Short Course Adjuvant Vaginal Cuff Brachytherapy (VCB) in Early Endometrial Cancer Compared to Standard of Care (SAVE)
Phase: PHASE3
Conditions: Endometrial Clear Cell Adenocarcinoma, Endometrial Endometrioid Adenocarcinoma, Endometrial Serous Adenocarcinoma, Stage I Uterine Corpus Cancer, Stage IA Uterine Corpus Cancer, Stage IB Uterine Corpus Cancer, Stage II Uterine Corpus Cancer, Uterine Corpus Carcinosarcoma, Uterine Corpus Sarcoma
Sponsor: University of Utah

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date:18JUN2025 
Principal Investigator: Cristina DeCesaris, MD 
 
 
 
Short Course Adjuvant Vaginal Cuff Brachytherapy (VCB) in Early Endometrial 
Cancer Compared to Standard of Care (SAVE) 
Lead Org. ID #HCI103841/ IRB# 103841 
NCT03422198/HCI-17-GYN-09 
 
Coordinating Center 
 
Principal Investigator 
 
 
 
 
 
Statistician 
 
 
 
 
 
Medical Monitor 
 
 
 
 
Coordinating Center Site 
Contact 
Huntsman Cancer Institute- University of Utah 
 
Cristina DeCesaris, MD 
Huntsman Cancer Institute/University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Cristina.DeCesaris@hci.utah.edu   
 
Kenneth Boucher, PhD 
Huntsman Cancer Institute/University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Kenneth.boucher@hci.utah.edu 
 
Bismarck Odei, MD 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Bismarck.Odei@hci.utah.edu 
 
Research Compliance Office 
2000 Circle of Hope 
Salt Lake City, UT 84112 
HCI-RCO@utah.edu 
 
 
Historical Protocol Versions 
Version 1: 12OCT2017 
 
Version 2: 02MAR2018 
Version 3: 29AUG2018 
Version 4: 27NOV2018 
Version 5: 28JAN2020 
Version 6: 30JUN2020 
Version 7: 21SEP2020 
Version 8: 07JUL2021 
Version 9: 11MAY2023 
Version 10: 03JUL2024 
Version 11: 18DEC2024 
Version 12: 18JUN2025 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 2 of 53 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................. 2 
PROTOCOL SIGNATURE ............................................................................................. 4 
STUDY SUMMARY ......................................................................................................... 5 
1 
OBJECTIVES ............................................................................................................. 8 
1.1 
Primary Objectives and Endpoint ........................................................................ 8 
1.2 
Secondary Objectives and Endpoint .................................................................... 8 
1.3 
Exploratory Objectives and Endpoints:................................................................ 8 
2 
Cohort 2 (Pilot Expansion) ......................................................................................... 9 
2.1 
Primary Objective and Endpoint .......................................................................... 9 
2.2 
Exploratory Objectives:........................................................................................ 9 
3 
BACKGROUND ...................................................................................................... 10 
3.1 
Rationale for 2 fractions of vaginal cuff brachytherapy of 11 Gy at the surface 13 
3.2 
Rationale for short course vaginal brachytherapy .............................................. 13 
3.3 
Rationale for Pilot Expansion (Cohort 2) ........................................................... 13 
4 
STUDY DESIGN...................................................................................................... 15 
4.1 
Description: ........................................................................................................ 15 
4.2 
Enrollment and data analysis for Cohort 1 has been completed. Cohort 2 will 
mirror the design of Cohort 1, but include additional outcome measures. ................... 15 
4.3 
Number of Patients: ............................................................................................ 15 
4.4 
Number of Study Centers ................................................................................... 15 
4.5 
Study Duration ................................................................................................... 16 
5 
ELIGIBILITY CRITERIA........................................................................................ 17 
5.1 
Inclusion Criteria ................................................................................................ 17 
5.2 
Exclusion Criteria ............................................................................................... 17 
6 
TREATMENT PLAN ............................................................................................... 18 
6.1 
Administration Schedule .................................................................................... 18 
6.2 
Prohibited Concomitant Medications/Treatments .............................................. 18 
6.3 
Duration of Therapy ........................................................................................... 18 
7 
TOXICITIES AND DOSEAGE MODIFICATION ................................................. 18 
7.1 
Dose Modifications ............................................................................................ 18 
7.2 
Supportive Care .................................................................................................. 19 
8 
STUDY CALENDAR .............................................................................................. 20 
9 
CRITERIA FOR EVALUATION AND ENDPOINT (Cohort 1) ............................ 22 
9.1 
Primary Objective .............................................................................................. 22 
9.2 
Secondary Objectives ......................................................................................... 22 
9.3 
Exploratory objectives........................................................................................ 23 
9.4 
Stopping Rules ................................................................................................... 23 
10 
STATISTICAL CONSIDERATIONS................................................................... 24 
10.1 
COHORT 1 ..................................................................................................... 24 
10.2 
COHORT 2 ..................................................................................................... 25 
11 
REGISTRATION GUIDELINES .......................................................................... 26 
12 
DATA REPORTING ............................................................................................. 26 
12.1 
Source documents and access to source data .................................................. 26 
12.2 
Quality assurance ............................................................................................ 26 
12.3 
Data collection and management responsibilities .......................................... 27 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 3 of 53 
 
 
12.4 
Study records retention ................................................................................... 27 
12.5 
Monitoring and Auditing ................................................................................ 27 
13 
SPECIAL INSTRUCTIONS ................................................................................. 28 
13.1 
Dosimetric review ........................................................................................... 28 
14 
ETHICAL AND REGULATORY CONSIDERATIONS ..................................... 28 
14.1 
Informed consent ............................................................................................ 28 
14.2 
Institutional Review ........................................................................................ 28 
14.3 
Data and Safety Monitoring Plan ................................................................... 28 
14.4 
Adverse Events / Serious Adverse Events ...................................................... 28 
14.5 
SAE Reporting Requirements ........................................................................ 30 
14.6 
Protocol Amendments .................................................................................... 30 
14.7 
Protocol Deviations ........................................................................................ 31 
14.8 
Clinical Trials Data Bank ............................................................................... 31 
15 
BIBLIOGRAPHY .................................................................................................. 32 
16 
Appendices ............................................................................................................. 35 
 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 4 of 53 
 
 
 
PROTOCOL SIGNATURE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein 
and according to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practice, and the applicable laws 
and regulations of the federal government. I will promptly submit the protocol to the IRB 
for review and approval. Once the protocol has been approved by the IRB, I understand 
that any modifications made during the study must first be approved by the IRB prior to 
implementation except when such modification is made to remove an immediate hazard 
to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the study treatment, the conduct of 
the study, and the obligations of confidentiality. 
This document is signed electronically through submission and approval by the Principal 
Investigator at Huntsman Cancer Institute in the University of Utah IRB Electronic 
Research Integrity and Compliance Administration (ERICA) system. For this reason, the 
Principal Investigator at Huntsman Cancer Institute will not have a hand-written 
signature on this signature page.  
Instructions to multi-site Investigators at locations other than Huntsman Cancer Institute: 
SIGN and DATE this signature page and PRINT your name. Return the original, 
completed and signed, to the HCI Research Compliance Office. Retain a copy in the 
regulatory binder.  
 
 
 
___________________________________  
_______________ 
Signature of Investigator 
 
 
            Date 
 
 
 
___________________________________ 
Investigator Name (Print) 
 
 
 
___________________________________ 
Name of Institution 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 5 of 53 
 
 
STUDY SUMMARY 
 
Title  
Short Course Adjuvant Vaginal Cuff Brachytherapy (VCB) in 
Early Endometrial Cancer Compared to Standard of Care 
(SAVE). 
 
Short Title 
VCB in Early Endometrial (SAVE) 
Protocol number 
IRB #103841 
IND 
This protocol will not hold an IND 
Study Design  
Open Label, Randomized trial of 2 fractions of VCB compared to 
the standard of 3-5 fractions. 
 
Phase 
Phase III 
Study Duration 
Cohort 1: Approximately 4 years 
Cohort 2: 2 years for accrual and 1 year for study treatment and 
follow up.  
Primary Study  
Objective:  
Cohort 1:  
Evaluate the non-inferiority of patient Health Related Quality of 
Life (HRQOL) in the experimental arm compared to the control 
arm using the Global Health Status from the EORTC QLQ-C30. 
 
Cohort 2: 
To evaluate the frequency and severity of patient-reported 
financial toxicity in patients with early-stage endometrial cancer 
treated with vaginal cuff-brachytherapy (VCB) at one-month post-
VCB. 
 
Secondary Study 
Objectives:  
Cohort 1: 
Secondary Objectives 
• Evaluate treatment related HRQOL using the EORTC 
EN24, question 48 between the two treatment arms.  
• Compare cost effectiveness between the two treatment arms 
Exploratory Objectives 
• Report vaginal, bowel, and bladder symptoms on HRQOL 
using the EORTC EN24 the two treatment arms.  
• Evaluate CTCAE v5.0 toxicities and subject compliance 
• Compare local recurrence and document patterns of 
recurrence 
• Evaluate doses to organs at risk and the prescribed target in 
the two trial arms and compare them to each other. 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 6 of 53 
 
 
•  Compare total distance traveled to the cancer center for study 
related visits. 
Cohort 2: 
Exploratory Objectives 
• Exploratory objectives will include evaluation of differences 
in patient-reported financial toxicity between cohorts, to 
assess any impact of treatment duration on outcomes 
• Exploratory objectives include evaluation of patient-reported 
diet and physical activity levels and quality of life in 
patients with early-stage endometrial cancer treated with 
vaginal cuff-brachytherapy (VCB) at one-month post-VCB. 
 
Inclusion Criteria  
 
• Histologically 
confirmed 
endometrial 
carcinoma: 
endometrioid type, serous, and clear cell to include tumors 
originating in the cervix, but are primarily located in the 
uterus, and for whom vaginal cuff brachytherapy is 
indicated. Carcinosarcoma and other sarcomas are 
permitted. FIGO stage I and stage II, with one of the 
following combinations of stage and grade:  
                    1. Stage IA, grade1 with LVSI, 2, 3  
                    2. Stage IB, grades 1-3 
                    3. Stage II, grades 1-3 
                    3. Stage IIIA, grades 1-3, not receiving EBRT as part 
of adjuvant therapy. 
• WHO-performance status 0-2 
• Written informed consent  
• Life expectancy > 2 years  
Exclusion Criteria:  
• Stages of endometrial carcinoma other than defined in 
inclusion criteria. 
• Previous pelvic radiotherapy. 
• Concurrent malignancy requiring non-protocol anti-cancer 
treatment other than surgery. 
  
Number of centers:  
This study will be conducted at the Huntsman Cancer Institute and 
up to 5 additional cancer centers.  
Number of patients:  
Cohort 1:108 (Randomized 1:1; 54 to each treatment arm) 
Cohort 2: 80 (Randomized 1:1; 40 to each treatment arm) 
Study Product, Dose, 
Route, Regimen and 
Duration 
Experimental Arm: 11Gy will be prescribed to the surface with a 
minimal treatment length of 3 cm. Two fractions will be given, 
one week apart.  
 
Control Arm options:  

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 7 of 53 
 
 
• 7 Gy at ½ cm x 3 fractions over no more than three weeks. 
• 5-5.5 Gy at ½ cm x 4 fractions over no more than three weeks. 
• 6 Gy at the surface of the cylinder x 5 fractions over no more than 
three weeks. 
 
Statistical Methodology 
The primary endpoint will be the Global Health Status from the 
QLQ-30. The hypothesis to be tested is that the mean Global Health 
Status will be no more than 15 points lower one month after 
treatment in the Experimental Arm compared to the Control Arm. 
The primary non-inferiority analysis will be using a two-sample t 
test. 
Additional analyses will evaluate cost effectiveness, toxicity, 
vaginal, bladder and bowel symptoms affecting HRQOL, doses to 
organs at risk and the prescribed target, and patterns of recurrence. 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 8 of 53 
 
 
1 
OBJECTIVES 
Hypothesis: A shorter treatment course will not be inferior to patient HRQOL using the 
Global Health Status from the QLQ-C30 one month after treatment in the two arms. 
1.1 
Primary Objectives and Endpoint 
1.1.1 Evaluate the non-inferiority of patient Health Related Quality of Life (HRQOL) 
using the Global Health Status from the QLQ-C30 in the 2 arms one month after 
treatment. 
ENDPOINT: Scores determined from patient completed questionnaires will be 
compared between the two treatment arms one month after treatment 
completion. 
1.2 
 Secondary Objectives and Endpoint 
1.2.1 Compare treatment-related symptoms on HRQOL using EORTC EN24, 
question 48 between the two treatment arms.  
ENDPOINT: Scores determined from patient completed question, “Have you 
felt less feminine due to your disease or treatment” will be compared between 
the two treatment arms.  
1.2.2 Compare cost effectiveness between the two treatment arms. 
ENDPOINT: Cost of procedures will be compared between the two treatment 
arms. 
1.3 
Exploratory Objectives and Endpoints: 
1.3.1 Report vaginal, bowel, and bladder symptoms on HRQOL using the EORTC 
EN24 the two treatment arms.  
ENDPOINT: “Sexual/vaginal problems", "Gastrointestinal symptoms" and 
"Urological symptoms" symptom scales from the EORTC EN24.  
1.3.2 Evaluate toxicities between the two treatment arms. 
ENDPOINT: Patients will be monitored for adverse events using CTCAE V5.0 
criteria and the information will be tabulated. 
1.3.3 Compare local recurrence and document patterns of recurrence between the two 
treatment arms. There will be two analyses: A single interim evaluation of 
patterns of recurrence will be performed after a minimum of 75 patients have 
been accrued, and the second evaluation will be performed at the end of the 
study. 
ENDPOINT: Patients will have recurring pelvic exams to monitor for disease 
recurrence. Additionally, after brachytherapy, CT data sets without contours will 
be sent to HCI for data analysis in an anonymized fashion. 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 9 of 53 
 
 
1.3.4 Evaluate and compare doses to organs at risk (bladder, rectum, sigmoid colon, 
and urethra) and the prescribed target in the two arms.  
ENDPOINT: The radiation dose to organs at risk and the prescribed target in 
each treatment group and explore artificial intelligence approaches to aid in 
contouring.  
1.3.5 Compare total distance traveled to the cancer center for study related visits. 
 
ENDPOINT:  Total distance traveled, calculated by multiplying number of 
study visits by twice the distance to the cancer center. The distance to the cancer 
center will be calculated as the distance from the patient's zip code and the 
cancer center zip code  
 
2 
COHORT 2 (PILOT EXPANSION) 
2.1 
Primary Objective and Endpoint 
2.1.1 The primary objective is to evaluate the frequency and severity of patient-
reported financial toxicity in patients with early-stage endometrial cancer 
treated with vaginal cuff-brachytherapy (VCB) at one-month post-VCB.  
 
ENDPOINT:  
Patient-reported financial toxicity will be assessed through the Functional 
Assessment of Chronic Illness Therapy (FACIT)-Cost questionnaire, 
administered at 1 month post-brachytherapy  
 
2.2 
Exploratory Objectives: 
2.2.1 Exploratory objectives will include evaluation of differences in patient-reported 
financial toxicity between cohorts, to assess any impact of treatment duration on 
outcomes.  
 
ENDPOINT:  
Mean scores for each individual measure will be reported and compared 
between the two arms enrolled in Cohort 2.  
 
Using a COST < 26 as a cutoff for moderate financial distress, the proportion of 
patients experiencing moderate distress in each cohort will be reported and 
compared.  
2.2.2 Exploratory objectives include evaluation of patient-reported diet and physical 
activity levels and quality of life in patients with early-stage endometrial cancer 
treated with vaginal cuff-brachytherapy (VCB) at one-month post-VCB.  
 
ENDPOINT:   
Patient-reported diet and physical activity levels will be assessed through the 
Health Care Expense Survey, NCI Diet History Questionnaire III (DHQ-3), and 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 10 of 53 
 
 
Physical Activity Questionnaire (ACT24) administered at 1 month post-
brachytherapy. 
 
Quality-of-life will be assessed through to Evaluate responses to the QLQ30 
Questionnaire, EN24 Questionnaire in the patient population.  
 
Mean scores from FACIT-COST with be correlated with QlQ30 scores 
 
3 
BACKGROUND 
Endometrial cancer is the most common gynecologic cancer in the western world and 
primarily affects postmenopausal women. Approximately 85% of patients are diagnosed 
at an early stage.1 Additionally, many patients have comorbidities such as obesity, diabetes, 
and cardiovascular disease. The primary form of treatment is surgery consisting of a total 
abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. Major risk 
factors include stage, age, histologic type, grade, depth of myometrial invasion, and 
presence of lymphovascular space invasion.2-5  
Adjuvant radiotherapy for endometrial cancer has been studied in prospective trials for at 
least four decades. All trials have demonstrated an improvement in local regional control. 
However, improvement in survival has not been observed in prospective randomized trials 
in early stage patients. Adjuvant radiotherapy for endometrial cancer has been tailored to 
specific risks factors. Early-stage endometrial cancer patients have an approximately 95% 
overall survival rate or a survival rate consistent with the general population.6 Whereas, 
patients with deeply invasive, grade 3, stage I tumors have been documented in one study 
by Creutzberg et. al.9 to have a 58% overall survival rate.7 Hence, there is great 
heterogeneity in prognoses in stage I patients. National Comprehensive Cancer Network 
(NCCN) guidelines consequently recommend no treatment in general for low-stage 
patients, adjuvant brachytherapy for patients with intermediate- and high-intermediate-risk 
disease, and for patients with deeply invasive tumors with high-grade lesions, external 
beam radiotherapy is an option (NCCN Guidelines 2016). Over the ensuing decades, there 
has been a shift toward increasing use of vaginal cuff brachytherapy. 
In the Norwegian trial published in 1980 by Alders et al., after hysterectomy and 
postoperative vaginal brachytherapy (60 Gy to the mucosal surface), patients were 
randomized to observation or external beam.8 Vaginal and pelvic relapse rates were 
reduced with adjuvant external beam. However, survival was not improved (89% versus 
91% at 5 years). However, the subgroup with grade 3 tumors with deep myometrial 
invasion showed improved local control and survival after external beam (18% versus 27% 
cancer-related deaths). In PORTEC-1, 715 patients with stage I endometrial cancer, grade 
1 or 2 with deep myometrial invasion, or grade 2 or 3 with superficial invasion less than 
50% were randomized after hysterectomy and received external beam, 46 Gy in 2 Gy 
fractions or no additional treatment.9 The 10-year local regional relapse rates were 5% in 
the external beam group and 14% in the control group for a highly statistical advantage for 
external beam for local regional control. However, again there is no significant survival 
difference between the 2 arms. The GOG 99 trial had a similar design; however, patients 
underwent surgical staging10. A high-intermediate-risk group was defined based on the 
prognostic factors, age, histologic grade, myometrial invasion, and the presence of 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 11 of 53 
 
 
lymphovascular space invasion. The high-intermediate group (one-third of the study) had 
a 2-year incidence of relapse in the no adjuvant therapy arm of 27% in contrast to 6% in 
the low-intermediate group. Radiotherapy resulted in similar hazard reductions for the 
high-intermediate and low-intermediate groups (58% and 54%), but in absolute terms, the 
differences were greater in the high-intermediate group with a reduction of 4-year 
cumulative relapse from 27% to 13% in the radiotherapy group. In the pooled ASTEC/EN5 
trials, 905 patients with stage I endometrial cancer were randomly allocated to no adjuvant 
therapy or external beam radiotherapy.11 This trial confirmed the results of the PORTEC 
and GOG 99 trials. In the ASTEC/EN5 trial, brachytherapy was used in 51% of the patients. 
In patients who received no adjuvant therapy, the majority of the relapses occurred in the 
vagina, and hence vaginal brachytherapy has been advocated as a useful method for control 
of disease.9, 10 The PORTEC-2 randomized trial compared external beam (46 Gy in 23 
fractions) and vaginal cuff brachytherapy (7 Gy in 3 fractions one week apart, prescribed 
at ½ cm) for patients with high-intermediate-risk features.12 Four hundred twenty-seven 
patients were evaluated. There were similar rates of vaginal control between external beam 
and vaginal cuff brachytherapy in PORTEC-2. The 5-year rates of vaginal relapse were 
1.8% for vaginal brachytherapy and 1.6% for external beam radiotherapy in PORTEC-2, 
and the 5-year rates for local regional relapse (vaginal relapse and pelvic recurrence) were 
5.1% and 2.1%, respectively. Quality of life was significantly better in the vaginal 
brachytherapy arm.13 Importantly, patients who had brachytherapy reported better social 
functioning and lower symptoms scores for diarrhea, fecal leakage, the need to stay close 
to the toilet, and limitation in daily activities due to bowel symptoms. Sexual functioning 
did not differ between the 2 arms in PORTEC-2. Also, in PORTEC-2, there were no 
differences in 5-year overall survival between the two arms. 
The Sorbe et al., dose seeking trial in stage I endometrial cancer randomized patients 
between 2.5 Gy and 5.0 Gy in 6 fractions in 8 days prescribed to a depth of 5 mm from the 
vaginal surface.14 The trial included 300 patients, and there was one vaginal failure in each 
arm for a vaginal failure rate of 0.7%. The biologic effective dose was significantly less in 
the 2.5 Gy x 6 arm in the Sorbe trial compared to PORTEC-2 (Table1).  
Table 1. 
# of 
Fx 
Dose Per Fx at 
Surface (Gy/fx) 
Total 
Dose 
(Gy) 
α/β 
EQD2 
(Gy) 
BED (Gy) 
Origin 
6 
6.8a 
40.8 
3 
80 
133 
Sorbe et 
al. 
 
 
 
10 
57 
69 
 
 
6 
3.4a 
20.4 
3 
26 
44 
Sorbe et 
al. 
 
 
 
10 
23 
27 
 
 
5 
6 
30 
3 
54 
90 
 
 
 
 
10 
40 
48 
 
 
3 
10 
30 
3 
78 
130 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 12 of 53 
 
 
 
 
 
10 
50 
60 
 
 
3 
9.5a 
28.5 
3 
71 
119 
PORTEC2 
 
 
 
10 
46 
56 
 
 
3 
11 
33 
3 
92 
154 
 
 
 
 
10 
58 
69 
 
 
2 
10 
20 
3 
52 
87 
 
 
 
 
10 
33 
40 
 
 
2 
11 
22 
3 
62 
103 
 
 
 
 
10 
39 
46 
 
 
2 
12 
24 
3 
72 
120 
 
 
 
 
10 
44 
53 
 
EQD2: equivalent dose in 2Gy/fraction  
BED: biological effective dose 
aOriginally prescribed at 0.5 cm depth; surface dose estimated assuming using a 3 cm diameter cylinder.  
GOG 249 has been presented in abstract form.15 This trial included 601 patients with stage 
I and II endometrial cancer with high-intermediate or high-risk features and compared 
vaginal cuff brachytherapy and 3 cycles of carboplatin-paclitaxel with pelvic external 
beam. There were no differences in relapse-free survival (84% versus 82%) or overall 
survival between the 2 arms at a median follow-up of 24 months. 
Since completion of these randomized trials, there has been a decrease in external beam 
radiotherapy and a concomitant increase in vaginal cuff brachytherapy. In the PORTEC-2 
trial, Low Dose Radiation (LDR) was permitted, and 30 Gy was specified at a 5 mm depth 
at a dose rate of 60-65 cGy per hour. Nevertheless, most patients were treated with high-
dose-rate brachytherapy in PORTEC-2. Twenty-one Gy was specified at 5 mm depth in 3 
fractions of 7 Gy each given 1 week apart. Target length was the upper half of the vagina. 
It was recommended to choose the active length prescribing at 5 mm depth, 1 cm shorter 
than the upper half of the vagina resulting in the 100% isodose surface to cross the vaginal 
mucosa at 50% of the length. In PORTEC-2, grade 3 mucosal toxicity with narrowing or 
shortening was rare and was identified in 1.9% in the vaginal brachytherapy group 
compared to 0.5% in the external beam group. Also in the PORTEC-2 trial, physicians 
recorded more mild-to-moderate vaginal atrophy in the upper vagina in the vaginal 
brachytherapy group. At 30 months, atrophy was reported in 40% of the patients in the 
vaginal brachytherapy group, 18% grade 1 and 21% grade 2, but without narrowing or 
shortening of the vagina. These atrophic changes were without consequences for vaginal 
or sexual functioning. However, the difference in atrophy compared to external beam 
radiotherapy questioned if the dose of the mucosa may be higher than required in the 
PORTEC-2 study. Additionally, vaginal control was 99.3 % in the Sorbe randomized trial 
and a significantly lower biologic effective dose was used in the 2.5 Gy x 6 arm.14  Modern 
brachytherapy is now image-guided and planning CT scans allow individual planning of 
dose depth of bladder, rectum, and bowel if they are within 2-3 mm of the cylinder surface. 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 13 of 53 
 
 
3.1 
Rationale for 2 fractions of vaginal cuff brachytherapy of 11 Gy at the surface 
Since publication of PORTEC-2, the most common fraction scheme for adjuvant vaginal 
brachytherapy for endometrial cancer is 7 Gy prescribed at ½ cm (9.5 Gy at the vaginal 
surface for a 3 cm cylinder) delivered 3 times.16 This resulted in a vaginal control rate of 
>98%. Although the grade 3 vaginal toxicity rate was low at 1.9%, vaginal atrophy was 
reported in 40% of patients at 30 months. In the Sorbe randomized trial a significantly 
lower biologic effective dose was used and a vaginal control rate of >99% was achieved. 
Also, 6 Gy prescribed to the surface delivered 5 times was permitted in GOG 0249, an 
NCI-sponsored trial. The biologic effective dose with this regimen and the Sorbe et al., 
regimen of 2.5 Gy x 6 is significantly lower than the dose utilized in PORTEC-2 (Table 1). 
Two fractions of vaginal cuff brachytherapy of 11 Gy at the surface (7.3 Gy at ½ cm) given 
weekly is a lower biologic effective dose than utilized in PORTEC-2, yet higher than 
utilized by Sorbe et al where vaginal control was >99%. Thus, lowering the dose compared 
to PORTEC-2 should result in more convenience, a lower rate of acute and late side effects, 
and not significantly impact vaginal control.  
3.2 
Rationale for short course vaginal brachytherapy 
Gynecologic brachytherapy can be a challenging procedure for many women. In one study 
from the Medical University of Vienna, patients undergoing treatment for cervix cancer 
feared brachytherapy more than surgery or chemotherapy.7 Shortening a course of Vaginal 
Cuff Brachytherapy (VCB) would be convenient for patients. Currently, many women do 
not receive guideline-suggested treatment especially as they get older. In one study less 
than half of eligible women received guideline suggested adjuvant radiotherapy.17 A recent 
National Cancer Data Base analysis demonstrated that only a third of elderly women with 
endometrial cancer received standard of care VCB (Torgeson et al unpublished data). 
Additionally, across the United States there is significant variation in the use of 
radiotherapy for endometrial cancer.18 Fewer radiotherapy fractions should permit a higher 
percentage of women living in rural and frontier areas to receive radiotherapy. Distance 
from a radiotherapy center has shown to negatively impact compliance for radiation 
treatment in a number of malignancies.19 A shorter treatment course will be more patient 
friendly resulting in greater compliance, be less intensive on radiotherapy resources, be 
more cost effective, and result in less morbidity. We propose a study of 2 fractions of 
vaginal cuff brachytherapy of 11 Gy at the surface (7.3 Gy at ½ cm depth) given one week 
apart. The primary outcome variable is the Global Health Status from the EORTC QLQ-
C30. The primary hypothesis is that the Global Health Status from the EORTC QLQ-C30 
in experimental arm will be non-inferior to the Global Health Status from the EORTC 
QLQ-C30 in the control arm. The secondary outcome will evaluate the differences in PROs 
using the EORTC EN24 for vaginal, bladder, and bowel symptoms, cost effectiveness, 
toxicities as assessed by CTCAE v5.0, and document patterns of recurrence.  
3.3 
Rationale for Pilot Expansion (Cohort 2) 
 
 “Financial toxicity” is a term used to describe the harmful effect of treatment cost on a 
patient’s quality of life. For cancer patients, many factors can contribute to financial 
toxicity, including disease and treatment-related Risk Factors, sociodemographic factors, 
age, income, race and ethnicity, employment and health insurance status. Financial 
toxicity is unfortunately common in the oncology population, and can cause significant 

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distress to patients. Financial toxicity has been shown to manifest in specific 
consequences such as reduced leisure activities, withdrawals from savings accounts, 
selling of personal possessions to cover the cost of cancer care23, and decreased treatment 
compliance24.  
Hypofractionation, or the delivery of biologically equivalent doses of radiation in fewer 
total treatments, is a cost-effective intervention in the sense that it reduces healthcare 
expenditures. Beyond cost-efficacy, it is also critical to evaluate how changes in 
treatment duration directly affect costs that impact the healthcare expenses of patients, 
particularly as financial toxicity is compounded in patients from rural areas traveling 
great distances for care25. 
3.3.1 Rationale for Assessment of Patient-Reported Financial Toxicity: 
Accurate assessment of financial toxicity requires reporting from the patient perspective. 
Developed in conjunction with the University of Chicago, The Functional Assessment of 
Chronic Illness Therapy (FACIT)-Cost was created to quantitatively measure cancer 
patients' experience related to financial distress. The COST measure has demonstrated 
reliability and validity in measuring financial toxicity, and has been correlated with 
HRQOL, indicating that financial toxicity is a clinically relevant patient‐centered 
outcome26. Studies of financial toxicity in gynecologic oncology patients utilizing the 
COST measure have reported toxicity rates exceeding 50%27,28. 
Collecting patient-reported financial toxicity information will help inform on baseline 
degrees and frequencies experienced by patients undergoing adjuvant VCB. It will be 
particularly important to establish expected frequencies in this specific population as 
most prior studies of financial toxicity in gynecologic oncology patients were 
significantly impacted by treatment with chemotherapy, and may not be applicable to our 
study population. By establishing baselines within this specific population, financial 
toxicity can be included as a formal endpoint in future randomized trials involving VCB, 
to thoroughly assess any implications of short-course VCB on patient-reported financial 
toxicity. In addition, understanding what percentage of our VCB patients experience 
significant financial toxicity will help inform on potential needs for intervention.  
 
Lifestyle behaviors like diet and physical activity are critical considerations for 
endometrial cancer survivorship care, particularly since endometrial cancer patients are at 
elevated risk of cardiometabolic diseases than cancer-free women, even when matched by 
level of obesity29. Data from a US-representative sample shows that diet quality among 
cancer survivors in the US is generally poor30. Among endometrial cancer survivors, few 
dietary interventions have been conducted, but existing studies provide evidence that 
intervening to improve diet quality may improve physical functioning and fatigue in 
endometrial cancer survivors30–32. Physical activity has been shown to improve survival 
outcomes among endometrial cancer survivors as well32,33.  
3.3.2 Rationale for Assessment of Patient-Reported Dietary and Physical Activity 
Habits: 
Data on dietary pattern among endometrial cancer survivors is scarce, and existing 
recommendations are to follow guidelines for endometrial cancer prevention. The 
aforementioned studies are either non-specific to the endometrial cancer population, or 
include a large percentage of patients treated with surgery alone and no adjuvant 
therapy32. Changes to patterns of clinical care could impact the lifestyle of cancer patients 

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and consequently diet and physical activity-related outcomes including metabolic health. 
Consequently, we will describe diet quality (Healthy Eating Index measured by the NCI 
Diet History Questionnaire III) and physical activity (ACT24) 34,35 among early-stage 
endometrial cancer survivors, to prospectively characterize these aspects of our early-
stage endometrial cancer population. We will further evaluate whether urban versus rural 
designation modifies diet/activity levels. Collecting this information will help inform on 
baseline habits of a population controlled for cancer type and stage, and will help 
generate hypotheses on interventions beneficial to this specific cohort.  
 
4 
STUDY DESIGN 
4.1 
Description:  
This is a phase III, un-blinded, randomized trial comparing an experimental arm and a 
control arm of vaginal cuff brachytherapy: The experimental arm will treat subjects with 2 
fractions of vaginal brachytherapy. The control arm will treat subjects with standard of care 
vaginal cuff brachytherapy of 3-5 fractions. See schema below: Patients will be randomized 
1:1 to the different treatment arms. 
 
4.2 
Enrollment and data analysis for Cohort 1 has been completed. Cohort 2 will 
mirror the design of Cohort 1, but include additional outcome measures. 
4.3 
Number of Patients: 
108 total patients were enrolled in Cohort 1 (54 to each study arm). An additional 80 
patients will be enrolled in Cohort 2. 
4.4 
Number of Study Centers 
This is a multisite study to be conducted at Huntsman Cancer Institute at the University of 
Utah, Salt Lake City, Utah. Up to 5 additional sites may be included.  

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4.5 
Study Duration  
Patient enrollment in Cohort 1 occurred over 3 years and 9 months. Enrollment in Cohort 
2 is expected to occur over approximately 2 years. Total study duration is expected to be 
approximately 6 years.  
 
 

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5 
ELIGIBILITY CRITERIA 
This eligibility checklist is used to determine patient eligibility and filed with the 
enrolling investigators signature in the patient research chart.  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 
Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
5.1.1 _____ Histologically confirmed endometrial carcinoma: endometrioid type, 
serous, and clear cell to include tumors originating in the cervix, but are 
primarily located in the uterus, and for whom vaginal cuff brachytherapy is 
indicated. Carcinosarcoma and other sarcomas are permitted. FIGO stage I and 
stage II, with one of the following combinations of stage and grade (Appendix 
A and C): 
 
_____ Stage IA, grade 1 with LVSI, 2, 3 
 
_____ Stage IB, grades 1-3 
 
_____ Stage II, grades 1-3 
 
_____ Stage IIIA, grades 1-3, not receiving EBRT as part 
of adjuvant therapy. 
5.1.2 _____ Patients post hysterectomy and free from residual disease.  
5.1.3 _____ WHO/ECOG-performance status 0-2 (Appendix B). 
5.1.4 _____ Able to provide informed consent and willing to sign an approved 
consent form that conforms to federal and institutional guidelines. 
5.1.5 _____ Life expectancy of >2 years 
5.2 
Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
5.2.1 _____ Stages of endometrial carcinoma other than described in Inclusion 5.1.1.  
5.2.2 _____ Previous pelvic radiotherapy. 
5.2.3 _____ Concurrent malignancy requiring non-protocol anti-cancer treatment 
other than surgery.    
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment 
onto this study.  
 
______________________________ 
 
_________ 
_______ 
Investigator Signature  
 
 
 
Date  
Time 

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6 
TREATMENT PLAN 
6.1 
Administration Schedule  
Experimental arm: 11Gy will be prescribed to the surface with a minimal treatment length 
of 3 cm. Two fractions will be given, one week apart. For this instance a week apart 
indicates an intervening weekend between treatments. Ideally treatments would be 7 days 
apart. Inspection of the vaginal cuff is required to ensure there is no dehiscence. Dose 
should be optimized to the cylinder as seen in Figure 1, Appendix D, with dose normalized 
to 100% at the tip and at the midpoint of the active length. Dose at ½ cm will be recorded 
also. In cases of fulminant LVSI, the entire vagina may be treated per physician discretion. 
In most scenarios, the maximal treatment length should not exceed 5 cm. CT simulation 
shall be performed.  
Control arm: One of the following fractions schemes are permitted based on the decision 
of the treating physician:  
• 7 Gy at ½ cm x 3 fractions over no more than three weeks.  
• 5-5.5 Gy at ½ cm x 4 fractions over no more than three weeks. 
• 6 Gy at the surface of the cylinder x 5 fractions over no more than three weeks. 
 
6.1.1 Treatment Schedule 
If chemotherapy is going to be used, the preferred sequence is vaginal cuff brachytherapy 
first; however, treatment sequence may be determined at the investigator’s discretion.  
 
It is recommended that patients begin cuff brachytherapy within 16 weeks of 
hysterectomy. In the event chemotherapy precedes brachytherapy, it is recommended that 
brachytherapy begins 2-6 weeks after completion of chemotherapy. 
6.2 
Prohibited Concomitant Medications/Treatments 
Non-protocol anti-cancer therapy other than surgery for another malignancy.  
6.3 
Duration of Therapy  
Patients in the experimental arm should have treatment completed within two weeks of 
the first fraction given. Patients in the control arm should have treatment completed within 
three weeks of the first fraction given. 
7 
TOXICITIES AND DOSEAGE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 5.0 for adverse event and serious adverse event reporting.  
7.1 
Dose Modifications  
No dose modifications will be permitted. If dose to bowel or bladder is felt to be unsafe, 
evacuation of bowel or bladder is recommended. Treatment may be delayed for up to 2 
weeks longer due to medical necessity. 

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7.2 
Supportive Care 
All supportive measures consistent with optimal patient care will be given throughout the 
study.  
7.2.1 Emotional Distress  
Severe emotional distress will be defined by a QLQ-C30 total score of  ≤71. Study staff 
will notify the treating investigator of QLQ-C30 scores ≤71, and the participant may be 
referred to additional institutional resources to address emotional distress, as needed.  
7.2.2 Emotional Distress Due to Financial Toxicity 
Severe emotional distress due to financial toxicity will be defined by a FACIT-Cost score 
of <14. Study staff will notify the treating investigator of FACIT-Cost scores <14, and 
the participant may be referred to institutional resources for billing and financial services, 
as needed. 
 
 

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Version Date:18JUN2025 
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8 
STUDY CALENDAR 
Examination 
Screening1 
Brachytherapy 
Follow-up6 
Follow-up6 
Follow-up6 
Long term 
Follow-up6 
1 month  
+/- 12 weeks 
6 months 
+/- 12 weeks 
12 months 
+/- 12 weeks 
24 and 36 months 
+/- 12 weeks 
Informed consent 
X 
  
  
  
  
 
Medical history 
X 
  
 
  
  
 
Eligibility criteria 
X 
  
  
  
  
 
Vital signs 
X 
 
X 
X 
X 
 
Physical examination 
X 
  
X 
X 
X 
 
Pelvic exams 
X 
 
X 
X 
X 
 
WHO/ECOG performance status 
X 
 
X 
X 
X 
 
QLQ30 Questionnaire2 
  
X 
X 
X 
X 
 
EN24 Questionnaire2 
 
X 
X 
X 
X 
 
Collection of Cost Data4 
 
 
 
X 
 
 
Collection of Distance Data7 
 
 
 
 
X8 
 
Vaginal Cuff Brachytherapy3 
  
X 
  
  
  
 
Adverse Event assessments 
  
X 
X 
X 
X 
 
Chart Review5  
 
 
 
 
 
X 
COHORT 2 Only 
COST-FACIT10 
 
 
X 
 
 
 
Health Care Expense Survey11 
 
X 
X 
 
 
 
NCI Diet History Questionnaire III (DHQ-3)9 
 
 
X 
 
 
 
Physical Activity Questionnaire (ACT24)9 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
1. 
All Pre-study/Screening procedures should be completed less than or equal to 12 weeks before study treatment. 

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2. 
Both the QLQ30 and EN24 questionnaires (appendix E and F) should be administered at baseline (prior to the first brachytherapy fraction) and at the 1 month, 6 month, and 12 
month follow-up visits. See section 7.2.1 for guidance on participants experiencing severe emotional distress.  
3. 
Subjects randomized to the control arm will undergo one of the three treatment options described in section 5 over no more than 3 weeks. Subjects randomized to the 
experimental arm will undergo the treatment described in section 5 over no more than 2 weeks. See Appendix D for treatment planning and dose reporting form. 
4. 
Collection of cost data for analysis is described in section 9.2 
5. 
The PI will continue to review patient medical charts at 24 and 36 months for disease reoccurrence at one of the following locations: vaginal, pelvic, or distant. 
6. 
In person visits are preferred to allow for exams, so almost all visits will be done on site. If a patient is ill or cannot travel, questionnaires and history may be obtained via 
telemedicine. Missed exams will be considered deviations.   
7. 
Patient’s zip code and the location of the treatment facility will be collected and documented by the study staff.  
8.     If the information is not collected at the 12 month follow up visit, it will be collected at a subsequent time point or from patient’s medical record. 
9.     Completion of the DHQ-3 and ACT24 is strongly encouraged, however, incompletion will not result in a protocol deviation. 
10.   See section 7.2.2 for guidance on participants experiencing severe emotional distress due to financial toxicities.  
11.   It is recommended that the Healthcare Expense diary be given to the participant prior to radiation to accurately track expenses throughout treatment. The diary should be 
collected from the patient at a follow-up visit.  
  

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9 
CRITERIA FOR EVALUATION AND ENDPOINT (COHORT 1) 
9.1 
Primary Objective 
Evaluate the non-inferiority of patient HRQOL using the Global Health Status from the QLQ-C30 in the 2 arms 
one month after treatment. 
All patients with a valid baseline and with a follow-up QOL questionnaire at one month post treatment will be 
included in the analysis. We are accounting for an approximate 5 per cent drop out rate. We anticipate a high 
compliance rate due to the short follow up interval for the primary endpoint. Patients without valid questionnaires 
will not be replaced. The baseline questionnaire is considered valid if filled out and dated by the patient before 
the starting date of trial treatment. Reasons for missing baseline and follow-up questionnaires will be assessed.  
For the evaluation of the general quality of life the EORTC (European Organization for Research and Treatment 
of Cancer) Core questionnaire (QLQ-C30 version 3.0) will be used (Appendix E). The EORTC QLQ-C30 is a 
multidimensional, cancer-specific quality of life questionnaire developed by the EORTC Study Group on Quality 
of Life (QOL) for repeated assessments within clinical trials. It is developed in a cross- cultural setting and has 
been found valid and reliable for quality of life assessments in various cancer populations, irrespective of the 
specific diagnosis. Optional modules developed for specific diagnostic groups or specific treatment modalities 
can supplement it. The QLQ-C30 contains five functional scales (physical, cognitive, emotional, social and role 
functioning), a global health status/quality of life scale, three symptom scales (pain, fatigue and nausea/vomiting), 
and six single items assessing additional symptoms (dyspnoea, insomnia, loss of appetite, constipation, diarrhoea) 
and perceived financial impact. For the majority of the QLQ-C30 items a 4-point Likert-type response scale is 
used. Exceptions are the items for the global quality of life scale (where a 7-point scale is used). All subscale and 
individual item responses are linearly converted to 0 to 100 scales. A higher score for a functional and global 
quality of life scales represents a better level of functioning. For the symptom scales and items, a higher score 
reflects a higher level of symptoms and decreased quality of life.  
9.2 
Secondary Objectives 
Cost-effectiveness (CE) analyses will be explored using cost data (i.e., treatment related costs) for 2 fractions of 
VCB compared to standard of care brachytherapy (3, 4, or 5 fractions). A payer’s perspective will be applied for 
the analysis because the costs relevant to treatments will be considered. Cost for the intervention will be measured 
for the cost of therapy. If costs related to the intervention occurs in different years, costs will be adjusted to the 
most recent year US using the medical component of the Consumer Price Index (CPI). If charged amounts 
relevant to the treatments are available, they will be converted to costs by using cost-to-charge ratios. We will 
not compare charges or costs between institutions. There will be no publication of financial data from any 
individual participating site.  
The following data will be collected retrospectively at each patient’s six month visit: 
• Date of First Service 
• Total Professional Fees (reported in US dollars) 
• Total Technical Fees (reported in US dollars) 
*Subgroup analyses using available cost effectiveness data points, beyond those listed above, may be performed 
for patients treated at the Huntsman Cancer Institute. 
Patient reported HRQOL will be utilized for effect (i.e., effectiveness side). The HRQOL measure will be based 
on the EORTC QLQ-30 Global Health Status and will be used to calculate Quality Adjusted Life Years (QALYs). 

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An additional secondary analysis is obtained from EN 24 question 48, “Have you felt less feminine due to your 
disease or treatment.” The analysis will compare response between the two arms at the one month time point.  
9.3 
Exploratory objectives 
Evaluate CTCAE v5.0 toxicities 
Routine safety and tolerability will be evaluated from the results of reported signs and symptoms, scheduled 
physical examinations, vital sign measurements, and clinical laboratory test results.  
Evaluate and compare doses to organs at risk  
Doses to organs at risk including bladder, rectum, sigmoid colon, and urethra, and target in the two trial arms 
will be evaluated from CT data sets without contours that will be sent to HCI in an anonymized fashion and 
compared to each other. Artificial intelligence approaches to aid in contouring will be considered. Additionally, 
the dose to prescribed target in each group will be calculated.  
 
  Compare total distance traveled to the cancer center for study related visits. 
 
Total distance traveled, calculated by multiplying number of study visits by twice the distance to the cancer 
center. The distance to the cancer center will be calculated as the distance from the patient's zip code and the 
cancer center zip code. 
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a licensed physician (or physician’s 
assistant or nurse practitioner). 
Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate and temperature) will be obtained.  
Compare local recurrence and document patterns of recurrence 
Local recurrence will be assessed by pelvic exam. Time points for evaluation include screening, one, six, and 
twelve months via study visits, and via chart review at twenty-four, and thirty-six months post treatment. Imaging 
may be used at the physician’s discretion depending on the subject’s symptoms. Recurrences in the 2 arms will 
be assessed according to site: vaginal, pelvic, or distant. 
Report vaginal, bowel, and bladder symptoms on HRQOL using the EORTC EN24 the two treatment arms. 
In addition to the QLQ C-30 core questionnaire, the EORTC module for endometrial cancer EN24 will be used 
to descriptively report values for the following symptom scores; “Sexual/vaginal problems," 
"Gastrointestinal symptoms," and "Urological symptoms." Additional questions regarding sexual symptoms and 
distress will also be reported.  
9.4 
Stopping Rules 
If four discrete subjects present with grade 3 vaginal, rectal, or bladder toxicities considered related to 
brachytherapy in the experimental arm, it will result in trial closure. 

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10 
STATISTICAL CONSIDERATIONS 
10.1 COHORT 1 
10.1.1 Primary Objective 
The primary objective is to evaluate the non-inferiority of patient Health Related Quality of Life (HRQOL) in the 
Experimental arm compared to the Control arms one month after treatment. The primary efficacy variable is the 
Global Health status from the EORTC QLQ-C30. The EORTC QLQ-C30 is a multidimensional, cancer-specific 
quality of life questionnaire developed by the EORTC Study Group on Quality of Life (QOL) for repeated 
assessments within clinical trials. All patients with valid non-missing baseline and one month follow up Global 
Health Status will be included in the analysis. See below for handling of missing items. 
The primary hypothesis is that the Global Health Status is non-inferior in the Experimental Arm compared to the 
Control Arm. Let µE and µC be the mean Global Health status in the Experimental and Control Arms respectively. 
The null hypothesis (H0) and alternative hypothesis (H1) are 
H0: µE - µC ≤ -15 and H1: µE - µC > -15 
A two sample t test will be used for the primary analysis. As a sensitivity analysis we will be use analysis of 
covariance with Global Health Status at one month post therapy as Gaussian response variable, treatment group 
as a fixed effect and baseline Global Health Status as a continuous adjustment variable.  
10.1.2 Handling of missing items in the Global Health Status 
If at least half the items in the Global Health Status are present then the Global Health Raw Score will be calculated 
as the average of the items that are present. This method is effectively equivalent to replacing missing items by 
the average of the items that are present, and is a standard method for treating summary scores with missing items. 
If more than half the items are missing the Global Health Status will be treated as missing. Subjects with missing 
Global Health Status will be excluded from the primary analysis. This method provides valid estimates provided 
data is missing at random (MAR). Sensitivity analyses may be performed with multiple imputation used to impute 
missing data.  
10.1.3 Additional exploratory analysis of the Primary Endpoint (COHORT 1) 
Analysis of the Global Health Status at all time points (baseline, 1 month, 6 month, and 12 months) will use a 
normal repeated measures model with unstructured covariance matrix. Subjects with missing Global Health Status 
will be excluded from the analysis. Multiple imputation may be used in a sensitivity analysis. Change from 
baseline to each of the follow up times will be the focus of the exploratory analysis. 
10.1.4 Secondary Endpoints 
Vaginal HRQOL evaluation using question 48 of the EORTC EN24: “Have you felt less feminine due to your 
disease or treatment”. This item has a four point scale. Ordinal logistic regression will be used to analyze this 
question, with one month value as outcome variable, treatment arm as primary predictor, and the baseline value 
as covariate. A non-inferiority analysis will be performed with margin equal to 6.1 points, which represents 
approximately ½ standard deviation. Additional exploratory logistic regression analyses will include the values at 
all time points (baseline, one month, 6 months and 12 months). 
Cost effectiveness. Once parameters are computed: 1) mean differences in cost and effect between treatments, 2) 
variances for differences in costs and effects, and 3) covariance between effectiveness and cost difference, the 
incremental cost-effectiveness ratio (ICER) or incremental net benefits summarizing the monetary value of the 
intervention will be calculated.  
care
dard
s
Fractions
care
dard
s
Fractions
Effect
Effect
Cost
Cost
ICER
tan
2
tan
2
−
−
=
 

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A CE acceptability curve will be used to quantify and graphically depict uncertainty in the analysis. To consider 
uncertainty in parameters, probabilistic sensitivity analysis utilizing Monte Carlo simulation (i.e., second-order 
simulation) will be conducted. To reflect the uncertainties in costs and in effects, a gamma distribution for costs 
and a normal distribution for effects will be adopted. And univariate analyses will be conducted to consider an 
uncertainty of one parameter at a time over a range of 95% confidence interval in cost and effectiveness measures. 
10.1.5 Exploratory Endpoints (Cohort 1) 
We will descriptively evaluate patient reported HRQOL regarding bowel, bladder and vaginal symptoms using 
the validated instrument, EORTC QLQ- EN 24. We will report means, standard deviations, ranges and 95% 
confidence interval for “Sexual/vaginal problems", "Gastrointestinal symptoms", and "Urological symptoms" 
symptom scales. All these outcomes will be reported separately for each treatment arm. Doses to organs at risk 
(including bladder, rectum, sigmoid colon, and urethra) and prescribed target in the two arms of the trial will be 
analyzed using descriptive statistics such as mean, standard deviation and 95% confidence interval. Comparisons 
between arms will use exploratory t-tests or non-parametric Wilcoxon tests as appropriate.  
Exploratory endpoints will also include CTCAE v5.0 toxicities and patterns of recurrence in the two arms. 
Recurrences in the two arms will be tabulated as vaginal, pelvic, or distant. We will report counts, proportions, 
and exact 95% confidence intervals for adverse events. Kaplan-Meier curves and associated confidence intervals 
will be used to analyze time to recurrence. 
The mean, median, standard deviation and interquartile range of total distance traveled will be reported for each 
study arm. A Wilcoxon rank-sum test will be used to compare the total distance traveled between the arms.  
10.1.6 Sample Size Evaluation 
We base the sample size on the precision of estimation of the Global Heath Status from QLQ-C30. The 
hypothesis to be tested is that the mean Global Health Status will be the same or higher one month after 
treatment in the Experimental Arm compared to the Control Arm. The EORTC QLQ-C30 reference values 
manual gives the means and SD of the Global Health Status in genitourinary cancer patients as 62.6 ±22.2 
points.  We assume a standard deviation of 22.2 points for power calculations. Additional assumptions are 1:1 
randomization to one of two groups, a true difference of 0 points, a Gaussian response variable, a non-inferiority 
margin of 15 points, alpha = 0.025 (one sided), and the use of a two sample t-test for the primary analysis.  A 
non-inferiority margin of 15 points was chosen for this trial based on a combination of scientific and practical 
considerations. In a survey of 30 clinical trials, the definition of a clinical meaningful change in quality of life 
questionnaire data varies widely, with margins up to 10-15 point required for clinical significance (Cocks KT, et 
al 2008). With these assumptions a total evaluable sample size of 96 will provide 90% power. The planned 
sample size of 108 randomized equally to two arms allows for a dropout rate of approximately 10%. 
10.2 COHORT 2 
10.2.1 Sample Size Determination  
The primary endpoint for Cohort 2 is the Functional Assessment of Chronic Illness Therapy (FACIT)-COST 
score. A preliminary estimate of the mean COST score in each arm will be reported for cohort 2, along with a 
95% Gaussian confidence interval. The published standard deviation for FACIT-COST is approximately 12.36 
With the planned sample size of N = 40 subjects per arm, and assuming a standard deviation of approximately 
12, a 95% confidence interval for mean COST will have a width of approximately 7.6 points.  
10.2.2 Population for Analyses 
All subjects who have received one dose of radiation and have completed at least one set of questionnaires will 
be included in all data sets. Subjects who fail to begin study therapy will be replaced.  
 

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10.2.3 Primary Endpoint 
• Patient-reported financial toxicity will be assessed through the Functional Assessment of Chronic Illness 
Therapy (FACIT)-Cost questionnaire, administered at 1 month post-brachytherapy) 
o A preliminary estimate of the mean COST score in each arm will be reported for cohort 2, along 
with a 95% Gaussian confidence interval. 
10.2.4  Secondary Endpoints: 
• Quality-of-life will be assessed through to Evaluate responses to the QLQ30 Questionnaire and EN24 
Questionnaire in the patient population.  
o The analysis of this data will be descriptive and tabular. No formal statistical testing will be done. 
• Mean scores from FACIT-COST with be correlated with QlQ30 scores 
o Spearman correlation coefficients between FACIT-COST and QlQ30 summary scores will be 
reported for each arm. No statistical testing will be performed. 
10.2.5 Exploratory Endpoints 
The analysis of this data will be descriptive and tabular. No formal statistical testing will be done. 
 
 
11 
REGISTRATION GUIDELINES 
Patients must meet all of the eligibility requirements listed in Section 4 prior to registration.  
Study related screening procedures can only begin once the patient has signed a consent form. Patients 
must not begin protocol treatment prior to registration. 
Treatment should start less than or equal to 10 business days after registration. 
To register eligible patients on study, complete a Clinical Trials Office Patient Registration Form and submit to: 
CTORegistrations@hci.utah.edu. 
Treatment with experimental or control arms will be assigned at the time of enrollment. A randomization code 
will be created by a biostatistician and given to the Research Compliance Office to maintain and assign treatment 
to each patient as they are enrolled. 
12 
DATA REPORTING 
12.1 Source documents and access to source data 
Each participating site will maintain appropriate medical and research records for this trial, in compliance with 
ICH E6 and regulatory and institutional requirements for the protection of confidentiality of participants.  
Source data are all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial. CRFs can be source documents as well as the 
medical record.  
12.2 Quality assurance 
QC procedures will be implemented beginning with the data entry system and data QC checks that will be run 
on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 

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The investigational site will provide direct access to all trial related sites, source data/documents, and reports for 
the purpose of monitoring and auditing by HCI’s RCO, and inspection by local and regulatory authorities. 
12.3 Data collection and management responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. 
Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, cross out the 
original entry with a single line, and initial and date the change. DO NOT ERASE THE ORIGINAL. 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for recording 
data for each participant enrolled in the study. Data reported in the eCRF derived from source documents should 
be consistent with the source documents or the discrepancies should be explained and captured in a progress note 
and maintained in the participant’s official electronic study record. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into OnCore, a 21 CFR Part 11-compliant data capture system. The data system 
includes password protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
12.4 Study records retention 
Study documents should be retained for a minimum of 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 until 
at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period, however, if required by local regulations. No 
records will be destroyed without the written consent of the PI, if applicable. It is the responsibility of the sponsor 
to inform the investigator when these documents no longer need to be retained. 
12.5 Monitoring and Auditing 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance 
with the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). 
Centralized monitoring will occur after the first 2, 5, and 10 patients are accrued and treated; then monitoring 
will occur throughout the trial until 30 days after the last patient has been treated twice yearly. Monitoring will 
be centralized, with random review of 25% of data, including data reporting and research sample acquisition.  
Audits are performed independent of study monitoring. An initial audit will be conducted approximately one 
year after enrollment begins and annually thereafter. Audits may be conducted more frequently as requested by 
the Data and Safety Monitoring Committee (DSMC), RCO management, the Principal Investigator (PI), or 
Clinical Trials Office (CTO) depending on type and complexity of the trial, the level of risks to the trial subjects, 
and any identified problems or issues. Audit results will be reported to the HCI IRB as required. 
Each clinical site will perform internal quality management of study conduct, data collection, documentation and 
completion. 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
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13 
SPECIAL INSTRUCTIONS  
13.1 Dosimetric review 
Treatment length and active length will be recorded for all patients. CT simulation shall be performed. Dose 
should be optimized to the cylinder as seen in Figure 1, Appendix D with dose normalized to 100% at the tip and 
at the midpoint of the active length. Dose at ½ cm will be recorded.  
14 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 Informed consent  
Informed consent will be obtained from all research participants prior to performing any study procedures using 
the most recent IRB approved version.  
14.2 Institutional Review 
Study will be approved by the Institutional Review Board of University of Utah. 
14.3  Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman Cancer Institute (HCI) and 
approved by the NCI to assure the well-being of patients enrolled on Investigator Initiated Trials that do not have 
an outside monitoring review. Roles and responsibilities of the DSMC are set forth in the NCI approved plan. 
The activities of this committee include a quarterly review of adverse events including SAEs, important medical 
events, significant revisions or amendments to the protocol, and approval of cohort/dose escalations. If the DSMC 
and/or the PI have concerns about unexpected safety issues, the study will be stopped and will not be resumed 
until the issues are resolved. The DSMC also reviews and approves audit reports generated by the Research 
Compliance Office.  
This is a multicenter, phase III study classified as high risk per the NCI-approved DSM plan. Each high-risk study 
will be assigned a physician member of the DSMC as medical monitor, or in rare cases, an external medical 
monitor. The medical monitor will be notified of all serious adverse events (SAEs). Specific notifications will 
also be issued when a dose-limiting toxicity is encountered and when the MTD dose is defined. Approval of the 
medical monitor is required for all dose escalations. All serious adverse events (SAEs) occurring in patients treated 
at HCI or its affiliates will also be reviewed by the full DSMC monthly. The full committee will also review all 
toxicities for patients on treatment and less than or equal to 30 days of their last treatment on a quarterly basis.  
Each high-risk study will also be assigned a dedicated research compliance officer who will monitor the trial. 
High-risk studies will be monitored by RCO personnel after the first patient is enrolled and every three months 
thereafter during active enrollment. The RCO monitor will review the study status and summarize enrollment, 
toxicities, SAEs, dose escalation, statistical endpoints (e.g., stopping rules), deviations, etc. for the full DSMC 
membership at the regularly scheduled meetings. Amendments that increase risk, change dosing, or impact study 
objectives will be reviewed by the DSMC and approved by the PRMC and IRB. High-risk trials will be formally 
reviewed by the DSMC after the first patient is enrolled and then quarterly thereafter. 
An initial audit of high-risk studies will be conducted by the RCO approximately one year after enrollment begins 
and annually thereafter. Audits of high-risk studies may be conducted more frequently as requested by the DSMC, 
IRB, PRMC, RCO management, or the PI.  
14.4 Adverse Events / Serious Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for AE 
and SAE reporting.  

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14.4.1 Adverse Events (AE) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical condition 
occurring after starting the study drug even if the event is not considered to be related to study drug. For the 
purposes of this study, the terms toxicity and adverse event are used interchangeably. Medical 
conditions/diseases present before starting study drug are only considered adverse events if they worsen after 
starting study drug. Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, are considered clinically significant, or require therapy.  
Collection of adverse events will begin at start of brachytherapy and continue for 12 months after the start of 
brachytherapy. 
Information about all adverse events, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be collected and 
recorded and followed as appropriate. 
Adverse events should be evaluated to determine: 
1. The severity grade based on CTCAE v.5.0 (grade 1-5). 
2. Its relationship to the study treatment(s) (definite, probable, possible, unlikely, not related). 
3. Its duration (start and end dates or if continuing at final exam). 
4. Action taken (no action taken; study treatment temporarily interrupted; study treatment permanently 
discontinued due to this adverse event; concomitant medication taken; non-drug therapy given; 
hospitalization/prolonged hospitalization). 
5. Whether it constitutes an SAE. 
All adverse events will be treated appropriately. Such treatment may include changes in study drug treatment as 
listed in the dose modification section of this protocol (see section 6.1 for guidance). Once an adverse event is 
detected, it should be followed until its resolution, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
All adverse events will be immediately recorded in the patient research chart.  
14.4.2 
Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded.  
A serious adverse event is an undesirable sign, symptom or medical condition which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may require medical or 
surgical intervention to prevent one of the outcomes listed above 
• Causes congenital anomaly or birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition (procedures such as central line placements, paracentesis, pain control). 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under 
study and has not worsened since the start of study drug. 

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o Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE 
given above and not resulting in hospital admission. 
o Social reasons and respite care in the absence of any deterioration in the patient’s general condition. 
SAE evaluation will begin after the first treatment and will continue until the first follow up visit, 28 days (+/- 
14) after the completion of study treatment. If the patient is unable to attend the first follow up visit, the SAE 
reporting period will be extended to 56 days after the completion of study treatment. 
Any death from any cause while a patient is receiving treatment on this protocol or up to 30 days after the last 
dose of protocol treatment, or any death which occurs more than 30 days after protocol treatment has ended 
but which is felt to be treatment related, must be reported. 
Toxicities which fall within the definitions listed above must be reported as an SAE regardless if they are felt 
to be treatment related or not. Toxicities unrelated to treatment that do NOT fall within the definitions above, 
must simply be documented as AEs in the patient research chart.  
14.5 SAE Reporting Requirements 
All serious adverse events should be reported as soon as possible but no later than one business day after the 
Investigator becomes aware. All SAEs must be reported via the HCI CTMS (OnCore) and submitted to HCI-
RCO@utah.edu. The HCI Clinical Site Monitor will in turn, submit the report to the Medical Monitor. The RCO 
will summarize and present all reported SAEs according to the Data and Safety Monitoring Plan at the monthly 
DSMC meeting. 
At a minimum, initial SAE reports must include a description of the event, assessment of event causality, event 
grade, and the expectedness of the event. Although the Investigator may not know all the information at the time 
of the event, the available information should be reported. An SAE follow-up may be submitted at a later date 
once more information is known. It is required that follow-up reports be submitted until the SAE is resolved. 
The HCI DSMC will notify all participating sites of all unexpected and related SAEs via the Research 
Compliance Office (RCO). The RCO will also notify all investigators at remote clinical sites participating in a 
multisite trial of any other safety updates, including external safety reports, manufacturer’s reports, and updates 
to the investigator’s brochure. 
Follow-Up Information 
It is recommended that follow-up reports be submitted as new information becomes available, however, a follow-
up report should be submitted within 3 days of knowledge of event resolution. Follow-up information will be 
added to the SAE in OnCore and submitted to the DSMC via RCO.   
FDA Notifications: 
• This study is IND exempt; therefore, there are no SAE reporting requirements to the FDA.  
IRB Notification: 
• Events meeting the University of Utah IRB or local IRB reporting requirements will be submitted per local 
guidelines. 
14.6 Protocol Amendments 
Any amendments or administrative changes in the research protocol during the period, for which the IRB 
approval has already been given, will not be initiated without submission of an amendment for IRB review and 
approval.  

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These requirements for approval will in no way prevent any immediate action from being taken by the 
investigator in the interests of preserving the safety of all patients included in the trial.  
14.7 Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and treatment plans as outlined 
in the protocol version submitted and previously approved by the IRB. Protocol deviations have the potential to 
place participants at risk and can also undermine the scientific integrity of the study thus jeopardizing the 
justification for the research. Protocol deviations are unplanned and unintentional events.  
Because some protocol deviations pose no conceivable threat to participant safety or scientific integrity, reporting 
is left to the discretion of the PI within the context of the guidelines below. The sponsor requires the prompt 
reporting to HCI RCO of protocol deviations which are: 
• 
Exceptions to eligibility criteria. 
• 
Intended to eliminate apparent immediate hazard to a research participant or  
• 
Harmful (caused harm to participants or others, or place them at increased risk of harm - including 
physical, psychological, economic, or social harm), or  
• 
Possible serious or continued noncompliance  
• 
Participating external sites should follow their local IRB requirements regarding the reporting of protocol 
deviations 
14.8 Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical Trials Reporting Program) 
by the Clinical Trials Office. 
 
 

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15 
BIBLIOGRAPHY 
1. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 
2009;105: 103-104. 
2. Briët JM, Hollema H, Reesink N, et al. Lymphvascular space involvement: an independent prognostic factor in 
endometrial cancer. Gynecol Oncol. 2005;96: 799-804. 
3. Cohn DE, Horowitz NS, Mutch DG, Kim SM, Manolitsas T, Fowler JM. Should the presence of lymphvascular 
space involvement be used to assign patients to adjuvant therapy following hysterectomy for unstaged endometrial 
cancer? Gynecol Oncol. 2002;87: 243-246. 
4. Thomas GM. A role for adjuvant radiation in clinically early carcinoma of the endometrium? Int J Gynecol 
Cancer. 2010;20: S64-66. 
5. Bosse T, Peters EE, Creutzberg CL, et al. Substantial lymph-vascular space invasion (LVSI) is a significant 
risk factor for recurrence in endometrial cancer--A pooled analysis of PORTEC 1 and 2 trials. Eur J Cancer. 
2015;51: 1742-1750. 
6. Lee CM, Szabo A, Shrieve DC, Macdonald OK, Gaffney DK. Frequency and effect of adjuvant radiation 
therapy among women with stage I endometrial adenocarcinoma. JAMA. 2006;295: 389-397. 
7. Kirchheiner K, Czajka-Pepl A, Ponocny-Seliger E, et al. Posttraumatic stress disorder after high-dose-rate 
brachytherapy for cervical cancer with 2 fractions in 1 application under spinal/epidural anesthesia: incidence and 
risk factors. Int J Radiat Oncol Biol Phys. 2014;89: 260-267. 
8. Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external irradiation and prognostic parameters in stage 
I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol. 1980;56: 419-427. 
9. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone 
for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post 
Operative Radiation Therapy in Endometrial Carcinoma. Lancet. 2000;355: 1404-1411. 
10. Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external 
pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. 
Gynecol Oncol. 2004;92: 744-751. 
11. Blake P, Swart AM, Orton J, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer 
(MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. 
Lancet. 2009;373: 137-146. 
12. Nout RA, Smit VT, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for 
patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, 
randomised trial. Lancet. 2010;375: 816-823. 
13. Nout RA, Putter H, Jürgenliemk-Schulz IM, et al. Quality of life after pelvic radiotherapy or vaginal 
brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial. J Clin Oncol. 2009;27: 
3547-3556. 
14. Sorbe B, Straumits A, Karlsson L. Intravaginal high-dose-rate brachytherapy for stage I endometrial cancer: 
a randomized study of two dose-per-fraction levels. Int J Radiat Oncol Biol Phys. 2005;62: 1385-1389. 
15. McMeekin DS, The University of Oklahoma OC, OK, United States, Filiaci VL, et al. 1A randomized phase 
III trial of pelvic radiation therapy (PXRT) versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
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chemotherapy (VCB/C) in patients with high risk (HR), early stage endometrial cancer (EC): A Gynecologic 
Oncology Group trial. Gynecol Oncol. 2014;134: 438. 
16. Harkenrider MM, Block AM, Alektiar KM, et al. American Brachytherapy Task Group Report: Adjuvant 
vaginal brachytherapy for early-stage endometrial cancer: A comprehensive review. Brachytherapy. 2017;16: 95-
108. 
17. Delaney G, Jacob S, Barton M. Estimation of an optimal radiotherapy utilization rate for gynecologic 
carcinoma: part II--carcinoma of the endometrium. Cancer. 2004;101: 682-692. 
18. Lee CM, Szabo A, Shrieve DC, et al. Descriptive nomograms of adjuvant radiotherapy use and patterns of 
care analysis for stage I and II endometrial adenocarcinoma: A surveillance, epidemiology, and end results 
population study. Cancer. 2007;110: 2092-2100. 
19. Punglia RS, Weeks JC, Neville BA, Earle CC. Effect of distance to radiation treatment facility on use of 
radiation therapy after mastectomy in elderly women. Int J Radiat Oncol Biol Phys. 2006;66: 56-63. 
20. Scott NW, Fayers PM, Aaronson NK et al (2008) EORTC QLQ-C30 Reference Values. European 
Organization for Research and Treatment of Cancer. 
21. Cocks K, King MT, Velikova G, Fayers PM, Brown JM (2008) Quality, interpretation and presentation of 
European organization for research and treatment of cancer quality of life questionnaire core 30 data in 
randomized controlled trials. Eur J Cancer 44:1793–1798. 
22. Maringwa, J.T., Quinten, C., King, M. et al. Support Care Cancer (2011) 19: 1753. doi:10.1007/s00520-010-
1016-5 
23. Zafar SY, Peppercorn JM, Schrag D, et al. The Financial Toxicity of Cancer Treatment: A Pilot Study 
Assessing Out-of-Pocket Expenses and the Insured Cancer Patient’s Experience. Oncologist. 2013;18(4):381-390. 
doi:10.1634/THEONCOLOGIST.2012-0279 
24. 
Neugut AI, Subar M, Wilde ET, et al. Association between prescription co-payment amount and 
compliance with adjuvant hormonal therapy in women with early-stage breast cancer. Journal of Clinical 
Oncology. 2011;29(18):2534-2542. doi:10.1200/JCO.2010.33.3179 
25. 
Punglia RS, Weeks JC, Neville BA, Earle CC. Effect of distance to radiation treatment facility on use of 
radiation therapy after mastectomy in elderly women. Journal of Clinical Oncology. 2006;24(18_suppl):6030-
6030. doi:10.1200/JCO.2006.24.18_SUPPL.6030 
26. 
de Souza JA, Yap BJ, Wroblewski K, et al. Measuring financial toxicity as a clinically relevant patient‐
reported outcome: The validation of the COmprehensive Score for financial Toxicity (COST). Cancer. 
2017;123(3):476. doi:10.1002/CNCR.30369 
27. 
Bouberhan S, Shea M, Kennedy A, et al. Financial Toxicity in Gynecologic Oncology. Gynecol Oncol. 
2019;154(1):8. doi:10.1016/J.YGYNO.2019.04.003 
28. 
Liang MI, Summerlin SS, Blanchard CT, et al. Measuring Financial Distress and Quality of Life Over 
Time in Patients With Gynecologic Cancer—Making the Case to Screen Early in the Treatment Course. JCO 
Oncol Pract. 2021;17(10):e1576. doi:10.1200/OP.20.00907 
29. 
Soisson S, Ganz PA, Gaffney D, et al. Long-term Cardiovascular Outcomes Among Endometrial Cancer 
Survivors in a Large, Population-Based Cohort Study. JNCI Journal of the National Cancer Institute. 
2018;110(12):1342. doi:10.1093/JNCI/DJY070 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
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Page 34 of 53 
 
30. 
Lee E, Zhu J, Velazquez J, et al. Evaluation of Diet Quality Among American Adult Cancer Survivors: 
Results From 2005-2016 National Health and Nutrition Examination Survey. J Acad Nutr Diet. 2021;121(2):217-
232. doi:10.1016/j.jand.2020.08.086 
31. 
Smits A, Lopes A, Das N, Bekkers R, Massuger L, Galaal K. The effect of lifestyle interventions on the 
quality of life of gynaecological cancer survivors: A systematic review and meta-analysis. Gynecol Oncol. 
2015;139(3):546-552. doi:10.1016/J.YGYNO.2015.10.002 
32. 
Friedenreich CM, Cook LS, Wang Q, et al. Prospective Cohort Study of Pre- and Postdiagnosis Physical 
Activity and Endometrial Cancer Survival. J Clin Oncol. 2020;38(34):4107-4117. doi:10.1200/JCO.20.01336 
33. 
Kitson S, Ryan N, Mackintosh ML, Edmondson R, Duffy JMN, Crosbie EJ. Interventions for weight 
reduction in obesity to improve survival in women with endometrial cancer. Cochrane Database of Systematic 
Reviews. 2018;2018(2). doi:10.1002/14651858.CD012513.PUB2/EPDF/ABSTRACT 
34. 
Diet History Questionnaire III (DHQ III) | EGRP/DCCPS/NCI/NIH. Accessed October 29, 2022. 
https://epi.grants.cancer.gov/dhq3/ 
35. 
Krebs-Smith SM, Pannucci TRE, Subar AF, et al. Update of the Healthy Eating Index: HEI-2015. J Acad 
Nutr Diet. 2018;118(9):1591-1602. doi:10.1016/J.JAND.2018.05.021 
36. 
de Souza JA, Yap BJ, Wroblewski K, Blinder V, Araújo FS, Hlubocky FJ, Nicholas LH, O'Connor JM, 
Brockstein B, Ratain MJ, Daugherty CK, Cella D. Measuring financial toxicity as a clinically relevant patient-
reported outcome: The validation of the Comprehensive Score for financial Toxicity (COST). Cancer. 2017 Feb 
1;123(3):476-484. doi: 10.1002/cncr.30369. Epub 2016 Oct 7. PMID: 27716900; PMCID: PMC5298039. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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16 
APPENDICES  
 
APPENDIX A. FIGO STAGING FIGO 2009 staging for carcinoma of the endometrium  
Stage I*  
Tumor confined to the corpus uteri  
stage IA*  
No or less than half myometrial invasion 
stage IB*  
More than half myometrial invasion 
Stage II*  
Tumor invades cervical stroma, but does not extend beyond the uterus**  
Stage III*  
Local and/or regional spread of the tumor 
stage IIIA*  
Tumor invades the serosa of the corpus uteri and/or adnexae  
stage IIIB*  
Vaginal and/or parametrial involvement 
stage IIIC*  
Metastasis to pelvic and/or para-aortic lymph nodes 
IIIC1*  
Positive pelvic lymph nodes 
IIIC2*  
Positive para-aortic lymph nodes with or without pelvic nodes  
Stage IV*  
Tumor invades bladder and/or bowel mucosa, and/or distant metastasis  
stage IVA*  
Tumor invasion of bladder and/or bowel mucosa 
stage IVB*  
Distant metastasis, including intra-abdominal metastases and/or inguinal lymph nodes 
Either G1, G2 or G3 (G is FIGO grade) Endocervical glandular involvement only should be considered as Stage 
I and no longer as Stage II Positive cytology has to be reported separately, without changing the stage.  
 
 

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APPENDIX B. PERFORMANCE STATUS (WHO-ECOG)  
Grade 0  
Fully active, able to carry out all normal (pre-disease) activity without restriction  
Grade 1  
Restricted in physically strenuous activity but ambulatory and able to carry out light work, e.g., 
light house work, office work  
Grade 2  
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours  
Grade 3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours  
Grade 4   
Completely disabled; cannot carry out any self-care; totally confined to bed or chair  
 
 

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APPENDIX C. HISTOLOGIC CLASSIFICATION AND GRADING SYSTEM International Society of 
Gynecologic Pathologists Classification for Endometrial Carcinomas  
 
. 
Endometrioid adenocarcinoma  
. 
Mucinous carcinoma  
. 
Serous carcinoma  
. 
Clear-cell carcinoma  
. 
Squamous carcinoma  
. 
Undifferentiated carcinoma  
. 
Mixed types  
. 
Miscellaneous carcinoma  
. 
Metastatic carcinoma  
 
Histologic classification of mixed carcinomas: Mixed serous and endometrioïd carcinomas and mixed clear 
cell and endometrioid carcinomas should be classified as serous or clear cell carcinomas if they contain at least 
10% of a serous or clear cell component, respectively, and otherwise be classified as endometrioid.  
 
International Federation of Gynecology and Obstetrics (FIGO) and Armed Forces Institute of Pathology 
(AFIP) histologic grading system  
G1 tumors have 5% or less of a nonsquamous or nonmorular solid growth pattern  
G2 tumors have 6% to 50% of a nonsquamous or nonmorular solid growth pattern  
G3 tumors have more than 50% of a nonsquamous or nonmorular solid growth pattern  
A higher degree of nuclear atypia (in comparison with the architectural grade) raises the grade of a G1 or G2 
tumor by 1.  
Adenocarcinomas with squamous differentiation are graded according to the nuclear grade of the glandular 
component.  
Where the treatment plan after hysterectomy is radiation with vaginal cuff brachytherapy without external beam, 
uterine sarcomas may be included. 
 
 

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APPENDIX D. VAGINAL BRACHYTHERAPY TREATMENT PLANNING AND DOSE REPORTING 
FORM 
Figure 1 below shows a coronal schematic view of a standard vaginal cylindrical applicator, 3.5 cm in diameter, 
and 3.5 cm active length. Active length is the distance between the first (most cranial) and the last active source 
positions. All applicator points A are at the surface of the applicator. Applicator points A1 and A2 are located 
at the tip and on the side of the cylinder surface, respectively. Applicator points B1, and B2 are at 0.5 cm cranial 
and parallel to the central axis. Point A2 is half way the active length which, in this case, is 1.75 cm. Depending 
on the anisotropy of the source used, point A1 can receive a (5-10%) lower dose than the prescribed dose and 
point A2 a (5-10%) higher dose. The mean dose to points A1 and A2 should be 100%.  A2 and B2 should be 
measured at the half way point of the active length. 
Planned Treatment 
Do you provide separate plans 
for each insertion? 
 Experimental Arm: 11 Gy at surface x 2 Fractions   
 Standard of Care Arm: 7 Gy at 0.5 cm x 3 Fractions   
 Standard of Care Arm: 5-5.5 Gy at 0.5 cm x 4 Fractions   
 Standard of Care Arm: 6 Gy at surface x 5 Fractions 
 Yes* 
 No 
*If yes, provide a planning 
form for each fraction 
Treatment Start Date 
A1 Dose 
A2 Dose 
 
                         cGy 
                         cGy 
B1 Dose 
B2 Dose 
Active Treatment Length 
                         cGy 
                         cGy 
                         cm 
Additional Treatment Dates 
 
 
 
 
 
Figure 1.  
 
   Patient Initials: _____________ 
 
   Study ID: __________________ 
 
 
 
 
   Investigator Signature: 
 
 
   ___________________________ 
 
    
 
   Date: ______________________ 
 
 
 
 
0.5 cm 
 
 
 
0.5 cm 
3.5 cm 
3.5 cm 
A2 
A1 
B2 
B1 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 39 of 53 
 
APPENDIX E. QUALITY OF LIFE QUESTIONNAIRE (ENGLISH)         
EORTC QLQ-C30 (version 3)  
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the number that 
best applies to you. There are no "right" or "wrong" answers. The information that you provide will remain strictly confidential.  
Patient Study #: ____________ 
Please fill in your initials: ______ 
Your birthdate (Day, Month, Year):_______ 
Today's date (Day, Month, Year):_______ 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or 
other leisure time activities? 
 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
 
Please go on to the next page 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 40 of 53 
 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical 
treatment interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
For  the  following  questions  please  circle  the  number  between  1  and  7  that best applies to 
you 
 
29. 
How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
 
30. 
How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 41 of 53 
 
 
 
APPENDIX F. EORTC QLQ – EN24 
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to 
which you have experienced these symptoms or problems. 
 
During the past week: 
Not at 
all 
A 
little 
Quite 
a bit 
Very 
much 
1. Have you had swelling in one or both legs? 
1 
2 
3 
4 
2. 
Have you felt heaviness in one or both legs? 
1 
2 
3 
4 
3. 
Have you had pain in your lower back and / or pelvis? 
1 
2 
3 
4 
4. 
When you felt the urge to pass urine, did you have to hurry to 
get to the toilet? 
1 
2 
3 
4 
5. 
Have you passed urine frequently? 
1 
2 
3 
4 
6. 
Have you had leaking of urine? 
1 
2 
3 
4 
7. 
Have you had pain or a burning feeling when passing urine? 
1 
2 
3 
4 
8. 
When you felt the urge to move your bowels, did you have to 
hurry to get to the toilet? 
1 
2 
3 
4 
9. 
Have you had any leakage of stools? 
1 
2 
3 
4 
10. Have you been troubled by passing wind? 
1 
2 
3 
4 
11. Have you had cramps in your abdomen? 
1 
2 
3 
4 
12. Have you had a bloated feeling in your abdomen? 
1 
2 
3 
4 
13. Have you had tingling or numbness in your hands or feet? 
1 
2 
3 
4 
14. Have you had aches or pains in your muscles or joints? 
1 
2 
3 
4 
15. Have you lost hair? 
1 
2 
3 
4 
16. Has food and drink tasted differently from usual? 
1 
2 
3 
4 
 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 42 of 53 
 
During the past week: 
Not at 
all 
A 
little 
Quite 
a bit 
Very 
much 
17. Have you felt physically less attractive as a result of your 
disease or treatment? 
1 
2 
3 
4 
18. Have you felt less feminine as a result of your disease or 
1 
2 
3 
4 
 
During the past 4 weeks: 
Not at 
all 
A 
little 
Quite 
a bit 
Very 
much 
19. To what extent were you interested in sex? 
1 
2 
3 
4 
20. To what extent were you sexually active? 
1 
2 
3 
4 
Answer these questions only if you have 
been sexually active during the past 4 
weeks: 
21. Has your vagina felt dry during sexual activity? 
1 
2 
3 
4 
22. Has your vagina felt short and / or tight? 
1 
2 
3 
4 
23. Have you had pain during sexual intercourse or other 
sexual activity? 
1 
2 
3 
4 
24. Was sexual activity enjoyable for you? 
1 
2 
3 
4 
 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 43 of 53 
 
Appendix G EORTC QLQ-C30 Spanish Version  
 
 
 
 
 
 SPANISH (US) 
 
EORTC QLQ-C30 (versión 3) 
Estamos interesados en algunas cosas sobre usted y su salud. Por favor, conteste todas las preguntas usted mismo/a  
marcando uncirculo el número que major se aplique a su caso. No hay respuestas “correctas” ni “incorrectas”. La 
información que nos proporcione se mantendrá estrictamente confidencial. 
 
Por favor, escriba sus iniciales:  
Su fecha de nacimiento (día, mes, año):  
          
 
La fecha de hoy (día, mes, año): 
 
     31
 
 
 
Para  Un  
Bastante 
Extremada-  
nada 
poco   
 
mente 
1.  ¿Tiene alguna dificultad para realizar actividades que requieran un 
gran esfuerzo como llevar una bolsa de compras pesada o una maleta? 
1 
2 
3 
 
 
4 
 
2. ¿Tiene alguna dificultad para salir a caminar por largo tiempo? 
1 
2 
 
3 
 
 
4 
 
3. ¿Tiene alguna dificultad para salir a caminar por 
 corto tiempo fuera de la casa? 
1 
2 
 
3 
 
 
4 
 
4. ¿Necesita quedarse en cama o en una silla durante el día? 
1 
2 
 
3 
 
 
4 
 
5. ¿Necesita ayuda para comer, vestirse, bañarse o ir al baño? 
1 
2 
 
3 
 
 
4 
 
Durante la última semana: 
Para 
nada 
Un 
poco 
Bastante Extremada- 
mente 
6. ¿Estuvo limitado/a al hacer su trabajo u otras actividades diarias? 
1 
2 
3 
4 
7. ¿Estuvo limitado/a al hacer sus pasatiempos u otras 
actividades de tiempo libre? 
1 
2 
3 
4 
8. ¿Le faltó el aire? 
1 
2 
3 
4 
9. ¿Ha tenido dolor? 
1 
2 
3 
4 
10. ¿Necesitó descansar? 
1 
2 
3 
4 
11. ¿Ha tenido problemas para dormir? 
1 
2 
3 
4 
12. ¿Se ha sentido débil? 
1 
2 
3 
4 
13. ¿Le ha faltado el apetito? 
1 
2 
3 
4 
14. ¿Ha sentido náuseas? 
1 
2 
3 
4 
15. ¿Ha vomitado? 
1 
2 
3 
4 
16. ¿Ha estado estreñido/a? 
1 
2 
3 
4 
 
 Por favor, continúe en la página siguiente 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 44 of 53 
 
SPANISH (US) 
Durante la última semana: 
Para 
nada 
Un 
poco 
Bastante Extremada- 
mente 
17. ¿Ha tenido diarrea? 
1 
2 
3 
4 
18. ¿Estuvo cansado/a? 
1 
2 
3 
4 
19. ¿Interfirió el dolor en sus actividades diarias? 
1 
2 
3 
4 
20. ¿Ha tenido dificultad para concentrarse en cosas 
como leer el periódico o ver televisión? 
1 
2 
3 
4 
21. ¿Se sintió tenso/a? 
1 
2 
3 
4 
22. ¿Se preocupó? 
1 
2 
3 
4 
23. ¿Se sintió irritable (enojado/a)? 
1 
2 
3 
4 
24. ¿Se sintió deprimido/a? 
1 
2 
3 
4 
25. ¿Ha tenido dificultad para recordar cosas? 
1 
2 
3 
4 
26. ¿Ha interferido su condición física o su 
tratamiento médico en su vida familiar? 
1 
2 
3 
4 
27. ¿Ha interferido su condición física o su 
tratamiento médico en sus actividades sociales? 
1 
2 
3 
4 
28. ¿Le ha causado su condición física o su 
tratamiento médico dificultades económicas? 
1 
2 
3 
4 
 
Para las siguientes preguntas, por favor, marque con un círculo el número del 1 al 7 
que mejor se aplique a su caso 
29. ¿Cómo calificaría su salud en general durante la última semana? 
 
1   
2  
3  
4  
5  
6  
7 
 
Muy mala  
 
 
 
 
Excelente 
 
30. ¿Cómo calificaría su calidad de vida en general durante la última semana? 
 
1   
2  
3  
4  
5  
6  
7 
 
Muy mala  
 
 
 
 
Excelente 
 
© QLQ-C30 Copyright 1995 EORTC Quality of Life Group. Todos los derechos reservados. Versión 3.0 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 45 of 53 
 
Appendix H EORTC QLQ –EN24 Spanish Translation  
SPANISH (US) 
 
 
 
EORTC QLQ – EN24 
 
Las pacientes a veces dicen que tienen los siguientes síntomas o problemas. Por favor, indique hasta qué punto ha 
experimentado estos síntomas o problemas. 
 
Durante la última semana: 
Para 
nada 
Un 
poco 
Bastante Muchí- 
simo 
1. ¿Tuvo hinchazón en una o ambas piernas? 
1 
2 
3 
4 
2. ¿Sintió pesadez en una o ambas piernas? 
1 
2 
3 
4 
3. ¿Tuvo dolor en la parte baja de la espalda y/o en la pelvis? 
1 
2 
3 
4 
4. Cuando sintió la necesidad urgente de orinar, ¿tuvo que ir de prisa 
al baño? 
1 
2 
3 
4 
5. ¿Orinó con frecuencia? 
1 
2 
3 
4 
6. ¿Tuvo pérdidas de orina involuntarias? 
1 
2 
3 
4 
7. ¿Tuvo dolor o ardor al orinar? 
1 
2 
3 
4 
8. Cuando sintió la necesidad urgente de defecar, ¿tuvo que ir de prisa 
al baño? 
1 
2 
3 
4 
9. ¿Tuvo pérdidas de heces involuntarias? 
1 
2 
3 
4 
10. ¿Se sintió molesta por haber tenido flatulencia (expulsar gases)? 
1 
2 
3 
4 
11. ¿Sintió retortijones (cólicos) en el abdomen? 
1 
2 
3 
4 
12. ¿Tuvo sensación de hinchazón en el abdomen? 
1 
2 
3 
4 
13. ¿Sintió hormigueos o adormecimiento en las manos o en los pies? 
1 
2 
3 
4 
14. ¿Sintió dolores o molestias en los músculos o articulaciones 
(coyunturas)? 
1 
2 
3 
4 
15. ¿Se le cayó algo de pelo? 
1 
2 
3 
4 
16. ¿Sintió que el sabor de la comida y la bebida es diferente de lo 
normal? 
1 
2 
3 
4 
 
Por favor, continúe en la página siguiente 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date:18JUN2025 
Principal Investigator: Cristina DeCesaris, MD 
 
 
SPANISH (US) 
 
Durante la última semana: 
Para 
nada 
Un 
poco 
Bastante Muchí- 
simo 
17. ¿Se sintió menos atractiva físicamente a consecuencia de su 
enfermedad o tratamiento? 
1 
2 
3 
4 
18. ¿Se sintió menos femenina como consecuencia de su enfermedad 
o tratamiento? 
1 
2 
3 
4 
Durante las últimas 4 semanas: 
Para 
nada 
Un 
poco 
 
Bastante Muchí- 
simo 
19. ¿Hasta qué punto estuvo interesada en actividad sexual? 
1 
2 
3 
4 
20. ¿Hasta qué punto tuvo una vida sexual activa? 
1 
2 
3 
4 
Conteste las siguientes preguntas solo si usted estuvo 
activa sexualmente durante las últimas 4 semanas: 
21. ¿Sintió sequedad vaginal durante la actividad sexual? 
1 
2 
3 
4 
22. ¿Sintió la vagina acortada y/o estrecha? 
1 
2 
3 
4 
23. ¿Tuvo dolor durante el coito u otra actividad sexual? 
1 
2 
3 
4 
24. ¿Le resultó placentera la actividad sexual? 
1 
2 
3 
4 
 
 QLQ-EN24 Copyright 2010 EORTC Quality of life Group. Todos los derechos reservados. 
 
 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 47 of 53 
 
 
APPENDIX I. Health Care Expense Survey 
 
Health Care Expense Survey 
 
Patient Study ID: ____ ____ ____ 
 
Patient Initials: ____ ____ ____ 
 
Date of Completion: ____ / ____ / ______ 
 
 
 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 48 of 53 
 
 
Health Care Expense Survey 
 
Before you were diagnosed with endometrial cancer, did you do paid or unpaid work 
outside the home?  
Yes     
No 
 
If you worked outside the home, which of the following best applies to you? 
Paid work outside the home 
Yes     
No 
Unpaid work outside the home 
Yes     
No (including work in a family farm or 
business). 
Self-employed / business owner 
Yes     
No 
 
If you worked outside the home:  
How many days per week did you work? __ (days) 
How many hours per day did you work? __ __ (hours) 
What is your profession? 
_____________________________________________________ 
In what industry do you work?  
________________________________________________ 
What is / was your job title? 
___________________________________________________ 
 
NOTE: This section is designed to capture the out of pocket expenses associated with 
radiation therapy. 
How many hours were spent in total for each radiation treatment (time from leaving 
home/other accommodation or work to return to home/other accommodation or work)?  
__ __ (hours) 
What is the distance from the radiation treatment facility from home/other 
accommodation or work? __ __ __ (miles) 
 
Did you commute daily to radiation treatment from your home? 
Yes     
No 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 49 of 53 
 
 
(If yes), method of transport used to get to the radiation therapy facility (Check all that 
apply)  
 
Car   
Yes     
No  
 
(If yes) approximate cost for parking per visit $__ __.__ __ 
 
Did you drive yourself? 
Yes     
No 
 
Were you driven? 
Yes     
No 
 
 
Was it a combination of driving yourself or being driven  
Yes     
No 
 
Shuttle  
Yes     
No  
 
(If yes) Approximate cost per visit $__ __.__ __ 
Public transport 
Yes     
No  
 
(If yes) Approximate cost per visit $__ __.__ __ 
On foot 
Yes     
No  
Taxi/car service 
Yes     
No 
(If yes) Approximate cost per visit (both ways) $__ __ __    
 
(If no), which of the follow apply (check one): 
 
  I was in a health care facility during radiation 
 
  I was living with a friend/family member during radiation (answer the 
commuting questions above) 
  I stayed hotel, apartment, or similar facility during radiation (answer the 
commuting questions above) 
If hotel, apartment or similar facility, estimated cost of lodging during your 
radiation treatment $__ __ __ __   
 
Number of radiation treatments during which at least one other person accompanied 
patient __ __ 
Number of visits to radiation treatment facility since completing radiation therapy (follow 
up visits) __ __ 
 
From the 1st day of starting radiation, until 40 days after the completion of radiation: 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 50 of 53 
 
 
Number of days the patient was unable to go to work at all __ __ 
Number of days the patient went to work part-time __ __ 
If part time, number of hours reduced from typical work day __ __ 
Estimate child care costs due to radiation therapy $__ , __ __ __   
Estimate wages lost due to radiation therapy $__ __ , __ __ __ 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 51 of 53 
 
 
Appendix J - HEALTH CARE EXPENSE DIARY FOR SURVEY COMPLETION 
 
Use this diary to record your health care-related expenses from the time you start 
radiation therapy until 6 to 10 weeks after you have completed radiation therapy. A copy 
of the survey questions is included with this diary for your reference. 
 
Date 
Type of expense 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 52 of 53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol name: Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care 
Version Date: 18JUN2025 
Principal Investigator:  Cristina DeCesaris, MD 
Page 53 of 53 
 
 
 
APPENDIX K. COST-FACIT