Randomized Controlled Phase II Trial of Liver Resection Versus No Surgery in Patients With Liver and Unresectable Pulmonary Metastases From Colorectal Cancer
Phase: PHASE2
Conditions: Metastatic Colorectal Carcinoma, Metastatic Malignant Neoplasm in the Liver, Metastatic Malignant Neoplasm in the Lung, Recurrent Colorectal Carcinoma, Resectable Colorectal Carcinoma, Stage IV Colorectal Cancer AJCC v7, Stage IVA Colorectal Cancer AJCC v7, Stage IVB Colorectal Cancer AJCC v7
Sponsor: M.D. Anderson Cancer Center

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TITLE: Randomized Controlled Phase II Trial of Liver Resection Versus No Surgery 
in Patients with Liver and Unresectable Pulmonary Metastases from 
Colorectal Cancer 
Study Chair: 
   Yun Shin Chun, MD, FACS 
     Department: Surgical Oncology 
     Phone: 713‐563‐9682 
  Unit: 1484 
Study Co‐Chair: 
Scott Kopetz, MD, PhD 
Department of Gastrointestinal Medical Oncology 
Collaborators: 
Jean‐ Nicolas Vauthey, MD  
Ching-Wei Tzeng, MD 
Hop Tran Cao, MD 
Department of Surgical Oncology 
Michael Overman, MD 
Benny Johnson, DO 
Bryan Kee, MD 
Christine Parseghian, MD 
Department of Gastrointestinal Medical Oncology 
Reza Mehran, MD 
Department of Thoracic Surgery 
Lianchun Xiao, MS  
Ryan Sun, PhD 
Division of Quantitative Sciences 
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Table of Contents 
1.0 Objectives .............................................................................................................................................. 3 
2.0 Rationale ................................................................................................................................................ 3 
3.0 Eligibility of Subjects .............................................................................................................................. 6 
4.0 Research Plan and Methods .................................................................................................................. 7 
5.0 Endpoints ............................................................................................................................................. 12 
6.0 Statistics and Justification of Sample Size ............................................................................................ 12 
7.0 Informed Consent ................................................................................................................................ 14 
8.0 Data Safety and Monitoring Board ...................................................................................................... 15 
9.0 Data Confidentiality…………………………………………………………………………………………….. .......................... 15 
10.0 References ......................................................................................................................................... 16 
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1.0 Objectives 
 
 
1.1 Primary objective 
 
1.1.1 To estimate a survival benefit of liver resection in patients with resectable liver and  
 
unresectable low-volume pulmonary metastases from colorectal cancer. 
 
1.2 Secondary objective 
 
1.2.1 To identify biomarkers in blood and resected liver specimens that correlate with  
 
survival and development of extrahepatic and extrapulmonary metastases. 
 
1.2.2 To assess patients’ quality-of-life in each treatment arm with serial questionnaires. 
 
 
2.0 Rationale 
 
 
2.1 Introduction 
 
Liver metastases occur in approximately 30% of all patients with colorectal cancer and account 
for at least two-thirds of colorectal cancer deaths.1 Both hepatic and pulmonary metastases will 
develop in 5-10% of colorectal cancer patients.2 Data supporting liver metastasectomy for stage 
IV colorectal cancer dates back to the 1970s, when 5-year overall survival of patients who 
underwent resection of solitary colorectal liver metastases (CLM) was reported to be 42%.3 The 
survival benefit of liver resection was attributed to the unique tumor biology of an isolated liver 
metastasis from colorectal cancer. In 1995, Hellman and Weichselbaum coined the term 
“oligometastases,” defined as metastases limited to a single or limited number of organs 
amenable to surgical resection as a curative therapeutic strategy.4 They also described the 
potential for effective chemotherapy to convert patients with widespread polymetastatic disease 
to an oligometastatic state. 
 
Multiple studies have established hepatic resection as the only potentially curative treatment for 
patients with CLM, resulting in a 5-year overall survival rate of 58%.5 A study of nearly 2500 
patients with stage IV colorectal cancer treated at MD Anderson and the Mayo Clinic 
demonstrated a median survival of 65.3 months in patients undergoing liver resection, compared 
to only 26.7 months with chemotherapy alone.1 With the advent of effective chemotherapy that 
can downsize liver metastases, more patients are eligible for hepatic resection, regardless of 
tumor size, number, or distribution in the liver. 
 
Resectability of liver metastases is defined as the ability to preserve two contiguous hepatic 
segments, preservation of adequate vascular inflow and outflow and biliary drainage, and the 
ability to preserve adequate future liver remnant.6 
 
2.2 Extrahepatic metastases 
 
In earlier studies, patients undergoing liver resection in the presence of extrahepatic disease 
had a particularly poor outcome, and the presence of extrahepatic disease was considered a 
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contraindication to liver resection. The presence of both hepatic and extrahepatic metastases 
was thought to represent systemic dissemination, or polymetastatic disease. However, more 
recently, studies have shown that carefully selected patients may have improved survival with 
complete resection of liver metastases and low-volume extrahepatic disease.7 Among sites of 
extrahepatic disease, pulmonary metastases are associated with favorable survival. 
 
Retrospective studies have shown that patients undergoing resection of both pulmonary and 
hepatic metastases have survival comparable to that of patients undergoing resection of isolated 
hepatic metastases.8 In a report from MD Anderson of 41 patients undergoing both pulmonary 
and hepatic metastasectomy, the 5-year overall survival rate was 57%. In this study, patients 
had a mean number of 2.3 lung metastases, with a mean size of 1.5 cm, and 31% bilateral. 
 
Most colorectal cancer patients with hepatic metastases and pulmonary nodules do not undergo 
lung biopsy. The diagnosis of pulmonary metastases is based on radiologic features and clinical 
suspicion when pulmonary nodules progress or regress with chemotherapy. A study from 
Memorial Sloan-Kettering Cancer Center evaluated patients with subcentimeter pulmonary 
nodules who underwent hepatic resection for metastatic colorectal cancer. After median follow-
up of 31 months, factors associated with non-progression of pulmonary nodules included 
calcification and spiculated contours.9 
 
Currently, there are no limits on number, size, or bilaterality for resection of pulmonary 
metastases from colorectal cancer.10 The main determinant of irresectability of pulmonary 
metastases is inadequate pulmonary reserve to sustain a good performance status after the 
largest likely loss of pulmonary parenchyma. 
 
2.3 Preliminary data 
 
The role of liver resection in the setting of unresectable extrahepatic metastases was not 
reported until our recent retrospective study of patients who underwent resection of liver 
metastases in the presence of unresectable pulmonary metastases.8 This study was undertaken 
to clarify the impact of lung metastases, which are the most frequent form of extrahepatic 
colorectal cancer metastasis. With effective cytotoxic chemotherapy and biologic agents, long-
term disease control can be expected in patients with unresectable lung metastases, which are 
often small-volume and have indolent tumor biology. In contrast, liver metastases typically 
represent a greater tumor burden and the primary determinant of patient survival. 
 
For the retrospective study, 98 patients were identified who underwent hepatic resection for 
metastatic colorectal cancer with known pulmonary nodules that progressed after hepatectomy. 
In this study population, median number of lung nodules that progressed after hepatectomy was 
3 (range, 1‒14), all < 2 cm in size, and 60% bilateral.8 
 
Independent predictors of poorer survival were Kras mutation and rectal primary tumor. The 
study population was matched with a group of patients (n=64) treated with chemotherapy only. 
The 3-year and 5-year overall survival rates were 43% and 13% for patients who underwent 
resection of their liver metastases, in contrast to 14% and 2% for those treated with 
chemotherapy only (P<0.01, figure 1). These nonrandomized analyses suggest that removal of 
the liver metastases may substantially prolong survival of patients with both hepatic and 
pulmonary metastases. 
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Figure 1. In patients with liver and unresectable, low-volume pulmonary metastases from 
colorectal cancer, retrospective analysis demonstrated improved survival with liver resection, 
compared to chemotherapy alone.8 
 
2.4 Rationale for randomized trial 
 
Current standard of care for patients with resectable liver and unresectable pulmonary 
metastases from colorectal cancer is chemotherapy. Our previous study of patients who 
underwent hepatic resection with unresected pulmonary metastases was limited by its 
retrospective design. A prospective, randomized trial is needed to support the use of liver 
resection over chemotherapy alone in this patient population. Furthermore, the proposed study 
is expected to identify surrogates of tumor biology to optimize selection of patients most likely to 
benefit from hepatectomy in the setting of unresectable pulmonary metastases. 
 
2.5 Safety of liver surgery 
 
Advances in imaging, anesthesia, perioperative care, and surgical technique have increased the 
safety of hepatic resection. Currently, the mortality and major morbidity rates after liver resection 
at MD Anderson are 2% and 14%, respectively.11 The two most significant potential 
complications after liver resection are liver failure and bile leak. At MD Anderson, we precisely 
measure liver volumes, and if the volume of the liver remaining after surgery is insufficient, then 
we perform portal vein embolization to induce hypertrophy of the remnant liver. After portal vein 
embolization, we measure the kinetic growth rate (KGR), which is the growth rate of the remnant 
liver divided by the number of weeks since portal vein embolization. Previously, we showed that 
patients with KGR of ≥ 2% per week have a 0% risk of liver failure and liver- related mortality.12 
Furthermore, after major hepatectomy, we perform an intraoperative bile leak test by 
cannulating the bile duct and insufflating air to detect bile leaks, which are repaired 
intraoperatively. By using this technique, we have reduced the rate of postoperative bile leak to 
1.9%.13 
 
2.6 Correlative studies 
 
2.6.1 Biomarkers 
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Patient selection is critical to achieving favorable outcomes after liver resection in the setting 
of unresectable pulmonary metastases. In a study from Memorial Sloan-Kettering Cancer 
Center of patients undergoing resection of both hepatic and pulmonary metastases, 80% of 
patients developed disease recurrence.14 Among the sites of disease recurrence, 9% 
involved extrahepatic and extrapulmonary sites, including the bone, brain, and adrenal, 
indicating a polymetastatic disease pattern. Recently, Uppal and colleagues analyzed 
resected lung metastases from various primary disease sites and found microRNAs 
encoded in the 14q32 microRNA cluster to mediate an oligometastatic phenotype.15 Such 
biomarkers can serve as surrogates for favorable biology confined to the lung and liver to 
help select subsets of patients for hepatic resection. 
 
2.6.2 Quality-of-Life 
 
Prior quality-of-life studies after hepatectomy have shown severe deterioration of function in 
30% of patients but functional recovery by 6 months.16 In patients with hepatic and 
unresectable pulmonary metastases, whose median survival is reportedly less than 3 years, 
quality-of-life with hepatic resection or chemotherapy alone is important to evaluate. 
 
 
3.0 Eligibility of Subjects 
 
 
3.1 Inclusion criteria 
 
3.1.1 Patients with synchronous or metachronous diagnosis of resectable liver metastases  
by computed tomography (CT) or magnetic resonance imaging (MRI) of the    
abdomen. 
 
3.1.1a 
Patients requiring percutaneous or intraoperative ablation of liver metastases 
< 2 cm in size are  eligible. 
 
3.1.1 b 
Patients who underwent prior liver resection or ablation for colorectal liver 
metastases are eligible. 
 
3.1.2 Patients previously treated with systemic chemotherapy and/or biologic agents for  
 
colorectal cancer are eligible. 
 
3.1.3 The primary tumor in the colon or rectum may be intact or resected. 
 
3.1.4 Low-volume lung metastases are defined as solid pulmonary nodules < 2 cm with  
 non-spiculated contours, no benign-appearing calcifications, and ≤ 14 in number,   
 diagnosed by computed tomography of the chest or positron emission tomography  
 (PET). 
 
3.1.5 Lung metastases will be unresectable due to anatomic location, distribution, or  
 patients’ comorbidities, as determined by review of imaging by a faculty member in    
  the Department of Thoracic & Cardiovascular Surgery. 
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3.1.6 Patients 18 years of age and older. 
 
3.1.7 Patients must sign a study-specific consent form. 
 
3.1.8 Patients will undergo CT imaging of the chest, abdomen, and pelvis to evaluate lung  
 and liver metastases within 60 days of registration. For patients who cannot tolerate   
 CT contrast or have hepatic steatosis that reduces the sensitivity of CT, MRI of the  
 liver will be performed. 
 
3.2 Exclusion criteria 
 
3.2.1 Radiographic evidence of disease other than liver and lungs, with the exception of 
mediastinal lymph nodes < 2 cm and hepatoduodenal ligament lymphadenopathy, 
diagnosed by computed tomography, magnetic resonance imaging, or positron 
emission tomography. 
 
3.2.2 Inadequate liver function, as evidenced by serum bilirubin > 2 mg/dL and/or platelet 
count < 50,000/µL. 
 
3.2.3 ECOG performance status of 3-4. 
 
3.2.4 Patient refusal to participate in randomization. 
 
3.2.5 Pregnant women are excluded from this study. 
 
3.2.6 Planned stereotactic body radiation therapy (SBRT) for the pulmonary metastases. 
 
3.2.7 Non-English-speaking patients are not eligible for participation. 
 
 
4.0 Research Plan and Methods 
 
 
4.1 Protocol schema 
 
This is a randomized, non-blinded, controlled phase II trial of liver resection vs. no surgery in 
patients with liver and unresectable pulmonary metastases from colorectal cancer. 
 
Standard resources needed for routine clinical care will be utilized for this protocol. The 
Institutional Tissue Bank (LAB03-0320 and PA14-0241) will be utilized for patients whose 
tissues are collected. Clinics of faculty in the Gastrointestinal Medical Oncology department are 
screened by designated study staff for potentially eligible patients. 
 
Eligible patients will be randomized in a 1:1 allocation ratio to the treatment group of liver 
resection or control group of no liver resection. The randomization will be conducted by the 
Clinical Oncology Research System (CORe) after consent and registration. Randomization will 
occur when patients are being considered for liver surgery. 
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Patients whose pulmonary metastases become resectable with chemotherapy will be 
considered for pulmonary metastasectomy. A patient who changes treatment plan (surgery or 
chemotherapy), per patient or physician discretion, will continue to be followed on the study for 
the primary endpoint of overall survival, and analysis will be performed in an intent-to-treat 
fashion. 
 
Potential benefits for the patient are being evaluated by a hepatobiliary surgeon for possible 
liver resection, which may or may not be associated with longer recurrence-free survival.  
Potential risks are complications of liver surgery for patients randomized to the surgery arm. If 
participants suffer injury as a direct result of taking part in this study, MD Anderson health 
providers will provide medical care. However, this medical care will be billed to their insurance 
provider or the participant in the ordinary manner. The participant will not be reimbursed for 
expenses or compensated financially by MD Anderson for this injury. We do not anticipate any 
economic burdens beyond those that the patient would experience with standard of care 
treatment. Patients who withdraw from the study will continue to receive care under the 
discretion of their treating physician(s).  
 
4.2 Treatment scheme 
 
4.2.1 Liver resection 
 
Laboratory studies, imaging, and correlative studies will be performed at time-points shown 
in Table 1. All hepatectomies will be performed at MD Anderson by one of four dedicated 
liver surgeons, using either a laparoscopic or open approach. Postoperative chemotherapy 
may be deferred in patients suffering from major postoperative complications. 
 
All postoperative complications will be assessed by the attending surgeon and graded by a 
well-established classification system by Dindo et al. and managed as part of routine 
standard of care, including percutaneous drain placement for symptomatic fluid collections.17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 2. Study schema 
 
 
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Table 1. Schedule of events 
 
At 
registration 
Restaging 
Appointments** 
Liver 
resection* 
Restaging 
appointments 
Post-treatment 
follow-up** 
Tests & Observations 
History and Physical Examination 
x 
x 
x 
x 
Performance Status 
x 
x 
x 
x 
Staging 
Chest x-ray or chest CT 
x 
x 
x 
x 
Abdominal/pelvic imaging (CT, MRI, 
or PET scan) 
x 
x 
x 
x 
Companion Studies 
Quality-of-life survey** 
x 
x 
x 
x 
Tumor block 
x 
Plasma, when available 
x 
x 
x 
x 
Primary tumor block, when available 
x 
 
* For patients randomized to surgery. 
   ** Every 3-6 months until 3 years after randomization or until death. Patients may or may not continue    
       on chemotherapy during this time period.  For patients who do not return to MD Anderson, attempts will 
be made to obtain outside medical records for determination of the primary endpoint. 
        
 
Residual tumor and non-tumorous liver tissue will be collected from surgical resection 
specimens. All samples will be residual samples removed as part of the planned surgical 
procedure. Prior to surgery, a research study assistant will communicate with the surgeon 
regarding a consented patient. 
 
For patients who consent to tissue collection, residual tissue samples will be snap-frozen in 
liquid nitrogen, including a portion embedded in optimum cutting temperature (OCT) 
compound. Each sample will be assigned a unique identifier code and stored in the 
laboratory of Dr. Scott Kopetz. Future studies on this tissue may include examining tumor 
DNA and protein. 
 
 
4.2.2  Chemotherapy alone 
 
Patients randomized to chemotherapy alone will receive chemotherapy at the discretion of 
the treating oncologist as routine standard of care. 
 
4.3 Blood collection 
 
Blood collection will occur at time-points specified in Table 1 and will be coordinated with each 
patient’s standard of care blood draw to minimize additional venipuncture. Specimens will be 
labeled with a unique identifier code. A research study assistant will collect and transport the 
blood to the laboratory of Dr. Scott Kopetz as detailed in Table 2. Plasma samples will be stored 
in -80ºC freezers. 
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Table 2. Blood collection, processing, and storage 
Sample 
type 
BD 
vacutainer 
color 
Volume 
collected 
Transport 
conditions 
Centrifuge 
Transfer and aliquot 
Plasma 
Lavender 
9 ml 
Invert 10 times 
after 
collection. Then 
transport on ice. 
2500 rpm 
(1160xG) x 10 
min at 4ºC 
Transfer plasma layer 
into 500 μl cryovials 
 
4.4 Assessment of stratification factors 
 
The following stratification factors, shown to be significant in the prior retrospective study, shall 
be observed throughout the enrollment period of the study: 
 
• 
Tumor RAS mutational status 
 
• 
 Site of primary tumor, colon vs. rectum8 
 
4.5 Follow-up 
 
Patients will be followed for quality-of-life and survival as shown in Table 1. 
 
4.6 Data collection 
 
Data collection will include the following: 
• 
Patient age and gender 
 
• 
Dates of diagnosis and treatment 
 
• 
Number, size, and distribution of liver and pulmonary metastases 
 
• 
Primary tumor TNM stage, lymphovascular and perineural invasion 
 
• 
Blood CEA levels 
 
• 
Quality-of-life surveys 
 
• 
Perioperative morbidity and mortality 
 
• 
New lung metastases 
 
• 
New liver metastases 
 
• 
Development of tumors outside the liver and lung 
 
• 
Blood loss and transfusions associated with hepatectomy 
 
• 
Molecular testing, including tumor RAS mutational status 
 
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• 
Surgical margins 
 
• 
Site of primary tumor (colon vs. rectum) 
 
• 
Extent of liver resection required (major vs. minor hepatectomy) 
 
• 
Interval since primary resection 
 
 
5.0 Endpoints 
 
 
5.1 Primary endpoint 
 
The primary endpoint is overall survival. 
 
5.2 Secondary endpoints 
 
 
5.2.1 Time to development of extrahepatic, extrapulmonic metastases. 
 
5.2.2 Quality-of-life 
Patients will be asked to complete the Functional Assessment of Cancer Therapy-   
General 7 (FACT-G7) quality-of-life survey at specified time-points listed in Table 1.18 
 
5.2.3 Intrahepatic recurrence among patients randomized to surgery. 
 
5.2.4 Associations between biomarkers and survival. 
 
 
6.0 Statistics and Justification of Sample Size 
 
 
This is a single-center, non-blinded, randomized controlled phase II trial of liver resection or no 
surgery in patients with hepatic and unresectable pulmonary metastases from colorectal cancer. 
Patients will be 1:1 randomized to the surgery arm and non-surgery arm. The primary objective is to 
compare overall survival between the two arms. The overall survival time is defined as the time 
period from the date of randomization to the date of death or the date of last follow-up if the patients 
are alive at the time of last follow-up. 80 patients were planned to be randomized with 40 patients 
per arm, and the randomization was planned to be stratified by tumor Kras mutational status and 
site of primary tumor (colon versus rectum). We are now revising the protocol to randomize 40 
patients with 20 patients per arm. 
 
   Sample size and power 
 
A group sequential design with one interim analysis was initially implemented for the study. The 
primary endpoint is overall survival. A retrospective study showed that the median overall survival 
was 17 months for patients without surgery and 34 months with surgery. A sample size of 80 with 
55 deaths was calculated to have 80% power to detect a difference of 17 months and 34 months 
using a log-rank test at a one-sided significant level of 0.05. Assuming accrual rate is 2 patients per 
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month, the accrual time will be 40 months, and the maximum study duration will be approximately 
60 months. 
 
Due to slower accrual than expected, the trial objectives and statistical analysis plan have 
undergone redesign to account for a smaller sample size. 
 
The study is now targeting an accrual rate of 0.53 patients per month, for a total of 21 patients in 
the next 40 months. Thus, there are expected to be 40 patients in the entire study by the end of 
April 2024.  
 
Due to the lower sample size, no hypothesis testing will be performed. With only 40 subjects, we 
calculate that the originally-planned log-rank test will only have 55% power to detect the assumed 
difference between treatment and control groups. The interim analysis will also be removed due to 
the smaller sample size, although we will continue monitoring for early death. 
 
The primary objective of the adjusted study will be to estimate the survival benefit of liver resection 
in patients with resectable liver and unresectable low-volume pulmonary metastases from colorectal 
cancer. Secondary objectives will remain unchanged. We will accomplish the primary objective by 
calculating the median survival times and restricted mean survival times in both treatment and 
control arms. We will also calculate the differences in median survival and restricted mean survival. 
This information will offer suggestive evidence of the benefit or lack of benefit of liver resection and 
may possibly lead to future trials with a larger sample size.  
 
 
    Monitoring for early death 
 
Death within 30 days from surgery will be monitored. Denote the probability of early death rate by 
TdeathD30. We assume TLE ~ beta (0.05, 0.95). We will stop the enrollment if at any point Pr(TdeathD30 
> 0.05 | data) >0.9. That is, we will stop the trial if, at any time during the study, we determine that 
there is more than 90% chance that the rate of death within 30 days is more than 5%. This toxicity 
monitoring rule will be applied after the first 10 patients have been enrolled. The corresponding 
stopping boundaries are to stop the trial if (number of patients died in 30 days from surgery / number 
of patients) ≥2/10-11, 3/12-19, The operating characteristics are listed in table 3. 
 
Table 3: Operating Characteristics (OCs) for early death monitoring 
True Prob(death in 30 
days from surgery) 
Pr(stop) 
Average # Pts treated 
0.01 
0.006 
 19.94 
0.03 
0.048 
19.57 
0.05 
0.124 
 18.93 
0.08 
0.276 
 17.67 
0.10 
0.386 
 16.74 
0.15 
0.637 
 14.54 
 
Multc Lean V2.1 software developed in the Department of Biostatistics, UT MDACC was used for 
design of monitoring early death. 
    
 
 
    Analysis method 
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The primary analysis will be performed in an intention-to-treat data set. No hypothesis testing will 
be performed. We will calculate the median survival time in both the treatment and control arm, as 
well as the difference in median survival across arms. Additionally, we will calculate the restricted 
mean survival time up to four years in both arms, as well as the difference across arms. 
 
The hazards ratio of overall survival for the surgery arm compared to the non- surgery arm will be 
estimated by fitting Cox proportional hazards regression models, adjusting for the effects of 
covariates including stratification factors. 
 
Adverse events will be tabulated by frequency and percentages, by grade, and by their relations to 
surgical treatment. For secondary analyses, the Kaplan-Meier method will be used to estimate time 
to extrahepatic and extrapulmonary metastases, as well as time to time to intrahepatic recurrence 
among patients randomized to surgery. Univariate and multivariate Cox proportional hazards 
models will be fitted to evaluate the association between biomarkers in blood and resected liver 
specimens and time to event outcomes, including overall survival development of extrahepatic and 
extrapulmonary metastases, and time to intrahepatic recurrence among patients randomized to 
surgery. Univariate and multivariate logistic regression will be used to assess the association 
between biomarkers and response to chemotherapy. 
 
Descriptive statistics including mean, standard deviation, median, and range will be used to 
summarize scores of the FACT-G7 questionnaire for each item. Summation of item GP1, GP4, GP2, 
and GE6 (higher score indicates worse condition) and summation of GF5, GF3 and GF7 (higher 
score indicates better condition) will be calculated for each patient. Two sample t-tests will be used 
to compare scores of each item or summations between the two treatment arms, and also to 
compare their changes after treatment. Linear mixed models will be fitted to compare each item 
between two treatment arms.  
 
 
7.0 Informed Consent/Authorization Procedures 
 
 
Patients will be identified primarily from medical oncology and surgical oncology clinics and will 
require signed consent for participation in this protocol. Patients will be approached by a member 
of the research team in the clinic to request consent. 
 
The investigator must obtain documentation of consent from each potential subject prior to 
participating in a clinical trial. Informed Consent will be conducted in compliance with the Clinical 
Research Administration SOP 4.0 and Institutional Informed Consent Policy 44.0. 
 
The protocol and informed consent documentation for this study must conform to institutional 
regulations and local and national laws and regulations. As soon as a potential subject is considered 
for this study and prior to any other study procedures, each prospective subject will be given a full 
explanation of the purpose of the study, the procedures to be carried out and the potential hazards. 
Once this essential information is provided to the subject and once the Investigator believes that 
the subject understands the implications of participating in the study, the subjects will be asked to 
provide written informed consent and authorization to access medical records needed for study 
documentation.  Subjects will be required to read, sign, and date a properly executed written 
Informed Consent Form prior to enrollment and will be assured that they may withdraw from the 
study at any time without jeopardizing their medical care. They will be given a copy of their Informed 
Consent Form. 
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Patients will either be consented in person, via phone, or through an Institutionally-approved 
teleconferencing system (i.e., Zoom). For patients who are identified as eligible but not available to 
approach and consent in person, a letter will be sent via MyChart to introduce the study prior to 
attempts to contact (see Appendices D and E). These patients will be contacted by phone or 
approved teleconferencing system to assess interest and complete the consent process through 
Institutionally-approved remote-consenting procedures. The same process and language used for 
in-person consenting will be used when remote-consenting participants. 
 
 
8.0 Data Safety and Monitoring Board 
 
 
This study will be monitored by The Data Safety and Monitoring Board (DSMB), through routine 
reviews and/or institutional audits. The DSMB reports to the President, or his designee, as the on- 
campus representative of The University of Texas Board of Regents. It oversees the data and 
patient safety issues for randomized clinical trials that originate at MD Anderson; that are 
coordinated or analyzed by MD Anderson and are not being monitored by any other DSMB; or has 
been designated as the DSMB for any trial at the request of the IRB, the CRC, or institution. The 
primary objectives of the DSMB are to ensure that patients’ rights pertaining to participation in a 
research study are protected, and that patients’ interests are prioritized over the interests of the 
scientific investigation. Responsibilities include: 
 
(a) 
Review interim analyses of outcome data; 
 
(b) 
Determine whether, and to whom, outcome results should be released prior to the 
reporting of study results; 
 
(c) 
Review interim toxicity data and efficacy of treatment; 
 
(d) 
Review major research modifications proposed by the investigator or appropriate 
study committee prior to implementation (e.g., termination, dropping an arm based on 
toxicity results from the study or results of other studies, increasing target sample 
size). 
 
The DSMB consists of not more than 15 members (including the Chair) as recommended by the 
President, or his designee, for each fiscal year. The committee includes physicians, statisticians 
and lay member(s), and will be selected based on their experience, reputation for objectivity, 
absence of conflicts of interest (or the appearance of the same), and knowledge of good clinical trial 
methodology. The committee meets 5 times per year, and may schedule additional meetings if 
needed. 
 
 
9.0 Data Confidentiality: 
 
 
Data will be available to the Principal Investigator (PI) and people directly involved with the collection 
and analysis of data related to this project. IRB approval will be obtained for any exchange of data 
within and outside of MD Anderson. 
 
Collection of Identifiers: Identifiers (name, medical record number and dates) will be collected. 
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Name and MRN will be replaced by study numbers in the analytic file. The key linking these numbers 
will be retained in a locked file by the investigator’s designated personnel. Dates will be retained as 
a limited data set. Data will not be shared with any party outside of MD Anderson and will not be 
retained or disseminated for other research without prior IRB approval.   
 
Training of Personnel: Only MD Anderson personnel designated by the Principal Investigator will 
have access to study records. These personnel will be fully trained to maintain the patient health 
information confidentially. Training will be documented as required by institutional policy. 
 
Data Storage: The PI and research staff will attempt to minimize risk through only storing information 
containing subject identifiers in locked file storage, on password-protected computers, on encrypted 
servers behind an institutional firewall and according to current institutional and federal data security 
requirements. In addition, access to patient identifiers will be limited to the minimum number of 
necessary research personnel, and only to those research personnel directly involved with obtaining 
patient information and assigning random study identifiers. Keys containing information linking study 
subjects to personal identifiers will be maintained in locked storage for paper records or behind 
institutionally-approved firewall and electronic security measures for electronic keys, and available 
ONLY to the PI and research personnel directly involved in creating random study identifiers. 
Information containing subject personal identifiers will not be removed from MD Anderson Cancer 
Center without IRB approval and will not be shared in publications or reports concerning this 
research study. 
 
Data Sharing: Study data will not be shared with any individuals or entities that are not involved in 
the study without IRB approval. No identifying information will be shared with outside collaborating 
sites or outside collaborating research staff without prior IRB approval and a data use or material 
transfer agreement has been implemented. If approval is obtained, sharing of data would be done 
after approval of the PI and only by secure mechanisms, as approved by MD Anderson Information 
Security. 
 
Final Disposition of Study Records: These data will be used for this research study.  Data that is in 
hard-copy form will be retained on site until the study is terminated, and may be stored indefinitely, 
per institutional standards, in long-term off-site storage with an MD Anderson approved, secured 
contract site.  Electronic data will be retained indefinitely on MD Anderson servers behind the 
institutional firewall. Data will not be shared with any party outside of MD Anderson without IRB 
approval and will not be retained or disseminated for other research without prior IRB approval. 
Study data and paper records will not be destroyed but will be retained permanently.  
 
 
10.0 References 
 
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Is Associated with Sequential Adoption of Hepatic Resection and Improved Chemotherapy: A 
Large Clinic‐Based Analysis of Two Institutions. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. 2009:In press. 
2. 
Gonzalez M, Poncet A, Combescure C, Robert J, Ris HB, Gervaz P. Risk factors for survival 
after lung metastasectomy in colorectal cancer patients: a systematic review and meta‐
analysis. Annals of surgical oncology. 2013;20(2):572‐579. 
3. 
Wilson SM, Adson MA. Surgical treatment of hepatic metastases from colorectal cancers. 
Archives of surgery. 1976;111(4):330‐334. 
4. 
Hellman S, Weichselbaum RR. Oligometastases. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. 1995;13(1):8‐10. 
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5. 
Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, 
radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. 
Annals of surgery. 2004;239(6):818‐825; discussion 825‐817. 
6. 
Charnsangavej C, Clary B, Fong Y, Grothey A, Pawlik TM, Choti MA. Selection of patients for 
resection of hepatic colorectal metastases: expert consensus statement. Annals of surgical 
oncology. 2006;13(10):1261‐1268. 
7. 
Elias D, Faron M, Iuga BS, et al. Prognostic similarities and differences in optimally resected 
liver metastases and peritoneal metastases from colorectal cancers. Annals of surgery. 
2015;261(1):157‐ 163. 
8. 
Mise Y, Kopetz S, Mehran RJ, et al. Is complete liver resection without resection of synchronous 
lung metastases justified? Annals of surgical oncology. 2015;22(5):1585‐1592. 
9. 
Maithel SK, Ginsberg MS, D'Amico F, et al. Natural history of patients with subcentimeter 
pulmonary nodules undergoing hepatic resection for metastatic colorectal cancer. Journal of the 
American College of Surgeons. 2010;210(1):31‐38. 
10. Blackmon SH, Stephens EH, Correa AM, et al. Predictors of recurrent pulmonary metastases 
and survival after pulmonary metastasectomy for colorectal cancer. The Annals of thoracic 
surgery. 2012;94(6):1802‐1809. 
11. Zimmitti G, Roses RE, Andreou A, et al. Greater complexity of liver surgery is not associated 
with an increased incidence of liver‐related complications except for bile leak: an experience 
with 2,628 consecutive resections. Journal of gastrointestinal surgery : official journal of the 
Society for Surgery of the Alimentary Tract. 2013;17(1):57‐64; discussion p 64‐55. 
12. Shindoh J, Truty MJ, Aloia TA, et al. Kinetic growth rate after portal vein embolization predicts 
posthepatectomy outcomes: toward zero liver‐related mortality in patients with colorectal liver 
metastases and small future liver remnant. Journal of the American College of Surgeons. 
2013;216(2):201‐209. 
13. Zimmitti G, Vauthey JN, Shindoh J, et al. Systematic use of an intraoperative air leak test at the 
time of major liver resection reduces the rate of postoperative biliary complications. Journal of 
the American College of Surgeons. 2013;217(6):1028‐1037. 
14. Miller G, Biernacki P, Kemeny NE, et al. Outcomes after resection of synchronous or 
metachronous hepatic and pulmonary colorectal metastases. Journal of the American College 
of Surgeons. 2007;205(2):231‐238. 
15. Uppal A, Ferguson MK, Posner MC, Hellman S, Khodarev NN, Weichselbaum RR. Towards a 
molecular basis of oligometastatic disease: potential role of micro‐RNAs. Clinical & 
experimental metastasis. 2014;31(6):735‐748. 
16. Rees JR, Blazeby JM, Fayers P, et al. Patient‐reported outcomes after hepatic resection of 
colorectal cancer metastases. Journal of clinical oncology: official journal of the American 
Society of Clinical Oncology. 2012;30(12):1364‐1370. 
17. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal 
with evaluation in a cohort of 6336 patients and results of a survey. Annals of surgery. 
2004;240(2):205‐ 213. 
18. Yanez B, Pearman T, Lis CG, Beaumont JL, Cella D. The FACT‐G7: a rapid version of the 
functional assessment of cancer therapy‐general (FACT‐G) for monitoring symptoms and 
concerns in oncology practice and research. Annals of oncology: official journal of the 
European Society for Medical Oncology / ESMO. 2013;24(4):1073‐1078. 
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