RTOG 1112:

RANDOMIZED PHASE III STUDY OF SORAFENIB VERSUS STEREOTACTIC BODY

RADIATION THERAPY FOLLOWED BY SORAFENIB IN HEPATOCELLULAR
CARCINOMA (HCC)

Presented by Joseph Bryant

University of Wisconsin-La Crosse
DOS 741: Protocols and Studies in Radiation Oncology
Cooperative Groups & Principal Investigators

● Radiation Therapy Oncology Group (RTOG) of the American College of Radiology (ACR)
○ RTOG currently conducts federally-funded clinical research under their membership in NRG
Oncology (as of 2014)

● Principle Investigator – Laura A. Dawson, MD of Princess Margaret Hospital (PMH)

○ Research team consisted of seven additional medical doctors, members of the quality of life
board, medical physics department, and a senior statistician.
Phases

Phase III Clinical Trial

● Compare the safety and effectiveness of the new treatment modality against the current
standard treatment methods.
○ In this case, treatment of HCC with RT and Sorafenib has been proven to be safe and effective
○ RTOG 1112 sought to answer the question of whether or not SBRT was more effective than the
standard treatment of using Sorafenib alone.

● In phase III clinical trials, since doctors and researchers do not know which treatment
method is best, the participants are randomly selected to be given the standard
treatment or the new treatment.
○ Gives more credibility to the results when interpreting blind data
Previous Studies

● 23 patients treated with Tyrosine kinase inhibitor (TKI) which is similar to Sorafenib and
Radiation Therapy (RT), in Taiwan
○ Conventional hypofractionation (median dose of 52.5 Gy in 15 fractions)
○ Determined that hypofractionated RT and TKI can safely be delivered in HCC patients

● Phase one trial of Sorafenib and RT for HCC patients conducted in Toronto, Canada
○ Conventional hypofractionation (30 Gy in 10 fractions) combined with elevated Sorafenib use
before, during and after RT.
○ No dose limiting toxicity found in patients

● Two phase I trials of six fraction SBRT (24 - 54 Gy) and Sorafenib were conducted at
PMH
○ Twelve patients were included, one of the twelve experienced dose limiting toxicity (tumor
rupture).
○ Used reduced RT doses to normal tissues to reduce risk of toxicity
Trial Background & Purpose

● RTOG 1112 sought to address the questions that were left unanswered by these
previous clinical trials.
○ How does SBRT (27.5 - 50 Gy in 5 fractions) affect the survival, disease progression, and quality
of life compared to Sorafenib use alone?

○ Are there any special considerations that must be taken into account when using SBRT and
Sorafenib compared to typical fractionation?

○ Does this hypofractionated treatment regimen impact control of toxicity, dose to surrounding
organs and acceptable dose to the CTV?
Trial Schema

Stratify:
●Vascular involvement
●Hepatitis B or C or neither
●North American site or Non-North American site
●HCC volume/liver volume (<10% vs. 10-40% vs. >40%)
ARM 1: Daily Sorafenib
ARM 2 : SBRT alone (27.5 Gy - 50 Gy in 5 fractions), followed by Sorafenib daily

**Study required at least 368 participants for the sample size

**Treatment protocol must begin within 14 days after registration
Primary Objectives
The primary objective of RTOG 1112 is to demonstrate the effect of SBRT and Sorafenib in
HCC patients and their overall survival

Secondary Objectives :

● Observe the effect of SBRT and Sorafenib on:

○ The time of disease progression
○ Level of disease progression
○ Toxicity
○ The patients’ quality of life
Patient Selection
● All participants included in this clinical trial must have proven hepatocellular carcinoma
(HCC) within 180 days of study entry by one of the three following criterion.
○ Pathologically proven diagnosis of HCC
○ At least one solid liver lesion greater than 1 cm in diameter
○ Vascular involvement of the portal vein, inferior vena cava, and/or hepatic vein
 Pre-Treatment Evaluation
● Zubrod Performance Status, BCLC stage, Child-Pugh score 14 days prior to study entry
● Must be 18 years of age or older
● Blood work done no more than 14 days prior to study entry to ensure proper organ and
marrow function

Absolute Neutrophil Count > 1,500 cells/mm3

Platelets > 70,000 cells/mm3

Hemoglobin > 8.0 g/dl

Total Bilirubin < 2 mg/dl

Albumin > 28 g/L

Planning Considerations

Technical Factors:
● Linear Accelerator capable of AT LEAST 6 MV, daily IGRT, MLC, IMRT
○ Inverse planning, forward planning, 3D CRT, permitted
○ Proton use permitted

● CT based planning required

○ Minimum of 5 beams strongly recommended, arc plans recommended.
○ IV contrast used for target delineation, if contraindicated, MRI permitted
○ PET/CT and MRI should be used for target delineation

● Daily imaging is required

● Breathing motion management recommended if motion > 5 mm
○ 4DCT assessment and treatment if motion > 20 mm
Planning Considerations

● Custom Immobilization Recommendations

○ VacLok system, patient positioning boards, and/or breath-hold technique

● CTV is considered to be equivalent to the GTV

○ Some expansion can be used to include areas of high-risk disease but may lead to reduced dose
permitted
Planning Considerations

● Non-liver OAR should be contoured and protected

● These dose constraints, along with the aforementioned liver dose, decide which dose
prescription can be tolerated based on patient anatomy, organ function, and dosimetric
planning
Radiation Therapy

● The primary tumor and any involved vascular thrombi must be treated
● Treatment will be delivered in 5 fractions
○ Time between fraction: between 24 and 72 hours
○ Total treatment course duration: 15 or fewer days
○ Prescription Dose: 27.5 Gy to 50 Gy in 5 fractions, depending on dose constraints
■ Prescription dose should cover 95 percent of the PTV
■ The highest allowable doses to the target volumes that maintain normal tissue
constraints should be used.
Radiation Therapy
Drug Therapy

● Each patient begins by taking 800 mg of Sorafenib by mouth each day

○ If a patient’s health changes, their dose can be reduced to 400 mg per day, then to 200 mg.

● Throughout the trial, patients are monitored for abnormal changes to their health.
● Under certain extreme circumstances they can come off Sorafenib entirely to reduce
toxicity and preserve liver function
Results & Outcomes
● Patients with HCC and
were treated with SBRT
and Sorafenib had
improved overall and
progression free
survival.
● Median overall survival
was 15.8 months with
SBRT versus 12.3
months with Sorafenib
alone
References

1. Dawson LA, Winter K, Knox J, et al. NRG/RTOG 1112: Randomized phase III study of Sorafenib vs.
stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC)
(NCT01730937). International Journal of Radiation Oncology*Biology*Physics. 2022;114(5):1057.
doi:10.1016/j.ijrobp.2022.09.002
2. About Us. RTOG. Accessed July 25, 2023. https://www.rtog.org/About-Us.
3. Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body radiotherapy for
locally advanced hepatocellular carcinoma. Journal of Clinical Oncology. 2013;31(13):1631-1639.
doi:10.1200/jco.2012.44.1659
4. Sorafenib added to SBRT improves survival in hepatocellular carcinoma. ASCO Daily News. January
23, 2023. Accessed July 25, 2023. https://dailynews.ascopubs.org/do/sorafenib-added-sbrt-improves-
survival-hepatocellular-carcinoma.