Carcinoma, Hepatocellular
Conditions
Brief summary
The purpose of this study is to determine the maximum tolerated dose of limited fractions of large dose radiation in an effort to achieve a biologically potent cancer therapy in selected patients with primary hepatocellular carcinoma.
Detailed description
Despite recent advances in early detection and diagnosis, only 30-40% of patients with hepatocellular carcinoma may benefit from radical therapies. Liver transplantation offers the best chance for cure. Surgical resection has been the only other potentially curative option, but the majority of patients are not candidates for resection. This reflects the usual comorbidity of severe underlying liver disease that either precludes surgery or makes the surgical approach extremely dangerous.
Interventions
RADIATIONStereotactic Body Radiation
Arm A: Childs A - receive 3 fractions. Arm B: Childs B - receive 5 fractions.
Sponsors
University of Colorado, Denver
Indiana University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Evaluation by the Surgery and/or Liver Transplant Team has been performed and the patient is not considered a candidate for either standard therapy to target area (upper abdomen) * Adequate liver function defined as: * total bilirubin \< 3mg/dl, albumin \> 2.5 g/dl * normal PT/PTT unless on anticoagulants * mild elevation of liver enzymes acceptable (must be less than three times upper limit of normal) * Adequate renal function (creatinine \< 1.8 mg/dl or creatinine clearance ≥ 50 ml/min) * Adequate bone marrow reserve: * ANC count ≥ 1500 mm3 * Platelets ≥ 50,000/mm3 * Hemoglobin \> 9 g/dL NOTE: Lab values must be obtained within 2 weeks prior to being registered for protocol therapy.
Exclusion criteria
* No history of systemic lupus erythematous, rheumatoid arthritis, systemic sclerosis or scleroderma * No chemotherapy within 14 days before radiotherapy (chemotherapy may cause transient hepatitis with hepatomegaly) * No subsequent chemotherapy planned within 2 weeks of radiotherapy * No active liver infection * No acute Hepatitis. Definition of active disease: * Hepatitis A: Acute hepatitis determined by presence of Anti-HAV- IgM * Hepatitis B: 1. HBsAg (HB surface Antigen): present in patients with acute and chronic hepatitis 2. HBV DNA present in patients with active viral replication in amounts greater than 100,000 copies 3. HBeAg is present in wild type HBV infection and suggests active replication 4. Anti-HBs: Antibody against HBsAg appears after HBV infections and confers immunity 5. Anti-HBc-IgM: Antibody against HBcAg, fraction IgM, present in acute infection and often could be detected during periods of high viral replication in chronic disease 6. Anti-HBc-IgG: is present in chronic disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With DLTs | 6 weeks | Number of patients experiencing a Dose Limiting Toxicity during the Phase I portion of the trial. |
| 6 Month Local In-field Control | 6 months | Percent of patients and the 95% Binomial Confidence interval who were free of in-field progression at 6 months following treatment for the patients in Phase II |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to In-field Failure | up to 4 yrs | Kaplan-Meier Analyses will be used to calculate the median and 95% Confidence Interval for the time until in-field failure. This will be calculated from the time of treatment until the time of in-field failure. If a patient did not have in-field failure, the patient will be censored at their last evaluation date. |
| Overall Survival | Up to 8 years | Kaplan-Meier Analysis will be used to calculate the median and 95% CI for overall survival. This will be calculated from the time of treatment until death. If a patient did not die, the patient will be censored at their last known alive date. |
| Phase II: Number of Patients With Treatment Related Grade 3 or 4 Adverse Events | up to 4 years | Number of unique patients who had grade 3 or 4 adverse events that were possibly, probably or definitely related to study treatment. |
Countries
United States
Participant flow
Pre-assignment details
This is a Phase I/II study. Phase I is a dose finding study, and Phase II will use the doses determined by the Phase I portion to further look at efficacy. During Phase I, it was determined to look at Childs A patients separately from Childs B patients. Patients who were Childs B required a dose reduction during Phase I.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Dose escalation to 48 Gy (16Gy/fraction) in Childs A and to 42 Gy (14 Gy/fraction) down to 40 Gy (8Gy/fraction) for Childs B | 17 |
| Phase II Childs A Patients in Phase II with a score of Childs A Will receive 3 fractions (48 Gy) of radiation over 5-10 days | 39 |
| Phase II Childs B Patients in Phase II with a score of Childs B will receive 5 fractions (40 Gy) of radiation over 2-6 weeks. | 21 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Phase I | Phase II Childs A | Phase II Childs B | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 12 Participants | 4 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 27 Participants | 17 Participants | 54 Participants |
| Age, Continuous | 60.8 years STANDARD_DEVIATION 9.76 | 60.9 years STANDARD_DEVIATION 10.62 | 58.5 years STANDARD_DEVIATION 7.55 | 60.2 years STANDARD_DEVIATION 9.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 38 Participants | 20 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 7 Participants | 2 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 30 Participants | 19 Participants | 64 Participants |
| Sex: Female, Male Female | 1 Participants | 11 Participants | 4 Participants | 16 Participants |
| Sex: Female, Male Male | 16 Participants | 28 Participants | 17 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 4 / 6 | 4 / 5 | 2 / 3 | 19 / 39 | 13 / 21 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 5 / 5 | 3 / 3 | 39 / 39 | 21 / 21 |
| serious Total, serious adverse events | 1 / 3 | 1 / 6 | 1 / 5 | 1 / 3 | 1 / 39 | 1 / 21 |
Outcome results
Primary
6 Month Local In-field Control
Percent of patients and the 95% Binomial Confidence interval who were free of in-field progression at 6 months following treatment for the patients in Phase II
Time frame: 6 months
Population: All patients who received treatment and had a post-baseline assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: 36 Gy | 6 Month Local In-field Control | 92.3 percentage of participants |
| Phase I: 42 Gy | 6 Month Local In-field Control | 87.5 percentage of participants |
Primary
Number of Patients With DLTs
Number of patients experiencing a Dose Limiting Toxicity during the Phase I portion of the trial.
Time frame: 6 weeks
Population: All patients who received treatment in Phase I
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: 36 Gy | Number of Patients With DLTs | 0 Participants |
| Phase I: 42 Gy | Number of Patients With DLTs | 2 Participants |
| Phase I: 40 Gy | Number of Patients With DLTs | 1 Participants |
| Phase I: 48 Gy | Number of Patients With DLTs | 0 Participants |
Secondary
Overall Survival
Kaplan-Meier Analysis will be used to calculate the median and 95% CI for overall survival. This will be calculated from the time of treatment until death. If a patient did not die, the patient will be censored at their last known alive date.
Time frame: Up to 8 years
Population: all patients who received treatment and had a post-baseline assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: 36 Gy | Overall Survival | 50.43 months |
| Phase I: 42 Gy | Overall Survival | 21.40 months |
Secondary
Phase II: Number of Patients With Treatment Related Grade 3 or 4 Adverse Events
Number of unique patients who had grade 3 or 4 adverse events that were possibly, probably or definitely related to study treatment.
Time frame: up to 4 years
Population: All patients who received treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: 36 Gy | Phase II: Number of Patients With Treatment Related Grade 3 or 4 Adverse Events | 5 Participants |
| Phase I: 42 Gy | Phase II: Number of Patients With Treatment Related Grade 3 or 4 Adverse Events | 9 Participants |
Secondary
Time to In-field Failure
Kaplan-Meier Analyses will be used to calculate the median and 95% Confidence Interval for the time until in-field failure. This will be calculated from the time of treatment until the time of in-field failure. If a patient did not have in-field failure, the patient will be censored at their last evaluation date.
Time frame: up to 4 yrs
Population: All pts who received treatment and had a post-baseline assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: 36 Gy | Time to In-field Failure | NA months |
| Phase I: 42 Gy | Time to In-field Failure | 32.2 months |