A Multi-Center Randomized Controlled Trial of Perioperative Palliative Care Surrounding Cancer Surgery for Patients and Their Family Members (the PERIOP-PC Trial)
Phase: NA
Conditions: Gastrointestinal Cancer
Sponsor: Stanford University

    NCT03611309

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PROTOCOL CHANGES BY VERSION 
Version 5 
• Spelling and grammar corrections (throughout document). 
• Updating project manager contact information. 
• Update to the estimation of the required sample size (p.22) 
• Updates to the final sample size number (throughout 
document). 
• Clarification of the time windows for completing survey 
instruments (pp. 16-17) 
Version 4 
• Study coordinator information (pg. 2) 
• Study Completion Date (pg. 12) 
• Additional information regarding the re-estimation of the 
required sample size (pg. 22) 
Version 3 
• Spelling and grammar corrections (throughout document). 
• Clarification of recruitment goal from 380 to 420. The 
recruitment goal was increased due to incomplete data from 
one of the study sites due to research coordinator abruptly 
leaving the position. (pg 22) 
• Clarifications about changes made for the COVID pandemic to 
ensure phone enrollment and that enable the consent process 
and entire study to be completed virtually (no in-person 
interaction needed) (pgs 11-12, 21). 
• Clarification that funder, the Patient-Centered Outcomes 
Research Institute (PCORI), closely communicates with the 
study team and is committed to working with the team and 
extending enrollment dates so as to facilitate meeting study 
enrollment goals despite both initial delays in enrollment 
initiation at some study sites and delays related to the ongoing 
COVID-19 pandemic (pgs 11-12). 
• Revised references with in-manuscript citations (throughout 
document). 
• Updated Table of Contents numbering (pgs 4-5) 

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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 6 
SCHEMA ....................................................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  ............................................. 8 
1. OBJECTIVES ........................................................................................................................ 8 
1.1. PRIMARY OBJECTIVE ......................................................................................................... 8 
1.2. SECONDARY OBJECTIVES ................................................................................................... 8 
2. BACKGROUND .................................................................................................................... 8 
2.1 STUDY DISEASE .................................................................................................................. 8 
2.2 STUDY AGENT/DEVICE/PROCEDURE ................................................................................... 9 
2.3 RATIONALE ......................................................................................................................... 9 
2.4 STUDY DESIGN ................................................................................................................... 9 
2.5 CORRELATIVE STUDIES BACKGROUND ............................................................................. 10 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ................... 1010 
3.1 INCLUSION CRITERIA ........................................................................................................ 10 
3.2 EXCLUSION CRITERIA ....................................................................................................... 10 
3.3 INFORMED CONSENT PROCESS .......................................................................................... 11 
3.4     REGISTRATION PROCESS…………………………………………………………………11 
3.5     RANDOMIZATION PROCEDURES ........................................................................................ 11 
3.6 STUDY TIMELINE .............................................................................................................. 12 
4. TREATMENT PLAN .......................................................................................................... 13 
4.1 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .................. 13 
4.2 CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 13 
4.3 ALTERNATIVES ................................................................................................................. 13 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ................ 13 
5.1 
 INVESTIGATIONAL AGENT/DEVICE/PROCEDURE .............................................................. 13 
5.2 AVAILABILITY .................................................................................................................. 13 
5.3 AGENT ORDERING ............................................................................................................ 13 
5.4 AGENT ACCOUNTABILITY ................................................................................................. 13 
6. DOSE MODIFICATIONS .................................................................................................. 13 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 13 
7.1 POTENTIAL ADVERSE EVENTS .......................................................................................... 13 
7.2 ADVERSE EVENT REPORTING............................................................................................ 14 
8. CORRELATIVE/SPECIAL STUDIES ............................................................................. 14 
9. STUDY CALENDAR .......................................................................................................... 15 
10. MEASUREMENT.............................................................................................................. 15 
10.1  PRIMARY AND SECONDARY OUTCOME MEASURES ......................................................... 15 
10.2  SECONDARY OUTCOME .................................................................................................. 15 
11. REGULATORY CONSIDERATIONS ........................................................................... 18 

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11.1 INSTITUTIONAL REVIEW OF PROTOCOL ........................................................................... 18 
11.2 DATA AND SAFETY MONITORING PLAN .......................................................................... 18 
11.3 DATA MANAGEMENT ...................................................................................................... 18 
    11.4    STUDY DOCUMENTATION…………………………………………...……………19 
    11.5    SITE COMMUNICATION…………………………………………………………....19 
 
12. STATISTICAL CONSIDERATIONS ............................................................................. 19 
12.1 STATISTICAL DESIGN ...................................................................................................... 19 
12.2 INTERIM ANALYSES ......................................................................................................... 20 
12.3 DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS .................................... 20 
12.4 PRIMARY ANALYSIS ........................................................................................................ 20 
12.5 SECONDARY ANALYSIS ................................................................................................... 21 
12.6  SAMPLE SIZE .................................................................................................................. 21 
12.7 CRITERIA FOR FUTURE STUDIES ...................................................................................... 22 
13. REFERENCES ................................................................................................................... 23 
 
 

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PROTOCOL SYNOPSIS 
 
TITLE 
A Multi-Center Randomized Controlled 
Trial of Perioperative Palliative Care 
Surrounding Cancer Surgery for Patients 
and their Family Members 
INDICATION 
Curative-Intent, Surgery for Upper GI 
cancer 
PRIMARY OBJECTIVE(S) 
Patient Quality of Life 
SECONDARY OBJECTIVE(S) 
Patient: symptom experience, spiritual 
distress, prognostic awareness, health care 
utilization, and mortality. 
Caregiver: quality of life, caregiver burden, 
spiritual distress, and prognostic 
awareness. 
TREATMENT SUMMARY 
Participants randomized to the intervention 
arm receive five (5) visits with a Palliative 
Care specialist clinician 
SAMPLE SIZE  
380 participants 
 

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SCHEMA 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADL 
Activities of daily living 
AE 
Adverse event 
CRF 
Case report/Record form 
CR 
Complete response 
DSMC 
Data Safety Monitoring Committee  
GI 
Gastrointestinal 
IRB 
Institutional Review Board 
PC 
Palliative Care 
PR 
Partial response 
PRO 
Patient-reported outcomes 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
 
 
Of Note: Protocol has been peer-reviewed and published, please see: 
RA Aslakson, et. al. “A Multicenter, Randomized Controlled Trial of Perioperative 
Palliative Care Surrounding Cancer Surgery for Patients and Their Family Members 
(PERIOP-PC).” Journal of Palliative Medicine.Sep 2019.S-44-S-
57.http://doi.org/10.1089/jpm.2019.0130. PMID: 31486730 
 
 
1. 
OBJECTIVES 
 
1.1. 
Primary Objective  
Complete a multi-center, comparative effectiveness, randomized controlled trial comparing the 
impact of surgeon-palliative care team co-management versus surgeon alone management on 
multiple patient-reported outcomes (PROs), including patient quality of life at 12 weeks after 
surgery (primary outcome) (n=380; months 1-36). 
 
1.2. 
Secondary Objectives 
 
Patient: symptom experience, mood symptoms, spiritual distress, prognostic awareness, health 
care utilization, and mortality. Caregiver: mood symptoms, caregiver burden, spiritual distress, 
and prognostic awareness. 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
Despite positive outcomes associated with specialist palliative care in diverse medical oncologic 
populations1-5, no research has investigated specialist palliative care in surgical oncologic ones6. 

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Moreover, although cancer surgery is predominantly safe, operations can be extensive and with 
not insignificant potential for perioperative morbidity and/or mortality7-12. 
 
2.2 
Study Agent/Device/Procedure 
N/A 
 
For clinicaltrials.gov compliance 
N/A, this study does not involve any drug or biologic treatment, and does not require an 
Investigational New Drug application (IND). 
 
2.3 
Rationale 
Although cancer surgery is safer than ever before, perioperative morbidity and mortality are not 
inconsequential and studies suggest that cancer patients and their families suffer significant 
psychological and physical symptoms surrounding surgery and for weeks to months after 
surgery7-13. Palliative care is patient- and family-centered care that symptomatically and 
psychosocially supports seriously ill patients and their families and optimizes quality of life, 
regardless of diagnosis, prognosis, or care goals14,15. Studies among medical oncology patients 
support that proactive palliative care: improves quality of life1-5, betters physical and 
psychological symptom management1-5,16, betters understanding of prognosis17, lessens spiritual 
distress4, lessens caregiver burden4, improves caregiver social well-being18, decreases caregiver 
psychological distress5,18, lowers care costs16,19,20, decreases aggressive end-of-life care 
interventions1,21,22, and may even prolong patient survival1,22. Although frequently conflated with 
hospice14, palliative care is for any patient with serious illness and their caregivers; evidence 
from a randomized controlled trial in patients undergoing curative-intent bone marrow 
transplantation for treatment of hematologic malignancies supports that proactive palliative care 
improves patient quality of life, decreases patient physical and psychological symptoms, and 
decreases caregiver psychological symptoms5. Despite these benefits, there have been no studies 
translating proactive palliative care from a medical oncologic to a surgical oncologic population 
and none comparing surgeon-palliative care team co-management versus surgeon alone 
management across patient-reported outcomes (PROs)6. Indeed, multiple studies even document 
surgical culture resistance to palliative care involvement, particularly any discussions that might 
concern end-of-life care6,23-26. 
2.4 
Study Design 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
This study is a randomized control trial. The primary purpose of this protocol is Supportive Care, 
designed to evaluate one or more interventions where the primary intent is to maximize comfort, 
minimize side effects or mitigate against a decline in the subject’s health or function. In general, 
supportive care interventions are not intended to cure a disease. The interventional model is a 
Parallel study, in which one of two groups in parallel is exposed to the intervention for the 
duration of the study. There is only one intervention arm. This study is single blinded, in which 
the PI and analysts are blinded to randomization. The outcomes of this protocol are designed to 
evaluate Efficacy.  
 
 

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2.5 
Correlative Studies Background 
 
 
N/A, there are no correlative studies planned. 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
3.1 
Inclusion Criteria 
 
3.1.1  Patient is pursuing non-emergent, upper gastrointestinal cancer-related surgery with a 
goal of primary resection of the tumor – optimal surgical goal is cure, not merely 
disease palliation.  
 
3.1.2 Eligible cancers for this study include pancreatic, hepatocellular, esophageal, gastric, 
and/or cholangio-carcinomas. 
 
3.1.3 Must have no previous involvement of specialist palliative care providers in their care 
course. 
  
3.1.4 Potential study patients must be able to give informed consent and be at least 18 years of 
age. As assessment for capacity for informed consent is a standard part of the surgical 
consent process, no patient is referred for the study without having been seen by the 
surgeon and deemed competent per the surgical team standard protocols. 
 
 
3.1.5 No ECOG or Karnofsky Performance Status will be utilized.  
 
 
3.1.6 One caregiver per patient is also asked to participate. In addition to being identified by 
the patient as being a key caregiver throughout the surgery period, these caregivers must 
also be able to give informed consent and be at least 18 years of age. 
 
3.1.7 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Previous involvement of palliative care providers in patient’s care course. 
 
3.2.2 Not having one of the eligible cancers: Pancreatic, hepatocellular, esophageal, gastric, or 
cholangio-carcinoma. 
 
3.2.3 Pursuit of emergent surgery for the upper gastrointestinal cancer. 
 
3.2.4 No exclusion requirements due to co-morbid disease or incurrent illness. 
 
3.2.5 Pregnant or nursing patients will not be excluded from the study.  
 

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3.2.6 Patients who are cancer survivors or those who are HIV-positive will be not excluded 
from the study.   
 
3.3 
Informed Consent Process 
All participants are provided a consent form describing the study with sufficient information for 
participants to make an informed decision regarding their participation.  Participants either sign 
the IRB approved informed consent prior to participation in any study specific procedure or, 
through a waiver due to the COVID-19 pandemic, provide verbal consent with waiver of 
signature. The participant receives a copy of the consent document.  The original signed copy of 
the consent document or documentation of the verbal consent under the COVID-19 pandemic-
related waiver is retained by the research team.  
 
3.4  Registration Process 
A trained research coordinator obtains consent. The research coordinator is familiar with all 
aspects of the study. Consent is obtained either in-person at Stanford Hospital or clinics after the 
research coordinator approaches potential patients about the study or via telephone after the 
study has been introduced by the patient’s surgical oncologist. As much time as necessary is 
devoted to consent discussion, with ample time for patients or caregivers to ask any questions. If 
participants are unsure about their participation, they have the opportunity to contact the study 
team prior to their surgery. To minimize the possibility of coercion, the research coordinator 
emphasizes that participation is completely voluntary and that patients or caregivers are not 
required to participate in the study. During the consenting process, the research coordinator 
questions the patient or caregiver to verify that they understand the purpose and summary of the 
study as what would be required of them; if participants do not understand English or have a 
hearing impairment, we use translators in the consent process. 
 
To register the subject, the study site utilizes the central Stanford study REDcap database. The 
individual enters all subject eligibility and consent information. No subject begins treatment 
prior to registration and assignment of a subject identification number.  
 
At registration, each study site coordinator assigns eligible subject an identification number. This 
identification number is used on the shared Stanford REDcap database as the record indicator. 
The subject’s identification number is used on all subject-specific Case Report Forms (CRFs) 
and serious adverse event (SAE) forms. Participant information is entered into Oncore within 7 
days. 
 
3.5  Randomization Procedures 
Randomization is immediately after enrollment, stratified by study site, and completed via 
computer-generated random allocation with a block size of 6 by using the REDcap database. 
Understandably, neither the patient, caregiver, nor surgeon can be blinded to intervention 
allocation. However, the principal investigator (PI) and analysis team are blinded to participant 
randomization and the research team acquiring outcome data, whenever possible, is blinded to 
participant randomization. 
 
 

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3.6 
Study Timeline 
Primary Completion: 
The study was scheduled to reach primary completion 24 months from the time the study opens 
to accrual. Initial delay in enrollment at some of the study sites and the ongoing COVID 
pandemic have led to enrollment delays.  Yet, the study team communicates closely with the 
funder (the Patient-Centered Outcomes Research Institute; PCORI); PCORI is committed to this 
study and its success and willing to support a longer study duration, if that is needed to enable 
full study enrollment. 
 
Study Completion: 
The study was to reach completion approximately 24 months from the time the study opened for 
accrual. Yet, as previously mentioned, that accrual has been delayed due to study site delays in 
starting enrollment and the ongoing COVID-19 pandemic.  Yet, the study team and PCORI 
communicate closely and PCORI is supportive of continuing the trial as needed to ensure 
meeting enrollment goals.  Based on the most recent call with our program officer (June 23, 
2021), our current tentative end date is December 31, 2022. 
 
Study start date: March 2019. 
Anticipated study completion date: December 2022 
 
4. 
TREATMENT PLAN 
This is a multi-center, comparative effectiveness randomized controlled trial comparing the 
impact of surgeon-palliative care team co-management versus surgeon alone management on 
PROs, including quality of life (primary outcome), symptom score, caregiver burden and 
spiritual distress. The two study arms are below: 
 
1) Surgeon alone management (Enhanced control) – considered “enhanced usual care” this 
involves surgeon and surgical team management of symptoms, psychosocial support, and 
prognostic-related communication. The surgeon and surgical team care for the patient and their 
family both prior to and following surgery. As consistent with standard practice, the surgeon may 
consult the palliative care team at any time, if desired. Per PCORI’s request, this study arm is 
“enhanced” in that surgical oncologists are provided and encouraged to consider following 
National Comprehensive Cancer Network guidelines as to when to consider formal palliative 
care consultation. 
 
2) Surgeon palliative care team co management (Intervention) – All patients receive the care 
described in the “Surgeon alone management” arm. In addition to this, palliative care is provided 
by a specialist team and in a way consistent with the palliative care team co-management 
evaluated in clinical trials of specialist palliative care team co-management for medical 
oncologic populations. For patients in this arm, patients and/or family members are seen by the 
palliative care team: (1) prior to surgery, (2) during their hospitalization for their surgery, and (3) 
on an at least monthly basis until 12 weeks following surgery. Consistent with previous palliative 
care interventions, post-operative palliative care interactions following patient discharge from 
the hospital can be in person at the outpatient clinic, via a telehealth visit, or via telephone, 
Facetime, or Skype, whichever is preferred by the patient and family. 

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4.1 
General Concomitant Medication and Supportive Care Guidelines 
N/A, there is no use of concomitant medications or additional appropriate supportive care 
medications or treatments. Any palliative care-related medication changes for patients in the 
intervention arm are determined through discussion between the palliative care specialist and 
surgical teams. 
 
4.2 
Criteria for Removal from Study 
Participants could be removed from study at any time if they choose to withdraw, or if the 
surgeon chooses to withdraw the patient from the study. 
4.3 
Alternatives 
N/A, this has been deemed a low-risk study; the only potential risk to participants is considered 
to be breach of confidentiality.  
 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1 
 Investigational Agent/Device/Procedure   
 
 
 
N/A 
 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
 
 
 
N/A 
 
5.2 
Availability 
 
N/A 
 
5.3 
Agent Ordering 
 
N/A 
 
5.4 
Agent Accountability 
 
N/A 
 
6. 
DOSE MODIFICATIONS 
 
 
 
N/A 
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
We do not anticipate adverse events related to the study, as this is a low-risk complex behavioral 
study. No investigational agents or procedures are being studied. 
 

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7.2 
Adverse Event Reporting 
 
Adverse Events will be clearly noted in source documentation and listed on study specific Case 
Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each Adverse Event 
(AE) to determine whether it is unexpected according to the Informed Consent, Protocol 
Document, or Investigator’s Brochure, and related to the investigation.  
 
Regulatory and reporting requirements 
It is the responsibility of the investigator to document all adverse events which occur 
during the investigation. Anticipated day-to-day fluctuations of the disease under 
study that do not represent a clinically significant exacerbation or worsening need not 
be considered an adverse event. 
 
Reporting Serious Adverse Events 
 
N/A there are no investigational agents being studied. 
Any SAEs which occur as a result of protocol specific diagnostic procedures or interventions 
must be reported to the local DSMC and local IRB (using the formed attached or an allowable 
local form) and to the coordinating site (Stanford University). 
 
 
8. 
CORRELATIVE/SPECIAL STUDIES  
N/A There are no correlative studies planned in relation to this randomized clinical trial. 

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9. 
STUDY CALENDAR 
 
   
Pre-
Study 
1 Week 
Before 
Surgery 
1 Week 
After 
Surgery 
1 
Month 
After 
Surgery 
2 
Months 
After 
Surgery 
3 
Months 
After 
Surgery 
4 
Months 
After 
Surgery 
5 
Months 
After 
Surgery 
6 
Months 
After 
Surgery 
Off Studyd 
 
Palliative Care Visit 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical Abstraction 
 
 
 
 
 
 
 
 
 
X 
 
FACIT-PaL 
 
X 
X 
X 
 
X 
 
 
X 
 
 
ESAS 
 
X 
X 
X 
 
X 
 
 
X 
 
 
FACIT-Sp-12 
 
X 
X 
X 
 
X 
 
 
X 
 
 
PROMIS-29 
 
X 
X 
X 
 
X 
 
 
X 
 
 
Presence 
of 
Advance 
Care 
Planning 
X 
 
 
 
 
 
 
 
X 
 
 
(Caregivers) ZBI-12, PROMIS 
29, FACIT-Sp-12 
 
X 
X 
X 
 
X 
 
 
X 
 
 
Adverse event evaluation 
 
 
  X……………………………………………………….……………………..X 
 
 
X 
 
Other tests, as appropriate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other correlative studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. 
MEASUREMENTS 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
Note: Each outcome measure listed within the protocol will necessitate legally 
required results reporting to clinicaltrials.gov within one year after the completion 
of the primary outcome measure.   
 
10.1  Primary and Secondary Outcome measures 
The primary outcome variable of this project is patient-reported quality of life.  
 
10.1.1 Relevant Subset 
 
All participants will be assessed for primary outcome. 
  
10.1.2 Measurement Definition 
 

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The primary outcome variable of this project is patient quality of life, measured by the 
Functional Assessment of Chronic Illness Therapy—Palliative Care (FACIT-PaL) Subscale.  
 
 
10.1.3 Measurement Methods 
The primary outcome variable of this project is patient quality of life, measured by the 
Functional Assessment of Chronic Illness Therapy—Palliative Care (FACIT-PaL) Subscale27-29. 
This subscale has not been previously used in a surgical population; however, FACIT-PaL 
includes all of the elements of Functional Assessment of Cancer Therapy-General (FACT-G), 
which have been used extensively as a quality-of-life outcome in cancer populations. 
 
10.1.4 Measurement Time Points 
The outcome of quality of life will be assessed at baseline during enrollment, one week after 
surgery, one month after surgery, 3 months after surgery, and 6 months after surgery. 
Participants will have a window of +/-7 days to complete the surveys for each timepoint before it 
is considered “missed.”  
 
10.1.5 Response Review 
N/A 
 
10.2  Secondary Outcome 
Patient: symptom experience, spiritual distress, prognostic awareness, health care utilization, and 
mortality. Caregiver: Quality of life, caregiver burden, spiritual distress, and prognostic 
awareness. 
 
10.2.1 Relevant Subset 
 
All participants will be assessed for secondary outcomes. 
  
10.2.2 Measurement Definition 
 

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11. 
MULTISITE REGULATORY CONSIDERATIONS 
 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring board for this study, please refer to the Data and Safety Monitoring Committee SOP 
for more information.  
 
11.1 
Monitoring plan 
 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study. The DSMC will audit study-related activities approximately 
once per year to determine whether the study has been conducted in accordance with the 
protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice 
(GCP).  This may include review of the following types of documents participating in the study: 
regulatory binders, case report forms, eligibility checklists, and source documents.  In addition, 
the DSMC will regularly review serious adverse events and protocol deviations from all sites 
associated with the research to ensure the protection of human subjects. Results of the DSMC 
audit will be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as needed.  
 
11.2  Protocol Review and Amendments 
 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior 
to implementation.  The Protocol Director will disseminate the protocol amendment to all 
participating investigators.  Investigators will be expected to obtain IRB approval within 90 days 
for all amendments.   
 
11.3  Data management  
The electronic dataset and recordings are stored on an encrypted computer that is password 
protected with a secure server. All paper copies of the consent form are stored in a locked filing 
cabinet. During the data collection period, only the study team has access to the Stanford-hosted 
REDCap database that contains protected health information. 
 
All data will be stored in HIPAA compliant Stanford Medicine Box and/or REDcap. All 
electronic devices used to store study data, including but not limited to: computers, smartphones, 
tables, external hard disks USB drives, etc. that any hold identifiable participant data will be 
password protected, backed, up and encrypted per Stanford policy. All participants will be given 
a unique identifier number with data storage linked to the UIN and all data stored in a password-
protected, secure database.  

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11.4 
Study Documentation 
 
The Protocol Director and participating site investigators must maintain adequate and accurate 
participant case histories with observations and other data pertinent to the study.  Original source 
documents should be transcribed to Case Report Forms (CRFs) and used to communicate study 
data to the lead site.  Source documents include informed consent forms and electronic medical 
data. 
 
Participating Center’s PIs will be responsible for maintaining the clinical protocol and subjects’ 
study charts, reporting adverse events, assuring that consent is obtained and documented, and 
reporting the status of the trial in continuing renewals submitted to their IRB and trial monitoring 
group(s) as per their facility protocol.    
 
 
 
11.5 
Site Communication 
 
Teleconferences are convened weekly between all sites to discuss participants and study-related 
matters; calls may also occur more frequently if needed. Teleconferences are coordinated by the 
Stanford site coordinator and include study PI and all research coordinators. Any issues with 
patient compliance, database entry, or other items will also be discussed in these calls. Once a 
month, the call includes the study PI, all research coordinators, and all study site PI’s.  
 
12. 
STATISTICAL CONSIDERATIONS 
 
Since funding in 2017, this study has been in collaboration with the Palliative Care Research 
Cooperative (PCRC), which is based out of the University of Colorado in Denver.  The initial 
study biostatistician was Suwei Wang of Stanford University but Dr. Wang departed from 
Stanford.  Consequently, through the study team’s longitudinal relationship with the PCRC, the 
current study biostatistician is Kathryn Colborn, PhD, MSPH, Assistant Research Professor at 
the University of Colorado Anschutz Medical Campus in Denver, CO. 
 
12.1 
Statistical Design 
Differences in primary and secondary outcomes between intervention and control arms will be 
evaluated at each individual time point as well as across the intervention period. 
 
12.1.1 Randomization 
Randomization occurs immediately after enrollment. Participants are stratified by study site. Using 
the REDCap database, group assignment (intervention or control) is determined via a computer-
generated random allocation with a block size of 6. Patients, caregivers, and surgeons cannot be 
blinded to group assignment due to practical considerations; however, the principal investigator 
and analysis team are blinded to participant randomization. The research team collecting outcome 
data are blinded to participant randomization, whenever possible. 

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 12.2 Interim analyses 
 
No interim analyses will be conducted. 
 
12.3 
Descriptive Statistics and Exploratory Data Analysis 
Descriptive statistics will be calculated to summarize patients’ characteristics and other baseline 
variables. Comparability of the intervention arm and the control arm will be assessed with regard 
to preintervention sociodemographic and health status measures derived from the Medical Record 
Abstraction. Although randomization should account for such differences, a two-sample t-
test/Mann-Whitney test will be performed to investigate the differences between intervention and 
control group for continuous variables and Fisher’s exact test or chi-squared test will be used to 
investigate differences between intervention and control group for binary or categorical variables.  
 
For primary and secondary outcomes, based in the type of the data, summary univariate 
(descriptive) statistics (e.g., mean, standard deviation, median, interquartile range, maximum, 
minimum, count, percentage) will be determined for all outcomes stratified by group assignment. 
Descriptive time trend plots (multiple visits) stratified by group assignment will be presented for 
outcomes that are measured at multiple visits to allow for the visual comparison of change patterns 
before and after the intervention.  
 
12.4 
Primary Analysis  
The primary outcome for this study is quality of life three months following surgery.  
 
12.4.1 Analysis Population 
Our study will use an intent-to-treat approach in which all data from study patients in both 
intervention and control arms are used, regardless of the level of adherence to the study arm. 
 
12.4.2. Analysis Plan 
The effect of group assignment (intervention or control) on the quality of life will be tested. 
Differences in outcomes between two arms at each visit will be tested by the two-sample t-
test/Mann-Whitney test or Fisher’s exact test/chi-squared test based on the data types of the 
outcomes. The effect of intervention on the quality of life after accounting for various confounding 
variable will be determined using a linear mixed model that accounts for within-subject variations 
due to repeated measures. Sensitivity analyses will assess whether there are differential effects on 
contingent on patient or study site characteristics on the primary outcomes. 
 
The overall level of statistical significance was set at p<0.05. For all models, the research team 
will identify possible confounding variables for model adjustment, including baseline attributes. 
Using peer-reviewed literature, the research team has identified confounding variables that models 
will be adjusted for. These covariates include patient gender, age, race, education, and health 
status. 
 
Qualitative data related to secondary outcomes will be transcribed, de-identified, and analyzed 

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based on qualitative description 36,37. A HIPPA-compatible, professional transcription service will 
be used for interview transcription. NVivo software will be used for qualitative analyses. A 
codebook will be determined by a three-person team with a single coder then analyzing the 
transcripts. Line-by-line, axial, and theoretical consensus coding will be used to organize and 
summarize findings, which will be validated through triangulation, member checking, and search 
for disconfirming data. 
12.5 
Secondary Analysis 
Secondary outcomes include physical symptom assessment, mood symptoms (measured through 
a subscale of PROMIS-29), spiritual distress assessment, mortality, and assessment of caregiver 
burden by the linear mixed model.  
 
12.5.1 Analysis Population 
Our study will use an intent-to-treat approach in which all data from study patients in both 
intervention and control arms are used, regardless of the level of adherence to the study arm. 
 
12.5.2  Analysis Plan 
Depending on the format of the variable, the effect of group assignment (intervention or control) 
on the secondary outcomes will be tested at each visit with two-sample t-test/Mann-Whitney test 
or Fisher’s exact test/chi-squared test. The effect of intervention on secondary variables after 
accounting for various confounding variables will be determined using a linear mixed model that 
accounts for within-subject variations due to repeated measures. For end-point secondary 
outcomes, Kaplan-Meier method or Cox proportional hazards models will be used.  
 
The overall level of statistical significance was set at p<0.05. For all models, the research team 
will identify possible confounding variables for model adjustment, including baseline attributes. 
Using peer-reviewed literature, the research team has identified confounding variables that models 
will be adjusted for. These covariates include patient gender, age, race, education, and health 
status. 
 
12.6  Sample Size 
12.6.1 Accrual estimates  
 
Target enrollment was approximately 30 participants per month with 6-10 per site. As of March 
31, 2022 and with 34 months of enrollment, we have enrolled 381 participants. Enrollment 
slowed due to the COVID-19 pandemic. We have been in close communication with PCORI 
who were supportive of our continuing enrollment, as safe and feasible, through the pandemic 
until we met our target enrollment goals. PCORI has been supportive of the extended timeline to 
enroll patients. 
 
12.6.2 Sample size justification 
 
It is hypothesized that surgeon-palliative care co-management (intervention) perioperative 
palliative care will improve patient postsurgical quality of life as compared to surgeon-alone 
management of care (control). Thus, the null hypothesis is that the intervention and control 
groups will not differ in postsurgical quality of life measures. 
 

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The estimated sample size is 186 patients per arm or 372 patients total (380 patients was our 
goal). The sample size and power of this study was based on the primary outcome quality of life 
measure, FACIT-Pal. With this sample size, using an unpaired two-sample t-test, the present 
study is powered to detect an anticipated small-to-moderate effect size of 0.4 at 12 weeks with 
90% power and probability type I error of 0.05 (two-sided). This power analysis includes a 86% 
participant completion rate as well as a variance inflation factor of 20%. 
 
One of the study sites had a study coordinator abruptly quit the position in 2019 and 
consequently data on 20 participants from that site were compromised. Following the same 
methodological approach described in the published protocol paper (which anticipated a LTFU 
rate of 14%), we performed a re-estimate of the required sample size for this study in December 
2020 and discovered that it was higher than anticipated (28%) due to the study coordinator 
turnover and interruptions caused by the pandemic. This was discussed with the funder (PCORI); 
the study team and PCORI had consequently agreed to target 420 enrollees to ensure sufficient 
sample size and study power. However, in December 2021, we re-evaluated our LTFU rate and 
found that it had markedly improved during the most recent year of enrollment and was now the 
same as was originally anticipated. In communication with PCORI, we returned the enrollment 
rate to 380.  
 
12.6.3 Effect size justification 
 
The means, standard deviations, and effect sizes were based on previous research 1 supporting 
that patients receiving medical oncologist-palliative care co-management had better quality of 
life (measured by Functional Assessment of Cancer Therapy – Lung; FACT-L38) than patients 
receiving medical oncologist alone management. Mean score differences in FACT-L were 98.0 ± 
16.7 (n = 74) in the intervention group and 91.5 ± 16.5 (n = 77) in the control group resulting in 
an effect size of 0.42 (unpaired two-sample t-test). Since the FACIT-Pal scale27-29 used in this 
study is a direct corollary of the FACT-L38 scale, this effect size was used to estimate the sample 
size for the present study.  The sample size and power of this study are based on the quality of 
life measure, FACIT-Pal. Based on the unpaired two-sample t-test, the present study was 
powered to detect an anticipated small-to-moderate effect size of 0.4 at 12 weeks with 90% 
power and probability type I error of 0.05 (two-sided). Patients will be nested within the four 
intervention sites, which will introduce some within-site correlation that could decrease the 
efficiency of these estimators. Thus, a variance inflation factor of 20% was incorporated in the 
sample size estimation. Additionally, it is predicted that this study will have missing data due to 
patients discontinuing participation in the study and death. Based both on the research team’s 
past experiences conducting studies in this population and already published perioperative 
mortality data, we assumed a dropout rate of 11% and a mortality rate at 12 weeks of 3%; thus, 
patient completion rate was estimated to be 0.86. Together, with the assumptions outlined here, 
the estimated sample size needed for the present study is a total of 186 patients per arm (372 
patients total) and our goal was to recruit 380 patients.  
 
12.7 
Criteria for future studies 
This is a randomized controlled superiority trial that is powered to detect a difference in the 
primary outcome, quality of life as measured by FACIT-PAL.  It is neither a pilot study nor a 
part of a sequence of trials. 

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13. 
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