		36 43.4%
ECOG Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	83 participants
0		28 33.7%
1		52 62.7%
2		3 3.6%
		[1] Measure Description: Eastern Cooperative Oncology Group (ECOG) score: 0 - Asymptomatic (Fully active, able to carry on all predisease activities without restriction); 1 - Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work); 2 - Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours)
Child-Turcotte-Pugh Class [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	83 participants
A		66 79.5%
B		15 18.1%
C		0 0.0%
No Cirrhosis		4 4.8%
		[1] Measure Description: Child-Turcotte-Pugh Class is used to evaluate the prognosis of chronic liver disease (primarily cirrhosis). Classes are determined using 5 clinical measures of liver disease with 1 to 3 points given for each measure, with more points given for less favorable clinical criteria. The 5 measures are total bilirubin, serum albumin, prothrombin time/international normalized ratio (INR), Ascites, and hepatic encephalopathy grade. The classes are A (5-6 points), B (7-9 points), and C (10-15 points) with 'A' having the best survival outcomes and C having the worst.
Disease Status; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	83 participants
Locally Recurrent		5 6.0%
Newly Diagnosed		78 94.0%
Number of Nodular Tumors; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	83 participants
1		66 79.5%
2		15 18.1%
3		4 4.8%
Previous Therapy; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	83 participants
Any surgical resection		4 4.8%
Any transarterial chemoembolization		5 6.0%
Any radiofrequency ablation		2 2.4%
Any chemotherapy		27 32.5%
Any other		15 18.1%
None		45 54.2%

Outcome Measures

1. Primary Outcome

Title	2 Year Local Control Rate
Description	The percentage of participants with local control after two years as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. The duration of control was measured from the start of treatment. Local control is the absence of local failure. Local Failure is defined as evidence of tumor growth/regrowth in any direction beyond that present of the pre-treatment imaging studies in the treated lesion(s).
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Proton Beam Irradiation
Arm/Group Description:	This is a single arm study. All study participants will receive proton radiation therapy. Proton Beam Irradiation: Given once a day, 5 days a week, for 3 weeks
Overall Number of Participants Analyzed	83
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	94.4; (87.2 to 98.2)

2. Primary Outcome

Title	Median Overall Survival
Description	The median survival time in months as measured from the start of treatment until death due to any cause or until the participants is censored. Participants are censored at the date of their last follow-up.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Proton Beam Irradiation
Arm/Group Description:	This is a single arm study. All study participants will receive proton radiation therapy. Proton Beam Irradiation: Given once a day, 5 days a week, for 3 weeks
Overall Number of Participants Analyzed	83
Median (95% Confidence Interval); Unit of Measure: Months
	49.9 [1]; (17.8 to NA)

[1]

Upper bound not reached because of living subjects

3. Secondary Outcome

Title	Number of Participants With Treatment Related Adverse Events ≥ Grade 3
Description	Summary of the proton radiation related grade 3 or greater adverse events that participants experienced. Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE v3).
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Proton Beam Irradiation
Arm/Group Description:	This is a single arm study. All study participants will receive proton radiation therapy. Proton Beam Irradiation: Given once a day, 5 days a week, for 3 weeks
Overall Number of Participants Analyzed	83
Measure Type: Count of Participants; Unit of Measure: Participants
Liver Failure	1 1.2%
Platelets	1 1.2%
Ascites (nonmalignant)	1 1.2%
Ulcer, GI - stomach	1 1.2%
Bilirubin (hyperbilirubinemia)	1 1.2%

4. Secondary Outcome

Title	Patterns of Failure
Description	A summary of the patterns of treatment failure, shown as the number of participants that fall into each category at the end of study follow-up
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Proton Beam Irradiation
Arm/Group Description:	This is a single arm study. All study participants will receive proton radiation therapy. Proton Beam Irradiation: Given once a day, 5 days a week, for 3 weeks
Overall Number of Participants Analyzed	83
Measure Type: Count of Participants; Unit of Measure: Participants
Alive, no progression	26 31.3%
Distant metastases	38 45.8%
Local failure and distant metastases	3 3.6%
Isolated local failure	5 6.0%
Dead of disease, no progression	2 2.4%
Dead of other causes, no progression	9 10.8%

Adverse Events

Time Frame	Adverse event information was collected from the start of treatment until 30 days after the last study visit. Radiation was delivered in 15 fractions Monday through Friday over a period of three weeks. Follow-up visits occurred at 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months post treatment. Median follow-up was 19.5 months.
Adverse Event Reporting Description	Adverse events were assessed with the use of regularly scheduled visits which involved physical exams, CT and/or MRI scans, laboratory tests, and patient self reporting. If an adverse event did not match any of the existing CTCAE 3 terms, it was noted as being 'other'. Adverse events noted as being 'other' were only grouped together by organ system due to incomplete data about what specific adverse event was being recorded as 'other'.
Arm/Group Title	Proton Beam Irradiation
Arm/Group Description	This is a single arm study. All study participants will receive proton radiation therapy. Proton Beam Irradiation: Given once a day, 5 days a week, for 3 weeks
All-Cause Mortality
	Proton Beam Irradiation
	Affected / at Risk (%)
Total	11/83 (13.25%)
Serious Adverse Events
	Proton Beam Irradiation
	Affected / at Risk (%)	# Events
Total	8/83 (9.64%)
Gastrointestinal disorders
Ascites (non-malignant) † 1	1/83 (1.20%)	1
General disorders
Fatigue (asthenia, lethargy, malaise) † 1	1/83 (1.20%)	1
Infections and infestations
Infection with unknown ANC - Abdomen NOS † 1	1/83 (1.20%)	1
Injury, poisoning and procedural complications
Fracture † 1	2/83 (2.41%)	2
Investigations
Bilirubin (hyperbilirubinemia) † 1	1/83 (1.20%)	1
Platelets † 1	1/83 (1.20%)	2
Metabolism and nutrition disorders
Sodium, serum-low (hyponatremia) † 1	1/83 (1.20%)	1
Nervous system disorders
Encephalopathy † 1	1/83 (1.20%)	1
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/83 (1.20%)	1
1 Term from vocabulary, CTCAE (3.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Proton Beam Irradiation
	Affected / at Risk (%)	# Events
Total	81/83 (97.59%)
Blood and lymphatic system disorders
Blood/Bone Marrow - Other † 1	16/83 (19.28%)	47
Hemoglobin † 1	9/83 (10.84%)	25
Cardiac disorders
Cardiac General - Other † 1	5/83 (6.02%)	14
Gastrointestinal disorders
Ascites (non-malignant) † 1	20/83 (24.10%)	43
Constipation † 1	14/83 (16.87%)	33
Diarrhea † 1	18/83 (21.69%)	31
Distension/bloating, abdominal † 1	16/83 (19.28%)	29
Gastrointestinal - Other † 1	13/83 (15.66%)	29
Heartburn/dyspepsia † 1	11/83 (13.25%)	25
Nausea † 1	40/83 (48.19%)	104
Vomiting † 1	18/83 (21.69%)	22
General disorders
Edema: limb † 1	22/83 (26.51%)	60
Extremity-lower (gait/walking) † 1	5/83 (6.02%)	12
Fatigue (asthenia, lethargy, malaise) † 1	67/83 (80.72%)	316
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L) † 1	9/83 (10.84%)	25
Pain - Chest/thorax NOS † 1	6/83 (7.23%)	8
Pain - Other † 1	14/83 (16.87%)	33
Rigors/chills † 1	9/83 (10.84%)	13
Injury, poisoning and procedural complications
Bruising (in absence of Grade 3 or 4 thrombocytopenia) † 1	8/83 (9.64%)	23
Fracture † 1	7/83 (8.43%)	20
Investigations
Alkaline phosphatase † 1	13/83 (15.66%)	40
ALT, SGPT (serum glutamic pyruvic transaminase) † 1	11/83 (13.25%)	41
AST, SGOT(serum glutamic oxaloacetic transaminase) † 1	21/83 (25.30%)	75
Bilirubin (hyperbilirubinemia) † 1	18/83 (21.69%)	79
Leukocytes (total WBC) † 1	7/83 (8.43%)	21
Metabolic/Laboratory - Other † 1	5/83 (6.02%)	10
Neutrophils/granulocytes (ANC/AGC) † 1	7/83 (8.43%)	12
Platelets † 1	24/83 (28.92%)	90
Weight loss † 1	12/83 (14.46%)	40
Metabolism and nutrition disorders
Anorexia † 1	38/83 (45.78%)	92
Glucose, serum-high (hyperglycemia) † 1	9/83 (10.84%)	34
Sodium, serum-low (hyponatremia) † 1	8/83 (9.64%)	16
Musculoskeletal and connective tissue disorders
Arthritis (non-septic) † 1	5/83 (6.02%)	10
Muscle weakness, generalized or specific area (not due to neuropathy) - Whole body/generalized † 1	8/83 (9.64%)	13
Musculoskeletal/Soft Tissue - Other † 1	7/83 (8.43%)	15
Pain - Abdomen NOS † 1	36/83 (43.37%)	136
Pain - Back † 1	12/83 (14.46%)	21
Pain - Chest wall † 1	9/83 (10.84%)	17
Pain - Extremity-limb † 1	9/83 (10.84%)	19
Pain - Joint † 1	8/83 (9.64%)	16
Nervous system disorders
Dizziness † 1	11/83 (13.25%)	25
Encephalopathy † 1	5/83 (6.02%)	6
Memory impairment † 1	5/83 (6.02%)	9
Neuropathy: sensory † 1	5/83 (6.02%)	18
Pain - Head/headache † 1	6/83 (7.23%)	11
Somnolence/depressed level of consciousness † 1	5/83 (6.02%)	5
Psychiatric disorders
Insomnia † 1	10/83 (12.05%)	25
Mood alteration - Anxiety † 1	10/83 (12.05%)	22
Depression † 1	8/83 (9.64%)	24
Renal and urinary disorders
Urinary frequency/urgency † 1	8/83 (9.64%)	18
Urine color change † 1	5/83 (6.02%)	5
Respiratory, thoracic and mediastinal disorders
Cough † 1	13/83 (15.66%)	23
Dyspnea (shortness of breath) † 1	23/83 (27.71%)	38
Pleural effusion (non-malignant) † 1	7/83 (8.43%)	13
Pulmonary/Upper Respiratory - Other † 1	7/83 (8.43%)	17
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other † 1	13/83 (15.66%)	41
Hyperpigmentation † 1	13/83 (15.66%)	32
Pruritus/itching † 1	6/83 (7.23%)	13
Rash/desquamation † 1	5/83 (6.02%)	8
Rash: dermatitis associated with radiation - Chemoradiation † 1	5/83 (6.02%)	5
Rash: dermatitis associated with radiation - Radiation † 1	51/83 (61.45%)	194
Ulceration † 1	5/83 (6.02%)	8
Vascular disorders
Hypertension † 1	5/83 (6.02%)	10
Hypotension † 1	9/83 (10.84%)	16
1 Term from vocabulary, CTCAE (3.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Theodore Sunki Hong, MD
• Organization: Massachusetts General Hospital
• Phone: 617-724-1159
• EMail: tshong1@mgh.harvard.edu

• Responsible Party: Theodore Sunki Hong, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00976898
• Other Study ID Numbers: 09-131; P01CA021239 ( U.S. NIH Grant/Contract )
• First Submitted: September 11, 2009
• First Posted: September 15, 2009
• Results First Submitted: December 7, 2017
• Results First Posted: January 31, 2018
• Last Update Posted: August 15, 2018