Phase III Study of Palliative Radiotherapy for Symptomatic Hepatocellular Carcinoma and Liver Metastases
Phase: NA
Conditions: Hepatocellular Carcinoma, Liver Metastases
Sponsor: Canadian Cancer Trials Group

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
AMENDMENT #1: 2018-JUL-31 
 
ADMINISTRATIVE UPDATE #1: 2018-NOV-07 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A PHASE III STUDY OF PALLIATIVE RADIOTHERAPY FOR SYMPTOMATIC 
HEPATOCELLULAR CARCINOMA AND LIVER METASTASES 
 
CCTG Protocol Number: HE.1 
 
 
 
STUDY CHAIR: 
Laura A. Dawson 
 
 
TRIAL COMMITTEE: 
Derek Jonker 
 
 
Jennifer Knox 
 
 
Camilla Zimmerman 
 
 
Philip Wong 
 
 
SENIOR INVESTIGATOR: 
Chris O’Callaghan 
 
 
BIOSTATISTICIAN: 
Dongsheng Tu 
 
 
PHYSICIST: 
Tom Purdie 
 
 
RADIATION THERAPY REVIEWER: 
Alysa Fairchild 
 
 
SYMPTOM CONTROL COMMITTEE 
 
COORDINATOR: 
Rebecca Wong 
 
 
QUALITY OF LIFE COORDINATOR: 
Jolie Ringash 
 
 
STUDY COORDINATOR: 
Paul Stos 
 
 
REGULATORY SPONSOR: CCTG  
 
 
(For contact information of study personnel see Final Page.) 
 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) ........................................................................................... 1 
 
TREATMENT SCHEMA ............................................................................................................................................. 2 
 
1.0 
OBJECTIVES ................................................................................................................................................. 3 
1.1 
Primary Objective ............................................................................................................................ 3 
1.2 
Secondary Objectives....................................................................................................................... 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ............................................................................... 4 
2.1 
Liver Cancer .................................................................................................................................... 4 
2.2 
Symptoms from End-Stage Liver Cancer ........................................................................................ 4 
2.3 
Radiation Therapy in Liver Cancer .................................................................................................. 5 
2.4 
Rationale for a Phase III Study in Symptomatic Liver Cancer Patients .......................................... 5 
2.5 
Rationale for Patient-Reported Instruments ..................................................................................... 6 
2.6 
Correlative Studies ........................................................................................................................... 7 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION .................................................................................... 8 
 
4.0 
TRIAL DESIGN ............................................................................................................................................. 9 
4.1 
Stratification ..................................................................................................................................... 9 
4.2 
Randomization ................................................................................................................................. 9 
4.3 
Inclusion of Women and Minorities ................................................................................................ 9 
 
5.0 
STUDY POPULATION................................................................................................................................ 10 
5.1 
Eligibility Criteria .......................................................................................................................... 10 
5.2 
Ineligibility Criteria ....................................................................................................................... 12 
 
6.0 
PRE-RANDOMIZATION EVALUATION .................................................................................................. 14 
 
7.0 
ENTRY/RANDOMIZATION PROCEDURES ............................................................................................ 16 
7.1 
Entry Procedures ............................................................................................................................ 16 
7.2 
Stratification ................................................................................................................................... 16 
7.3 
Randomization ............................................................................................................................... 16 
 
8.0 
TREATMENT PLAN ................................................................................................................................... 17 
8.1 
Best Supportive Care (Arms 1 and 2) ............................................................................................ 17 
8.2 
Arm 1: Best Supportive Care Alone .............................................................................................. 17 
8.3 
Arm 2: Radiation Therapy plus Best Supportive Care .................................................................. 18 
8.4 
Radiation Treatment Plan .............................................................................................................. 19 
8.5 
Concomitant Therapy..................................................................................................................... 25 
 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT ...................................................... 27 
9.1 
Compliance .................................................................................................................................... 27 
9.2 
Adverse Events .............................................................................................................................. 27 
9.3 
Evaluation During/After Protocol Treatment ................................................................................ 28 
9.4 
Evaluation After Protocol Treatment ............................................................................................. 28 
 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ................................................................. 29 
10.1 
Definitions ..................................................................................................................................... 29 
10.2 
Measurement Tools ........................................................................................................................ 29 
 
 
 

 
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11.0 
SERIOUS ADVERSE EVENT REPORTING .............................................................................................. 30 
11.1 
Definition of a Reportable Serious Adverse Event ........................................................................ 30 
11.2 
Serious Adverse Event Reporting Instructions .............................................................................. 30 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting ............................................................ 31 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .......................... 32 
11.5 
Reporting Serious Adverse Events to Investigators ....................................................................... 32 
 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ..................... 33 
12.1 
Therapy After Protocol Treatment is Stopped ............................................................................... 33 
 
13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION ....................................................... 34 
13.1 
Central Radiology Review ............................................................................................................. 34 
13.2 
Central Pathology Review ............................................................................................................. 34 
13.3 
Radiotherapy Quality Assurance (RTQA) ..................................................................................... 34 
13.4  
Blood Collection ............................................................................................................................ 34 
 
14.0 
STATISTICAL CONSIDERATIONS .......................................................................................................... 35 
14.1 
Objectives and Design ................................................................................................................... 35 
14.2 
Endpoints and Analysis.................................................................................................................. 35 
14.3 
Sample Size and Duration of Study ............................................................................................... 35 
14.4 
Safety Monitoring .......................................................................................................................... 36 
14.5 
Interim Analysis ............................................................................................................................. 36 
 
15.0 
PUBLICATION POLICY ............................................................................................................................. 37 
15.1 
Authorship of Papers, Meeting Abstracts, Etc ............................................................................... 37 
15.2 
Responsibility for Publication ........................................................................................................ 37 
15.3 
Submission of Material for Presentation or Publication ................................................................ 37 
 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES .............................................................. 38 
16.1 
Regulatory Considerations ............................................................................................................. 38 
16.2 
Inclusivity in Research ................................................................................................................... 38 
16.3 
Obtaining Informed Consent .......................................................................................................... 38 
16.4 
Discontinuation of the Trial ........................................................................................................... 39 
16.5 
Retention of Patient Records and Study Files ................................................................................ 40 
16.6 
Centre Performance Monitoring .................................................................................................... 40 
16.7 
On-Site Monitoring/Auditing ......................................................................................................... 40 
16.8 
Case Report Forms ......................................................................................................................... 40 
 
17.0 
REFERENCES .............................................................................................................................................. 41 
 
APPENDIX I - PATIENT EVALUATION FLOW SHEET ....................................................................................... 43 
APPENDIX II - PERFORMANCE STATUS SCALES/SCORES ............................................................................. 44 
APPENDIX III - GUIDANCE FOR DETERMINING “STABLE” PAIN PRE-RANDOMIZATION ...................... 45 
APPENDIX IV - DETERMINING CHILD-PUGH SCORE ...................................................................................... 47 
APPENDIX V - DOCUMENTATION FOR STUDY ................................................................................................ 48 
APPENDIX VI - TRIAL OVERVIEW ....................................................................................................................... 50 
APPENDIX VII - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ................................ 52 
APPENDIX VIII - EXAMPLES OF TYPICAL PALLIATIVE RADIOTHERAPY TO THE LIVER ...................... 53 
APPENDIX IX - QUALITY OF LIFE ASSESSMENT ............................................................................................. 56 
APPENDIX X - PRE-BASELINE PAIN/DISCOMFORT QUESTIONNAIRE ........................................................ 64 
APPENDIX XI - PAIN/DISCOMFORT AND MEDICATION QUESTIONNAIRE ................................................ 67 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 

 
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AMEND #1: 2018-JUL-31 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to CCTG. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and any 
applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate resource 
to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG to study personnel 
under my supervision. I will discuss this material with them to ensure that they are fully informed about the 
investigational product and the study.  
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of CCTG. The foregoing shall not apply to disclosure required 
by governmental regulations or laws; however, I will give prompt notice to CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
 
Protocol Number: CCTG HE.1 
 
CENTRE: ___________________________________________ 

 
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AMEND #1: 2018-JUL-31 
TREATMENT SCHEMA 
 
This is a multi-centre, randomized, phase III trial of best supportive care (BSC) with or without single 
fraction liver radiation therapy (8 Gy) in patients with end-stage, painful, hepatocellular carcinoma (HCC) 
or liver metastases. 
 
Stratification: 
• 
Centre 
• 
Type of liver cancer (HCC versus liver metastases) 
 
Patients with 
HCC or liver mets 
are assessed for 
stable pain / 
discomfort  
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
ARM 1: 
Best Supportive Care 
 
ARM 1 patients may receive RT (8Gy/1*)  
if desired after 1 month assessment 
 
Assessment of 
pain/discomfort on 
day 30 
 
Assessment of 
pain/discomfort on 
day 90 
 
 
 
 
 ARM 2: 
Best Supportive Care 
+ RT 8 Gy/1* 
 
 
 
 
 
 
* Patients will also receive anti-emetic pre-medications 
Planned sample size: 45 eligible (approximately 65 randomized) 
 
Primary Endpoint 
• 
Proportion of patients achieving improvement of liver cancer pain/discomfort by ≥ 2 points in pain 
"intensity at worst " on Brief Pain Inventory (BPI) from baseline to day 30. 
 
Secondary Endpoints  
• 
Proportion of patients experiencing grade ≥ 2 adverse events at day 30 and day 90. 
• 
Proportion of patients alive at day 90. 
• 
Proportion of patients achieving improvement of liver cancer pain/discomfort by ≥ 2 points from 
baseline to day 30 and day 90 in all BPI pain scores. 
• 
Proportion of patients reporting clinically significant improvement in QoL from baseline to day 30 and 
day 90 as defined by a ≥ 5 point change in the Functional Assessment of Cancer Therapy (FACT) 
Hepatobiliary Subscale (FACT-HBS) and Trial Outcome Index (FACT-TOI). 
• 
Proportion of patients achieving a 25% reduction in opioid use at 30 days (employing daily morphine 
equivalence scale). 
• 
Proportion of patients achieving improvement of liver cancer pain/discomfort by ≥ 2 points in pain 
"intensity at worst " AND with no increase in opioid use (employing daily morphine equivalence scale) 
on BPI from baseline to 30 days. 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To determine if patients with symptomatic liver tumours (either HCC or liver metastases) who 
undergo best supportive care (BSC) plus a single 8 Gy fraction of radiation therapy to the liver 
experience a significant improvement in symptoms (defined as a ≥ 2 point decrease in their pain 
“intensity at worst” score on the Brief Pain Inventory (BPI)) from baseline to 30 days as compared 
to patients receiving BSC alone. 
 
1.2 
Secondary Objectives 
 
To compare the two treatment arms with respect to: 
• 
Proportion of patients experiencing grade ≥ 2 adverse events at 30 days and 90 days. 
• 
Proportion of patients alive at 90 days. 
• 
Proportion of patients achieving improvement of liver cancer pain/discomfort by ≥ 2 points 
from baseline to day 30 and day 90 in all BPI pain scores. 
• 
Proportion of patients reporting clinically significant improvement in QoL from baseline to day 
30 and day 90 as defined by a ≥ 5 point change in the Functional Assessment of Cancer Therapy 
(FACT) Hepatobiliary Subscale (FACT-HBS) and Trial Outcome Index (FACT-TOI). 
• 
Proportion of patients achieving a 25% reduction in opioid use at 30 days (employing daily 
morphine equivalence). 

 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
2.1 
Liver Cancer 
 
Hepatocellular carcinoma (HCC) is a top cause of cancer-related death globally and the most 
rapidly increasing cause of cancer death in Canada. In 2013, in Canada, there were over 2000 new 
HCCs and 1000 deaths due to HCC [2013 Canadian Cancer Society Statistics]. HCC is often diagnosed at 
an advanced stage, and symptoms of pain, anorexia and fatigue are common, especially in patients 
unsuitable for or refractory to standard local, regional and systemic therapies [Zhu 2003].  
 
The liver is a common site for metastases from a variety of gastrointestinal malignancies (e.g. 
colorectal and pancreatic cancer), as well as non-gastrointestinal malignancies, including, 
melanoma, breast and gynecological cancers. It is estimated that approximately 25,000 Canadian 
patients die with liver metastases each year [2013 Canadian Cancer Society Statistics]. Surgery and other 
local therapies are treatment options for the minority of patients with ‘oligo’ or few hepatic 
confined metastases; however the majority of patients are not suitable for local therapies due to 
insufficient hepatic reserve and/or a high risk of extra-hepatic disease.  
 
2.2 
Symptoms from End-Stage Liver Cancer 
 
The majority of HCC patients experience liver pain or discomfort at some point during their disease 
course. Pain is likely under-reported in these patients and sometimes dismissed as “discomfort”, 
despite the significant negative impact on patients’ lives [Kaiser 2014]. It has been suggested that 
there is a need for routine pain assessment as an integral component of advanced HCC patient care 
[Kaiser 2014]. While pain related to liver metastases is not as common as in HCC patients, in later 
stages, diffuse and/or large hepatic metastases may invade into or stretch the liver capsule causing 
substantial discomfort. For HCC and liver metastases, the majority of patients become refractory 
to all therapy for a period of time prior to death and a substantial proportion of these patients suffer 
from hepatic pain. Effective palliation of hepatic pain can be challenging for these patients and 
there is a need for improved palliative treatments.  
 
Opioids are commonly used for the palliation of cancer bone pain or other cancer pain outside the 
liver. However, in patients with impairment of liver function from underlying liver disease, which 
is common in patients with liver cancer, there is often reduced hepatic blood flow, limiting first 
pass metabolism, and phase I metabolism (P450 system) and phase II metabolism (glucuronidation) 
do not work as well. Thus, the parent drug or its metabolites can accumulate, which may precipitate 
encephalopathy or excessive sedation causing difficulty with compliance and/or in attaining 
analgesia without toxic side effects. The therapeutic index for opioid-induced pain relief is 
narrowed in many patients with hepatic pain from liver cancer. Alternate and additional strategies 
for hepatic pain from end-stage HCC or liver metastases are warranted to reduce pain and improve 
quality of life (QoL) in these patients. 

 
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The natural history of patients with symptomatic liver cancer has not been well researched and 
there are only a few studies of patient-reported QoL or symptom trials in patients with symptomatic 
liver cancer. In one study of patients treated with chemotherapy for asymptomatic liver metastases 
from colorectal carcinoma, there was no improvement in QoL (assessed using EORTC QLQ-C30 
and QLQ-LMC21) and more problems with taste, sore mouth, and neuropathy 3 months after 
chemotherapy [Blazeby 2009]. Although these results are not directly comparable with the HE.1 study 
cohort who are selected as being unfit for or refractory to systemic agents, it seems unlikely that 
QoL in patients with more advanced liver metastases or HCC may improve with no interventions 
or with best supportive care (BSC) alone. There is a paucity of studies that have evaluated the 
impact of BSC or other treatments on symptoms in patients with end-stage primary or metastatic 
liver cancer and there is a strong need for prospective evaluation of patient-reported outcomes in 
such patients treated with novel interventions, such as radiation therapy (RT) or BSC alone. 
 
2.3 
Radiation Therapy in Liver Cancer 
 
In selected patients with focal HCC or liver metastases unsuitable for surgery, high dose, conformal 
RT or stereotactic body radiation RT (SBRT) are being increasingly used. Phase I and II studies 
have demonstrated tumour control at 1 and 2 years in the majority of patients [Bujold 2013; Herfarth 
2003(b); Hoyer 2006; Lee 2009; Mendez 2006; Pan 2010; Seong 2000]. However, due to the extent of liver 
involvement with cancer (e.g. diffuse metastases), poor underlying liver function, and/or presence 
of extra-hepatic metastases, the majority of patients with primary or metastatic liver cancer are not 
candidates for conformal RT or SBRT. The tolerance of the whole liver to radiation therapy is low, 
and radiation-induced liver toxicity can result if the whole liver is treated with more than 
approximately 30 Gy in 2 Gy per fraction (a dose too low to lead to tumour ablation). 
 
There have been few studies of low-dose liver RT to palliate symptoms from liver cancer and most 
have not included patient-reported outcomes [Borgelt 1981; Bydder 2003; Ingold 1965; Prasad 1977; Sherman 
1978; Turek-Maischeider 1975; Wharton 1973]. The largest of these studies delivered 21 Gy in 7 fractions 
to the whole liver and randomized patients to misonidazole; there was an 80% response rate of 
abdominal pain, with a median duration of response of 13 weeks [Leibel 1987]. A Trans-Tasman 
Radiation Oncology Group study observed a physician-reported symptom response of 54% at 2 
weeks following 10 Gy in 2 fractions to the whole liver to palliate symptoms from liver metastases 
with two grade 3 toxicities [Bydder 2003]. 
 
2.4 
Rationale for a Phase III Study in Symptomatic Liver Cancer Patients 
 
A phase II study of 8 Gy in one fraction to the whole (or near-whole) liver for the palliation of 
symptoms from liver cancer was conducted at the Princess Margaret Cancer Center by Dr. Dawson 
and colleagues [Soliman 2013]. The rationale for the use of a single fraction of RT was multi-fold. 
Using the shortest effective fractionation (ideally over one day) is more convenient for patients 
with a limited life expectancy, such as those in the HE.1 study. Eight Gy in one fraction is the 
lowest dose that has been used successfully to palliate cancer pain in other body parts, including 
bone metastases, even in the absence of objective radiological responses [Lutz 2014; Salazar 2001]. 
RT-induced liver toxicity can result if the whole liver is treated with doses higher than 30 Gy in 15 
fractions [Pan 2010], and 8 Gy in one fraction is a much lower biologic dose than 30 Gy in 15 
fractions. Also, 8 Gy in one fraction has been shown to be safely used in the setting of hemi-body 
irradiation of patients with bony metastases in which the liver was included in the irradiated 
volume; although grade 3-4 toxicity was seen in 12% of patients treated with hemibody RT, it was 
primarily hematologic [Salazar 2001]. 

 
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The Princess Margaret Cancer Centre study investigated 41 patients with diffuse HCC (21) or liver 
metastases (20, 50% from a gastrointestinal primary site) who had pain (27), discomfort (6) or other 
(5) symptoms [Soliman 2013]. The use of 8 Gy in one fraction to the whole (or near whole) liver, with 
an anti-emetic to prevent nausea, resulted in a clinically meaningful improvement in average index 
symptom intensity assessed using the BPI in 48% (95% CI: 28-68%) of patients one month 
following RT with no differences between patients with HCC and liver metastases. In patients with 
pain or abdominal discomfort as their index symptom, pain relief tended to occur within a few days 
and was sustained with a clinically significant improvement at one month in 55% (95% CI: 32-
76%) of patients when evaluating “average” pain/discomfort, and in 59% (95% CI: 36-79%) when 
evaluating “worst” pain/discomfort in the past 24 hours. The pathophysiology of pain relief is not 
clearly understood; however objective tumour shrinkage is not required for effective pain relief. 
There was no reduction in symptoms in patients who had nausea or fatigue as their index symptom. 
RT treatment was well tolerated. Grade 1 or 2 fatigue, often present at baseline, was common; grade 
1 or 2 nausea was seen in 3 patients, and grade 2 gastritis was seen in 1 patient. One patient, who 
declined anti-emetics prior to RT, developed grade 3 vomiting. There was no other reported 
toxicity. From a QoL perspective, the benefits were less. Twenty-nine percent (95% CI: 8 – 45%) 
of patients treated with RT had a significant improvement in FACT-HBS at 30 days and 25% (95% 
CI: 10- 47%) of patients had significant improvement in FACT- TOI at 30 days. Based on the 
results of this pilot study, the next logical step is to test, in a multi-institutional randomized study, 
that RT may lead to a clinically significant hepatic pain reduction and QoL improvement in a 
greater proportion of patients compared to BSC alone [Hoyer 2012]. 
 
2.5 
Rationale for Patient-Reported Instruments 
 
Patient-reported symptoms will be recorded using the Brief Pain Inventory (BPI), which consists 
of 4 pain intensity and 7 pain interference 11-point Likert-scale questions (range 0-10) [Cleeland 
1994]. BPI is easy to administer, imposing minimum burden to patients. It also has been translated 
and validated into many different languages. Patients who report liver discomfort (as opposed to 
liver “pain”), will still complete the “pain” questions. Although the BPI has not been validated for 
measuring ‘discomfort’, it has face validity for this use, and its 0-10 scale is also used in the 
Edmonton Symptom Assessment Scale (ESAS) [Bruera 1991] and the MD Anderson Symptom 
Inventory [Cleeland 2000], which are both validated and include a wide variety of symptoms. This 
was shown to be feasible in the study by Soliman and colleagues [Soliman 2013]. A reduction by ≥ 2 
from baseline score is considered clinically significant [Chow 2002]. The primary outcome measure 
for the present study will be the proportion of patients experiencing improvement by ≥ 2 points 
from baseline to 30 days on "worst pain" in past 24 hours on BPI. Worst pain and average pain in 
the past 24 hours were the most sensitive metrics to detect change in symptoms in the study by 
Soliman and colleagues [Soliman 2013]. Worst pain was chosen as the primary endpoint since it (a) 
has the highest short term reliability (0.93) of all the BPI pain intensity scales [Cleeland 1994, BPI user 
guide 2009], (b) is recommended as the primary pain endpoint in trials assessing response to palliative 
radiation therapy for bone metastases, and (c) has higher correlations with functional interference 
scores and is felt to be most important to patients, compared with other BPI scores [Harris 2007]. 

 
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Patient-reported QoL will be recorded using the Functional Assessment of Cancer Therapy 
Hepatobiliary (FACT-Hep) questionnaire, a 45-item instrument consisting of the 27-item cancer 
specific FACT-General (FACT-G), and a site-specific 18-item hepatobiliary subscale (HBS) 
(Heffernan 2002). The FACT-G consists of four subscales: 1) physical well-being (PWB); 2) social 
and family well-being; 3) emotional wellbeing; and 4) functional well-being (FWB). The Trial 
Outcome Index (TOI) is the sum of the PWB, FWB and HBS subscales [Cella 1993]. The total FACT-
TOI score, FACT-Hep score, FACT-G score and individual scores for each subscale will be scored. 
FACT was chosen for measuring QoL in these patients since, in the Phase II study, patient 
compliance was better with FACT versus EORTC [Soliman 2013], and FACT was more sensitive to 
demonstrating benefits in patients than EORTC. FACT QoL has been validated in the use of bone 
metastases response to radiation therapy and is available in different languages. Changes in QoL 
are secondary endpoints of this study. The FACT HBS and TOI QoL endpoints are expected to be 
most likely to discriminate between differences in QoL in the two treatment arms. A change in 
scores of the FACT-G, FACT-HBS, FACT-TOI and FACT-Hep total score by ≥ 6, ≥ 5, ≥ 7 and 
≥ 8 respectively are considered clinically significant [Heffernan 2002]. 
 
2.6 
Correlative Studies 
 
The mechanism of liver-related cancer pain and how radiation therapy may reduce pain is not well 
understood. Hepatic pain may be caused by direct tumour invasion or stretch of the hepatic capsule, 
by infiltration of adjacent organs (such as diaphragm or chest wall), or from a large burden of cancer 
causing mass effect in the abdomen and/or releasing chemicals that may increase the pain response 
to otherwise non-painful stimuli. Furthermore, hepatic visceral pain can be diffuse and difficult for 
patients to describe. The rapid benefit to patients following low dose radiation therapy seen in the 
Soliman study [Soliman, 2013] (at 1 week and 1 month post radiation therapy) suggests that reduction 
in pain is not due to objective tumour responses that would be unexpected following such low dose 
radiation therapy (8 Gy in one fraction). Radiation has been postulated to reduce bone pain from 
metastases from a direct tumour effect on tumours stimulating them to reduce their production of 
pain “promoting” cytokines [Goblirsch 2005]. This may be mediated by an inflammatory pathway. 
Pro-inflammatory cytokines been associated with pain and changes in serum cytokines (including 
C-reactive protein, TGFβ, interleukin-1 (IL-1) and IL-6) have has been observed following 
radiation therapy [Menard 2006, Bower 2009]. Changes in IL-6 have been correlated with radiation 
associated fatigue. 
 
It is hypothesized that larger changes in the inflammatory cytokines post radiation therapy will be 
more highly correlated with patient reported reduction of pain. In the present study, by collecting 
serum at the time of planned blood draws (baseline, 30 days and 90 days post randomization), 
changes in cytokines or other proteins can be measured. If there are patterns of change in 
inflammatory cytokines highly correlated with the strongest responders post radiation therapy, this 
may provide some insight to the mechanism of pain relief from radiation therapy, which may help 
in future research to try to exploit the palliative benefit of radiation therapy. 

 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
There are no therapeutic agents involved in this study. 
 

 
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AMEND #1: 2018-JUL-31 
4.0 
TRIAL DESIGN 
 
Please see Appendix VI for a schematic overview of the trial. 
 
4.1 
Stratification 
 
Patients will be stratified by: 
• 
Centre 
• 
Type of liver cancer (HCC versus liver metastases) 
 
4.2 
Randomization 
 
Patients will be randomized 1:1 to receive best supportive care alone or best supportive care plus 
radiation therapy (8 Gy in 1 fraction), to a planned sample size of  approximately 65 patients (45 
eligible). 
 
Arm 
Agent(s) 
Dose 
Volume 
Duration 
1 
Best Supportive Care* 
--- 
--- 
90 days 
2 
Best Supportive Care* 
--- 
--- 
90 days 
Palliative Radiation 
Therapy ** 
8 Gy in 1 fraction 
Whole liver or near 
whole liver 
--- 
* 
Including analgesics, palliative care and/or pain specialist assessment as needed. 
** 
Including anti-emetic pre-medications. 
 
4.3 
Inclusion of Women and Minorities 
 
There are no exclusions based on race or ethnicity in this trial. 
 
To date, there is no evidence of superiority of one form of treatment over another according to 
racial or ethnic group. The appropriate racial/ethnic mix will be recruited to this study based on the 
epidemiology of cancer in the participating centres. 

 
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5.0 
STUDY POPULATION 
 
This study will recruit patients with hepatic pain or discomfort from HCC or liver metastases. In 
the 7 days prior to randomization, patients must have no significant change (range of 3 points is 
allowable) in pain score as measured over 2 days. All patients will receive best supportive care, 
and it is recommended that this include a palliative care or pain specialist assessment prior to 
randomization, when available. 
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed prior to randomization. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfil all of the following criteria to be eligible for admission to the study: 
 
5.1.1 
A diagnosis of cancer by at least one criterion listed below: 
• 
Pathologically or cytologically proven carcinoma from primary site or site of metastases; 
• 
Pathologically or cytologically proven HCC; 
• 
HCC diagnosed by standard imaging criteria: arterial enhancement and delayed washout on 
multiphasic computerized tomography (CT) or magnetic resonance imaging (MRI) in the 
setting of cirrhosis or chronic hepatitis B or C without cirrhosis. 
 
5.1.2 
Largest burden of cancer in the liver is confirmed with CT scan or MRI  corresponding to the 
clinically painful area done within 120 days prior to randomization. 
 
5.1.3 
Diffuse (infiltrative involving > 50% of the liver), multifocal (> 10 lesions) or locally advanced 
cancer (at least one lesion > 10cm, vascular invasion, or multiple lesions with at least one > 6cm) 
involving the liver. 
 
5.1.4 
In the investigator’s opinion, patient is unsuitable for or refractory to standard local and regional 
therapies. For example: 
• 
HCC unsuitable for resection, radiofrequency ablation (RFA), transarterial chemo 
embolization (TACE) or radical intent, ablative dose stereotactic body radiation therapy 
(SBRT); 
• 
Colorectal carcinoma metastases unsuitable for resection, RFA or radical intent, ablative dose 
SBRT (e.g. SBRT, > 30 Gy in 5 fractions, may be an option for up to 3 metastases < 5cm each, 
or up to 5 metastases < 3 cm each). 
 
5.1.5  Unsuitable for, high risk for, or refractory to, standard systemic chemotherapy or targeted therapy 
(e.g. sorafenib). 

 
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5.1.6 
Patient reports moderate or severe pain/discomfort prior to the baseline evaluation and this pain is 
considered “stable” over a period of up to 7 days prior to randomization (see Appendix III for full 
details); 
 
Definition of moderate pain: 
Patient reports level of 4-6 (on a BPI scale from 0 to 10) pain or discomfort “at its worst in the 
past 24 hours”, occurring in the right upper quadrant of the abdomen, the upper abdomen and/or 
referred to the right shoulder, attributable to liver cancer. 
 
Definition of severe pain: 
Patient reports level of 7-10 (on a BPI scale from 0 to 10) pain or discomfort “at its worst in 
the past 24 hours”, occurring in the right upper quadrant of the abdomen, the upper abdomen 
and/or referred to the right shoulder, attributable to liver cancer. 
 
Definition of “stable” pain: 
Patient must show moderate or severe “stable” pain by reporting a score of 4 or greater (on 2 
separate days within the 7 day period prior to randomization) with the difference of these scores 
being 0, 1, 2 or 3. 
 
5.1.7 
Patient reports moderate or severe pain (i.e. pain score is 4 or higher). This baseline score must also 
be stable compared to the most recent pre-baseline pain score with the difference between these 
scores being 0, 1, 2, or 3 (see Appendix III for full details). 
 
5.1.8 
Blood work obtained within 14 days prior to randomization as follows: 
• 
Hemoglobin > 70 g/L; 
• 
Platelets > 25 x 109/L; 
• 
Absolute neutrophil count (ANC) > 1.0 x 109/L; 
• 
INR < 3; 
• 
Bilirubin < 2.5 UNL (except for subjects with Gilbert’s Disease who are eligible despite 
elevated serum bilirubin level); 
• 
AST or ALT < 10 x ULN. 
 
5.1.9 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-3 within 14 days of 
Randomization (see Appendix II). 
 
5.1.10 Life expectancy of > 3 months. 
 
5.1.11 18 years of age or older at the time of randomization. 
 
5.1.12 Patient is willing to complete the Pre-Baseline Pain/Discomfort Questionnaire and the 
Pain/Discomfort and Medication Questionnaire in English, French or other validated language 
(please contact the HE.1 Study Coordinator). The baseline assessment must be completed within 
required timelines prior to randomization. Unwillingness to complete the Pre-Baseline 
Pain/Discomfort Questionnaire and Pain/Discomfort and Medication Questionnaire will make the 
patient ineligible for the study. 

 
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AMEND #1: 2018-JUL-31 
5.1.13 Patient is able (i.e. sufficiently fluent) and willing to complete the QoL questionnaires in English, 
French or other languages in which the FACT-Hep is available (please contact the HE.1 Study 
Coordinator). The baseline assessment must be completed within required timelines prior to 
randomization.  
 
Inability (illiteracy in languages listed above, loss of sight, or other equivalent reason) to complete 
the questionnaires will not make the patient ineligible for the study. However, ability but 
unwillingness to complete the QoL questionnaires will make the patient ineligible for QoL 
assessment. 
 
5.1.14 Patient is not pregnant, planning on becoming pregnant or planning on fathering a child in the next 
90 days. 
 
Women/men of childbearing potential must have agreed to use a highly effective contraceptive 
method. A woman is considered to be of "childbearing potential" if she has had menses at any time 
in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or 
with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously 
celibate patient chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive 
measures. 
 
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the 
Pre-Study Evaluation (see Appendix I); this may include an ultrasound to rule-out pregnancy if a 
false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and 
partner is vasectomized, it may be associated with tumour production of hCG, as seen with some 
cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 
5.1.15 Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrolment in the trial to document 
their willingness to participate; 
 
5.1.16 Patients must be accessible for treatment and follow-up. Investigators must ensure the patients 
randomized on this trial will be available for complete documentation of the treatment, adverse 
events, and follow-up. 
 
5.1.17 In accordance with CCTG policy, protocol treatment is to begin within 5 working days of patient 
randomization (earlier is preferred). 
 
5.2 
Ineligibility Criteria 
 
Patients who fulfil any of the following criteria are not eligible for admission to the study: 
 
5.2.1 
Prior radiotherapy to the upper abdomen that would result in substantial overlap of the irradiated 
volume (e.g. > 50% of liver receiving > 24 Gy in 2 Gy equivalent dose). 
 
5.2.2 
Prior selective internal radiotherapy directed to the liver or hepatic arterial yttrium therapy, at any 
time. 

 
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5.2.3 
Cholangitis or acute bacterial infection requiring intravenous antibiotics within 28 days prior to 
study entry. 
 
5.2.4 
Radiographic evidence of intrabiliary cancer within the common or main branches of the biliary 
system, < 4 months prior to randomization. 
 
5.2.5 
Child-Pugh score greater than C10 (a score of C10 is allowed). 
 
5.2.6 
Chemotherapy or TACE administered within the past 4 weeks. 
 
5.2.7 
Targeted therapy (e.g. Sorafenib) received within the past 2 weeks. 
 
5.2.8 
Plans for chemotherapy, targeted therapy or TACE in the next 4 weeks. 

 
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ADMIN UPDATE #1: 2018-NOV-07 
6.0 
PRE-RANDOMIZATION EVALUATION 
(See Appendix I) 
 
In order to avoid enrolling patients with rapidly escalating or diminishing pain/discomfort, patients 
will be asked to demonstrate that they have moderate or severe, stable pain/discomfort. In addition, 
it is strongly recommended that the patient’s use of analgesia is “stable” in the opinion of the 
investigator. Thus, all patients will need to assess their pain/discomfort over the previous 24 hours 
on 2 separate days during the week prior to study randomization. It is envisioned that this 
assessment will be after the patient signs the informed consent document and will involve 
completion of Pre-Baseline Pain/Discomfort Questionnaires, however, where a patient-reported 
pain score was obtained using the BPI pain questionnaire as part of routine clinical care and has 
been recorded in the patient medical record (i.e. as verifiable source documentation) prior to the 
patient consenting to participation on the trial, this score may be used as a “Pre-Baseline” value to 
demonstrate the patient has met the eligibility criteria concerning adequate and stable pain. All Pain 
scores must be collected and reported using the trial specific Pre-Baseline BPI pain questionnaire.  
 
Patients will be given several copies of the Pre-Baseline Pain/Discomfort Questionnaire that they 
are to complete on two separate days within one week. The questionnaire will contain the “pain at 
worst in the past 24 hours” intensity question from the BPI. 
 
Sites will use this information to determine if the patient has stable pain/discomfort (as described 
in Appendix III, with a range in scores of 0, 1, 2, or 3). The questionnaires may be completed at 
home by the patient and the site staff will phone the patient to help serve as a reminder.  
 
If patients have changing pain/discomfort, (as described in Appendix III, with a range in scores of 
4 or more) then they are not suitable for randomization. They may have their analgesia optimized 
and/or may repeat the 2 day assessment until they have stable pain/discomfort (with range in scores 
of 3 or less) over a 7 day time period, at which point they may be considered for the study. It is 
expected that it may take more than 2 days for some patients to reach a “steady state” pain score, 
and patients with high variability in their pain scores at first attempt are encouraged to be re-
considered for participation in the study at any time, if they develop stable pain. 
 
After stable pain is determined, the patient will be asked to complete the baseline Pain/Discomfort 
and Medication Questionnaire. If the baseline “worst” pain score is 4 or greater and if it is within 
3 points of the most recent pre-baseline pain score, the patient is considered eligible. The patient 
will complete the baseline QoL Questionnaire and will undergo an adverse event evaluation by the 
investigator. These assessments will provide the necessary baseline data for analysis of the trial 
endpoints. 
 
Please see Appendix III for guidance in determining “stable” pain/discomfort during the pre-
baseline screening period and for examples of different scenarios that might occur. 
 
It is recommended that BSC practices be initiated for all patients prior to randomization. BSC for 
this population may include an assessment by a palliative care or a pain specialist team (per local 
policy). This should help to avoid confounding effects from palliative care/pain specialist 
assessment if the first such visit was post randomization but prior to the day 30 primary endpoint 
assessment. 
 
 

 
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Investigations 
Timing 
History and 
Physical Exam 
including: 
• 
ECOG PS (see Appendix II) 
• 
weight 
• 
assessment of ascites and encephalopathy (Child 
Pugh score – see Appendix IV) 
≤ 14 days prior to randomization 
Hematology 
• 
hemoglobin 
• 
platelets 
• 
INR 
• 
neutrophils 
≤ 14 days prior to randomization 
Biochemistry 
• 
albumin 
• 
bilirubin 
• 
AST and/or ALT 
• 
ALP 
• 
creatinine 
• 
alpha-fetoprotein (for HCC patients only) 
≤ 14 days prior to randomization 
Radiology 
• 
CT or MRI scan of abdomen which establishes 
liver metastases or HCC per eligibility criteria 
≤ 120 days prior to randomization 
Pre-Baseline Stable 
Pain/Discomfort 
Assessment 
• 
Pre-Baseline Pain/Discomfort Questionnaire x2 
days within a one week period prior to 
randomization (range in BPI pain/discomfort 
scores up to 3 permitted) 
≤ 7 days prior to randomization 
Baseline 
Pain/Discomfort 
Assessment 
• 
Pain/Discomfort and Medication Questionnaire 
Following the completion of the last 
Pre-Baseline Pain/Discomfort 
Questionnaire that defined stability 
and on or prior to the date of 
randomization 
Baseline Analgesia 
Assessment 
• 
Pain/Discomfort and Medication Questionnaire 
Following the completion of the last 
Pre-Baseline Pain/Discomfort 
Questionnaire that defined stability 
and on or prior to the date of 
randomization 
Adverse Events* 
• 
Baseline adverse event evaluation (to document 
residual adverse event from previous therapy and 
baseline symptoms) 
Following the completion of the last 
Pre-Baseline Pain/Discomfort 
Questionnaire that defined stability 
and on or prior to the date of 
randomization 
Quality of Life 
• 
FACT-Hep 
Following the completion of the last 
Pre-Baseline Pain/Discomfort 
Questionnaire that defined stability 
and on or prior to the date of 
randomization 
Other Assessments 
• 
Pregnancy test which may include an ultrasound 
to rule out pregnancy (for women of child 
bearing potential only) 
≤ 14 days prior to randomization 
Correlative Studies • 
Blood draw for correlative studies (for 
consenting patients only) 
≤ 14 days prior to randomization 
*  
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) (Appendix VII). Only AEs 
deemed grade ≥ 2 are required to be reported. 
 
 

 
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AMEND #1: 2018-JUL-31 
7.0 
ENTRY/RANDOMIZATION PROCEDURES 
 
7.1 
Entry Procedures 
 
All randomizations will be done through the CCTG web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
randomizing patients will be provided at the time of study activation and will also be included in 
the “EDC Data Management Guidebook”, posted on the HE.1 trial specific web-site. If sites 
experience difficulties accessing the system and/or randomizing patients please contact the help 
desk (link in EDC) or the HE.1 Study Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with CCTG. 
 
The following information will be required at the time of randomization: 
• 
trial code (CCTG HE.1) 
• 
investigator CCTG user ID 
• 
patient's initials (may be coded)  
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
optional consent version date 
• 
confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values 
• 
stratification factors  
 
7.2 
Stratification 
 
Subjects will be stratified by: 
• 
Centre 
• 
Type of liver cancer (HCC versus liver metastases) 
 
7.3 
Randomization 
 
Randomization will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws from the trial and requests that 
data collection/submission cease from the point in time of withdrawal. 
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting randomization. 
 
All randomized patients are to be followed for 90 days after randomization. Data submission for 
ineligible participants should be followed according to the protocol to allow for pain/discomfort 
and adverse event assessment.  
 
 

 
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8.0 
TREATMENT PLAN 
 
Although the  Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 5 working days of patient 
randomization (earlier is preferred). 
 
8.1 
Best Supportive Care (Arms 1 and 2) 
 
Patients on both treatment arms will receive BSC, with analgesia as needed and palliative care/ 
pain specialist involvement in their care (per local policy). The treating team will determine the 
most appropriate interventions for individual patients. In general, analgesia strategies that may be 
considered include: 
• 
Opioids: Short-acting hydromorphone q 2-4 hours prn is the opioid of choice with the dose 
individualized and titrated to maximize pain relief effect and minimize side effects. A longer 
interval between dosing may be needed for patients with more impaired liver function. Long 
acting hydromorphone may also be used if around-the-clock pain relief is required. The 
pharmacokinetics of fentanyl and methadone are not significantly affected by hepatic 
impairment, so they are alternatives in the setting of liver failure [Smith 2009]. Other opioids are 
also permitted; 
• 
Steroids: Dexamethasone is sometimes useful in these patients. If patients are on 
dexamethasone, it is recommended that they stay on the same dose for at least 3 days before 
entering the trial with no plans for altering the dose during the first month of the study, if 
clinically suitable. Note that even if patients are taking regular steroids, anti-emetics one hour 
prior to RT delivery, including a steroid, should be delivered (see section 8.3.1); and, 
• 
Acetaminophen: 325 mg to 1 g q 4 hours, up to 3 g per day. 
 
It is recommended that patients bring their pain medication pill bottles to each follow-up 
appointment and that the study nurse or CRA review the medication table completed by the patient 
(in Part Two of the Pain/Discomfort and Medication Questionnaire). All changes in pain 
medication, including steroid and over the counter analgesia, should be recorded. 
 
8.2 
Arm 1: Best Supportive Care Alone 
 
8.2.1 
Premedication (Arm 1) 
 
Not applicable. 
 
8.2.2 
Patient Monitoring (Arm 1) 
 
Patients will be seen at 30 and 90 days post randomization. 
 
8.2.3 
Dose Adjustments (Arm 1) 
 
Not applicable. 

 
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8.2.4 
Non-hematologic Adverse Events (Arm 1) 
 
The major adverse effects are expected to be related to underlying disease (cancer and/or liver 
disease such as cirrhosis) and from analgesia use. The most likely toxicities from analgesia use 
and/or underlying cancer and/or liver disease are confusion, fatigue, nausea, vomiting, constipation, 
encephalopathy, insomnia, and decline in liver function.  
 
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix VII). 
 
8.2.5 
Duration of Therapy (Arm 1) 
 
Patients will be followed for 90 days post-randomization.  
 
8.2.6 
Patient Compliance (Arm 1) 
 
Pain/Discomfort and Medication Questionnaire and FACT-Hep QoL compliance will be measured 
at baseline, 30 days and 90 days. 
 
In addition, the Pain/Discomfort and Medication Questionnaire will record analgesia use from the 
past 24 hours at baseline, 30 days and 90 days. 
 
8.2.7 
Patient Cross-Over (Arm 1) 
 
Following completion of the day 30 assessment, patients on Arm 1 who continue to be bothered by 
pain/discomfort may choose to receive palliative radiation therapy as described below for Arm 2 
patients, including completion of appropriate quality assurance (see protocol sections 8.4.12 and 
8.4.13). These patients must still return for the 90 day post-randomization visit and undergo the 
required assessments. Change in pain BPI scores from 30 days to 90 days will be evaluated in Arm 
1 patients who receive radiation therapy.  
 
8.3 
Arm 2: Radiation Therapy plus Best Supportive Care 
 
A single fraction of 8 Gy in 1 fraction to the liver will be delivered, with dexamethasone 4 mg and 
granisetron 1 mg (ondansetron 8 mg substitution permitted) given one hour (+/- 1 hour allowable) 
prior to RT to prevent nausea and vomiting. 
 
8.3.1 
Premedication (Arm 2) 
 
All Arm 2 patients will be pre-medicated with: 
 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
Dexamethasone 
4 mg 
po 
60 min pre RT 
once 
Granisetron * 
1 mg 
po 
60 min pre RT 
once 
*Substitution with Ondansetron permitted 
*8 mg 
*po 
*60 min pre RT 
*once 
 
8.3.2 
Patient Monitoring (Arm 2) 
 
Patients will be seen at 30 and 90 days post-randomization. 

 
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8.3.3 
Dose Adjustments (Arm 2) 
 
Not applicable. 
 
8.3.4 
Non-hematologic Adverse Events (Arm 2) 
 
The major adverse effects are expected to be related to underlying disease and from analgesia use. 
The most likely toxicities from analgesia use and/or underlying cancer and/or liver disease are 
confusion, fatigue, nausea, vomiting, constipation, encephalopathy, insomnia, and decline in liver 
function.  
 
In addition to the above toxicities, radiation related toxicities may occur such as anorexia, nausea, 
vomiting, diarrhea, fatigue, gastritis, esophagitis or duodenitis. It is possible that a pain flare and 
worsening of liver function may occur within the first 2-3 days post RT.  
 
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix VII). 
 
8.3.5 
Duration of Therapy (Arm 2)  
 
Patients will be followed for 90 days post-randomization.  
 
8.3.6 
Patient Compliance (Arm 2) 
 
Pain/Discomfort and Medication Questionnaire and FACT-Hep QoL compliance will be measured 
at baseline, 30 days and 90 days. 
 
In addition, the Pain/Discomfort and Medication Questionnaire will record analgesia use from the 
past 24 hours at baseline, 30 days and 90 days. 
 
8.4 
Radiation Treatment Plan 
 
The radiation therapy plan is designed to deliver 8 Gy in one fraction to the symptomatic liver 
cancer. This will require whole (or near whole) liver irradiation, generally using simple techniques 
such as an oblique or anterior-posterior parallel pair beam arrangement (see Appendix VIII).  
 
8.4.1 
Patient Evaluation 
 
Patients must be able to lie supine for the duration of treatment (e.g. 30 minutes).  
 
8.4.2 
Equipment and Treatment Delivery 
 
8.4.2.1 Equipment 
 
Treatment is to be delivered using 4-18 MV photons.  
 
8.4.2.2 Treatment Delivery 
 
3D conformal radiation or IMRT, with multi-leaf collimators, blocks or wedges is permitted.  

 
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8.4.3 
Positioning, Immobilization and Localization/Simulation  
 
8.4.3.1 Positioning 
 
Patients will be positioned supine with arms above their head. If not possible, one or both arms at 
the sides is permitted, although this will require care to avoid irradiation through the arms. 
 
8.4.3.2 Immobilization  
 
Use of chest board or vacuum lock bag is recommended, in combination with calf and knee 
supports. For anterior-posterior beam arrangements, no such devices are required. 
 
8.4.3.3 Localization Imaging/Simulation 
 
Unenhanced computed tomography (CT) scan is recommended for simulation. The CT scanner 
should be 8-slice at minimum, ideally 16-slice or higher, with a slice thickness of 5 mm or less. 
The scan volume must include the whole liver and both kidneys plus a margin superiorly and 
inferiorly of at least 2 cm. 
 
CT scanning may be done during a voluntary breath hold (exhale preferred) or during free 
breathing. 4D CT or use of inspiration and expiration scans on a fast CT scanner are permitted, but 
not required.  
 
Fusion of the diagnostic CT or MRI delineating the GTV is recommended if anything other than 
the whole liver is to be treated. 
 
8.4.3.4 Motion Management 
 
Motion management is not mandatory, as these patients are unwell and the treatment intent is 
palliative using large treatment volumes. 
 
Imaging studies to measure and/or estimate liver motion, including kV fluoroscopy (to assess 
diaphragm caudal-cranial motion), 4D CT and inspiration and expiration scans on a fast CT scanner 
may be used.  
 
Active or passive breath hold for liver immobilization during treatment delivery is not 
recommended. Gating, tracking and abdominal compression are not permitted. 
 
8.4.4 
Volume Definitions  
 
8.4.4.1 Gross Tumour Volume (GTV) 
 
The GTV includes all hepatic tumour(s) causing pain, based on a contrast enhanced diagnostic CT 
or MRI. However, GTV(s) do not need to be contoured. 
 
8.4.4.2 Clinical Target Volume (CTV) 
 
Delineation of a CTV is required. The minimum margin around the GTV to form the CTV is 0 mm. 
Most commonly, the CTV will consist of the whole liver. In situations where one lobe is spared 
from cancer, the spared portion of the liver may be excluded from the CTV. 

 
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8.4.4.3 Internal Margin (IM) 
 
An IM is not mandatory. If individual patient liver motion is measured, an IM can be used. 
 
8.4.4.4 Set up Margin (SM) 
 
If an IM is used, the SM to be added to the IM should be between 5 and 10 mm (10 mm is preferred).  
 
8.4.4.5 Planning Target Volume (PTV) 
 
The minimum PTV margins to be used (regardless of use of IM) are 15 mm in superior and 
inferior directions and 10 mm in other directions. 
 
The maximum PTV margins are 30 mm inferiorly, 20 mm superiorly, anteriorly and posteriorly, 
and 15 mm in the right and left directions. 
 
A modification of the PTV (modPTV) must be used for dose reporting for PTVs that are close to 
(< 5 mm from) skin. The modPTV is created by contracting the PTVs by 5mm from the surface of 
the skin.  
 
8.4.4.6 Organs at Risk (OAR) 
 
The dose limiting OARs which must contoured in all patients include: 
Spinal canal 
Liver (no need to edit out the GTV) 
Right kidney  
Left kidney  
Bilateral kidneys 
 
If the maximal point dose in the plan is 9.5 Gy or higher, then the following OARs must be 
contoured in axial slices in the region of the PTV: 
Stomach 
Duodenum 
Small bowel* 
Large bowel* 
* Alternatively, instead of small bowel and large bowel, the peritoneal cavity in the axial contours 
of the PTV may be contoured.  
 
It is highly recommended that the RTOG upper abdominal OAR contouring atlas be consulted 
[Jabbour 2013]. 
 
8.4.4.7 Nomenclature 
 
If multiple CTVs are contoured, they may be labelled as CTV1, CTV2, CTV3 etc., which then 
should be combined within one PTV. Alternatively, all CTVs may be included within one contour 
labelled CTV. 
 
‘R’ or ‘L’ should be used to represent the right or left kidney as follows: Kidney_R and Kidney_L. 
 
Please refer to Santanam and colleagues [Santanam 2012] for standard OAR nomenclature. 

 
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8.4.5 
Dose Specification  
 
8.4.5.1 Target 
 
The goal is that 95% of the modPTV receives 8 Gy in one fraction. 
 
8.4.5.2 OAR 
 
Critical OARs dose limits are: 
Maximum permitted dose to spinal canal < 10 Gy 
Maximal permitted mean liver (including GTV) dose < 9 Gy 
 
Non-critical OAR dose limits are: 
Maximal permitted dose to stomach < 9.5 Gy 
Maximal permitted dose to duodenum < 9.5 Gy 
Maximal permitted dose to small bowel < 9.5 Gy 
Maximal permitted dose to large bowel < 10 Gy. 
Maximal permitted dose to peritoneal cavity < 9.5Gy 
The kidneys: One kidney is recommended to be spared from radiation if possible. If the 
mean dose to one kidney is > 6 Gy, then the mean dose to the other kidney should be < 3 
Gy. The mean dose to bilateral kidneys should not exceed 4.5 Gy. 
 
8.4.5.3 Fractionation  
 
Radiation will be delivered in one fraction. 
 
8.4.5.4 Corrections for Interruptions  
 
Not applicable.  
 
8.4.6 
Treatment Planning 
 
8.4.6.1 Beam Energy 
 
4 – 18 MV beam energies are permitted.  
 
8.4.6.2 Beam Arrangement 
 
In order to deliver whole (or near whole) liver irradiation, simple beam arrangements are 
recommended. The most common technique is an oblique parallel opposed pair with shaped 
apertures to reduce the dose to surrounding stomach and bowel. An alternative technique is an 
anterior-posterior parallel opposed pair which is best suited for right sided liver cancer (away from 
majority of the stomach). Appendix VIII demonstrates examples of these two beam arrangements.  
 
Modulation of beams may be needed for some patients, and wedges, virtual wedges and IMRT are 
permitted. The minimum permitted number of beam angles is 2. It is recommended that no more 
than 5 beam angles and no more than 10 segments be used. 

 
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8.4.6.3 Beam Modifiers 
 
Multi-leaf collimators are recommended for field shaping. Field-in-field IMRT may be used to 
improve dose homogeneity and reduce the volume receiving > 8 Gy. The maximum number of 
segments recommended is 10.  
 
Blocks are permitted for field shaping. Physical wedges are permitted.  
 
8.4.6.4 Field Junctioning 
 
Not applicable. 
 
8.4.6.5 Planning Priorities 
 
The protocol priorities are: 1) critical OAR, 2) PTV coverage, 3) non-critical OAR. 
 
8.4.6.6 Inhomogeneity Corrections 
 
Inhomogeneity corrections are recommended. 
 
8.4.6.7 Acceptable Dose Heterogeneity 
 
The goal is that the modPTV receive 8 Gy in one fraction +/- 10%; however, a greater degree of 
heterogeneity is often seen and is acceptable.  
 
The minimum dose to 0.5 cc of the modPTV should be 6.4 Gy. 
 
The maximum dose to the modPTV should be no higher than 11.5 Gy. 
 
8.4.6.8 Planning technique 
 
Forward planning is recommended. Inverse planning is permitted for IMRT plans. 
 
The dose calculation grid should include the PTV, the liver and bilateral kidneys with at least a 1 
cm margin. 
 
8.4.6.9 Treatment Delivery Constraints 
 
When a IMRT technique is used, up to 10 segments are permitted. 
 
8.4.7 
Verification 
 
8.4.7.1 Position Verification/Correction  
 
Verification of positioning before treatment is recommended, using MV or kV portal imaging or 
volumetric imaging such as kV CBCT. Alignment based on bone or liver may be used. Maximal 
dose per portal image/image guidance technique should not exceed 20 MU. 
 
8.4.7.2 Dose Verification  
 
An independent monitor unit check or automated dose check is required. No measurements such 
as irradiation of a phantom, portal dosimetry or diode arrays are required.  

 
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8.4.8 
Concurrent Therapy 
 
Chemotherapy or biologic systemic therapy is not permitted to be delivered within 4 weeks of 
randomization or prior to completion of the 30 day post randomization Pain/Discomfort and 
Medication Questionnaire. 
 
8.4.9 
Patient Specific Documentation Requirements  
 
8.4.9.1 Volumes 
 
The volume of the GTV(s) (if contoured), the sum of all CTVs, PTV, modPTV and the liver 
(without editing out the GTV/CTV) are to be documented. 
 
The CTV(s) and PTV, along with the GTV(s) if contoured, should be displayed on the planning 
CT.  
 
8.4.9.2 Dose Summary Statistics 
 
The volume, minimum dose, mean dose and maximum dose must be reported for the sum of all 
GTVs (if contoured), the sum of all CTVs, the modPTV (or PTV if there is no modPTV) and for 
the following OARs –spinal canal, liver (including GTVs/CTVs), the right and left kidney, and 
bilateral kidneys. The global maximum point dose must be reported. If it is < 9.5 Gy, stomach, 
duodenum, small and large bowel (or peritoneal cavity) dose metrics do not need to be reported. If 
it is 9.5Gy or higher, maximum doses to these OARs must be reported.  
 
The dose delivered to 95% of modPTV (or PTV if no modPTV) must be reported  
 
8.4.9.3 Dose Distributions 
 
Dosimetry through orthogonal planes at the isocenter are required, with the 11 Gy, 10 Gy, 9 Gy, 
8 Gy, 7 Gy, 6.4 Gy, 6 Gy and 4 Gy isodoses displayed. 
 
8.4.9.4 Dose Volume Histogram (DVHs) 
 
Graphical cumulative DVHs (with percent volume) of all CTVs, PTVs and contoured OARs, 
including the liver, along with GTV(s) if contoured, must be reported.  
 
8.4.10 Quality Assurance Review Criteria 
 
Treatment-related deviations outside protocol guidelines will be reported as minor or major. In 
general, minor protocol deviations will be reported but will not preclude patient treatment, while 
major protocol deviations will require re-planning prior to patient treatment. Please see 
Radiotherapy Quality Assurance Manual for more details.  
 
8.4.11 Credentialing Requirements 
 
All centres participating in the study will require credentialing prior to local activation. This 
credentialing will consist of completion of a Facility Questionnaire, submission of a beam output 
audit (see below), and demonstration of the ability to comply with protocol specifications using 
anonymized archival data provided by CTG (dummy run with delineation exercise).  
 
 

 
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In addition, for sites planning to deliver IMRT, evidence of previous successful IMRT credentialing 
must be provided.  
 
Institutions must be participating in IROC TLD Remote Monitoring Program and provide the most 
recent TLD/OSL irradiation report. 
 
All credentialing documents must be uploaded to a secure website and CCTG OwnCloud created 
to facilitate radiotherapy QA review for this trial. 
 
Please review the Radiotherapy Quality Assurance Manual for more details.  
 
8.4.12 Prospective Centre Based Individual Pre- Treatment Case Review  
 
Radiation treatment plans will be reviewed for every patient treated on study, prior to the 
commencement of radiotherapy, by another investigator designated for this purpose and identified 
as “local QA reviewer”.  
 
The following will be reviewed: contoured volumes, dose summary statistics, dose distributions, 
and DVHs. Sites must also submit for review the “Delivery Technique, Motion Management and 
Verification Imaging" form for each patient, available on the RTQA website.  
 
The local reviewer will verify that there are no major deviations as defined in the Radiotherapy 
Quality Assurance Manual prior to approving the delivery of the radiotherapy and submit a 
Radiotherapy Reviewer form to central office reflecting this approval through the RTQA website. 
Once this is obtained, the patient may proceed with radiotherapy. Specifications for the review are 
included in the Radiotherapy Quality Assurance Manual.  
 
8.4.13 Retrospective Individual External Post-Treatment Case Review  
 
An external post-treatment review will be performed for all patients completing radiotherapy.  
 
Sites must upload the required documentation to the RTQA website within 4 weeks of the 
completion of radiotherapy. The Central QA Reviewer will document the Post-Treatment Review 
within 4 weeks of data submission. 
 
Anonymized radiotherapy treatment documentation as well as site credentialing documentation 
will also be submitted online to the CCTG OwnCloud platform for additional RTQA review.  This 
additional RTQA central review will be conducted by using software from Princess Margaret 
Hospital in Toronto, Ontario, Canada, and from a company called MIM Software in Cleveland, 
Ohio, USA. 
 
Specifications for the review are included in the Radiotherapy Quality Assurance Manual.  
 
8.5 
Concomitant Therapy 
 
8.5.1 
Permitted 
 
Analgesia and medications used for best supportive care should continue to be delivered with no 
alteration. However, dramatic changes in analgesia are not recommended prior to the 30 day post-
randomization study visit, unless clinically required. 
 
 

 
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Pre-radiation anti-emetics should be delivered to all patients receiving radiation therapy, even those 
who are already on regular steroids. 
 
Bisphosphonates, herceptin, tamoxifen, aromatase inhibitors and other hormonal therapies are 
permitted to be continued if thought to be in the patient’s best interest by the treating oncologist.  
 
8.5.2 
Not Permitted 
 
Chemotherapy, including oral chemotherapy, immunotherapy and targeted agents such as 
sorafenib, avastin, sunitinib, iressa or cetuximab, are not permitted to be delivered concurrently 
with radiation therapy and are not permitted to be used prior to the 30 day post-randomization study 
visit. 
 
 

 
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9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix V. 
 
Patients will be assessed with a history and physical and for toxicity (CTCAE v4.0) at baseline and 
again on day 30 and day 90. Bloodwork, including albumin, bilirubin, CBC and liver enzymes will 
be collected at baseline, day 30 and day 90. 
 
In both arms, patients will complete the Pain/Discomfort and Medication Questionnaire (containing 
the validated patient-reported symptom assessment (BPI)) at baseline and on day 30 and day 90 
from randomization. This questionnaire must be completed correctly and in full for the patient 
to data to be included in the endpoint analyses. The Pain/Discomfort and Medication 
Questionnaire is a patient reported outcome; however, the study nurse/CRA can help the patient to 
complete this questionnaire during the clinic visit. If the patient is too unwell to be seen in clinic, 
the study nurse/CRA can phone the patient and complete the questionnaire on the patient’s behalf.  
 
In both arms, patients will also complete the FACT-Hep QoL questionnaire at baseline, on day 30 
and on day 90 from randomization. This is also a patient reported outcome but in this case the 
patient must complete the questionnaire on their own. It is not acceptable for the study nurse/CRA 
to complete the QoL questionnaire on the patient’s behalf via a telephone call and the use of a 
translator is not allowed. For more information, please refer to Appendix IX. 
 
9.1 
Compliance 
 
Patient compliance with Pain/Discomfort and Medication Questionnaire and FACT-Hep QoL will 
be measured at baseline, on day 30 and on day 90. The same Pain/Discomfort and Medication 
Questionnaire will be used to record analgesia use in the past 24 hours at these same time points. 
 
9.2 
Adverse Events 
 
Adverse events will be monitored by CCTG Central Office using CTCAE and their frequencies 
reported annually at investigator meetings. Standard CCTG auditing and monitoring will occur 
(10% of data from 10% of forms for 10% of patients randomly selected) with sites visited at least 
once during the trial. 

 
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9.3 
Evaluation During/After Protocol Treatment 
 
Investigations 
Timing 
History and Physical 
Exam including: 
• ECOG PS (see Appendix II) 
• weight 
• assessment of ascites and encephalopathy (Child 
Pugh score – see Appendix IV) 
On day 30 and day 90 post 
randomization 
Hematology 
• platelets 
• INR 
• hemoglobin 
On day 30 and day 90 post 
randomization 
Biochemistry 
• albumin 
• bilirubin 
• AST and/or ALT 
• ALP 
• creatinine 
• alpha-fetoprotein (for HCC patients only) 
On day 30 and day 90 post 
randomization 
Pain/discomfort 
Assessment 
• Pain/Discomfort and Medication Questionnaire* 
On day 30 and day 90 post 
randomization 
Analgesia 
Assessment 
• Pain/Discomfort and Medication Questionnaire* 
On day 30 and day 90 post 
randomization 
Adverse Events 
• Adverse events (grade ≥ 2) will be recorded and 
graded according to the NCI Common 
Terminology Criteria for Adverse Events 
(CTCAE) (Appendix VII)*  
On day 30 and day 90 post 
randomization 
Quality of Life 
• FACT-Hep 
On day 30 and day 90 post 
randomization 
Correlative Studies 
• Blood draw for correlative studies (for 
consenting patients only) 
On day 30 and day 90 post 
randomization 
* 
If the patient is too unwell to be seen in the clinic for the day 30 and day 90 follow-up visits, the 
Pain/Discomfort and Medication Questionnaire and adverse events assessment may be done over the 
telephone. It is critical to the study endpoints that the Pain/Discomfort and Medication Questionnaire be 
completed in full at the required time points. 
 
9.4 
Evaluation After Protocol Treatment 
 
There will be no further follow-up after the 90 day post-randomization visit. 

 
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10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
10.1 
Definitions 
 
10.1.1 Evaluable for adverse events. All patients will be evaluable for adverse event evaluation from the 
time of randomization. 
 
10.1.2 Evaluable for BPI response. All patients who have completed a baseline and 30 days follow-up BPI 
will be considered evaluable for the primary endpoint. Patients who complete a baseline and a day 
90 follow-up BPI will be considered evaluable for secondary BPI endpoints.  Patients from Arm 1 
who cross over to Arm 2 after their day 30 assessment are evaluable for BPI response from day 30 
to day 90, if they have completed their day 30 and day 90 BPI. 
 
10.1.3 Evaluable for quality of life assessment. All patients who have completed the quality of life 
questionnaire at baseline and on days 30 and 90 are evaluable for the quality of life endpoint. 
 
10.1.4 Evaluable for change in opioid analysis. All patients who have completed Pain/Discomfort and 
Medication Questionnaires at baseline and within 24 hours of the 30 day visit are eligible for 
assessment. Only analgesic use in the past 24 hours will be recorded to increase compliance. If the 
patient is too unwell to visit the clinic, the Pain/Discomfort and Medication Questionnaire can be 
completed by the study nurse following a telephone call to the patient. Note: large fluctuations in 
opioid use are unlikely to occur due to intolerability of medications for many patients.  
 
10.2 
Measurement Tools 
 
10.2.1 Brief Pain Inventory (BPI) 
 
The BPI consists of 4 pain/discomfort intensity and 7 pain/discomfort interference 11-point Likert-
scale questions (range 0-10) [Cleeland 1994]. 
 
Patients who identify their index symptom as abdominal discomfort are still to complete the 
Pain/Discomfort and Medication Questionnaire even though the questions refer to “pain”. 
 
10.2.2 Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep)  
 
The FACT-Hep questionnaire is a 45-item instrument consisting of the 27-item cancer-specific 
QoL instrument FACT-G, and a site-specific 18-item hepatobiliary subscale (HBS) [Heffernan 2002]. 
The FACT-G consists of four subscales: (1) physical well-being (PWB); (2) social and family well-
being (SFWB); (3) emotional well-being (EWB); and functional well-being (FWB). The total 
FACT-Hep score, FACT-G score, individual scores for each subscale, and the trial outcome index 
(TOI) will be scored according to the paper by Cella et al [Cella 1993].  

 
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11.0 
SERIOUS ADVERSE EVENT REPORTING 
 
This protocol does not contain investigational agent(s), and adverse events occurring as a result of 
the radiation therapy and/or the anti-emetic pre-medications should be reported to CCTG in the 
manner described below. In addition, your local Research Ethics Board (REB) should be notified. 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix VII). All appropriate treatment areas should have access to a copy of the CTCAE which 
can be downloaded from the CTEP web-site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG. 
 
11.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events which are unexpected and related to protocol treatment (radiation 
therapy) must be reported in an expedited manner (see Section 11.2 for reporting instructions). 
These include events occurring during the treatment period (until 30 days after the date of RT) 
and at any time afterwards. 
• 
Unexpected adverse events are those which are not consistent in either nature or severity with 
information contained in the sample consent form. 
• 
Adverse events considered related to protocol treatment (radiation therapy) are those for which 
a relationship to the protocol treatment cannot reasonably be ruled out. 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
11.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported via the web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CCTG Generic Data Management Guidebook for 
EDC Studies posted on the HE.1 section of the CCTG website (www.ctg.queensu.ca). 
 
 

 
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Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
HE.1 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2941 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application.  
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone HE.1 trial team (613-533-6430) to obtain a copy of the SAE 
Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated above. 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application.  
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430).  
 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting  
 
11.3.1 Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criterion 5.1.15. Investigators may 
wish to additionally advise the female partners of male participants about pregnancy prevention 
guidelines when appropriate and compliant with local policy.  
 
11.3.2 Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants.  
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CCTG Pregnancy Reporting Form available from the trial webpage. 
 
 

 
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Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CCTG in a timely manner. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca). 
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada  
(Office of Clinical Trials and Marketed Health Products Directorate (MHPD)) 
 
The CCTG will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials and 
to Marketed Health Products Directorate (MHPD)) for those events which meet regulatory 
requirements for expedited reporting, i.e. events which are BOTH serious AND unexpected, AND 
which are thought to be related to protocol treatment (or for which a causal relationship with 
protocol treatment cannot be ruled out). 
 
11.5 
Reporting Serious Adverse Events to Investigators 
 
CCTG will notify Investigators of all serious adverse events from this trial that are reportable to 
regulatory authorities in Canada as reported to CCTG. This includes all serious events that are 
unexpected and related (i.e. possibly, probably, or definitely) to protocol treatment. The reports 
will be posted to the CCTG trial HE.1 web-based safety monitoring utility. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs will need to be entered into the CCTG trial HE.1 web 
based safety monitoring utility and documentation of REB submission must be retained in the study 
binder on site. The REB submission template provided by CCTG can be used to assist with tracking, 
submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 

 
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12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
12.1 
Therapy After Protocol Treatment is Stopped 
 
No systemic therapy is permitted prior to the 30 days post randomization assessment. It is expected 
that the majority of patients will be not candidates for further line systemic therapy, but if they 
develop progressive disease and are recommended for systemic therapy, they may be treated 
following completion of the 30 day Pain/Discomfort and Medication Questionnaire and FACT-
Hep assessment. Patients who receive systemic therapy prior to the day 90 post-randomization visit 
will be inevaluable for the secondary endpoints.  
 
 
 

 
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13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION 
 
13.1 
Central Radiology Review 
 
Not applicable. 
 
13.2 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
13.3 
Radiotherapy Quality Assurance (RTQA) 
 
All sites will be credentialed for RT prior to site activation. All patients who receive radiation 
therapy on study will undergo prospective Centre Based Individual Pre-Treatment Case Review 
prior to receiving radiation therapy, as well as an external, retrospective Individual External Post-
Treatment Case Review. Please see Section 8.4 and the RTQA Manual for complete details. 
 
13.4  
Blood Collection 
 
The collection of blood is an important part of this trial. This is not mandatory for entry in the study, 
but the participation of all centres is strongly encouraged. Blood will be carefully banked as part of 
the CCTG tissue bank at Queen’s University in Kingston, Ontario. 
 
The blood may be used by researchers now or in the future to better understand the nature of 
palliative radiation therapy and how patients respond to treatment. Samples will be used for 
research purposes only and will not be sold. A scientific review process of any proposals to use the 
blood will take place and any successful proposals will also undergo ethics review and approval. 
Patients will not be identified by name. The only identification of tissue will be by a patient study 
number assigned at the time of randomization to the trial and patient initials. Material issued to 
researchers will be anonymized and only identified by a coded number. 
 
Testing for hereditary genetic defects predisposing to malignant disease will not be carried out 
without the expressed consent of the patient.  
 
All patients for whom a blood sample is collected will be aware of this retrieval and will have given 
their consent. 
 
Blood, plasma and serum samples will be collected at baseline and at day 30 and day 90 post-
randomization. 
 
There will be no specimen collection kits provided for this study; however, pre-printed labels will 
be sent to each centre at the time of local activation. For complete details regarding the procedures 
for optional blood collection, please refer to the HE.1 Correlative Studies Lab Manual which has 
been posted to the HE.1 trial website. 
 
 
 

 
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14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
The primary objective of this multi-centre, randomized, phase III trial is to determine whether a 
single 8 Gy dose of RT with best supportive care (BSC) would show an improvement of ≥ 2 points 
in pain "intensity at worst" on the Brief Pain Inventory (BPI) from baseline to day 30 relative to 
BSC alone in patients with painful liver tumours (either HCC or liver metastases).  
 
Patients will be randomized to receive either a single 8 Gy dose of RT with BSC or BSC alone in 
a 1:1 ratio using a minimization method after stratification by centre and type of liver cancer (HCC 
versus liver). Secondary objectives include comparison of proportion of patients experiencing 
adverse events at day 30 and day 90; proportion of patients alive at day 90; proportion of patients 
achieving improvement of liver cancer pain/discomfort by ≥ 2 points in pain "intensity at worst" 
on Brief Pain Inventory (BPI) from baseline to day 30; proportion of patients achieving 
improvement of liver cancer pain/discomfort by ≥ 2 points from baseline to day 30 and day 90 in 
other BPI pain scores; proportion of patients reporting clinically significant improvement in QoL 
from baseline to day 30 and day 90 as defined by a ≥ 5 point change in the Functional Assessment 
of Cancer Therapy (FACT) Hepatobiliary Subscale (FACT-HBS) and Trial Outcome Index 
(FACT-TOI), proportion of patients achieving a 25% reduction in opioid use (employing daily 
morphine equivalence scale) at 30 days and proportion of patients achieving improvement of liver 
cancer pain/discomfort by ≥ 2 points in pain “intensity at worst” AND with no increase in opioid 
use (employing daily morphine equivalence scale) on BPI from baseline to 30 days. 
 
14.2 
Endpoints and Analysis 
 
A stratified Cochran–Mantel–Haenszel (CMH) test adjusting for the stratification factor (HCC 
versus liver metastases) will be used to compare between two treatment arms for binary endpoints, 
such as proportion of patients with symptomatic HCC or liver metastases who report an 
improvement in pain/discomfort “intensity at worst” on BPI from baseline to day 30, proportion of 
patients with a clinically significant favourable change from baseline to day 30 and day 90 in other 
BPI scores, QoL on FACT-HBP, TOI and FACT-Hep and subscales, and proportion of patients 
with a 25% reduction in opioid use at 30 days. Primary analysis will include all patients who are 
assessed at both baseline and follow-up time of interest. Sensitivity analysis will also be performed 
by including those without assessment at specific follow-up time in the “no improvement” group. 
As cross-over of control patients to the RT Arm is permitted after day 30, after the primary endpoint 
(change in BPI on average) is assessed, the proportion of crossover patients who have RT at day 
30 who have a subsequent clinically significant improvement in BPI at day 90 will be reported. 
The stratified logrank test will be used for time-to-event outcomes such as survival. A subgroup 
analysis will be performed based on the location of the metastases (HCC versus liver). 
 
14.3 
Sample Size and Duration of Study 
 
Forty-five eligible patients with BPI at baseline and at day 30 are required to detect a change in 
proportion of patients with a significant improvement in BPI from 5% (no radiation) to 45% (with 
radiation therapy) with 80% power and α= 0.05. Sixty patients are to be accrued allowing for 25% 
drop out (which was seen in the pilot study [Soliman 2013] and is consistent with other end-of-life 
studies). The final analysis will be performed after when 45 evaluable patients are available 
(approximately 65 randomized patients). 

 
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RT quality assurance criteria, educational RT case examples and accrual initiatives will be 
developed in the first 3-6 months. Based on a national survey and accrual from the Princess 
Margaret Cancer Centre study, the estimated time for trial accrual is 24 months at an accrual rate 
of 2-3 cases/month, excluding a 6-month ‘ramp-up’ in accrual as sites locally activate the trial. 
There will be 3-months follow-up from the last accrued patient and 3 additional months required 
for data collection, cleaning and collation for the final analysis and trial closure, for a total duration 
of 36 months. 
 
14.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators’' meetings. 
 
14.5 
Interim Analysis 
 
There are no planned interim analyses for this trial. 
 
 

 
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15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc 
 
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian CancerTrials Group may be credited as 
authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
• 
In the event of a separate paper dealing with the quality of life outcomes, the first author will 
generally be the Quality of Life Coordinator on the trial committee. 
 
15.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
“A study coordinated by the  Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions).” 
 
15.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following the analysis of study results the 
draft is not substantially complete, the central office reserves the right to make other arrangements 
to ensure timely publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The complete 
journal reference and, if where publicly available, the direct link to the article will be posted on the 
Clinical Trial Results public site of the CCTG web-site (http://www.ctg.queensu.ca). 
 
15.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by the CCTG 
Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study Chair. 
Individual participating centres may not present outcome results from their own centres separately. 
Supporting groups and agencies will be acknowledged. 

 
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16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
16.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
16.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion.  
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs.  
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately.  
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs.  
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable).  
 
Subjects who were competent at the time of enrolment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation.  
 
16.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in an CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
 

 
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Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study.  
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial.  
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject.  
 
16.3.1 Obtaining Consent for Pregnancy Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant) should not 
be collected about or from them unless or until they are a willing participant in the research. The 
rights and protections offered to participants in research apply and consent must be obtained prior 
to collecting any information about or from them.  
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy. 
 
16.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CCTG will provide this 
information to centres as well. 
 
If this trial is discontinued at any time by the centre (prior to closure of the trial by the CCTG), it 
is the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the 
reason(s) why.  
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons. 
 
 

 
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16.5 
Retention of Patient Records and Study Files 
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site.  
 
Essential documents must be retained for 25 years following the completion of the trial at the centre 
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later), 
or until notified by CCTG that documents no longer need to be retained.  
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access.  
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained.  
 
In accordance with GCP 4.9.5, essential documents must be retained for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. In most cases, this 
will be for 10 years following the completion of the trial (10 years post final analysis, last data 
collected, or closure notification to REB, whichever is later) at the centre, or until notified by CCTG 
that documents no longer need to be retained.  
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access.  
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained.  
 
16.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI).  
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 
 
16.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 
 
16.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, is to be found in Appendix V. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except 
the Pre-Baseline Pain/Discomfort Questionnaire, the Pain/Discomfort and Medication 
Questionnaire and the QoL questionnaire. For details of accessing the EDC system and completing 
the on-line Case Report Forms please refer to the “Registration/Randomization and Data 
Management Guidebook” posted on the HE.1 area of the CCTG web-site (www.ctg.queensu.ca). 

 
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17.0 
REFERENCES 
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of Cancer QLQ-LMC21 questionnaire for assessment of patient-reported outcomes during treatment of 
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Borgelt BB, Gelber R, Brady LW, et al. The palliation of hepatic metastases: results of the Radiation Therapy 
Oncology Group pilot study. Int J Radiat Oncol Biol Phys. 1981; 7:587-591. 
Bower JE, Ganz PA, Tao ML, et al. Inflammatory biomarkers and fatigue during radiation therapy for breast 
and prostate cancer. Clinical Cancer Research. 2009; 15(17): 5534-5540. 
BPI user guide in 2009 - http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-tools/bpi_userguide.pdf 
Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment System (ESAS): a simple method 
for the assessment of palliative care patients. J Palliat Care. 1991; 7:6-9. 
Bujold A, Massey CA, Kim JJ, et al. Sequential Phase I and II Trials of Stereotactic Body Radiotherapy for 
Locally Advanced Hepatocellular Carcinoma. J Clin Oncol. 2013; 31(13):1631-9. 
Bydder S, Spry NA, Christie DR et al. A prospective trial of short-fractionation radiotherapy for the palliation 
of liver metastases. Australas.Radiol. 2003; 47:284-288. 
Canadian Cancer Statistics 2013 at http://www.cancer.ca. 
Cella,DF, Tulsky,DS, Gray,G et al. The Functional Assessment of Cancer Therapy scale: development and 
validation of the general measure. J Clin Oncol. 1993; 11:570-579. 
Chow E, Wu JS, Hoskin P, et al. International consensus on palliative radiotherapy endpoints for future clinical 
trials in bone metastases. Radiother.Oncol. 2002; 64:275-280. 
Cleeland CS, Mendoza TR, Wang XS et al. Assessing symptom distress in cancer patients: the M.D. Anderson 
Symptom Inventory. Cancer. 2000; 89:1634-1646. 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 
1994; 23:129-138. 
Goblirsch M, Lynch C, Matthews W, et al. Radiation treatment decreases bone cancer pain through direct effect 
on tumor cells. Radiation research. 2005; 164: 400-408. 
Harris K, Li K, Flynn C, et al. Worst, Average or Current Pain in the Brief Pain Inventory: Which Should be 
Used to calculate the Response to Palliative Radiotherapy in Patients with Bone Metastases? Clin Oncol 2007; 
19:523-7. 
Heffernan N, Cella D, Webster K et al. Measuring health-related quality of life in patients with hepatobiliary 
cancers: the functional assessment of cancer therapy-hepatobiliary questionnaire. J Clin Oncol. 2002; 20:2229-
2239. 
Herfarth KK, Hof H, Bahner ML et al. Assessment of focal liver reaction by multiphasic CT after stereotactic 
single-dose radiotherapy of liver tumors. Int J Radiat Oncol Biol Phys. 2003; 57:444-451. 
Hoskin PJ.  Radiation may lead to a direct reduction of the tumors production of pain promoting chemicals. 
Radiotherapy. In: Sykes N, Bennett MI & Yuan C-S. Clinical pain management: Cancer pain. 2nd ed. London: 
Hodder Arnold; 2008. ISBN 978-0-340-94007-5. p. 251–55. 
Hoyer M, Roed H, Traberg HA et al. Phase II study on stereotactic body radiotherapy of colorectal metastases. 
Acta Oncol. 2006; 45:823-830. 
Hoyer M, Swaminath A, Bydder S et al. Radiotherapy for Liver Metastases: A Review of Evidence. Intl J Rad 
Onc Bio Phys. 2012; 82(3): 1047-1057. 
Ingold JA, Reed GB, Kaplan HS, et al. Radiation Hepatitis. Am J Roentgenol Radium.Ther Nucl Med. 1965; 
93:200-208. 

 
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Jabbour S, Hashem SA, Bosch W, et al. Upper abdominal Normal Organ Contouring Guidelines and Atlas: A 
Radiation Therapy Oncology Group Consensus. Practical Radiation Oncology. 2013; 4(2):82-89. 
Kaiser K, Mallick R, Mulcahy MF, et al. Important and relevant symptoms including pain concerns in 
hepatocellular carcinoma (HCC): a patient interview study. Support Care Cancer. 2014; 22(4): 919-26. 
Lee MT, Kim JJ, Dinniwell R et al. Phase I study of individualized stereotactic body radiotherapy of liver 
metastases. J Clin Oncol. 2009; 27:1585-1591. 
Leibel SA, Pajak TF, Massullo V et al. A comparison of misonidazole sensitized radiation therapy to radiation 
therapy alone for the palliation of hepatic metastases: results of a Radiation Therapy Oncology Group 
randomized prospective trial. Int J Radiat Oncol Biol Phys. 1987; 13:1057-64. 
Lutz ST, Jones J, Chow E. Role of Radiation Therapy in Palliative Care of the Patient with Cancer. J of Clin 
Oncol. 2014; 32(26): 2913-2919. 
Ménard C, Johann, D, Lowenthal M, et al. Discovering clinical biomarkers of ionizing radiation exposure with 
serum proteomic analysis. Cancer Research (2006); 66(3): 1844-1850. 
Mendez RA, Wunderink W, Hussain SM et al. Stereotactic body radiation therapy for primary and metastatic 
liver tumors: A single institution phase i-ii study. Acta Oncol. 2006; 45:831-837. 
Pan CC, Kavanagh BD, Dawson LA et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys. 2010; 
76: S94-100. 
Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55:74-108. 
Prasad B, Lee M.S, Hendrickson F.R. Irradiation of hepatic metastases. Int J Radiat Oncol Biol Phys. 1977; 
2:129-132. 
Salazar OM, Sandhu T, da Motta NW, et al. Fractional half-body irradiation (HBI) for the rapid palliation of 
widespread, symptomatic, metastatic bone disease: a randomization Phase III trial of the International Atomic 
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Santanam L, Hurkmans C, Mutic S, et al. Standardizing naming conventions in radiation oncology. Int J Radiat 
Oncol Biol Phys. 2012; 85(4): 1344-1349. 
Seong J, Park HC, Han KH et al. Local radiotherapy for unresectable hepatocellular carcinoma patients who 
failed with transcatheter arterial chemoembolization. Int J Radiat Oncol Biol Phys. 2000; 47:1331-1335. 
Sherman DM, Weichselbaum R, Order SE, et al. Palliation of hepatic metastasis. Cancer. 1978; 41:2013-2017. 
Smith HS. Opioid Metabolism. Mayo Clin Proc. 2009; 84(7): 613-624.  
Soliman H, Ringash J, Jiang H, et al. Phase II Trial of Palliative Radiotherapy for Hepatocellular Carcinoma 
and Liver Metastases. J Clinl Onc. 2013; 31(31): 3980-3986. 
Turek-Maischeider M, Kazem I. Palliative irradiation for liver metastases. JAMA. 1975; 232:625-628. 
Wharton JT, Delclos L, Gallager S, Smith JP. Radiation hepatitis induced by abdominal irradiation with the 
cobalt 60 moving strip technique. Am J Roentgenol Radium.Ther Nucl Med. 1973; 117:73-80. 
Zhu AX. Hepatocellular carcinoma: are we making progress? Cancer Invest. 2003; 21:418-428. 

 
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APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
 
Pre-
Baseline 
Baseline  
(Pre-Randomization) 
Day 30 Post 
Randomization 
Day 90 Post 
Randomization 
Physical 
 
 
 
 
ECOG PS 
 
X 
X 
X 
Weight 
 
X 
X 
X 
Assessment of ascites and encephalopathy 
(Child Pugh score – see Appendix IV) 
 
X 
X 
X 
Hematology 
 
 
 
 
Platelets 
 
X 
X 
X 
INR 
 
X 
X 
X 
Hemoglobin 
 
X 
X 
X 
Neutrophils 
 
X 
 
 
Biochemistry 
 
 
 
 
Albumin 
 
X 
X 
X 
Bilirubin 
 
X 
X 
X 
AST and/or ALT 
 
X 
X 
X 
ALP 
 
X 
X 
X 
Creatinine 
 
X 
X 
X 
Alpha-Fetoprotein (for patients with HCC only) 
 
X 
X 
X 
Radiology 
 
 
 
 
CT or MRI scan of abdomen which establishes 
diffuse liver metastases per eligibility criteria 
 
X 
 
 
Other Investigations 
 
 
 
 
Two Pre-Baseline Pain / Discomfort 
Questionnaires 
X 
 
 
 
Pain/Discomfort and Medication Questionnaire 
 
X 
X 
X 
Pregnancy test which may include an 
ultrasound (WOCBP only) 
 
X 
 
 
Adverse Events 
 
 
 
 
Baseline adverse event evaluation (to document 
residual adverse event from previous therapy 
and baseline symptoms - grade ≥ 2 only) 
 
X 
 
 
Adverse events on study (grade ≥ 2 only) 
 
 
X 
X 
Quality of Life 
 
 
 
 
FACT-Hep 
 
X 
X 
X 
Correlative Studies 
 
 
 
 
Serum, plasma and whole blood collection 
 
X 
X 
X 
 

 
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APPENDIX II - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g. light housework, 
office work. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 

 
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APPENDIX III - GUIDANCE FOR DETERMINING “STABLE” PAIN PRE-RANDOMIZATION 
 
Pre-Baseline: 
 
The Pre-Baseline Pain Scores are obtained by answering the single BPI question within the Pre-Baseline 
Pain/Discomfort Questionnaire: Pain at its worst in the last 24 hours. 
 
Stable pain is determined using pain scores taken on two separate days. These two scores must meet each 
of the following criteria: 
• 
Both scores must be ≥ 4 
• 
Both scores must be completed on different days AND BOTH must be done ≤ 7 days prior to 
randomization  
• 
The DIFFERENCE between the two scores must be 0, 1, 2 or 3 (i.e. the range is ≤ 3) 
• 
If more than 2 pre-baseline scores are obtained, it is the final two scores that must be used in the 
determination of stable pain. 
 
If any one of these criteria is NOT MET, pain is NOT considered STABLE and the patient is not yet 
eligible to undergo baseline testing for the HE.1 study. Patients are encouraged to continue to complete 
additional Pre-Baseline Pain/Discomfort Questionnaires until all of the criteria for Stable pain have been 
met. 
 
If all of the above criteria ARE MET, pain is considered STABLE and the patient can be scheduled for a 
Baseline visit. 
 
Baseline Visit: 
 
Please refer to the table in Section 6 of the protocol for a list of the required baseline evaluations. 
 
At the baseline visit, the patient completes the Pain/Discomfort and Medication Questionnaire which 
contains several additional BPI questions as well as information related to the pain medications that the 
patient has received in the past 24 hours. 
 
The Baseline Pain Score is obtained from the Pain/Discomfort and Medication Questionnaire done at the 
baseline visit: Part One – Question #1 – Pain at its worst in the last 24 hours. 
  
In order to be eligible for the HE.1 study, the Baseline Pain Score must meet all of the following criteria: 
• 
Score must be ≥ 4 
• 
Score must be obtained prior to randomization - please note the BL score may be obtained on the same 
date (for example, later in the day) as the second pre-baseline pain score. 
• 
The DIFFERENCE between the most recent Pre-Baseline Pain Score and the Baseline Pain Score must 
be 0, 1, 2, or 3 (i.e. the range between these two values must be ≤ 3). 
 
Please refer to the Flow Diagram on the next page. A Pain/Discomfort Stability Worksheet is available on 
the HE.1 trial website to assist study nurses/CRAs in determining if pre-baseline/baseline scores represent 
stable pain. 

 
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APPENDIX IV - DETERMINING CHILD-PUGH SCORE 
 
CHILD-PUGH SCORE - Patients must be class A, B or C10 to be eligible for the HE.1 study. 
 
Clinical and Biochemical 
Parameters 
Score 
1 
2 
3 
Encephalopathy 
None 
Slight (stage* 1-2) 
Or suppressed with medication 
Severe  
(stage* 3-4) 
Ascites 
None 
Slight 
(grade+ 1) 
Moderate 
(grade+ 2-3) 
Albumin (g/L) 
>35 
28-35 
<28 
INR□ 
<1.7 
1.7-2.3 
>2.3 
Bilirubin (umol/L) 
<35 
35-50 
>50 
Class A = 5-6 points 
FINAL SCORE (5-15): _____________ 
Class B = 7-9 points 
 
Class C = 10-15 points 
CLASS (A, B or C): ________ 
* Stages of Hepatic Encephalopathy 
Stage 1: 
Euphoria or depression, mild confusion, slurred speech, disordered sleep 
Stage 2: 
Lethargy, moderate confusion 
Stage 3: 
Marked confusion, incoherent speech, sleeping but arousable 
Stage 4: 
Coma 
 
+ Grades of ascites: 
Grade 1:  
mild, only visible on ultrasound and CT# 
Grade 2:  
detectable with flank bulging and shifting dullness 
Grade 3:  
directly visible, confirmed with the fluid wave/thrill test 
 
#  Note that trace ascites on imaging may be counted as ‘none’ for this study. 
 
□  INR = International Normalized Ratio for Prothrombin Time 
 
References:  
Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg. 1964;1:1-85. 
Moore K P, Wong F, Gines, P et al. The management of ascites in cirrhosis: Report on the consensus conference of 
the international Ascites club. Hepatology, 2003; 38: 258–266. 
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J 
Surg. 1973;60(8):646-9.  
 
 

 
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AMEND #1: 2018-JUL-31 
APPENDIX V - DOCUMENTATION FOR STUDY 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except for the 
Pre-Baseline Pain/Discomfort Questionnaire, Pain/Discomfort and Medication Questionnaire and Quality 
of Life Questionnaire which will be completed by the patient on paper. However, even in the case of these 
paper forms, electronic “submission” will be necessary as follows: 
• 
The Pre-Baseline Pain/Discomfort Questionnaires and the Pain/Discomfort and Medication 
Questionnaires will be scanned and uploaded into the EDC system as “Supporting Documentation” 
• 
The Quality of Life Questionnaire data will be entered by the site CRA into the EDC system within the 
appropriate folders 
 
For details of accessing the EDC system and completing the on-line Case Report Forms please refer to the 
“CCTG EDC Generic Data Management Guidebook” posted on the HE.1 area of the CCTG web-site 
(www.ctg.queensu.ca).  
 
The electronic CRFs to be used in this trial, through the EDC system, are as follows: 
 
Electronic Folder 
Required at 
To be completed electronically 
Supporting Documentation 
Required+ 
Eligibility Checklist 
Prior to randomization 
At the time of randomization 
Consent form* 
Pre-Baseline Pain/Discomfort 
Questionnaire ♦ 
Pain/Discomfort and Medication 
Questionnaire 
Pathology Report(s) 
CT/MRI Abdomen Report♦♦ 
Child Pugh Score Sheet 
Baseline Report 
At the time of 
randomization 
Within 2 weeks after 
randomization 
Correlative Studies Report 
(Blood) 
Continuous Running  
Log folder 
Within 2 weeks after 
randomization (Baseline blood 
draw) AND within 2 weeks after 
30 day visit (30 day blood draw) 
AND within 2 weeks after 90 day 
visit (90 day blood draw) 
Consent form* 
Concomitant Medications 
Report♦♦♦ 
Continuous Running  
Log folder 
Update as/if necessary at the time 
of submission of the Baseline /  
Follow-Up Reports  
- 
Radiotherapy Report 
At the time of  
radiotherapy delivery 
Within 2 weeks after radiotherapy 
delivery 
- 
Follow-up Report –  
30 day Visit 
At the 30 day  
follow-up visit  
Within 2 weeks after the 30 day 
follow-up visit 
Pain/Discomfort and Medication 
Questionnaire 
Follow-up Report –  
90 day Visit 
At the 90 day  
follow-up visit  
Within 2 weeks after the 90 day 
follow-up visit 
Pain/Discomfort and Medication 
Questionnaire 
Death Report 
At the time of  
patient death** 
Within 2 weeks after knowledge 
of patient’s death 
Not required unless requested 
SAE Report*** 
At the time of SAE*** 
Within 24 hours of the event*** 
Not required unless requested 
+ 
Scan and upload into the EDC Supporting Document Upload Tool 
* 
Submit only the signature page(s) of the main consent and only the check box page(s)/signature page(s) of the optional 
consent provided that the version date of the consent form is indicated.  
**  Deaths are only to be recorded on the CRFs if they occur within the study treatment / follow-up period (i.e. up to 90 days 
post-treatment). Deaths occurring after that time are outside the scope of this study and do not need to be reported. 
*** See section 11.0 Serious Adverse Event Reporting for details. 
♦  
Include both pre-baseline assessments. 
♦♦  
Report that established diffuse liver metastases per eligibility criteria (see section 5.0) 
♦♦♦  Note: captures medication use that does NOT pertain to analgesia. Analgesic use is captured in the Pain/Discomfort and 
Medication Questionnaire and is meant to be entered in other relevant EDC folders. 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
49 
CONFIDENTIAL 
The collection of the following information will be done on paper: 
 
Paper-Based Data 
Collection 
Required at 
Submission 
Comments 
Pre-Baseline 
Pain/Discomfort 
Questionnaire 
Prior to baseline on two 
separate occasions 
Enter information (as 
required) in the EDC 
system within 
corresponding folder 
Also scan and upload in the 
EDC Supporting Document 
Upload Tool 
Pain/Discomfort and 
Medication Questionnaire 
Baseline and at each 
follow-up visit  
(30 and 90 days) 
Enter information (as 
required) in the EDC 
system within 
corresponding folder  
Also scan and upload in the 
EDC Supporting Document 
Upload Tool  
Quality of Life 
Questionnaire 
(FACT-Hep) 
Prior to randomization and 
at each follow-up visit (30 
and 90 days) 
Enter information in the 
EDC system within 
corresponding folder  
- 
 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
50 
CONFIDENTIAL 
Day -14 
Day -7 
Day 0 
Day 30 
Day 90 
PtD = Pain/Discomfort and Medication Questionnaire 
PtD/QoL 
PtD/QoL 
BA= Baseline Assessments 
•
ECOG PS 
•
Weight 
•
Assessment of ascites and encephalopathy  
•
AE 
•
Hematology  
•
Biochemistry  
•
Pregnancy Test (WOCBP only) 
•
Blood draw for correlative studies  
PtD/QoL 
BA 
FUA 
FUA 
FUA = Follow-Up Assessments 
•
ECOG PS 
•
Weight 
•
Assessment of ascites and encephalopathy  
•
AE 
•
Hematology  
•
Biochemistry  
•
Blood draw for correlative studies  
R 
 = Randomization 
Abdominal CT or MRI 
(within 120 days of Randomization) 
Optional Palliative RT 
(for patients who have successfully 
completed the Day 30 evaluations) 
Arm 1 
Continue BSC 
BSC = Best Supportive Care 
QoL = Quality of Life 
PBPQ = Pre-Baseline Pain/Discomfort Questionnaire  
2x PBPQ 
APPENDIX VI - TRIAL OVERVIEW 
 
 
 
 
 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
51 
CONFIDENTIAL 
Day -14 
Day -7 
Day 0 
Day 30 
Day 90 
PtD = Pain/Discomfort and Medication Questionnaire 
PtD/QoL 
PtD/QoL 
BA= Baseline Assessments 
•
ECOG PS 
•
Weight 
•
Assessment of ascites and encephalopathy  
•
AE 
•
Hematology  
•
Biochemistry  
•
Pregnancy Test (WOCBP only) 
•
Blood draw for correlative studies  
PtD/QoL 
BA 
FUA 
FUA 
FUA = Follow-Up Assessments 
•
ECOG PS 
•
Weight 
•
Assessment of ascites and encephalopathy  
•
AE 
•
Hematology  
•
Biochemistry  
•
Blood draw for correlative studies  
R 
 = Randomization 
Abdominal CT or MRI 
(within 120 days of Randomization) 
BSC = Best Supportive Care 
QoL = Quality of Life 
PBPQ = Pre-Baseline Pain Questionnaire  
2x PBPQ 
Day 1, 2, 3, 4, or 5 
Palliative RT  
Continue BSC 
Arm 2 
 
 
 
 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
52 
CONFIDENTIAL 
APPENDIX VII - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
53 
CONFIDENTIAL 
APPENDIX VIII - EXAMPLES OF TYPICAL PALLIATIVE RADIOTHERAPY TO THE LIVER 
 
Example 1: CTV (liver) in purple, and PTV in green: Oblique parallel pair fields.  
 
The full “published plan” (HE.1 RT Protocol-1) is available on the HE.1 trial website under the heading 
Data Collection / Data Management. 
 
 
 
 
 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
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CONFIDENTIAL 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
55 
CONFIDENTIAL 
Example 2: CTV (liver) in yellow, and PTV in green. Anterior-posterior parallel fields.  
 
The full “published plan” (HE.1 RT Protocol-2) is available on the HE.1 trial website under the heading 
Data Collection / Data Management. 
 
  
 
 
 
 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
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CONFIDENTIAL 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
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CONFIDENTIAL 
APPENDIX IX - QUALITY OF LIFE ASSESSMENT 
 
Introduction 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
Instructions for Administration of a Quality of Life Questionnaire: The instructions below are intended as 
a guide for the administration of the Quality of Life questionnaire. 
 
1. Preamble 
 
Quality of life data are collected for research purposes, and will usually not be used for the patient’s 
individual medical care. The assessment is in the form of a self-report questionnaire. Therefore, it must 
be completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 
 
For the HE.1 study, the scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization (baseline) 
• 
Day 30 
• 
Day 90 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
58 
CONFIDENTIAL 
2. Pre-treatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire as soon as it has been completed, check to see that each 
question has been answered and gently remind the patient to answer any inadvertently omitted 
questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the 
reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be 
noted on the questionnaire. 
 
3. Assessments on Day 30 and Day 90 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor. If the 
patient does not have a doctor visit scheduled, or if it was not possible for the patient to complete the 
questionnaire before being seen by the doctor, s/he should still complete the questionnaire. 
 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell. In that 
case, you may express sympathy that things are below par, but state that this is exactly the information we 
require if we are to understand more about how quality of life is affected. You may also remind them that 
it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!  
 
5. What If . . .  
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can still 
be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient.  
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over the 
phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report form. 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
59 
CONFIDENTIAL 
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible.  
 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and 
failing to comply with the patient's wishes is likely to result in the questionnaire not being completed 
at all, then the patient may take the questionnaire home with instructions that it is to be completed the 
same day. When the questionnaire is returned, the date on which the questionnaire was completed 
should be noted and a comment made on the questionnaire as to why the patient took it away from the 
clinic before completion.  
 
6. Waiving the Quality of Life Component 
 
The only time that we will not require a patient to complete the quality of life questionnaires is if s/he 
is not literate in either English or French (or other languages that the questionnaire may be available 
in). In other words, if the assistance of a translator is required to comprehend the questions and reply, 
the questionnaires should not be completed. Translation of the questions is not acceptable. Please 
indicate on questionnaire. 
 
7. Unwillingness to Complete Quality of Life Questionnaire 
 
If a patient speaks and reads English or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then s/he is NOT eligible and should 
NOT be put on study. 
 
8. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the QoL assessment in the clinic, the questionnaire 
should be read to them and the answers recorded by a health care professional (e.g. preferably the 
clinical research associate assigned to the trial, but another clinic nurse, a doctor or social worker who 
is familiar with the instructions for administering the questionnaires would be acceptable). If the patient 
is completing the questionnaire at home, and a telephone interview by the clinical research associate is 
not possible, then a spouse or friend may read the questions to the patient and record the answers. 
However, this method should be a last resort, and the spouse or friend should be instructed to not coach 
or suggest answers to the patient. Whichever method is used, it should be recorded on the questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 
 

 
 
 
AMEND #1: 2018-JUL-31 
Quality of Life Questionnaire – ENGLISH 
 
CCTG Trial: HE.1 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: ____ ____ ____ 
 
(first-middle-last)  
Institution: __________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to randomization 
On Study: 
 Day 30      Day 90 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ - __ __ __ - __ __ __ __ 
 
   dd          mmm           yyyy 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
 
 

FACT-Hep (Version 4) 
 
English (Universal) 
 
16 November 2007 
Copyright  1987, 1997 
 
Page 1 of 3 
 
Below is a list of statements that other people with your illness have said are important. Please circle or 
mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy 
0 
1 
2 
3 
4 
GP2 
I have nausea 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble meeting 
the needs of my family 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family 
0 
1 
2 
3 
4 
GS3 
I get support from my friends 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 

FACT-Hep (Version 4) 
 
English (Universal) 
 
16 November 2007 
Copyright  1987, 1997 
 
Page 1 of 3 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness 
0 
1 
2 
3 
4 
GE4 
I feel nervous 
0 
1 
2 
3 
4 
GE5 
I worry about dying 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse 
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness 
0 
1 
2 
3 
4 
GF5 
I am sleeping well 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now 
0 
1 
2 
3 
4 
 

FACT-Hep (Version 4) 
 
English (Universal) 
 
16 November 2007 
Copyright  1987, 1997 
 
Page 3 of 3 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
C1 
I have swelling or cramps in my stomach area 
0 
1 
2 
3 
4 
C2 
I am losing weight 
0 
1 
2 
3 
4 
C3 
I have control of my bowels 
0 
1 
2 
3 
4 
C4 
I can digest my food well 
0 
1 
2 
3 
4 
C5 
I have diarrhea (diarrhoea) 
0 
1 
2 
3 
4 
C6 
I have a good appetite 
0 
1 
2 
3 
4 
Hep
1 
I am unhappy about a change in my appearance 
0 
1 
2 
3 
4 
CNS
7 
I have pain in my back 
0 
1 
2 
3 
4 
Cx6 
I am bothered by constipation 
0 
1 
2 
3 
4 
H17 
I feel fatigued 
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities 
0 
1 
2 
3 
4 
Hep
2 
I am bothered by jaundice or yellow color to my skin 
0 
1 
2 
3 
4 
Hep 
3 
I have had fevers (episodes of high body temperature) 
0 
1 
2 
3 
4 
Hep 
4
I have had itching 
0 
1 
2 
3 
4 
Hep 
5 
I have had a change in the way food tastes 
0 
1 
2 
3 
4 
Hep 
6 
I have had chills 
0 
1 
2 
3 
4 
HN 
2 
My mouth is dry 
0 
1 
2 
3 
4 
Hep 
8 
I have discomfort or pain in my stomach area 
0 
1 
2 
3 
4 
 
 
 
 

 
 
 
AMEND #1: 2018-JUL-31 
APPENDIX X - PRE-BASELINE PAIN/DISCOMFORT QUESTIONNAIRE 
 
 
 
CCTG Trial HE.1 
 
A PHASE III STUDY OF PALLIATIVE RADIOTHERAPY FOR SYMPTOMATIC HEPATOCELLULAR 
CARCINOMA AND LIVER METASTASES 
 
 
 
 
Patient Initials: 
_____ - _____ - _____ 
 
 
  First         Middle         Last 
 
 
 
Patient Serial #: 
CA__ __ __ __ __ __  
 
 
Institution: 
_______________________________________ 
 
 
Investigator: 
_______________________________________ 
 
 
 
PRE-BASELINE PAIN/DISCOMFORT QUESTIONNAIRE  
 
To the Patient: 
 
If you have any questions about how or when to complete this questionnaire, please telephone the study nurse 
or Clinical Research Associate (CRA) listed below. 
 
_______________________________________________ 
____________________ 
 
(Name) 
(Number) 
 
Hours of Availability: 
 
______________________________________________________________________________ 
 
 

 
CCTG - HE.1 Pre-Baseline Pain/Discomfort Questionnaire 
Page 1 of 2 
 
INFORMATION AND INSTRUCTIONS FOR THE PATIENT 
 
Thank you for considering participating in this research study. Before you can enrol in the study, there is a 
short exercise that needs to be completed to ensure that this study is the right fit for you. 
 
This document contains one question that will ask you to record your abdominal pain/discomfort. Below are 
instructions to help answer this question. Please note that the question within this document will refer to “pain”. 
Some patients describe abdominal “discomfort” rather than “pain”, and if this is the case, you may still 
complete this questionnaire. “Pain” in the questionnaire is meant to reflect abdominal “pain” or “discomfort” 
from your liver cancer. 
 
You are being asked to fill in the questionnaire on two separate days within the same week to help determine 
if your pain/discomfort is “stable” (i.e. not changing too much from day to day). 
 
If you have any questions, please ask the CRA or study nurse to help you. 
 
Your Abdominal Pain/discomfort 
 
To tell us about your abdominal pain/discomfort, you will be provided with a list of numbers and asked to rate 
your pain/discomfort by choosing one number from 0 (no pain/discomfort) to 10 (pain/discomfort as bad 
as you can imagine) that best describes your pain/discomfort in the last 24 hours. 
 
This is what that question looks like: 
 
Please rate your abdominal pain by circling the one number that best describes your pain at its  
WORST in the last 24 hours: 
 
 
     0         1         2          3          4         5          6         7         8          9          10 
 
No pain 
Pain as bad as 
 
you can imagine 
 
Some correct and incorrect sample answers are shown below: 
 
Correct: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Incorrect: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Incorrect: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
Now you are ready to fill out your questionnaire. 
 
Please go to the next page. 
 

PATIENT QUESTIONNAIRE 
 
CCTG - HE.1 Pre-Baseline Pain/Discomfort Questionnaire 
Page 2 of 2 
 
Date:   _______ - _______ -  _______ 
               Day         Month          Year 
Day of week: ____________________________          
 
 
1. Please rate your abdominal pain by circling the one number that best describes your abdominal pain 
at its WORST in the last 24 hours: 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
Pain as 
bad as 
you can 
imagine 
 
 
You have now completed the questionnaire. 
 
 
If this is the first questionnaire you have completed please complete a second one in the next few days.   
 
If this is the second questionnaire you have completed, the study nurse or CRA will be phoning you in the 
next few days with instructions regarding what happens from here. 
 
 
Please remember to bring this questionnaire back to the  
hospital when you return for your next study visit. 
 
 
Thank you for your consideration of this research study.  
 
 
 

PATIENT QUESTIONNAIRE – PATIENT TO COMPLETE 
 
CCTG - HE.1 Pre-Baseline Pain/Discomfort Questionnaire 
Page 2 of 2 
 
AMEND #1: 2018-JUL-31 
APPENDIX XI - PAIN/DISCOMFORT AND MEDICATION QUESTIONNAIRE 
 
 
 
CCTG Trial HE.1 
 
A PHASE III STUDY OF PALLIATIVE RADIOTHERAPY FOR SYMPTOMATIC HEPATOCELLULAR 
CARCINOMA AND LIVER METASTASES 
 
 
 
 
Patient Initials:_____ - _____ - _____ 
 
 
  First         Middle         Last 
 
 
 
Patient Serial #:CA__ __ __ __ __ __  
 
 
Institution:_______________________________________ 
 
 
Investigator:_______________________________________ 
 
 
 
PAIN/DISCOMFORT AND MEDICATION QUESTIONNAIRE  
 
To the Patient: 
 
If you have any questions about how or when to complete this questionnaire, please telephone the study nurse 
or CRA listed below. 
 
_______________________________________________ 
____________________ 
 
(Name) 
(Number) 
 
Hours of Availability: 
 
______________________________________________________________________________ 
 

PATIENT QUESTIONNAIRE – PATIENT TO COMPLETE 
 
CCTG - HE.1 Pain/Discomfort Questionnaire 
Page 1 of 8 
 
INFORMATION AND INSTRUCTIONS FOR THE PATIENT 
 
Thank you for participating in this research study. 
 
This document is a questionnaire that is split up into two parts that both relate to your 
abdominal pain/discomfort:  
 
Part One will be used to record your level of abdominal pain/discomfort. Please note 
that the questions within this document will refer to “pain”. Some patients describe 
abdominal “discomfort” rather than “pain”, and if this is the case, you may still 
complete this questionnaire. “Pain” in the questionnaire is meant to reflect abdominal 
“pain” or “discomfort” from your liver cancer.  
 
Part Two will record the medication you take to treat your pain/discomfort. When you 
receive the questionnaire, the clinical research associate (CRA) or study nurse may 
have already filled in the names and doses of the medications you regularly take to treat 
your pain. 
 
The next pages contain instructions to help you fill in Part One of the questionnaire and 
the instructions for Part Two will come later on.  
 
You are being asked to fill in the questionnaire: 
• Before you enter the study, 
• about 30 days after you have started the study, and 
• about 90 days after you have started the study. 
 
Each time you fill in the questionnaire, you will be asked to give us information related 
to: 
• your abdominal pain/discomfort and its effect on your life, 
• how much medication you have taken to treat your abdominal 
pain/discomfort, and 
• any symptoms you have and any medications you have taken for reasons 
other than pain/discomfort control. 
 
If you have any questions, please ask the CRA or study nurse to help you. 
 
 
Please go to the next page. 
 

 
CCTG - HE.1 Pain/Discomfort Questionnaire 
Page 2 of 8 
INSTRUCTIONS FOR PART ONE 
 
Your Abdominal Pain/discomfort 
 
We will ask you about your level of pain/discomfort in this section of the questionnaire. 
 
To tell us about your abdominal pain/discomfort, you will be provided with a list of numbers and asked to 
rate your pain/discomfort by choosing one number from 0 (no pain/discomfort) to 10 
(pain/discomfort as bad as you can imagine) that best describes your pain/discomfort in the 
last 24 hours. 
 
This is what that question looks like: 
 
Please rate your abdominal pain by circling the one number that best describes your pain at its WORST 
in the last 24 hours: 
 
 
     0         1         2          3          4         5          6         7         8          9          10 
 
No painPain as bad as 
 
you can imagine 
 
Some correct and incorrect sample answers are shown below: 
 
Correct: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Incorrect: 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Incorrect: 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
Now you are ready to fill out Part One of the questionnaire. 
 
If you have any questions or need help, please contact the CRA or study nurse 
(contact information provided on the cover page). 
 
 
Thank you for valuable contribution to this research study 
 
 
Please go to the next page 
 

 
CCTG - HE.1 Pain/Discomfort Questionnaire 
Page 3 of 8 
PART ONE: PATIENT QUESTIONNAIRE – PATIENT TO COMPLETE 
 
CRA / Study Nurse to complete below, in advance: 
Please check the timing of the questionnaire: 
□  Baseline Questionnaire 
 
□  30 day Post-Randomization Questionnaire 
□  90 day Post-Randomization Questionnaire 
NOTE: At the baseline visit, please ask the 
patient if they would describe their abdominal 
symptoms as “pain” or “discomfort”.  This 
information will be required at the time of 
randomization. 
 
Patient describes abdominal symptoms as: 
□ Pain 
 □ Discomfort 
 
Date:   _______ - _______ -  _______ 
               Day               Month               Year 
Day of week: ____________________________          
 
1. Please rate your abdominal pain by circling the one number that best describes your pain at its 
WORST in the last 24 hours: 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
Pain as 
bad as 
you can 
imagine 
 
2. Please rate your abdominal pain by circling the one number that best describes your pain at its 
LEAST in the past 24 hours. 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
Pain as 
bad as 
you can 
imagine 
 
3. Please rate your abdominal pain by circling the one number that best describes your pain on 
AVERAGE. 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
Pain as 
bad as 
you can 
imagine 
 
Please go to the next page 

 
CCTG - HE.1 Pain/Discomfort Questionnaire 
Page 4 of 8 
PART ONE: PATIENT QUESTIONNAIRE – PATIENT TO COMPLETE 
 
4. Please rate your abdominal pain by circling the one number that tells how much pain you have  
RIGHT NOW. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
Pain as 
bad as 
you can 
imagine 
 
 
5. In the last 24 hours, how much relief have pain treatments or medications provided?  Please circle the 
one percentage that most shows how much how much relief you have received. 
 
 
0% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
100% 
No 
Relief 
 
 
 
 
 
 
 
 
 
Complete 
Relief 
 
 
6. Circle the one number that describes how, during the past 24 hours, abdominal pain has interfered 
with your:  
 
A. General Activity 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
Interfere 
 
 
 
 
 
 
 
 
 
Completely 
Interferes 
 
 
B. Mood 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
Interfere 
 
 
 
 
 
 
 
 
 
Completely 
Interferes 
 
 
C. Walking ability 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
Interfere 
 
 
 
 
 
 
 
 
 
Completely 
Interferes 
 
Please go to the next page 

 
CCTG - HE.1 Pain/Discomfort Questionnaire 
Page 5 of 8 
PART ONE: PATIENT QUESTIONNAIRE – PATIENT TO COMPLETE 
 
D. Normal Work (includes both work outside the home and housework) 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
Interfere 
 
 
 
 
 
 
 
 
 
Completely 
Interferes 
 
 
E. Relations with other people 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
Interfere 
 
 
 
 
 
 
 
 
 
Completely 
Interferes 
 
 
F. Sleep 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
Interfere 
 
 
 
 
 
 
 
 
 
Completely 
Interferes 
 
 
G. Enjoyment of life 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does not 
Interfere 
 
 
 
 
 
 
 
 
 
Completely 
Interferes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please go to the next page 

 
CCTG - HE.1 Pain/Discomfort Questionnaire 
Page 6 of 8 
INSTRUCTIONS FOR PART TWO 
 
Your Pain/Discomfort Medication 
 
To tell us how much pain/discomfort medication you took in the last 24 hours, you will be asked to fill in 
a table. In most cases, the CRA or study nurse will have already filled in some information about the 
medications you usually take for pain/discomfort. For example, if you use 10 mg tablets of Medication A 
and 2 mg tablets of Medication B, the table will look like this: 
 
Name of medication 
Strength of each unit 
of medication* 
How is medication 
taken? ** 
Number of units taken  
Medication A 
10 mg 
By mouth 
 
Medication B 
2 mg 
By mouth 
 
 
 
 
 
 
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units. 
* 
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch. 
** 
For example, medications can be taken by mouth, rectally, or in patch form. 
 
 
 
Here are some examples of how to fill in the medication table: 
 
Ex. 1: Your doctor has prescribed 10 mg tablets of Medication A for your pain/discomfort and told you to 
take one tablet in the morning and one at night. Your doctor has also prescribed 2 mg tablets of 
Medication B and told you to take one tablet as needed when you have extra pain/discomfort (also 
called breakthrough pain/discomfort), up to four times a day. In the last 24 hours, you took both of 
the 10 mg Medication A tablets and three of the 2 mg Medication B tablets. 
 
This is the correct way to fill in the table: 
 
Name of medication 
Strength of each unit 
of medication* 
How is medication 
taken? ** 
Number of units taken  
 
Medication A 
10 mg 
By mouth 
2 
 
Medication B 
2 mg 
By mouth 
3 
 
 
 
 
 
 
 
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units. 
* 
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch. 
** 
For example, medications can be taken by mouth, rectally, or in patch form. 
 

 
CCTG - HE.1 Pain/Discomfort Questionnaire 
Page 7 of 8 
This is an incorrect way to fill in the table: 
 
Name of medication 
Strength of each unit 
of medication* 
How is medication 
taken? ** 
Number of units taken  
 
Medication A 
10 mg 
By mouth 
2 
 
Medication B 
2 mg 
By mouth 
1 as needed 
 
 
 
 
 
 
 
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units. 
* 
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch. 
** 
For example, medications can be taken by mouth, rectally, or in patch form. 
 
This is incorrect because it does not tell us exactly how much of Medication B you took before filling in 
the table.  We need to know this to be able to get complete results for the study. 
 
 
 
 
 
Here are some examples of how to record your medication if you use formats other than tablets: 
 
Ex. 2: You use a patch on your skin that delivers 25 mcg of Medication C every hour.  You change this 
patch every three days. 
 
Name of medication 
Strength of each unit 
of medication* 
How is medication 
taken? ** 
Number of units taken  
 
Medication C 
25 mcg / h 
Patch 
1 every 3 days 
 
* 
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch. 
 
 
Ex. 3:  Some pain/discomfort medications are available in liquid or syrup form.  Your doctor has prescribed 
2 mg/mL Medication D to you.  You can take 1 to 3 mL of this liquid when you have 
pain/discomfort, up to six times a day.  Today, you took 2 mL of Medication D just before lunch, 
1 mL in the middle of the afternoon, and 3 mL just before going to bed (for a total of 6 mL). 
 
Name of medication 
Strength of each unit 
of medication* 
How is medication 
taken? ** 
Number of units taken  
 
Medication D 
2 mg / mL 
By mouth 
2 + 1 + 3 = 6 
 
* 
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch. 
 
 
 
Please go to the next page 
 

 
CCTG - HE.1 Pain/Discomfort Questionnaire 
Page 8 of 8 
PART TWO: PATIENT QUESTIONNAIRE – PATIENT TO COMPLETE 
 
 
Please record all the medications you took for pain/discomfort today, including what you have already taken 
since getting up this morning. Please make sure you record all the medication you take for breakthrough 
pain/discomfort, and any medication you take for pain/discomfort that wakes you up while sleeping at night.  
 
In the following table, the CRA or study nurse has listed all the medications you usually take to treat your 
abdominal pain/discomfort.  If you did not use any of a particular medication in the last 24 hours, please 
note this by writing “zero” (0) in the dose column. 
 
If you took other medications to treat your pain/discomfort that are not included in the table, please write 
them in the table and fill in all the columns. 
 
Name of medication 
Strength of each unit 
of medication* 
How is medication 
taken? ** 
Number of units taken  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units. 
* 
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch. 
** 
For example, medications can be taken by mouth, rectally, or in patch form. 
 
If you have any questions about how to complete this table, please ask the CRA or study nurse. 
 
 
If you wish, you can write down any other medications you have taken today here: 
 
________________________________________________________________________________ 
 
If you wish, you can write down any symptoms you are having here: 
 
________________________________________________________________________________ 
 
 
You have now completed the study questionnaire. 
 
Please remember to bring this questionnaire back to the hospital 
when you return for your next study visit. 
 
Thank you for your valuable contribution to this research study. 
 
 
 

 
PROTOCOL DATE: 2015-JUL-22 
 
CCTG TRIAL: HE.1 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
 
AMEND #1: 2018-JUL-31 
LIST OF CONTACTS 
 
 
Contact 
Tel. # 
Fax # 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Paul Stos 
Study Coordinator 
CCTG 
Email: 
pstos@ctg.queensu.ca 
613-533-6430 
613-533-2941 
or: 
Dr. Chris O’Callaghan 
Senior Investigator 
CCTG 
Email: 
cocallaghan@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CHAIR 
Dr. Laura Dawson 
Study Chair 
Email: 
laura.dawson@rmp.uhn.on.ca 
416-946-2125 
416-946-6566 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for 
details of reportable events. 
Paul Stos 
Study Coordinator 
CCTG 
613-533-6430 
613-533-2941