Prospective Evaluation of Quality of Life and Treatment-related Side Effects of Women Undergoing Multimodality Treatment for Advanced Stage Endometrial Carcinoma
Phase: PHASE2
Conditions: Endometrial Cancer
Sponsor: Henry Ford Health System

 
 
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Study Protocol 
 
STUDY TITLE: Prospective evaluation of quality of life and treatment-related side effects of women 
undergoing multimodality treatment for advanced stage endometrial carcinoma  
 
1. STUDY AIM, BACKGROUND, AND DESIGN ABSTRACT  
Purpose: To prospectively determine patients’ quality of life (QOL) and treatment-related toxicity outcomes 
with adjuvant multimodality treatment (chemotherapy and radiation treatment) in women with advanced 
endometrial carcinoma after surgical staging.  
Specific Aim: 
1. To prospectively determine QOL after adjuvant treatment using the prospectively-validated FACT 
questionnaires at baseline, 3, 6, 12, and 24 months after surgical staging 
2. To prospectively determine the rate of any grade 2 or higher treatment-related side effects: mainly bone 
marrow suppression, lymphedema, diarrhea, and others. Additionally, we will collect information about 
the rate of completion of planned adjuvant treatment (number of chemotherapy cycles, dose reduction 
or chemotherapy delay, radiation treatment interruption, etc.). 
3. To prospectively collect survival outcome endpoints after adjuvant treatment (recurrence-free, disease-
specific and overall survival). 
 
Introduction and Rationale: Endometrial cancer is the most common gynecologic malignancy in the United 
States and ranks second in gynecologic cancer mortality following only ovarian cancer. More than 84% of 
patients present with International Federation of Gynecology and Obstetrics (FIGO) stage I-II disease. By 
definition, patients with advanced-stage uterine carcinoma (FIGO stages III-IV) are those with extrauterine 
disease and are at significant risk of dying from uterine cancer. They constitute a very heterogeneous group of 
patients with varying risk factors yielding highly variable clinical outcomes. Within the same FIGO stage, 
patients with disease involving multiple extrauterine sites fare worse compared to patients with involvement of 
a single site1. 
Postoperatively, patients with advanced stage disease often require adjuvant therapy(s) to reduce the chance 
of tumor recurrence with the potential to improve survival. However, the optimal adjuvant therapy is yet to be 
established with several options available for adjuvant treatment. 
Rationale for multimodality treatment with chemotherapy and radiation treatment (CMT) 
Current treatment recommendations for advanced stage endometrial cancer consist of multiple approaches 
including chemotherapy alone, radiotherapy (RT) alone, or combined modality treatment (CMT)2.  
GOG 122 study, which was a phase III trial, randomized patient with advanced endometrial carcinoma to 
adjuvant chemotherapy alone versus whole abdomen RT (WART). Outcomes of this study showed that the 
chemotherapy arm had an improved 5-year progression-free survival (PFS) and overall survival (OS) 
compared to RT alone. However, this trial showed that if chemotherapy is given alone, that rate of local 
recurrence approaches 20%3.   
The safety of CMT with concurrent chemotherapy and RT (chemoRT) was explored in RTOG 9708, which was 
a phase II trial that evaluated outcomes in patients receiving concurrent chemoRT. All patients received 
adjuvant pelvic RT (45 Gy) concurrent with cisplatin followed by four additional cycles of cisplatin and 
paclitaxel.  The 4-year OS and PFS for patients with stage III disease were 77% and 72%, respectively. Rates 

 
 
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of grade 1 toxicity were found in 16% of patients, grade 2 in 41%, grade 3 in 16%, and grade 4 in 5%. This 
study demonstrated that concurrent chemoRT is safe with excellent local control4. 
More recent studies have sought to compare chemoRT to chemotherapy or radiation alone. PORTEC-3 was a 
phase III randomized trial comparing adjuvant RT alone to concurrent chemoRT. The RT dose was 48.6 Gy in 
27 fractions and chemotherapy was concurrent cisplatin followed by an additional 4 cycles of carboplatin and 
paclitaxel. For women with stage III disease, the addition of chemotherapy to radiation treatment showed 
benefit in terms of improvement in FFS. An analysis of toxicity outcomes found that 60% of patients in the 
chemoRT arm experienced a grade 3 or greater adverse event compared to 12% in the RT alone arm 
(p<0.0001)5.  
GOG 258 study was recently published and was similar to PORTEC-3 except that it compared concurrent 
chemoRT to adjuvant chemotherapy alone. Patients were randomized to receive concurrent chemoRT (45 Gy 
in 25 fractions concurrent with cisplatin followed by 4 cycles of carboplatin and paclitaxel) or chemotherapy 
alone. The results of this study showed that chemoRT was associated with a lower 5-year incidence of vaginal 
and regional lymphatic recurrence. However, distant recurrence rates were higher in the chemoRT arm 
compared to chemotherapy alone6.  
The above studies helped to establish concurrent chemoRT with cisplatin followed by adjuvant 
carboplatin/paclitaxel as a valid adjuvant treatment approach for women with advanced endometrial 
carcinoma.  
A retrospective review from Washington University included 51 women with stage III-IV endometrial carcinoma 
who received CMT with carboplatin/paclitaxel-based regimen concurrent with RT and assessed survival and 
toxicity outcomes. The chemotherapy regimen given was carboplatin/paclitaxel for 4-6 cycles and RT was 48-
51.2 Gy. Patients also received a vaginal brachytherapy boost. They found that 48 patients (94%) completed 
chemotherapy and 16 patients (30%) required chemotherapy dose-reduction. Thirty-four patients experienced 
grade 3-4 toxicities, most of which were hematologic. Over 80% of patients required leukocyte growth factor 
injections. There were seven late grade 3-4 toxicities (4 GI, 2 GU, and 1 ongoing neuropathy). They found a 
median PFS of 42.8 months, median OS of 44.9 months, and 3-year OS of 80%7. This study suggests that 
concurrent chemoRT using a carbotaxol-based regimen has favorable outcomes, a tolerable side effect profile, 
and the potential to reduce overall treatment duration. 
Building off of the results of the above retrospective study as well as the aforementioned randomized trials, we 
wish to PROSPECTIVELY assess outcomes of women with advanced endometrial carcinoma who receive the 
same concurrent chemoRT with a carboplatin/paclitaxel-based regimen. 
 
 
2. SUBJECT POPULATION AND ELIGIBILITY 
A total of 60 patients with FIGO stage III uterine carcinoma will be prospectively enrolled in this study.  All 
patients will have undergone hysterectomy and should be eligible candidates for the standard multimodality 
treatment with the standard doses and frequency of administration (radiation treatment and chemotherapy). 
Patients will be identified during gynecologic oncology physician consult. Study eligibility will be determined 
from the treating physician chart review. Vulnerable population will not be targeted for this study; however, 
women with low educational attainment and low income status may still be enrolled if they meet eligibility 
criteria. Eligibility/exclusion will be documented in the legal medical record. Considering our current volume of 

 
 
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patients, it would take about 24 months to enroll these patients in the study. The study would not compete with 
other local or national studies. 
3. STUDY PROCEDURES 
All patients will undergo surgical staging with TAH/BSO and lymph node dissection. As stated above, patients 
with surgically-staged FIGO stage III uterine carcinoma (all histological types including carcinosarcoma) will be 
enrolled in the study. 
Following surgical staging and enrollment in the study, chemotherapy and RT will start approximately 4 weeks 
following the date of surgery. For chemotherapy administration, patients will receive the standard 6 cycles of 
both carboplatin (AUC 6) and paclitaxel (175 mg/m2). All women will receive growth factor injections as 
clinically indicated while undergoing treatment in order to reduce the risk of severe hematologic toxicity. 
Chemotherapy dose-reduction will be at the discretion of the treating gynecologic oncologist. 
Radiation treatment will start within 7-10 days  of the first chemotherapy cycle and will be given during cycles 
1-3. Prior to the start of RT a CT simulation will be performed for each patient using a Philips Brilliance Big 
Bore CT scanner (Philips Medical Systems, Andover, MA) with a slice thickness of 3 mm. Following simulation, 
external beam radiation will be given via intensity-modulated RT (IMRT) in once-daily fractions of 1.8-2.0 Gy 
for a total dose of 44-45 Gy to the pelvis (vaginal cuff, pelvic LN, and para-aortic lymph nodes). If there is 
grossly visible nodal disease seen at the time of treatment planning, a boost to 54 Gy will be given to the gross 
disease. If the patient is found to have cervical stromal invasion, we will recommend that she receive a 
brachytherapy boost of 21 Gy in 3 fractions prescribed to the upper 4.0 cm of the vaginal surface using a 
vaginal cylinder applicator. The patient will be fitted for the cylinder (0.5, 1.0, or 1.5 cm diameter depending on 
the size of the vaginal vault) in the final weeks of RT. Cylinder treatments are given approximately every other 
day of the week. A separate simulation process will be performed near the end of the EBRT course for the 
cylinder treatment. 
Patients will be followed as per the standard of care and data will be collected on OS and PFS endpoints. Data 
will also be collected on treatment toxicity (diarrhea, dysuria, anemia, leukopenia, etc). We will also evaluate 
patients’ quality of life with a series of questionnaires (Appendix A) at baseline, 3, 6, 12, and 24 months after 
surgical staging. These are prospectively validated questionnaires and include FACT-G (physical and 
functional well-being sections), FACT-En (additional concerns section), FACT/GOG-NTX-4 (additional 
concerns section), and FACT-C (items C3 and C5).These sections will be combined into one single form for 
ease of completion for the patients (a total of 36 items). 
 This data will be stored in a secure database/spreadsheet. Patient questionnaires will be kept in a binder. 
Once the patient has completed the study, these data points will be entered into the spreadsheet, and the 
paper copies will be destroyed. Please see Figure 1 below for clinical flow of the study as well as Table 1 
regarding experimental vs standard of care components of the study. 

 
 
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Figure 1. Clinical workflow and time frame of the study 
Experimental Components 
Standard Components 
QoL questionnaire at baseline, 3, 6, 12, and 24 
months 
Combined modality treatment (chemo and RT), 
growth factor administration/treatment of side effects 
Table 1. Comparison of experimental and standard of care components 
Data analysis: 
After data collection, we will pursue statistical analysis of the data using the appropriate software in our 
department. If further biostatistical consultation is required, Charlotte Burmeister MS will help with the analysis. 
Because this is a simple exploratory study, a total of 60 patients were felt to be adequate. We will collect data 
for OS, PFS, toxicity outcomes, and quality of life metrics using the aforementioned questionnaires. The 
variables will be analyzed as continuous variables (mean, standard deviation, minimum, median, and 
maximum). Categorical variables will be also analyzed (count and percent). Kaplan-Meier survival estimates 
will be calculated for local control and survival end points. Each patient, disease characteristic and adjuvant 
treatment will be placed in a simple logistic regression models on predicting survival endpoint. A multivariate 
analysis will be performed for exploratory purposes. Hazard ratios and 95% confidence intervals for the hazard 
ratios will be reported. Tests will be considered significant at p < 0.05.  All analyses will be performed using 
SAS 9.4. 
 
4. ANTICIPATED RISKS  
The chemotherapy therapy regimen and the radiation treatment will be delivered as per the standard of care to 
this protocol. Concurrent carbotaxol-based chemotherapy and radiation carries the risks of GI toxicity 
(diarrhea, nausea/vomiting leading to dehydration and weight loss, hematochezia), GU toxicity (dysuria, 
frequency, hematuria), hematologic toxicity (leukopenia leading to infection/sepsis, anemia, thrombocytopenia 
leading to bleeding), and neuropathy. Late effects can manifest as well including scarring of pelvic tissues 
leading to small bowel obstruction, persistent hematuria and GI bleeding, vaginal dryness/stenosis that may 
result in dyspareunia, and persistent neuropathy. These toxicities may result in death. Some toxicities including 
diarrhea and dysuria can be managed symptomatically with OTC medications. In order to prevent 
immunosuppression and severe hematologic toxicity, we will prophylactically administer growth factors during 

 
 
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treatment whenever there are signs of marrow suppression. If toxicities become severe, interruptions in 
treatment or dose-reduction in chemotherapy/radiation will be determined by the treating physicians. Regular 
follow-up with the treating physicians will help to identify and treat these side effects that may occur. 
There is a low risk of breach of confidentiality on this study. Questionnaires with any identifying patient 
information on them will be entered into a database following completion of trial and immediately destroyed. 
 
5. ANTICIPATED BENEFITS 
There is the possibility that this regimen will improve the patient’s outcomes in term of OS and disease 
recurrence. This study will also help us to determine QoL and toxicity patterns in patients receiving this 
therapy. 
 
 
6. RENUMERATION/COMPENSATION 
No payment will be provided for participation in the study. 
 
7. COSTS 
Patients will not incur any costs associated with this study. Patients are not compensated for their participation. 
 
8. ALTERNATIVES 
The alternative to the study is not participating in this trial. If the patient does not wish to participate, then she 
will be recommended to receive the standard of care at Henry Ford Cancer Institute, which involves combined 
modality treatment with radiation and chemotherapy with the sequence either a “sandwich” technique of 3 
cycles of carboplatin/paclitaxel followed by external beam RT +/- brachytherapy followed by an additional 3 
cycles of chemotherapy or concurrent chemotherapy and radiation with cisplatin following by several cycles of 
carboplatin/paclitaxel. 
 
9. CONSENT PROCESS AND DOCUMENTATION 
Gynecology oncology physicians will obtain consent during the first post-op visit. Patient will be given the 
opportunity to ask questions.. The consent form will be explained to the patient, and the purpose, duration, 
procedures, and risks will be made clear. Patient will be made aware of alternatives to participating in the 
study, and they will be told that not participating will have no impact on the quality of care they receive. If non-
English speaking patients are enrolled, a translator will be used during the consent process. If patient agrees to 
participate and signs consent, this will be documented in the legal EMR. The consent form will be scanned and 
stored in a folder on the HFHS shared drive. 
 
Patients will also be provided with the HIPAA authorization form for prospective studies. Regarding data 
collected during the study process, questionnaires will have patient label information on these forms so that 
data can be organized during input into the computer. These data will also be saved on a secure HFHS shared 
drive. Following entering these data into the computer, these documents will be destroyed. This data will be 
maintained indefinitely as this data may be used for future studies following completion of this trial. 
 
 
10. WITHDRAWAL OF SUBJECTS 
Patients will be withdrawn from the trial if they exhibit poor tolerance and severe toxicity to the therapy. These 
situations include hematologic toxicity refractory to growth factor injections and transfusions or the 

 
 
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development of sepsis requiring hospitalization. Patient may also be terminated from the study if they develop 
any acute grade 4 toxicity. 
 
11. PRIVACY AND CONFIDENTIALITY  
All patient data and identifiers will be stored in a secure file and drive on the HF network. Only staff associated 
with the trial will have access to the data including nursing, physicians, statisticians, and others involved in the 
project. The only identifiable data will be patient stickers on the questionnaires. These questionnaires will be 
destroyed (by shredding) following patient’s completion of the study and once data has been entered. 
Authorization for PHI access for screening purposes will be obtained at physician visit before enrollment in trial 
is performed. 
12. DATA AND SAFETY MONITORING PLAN 
The PI of the study will meet at least twice a month with other co-investigators and nurse teams to objectively 
evaluate adherence to the protocol and patient compliance with the study protocol. An update to the group will 
be conducted at the time of the weekly gynecologic oncology tumor board.  
The group will decide whether or not any amendment to the protocol is needed. 
If an unexpected event is encountered, the PI of the study will report it immediately to the IRB and other co-
investigators.  
 
13. QUALIFICATIONS OF THE INVESTIGATOR(S) 
The PI of the study is a well-established national researcher with more than 200 published abstracts and 
peer-reviewed manuscripts in endometrial cancer. Charlotte Burmeister has been conducting statistical 
analysis for our work for more than 7 years now. 
 
14. REFERENCES 
 
1. Elshaikh MA, Yashar CM, Wolfson AH et al., ACR Appropriateness Criteria Advanced Stage 
Endometrial Cancer. Am J Clin Oncol. 2014;37:391-396 
2. NCCN Guidelines Version 3.2019 Endometrial Carcinoma  
3. Randall ME, Filiaci VL, Muss H et al. Randomized Phase III Trial of Whole-Abdominal Irradiation 
Versus Doxorubicin and Cisplatin Chemotherapy in Advanced Endometrial Carcinoma: A Gynecologic 
Oncology Group Study. J Clin Oncol. 2006;24:36-44 
4. Greven K, Winter K, Underhill k et al. Final analysis of RTOG 9708: adjuvant postoperative irradiation 
combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk 
endometrial cancer. Gynecol Oncol. 2006;103:155-159 
5. De Boer SM, Powell ME, Mileshkin L el al. Adjuvant chemoradiotherapy versus radiotherapy alone for 
women with high-risk endometrial cancer (PORTEC-3):final results of an international, open-label, 
multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:295-309 
6. Matei D, Filiaci V, Randall ME et al. Adjuvant Chemotherapy plus Radiation for Locally Advanced 
Endometrial Cancer. N Engl J Med. 2019;380:2317-2326 
7. Wilkinson-Ryan I, Binder PS, Pourabolghasem S et al. Concomitant chemotherapy and radiation for the 
treatment of advanced-stage endometrial cancer. Gynecol Oncol. 2014;134:24-28 
 
 

 
 
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APPENDIX A-QUALITY OF LIFE QUESTIONNAIRE 
FACT-G (Version 4-Physical and Functional Well-Being) 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Som
e-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life .................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness .........................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ......................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ...............
0 
1 
2 
3 
4 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Som
e-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of energy ...............................................
0 
1 
2 
3 
4 
GP2 
I have nausea ............................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain .................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .................
0 
1 
2 
3 
4 
GP6 
I feel ill ........................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ................................
0 
1 
2 
3 
4 
 

 
 
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GF7 
I am content with the quality of my life right now ........
0 
1 
2 
3 
4 
 
FACT-En (Version 4-Additional Concerns Section) 
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
ADDITIONAL CONCERNS 
Not 
at all 
A little 
bit 
Som
e-
h
Quite 
a bit
Very 
much 
O1 
I have swelling in my stomach area ...........................
0 
1 
2 
3 
4 
O3 
I have cramps in my stomach area ............................
0 
1 
2 
3 
4 
Hep
8
I have discomfort or pain in my stomach area............
0 
1 
2 
3 
4 
ES6 
I have vaginal bleeding or spotting .............................
0 
1 
2 
3 
4 
ES4 
I have vaginal discharge ............................................
0 
1 
2 
3 
4 
Hep
1
I am unhappy about a change in my appearance ......
0 
1 
2 
3 
4 
ES1 
I have hot flashes/hot flushes.....................................
0 
1 
2 
3 
4 
ES2 
I have cold sweats .....................................................
0 
1 
2 
3 
4 
ES3 
I have night sweats ....................................................
0 
1 
2 
3 
4 
HI7 
I feel fatigued .............................................................
0 
1 
2 
3 
4 
ES8 
I have pain or discomfort with intercourse ..................
0 
1 
2 
3 
4 
En1 
I have trouble digesting food ......................................
0 
1 
2 
3 
4 
B1 
I have been short of breath ........................................
0 
1 
2 
3 
4 
Cx6 
I am bothered by constipation ....................................
0 
1 
2 
3 
4 
BL2 
I urinate more frequently than usual ...........................
0 
1 
2 
3 
4 
En2 
I have discomfort or pain in my pelvic area ................
0 
1 
2 
3 
4 
 
 
 

 
 
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FACT/GOG-NTX-4 (Version 4) 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
 
Not 
at all 
A little 
bit 
Som
e-
what 
Quite 
a bit 
Very 
much 
 
NTX
1 
I have numbness or tingling in my hands ...................
0 
1 
2 
3 
4 
NTX
2 
I have numbness or tingling in my feet .......................
0 
1 
2 
3 
4 
NTX
3 
I feel discomfort in my hands .....................................
0 
1 
2 
3 
4 
NTX
4 
I feel discomfort in my feet .........................................
0 
1 
2 
3 
4 
 
FACT-C (Version 4, Items C3 and C5) 
C3 
I have control of my bowels .......................................
0 
1 
2 
3 
4 
C5 
I have diarrhea (diarrhoea) ........................................
0 
1 
2 
3 
4