A Pilot Phase II Trial of Intravenous Paclitaxel and Intraperitoneal Carboplatin/Taxol Followed by Radiation in Patients With Advanced Stage Uterine Serous Carcinoma
Phase: PHASE1
Conditions: Uterine Carcinoma
Sponsor: Northwell Health

 
A Pilot Phase II Trial of Intravenous Paclitaxel and Intraperitoneal 
Carboplatin/Taxol Followed by Radiation in Patients with Advanced Stage 
Uterine Serous Carcinoma  
 
Principal Investigator:  
 
Karin Shih, MD 
 
Co-Investigators:  
 
Janna Andrews, MD 
Beatrice Bloom, MD 
Kit Cheng, MD 
Lisa dos Santos, MD 
Marina Frimer, MD 
Gary L. Goldberg, MD 
Mark Hoffman, MD 
Veena John, MD 
Arisa Kapedani 
Andrew Menzin, MD 
Elena Pereira, MD 
Antoinette Sakaris, MD 
Benjamin Schwartz, MD 
Anze Urh, MD 
Jeannine Villella, MD 
Jill Whyte, MD 
 
 
 
 
 
 
 
 
 
 
Document date: 7/19/2019 
 

 
INDEX  
 
SCHEMA Page 3  
1.0 BACKGROUND Page 4  
2.0 OBJECTIVES Page 6  
3.0 PATIENT SELECTION Page 6  
4.0 REGISTRATION PROCEDURES Page 8  
5.0 TREATMENT PLAN Page 8  
6.0 DOSE MODIFICATIONS and TOXICITY MANAGEMENT Page 12  
7.0 MEASUREMENT OF EFFECT Page 17  
8.0 DURATION OF STUDY Page 22  
9.0 ADVERSE EVENT REPORTING Page 22  
10.0 STUDY PARAMETERS Page 23  
11.0 DRUG FORMULATION AND PROCUREMENT Page 25  
12.0 STATISTICAL CONSIDERATIONS Page 27  
13.0 DATA SAFETY MONITORING PLAN Page 28  
14.0 RECORDS TO BE KEPT Page 28  
154.0 PATIENT CONSENT AND PEER JUDGEMENT Page 29  
16.0 MINORITIES AND WOMEN STATEMENT Page 29  
17.0 ETHICAL AND REGULATORY CONSIDERATIONS Page 29  
18.0 ELIGIBILITY CHECKLIST Page 30  
19.0 REFERENCES Page 31  
 
APPENDIX  
1. Study Schedule  
2. QoL Forms: Attached  
 
EORTC QLQ-C30  
EORTC QLQ-OV28  
QLQ score interpretation  
3. Carboplatin Calculation form  
4. FIGO Staging – endometrial cancer  
5. Abbreviation List  
6. Informed Consent Forms Attached  
 
 
SCHEMA 
 
Weeks 1-18  
 
Paclitaxel 135 mg/m2 over 3 hrs on day 1  
Carboplatin IP (AUC= 6.0) on day 1  
Paclitaxel 60 mg/m2 IP on Day 8 
Repeat q 21 days x 6 cycles  
CT Imaging after chemotherapy  

 
Weeks 19-23 **  
 
Pelvic 6MV Photon Beam Energy, or IMRT where appropriate  
1.8 Gy Dose/FX  Total Dose 45 Gy  
 
Weeks 24-26 **  
 
High Dose Radiation (HDR) x 3, or IMRT where appropriate  
5 Gy to 0.5cm Depth from the Vaginal Cylinder Surface  
Total Dose 15 Gy  
 
* Disease surveillance with CT imaging should be performed after six cycles of chemotherapy, 
prior to radiation. CT after 3 cycles of chemotherapy is permitted, depending upon physician’s 
discretion.  
** Radiotherapy is given to eligible patients who have not had prior radiation exposure radiation 
in the abdomen and pelvis.  
Quality of Life (QOL) surveys to be obtained at 3 time points  
Baseline (after surgery, prior to initiating first cycle)  
Completion of chemotherapy (18 weeks after Cycle 1 Day 1 if patient is no longer on protocol-
directed treatment)  
Completion of radiation therapy (26 weeks after Cycle 1 Day 1 if patient is no longer on 
protocol-directed treatment)  
Two years post diagnosis, if feasible.  
 
BACKGROUND  
 
Uterine corpus cancer is the most common gynecologic malignancy in the United States. If 
diagnosed at an early stage, it is associated with good prognosis, after surgery and adjuvant 
radiation +/- chemotherapy. However patients with high risk endometrial carcinoma have a 
significant risk for recurrent disease and mortality.  [1-3]  High risk features associated with poor 
prognosis include distinct histologic cell types (clear cell, serous and carcinosarcoma), grade (2 
or 3), and advanced stage. Uterine serous carcinoma (USC) is an uncommon, but aggressive 
variant of endometrial carcinoma that has poor response to standard therapy. In addition, it has a 
propensity for pelvic as well as abdominal recurrences and peritoneal carcinomatosis, similar to 
serous carcinoma of the ovary. In fact, many patients with disease apparently confined to the 
uterus will have microscopic intra-abdominal spread at the time of diagnosis. [4-8] After staging 
and surgical cytoreduction of gross disease, adjuvant radiation therapy is recommended to treat 
patients at high risk for recurrence.  [9-20] The Gynecologic Oncology Group (GOG 94) 
evaluated patients with high risk endometrial cancer treated with whole abdominal and pelvic 
radiation, which included 103 patients with stage III/IV high risk uterine cancer subtypes such as 
clear cell carcinoma and USC. The overall recurrence rates were 67% at 3 years for these 
patients, and 21% occurred within the abdomen.[21]  In another study detailing 21 patients with 
stage I/II USC, more than half of recurrences were within the radiation field. [22] Thus, it 
appears that while pelvic radiation can limit local recurrences, a significant percentage of 
patients, approximately 25-30%, with high-risk features will recur with distant metastases after 

radiation therapy (RT). Even patients treated with whole abdominal irradiation are at risk for 
extra-abdominal recurrences with progression-free intervals of 7 to 8 months.  [23-25] 
Chemotherapy is expected to control pelvic as well as distant sites of failures in advanced or 
recurrent endometrial carcinoma. There have been several randomized trials addressing the 
efficacy of optimal chemotherapy regimen. Doxorubicin, in combination with platinum, has a 
42% response rate, and a survival advantage against whole abdominal radiation. [26, 27] 
Paclitaxel has an overall response rate of 36% in patients with advanced and recurrent 
endometrial cancer.  [28] In combination with doxorubicin and cisplatin, paclitaxel has been 
shown to have a superior survival advantage. However, due to the high rate of toxicity of this 
intense regimen, a review of literature shows most practicing gynecologic oncologists use a 
modified regimen of carboplatin and paclitaxel in the adjuvant setting instead. [29, 30]. Due to 
the propensity for systemic metastasis and recurrence in high risk uterine cancers, several studies 
have studied the combination of chemotherapy and radiation. Carboplatin and paclitaxel 
followed by pelvic RT in patients with advanced endometrial cancer, including patients with 
USC, appear to have acceptable toxicity profile and favorable survival.  [31-34] More 
specifically, in a large prospective phase II trial of USC patients receiving RT ‘sandwiched’ 
between six cycles of carboplatin and paclitaxel, excellent survival was observed in the entire 
cohort, with 3-year probability of survival for advanced stage (III/IV) patients being 50%. In 
patients who completed the entire treatment course, their 3-year survival was 65%. This 
compares favorably with published existing literature for USC, and is associated with limited, 
manageable toxicities.[35] 
 
Recent phase III trials in ovarian cancer have shown the longest survival advantage (median 65 
months) when intraperitoneal (IP) cisplatin and paclitaxel, plus intravenous (IV) paclitaxel were 
utilized for optimally debulked ovarian cancer (GOG 172). The relative risk of progression was 
0.80 (95% CI 0.64, 1.00) for the intraperitoneal group (p=0.05, two-sided log-rank test). [36] To 
date, no trials utilizing intraperitoneal therapy for uterine cancer have been reported. In advances 
stage and recurrent setting, high risk uterine cancer mirrors ovarian cancer with it spread patterns 
and response to therapy. Based on these findings and the similarities as well as the clinical 
success of paclitaxel with IP platinum therapy in patients with ovarian serous carcinoma, we 
propose to prospectively assess IV/IP therapy in patients with advanced stage and recurrent USC. 
In GOG 172, patients in the IP arm experienced significantly worse quality of life (QoL) prior to 
cycle 4 (p<0.0001), and worse QoL 3-6 weeks post treatment (p=0.0035). However QoL 
differences resolved one year post-treatment.[36] Only 42% of patients in the IP group 
completed 6 cycles of chemotherapy, and 49% received 3 or fewer cycles. The main reasons for 
discontinuing IP chemotherapy were 1) catheter complications 2) intolerance of high dose 
cisplatin with nausea, renal dysfunction and electrolyte disturbances 3) intolerance of distention 
from IP infusion. Since GOG 172, it has been shown in a number of IP therapy trials in ovarian 
cancer that implementation of strict pre and post hydration schedules, routine utilization of anti-
emetics, and substitution of carboplatin for cisplatin would improve adherence (due to its 
improved toxicity profile and less need for hydration).[37, 38]  GOG is currently conducting a 
Phase III trial in ovarian cancer that includes comparison of intraperitoneal cisplatin 75 mg/m2 
IP to carboplatin AUC 6 IP (GOG 252).  Preliminary data indicated no difference in PFS in 
patients receiving IV or IP chemotherapy, however, it was limited given all arms of the trial 
received Avastin. Data from the Japanese GOG (JGOG 3016), suggests the superiority of weekly 
dose dense paclitaxel, IV 80mg/m2 administered compared to paclitaxel IV given every three 

weeks.[39] The PFS was 17.2 months for the three week schedule and 28 months for the weekly 
schedule (p=0.0015 HR=0.714 (0.581-0.879). The 2-year overall survival was 77.7% for the 
three-week schedule and 83.6% for the weekly regimen (p=0.496 HR 0.735: 0.54-1.0). MITO-7 
is a randomized multicenter phase III trial.  Weekly paclitaxel had similar PFS and no difference 
in estimated probability of survival, as well as lower rates of toxicity.  [40]  In addition, there is 
also support for a weekly schedule over an every 3-week in the breast cancer literature. The 
superiority of weekly paclitaxel in node positive, or high risk node-negative breast cancer was 
reported by Sparano et al (HR 1.32, p=0.01).[41]  The existing literature supports the superiority 
of weekly paclitaxel regimen, and GOG 252 has included a confirmatory arm of dose-dense 
weekly paclitaxel, 80 mg/m2 versus paclitaxel 135 mg/m2 every three weeks for treatment of 
epithelial ovarian cancer. GOG 9920 is a phase I study that evaluated the toxicity associated with 
modified paclitaxel/doxorubicin/cisplatin regimen followed by IP cisplatin/paclitaxel for patients 
with advanced endometrial cancer.  Most patients had stage IV disease and the majority (59%) 
had serous/clear cell histology.  At median followup of 22 months, 46% of patients remained 
progression free.  [42]Building on the success of some recent trials and what is now considered 
standard of care for serous ovarian cancer, we propose a safety and feasibility study using for 
adjuvant therapy in women with advanced stage USC.  
 
 
2.0 OBJECTIVES  
 
Primary Objectives  
 
2.11 To evaluate the toxicity (as defined by NCI Common Toxicity Criteria v. 4.0) of IP 
carboplatin/IV paclitaxel followed by Day 8 IP paclitaxel chemotherapy given in 3 week cycles, 
followed by RT in patients with advanced stage USC.  
 
2.12 To determine the feasibility of this regimen in women with advanced stage USC. Feasibility 
will be assessed by: Treatment completion proportion – the proportion of participants who 
complete the IV paclitaxel/IP carboplatin followed by IP paclitaxel/RT regimen  
Screening ratio – the number of potential participants screened per enrolled participant  
 
Secondary Objectives  
2.21 To assess the frequency and the reasons for early discontinuation of the study treatments.  
2.22 To describe patient-reported quality of life parameters at specified time points during the 
study using validated questionnaires:  
EORTC QLQ-C30 and QLQ-OV28  
 
Exploratory Objectives  
2.31 To define patterns of recurrence (e.g. local versus distant) and progression-free survival in 
patients with advanced and recurrent USC treated with IV paclitaxel/ IP carboplatin therapy and 
IP paclitaxel.  
2.32 To correlate surrogate endpoint biomarkers that is performed in standard histology 
processing (Estrogen receptor and Progesterone receptor status as well as Her2/ neu status, p53 
status) with progression-free survival and prognosis.  

2.33 To assess the potential late effects of combined IP chemotherapy and radiotherapy on the 
gastrointestinal, genito-urinary, bone marrow and other body systems beginning at 6 months post 
treatment completion during routine office visits.  
 
3.0 PATIENT SELECTION  
 
3.1 Inclusion Criteria  
Patients may be included in the study if all of the following criteria are met:  
 Histological/cytologically documented primary FIGO Stage IIIA, IIIB, IIIC1, IIIC2, IVA, 
and IVB uterine serous carcinoma.  
 Patients with stage IVB disease include abdominal metastasis only 
 Primary surgery with residual disease ≤ 1cm by surgeon report.   
 
 
 
b. All patients must have a procedure for determining the definitive diagnosis of USC. At the 
discretion of the surgeon, complete surgical staging should include: total hysterectomy, bilateral 
salpingo-oophorectomy, peritoneal washings, omental biopsy and lymph node evaluation.  
c. Age > 18 years.  
d. ECOG performance status of ≤ 2.  
e. Written voluntary informed consent.  
3.2 Exclusion Criteria  
Exclusion from the study will be required if any of the following criteria are met:  
a. Distant metastasis to the lung, bone or brain. Typically, most stage 4 USC is confined to the 
abdomen on presentation.  
b. Patient has impairment of hepatic, renal or hematologic function as defined by the following 
baseline laboratory values:  
Serum SGOT and /or SGPT > 2.5 times the institutional upper limit of normal (ULN)  
Total serum bilirubin > 1.5 mg/dl  
Serum creatinine > 2.0 mg/dl  
Platelets < 100,000/mm3  
Absolute neutrophil count (ANC) < 1500/mm3  
Hemoglobin < 8.0 g/dl (the patient may be transfused prior to study entry)  
c. History of abdominal/pelvic radiation therapy.  
d. Severe or uncontrolled, concurrent medical disease (e.g. uncontrolled diabetes, unstable 
angina, myocardial infarction within 6 months, congestive heart failure, etc.)  
e. Patients with dementia or altered mental status that would prohibit the giving and 
understanding of informed consent at the time of study entry.  
 
 
 
 
 
4.0 REGISTRATION PROCEDURES  
 

All patients must be registered. Any questions regarding eligibility should be addressed with the 
P.I. or the research coordinator.  
 
 
5.0 TREATMENT PLAN  
 
5.1 Dosing Guidelines  
5.1.1 Chemotherapy  
 
Paclitaxel is available commercially. Paclitaxel 135mg/m2 will be given over 1 hour in 250-500 
ml of 5% dextrose or normal saline. Premedication for prevention of anaphylactic reactions with 
anti-histamines and/or steroids should be administered as per standard practice. Paclitaxel should 
be given first given the risk of immediate drug sensitivity reaction. Following on Day 8 of the 
cycle, paclitaxel will be given IP at 60mg/m2. After infusion the patient will be asked to change 
position at 15-minute intervals for two hours to ensure adequate intra-abdominal distribution. No 
attempt will be made to retrieve the infusate, however if a large amount of ascites is present, 
ascites may be drained by paracentesis or accessed port prior to instillation of drug. 
Carboplatin is available commercially. Carboplatin should be reconstituted in 500-1000cc of 
normal saline warmed to 37 °C (when feasible) and infused through a peritoneal catheter as 
rapidly as possible. It is preferred that an additional 1000 ml of warm saline is infused after IP 
Carboplatin, or 500ml of warmed normal saline infused before and after IP Carboplatin to help 
with drug dispersion throughout the peritoneal cavity, for a total volume of approximately two 
liters. After infusion the patient will be asked to change position at 15-minute intervals for two 
hours to ensure adequate intra-abdominal distribution. No attempt will be made to retrieve the 
infusate, however if a large amount of ascites is present, ascites may be drained by paracentesis 
or accessed port prior to instillation of drug. Carboplatin at an AUC of 6.0 will be administered 
intraperitoneally (if there is a prior history of radiotherapy, AUC of 5 would be used). AUC 
based dosing as described by Calvert et al. will be according to the following formula:  Dose 
(mg) = AUC x (GFR + 25). 
The initial GOG trial using combination paclitaxel and carboplatin therapy was performed on 
patients with optimally debulked ovarian epithelial carcinoma.[43] At that time, the carboplatin 
dose was an AUC of 7.5. Since then, multiple large cooperative trials have been performed using 
AUCs of 6.0 and even 5.0. The lower dosage of carboplatin does not appear to compromise the 
efficacy of the drugs, and is associated with less toxicity.[44-46] 
Where AUC is as stated above and GFR is the calculated renal function according to the method 
of Cockcroft and Gault:  GFR (ml/min) = 0.85 x {(140-age)/Scr)} x {wt(kg)/72}.  
Where Scr is the serum creatinine level. We will use GFR of 125ml/min as cutoff as per NCI 
guidelines.  
Following 6 cycles of IV/IP chemotherapy, a CT of chest, abdomen and pelvis should be 
obtained for disease surveillance prior to proceeding with radiotherapy (See section 5.4). If 
clinically indicated, the primary oncologist may have the option to proceed with the CT imaging 
after 3 cycles of chemotherapy.  
5.1.2 Antiemetic Regimens  
Nausea and vomiting is anticipated as a side effect. The following representative antiemetic 
regimen is suggested:  

Ondansetron 8-32 mg IV or PO 30 minutes prior to administration of chemotherapy and 
dexamethasone 10-20 mg IV or PO 30 minutes prior to drug administration.  
Aprepitant 125 mg PO one hour prior to chemotherapy on day 1 and 80 mg daily PO on days 2 
& 3 for patients having nausea or vomiting with carboplatin (the intravenous formulations may 
be substituted when available).  
Granisetron 10 mcg/kg IV (or 2mg PO) 30 minutes prior to chemotherapy, dexamethasone 10-
20 mg IV 30 minutes prior to chemotherapy  
5.2 Intraperitoneal device specifications:  
Insertion of peritoneal catheter may be done by the following procedures as listed below: 1) at 
time of original laparotomy 2) laparoscopic placement 3) interventional radiology guided 
placement. Silicone catheters are preferred. Controversy exists between the use of venous 9.6 
silicone catheters or silicone IP ports with fenestrations. Bardport silicone peritoneal catheter 
14.3 Fr (Reorder number 0603006) is the preferred catheter. This has been FDA approved for IP 
therapy. The 9.6 Fr single lumen IV access device is also acceptable. Equivalent or similar 
devices are acceptable if silicone large enough not to kink and without a Dacron cuff.  
 
Procedure at time of original laparotomy:  
1) At the completion of the laparotomy just prior to closing the incision, make a 3-4 centimeter 
incision over the lower costal margin on the side where the catheter is to be placed. The incision 
is carried down to the fascia using blunt and sharp dissection.  
2) A subcutaneous pocket superior to the incision is fashioned slightly larger than the diameter of 
the portal.  
3) Select an area several centimeters below and lateral to the umbilicus as the peritoneal entrance 
site of the catheter. Prepare a subcutaneous tunnel from the portal pocket to the site in the 
peritoneal cavity you want the catheter to enter the abdomen and draw the catheter through the 
subcutaneous tissue into the abdomen using a tunneling device.  
4) Attach the catheter to the portal as per manufacturer’s instructions and suture the portal in 
place with permanent suture (i.e. 2-0 prolene) to the fascia overlying the rib cage. Be sure the 
chemotherapy nurses will be able to feel the port and stabilize it on the chest wall for easy access 
with Huber needle in the future. Be sure the Huber needle will not have to go through the wound 
to access the port; the port should lie superior to the port incision site.  
5) After flushing the system with heparin 100 units per ml to determine that flow is not 
obstructed and no leaks exist, place the distal end of the catheter to the desired infusion site, with 
at least 10 cm of free catheter in the abdomen. Do not allow the catheter to be long enough to 
reach the bladder, vagina or rectum.  
6) Close incisions and place a Huber needle trans-dermally into the portal if the catheter is going 
to be irrigated in the immediate postoperative period. Wait a minimum of 24 hours prior to 
treating patient after IP port placement, and wait for return of gastrointestinal function (regular 
diet tolerated and normal bowel movement) after major laparotomy.  
 
 
Postoperative procedure with mini laparotomy (video available at SGO.org and GOG.org)  
1) Select a site several centimeters below and lateral to the umbilicus and make an incision 
through skin, subcutaneous tissue and fascia. Separate rectus muscle and enter peritoneum. 
Knowledge of the previous surgical resections and current anatomy will assist in choosing 
location.  

2) Pull the catheter from subcutaneous tissue into the peritoneal cavity through the full thickness 
of the abdominal wall (fascia, muscle, peritoneum) from an adjacent location (not through the 
incision) while under direct visualization to prevent injury to bowel. This can be accomplished 
with a tonsil clamp or tunneling device.  
3) The catheter must be left in the abdominal cavity at least 10 cm to prevent migration out of the 
peritoneal cavity.  
4) The opposite end of the catheter is tunneled up to the costal margin where it is attached to an 
implanted port as described above. The catheter is left long enough to not retract, but not long 
enough to reach vagina, rectum or bladder. It is generally left at least 10 cm into the peritoneal 
cavity.  
 
Post-operative laparoscopically assisted surgical implantation of Port 
 
1) Laparoscopic placement of an IP catheter is usually feasible from a left upper quadrant 
approach. Knowledge of the previous procedures performed (i.e. bowel resections and 
anastomosis sites) and location of the tumor will inform the surgeon as to the best approach and 
what locations to avoid.  
2) Once the peritoneal cavity can be visualized, a second puncture can be used to gain access to 
the peritoneal cavity and then the catheter is tunneled in the subcutaneous tissues to the planned 
Port pocket.  
 
Port placement under Interventional Radiologic guidance  
 
Interventional radiology may also place IP catheters, if preferred by treating provider. 
Knowledge of anatomy and the best sites for placement should be communicated between the 
primary provider or surgeon and the radiologist. CT or ultrasound can allow direct access to 
peritoneal cavity, followed by subcutaneous tunneling to the anterior chest wall for appropriate 
port placement and catheter attachment.  
 
Radiation: 
 
Radiation therapy will be delivered at provider discretion after the 6th cycle of chemotherapy. 
Physical Factors: All treatment will be delivered by megavoltage equipment ranging from 6 MV 
to a maximum of 25 MV photons. Cobalt-60 equipment will not be acceptable for treatment on 
this protocol. Tomotherapy is allowed. 
Localization and Simulation Methods: Localization images taken on the conventional or CT-
simulator will be necessary in all cases. 
Treatment Plan and Dose Specification: Patients may be treated with either conventional 
radiation therapy approaches or with IMRT. The use of individualized custom blocking is 
required.  
Daily Tumor Dose, Total Dose, and Overall Treatment Time: A daily tumor dose of 180 cGy per 
day will be given to a total dose of 4500 cGy (180 cGy x 25 treatments) in approximately five 
weeks. Treatment will be given 5 days a week, from Monday through Friday 
Dose Distribution (Site): Dose to the CTV should not vary by more than +/- 5% from the 
prescribed dosage for 3D conformal plans. The use of tissue wedges and/or compensating filters 

may be necessary to accomplish this goal. As a general rule, only pelvic radiation therapy will be 
given, unless there is imaging, intra-operative, histologic, or other evidence of para-aortic node 
involvement 
. 
If there is tumor extension into the vagina, the external beam fields will be modified to include 
the disease volume with at least a 2 cm margin. For involvement of the distal 1/3 of the vagina, 
inguino-femoral nodes should also be covered in the external beam RT ports. If the patient’s 
tumor extends into the cervix, or invades deeply and extends into the lower uterine segment, or if 
there is lymph-vascular space invasion by tumor, or if the tumor has extended into the vagina, 
such a patient will receive intravaginal boost brachytherapy 
 
Radiation Therapy Volumes and Technique 
 
Pelvic field: 3D Conformal 
Portal and Treatment Volume Definition: 
The boundaries are as follows: 
AP/PA Fields: Cephalad Border: 
A transverse line drawn within 2 cm of the L5-S1 interspace or higher if necessary to include 
known areas of lymph node involvement by tumor. 
 
AP/PA Fields: Caudal Border: 
The mid-portion of the obturator foramen or a minimum of 4 cm margin on the vaginal cuff, 
preferably defined by marker seed placement or by placement of a vaginal swab at the time of 
simulation. 
Lateral Borders: >1 cm beyond the lateral margin of the true pelvis at its widest points. 
Alternatively, use of a CT scan to outline the target vessels with a border of at least 1 cm is 
acceptable. 
Lateral Pelvic Fields: 
The cephalad and caudal borders are same as above. 
Anterior Border: 
A horizontal line drawn anterior to the symphysis pubis. When extended in the cephalad 
direction, this line should pass at least 1 cm anterior to known nodal regions or, in the absence or 
radiographic documentation, the line should pass at least 1.5 cm anterior to the L5 vertebral 
body. Individualized custom blocks can be used to achieve this goal. 
Posterior Border: 
A cephalo-caudal line passing through the third sacral vertebra. Every effort should be made to 
include the upper vaginal stump with a margin of at least 3 cm. 
 
 
 
 
IMRT 
Patient Immobilization: Prior to simulation, it is recommended that radiopaque marker be 
inserted into the vaginal apex to help to identify the area by CT scan. Patients are to be 
immobilized in the supine position in an immobilization device. Patients are to be treated in the 

immobilization device. CT scan thickness should be 3 mm or smaller through the region that 
contains the PTV, extending from at least L3-4 level to below the perineum. 
Simulation: CT simulation is required to define clinical target volume (CTV) and planning target 
volume (PTV). The CT scan should be acquired in the same position and immobilization device 
as for treatment. The use of IV contrast and bowel prep-contrast are highly recommended for 
better delineation of the contrast-enhanced pelvic vessels used as a surrogate for regional nodal 
delineation, as well as small bowel contouring, respectively. 
Contouring the Target volumes: 
Please refer to the RTOG Gynecological Atlas for volume specification. The atlas may be 
accessed on the RTOG website at: http://www.rtog.org/gynatlas/main.html 
The Clinical Target Volume (CTV) is defined as the vaginal apex in addition to pelvic nodal 
regions lying within the field borders given in Section 4.61. If gas/stool distends the rectum, the 
CTV is to be expanded to include the anterior half of the rectum to account for evacuation of the 
rectum. The nodal portion of the CTV should include the internal (hypogastric and obturator), 
and external iliac lymph node regions. The CTV should be delineated using the contrast 
enhanced (preferably IV contrast administered) iliac vessels, in addition to the perinodal soft 
tissue (minimum of 6 mm axial margin around the vessels). Bone and intraperitoneal small 
bowel should be excluded from the CTV as much as possible (leaving at least 6 mm margin 
around the vessels). Approximately 1-2 cm of tissue anterior to the sacrum (S1-S3) may be 
added to the CTV for adequate coverage of pre-sacral nodes, although this is optional and at the 
discretion of the treating radiation oncologist. In addition the most antero-lateral margin of the 
external iliac nodes that lie just proximal to the inguinal canal should be excluded from the CTV 
(nodal CTV should stop at the femoral head). Proximally, the CTV should end 7 mm from the 
L5-S1 interspace to account for the PTV. The CTV should include the inguino-femoral nodes if 
the distal one-third of the vagina is involved with tumor. 
The PTV should provide a 7 mm-1 cm margin in all directions around the CTV. 
The definitions of volumes will be in accordance with the 1993 ICRU report #50. Prescribing, 
recording and reporting photon beam therapy and 1999 ICRU report #62. 
Critical normal surrounding structures: 
Bladder will be contoured in each slice in which it appears.  
Rectum will be contoured in each slice in which it appears. As a general guideline, the radiation 
oncologist can consider the maximum caudal extent of the rectum to lie 1.5-2.0 cm from the 
bottom of the ischial tuberosities. Superiorly, judgment will be required to establish where the 
rectum ends and the sigmoid colon begins. The transition to the sigmoid colon is marked by 
increased curvature and tortuosity in its path. Bowel will be contoured in each slice in which it 
appears, 2 cm above the PTV as bowel bag and inferiorly to the rectosigmoid junction. 
Femoral heads will be contoured in all the slices in which they appear. 
Constraints: Participants are strongly encouraged to respect the following limits, whether 3-D 
conformal or IMRT approaches are used. 
Small bowel: <30% to receive ≥ 40Gy, Dmax <46 Gy 
Rectum: < 80% to receive ≥ 40Gy, Dmax <55 Gy  
Bladder: < 50% to receive ≥ 45Gy, Dmax <60 Gy 
Femoral heads: < 50% to receive ≥ 40Gy, Dmax <50 Gy. 
 
No tissue outside the PTV will receive > 110% of the dose prescribed to the PTV. 

Extended Field Radiation Therapy: 3D Conformal Portal and Treatment Volume: The 
boundaries are as follows: 
AP/PA Fields: Cephalad Border: 
A transverse line drawn within 2 cm of the T11-T12 interspace. 
AP/PA Fields: Caudal Border: 
The mid-portion of the obturator foramen or a minimum of 4 cm margin on the vaginal cuff, 
preferably defined by marker seed placement or by placement of a vaginal swab at the time of 
simulation. 
Lateral Borders: 
In the pelvis >1 cm beyond the lateral margin of the true pelvis at its widest points. Alternatively, 
use of a CT scan to outline the target vessels with a border of at least 1 cm is acceptable. Moving 
superiorly, the width of the field will taper to the lateral aspects of the spinal transverse processes 
at L4 and superior to L4. The approximate field width for the para-aortic portion of the field 
should be 8 cm, although some variation is expected. 
Lateral Pelvic Fields: 
The cephalad and caudal borders are same as above. 
Anterior Border: 
A horizontal line drawn anterior to the symphysis pubis. When extended in the cephalad 
direction, this line should pass at least 1 cm anterior to known nodal regions or, in the absence or 
radiographic documentation, the line should pass at least 1.5 cm anterior to the L5 vertebral 
body. Individualized custom blocks can be used to achieve this goal. Moving superiorly, the 
anterior border of the para-aortic field should remain a minimum of 1.5-2 cm anterior to the 
anterior border of the vertebral body. Again, some variation is expected, particularly in patients 
who have positive PA nodes or in patients who kidneys are located more anteriorly than normal. 
The overall width of the PA field should be at least 5cm. 
 
Posterior Border: 
A cephalo-caudal line passing through the third sacral vertebra. Every effort should be made to 
include the upper vaginal stump with a margin of at least 3cm. Moving superiorly, the posterior 
border of the PA field should extend back approximately 50% of the width of each vertebral 
body. 
Suggested technique: Different techniques have been used to deliver extended field radiation 
therapy. The suggested technique for this study is to treat the pelvic and para-aortic fields in 
continuity, as opposed to splitting fields, or treating the para-aortic portion with AP-PA fields 
only. Treating in continuity, it is suggested that the AP-PA fields be weighted 70:30 in relation to 
the lateral fields, in terms of isocenter dose. This technique strikes an appropriate balance, 
in most cases, between small bowel dose and kidney dose. Other techniques or beam weightings 
are potentially permissible, if appropriate dose distributions to PTV and organs at risk (OAR’s) 
are obtained 
 
 
 
 
 
Extended Field Radiation Therapy: IMRT 
 

 
 
Portal and Treatment Volume Definition: 
Patient Immobilization: 
Prior to simulation, it is recommended that radiopaque marker seeds are inserted into the vaginal 
apex to help to identify the area by CT scan. Patients are to be immobilized in the supine position 
in an immobilization device such as Vac-lok or alpha-cradle, or similar. Patients are to be treated 
in the immobilization device. CT scan thickness should be 3 mm or smaller through the region 
that contains the PTV, extending from at least L3-4 level to below the perineum. 
Simulation: 
CT simulation is required to define clinical target volume (CTV) and planning target volume 
(PTV). The CT scan should be acquired in the same position and immobilization device as for 
treatment. The use of IV contrast and bowel prep-contrast are highly recommended for better 
delineation of the contrast-enhanced pelvic vessels used as a surrogate for regional nodal 
delineation, as well as small bowel contouring, respectively. 
 
The Clinical Target Volume (CTV) is defined as the vaginal apex with margins as given in the 
#d section. in addition to pelvic and para-aortic nodal regions lying within the field borders 
given in #d sections The nodal portion of the CTV should include the internal (hypogastric and 
obturator), external iliac lymph node, and para-aortic regions. The CTV should be delineated 
using the contrast-enhanced (preferably IV contrast administered) iliac vessels, in addition to the 
perinodal soft tissue (minimum of 6 mm axial margin around the vessels). Bone and 
intraperitoneal small bowel should be excluded from the CTV as much as possible (leaving at 
least 6 mm margin around the vessels). Approximately 1-2 cm of tissue anterior to the sacrum 
(S1-S3) may be added to the CTV for adequate coverage of presacral nodes, although this is 
optional and at the discretion of the treating radiation oncologist. In addition, the most 
anterolateral margin of the external iliac nodes that lie just proximal to the inguinal canal should 
be excluded from the CTV (nodal CTV should stop at the femoral head. Proximally, the CTV 
should end 7 mm from the T11-T12 interspace to account for the PTV. The PTV should provide 
a 7 mm-1 cm margin in all directions around the CTV. The definitions of volumes will be in 
accordance with the 1993 ICRU report #50. Prescribing, recording and reporting photon beam 
therapy and 1999 ICRU report #62. 
Critical normal surrounding structures:  
Bladder will be contoured in each slice in which it appears. 
Rectum will be contoured in each slice in which it appears. As a general guideline, the radiation 
oncologist can consider the maximum caudal extent of the rectum to lie 1.5-2.0 cm from the 
bottom of the ischial tuberosities. Superiorly, judgment will be required to establish where the 
rectum ends and the sigmoid colon begins. The transition to the sigmoid colon is marked by 
increased curvature and tortuosity in its path. 4Bowel will be contoured as bowel bag will be 
contoured in each slice in which it appears, 2 cm above the PTV.  
 
Femoral heads will be contoured in all the slices in which they appear. 
Constraints: Participants are strongly encouraged to respect the following limits, whether 3-D 
conformal or IMRT approaches are used.  
Bowel bag: <30% to receive ≥ 40Gy, Dmax <46 Gy 
Rectum: < 60% to receive ≥ 40Gy, Dmax <55 Gy 

Bladder: < 50% to receive ≥ 45Gy, Dmax <60 Gy 
Femoral heads: < 50% to receive ≥ 40Gy, Dmax <50Gy. 
Kidney volume (combined right and left): <40% to Receive>15 Gy 
No more than 1% or 1 ml (whichever is smaller) of the tissue outside the PTV will receive > 
110% of the dose prescribed to the PTV. 
The volume irradiated with the whole pelvic fields will include the CTV and PTV as defined 
above. The whole pelvis will receive a total dose of 4500 cGy in 25 fractions at 180 cGy/fx. For 
patients treated with IMRT, the prescription dose is the isodose that encompasses at least 97% of 
the PTV. No more than 20% of any PTV should receive >110% of the prescribed dose. No more 
than 1% of the PTV should receive <93% of the prescribed dose. No more than 1% or 1 cc 
(whichever is smaller) of the tissue outside the PTV will receive >110% of the dose prescribed to 
the PTV. However, with respect to this last constraint, it is recognized that there may be patients 
in which, due to obesity or other factors, this constraint may not be obtainable if other 
constraints, e.g. rectum, are met. In these cases it is recommended that the OAR constraints be 
favored to the extent possible that is consistent with good radiotherapy practice. 
 
Documentation requirements 
For 3-D conformal treatments, digital reconstructed radiographs (DRR) of the treatment fields 
with the three-dimensional reconstruction of the CTV are to be obtained  
For 3-D conformal plans, localization or block-check images of virtually simulated fields are to 
be obtained in the simulator and/or treatment machine for all the treatment fields independently, 
whether cerrobend blocks or multi-leaf collimators are used. 
 
For IMRT plans, Dose-Volume Histograms (DVHs) are to be obtained for each one of the target 
volumes defined above, as well as the critical surrounding structures, and need to be submitted 
for evaluation. For detailed description of radiation pelvic fields, please see Section 4.62. 
Therapy Interruptions: If interruption of two weeks or less occurs, radiation should be completed 
to the prescribed total dose. Therapy interruptions of more than two weeks will be considered a 
major or minor deviation from the protocol, depending on clinical circumstances, and resumption 
of therapy will be at the discretion of the radiation oncologist. Follow-up must continue 
regardless of radiation treatment received.  
Expected Toxicity: Toxicity will vary depending upon tolerance of individual patient’s daily 
dose, total dose, overall treatment time, associated illness, etc.  
The following toxicity criteria may be used: 
Gastrointestinal: Nausea and vomiting is unusual, but may be seen after pelvic radiation. Anti-
emetics may be used during treatment or may be given prophylactically the night prior to 
treatment. Intractable nausea or vomiting is rarely seen with pelvic radiation alone and is usually 
the result of another process, i.e., bowel obstruction. Increased bowel activity with diarrhea 
usually can be controlled with low- fiber, low-fat, bland diets and anti-diarrhea medication. 
Should G.I. toxicity become severe, hospitalization may be required, at which time the treatment 
is interrupted temporarily until the patient’s condition improves. 
Hematological: Hematological toxicity is seen infrequently, unless pelvic radiation is 
accompanied by chemotherapy. A CBC should be obtained weekly during radiotherapy. If the 
ANC falls below 1,000 /mcl or the platelet count below 50,000/mcl, the CBC should be obtained 
twice weekly. Radiotherapy should be stopped when ANC < 500 and/or platelets < 25,000.  
 

Radiotherapy 
Brachytherapy: If a vaginal brachytherapy boost is to be given based on the criteria given in the 
protocol. It should commence within 2 weeks of completion of the external beam RT. It should 
be delivered with a vaginal cylinder (HDR or LDR) or colpostats (LDR), and in the absence of 
gross residual disease following surgery the treating physician must choose one of the following: 
A) HDR: 600 cGy x 2-3, weekly, prescribed at the vaginal surface. Dose optimization should be 
used in an effort to create reasonable homogeneity of dose around the surface of the applicator. 
A minimum of 4 cm of vaginal length should be treated. 
B) LDR 2000-3500 cGy prescribed at the vaginal surface in 1 insertion at a dose rate of 40-100 
cGy/hr. A minimum of 4 cm of vaginal length should be treated. 
. 
Physical Factors  
If an intravaginal boost is to be used, it should be delivered with an intravaginal cylinder (HDR 
or LDR). Acceptable isotopes include cobalt or iridium for HDR, radium or cesium for LDR. 
 
Expected Toxicity (Gastrointestinal: Nausea and vomiting may occur after extended field 
Gastrointestinal: Nausea and vomiting may occur after extended field (PAN) treatments, but can 
be effectively treated with an appropriate antiemetic in most cases. Intractable nausea and 
vomiting beyond the first few days should arouse suspicion of recurrent tumor or other causes of 
bowel obstruction, as it is not commonly seen as a result of radiation alone. Increased bowel 
activity with diarrhea can be expected fairly routinely after the first two weeks of pelvic 
radiation. It is recommended that instructions be given to patients for low-fiber, low-fat, bland 
diet. Most patients will require anti-diarrheal medications such as Diphenoxylate 
HCL with atropine sulfate (Lomotil) or Loperamide HCL to control diarrhea. 
Hematological toxicity of a mild nature will be seen frequently with a decline in WBC and 
platelet count. 
 
 
 
. 
 
6.0 DOSE MODIFICATIONS AND TOXICITY MANAGEMENT  
 
No dose escalation is planned for this study. All dose modifications are relative to the actual 
starting dose of the original regimen. All dose modifications will be based on absolute neutrophil 
count (ANC) rather than total white blood cell (WBC).  
6.1 Hematologic Toxicities  
6.1.1 Treatment delay for IV Paclitaxel: Day 8 will be skipped if:  
ANC < 500 cells/mcl or  
Platelet < 50,000 / mcl  
6.1.2 Cycle delay: Day 1 of each cycle will be delayed if:  
ANC < 1000 cells/mcl  
Platelet < 75,000 / mcl  
If cycle is delayed for 2 weeks or more for reasons of toxicity, dose modification and/or growth 
factor support may be used and continued for 6 cycles of treatment.  

6.1.3 Hematopoietic Cytokines and Protective Agents: Patients will not receive prophylactic 
filgrastim (G-CSF), PEG-filgrastim (Neulasta), or sargramostim (GM-CSF) unless: treatment 
delays have been encountered neutropenic complications (e.g. neutropenic fever) in accordance 
with clinical treatment guidelines physicians are allowed flexibility for treatment for severe 
neutropenia in the elderly (ANC < 500 in women > 70 years old).  
Patients will not receive prophylactic thrombopoietic agents, iron supplements and/or 
transfusions as clinically indicated for anemia management erythropoiesis stimulating agents 
(Aranesp, Epogen, Procrit) are associated with a potential risk of shortening time to disease 
progression and are contraindicated in patients treated with curative intent. They are also 
associated with increased thrombotic events and should be administered only to avoid red blood 
cell transfusions as clinically indicated. Please consult updated package insert:  
http://www.fda.gov/Medwatch/safety/2007/safety07.htm  
Amifostine or other renal and neuropathy protective reagents should be avoided  
6.1.4 Dose modifications  
6.1.4.1 Initial occurrence of dose-limiting neutropenia (DLT-ANC) requiring dose reduction will 
be managed according to Table A. DLT-ANC is defined as:  febrile neutropenia: fever with or 
without clinically or microbiologically documented infection with ANC < 1000 and fever ≥ 
38.5°C. prolonged grade 4 neutropenia persisting > 7 days delay of Day 1 of any cycle by > 7 
days due to neutropenia  ANC between 1000 and 1500 on day 1 of any cycle, or omission of day 
8 or 15 IV paclitaxel due to neutropenia  Only one dose modification per cycle is allowed.  
 
6.1.4.2 Initial occurrence of dose limiting thrombocytopenia (DLT –PLT) requiring dose 
reduction will be managed according to Table ADLT-PLT is defined as:  
Grade 4 thrombocytopenia (<25,000/mcl)  
Bleeding associated with grade 3 thrombocytopenia (24,000 – 50,000/mcl)  
Delay of treatment on day 1 of any cycle > 7 days due to thrombocytopenia or inability to give 
day 8 or 15 due to thrombocytopenia.  Platelet count of 75,000 – 100,000/mcl on day 1 should 
have carboplatin dose reduction (Table A) 
  
 
 
Table A: Modification for DLT – Hematologic Toxicity  
 
DLT-  
ANC  
DLT-  
PLT  
First 
Occurrence  
Second 
Occurrence  
Third 
Occurrence  
Fourth 
Occurrence  
Yes  
No  
Reduce 
carboplatin by 
one AUC unit  
Omit day 15 
paclitaxel and 
add G-CSF* 
starting after 
day 8 
paclitaxel  
Reduce 
carboplatin by 
one AUC unit 
AND start G-
CSF* after day 
8 paclitaxel  
Off - study  
Yes  
Yes  
Reduce 
carboplatin by one 
AUC unit  
Omit day 15 
paclitaxel AND 
add G-CSF* 
starting after day 8 
paclitaxel AND 
Off-study  

reduce carboplatin 
by one AUC unit  
No  
Yes  
Reduce 
carboplatin by one 
AUC unit  
Decrease 
carboplatin by one 
AUC  
Off-study  
 
* G-CSF can be given daily starting on day 9 (for up to 10 days) or Peg-filgrastim can be given 
once on day 9.  
6.1.4.3 Dose modifications for delayed hematologic recovery  
Delayed hematologic recovery > 7 days is a DLT and modification should occur on the next 
cycle according to Table A. Delay due to neutropenia is defined as ANC <1000 cells/mcl within 
24 hours of scheduled Day 1 treatment  
Delay due to thrombocytopenia is defined as platelet < 75,000/mcl within 24 hours prior to the 
scheduled Day 1 treatment .Delay > 21 days would be an indication for off-study. Patient may, at 
discretion of physician, continue with non-protocol directed platinum/taxane therapy (with dose 
reductions and growth factors)  
 
Non-Hematologic Toxicity: Refer to Table B for dose level modifications for non-
hematologic toxicity  
 
Table B: Modification for Non-Hematologic Toxicity  
Drug  
Regimen Starting 
Dose  
Regimen -1 Level  
Regimen -2 Level  
Paclitaxel IV 
weekly  
135 mg/m2  
100 mg/m2  
80 mg/m2 
Carboplatin IP  
IP Paclitaxel Day 8 
AUC 6  
60 mg/m2 
AUC 5  
40 mg/m2 
AUC 4  
Omit day 8 IP 
Paclitaxel 
 
 
6.2.1 Neurologic: 
  
Persistent grade 2 or higher neurotoxicity require holding paclitaxel dose for maximum of three 
weeks until recovery to grade 1, and start next cycle at one level of dose reduction  
If neuropathy fails to recover to grade 1 by three weeks, patient should be deemed off-study, and 
docetaxel may be considered per primary physician discretion as a substitute.  
Ototoxicity and neurotoxicity are related to cumulative dose. Severe toxicity can be avoided by 
careful monitoring of symptoms. Patients should be queried about hearing loss and paresthesia 
prior to each course of carboplatin.  
 
 
6.2.2 Renal toxicity:  
Significant renal toxicity is not expected from carboplatin as a direct complication of 
chemotherapy. Target AUC dose of carboplatin must be recalculated each cycle in any patient 
who develops renal insufficiency, defined by serum creatinine > 1.5 times ULN (CTCAE grade 2 

or more). Severe renal toxicity can be prevented by intravenous hydration and administration of 
mannitol.  
 
6.2.3 Hepatic toxicity:  
Significant hepatic toxicity is not expected as a direct complication of chemotherapy in this 
patient population. Development of ≥ grade 3 increase in SGOT (AST), SGPT (ALT), or 
alkaline phosphatase require one dose level reduction in paclitaxel dose after delay in subsequent 
treatment for maximum of three weeks until recovery to grade 1.  
Development of abnormal bilirubin levels should prompt withholding treatment until resolution 
to normal for maximum of 3 weeks  
 
 
6.2.4 Gastrointestinal toxicity:  
Routine medical measures should be employed to manage nausea, vomiting. No dose adjustment 
is expected for these side effects  
Paclitaxel can cause severe diarrhea. For grade 3 diarrhea, hold weekly paclitaxel and resume 
with a two level dose reduction after resolution to grade 1 or less, unless there is a clear 
alternative cause (i.e. c. difficile infection) If hospital admission is required for IV hydration, 
consider assessment for bowel complications or IP access device complications.  
 
6.2.5 Alopecia  
There will no dose modifications for alopecia  
 
6.2.6 Hypersensitivity / allergic reaction:  
Hypersensitivity reaction to paclitaxel or carboplatin is generally not considered a DLT. 
Treatment should only be discontinued after documentation of failure to tolerate agent after all 
attempts being made to: 1) immediately treat hypersensitivity 2) titrate drug at slower rate on the 
same day  After recovery from immediate hypersensitivity and patient is table, steroid and H1 
blocking agents may be re-dosed  Remaining chemotherapy may be slowly infused with a dilute 
solution, or at a lower rate  If recurrent hypersensitivities occur, the chemotherapy should be 
discontinued and patient should be off-study.  
 
 
6.2.7 Unanticipated Surgical Procedures  
Treatment delay is not required for minor procedures including: 1) removal or insertion of 
central venous catheter, nephrostomy tube or ureteral stent and 2) thoracentesis or paracentesis 
for symptom relief in absence of disease progression.  All unanticipated surgeries performed for 
reasons other than disease progression, treatment should be held > 28 days post-operatively. All 
surgeries should be on the reporting form.  
 
 
 
6.2.8 IP Catheter Complications  
 
IP catheter may be replaced or revised  
IP catheter and ports may be removed without laparotomy.  

If IP catheter fails, and cannot be quickly revised, patients should be taken off-study and 
continue at primary physician’s discretion with IV therapy  
Pain related to IP therapy: (Table C) 
Decrease IP fluid volume down to one liter is allowed  
For persistent grade 3 abdominal pain, patients should not receive further IP therapy, and be 
taken off-study  
Peritonitis due to intestinal perforation related to IP catheter: is situation is suspected, appropriate 
evaluation of catheter for infection and removal should be considered. Cultures of the catheter 
are helpful when infection is suspected  
 
Table C: Abdominal Pain Score  
Grade  
Pain  
0  
None  
No pain  
1  
Mild  
Minimal interference 
with daily activity, lasting 
< 72 hours  
2  
Moderate  
Narcotic analgesia;  
Moderate interference 
with daily activity, lasting 
> 72 hr  
3  
Severe  
Narcotic analgesia;  
Confines pain to bed and 
cause severe interference 
with activity  
6.2.9 Cardiac Toxicity  
Symptomatic bradycardia is not an indication for removal from study or dose modification of 
paclitaxel. Any cardiac ischemia events experienced should prompt patients to be removed from 
study  
6.2.10 Radiation Toxicity  
Potential acute and sub-acute radiation toxicities are fatigue, diarrhea, fecal urgency, nausea, 
vomiting, proctitis, urinary frequency, urgency and dysuria, loss of pubic hair, 
hyperpigmentation and desquamation of skin in the irradiated field, and depression of blood 
counts.  Long-term side effects may include chronic malabsorption, rectal ulcer, bleeding or 
stricture, dysuria, hematuria, bowel obstruction, dryness and shortening of the vagina, 
dyspareunia, vaginal vault necrosis and fistula formation between pelvic tissues.  
 
7.0 MEASUREMENT OF EFFECT  
 
7.1 Antitumor Effect  
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria. For the purposes of this study, patients should be re-evaluated 
prior to each cycle. In addition to a baseline scan, confirmatory scans will also be obtained 
following completion of treatment or last cycle completed.  
Response will be evaluated using the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline version 1.1. Progression free survival (PFS) is defined as date of entry to 
date of reappearance of disease. Site(s) and date of relapse will be recorded. Recurrent disease 

will be defined as pelvic or distant. Pelvic sites will be specified as vaginal or other, and distant 
sites will be specified as to their anatomic location. Relapse should be confirmed by histological 
or cytological evaluation when possible.  
7.2 Definitions  
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment. 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.)  
7.3 Disease Parameters  
Measurable disease. Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters).  
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable.  
Target lesions. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will 
be calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor response.  
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 10 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence or absence 
of each should be noted throughout follow-up. 
  
7.4. Methods for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation. All baseline evaluations 
should be performed as closely as possible to the beginning of treatment and never more than 4 
weeks before the beginning of the treatment. The same method of assessment and the same 
technique should be used to characterize each identified and reported lesion at baseline and 
during follow-up. If there is no measurable disease at the beginning of treatment, the same 
method of assessment will apply only to the follow-up period. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. Non-measurable disease Patients with completely resected 
disease after primary surgery, or with non-measurable disease, will also be included for 

evaluation of response. In these patients, no new growth of measurable disease detected by any 
of the following method will be considered an adequate method of measurement.  
Clinical lesions Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  Conventional CT and MRI 
These should be performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT 
should be performed using a 5 mm contiguous reconstruction algorithm. This applies to tumors 
of the chest, abdomen, and pelvis. Head and neck tumors and those of extremities usually require 
specific protocols.  
PET/CT: At present, the low dose or attenuation correction of CT portion of a combined PET-CT 
is not always of optimal diagnostic quality for use with RECIST measurements. The PET portion 
of the CT introduces additional data which may bias an investigator if it is not routine or serially 
performed.  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at later date, and they are operator dependent; it cannot be guaranteed that 
the same technique and measurement will be taken from one assessment to the next. If there is 
concern about radiation exposure at CT, MRI may be used instead.  
Tumor markers Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. The Gynecologic Cancer Intergroup has developed CA-125 progression 
criteria that have been integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer.  [47] In women with high risk uterine carcinoma, CA-125 levels have been 
shown to correlate with advanced stage and prognosis1, [48, 49].  
Cytology, Histology These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). The cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the 
treatment) and progressive disease.  
 
7.5 Response Criteria  
7.51 Evaluation of Target Lesions  
Complete Response (CR): Disappearance of all target lesions  
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD  
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started or the appearance of one or 
more new lesions  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started. Or sustained 
non measurable disease, if there is no measurable disease at baseline.  
 

7.53 Evaluation of Non-Target Lesions  
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level  
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.  
Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits  
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Although a clear progression of “non-target” lesions 
only is exceptional, the opinion of the treating physician should prevail in such circumstances, 
and the progression status should be confirmed at a later time by the Principal Investigator.  
7.54 Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of the treatment. The best 
overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 
 
 
 
 
 
 
Non-Target 
Lesions  
 
 
 
 
 
 
 
New Lesions  
 
 
 
 
 
 
Overall 
Response  
 
 
 
 
 
 
Best Response 
for this 
Category Also 
Requires:  
CR  
CR  
No  
CR  
>4 wks. 
confirmation  
CR  
Non-CR/Non-
PD  
No  
PR  
>4 wks. 
confirmation  
PR  
Non-PD  
No  
PR  
SD  
Non-PD  
No  
SD  
documented at 
least once >4 
wks. from 
baseline  
PD  
Any  
Yes or No  
PD  
no prior SD, PR 
or CR  
Any  
PD*  
Yes or No  
PD  
Any  
Any  
Yes  
PD  
 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression.  
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 

“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.  
 
7.6 Duration of Response  
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.  
7.7 Progression-Free Survival (PFS)  
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever happens first.  
7.8 Overall Survival (OS)  
OS is defined as the duration of time from start of treatment to time of death or date of last 
contact, whichever happens first.  
 
8.0 DURATION OF STUDY  
 
Patients may continue therapy until disease progression, death (from cancer or other), prohibitive 
toxicity, or until patient decides to withdraw from the study. The duration of study lasts until the 
completion of 6th cycle of IV/IP chemotherapy  
8.1 Duration of Follow Up  
Patients will be followed for every 3 months for the first two years, and every 6 months for three 
years and yearly thereafter, or until death, whichever occurs first. In total, patients will be 
followed for a maximum of 10 years. Testing such as CA-125 or CT scans may be performed at 
discretion of the primary physician once off-study. Patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event.  
8.2 Criteria for Removal from Study  
Patients may voluntarily withdraw from study at any time  
Patients should be discontinued from study if there is clinical evidence of progression of disease, 
or prohibitive toxicity as indicated in section 6.0  
Inability to comply with study requirements  
9.0 Adverse Event Reporting  
An adverse event refers to any adverse medical change from the patient’s baseline (or pre-
treatment) condition which occurs during the course of a clinical study, after starting treatment, 
whether considered treatment related or not.  
Adverse events may be volunteered spontaneously by the patient, or be discovered as a result of 
general questioning by the investigator or by physical examination. Also to be reported is any 
patient requiring hospitalization while on protocol or any grade 4 hematologic or grade 3 or 4 
non-hematologic toxicity. All adverse events occurring during this clinical study must be 
reported to the PI and accurately recorded in the adverse events form within 10 days of the toxic 
event.  
Both chemotherapy and radiation treatment breaks should be noted and the reasons should be 
documented.  
 

9.0 Adverse Event Characteristics  
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting (http://ctep.cancer.gov).  
 
9.1.1 Attribution of the AE:  
Definite – The AE is clearly related to the study treatment.  
Probable – The AE is likely related to the study treatment.  
Possible – The AE may be related to the study treatment.  
Unlikely – The AE is doubtfully related to the study treatment.  
Unrelated – The AE is clearly NOT related to the study treatment.  
9.2 Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions.  
9.3 Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported.  
 
10.0 STUDY PARAMETERS  
 
10.1 Pre Study Evaluation  
This evaluation requires completion within 21 days of registration, unless otherwise described. 
Baseline requirements will consist of a thorough history and physical examination. An ECG < 6 
months prior to registration and laboratory tests will be obtained. Tests include, CBC with 
differential, platelet count, serum chemistry, including electrolytes, creatinine, BUN, glucose, 
magnesium, calcium, albumin, phosphorous, liver function tests, CA-125, and urinalysis.  
Histological documentation of UPSC is required. Pre-study CA125, CT scan of chest, abdomen 
and pelvis, and CXR (not required if CT of the chest is available) will be obtained. 
10.2 Tests during Treatment: Please refer to Appendix A (Study Schedule)  
Weekly: CBC with differential and platelet count  
Every 3 weeks (each cycle): CBC with differential and platelet count electrolytes, BUN, 
creatinine, glucose, magnesium, calcium, phosphorous, albumin, CA125. Every 3 weeks (each 
cycle): Complete review of systems and complete physical examination, including pelvic 
examination, clinical evaluation for ototoxicity and neuropathy. Weight and performance status 
will be documented.  
10.3 End of Study Evaluation  
This evaluation includes a complete history and physical examination and documentation of 
weight and performance status. Laboratory tests include a complete blood count with differential 
and platelet count, electrolytes, BUN, creatinine, glucose, magnesium, calcium, phosphorous, 
albumin, CA125 and urinalysis. CT scan of chest, abdomen and pelvis will be obtained at the 
completion of the entire IP/carboplatin protocol or earlier if indicated.  
10.4 Follow-up  
Patients will be evaluated every 3 months for the first 2 years and every 6 months for the next 3 
years. Evaluation at each visit includes a complete history and physical examination and 
documentation of weight and performance status. Laboratory tests to be performed in this 
follow-up period is up to primary provider’s discretion, but generally include a complete blood 

count with differential and platelet count, electrolytes, BUN, creatinine, glucose, magnesium, 
calcium, phosphorous, albumin, CA125, urinalysis. Surveillance imaging such as CT scan is 
performed up to provider’s discretion, but generally performed annually or earlier if clinically 
indicated. After a total of 5 years, patients will be seen annually.  
10.5 Quality of Life (QoL)  
QOL will be assessed using the validated European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire (EORTC QLQ-c30) version 3.0. To date, more than 2200 
studies using QLQ-C30 have been registered. This 30-item summary score captures the 
dimension of physical well-being, functional well-being, and symptom scales. In addition, the 
ovarian cancer module (QLQ-OV28) questionnaire will supplement the core QLQ-c30 module, 
and is designed for patients with local or advanced disease who receive treatment by surgery 
with or without chemotherapy. It consists of 28 items assessing symptoms addressing peripheral 
neuropathy, chemotherapy side effects, body image and sexuality. Scoring for these 
questionnaires is formalized (Appendix 2) 10.5.1. Quality of Life assessment Intervals Three 
assessment points are recommended:  
Prior to cycle 1  
At completion of IV/IP chemotherapy (or at time of discontinuation from study)  
At completion of the radiation therapy, if given.  
At two years post diagnosis, if feasible.  
 
Adverse Effects Profile: Neutropenia, thrombocytopenia, anemia, alopecia, injection sites 
reactions, radiation recall, rash, nausea, vomiting, mucositis, increased liver enzymes, hepatic 
failure and necrosis, sensory changes, peripheral neuropathy, arthralgia and myalgia, seizures, 
mood alterations, encephalopathy, motor and autonomic neuropathy, hypersensitivity (thought to 
be caused by Cremophor vehicle), atrial arrhythmia, sinus tachycardia and premature beats, 
syncope, hypotension, myocardial infarction, hypertension. Other: fatigue, headaches, light-
headedness, myopathy, elevated serum creatinine, elevated serum triglycerides, and visual 
abnormalities.  
 
Supplier: Commercially available.  
Carboplatin  
Other Names: CBDCA, Paraplatin ®, JM-8, NSC-241240  
Classification: Second generation tetravalent organic platinum compound.  
Mechanism of Action: Like cisplatin, carboplatin produces predominantly inter-strand DNA 
crosslinks rather than DNA-protein crosslinks. Cell-cycle nonspecific.  
Storage and Stability: Intact vials are stored at room temperature protected from light. The 
reconstituted solution is stable for at least 24 hours. When further diluted in glass or polyvinyl 
plastic to a concentration of 500ucg/ml, solutions have the following stability: in normal saline, 8 
hours at 25 C, 24 hours at 5 C; in 5% dextrose (when reconstituted in sterile water), 24 hours at 
25 or 5 C.  
Route of Administration: IP 
NOTE: Avoid the use of aluminum, as carboplatin forms a precipitate.  
Dose Specifics: The dose of carboplatin based on target AUC is calculated by the Calvert 
formula:  
Dose (mg) = AUC x (GFR + 25).  

Where AUC is 6.0 pre-radiation and 5.0 post-radiation and GFR is the calculated renal function 
according to the method of Cockcroft and Gault:  
GFR (ml/min) = 0.85 x {(140-age)/Scr)} x {wt(kg)/72}.  
Please refer to Appendix 3 for Carboplatin calculation form.  
The normal range of serum creatinine is from 0.5 to 1.5 mg/dl. In patients of the same age with 
“normal creatinine”, their carboplatin dosage may vary significantly if one has a value of 0.5 and 
the other has a value of 1.0. Patients of the same age with a creatinine of 0.5 would have a 
considerably higher carboplatin dose (two times) than a patient with the same age with a 
creatinine of 1.0. Therefore, we are using a creatinine of 0.8 mg/dl in the GFR calculation for all 
patients whose creatinine is at or below 0.8 mg/dl. While this may be arbitrary, it minimizes the 
potential significant toxicity associated with a very high carboplatin dosage, yet maintains 
dosages for all patients at therapeutic values.”  
Drug Interactions: Aminoglycosides may potentiate renal toxicity. Forms a precipitate when in 
contact with aluminum.  
Adverse Effects Profile: Neutropenia, thrombocytopenia, anemia, rash, rare alopecia, 
hypersensitivity reactions, nausea, vomiting, increased liver enzymes, nephrotoxicity, elevations 
in serum creatinine and BUN, electrolyte losses (Mg, K, Na, Ca), peripheral neuropathy, rare 
ototoxicity, hypotension, flushing, chest pain, pruritus, bronchospasm, Other: pain, asthenia, flu-
like syndrome.  
Supplier: Commercially available.  
 
8.1 Drug Information:  
 
Paclitaxel  
Other Names: Paclitaxel, NSC 673089  
Classification: Anti-microtubule Agent  
Mechanism of Action: Promotes microtubule assembly and stabilizes tubulin polymers by 
preventing their depolarization, resulting in the formation of extremely stable and nonfunctional 
microtubules, and consequently inhibition of many cell functions.  
Storage and Stability: Vials are stored at room temperature (approximately 25C F). Freezing 
does not adversely affect the product. Solutions diluted to a concentration of 0.3 to 1.2 mg/ml in 
normal saline or 5% dextrose are stable for up to 27 hours when stored at room temperature and 
normal room light. Analyses of solutions filtered through IVEX-2 and IVEX-HP (Abbott) 0.2-
micron filters showed no appreciable loss of potency.  
Route of Administration: Intravenous  
The concentrated solution must be diluted prior to use in normal saline, 5% dextrose and normal 
saline, or 5% dextrose in Ringer’s solution to a concentration of 0.3 to 1.2 mg/ml. In-line 
filtration with a 0.22-micron filter should be used. Solutions exhibit a slight haze, common to all 
products containing nonionic surfactants. Glass, polypropylene, or polyolefin containers and 
non-PVC containing (nitroglycerin) infusion sets should be used. NOTE: Avoid the use of PVC 
bags and infusion sets, due to leaching of DEHP (Plasticizer). Solutions exhibiting excessive 
particulate formation should not be used.  
Dose Specifics: Paclitaxel is given at a dose of 135 mg/m2, infused over one hour and given at a 
dose of 80 mg/m2 on Day 8 of treatment repeated every 3 weeks. In minimally pretreated 
patients, doses up to 200-250 mg/m2 have been used.  

Drug Interactions: Prior administration of cisplatin may increase myelosuppression because of 
reduced clearance of paclitaxel. Ketoconazole may inhibit paclitaxel metabolism, based on in 
vitro data.  
 
 
12.0 STATISTICAL CONSIDERATIONS  
 
The primary objectives of this pilot Phase II study are to determine the tolerability and feasibility 
of the proposed regimen. In patients with advanced ovarian cancer who received the same types 
and doses of IV/IP chemotherapy in a similar clinical trial (GOG 172), discontinuation of IP 
therapy was most commonly due to: 1) catheter complications; 2) intolerance of platinum with 
nausea, renal dysfunction and electrolyte disturbances; 3) intolerance to the abdominal distention 
from IP infusion[50]. Neuropathy also occurred in some, but was generally not evident until the 
later cycles. Generally, when subjects are unable to tolerate IP chemotherapy, they receive the 
remainder of their cycles IV. Since advanced endometrial cancer patients have generally more 
bulky disease than ovarian cancer patients and are less likely to have an immediate response, it is 
expected that there will be subjects on this trial who will not be able to complete this therapy.  
The degree of tolerability will be estimated by the proportion of participants who complete 6 
treatment cycles of IP-carboplatin. A total of 17 patients will be enrolled into the study. An early 
stopping rule for lack of tolerability will be implemented as follows, based on Simon’s Minimax 
two-stage design. After the first 13 patients have been enrolled and evaluated, the trial will be 
terminated early if fewer than 5 patients tolerated the treatment. If 5 or more patients are 
observed to complete the regimen, the trial will continue until a total of 17 patients have been 
evaluated. At the end of the trial, the treatment will be considered tolerable and worthy of further 
study if 9 or more patients completed the regimen out of 17 patients.  The target tolerability rate 
is assumed to be 60%. The design specified above has the following operating characteristics. 
The probability of accepting the treatment for further study if the tolerability rate is unacceptably 
low (< 40%) is at most 20%. In contrast, there is an 80% probability of accepting the treatment 
for further study if the tolerability rate is at least 60%. The expected sample size is 15.6 subjects. 
At the end of the study, the proportion of patients who tolerated the therapy will be estimated, 
along with corresponding 95% confidence intervals. Reasons for discontinuation of therapy will 
be categorized and summarized by computing frequencies. Response will be evaluated using an 
endpoint of one-year progression-free survival. The proportion of responders at one year will be 
estimated with the Kaplan-Meier method. Surrogate endpoint biomarkers including estrogen, 
progesterone, and Her2/neu receptor status will be correlated with progression-free survival 
using the Cox Proportional Hazards model, provided the availability of a sufficient number of 
events.  
Based on our tumor board reporting, the accrual is expected to be at most 1 every other month, 
for a total accrual period of about twenty four months. Follow up is a minimum of one year after 
the last patient is accrued in order to assess response. Therefore, total study time is expected to 
be at least 40 months.  
 
 
 
13.0 DATA SAFETY MONITORING PLAN  
 

This study will be added to the CSSRC for internal study review. All adverse events will be 
forwarded to the committee and monitored on a monthly basis  
 
14.0 RECORDS TO BE KEPT  
 
Forms to be submitted:  
ECOG Master On-Study Form Within one week of registration  
Pathology Report Within one week of registration  
ECOG CTC Flow Sheet Baseline within one week of registration.  
On Treatment: Every month  
Off Treatment: See Follow-up  
ECOG Follow-Up Form Every month while on study  
At completion of treatment  
Every 3 months if < 2years from study entry  
Adverse Reaction (ADR)  
Within 10 days of reportable toxic event  
 
15.0 PATIENT CONSENT AND PEER JUDGEMENT  
 
All institutional, state, and national guidelines concerning informed consent and peer review will 
be observed.  
 
 
16.0 MINORITIES AND WOMEN STATEMENT  
 
This study will be open to patients undergoing treatment at Northwell Health.  
Although distributions may vary by disease type, our recruitment procedures have been 
developed to enroll patients who are representative of the target population.  
 
17.0 ETHICAL AND REGULATORY CONSIDERATIONS  
All institutional, NCI and Federal regulations concerning the Informed Consent form will be 
fulfilled. Annual reports will be provided to the IRB.  
 
 
18.0 ELIGIBILITY CHECKLIST  
 
Histological/cytologically documented primary uterine serous carcinoma.  Surgical staging to 
include total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, 
peritoneal washings, and lymph node sampling or surgical cytoreduction to include total 
abdominal hysterectomy, bilateral salpingo-oophorectomy, debulking of intraperitoneal tumor.   
Residual disease after primary surgery ≤ 1 cm 
Age > 18 years. 
ECOG performance status of ≤ 2.  
Written voluntary informed consent.  
Patient has no impairment of renal, hepatic or hematologic function as defined in section 3.2  
Patient has not received myelo-suppressive therapy in the past 3 weeks. 

Patient does not have severe or uncontrolled concurrent medical disease (eg. uncontrolled 
diabetes, angina, myocardial infarction within 6 month, congestive heart failure, etc.)  
Patients has no dementia or altered mental status that would prohibit the give and understanding 
of informed consent at the time of study entry.  
 
Patient Name ________________________________  
 
Patient MR# _________________________  
 
Treating Physician ___________________________  
 
Principal Investigator (Signature)__________________  
 
 
 
APPENDIX 
1: STUDY 
SCHEDULE 
Parameter  
Pre-study  
(within 21 d)  
D1 of Each 
cycle  
D8of each 
cycle  
Completion 
of Study  
Follow-up 
Visit6  
Medical History 
& Physical 
Exam1  
X  
X  
X  
X7  
Informed Consent  
X  
X  
Weight, 
Height1  
X  
X  
X  
X  
X7  
Performance 
Status1  
X  
X  
X  
X7  
Vital Signs  
X  
X  
X7  
CBC with 
differential, 
platelets1  
X  
X  
X  
X  
X7  
Serum 
Chemistry1,2  
X  
X  
X  
X7  
Urinalysis1  
X  
X  
X7  
CA-1251  
X  
X  
X  
X7  
EKG3  
X  
X  
Serum Pregnancy Test4  
X  
Radiologic 
Evaluation5  
X  
X  
X7  
Adverse Event 
Evaluation1  
X  
X  
X  
X7  
QoL survey8  
X  
X  
 
1. May be performed within 7 days of start of new cycle  

2. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium.  
3. EKG within 6 months prior to registration is acceptable  
4. Women of child bearing potential  
5. CT scan including chest, abdomen and pelvis, with or without PO/IV contrast, or PET/CT  
6. Recommend follow up visit every 3 months for two years, then every 6 months for three 
years, then yearly thereafter.  
7. As clinically indicated.  
8. QoL survey at four time points: beginning of study, after completion of chemotherapy, and 
completion of radiation (if given radiation as judged by primary physician), and at two years 
post diagnosis, if feasible  
 
 
 
 
APPENDIX 2: See Attached  
 
APPENDIX 3: Carboplatin Calculation Worksheet  
 
CARBOPLATIN DOSE CALCULATION INSTRUCTIONS  
 
1) The Cockcroft-Gault formula will be used in GOG trials (not the Jelliffe formula).  
2) Conversion of IDMS creatinine levels to “non-IDMS” values will not be permitted.  
3) The carboplatin calculation tool on the GOG website has been updated. A legacy carboplatin 
calculator (using the Jelliffe formula and IDMS to “non-IDMS” conversion) is also available, if 
needed for dose modifications (see below).  
 
 
Dosing of Carboplatin:  
The carboplatin dose will be calculated to reach a target area under the curve (AUC) according 
to the Calvert formula using an estimated glomerular filtration rate (GFR) from the Cockcroft-
Gault formula.  
The initial dose of carboplatin must be calculated using GFR. In the absence of renal toxicity 
greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring 
dose modification, the dose of carboplatin will not need to be recalculated for subsequent 
cycles, but will be subject to dose modification for toxicity as noted in the protocol.  
Carboplatin doses will be based on the subject’s weight at baseline and will remain the same 
throughout the study. However, the doses will be recalculated if the patient has a weight change 
of greater than or equal to 10% from baseline.  
In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dl. If a patient is currently 
being dosed using a creatinine value less than 0.7 mg/dl, adjust dose with next planned 
treatment. 

For trials where patients enter and are treated within less than or equal to 12 weeks of surgery: If 
a more appropriate (higher) baseline creatinine value is available from the pre-operative period 
(within 4 weeks of surgery date), that value may also be used for the initial estimation of GFR.  
CALVERT FORMULA: Carboplatin dose (mg) = target AUC x (GFR + 25) NOTE: the GFR 
used in the Calvert formula should not exceed 125 ml/min. Maximum carboplatin dose (mg) = 
target AUC (mg/ml x min) x 150 ml/min. The maximum allowed doses of carboplatin are: 
AUC 6 = 900 mg  
GOG-0262/ACRIN 6695 
AUC 5 = 750 mg  
AUC 4 = 600 mg 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (ml/min) is calculated by the method of 
Cockcroft-Gault using the following formula:  
Creatinine Clearance (mL/min) = [140-Age (years)] x Weight (kg) x 0.85 72 x serum 
creatinine (mg/dl)  
Notes: 1) Weight in kilograms (kg):  
a. Body Mass Index (BMI) should be calculated for each patient. A BMI calculator is available at 
the following link: http://www.nhlbisupport.com/bmi/  
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25. c. 
Adjusted weight should be used for estimation of GFR for patients with BMI of greater than or 
equal to 25. 
 d. Adjusted weight calculation:  
Ideal weight (kg) = (Height (cm)/2.54) – 60) x 2.3) + 45.5  
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight  
e. If a patient with BMI of greater than or equal to 25 is currently being dosed using actual 
weight, adjust dose with next planned treatment. 2) The Cockcroft-Gault formula above is 
specifically for women (it includes the 0.85 factor).  
 
 
At the time of a dose modification for toxicity:  
If the creatinine at the time of a dose modification is lower than the creatinine used to calculate 
the previous dose, use the previous (higher) creatinine; if the creatinine at the time of a dose 
modification is higher than the creatinine used to calculate the previous dose, use the current 
(higher) creatinine. This will ensure that the patient is actually receiving a dose reduction. 2) If 
the dose of carboplatin (mg) at the time of dose modification, is higher than the previous dose 
due to the use of the Cockcroft-Gault formula [when the previous dose was calculated  
 
 
 
 

APPENDIX 4: FIGO Staging: Endometrial Cancer Stage  
Ib  
Tumor confined to the corpus uteri.  
IAb  
No or less than half myometrial invasion.  
IBb  
Invasion equal to or more than half of the 
myometrium.  
IIb  
Tumor invades cervical stroma but does 
not extend beyond the uterus. 
IIIb  
Local and/or regional spread of the tumor.  
IIIAb  
Tumor invades the serosa of the corpus 
uteri and/or adnexa.  
IIIBb  
Vaginal and/or parametrial involvement.  
IIICb  
Metastases to pelvic and/or para-aortic 
lymph nodes. 
IIIC1b  
Positive pelvic nodes.  
IIIC2b  
Positive para-aortic lymph nodes with or 
without positive pelvic lymph nodes.  
IVb  
Tumor invades bladder and/or bowel 
mucosa, and/or distant metastases.  
IVAb  
Tumor invasion of bladder and/or bowel 
mucosa.  
IVBb  
Distant metastases, including intra-
abdominal metastases and/or inguinal 
lymph nodes.  
 
aAdapted from FIGO Committee on Gynecologic Oncology.[1]  
bEither G1, G2, or G3 (G = grade).  
cEndocervical glandular involvement only should be considered as stage I and no longer as 
stage II.  
dPositive cytology has to be reported separately without changing the stage.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

APPENDIX 5: Abbreviation List  
 
QoL                                                       
Quality  of Life        
 
EORTC  
European Organization for 
Research and Treatment of 
Cancer  
QLQ  
Quality of Life Questionnaire  
FIGO  
International Federation of 
Gynecology and Obstetrics  
IV / IP  
Intravenous / Intraperitoneal  
Fx  
Fraction  
IMRT  
Intensity Modulated Radiation 
Therapy  
USC  
Uterine Serous Carcinoma  
HDR  
High Dose Radiation  
Gy  
Gray  
GOG  
Gynecologic Oncology Group  
RT  
Radiation therapy  
AUC  
Area Under Curve  
PFS  
Progression Free Survival  
EBRT  
External Beam Radiation Therapy  
NCI  
National Cancer Institute  
ECOG  
Eastern Cooperative Oncology 
Group  
ANC  
Absolute Neutrophil Count  
GFR  
Glomerular Filtration Rate  
CT  
Computed Tomography  
PO  
Per Os (by mouth)  
Fr  
French  
AP  
Anterior Posterior  
WBC  
White Blood Cells  
G-CSF  
Granulocyte colony – stimulating 
factor  
PEG_filgrastim  
Pegylated - filgrastim  
GM-CSF  
Granulocyte macrophage colony 
stimulating factor  
DLT  
Dose Limiting Toxicity  
PLT  
Platelet  
AST  
Aspartine Aminotransferase  
ALT  
Alanine Aminotransferase  
RECIST  
Response Evaluation Criteria in 
Solid Tumors  
MRI  
Magnetic Resonance Imaging  
LD  
Longest Diameter  
PET  
Positron Emission Tomography  

CR  
Complete Response  
PR  
Partial Response  
PD  
Progression Disease  
SD  
Stable Disease  
BUN  
Mg  
Magnesium  
K  
Potassium  
Na  
Sodium  
Ca  
Calcium  
19.0 References 
 
1. 
Abeler, V.M., et al., Clear cell carcinoma of the endometrium. Prognosis and metastatic 
pattern. Cancer, 1996. 78(8): p. 1740-7. 
2. 
Gupta, D., et al., Performance of serum CA125 as a prognostic biomarker in patients 
with uterine papillary serous carcinoma. Int J Gynecol Cancer, 2011. 21(3): p. 529-34. 
3. 
Major, F.J., et al., Prognostic factors in early-stage uterine sarcoma. A Gynecologic 
Oncology Group study. Cancer, 1993. 71(4 Suppl): p. 1702-9. 
4. 
Goff, B.A., et al., Uterine papillary serous carcinoma: patterns of metastatic spread. 
Gynecol Oncol, 1994. 54(3): p. 264-8. 
5. 
Hendrickson, M., et al., Uterine papillary serous carcinoma: a highly malignant form of 
endometrial adenocarcinoma. Am J Surg Pathol, 1982. 6(2): p. 93-108. 
6. 
Kato, D.T., et al., Uterine papillary serous carcinoma (UPSC): a clinicopathologic study 
of 30 cases. Gynecol Oncol, 1995. 59(3): p. 384-9. 
7. 
O'Hanlan, K.A., et al., Virulence of papillary endometrial carcinoma. Gynecol Oncol, 
1990. 37(1): p. 112-9. 
8. 
Sherman, M.E. and S.S. Devesa, Analysis of racial differences in incidence, survival, and 
mortality for malignant tumors of the uterine corpus. Cancer, 2003. 98(1): p. 176-86. 
9. 
Aalders, J., et al., Postoperative external irradiation and prognostic parameters in stage I 
endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet 
Gynecol, 1980. 56(4): p. 419-27. 
10. 
Calais, G., et al., Preoperative or postoperative brachytherapy for patients with 
endometrial carcinoma stage I and II. Int J Radiat Oncol Biol Phys, 1990. 19(3): p. 523-
7. 
11. 
Carey, M.S., et al., Good outcome associated with a standardized treatment protocol 
using selective postoperative radiation in patients with clinical stage I adenocarcinoma 
of the endometrium. Gynecol Oncol, 1995. 57(2): p. 138-44. 
12. 
Elliott, P., et al., The efficacy of postoperative vaginal irradiation in preventing vaginal 
recurrence in endometrial cancer. Int J Gynecol Cancer, 1994. 4(2): p. 84-93. 
13. 
Greven, K.M., et al., Analysis of failure patterns in stage III endometrial carcinoma and 
therapeutic implications. Int J Radiat Oncol Biol Phys, 1989. 17(1): p. 35-9. 
14. 
Greven, K.M., et al., Pathologic stage III endometrial carcinoma. Prognostic factors and 
patterns of recurrence. Cancer, 1993. 71(11): p. 3697-702. 
15. 
Greven, K.M., et al., Patterns of failure in patients with stage I, grade 3 carcinoma of the 
endometrium. Int J Radiat Oncol Biol Phys, 1990. 19(3): p. 529-34. 

16. 
Grigsby, P.W., et al., Stage II carcinoma of the endometrium: results of therapy and 
prognostic factors. Int J Radiat Oncol Biol Phys, 1985. 11(11): p. 1915-23. 
17. 
Lanciano, R.M., et al., Influence of grade, histologic subtype, and timing of radiotherapy 
on outcome among patients with stage II carcinoma of the endometrium. Gynecol Oncol, 
1990. 39(3): p. 368-73. 
18. 
Mayr, N.A., et al., Postoperative radiation therapy in clinical stage I endometrial cancer: 
corpus, cervical, and lower uterine segment involvement--patterns of failure. Radiology, 
1995. 196(2): p. 323-8. 
19. 
Morrow, C.P., et al., Relationship between surgical-pathological risk factors and 
outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic 
Oncology Group study. Gynecol Oncol, 1991. 40(1): p. 55-65. 
20. 
Randall, M.E., et al., Role of intracavitary cuff boost after adjuvant external irradiation 
in early endometrial carcinoma. Int J Radiat Oncol Biol Phys, 1990. 19(1): p. 49-54. 
21. 
Sutton, G., et al., Whole abdominal radiotherapy in the adjuvant treatment of patients 
with stage III and IV endometrial cancer: a gynecologic oncology group study. Gynecol 
Oncol, 2005. 97(3): p. 755-63. 
22. 
Sutton, G., et al., Adjuvant whole abdominal irradiation in clinical stages I and II 
papillary serous or clear cell carcinoma of the endometrium: a phase II study of the 
Gynecologic Oncology Group. Gynecol Oncol, 2006. 100(2): p. 349-54. 
23. 
Mackillop, W.J. and J.F. Pringle, Stage III endometrial carcinoma. A review of 90 cases. 
Cancer, 1985. 56(10): p. 2519-23. 
24. 
Martinez, A., et al., Results of whole abdominopelvic irradiation with nodal boost for 
patients with endometrial cancer at high risk of failure in the peritoneal cavity. A 
prospective clinical trial at the Mayo Clinic. Hematol Oncol Clin North Am, 1988. 2(3): 
p. 431-46. 
25. 
Smith, R.S., et al., Treatment of high-risk uterine cancer with whole abdominopelvic 
radiation therapy. Int J Radiat Oncol Biol Phys, 2000. 48(3): p. 767-78. 
26. 
Randall, M.E., 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(1): p. 36-44. 
27. 
Thigpen, J.T., et al., Phase III trial of doxorubicin with or without cisplatin in advanced 
endometrial carcinoma: a gynecologic oncology group study. J Clin Oncol, 2004. 22(19): 
p. 3902-8. 
28. 
Ball, H.G., et al., A phase II trial of paclitaxel in patients with advanced or recurrent 
adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol 
Oncol, 1996. 62(2): p. 278-81. 
29. 
Fleming, G.F., et al., Phase III trial of doxorubicin plus cisplatin with or without 
paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology 
Group Study. J Clin Oncol, 2004. 22(11): p. 2159-66. 
30. 
Moore, K.N. and A.N. Fader, Uterine papillary serous carcinoma. Clin Obstet Gynecol, 
2011. 54(2): p. 278-91. 
31. 
Geller, M.A., et al., A single institution experience using sequential multi-modality 
adjuvant chemotherapy and radiation in the "sandwich" method for high risk endometrial 
carcinoma. Gynecol Oncol, 2010. 118(1): p. 19-23. 

32. 
Lupe, K., et al., Adjuvant carboplatin and paclitaxel chemotherapy interposed with 
involved field radiation for advanced endometrial cancer. Gynecol Oncol, 2009. 114(1): 
p. 94-8. 
33. 
Obermair, A., et al., Prospective, non-randomized phase 2 clinical trial of carboplatin 
plus paclitaxel with sequential radical pelvic radiotherapy for uterine papillary serous 
carcinoma. Gynecol Oncol, 2011. 120(2): p. 179-84. 
34. 
Holman, L.L., et al., Factors prognostic of survival in advanced-stage uterine serous 
carcinoma. Gynecol Oncol, 2017. 146(1): p. 27-33. 
35. 
Einstein, M.H., et al., Phase II trial of adjuvant pelvic radiation "sandwiched" between 
combination paclitaxel and carboplatin in women with uterine papillary serous 
carcinoma. Gynecol Oncol, 2012. 124(1): p. 21-5. 
36. 
Armstrong, D.K., et al., Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N 
Engl J Med, 2006. 354(1): p. 34-43. 
37. 
Fujiwara, K., et al., Phase II study of intraperitoneal carboplatin with intravenous 
paclitaxel in patients with suboptimal residual epithelial ovarian or primary peritoneal 
cancer: a Sankai Gynecology Cancer Study Group Study. Int J Gynecol Cancer, 2009. 
19(5): p. 834-7. 
38. 
Fujiwara, K., et al., First-line intraperitoneal carboplatin-based chemotherapy for 165 
patients with epithelial ovarian carcinoma: results of long-term follow-up. Gynecol 
Oncol, 2003. 90(3): p. 637-43. 
39. 
Katsumata, N., et al., Dose-dense paclitaxel once a week in combination with carboplatin 
every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised 
controlled trial. Lancet, 2009. 374(9698): p. 1331-8. 
40. 
Pignata, S., et al., Carboplatin plus paclitaxel once a week versus every 3 weeks in 
patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, 
phase 3 trial. Lancet Oncol, 2014. 15(4): p. 396-405. 
41. 
Sparano, J.A., et al., Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl 
J Med, 2008. 358(16): p. 1663-71. 
42. 
McMeekin, D.S., et al., A phase I study of IV doxorubicin plus intraperitoneal (IP) 
paclitaxel and IV or IP cisplatin in endometrial cancer patients at high risk for peritoneal 
failure (GOG 9920): an NRG Oncology/Gynecologic Oncology Group study. Gynecol 
Oncol, 2015. 138(1): p. 36-40. 
43. 
Ozols, R.F., et al., Phase III trial of carboplatin and paclitaxel compared with cisplatin 
and paclitaxel in patients with optimally resected stage III ovarian cancer: a 
Gynecologic Oncology Group study. J Clin Oncol, 2003. 21(17): p. 3194-200. 
44. 
Bell, J., et al., Randomized phase III trial of three versus six cycles of adjuvant 
carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynecologic 
Oncology Group study. Gynecol Oncol, 2006. 102(3): p. 432-9. 
45. 
Colombo, N., et al., International Collaborative Ovarian Neoplasm trial 1: a randomized 
trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer 
Inst, 2003. 95(2): p. 125-32. 
46. 
Parmar, M.K., et al., Paclitaxel plus platinum-based chemotherapy versus conventional 
platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-
OVAR-2.2 trial. Lancet, 2003. 361(9375): p. 2099-106. 
47. 
Duffy, M.J., et al., CA125 in ovarian cancer: European Group on Tumor Markers 
guidelines for clinical use. Int J Gynecol Cancer, 2005. 15(5): p. 679-91. 

48. 
Huang, G.S., et al., Serum CA125 predicts extrauterine disease and survival in uterine 
carcinosarcoma. Gynecol Oncol, 2007. 107(3): p. 513-7. 
49. 
Olawaiye, A.B., et al., Utility of pre-operative serum CA-125 in the management of 
uterine papillary serous carcinoma. Gynecol Oncol, 2008. 110(3): p. 293-8. 
50. 
Wenzel, L.B., et al., Health-related quality of life during and after intraperitoneal versus 
intravenous chemotherapy for optimally debulked ovarian cancer: a Gynecologic 
Oncology Group Study. J Clin Oncol, 2007. 25(4): p. 437-43.