Stereotactic Body Radiation Therapy vs. Microwave Ablation for Colorectal Cancer Patients With Metastatic Disease in the Liver - a Randomized Phase II Trail
Phase: PHASE2
Conditions: Colorectal Carcinoma, Liver Metastases
Sponsor: Rigshospitalet, Denmark

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
1 
 
Stereotactic body radiation therapy vs. microwave ablation for colorectal 
cancer patients with metastatic disease in the liver – a randomized phase II 
trial 
 
Principal investigator 
Signe Normann Risum, MD, PhD 
Department of Oncology, Rigshospitalet 
 
Investigators 
Ivan Richter Vogelius, PhD, DMSc 
Department of Oncology, Rigshospitalet 
 
Mirjana Josipovic, MSc 
Department of Oncology, Rigshospitalet 
 
Line Bjerregaard Stick, MSc 
Department of Oncology, Rigshospitalet 
 
Bo Nyhuus, MD 
Department of Radiology, Rigshospitalet 
 
Peter Nørgaard Larsen, MD 
Department of Surgery, Rigshospitalet 
 
Nicolai Aagaard Schultz, MD 
Department of Surgery, Rigshospitalet 
 
Place of investigation 
Department of Oncology, Rigshospitalet 
Blegdamsvej 9, 2100 Copenhagen 
 

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
2 
 
1. Background 
Patients with colorectal cancer frequently presents with oligo metastases. The number of metastases 
generally accepted as truly “oligo” are less than or equal to five in no more than three different organs. 
Resection remains the first option for treatment of liver metastases but is often not the preferred 
treatment for technical or medical reasons. In these cases, patients can be considered for microwave 
ablation (MW-ablation) or stereotactic body radiation therapy (SBRT) [1] and 5-year survival can be 
expected to be in the range 15-50% depending on case selection, but there is an acknowledged lack of 
evidence in the field.  
In most European countries MW-ablation is used when resection is not preferred, but it has limitations 
related to the size and location of the target lesions.  
SBRT is a non-invasive technique based on high-precision high-dose radiotherapy suitable for treatment of 
small targets in the body. SBRT has proven effective to gain tumor control with reported local control rates 
of 80% after 3 years [2].  
No randomized studies exist comparing clinical results from MW-ablation and SBRT. 
 
2. Study design 
This study is a randomized phase II trial between MW-ablation and SBRT – two standard treatment 
modalities for colorectal patients with metastatic disease in the liver.  
The study will assess time to local lesion progression and is designed to have the ability to detect large 
differences in efficacy between the trial arms. In the absence of such large differences in efficacy, the 
protocol will for the first time provide descriptions of toxicity profiles in comparable populations treated 
with the two modalities and provide input to the design and feasibility of larger phase III trials. 
 
2.1 Purposes 
1. To investigate SBRT as an alternative to MW-ablation in patients with colorectal liver metastases 
sized ≤4.0 cm found eligible for thermo-ablation as first choice of treatment by the local HPB 
multidisciplinary team.  Does SBRT prolong freedom from local lesion progression compared to 
MW-ablation without decrease in overall survival (OS)? 
2. To establish prognostic factors for patients with colorectal liver metastases undergoing MW-
ablation or SBRT 

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
3 
 
2.2 Hypotheses 
In patients with colorectal liver metastases sized ≤4.0 cm the use of SBRT provides a different freedom from 
local lesion progression than MW-ablation. 
 
2.3 Endpoints 
Primary Outcome Measure: 
1. Freedom from local lesion progression analyzed on patient-level: 
- 
Defined as the time from randomization to local progression 
- 
Censoring: death from any cause, last follow-up 
- 
No censoring on disease progression outside of the treated lesions 
Secondary Outcome Measures: 
2. Overall survival:  
- 
Defined as the time from randomization to death from any cause 
- 
Censoring: last follow-up 
3. Freedom from local lesion progression analyzed on lesion-level: 
- 
Defined as the time from randomization to local progression 
- 
Censoring: death from any cause, last follow-up 
- 
No censoring on disease progression outside of the treated lesions 
4. ≥ grade 3 liver toxicity potentially associated with the treatment: 
- 
Defined as the time from randomization to first ≥ grade 3 toxicity using the Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 
- 
Censoring: death from any cause, last follow-up 
5. Liver toxicity profile as descriptive statistics using the Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 
6. Quality of life as descriptive statistics using EORTC QLQ-C30 
 
Details relating to freedom from local lesion progression outcomes 
Local lesion progression is defined as >20% increase in the longest diameter and minimum 5 mm increase 
talking as reference the smallest longest diameter recorded since the treatment started in any of the 
treated lesions. 
New lesions in the liver or recurrence of previously treated lesions in the liver are denoted regional lesions 
and does not lead to censoring. 
Extrahepatic disease does not lead to censoring 
The primary outcome measure will be analyzed on patient-level and the freedom from local lesion 
progression outcome in the secondary outcome measures will be analyzed on lesion-level. 

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
4 
 
Assessment of a potential impact of lesion size will be performed for the primary endpoint by a preplanned 
subgroup analysis between lesions <3 cm and lesions >= 3 cm. Hazard ratios in the two subgroups will be 
presented in a forest plot and a test for heterogeneity will be used to assess if the lesion size is predictive of 
treatment effect. 
 
 
3. Study population 
Our hospital gets referrals for more than 600 colorectal cancer patients with liver metastases each year. 
Patients fulfilling the eligibility criteria (see inclusion and exclusion criteria below) should be amenable for 
both treatment arms and the multidisciplinary team should agree that both MW-ablation and SBRT are safe 
treatment options. Eligible patients willing to be a part of the protocol are randomized after the signed 
informed consent is obtained. Patients are randomized 1:1 between the two treatment arms and will be 
analyzed according to the intention-to-treat principle. Patients will be offered to cross over to the 
alternative treatment arm if it turns out - after the pre-screening - that the assigned treatment arm is not a 
safe treatment option. Another treatment will be offered if none of the treatment arms are considered 
safe. We plan to include 100 patients in the study (see statistical considerations below).  
 
3. 1 Inclusion criteria 
1. Colorectal cancer patients with oligo metastatic disease in the liver (1 to 3 tumors), and where 
metastases are found unsuitable for resection because of  
a. non-resectability 
b. small metastasis localized deep in the liver, where a parenchyma sparing intervention is 
preferred over an extensive resection 
c. previous extensive liver surgery 
d. comorbidity 
2. The multidisciplinary team should all agree that both percutaneous or open surgical MW-ablation 
and SBRT are safe as first treatment choice for the individual patient. 
3. Tumor sizes ≤4.0 cm 
4. Age > 18 years 
5. Signed informed consent 
 
3.2 Exclusion criteria 
1. Previous radiotherapy to the liver 
2. Liver volume < 700 ml 

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
5 
 
3. Another active cancer disease within the past 36 months 
4. Not able to understand written or oral protocol information 
 
Curative treatment of extrahepatic disease has to be initiated in patients with lung metastases and/or 
primary tumors. 
 
5. Treatment 
Patients are randomized 1:1 between 
• 
Treatment arm A: MW-ablation 
• 
Treatment arm B: SBRT  
 
4.1 MW-ablation procedure 
MW-ablation is a procedure using microwaves to heat tumor tissue thereby killing the tumor cells.  MW-
ablation can be performed either percutaneously or if percutaneous approach not is possible, by open 
surgery. Guided by ultrasound a thin needle is introduced through the skin into the tumor by the 
percutaneous approach or directly through the liver into the tumor during laparotomy. The patient is fully 
anesthetized during the treatment.  
 
 
4.2 SBRT procedure 
Treatment planning 
Imaging for the treatment planning will be performed according to departmental guidelines for treatment 
and management of respiratory motion: 4D CT in free breathing with intra-venous contrast, followed by 
one or three breath hold CT scans (deep inspiration or expiration), depending on whether the treatment 
will be in free breathing (one scan) or in breath hold (three scans).  
 
Renography will be performed to monitor kidney function before treatment in patients where the kidneys 
can be expected to receive radiation. The renography is performed with technetium mag3 following the 
standard protocol at Rigshospitalet. 
 
Target(s) and organs at risk will be contoured by an experienced radiologist and clinical oncologist. 
 
Image guidance 

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
6 
 
The planning procedures for SBRT include implementation of three gold markers in order to identify the 
tumour on the planning CT and on the cone beam CT (CBCT), used for daily image guidance.  
 
 
Treatment 
SBRT: 3 fractions of 15 Gy (in total 45 Gy), 3 fractions per week. The dose is prescribed to the planning 
target volume (PTV) encompassing 67% isodose. The SBRT plan is normalized such that the mean dose to 
the gross tumor volume (GTV) is 100% = 67.5 Gy. The SBRT will be delivered in either free breathing or 
breath hold.  
 
4.3 Follow-up  
Patients will be followed for 5 years (1, 3, 9, 12, 18, 24, 36, 48, 60 months after treatment) 
1. CT of thorax and abdomen and toxicity scores 
2. Biochemical control of liver function and carcinoembryonic antigen (CEA) 
3. Quality of life registration using EORTC QLQ-C30 
 
6. Statistical considerations 
The protocol is designed as a randomized phase II trial to provide descriptive statistics of the incidence of 
local lesion progression and toxicity profile with the two studied modalities in comparable cohorts of 
patients. Patients will be analyzed according to the intention-to-treat principle. In the complete absence of 
randomized trials in the literature we design the trial to be able to detect large differences in efficacy, 
defined as time to local lesion progression, as follows: 
 
Sample size estimation 
It is assumed that freedom from local lesion progression in one trial arm is 94% after one year in one arm 
and 85% after one year in the comparing arm, corresponding to a hazard ratio of 0.38 between trial arms. It 
is assumed that patients are accrued over three years with one year additional follow-up and a median 
time to event of 4 years. In this case, a sample size of 35 patients will yield a power of ~80% to observe 
such difference with an associated type I error of 5%.  We plan accrual of 50 patients per arm in order to 
account for loss of patients to competing causes and to account for intention to treat analysis of patients 
crossing over. 
 

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
7 
 
In practice, we expect that the difference between the trial arms is smaller, in which case the main 
knowledge generated will be descriptive statistics of toxicity and local lesion control in the two treatment 
modalities and information about the possible benefits of a full phase III trial as a follow-up due to the 
comparable cohorts secured by randomization. For comparison, some of the best data available on SBRT is 
a single institutional retrospective series published in the leading radiotherapy journal in 2017 with 70 
patients [3]. 
 
Kaplan-Meier curves of time to local lesion progression with confidence bands will be provided as a key 
outcome of the trial.  
 
7. Risks, side effects and disadvantages 
7.1 MW-ablation 
In a period of 1-2 weeks after MW-ablation, the patient sometimes experiences influenza-like symptoms. 
The risks in relation to the procedure include bleeding, lesions of major bile ducts, perforation of the 
intestine and other adjacent structures.  These complications are rare, below 5%.  
If open approach by laparotomy is necessary, there is a 10-15 % risk of wound dehiscence and/or infection 
General anesthesia is associated with very low risk of complications. Moderate side effects are nausea and 
headache. 
 
7.2 SBRT 
Some patients will experience moderate toxicities short after treatment such as nausea (~35 in 100 
patients), diarrhea (~25 in 100 patients), skin reactions (~15 in 100 patients) [4] and pain in the treated 
area. SBRT is associated with an increased risk of server toxicities as hepatic failure (~1 in 100 patients), 
colonic perforation (~1 in 100 patients) and duodenal ulcer (~2 in 100 patients) [4]. 
 
If renography is performed, the patient might experience discomfort from injection of the tracer 
technetium Mag3. 
 
8. Information from medical records 
Information from medical records will be recorded and stored in RegionH approved databases (RedCap) in 
accordance with the rules of the Data Protection Authority. The information will include comorbidities 
required for the calculation of a Charlson comorbidity score, baseline disease data and all follow-up 
information related to control of the treated lesions. The purpose of data acquisition is to provide 

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
8 
 
descriptive statistics of the influence of patient and disease status on the compliance and precision of 
treatment and to assess the efficacy of the delivered treatment. 
 
The project investigator will have access to withdraw necessary information from patient records to 
accomplish the quality assurance of the project but only information already recorded and stored in the 
databases will be used. 
 
9. Respect for the subjects’ physical and mental integrity and privacy 
Data collection will be reported to the Danish Data Protection Authority as part of the collective reporting 
performed by the Capital Region of Denmark and following Rigshospitalet’s standard procedure. All 
information will be protected according to Danish data protection authority regulations and health law. The 
subjects and their relatives will be informed orally and in writing that participation is voluntary and that 
they may withdraw from the trial at any time, without providing reason. The Danish law on processing of 
person data will be obeyed. 
 
10. 
Economy 
All costs associated with the standard cancer treatment will be defrayed by the Danish national healthcare 
system.  The project is initiated by the investigators at Rigshospitalet. We have received 169.500 USD from 
Varian Medical Systems (radiation oncology treatments and software vendor) for the current project and 
associated projects in liver SBRT. The funding will be a part of the ordinary salary of researchers at the 
department. Therefore, the researches do not have economic gain in carrying out the research project. The 
funding from Varian will be used to pay salary for PhD student physicist Line Stick, senior physicist Mirjana 
Josipovic and chief consultant Signe Risum, all part time allocated to the current project. All funding is 
managed via Rigshospitalet's accounting system. Conflict of interest related to the company support will be 
declared in all disseminations of the results. The investigators will attempt to acquire further funding from 
foundations which, if successful, will be managed according to the same principles. The Committee on 
Health Research Ethics in the Capital Region of Denmark and study participants will be informed if further 
funding is achieved. 
 
11. 
Compensation 
The study participants will not be offered financial compensation for participating in the study. 
 

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
9 
 
12. 
Patient information 
Patients with liver metastases are referred to the multidisciplinary conference at Rigshospitalet. Patients 
fulfilling the inclusion criteria will be informed about the project at the following consultation. The patients 
will be information of their right to be accompanied by a family member, friend or acquaintance. The 
written participant information and the additional documents “Forsøgspersoners rettigheder i et 
sundhedsvidenskabeligt forskningsprojekt” and “Før du beslutter dig” will be handed out. The project will 
be presented in an easily understood manner without the use of technical or biased vocabulary. The 
interview is based on the written participant information and will take place undisturbed in an interview 
room. The participants are offered time to reflect for 24 hours before the informed consent is obtained. All 
participation is voluntary and the consent can be withdrawn at any given time. 
 
13. 
Dissemination of results 
The results of this study, including negative or inconclusive results, will be published in international peer-
reviewed scientific journals. Several manuscripts will be written and authorship will be decided according to 
the Vancouver guidelines.  
 
14. 
Ethical considerations 
The multidisciplinary team should agree that both MW-ablation and SBRT are safe treatment options. Both 
treatment arms’ therapies are therapy techniques used in the clinic following a standard procedure.  
The protocol complies with the Helsinki Declaration and national requirements for studies of patients with 
cancer. Patients will be fully informed about the treatment modalities and the risk of participating. 
 
15. 
Patient compensation 
The participants in the study are covered by the Patient Compensation Association. 
 
 
References 
[1] Wong SL, Mangu PB, Choti MA, Crocenzi TS, Lii GDD, Dorfman GS, et al. American Society of Clinical 
Oncology 2009 Clinical Evidence Review on Radiofrequency Ablation of Hepatic Metastases From Colorectal 
Cancer 2017;28. 
 
[2] Ahmed KA et al. Stereotactic body radiotherapy in the management of oligometastatic disease. 
Cancer Control. 2016 Jan;23(1):21-9. 

 
Protocol version 2.2 
Protocol no.: H-18000085 
April 16, 2019 
10 
 
 
[3] Joo JH, Park JH, Kim JC, Yu CS, Lim SB, et al. Local Control Outcomes Using Stereotactic Body Radiation 
Therapy for Liver Metastases From Colorectal Cancer. Int J Radiat Oncol Biol Phys. 2017 Nov 15;99(4):876-
883 
 
[4] Hoyer M. et al. Phase II study on stereotactic body radiotherapy of colorectal metastases. Acta 
Oncologica. 2016; 45: 823-830.