Clinical trial NCT01367301
Conditions: Stage IA Uterine Sarcoma Stage IB Uterine Sarcoma Stage IC Uterine Sarcoma Stage IIA Uterine Sarcoma Stage IIB Uterine Sarcoma Stage IIIA Uterine Sarcoma Stage IIIB Uterine Sarcoma Stage IIIC Uterine Sarcoma Stage IVA Uterine Sarcoma Stage IVB Uterine Sarcoma Uterine Carcinosarcoma
Sponsor: Albert Einstein College of Medicine
Start date: 2011-07-08; Completion date: 2018-08-15
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies radiation therapy, paclitaxel, and carboplatin in treating patients with uterine cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or stopping them from dividing. Giving radiation with chemotherapy may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the one year recurrence-free survival in patients with uterine carcinosarcoma treated with "sandwich" therapy-including defining the patterns of recurrence in patients with carcinosarcoma who were treated with this regimen.

II. To evaluate the toxicity and tolerability of pelvic radiation "sandwiched" between cycles of paclitaxel/carboplatin chemotherapy in patients with uterine carcinosarcoma.

III. To correlate surrogate endpoint biomarkers with progression-free survival and prognosis.

OUTLINE:

CHEMOTHERAPY (weeks 1-9, 14-22): Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 courses during weeks 1-9 and 14-22.

RADIATION THERAPY (weeks 8-16): Patients undergo external beam pelvic radiation therapy once a day, 5 days a week for 5 weeks during weeks 8-13. Patients then undergo high dose radiation (HDR) brachytherapy or intensity-modulated radiation therapy (IMRT) once weekly during weeks 14-16.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Arms: arm 1: CHEMOTHERAPY (weeks 1-9, 14-22): Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 courses during weeks 1-9 and 14-22.

RADIATION THERAPY (weeks 8-16): Patients undergo external beam pelvic radiation therapy once a day, 5 days a week for 5 weeks during weeks 8-13. Patients then undergo HDR brachytherapy or IMRT once weekly during weeks 14-16.
Interventions: intervention 1: paclitaxel intervention 2: carboplatin intervention 3: external beam radiation therapy intervention 4: brachytherapy intervention 5: intensity-modulated radiation therapy intervention 6: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo external beam radiation therapy intervention 4: Undergo HDR brachytherapy intervention 5: Undergo IMRT intervention 6: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
A Pilot Trial of Radiation Therapy “Sandwiched” between Paclitaxel and Carboplatin 
in Patients with Uterine Carcinosarcoma 
 
 
Principal Investigator: 
Akiva Novetsky, M.D. 
Division of Gynecologic Oncology 
Department of Obstetrics & Gynecology and Women’s Health 
1695 Eastchester Rd., Suite 601 
Bronx, NY 10461 
Phone: 718-405-8082 
Fax: 718-405-8087 
Email: ANOVETSK@montefiore.org 
 
Co-Investigators: 
Gary L. Goldberg, M.D. 
Harriet Smith, M.D. 
Dennis Yi-Shin Kuo, M.D. 
Gloria S. Huang, M.D. 
David Smotkin, M.D. 
Nicole Nevadunsky, M.D. 
 
Radiation Oncology 
Shalom Kalnicki, M.D. 
Keyur Mehta, M.D. 
Madhur Garg, M.D. 
 
Statistics 
Xiaonan (Nan) Xue, PhD 
 
Chemotherapy Nurses 
Lois Taylor-Pinnock, RN 
Eileen Burke, RN 
Amiee Rogado, RN 
Yokasta Garcia, RN   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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INDEX 
 
SCHEMA 
 
1.0 
BACKGROUND 
2.0 
OBJECTIVES 
3.0 
PATIENT SELECTION 
4.0 
REGISTRATION PROCEDURES 
5.0 
TREATMENT PLAN 
6.0 
MEASUREMENT OF EFFECT 
7.0 
STUDY PARAMETERS 
8.0 
DRUG FORMULATION AND PROCUREMENT 
9.0 
STATISTICAL CONSIDERATIONS 
10.0 
COLLECTION PROCEDURES 
11.0 
RECORDS TO BE KEPT 
12.0 
PATIENT CONSENT AND PEER JUDGEMENT 
13.0 
MINORITIES AND WOMEN STATEMENT 
14.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
15.0 
ELIGIBILITY CHECKLIST 
16.0 
REFERENCES 
APPENDIX 
1.  Study Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SCHEMA   
 
 
Weeks 1-9 
Paclitaxel 175mg/m2/3 hour & Carboplatin (AUC=6.0) 
Repeat q 21 days x 3 cycles 
 
 
 
 
 
Weeks 8-13 
Pelvic and Para-Aortic Radiation 6MV Photon Beam Energy 
1.8 Gy Dose/Fx 
Total Dose 45Gy 
 
 
 
 
 
Weeks 14, 15, 16 
High Dose Radiation (HDR) x3, or IMRT where appropriate 
Nucleotron Microselection Afterloading Technique 
5 Gy to 0.5cm Depth from the Vaginal Cylinder Surface 
Total Dose 15 Gy 
 
 
 
 
 
Weeks 14-22 
Paclitaxel 175mg/m2/3 hour & Carboplatin (AUC=5.0) 
Repeat q 21 days x 3 cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.0 
BACKGROUND  
 
Uterine carcinosarcomas represent approximately 4% of primary uterine malignancies 
[1].  However, our rates in the Bronx are about double the national rate likely due to a 
number of factors including the referral patterns and the ethnic and racial diversity of 
the community we serve at Montefiore Medical Center.  Carcinosarcoma is an 
aggressive uterine tumor with a poor prognosis and a recurrence rate of 53% [2].  
Sites of failure include pelvic and extrapelvic with most patients developing 
extrapelvic disease [3].  Pelvic radiation decreases the risk of pelvic recurrence, but 
has not been shown to improve overall survival [4, 5] secondary to extrapelvic 
recurrences and the hematogenous route of metastasis [3].  Chemotherapy agents 
demonstrating response in recurrent carcinosarcoma include adriamycin, cisplatin, 
ifosfamide and paclitaxel [6-10].  Combination chemotherapy has been shown to 
provide an improvement in response rate but with increased toxicity.  In one GOG 
study, the combination of ifosfamide and cisplatin was compared to ifosfamide alone 
in recurrent carcinosarcoma.  There was a 54% response rate with the doublet versus 
36% with single agent cisplatin, but no difference in overall survival and a 
significantly increased rate of grade 3-4 toxicity in the doublet arm [10].  The 
combination of paclitaxel with ifosfamide was also studied by the GOG and there was 
an improved overall survival, 14 months with the doublet versus 8 months with 
ifosfamide alone.  The response rate in the combination group was 45% compared to 
29% with ifosfamide alone [11].  Neurotoxicity was considerably worse with the 
doublet chemotherapy (8% versus 30%).    
 
The combination of paclitaxel and carboplatin has recently been studied for recurrent 
uterine carcinosarcoma.  A retrospective review of 6 patients (five with primary 
disease) with advanced or recurrent carcinosarcoma, with no prior adjuvant treatment, 
that were treated with paclitaxel and carboplatin showed a response rate of 80%, a 
median progression free interval of 18 months and a median overall survival of 25 
months [12].  This was one of the first studies that documented efficacy in an adjuvant 
setting with paclitaxel and carboplatin in carcinosarcoma.  In a separate study, similar 
response rates were noted in a prospective phase II trial evaluating carboplatin and 
paclitaxel in advanced or recurrent carcinosarcoma.  Patients that were treated with 
this regimen in the adjuvant setting had a median progression free interval of 15.8 
months and median overall survival of 20.2 months.  The overall response rate was 
64% [13].  Another study showed similar response rates (60% in newly diagnosed 
patients and 55% in recurrent disease) of carboplatin and paclitaxel in carcinosarcoma 
when compared to the combination of ifosfamide and paclitaxel but with better 
tolerability and more convenience due to outpatient administration, unlike ifosfamide 
which requires the addition of Mesna and often inpatient administration [14].  This 
study also included patients that had prior radiation therapy. In GOG 232, the 
combination of paclitaxel and carboplatin was given to patients with advanced stage 
or recurrent carcinosarcoma who had not had previous chemotherapy and had 
measurable disease.  46 patients were eligible, 65% had primary disease, 35% had 
recurrent disease, and 33% had prior radiation therapy.  59% of patients completed 6 
or more cycles.  The overall response rate was 54% which is comparable to the other 
studies using carboplatin and paclitaxel in uterine carcinosarcoma.  The median 
progression free survival was 7.6 months and overall survival was 14.7 months which 
is comparable to ifosfamide and paclitaxel.  The toxicity profile was more favorable 
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with the carboplatin and paclitaxel combination [15]. 
 
 
Use of radiotherapy alone does not control extrapelvic recurrences.  In one study, 
patients with stage I or II carcinosarcoma were treated with surgery versus surgery 
followed by radiotherapy.  There was a trend towards fewer pelvic recurrences in the 
patients who received whole pelvic radiotherapy compared to those who did not 
(p=0.09) [4].  Other studies showed a statistically significant lower rate of pelvic 
recurrence in patients who received radiotherapy compared to those who did not, 28% 
versus 48% (p=0.0002) [16] and 3% versus 55% (p<0.0001) [17].  In a separate study 
evaluating the impact of multi-modal therapy on survival in patients with uterine 
carcinosarcoma, there was noted a longer median disease specific survival (p<0.001) 
and disease free survival (p=0.02) in patients that received a combination of 
chemotherapy and radiotherapy [18]. 
 
 
Multiple studies have demonstrated a response of carcinosarcoma to carboplatin and 
paclitaxel as well as the role of adjuvant radiotherapy in improvement in local control.  
We have had considerable experience here at Montefiore combining sequenced 
radiation therapy sandwiched with chemotherapy before and after radiation therapy 
for both carcinosarcoma and uterine papillary serous carcinoma [19, 20].   In our most 
recent carcinosarcoma trial, 27 patients with surgical stage 1-4 uterine 
carcinosarcoma, without evidence of gross disease, were treated with adjuvant 
ifosfamide/cisplatin or ifosfamide for three cycles, then received pelvic external beam 
radiotherapy and brachytherapy followed by three more cycles of ifosfamide/cisplatin 
or ifosfamide.  The two year disease free survival for stage I patients was 18.75 
months and for stages II-IV was 15.81 months [20].  Similar to a GOG trial in the 
recurrent setting, in our adjuvant trial, toxicity was increased in patients who received 
ifosfamide with cisplatin without added efficacy [10].  Thus, in the last cohort of this 
trial, we dropped the cisplatin from the regimen because it was adding toxicity 
without benefit.  In our uterine papillary serous carcinoma “sandwich” trial, 30 
patients with surgical stages I-IV, without evidence of gross residual disease received 
adjuvant paclitaxel/platinum for three cycles, followed by external beam pelvic 
radiotherapy and brachytherapy, and then three more cycles of paclitaxel/platinum.  
The three year disease free survival for stage I/II patients was 69% and for stage 
III/IV patients was 54%.  29 out of the 30 patients completed the protocol with grade 
3/4 neutropenia occurring in 42% of cycles. 6 out of 177 cycles were delayed 1 week 
for neutropenia [19].  Both in-house trials of sequenced chemotherapy and radiation 
therapy resulted in higher than expected survival in the adjuvant setting.  Due to the 
recent reports of efficacy of paclitaxel and carboplatin in recurrent carcinosarcoma, 
this pilot protocol is designed to determine the toxicity and clinical benefit of 
radiation therapy “sandwiched” between three cycles of paclitaxel and carboplatin 
before and after radiation therapy.   
 
2.0 
OBJECTIVES 
 
2.1 
To assess the one year recurrence-free survival in patients with uterine 
carcinosarcoma treated with “sandwich” therapy-including defining the 
patterns of recurrence in patients with carcinosarcoma who were treated with 
this regimen. 
 
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2.2 
To evaluate the toxicity and tolerability of pelvic radiation “sandwiched” 
between cycles of paclitaxel/carboplatin chemotherapy in patients with uterine 
carcinosarcoma: [paclitaxel/carboplatin (x 3 cycles)* radiation therapy* 
paclitaxel/ carboplatin (x 3 cycles)].  
 
2.3      To correlate surrogate endpoint biomarkers with progression-free survival and 
prognosis. 
 
3.0     PATIENT SELECTION 
 
 3.1  Inclusion Criteria 
 
 Patients may be included in the study if all of the following criteria are met: 
 
 
a. Histologically documented uterine carcinosarcoma with no visible 
residual disease. 
 
b.  Surgical staging to include total abdominal hysterectomy, bilateral 
salpingo-     oophorectomy, peritoneal washings, and lymph node 
samplings. 
 
c.   Patients must be entered no more than 12 weeks post operatively 
 
 
d. Age > 18 years. 
 
 
e. ECOG performance status of < 2. 
 
 
f. Written voluntary informed consent. 
 
 
3.2 
  Exclusion Criteria 
 
Exclusion from the study will be required if: 
 
1.  Patient has impairment of hepatic, renal or hematologic function as defined by 
the following baseline laboratory values: 
 
 
 
a. Serum SGOT and /or SGPT > 2.5 times the institutional upper limit of 
normal 
 
 
b. Total serum bilirubin > 1.5 mg/dl 
 
 
c. History of chronic or active hepatitis 
 
 
d. Serum creatinine > 2.0 mg/dl 
 
 
e. Platelets < 100,000/mm3 
 
 
f. Absolute neutrophil count (ANC) < 1500/mm3 
 
g. Hemoglobin < 8.0 g/dl (the patient may be transfused prior to study 
entry) 
 
2. Patient has severe or uncontrolled concurrent medical disease (eg.       
uncontrolled diabetes, unstable angina, myocardial infarction within 6 months, 
congestive heart failure, etc.) 
 
3. Patient with any prior chemotherapy or radiotherapy for pelvic malignancy. 
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4. Patients with any history of cancer with the exception of non-melanoma skin 
cancer are excluded if there is any evidence of other malignancy being present 
within the past five years. 
5.  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 by calling Loraine Centrilla RN at (718) 405-8082 and 
faxing registration forms to (718) 829-2408.  Any questions regarding eligibility may 
be addressed with the P.I. or research coordinator. 
 
5.0   
TREATMENT PLAN 
 
5.1  Dosing Guidelines 
 
5.1.1  Chemotherapy 
 
Paclitaxel is available commercially.  Paclitaxel 175 mg/m2 will be given over 3 
hours in 250-500 ml of 5% dextrose or normal saline.  Premedication for prevention 
of anaphylactoid reactions with anti-histamines and/or steroids should be 
administered as per standard practice. 
 
Carboplatin is available commercially.  Carboplatin at an AUC of 6.0 prior to 
radiation and AUC of 5.0 following radiation is to be administered following 
paclitaxel in approximately 250 ml of normal saline over 30 minutes.  AUC based 
dosing as described by Calvert et al. will be according to the following formula:  Dose 
(mg) = AUC x (GFR + 25); the GFR is not to exceed 125ml/min.  The initial GOG 
trial using combination paclitaxel and carboplatin therapy was performed on patients 
with optimally debulked ovarian epithelial carcinoma [21]. At that time, the 
carboplatin dose was an AUC of 7.5.  Since then, multiple large cooperative trials 
have been performed using AUCs of 5.0.   Despite the lower dosage of carboplatin, it 
did not appear to compromise the efficacy of the drugs with improved toxicity profile 
[22-24].  
 
Where AUC is as stated above and GFR is the calculated renal function 
according to the method of Cockroft and Gault:  
 
            Creatinine Clearance (mL/min) = [140-Age (years)] x Weight (kg) x 0.85 
72 x serum creatinine (mg/dl), where weight is actual weight in kg. 
 
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 an astronomically higher dosage of carboplatin (two 
times) than the patient with a creatinine of 1.0.  Therefore, we opt to arbitrarily use a 
creatinine of 0.7 mg/dl in the GFR calculation for all patients whose creatinine is at or 
below 0.7 mg/dl.  While this may be arbitrary, it minimizes the potential significant 
toxicity associated with a very high carboplatin dosage, yet maintain doages for all 
patients at what we believe to be therapeutic values.  In patients with abnormally low 
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serum creatinine (less than or equal to 0.7mg/dl), the creatinine clearance should be 
estimated using a minimum of 0.7mg/dl. 
 
  
 
If a more appropriate (higher) baseline creatinine value is available from pre-
operative period (within 4 weeks of surgery date), that value may also be used for the 
initial estimation of GFR. 
 
The maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min 
 
The maximum allowed doses of carboplatin are: 
 
AUC 
Maximum Dose (mg) 
6 
900mg 
5.5 
825mg 
5 
750mg 
4.5 
675mg 
4 
600mg 
 
Chemotherapy will be administered every 21 days for 3 cycles.  This will be followed 
by a 5-week chemotherapy break, while external beam radiotherapy is underway.  The 
4th cycle of chemotherapy will overlap with the High Dose Radiation (HDR).  The 
remainder of the planned 6 cycles of paclitaxel/carboplatin therapy will continue to be 
administered every 21 days. 
 
 
5.1.2 Radiation  
 
Radiation therapy will be delivered after the 3rd cycle of chemotherapy.  The total 
dose of external beam pelvic radiation is 45 Gy over 5 weeks.  Patients will be treated 
once a day, 5 days a week, with a daily fraction size of 1.8 Gy.  Four-field technique 
(AP-PA opposed and lateral opposed fields) will be used with a megavoltage beam of 
> 6MV and a minimum source-axis distance of 100cm.  The fields may be extended 
in the case of ≥ 2 positive pelvic nodes or documented para-aortic lymph node 
disease.   
 
All fields treated require simulation and custom designed blocks, as well as portal 
verification on the treatment unit.  Small bowel series should be encouraged to 
exclude small bowel from the field.  Pretreatment CT scan of the abdomen and pelvis 
will be used for planning para-aortic fields if needed.  Sites of known positive nodes 
should be marked at the time of surgery with identifiable hemoclips. 
 
Fields should be calculated by optimizing the dose distribution by obtaining isodose 
curves of the pelvis.  All fields should be treated daily throughout the treatment 
course.  The specification of target dose is in terms of a dose to a point at or near the 
center of the target volume.  For the following portal arrangements, the target dose 
will be specified.  For a 4-field arrangement of beams:  at the isocenter of the beams, 
the maximum dose in the target volume should not exceed the central dose by more 
than 10%.  Doses to critical structures must be recorded. 
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Pelvic Portal (AP-PA fields):  Includes a superior border between L5 and S1; a lateral 
border 1-1.5 cm lateral to the widest true pelvic diameter; and an inferior border 
below the obturator foramen and at least 4 cm beyond the vaginal cuff.  A radio-
opaque marker in the vagina to mark the vaginal cuff will help to facilitate proper 
placement of the lower border. 
 
Pelvic Portal (lateral fields):  Includes a superior border identical to the AP-PA fields; 
an anterior border through the symphysis pubis and at least 1 cm anterior to common 
iliac nodes at L5-S1; a posterior border to include at least S1-S2; and an inferior 
border identical to AP-PA fields. 
 
Para-aortic Portal:  Includes a superior border of L1-L2 or 3 cm superior to the 
positive node site; an anterior border 3 cm anterior to the vertebral body; lateral 
borders 3 cm lateral to the vertebral body; and a posterior border that will exclude the 
spinal canal.   
 
HDR brachytherapy, or Intensity Modulated Radiation Therapy (IMRT) where 
appropriate, involves a proximal 2/3 vaginal boost using the nucleotron 
microselectron remote afterloading technique.  Three fractions of 5 Gy each will be 
prescribed to 0.5cm depth from the vaginal cylinder surface.  Three doses of HDR or 
IMRT will be completed with in three weeks of completion of external beam 
radiation. The vaginal surface dose may be calculated at the vaginal surface lateral to 
the midpoint of the surface of the cylinder. 
 
For HDR and IMRT, a report on the dose to bladder and rectum is mandatory.  The 
bladder dose may be calculated at a reference point, which is obtained as follows: A 
Foley catheter balloon must be filled with 7 cm3 of radio-opaque fluid.  On the lateral 
radiograph, the reference point is obtained on an anterior-posterior line drawn through 
the center of the balloon.  The reference point is taken on this line at the posterior 
surface of the balloon. On the frontal radiograph, the reference point is taken at the 
center of the balloon. The rectal dose at several points may be calculated by using a 
flexible radio-opaque rectal marker.   
 
 
5.2 
Prevention of Anticipated Toxicity 
  
The major toxicities to be expected from the combined modalities of treatment are 
hematologic and gastrointestinal.  Complete blood counts will be monitored weekly 
for evidence of toxicity.  Antiemetics and hydration will be administered to prevent 
nausea and vomiting.   
 
Toxicities particular to paclitaxel include hypersensitivity reactions.  Premedications 
(diphenhydramine, steroids, and H2 blockers) appear to reduce the incidence and 
severity of hypersensitivity reactions, but do not provide complete protection.  
Emergency agents (diphenhydramine, steroids and epinephrine) will be available.  IV 
sites should be evaluated regularly for signs of infiltration as the Cremophor vehicle 
may cause tissue damage.  In-line filtration with a 0.2-micron filter should be used. 
 
Toxicities particular to carboplatin include nephrotoxicity, ototoxicity, peripheral 
neuropathy, electrolyte imbalance, hypocalcemia, hypomagnesemia, amino-glycoside 
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ototoxicity, ocular toxicity, and allergic reaction.  Severe renal toxicity can be 
prevented by intravenous hydration and administration of mannitol. 
 
Monitoring of electrolytes and inclusion of potassium and magnesium in intravenous 
hydration may prevent electrolyte abnormalities.  Severe hypomagnesemia and 
hypocalcemia may require aggressive replacement therapy.  Aminoglycoside 
antibiotics may potentiate renal toxicity and should be avoided if possible. 
 
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 paresthesias prior to each course of carboplatin.   
Expected radiation toxicities are fatigue, diarrhea, nausea, vomiting, rectal irritation, 
urinary frequency and dysuria, loss of pubic hair, reddening and irritation 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. 
 
 
5.3 
Dose Reduction 
 
Dose-limiting neutropenia is defined by the occurrence of febrile neutropenia or 
prolonged Grade 4 neutropenia persisting ≥7 days.  Febrile neutropenia is defined 
within the NCI CTC v4.0 as an ANC <1000uL with a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of ≥ 38 degrees C (100.4 
degrees F) for more than one hour. 
 
 
Dose level 
before RT 
 
Carboplatin 
 
Paclitaxel 
0 
AUC 6.0 
175 mg/m2 
-1 
AUC 5.5 
175 mg/m2 
-2 
AUC 5.0 
175 mg/m2 
-3 
AUC 5.0 
Dose reduce by 20% 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing-limiting 
thrombocytopenia is defined 
by any occurrence of Grade 4 thrombocytopenia (25,000/uL) or bleeding associated 
with Grade 3 thrombocytopenia (25,000-<50,000/uL). 
Dose level 
after RT 
 
Carboplatin 
 
Paclitaxel 
0 
AUC 5.0 
175 mg/m2 
-1 
AUC 4.5 
175 mg/m2 
-2 
AUC 4.0 
175 mg/m2 
-3 
AUC 4.0 
Dose reduce by 20% 
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Dose level 
before RT 
 
Carboplatin 
 
Paclitaxel 
0 
AUC 6.0 
175 mg/m2 
-1 
AUC 5.5 
175 mg/m2 
-2 
AUC 5.0 
175 mg/m2 
-3 
AUC 5.0 
Dose reduce by 20% 
 
 
 
 
 
 
 
 
 
If the above occurs on day 
21, 
therapy 
should 
be 
withheld (for a maximum of 
21 days) until counts return to an ANC > 1500/uL and platelet count > 100,000/uL. 
Patients who received G-CSF prior to the current cycle may begin (day 1  
of cycle) with ANC ≥ 1000 cells/uL, to allow for transient reductions in ANC after 
discontinuation of G-CSF.  Patients who are delayed more than 7 days due to 
neutropenia may begin with ANC ≥ 1000 cells/uL if clinically appropriate; as they 
will receive G-CSF with subsequent therapy.  Patients who have been delayed for 
more than 7 days due to neutropenia should receive G-CSF with subsequent cycles 
prior to dose reduction. G-CSF should be considered in all patients that have 
experienced grade 4 neutropenia. 
 
All patients that exhibit chemotherapy related grade 3 and  non-hematologic (eg 
mucositis and neuropathy) toxicities will follow the same dose reductions as for grade 
4 hematologic toxicities displayed in the above tables.  
 
 
Dose reduction for delayed hematologic (neutropenia and/or thrombocytopenia) 
recovery is as follow: 
 
 
 
 
 
 
 
Patients may receive erythropoietin (EPO), iron supplements, and/or  
transfusions as clinically indicated for management of anemia.  
 
If there is an interruption of more than one week, during radiation therapy, it should 
be completed to the prescribed total dose.  If there are interruptions of more than two 
weeks, this will be considered a major deviation from the protocol, and resumption of 
therapy will be at the discretion of the principal investigator. 
Dose level 
after RT 
 
Carboplatin 
 
Paclitaxel 
0 
AUC 5.0 
175 mg/m2 
-1 
AUC 4.5 
175 mg/m2 
-2 
AUC 4.0 
175 mg/m2 
-3 
AUC 4.0 
Dose reduce by 20% 
Delay (days) 
Modification 
1-7 
No change 
8-14 
Reduce carboplatin by one AUC 
14-21 
Reduce paclitaxel by 20% 
>21 
Discontinue protocol 
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5.4 
Adverse Event Reporting 
 
An adverse event refers to any adverse medical change from the patient’s baseline (or 
pretreatment) 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 
principal investigator 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. 
 
6.0  
MEASUREMENT OF EFFECT 
 
6.1 Recurrence-Free Survival 
 
Recurrence-free survival 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 
histologic or cytologic evaluation when possible.   
 
 
6.2 Toxicity 
 
Toxicities will be graded according to the NCI Common Toxicity Criteria (version 4).   
Myelosuppressive toxicity shall be reported as the lowest observed white blood and 
platelet counts.  Anemia and red blood cell transfusions will be noted. 
 
Gastrointestinal toxicities shall be reported and hospitalizations for nausea, vomiting 
and diarrhea will be documented. 
 
Patients will be followed for potential long-term toxicities with complete histories and 
physical examinations.  
 
Any patient who receives at least one course of therapy and has follow-up information 
will be included for observation of toxicity. 
 
7.0   
STUDY PARAMETERS 
 
7.1 
Pre Study Evaluation 
 
This evaluation requires completion within 14 days of registration, unless otherwise 
described.  Baseline requirements will consist of a thorough history and physical 
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examination, including pelvic and rectovaginal exam.  Evaluation of hearing loss and 
neuropathy is required.  An ECG < 4 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, and urinalysis. 
 
Histologic documentation of uterine carcinosarcoma is required.  Prestudy CA125, 
CA19-9, CT scan of chest, abdomen and pelvis (within 28 days of therapy), and CXR 
(not required if CT of the chest) will be obtained.   
 
7.2 
Tests During Treatment 
 
Day 13-15:  CBC with differential and platelet count 
 
Every 3 weeks:  CBC with differential and platelet count electrolytes, BUN, 
creatinine, glucose, magnesium, calcium, phosphorous, albumin, CA125 and CA19-9. 
 
After 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. 
 
7.3   
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 CA19-9, urinalysis. 
 
CT scan of chest, abdomen and pelvis will be obtained at the completion of the entire 
“sandwich” protocol or earlier if indicated. 
 
7.4   
Follow-up 
 
Patients will be evaluated every 3 months for the first 2 years and every 6 months for 
the next 3 years.  Evaluations at each visit include 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 CA19-9, 
urinalysis.  CT Scans will be performed annually or earlier if indicated.  After a total 
of 5 years, patients will be seen annually. 
 
7.5   
Secondary Endpoints 
 
Staining of the pathologic specimens for ER/PR, HER2/neu and p53 will be 
performed by immunohistochemisty to assess for correlations with progression-free 
survival and prognosis.   
 
7.6   
Discontinuation 
 
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Criteria for stopping treatment include recurrence of disease; the development of 
unacceptable toxicity; and/or patient request. 
 
8.0  
DRUG FORMULATION AND PROCUREMENT 
 
8.1 
Drug Information:   
Paclitaxel 
 
Other Names:  Taxol, NSC 673089 
 
Classification: Antimicrotubule 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.  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 175 mg/m2 infused over three hours 
and repeated every 21 days.  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 taxol.  Ketoconazole may inhibit taxol metabolism, 
based on in vitro data. 
 
Adverse Effects Profile:  Neutropenia, thrombocytopenia, anemia, alopecia, injection 
sites reactions, radiation recall, rash, nausea, vomiting, mucositis, typhlitis, 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. 
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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 interstrand 
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:  Intravenous 
 
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 Cockroft and Gault:   
 
GFR (ml/min) = 0.85 x {(140-age)/Scr)} x {wt(kg)/72}.   
              
Where Scr is the serum creatinine level.  
In patients with abnormally low serum creatinine (less than 0.7mg/dL), the creatinine 
clearance should be estimated using a minimum of 0.7mg/dl or cap the estimated GFR 
at 125mL/min based on the NCI guidelines. 
 
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, pruritis, 
bronchospasm, Other:  pain, asthenia, flu-like syndrome. 
 
Supplier:  Commercially available. 
 
 
9.0   
STATISTICAL CONSIDERATIONS 
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To assess the one year recurrence-free survival in patients with uterine 
carcinosarcoma treated with “sandwich” therapy-including defining the patterns of 
recurrence in patients with carcinosarcoma who were treated with this regimen..  A 
total of 18 patients will be accrued to this study.  One-year recurrence-free survival 
probability will be estimated, with 95% confidence limits based on exact methods for 
the binomial distribution.  Conservatively, the sample size indicated will provide a 
95% confidence interval with width of +/- 0.23.  Frequencies will also be provided for 
side effects and adverse events. 
 
Based on past accrual rates in this patient population, it is expected that accrual will 
be at most 4-6 per year for a total accrual period of about 48 months.  Follow up will 
be a minimum of one year after the last patient is accrued in order to assess response.  
Therefore, total study time is expected to be 3.4-4.0 years. 
 
10.0  COLLECTION PROCEDURES 
 
Paraffin embedded tissue from uterine carcinosarcoma tumors will be stained for 
ER/PR, p53 and Her2Neu by immunohistochemistry. 
 
11.0  RECORDS TO BE KEPT 
 
Forms  
 
 
 
To Be Submitted 
 
 
Pathology Report 
 
 
Within one week of registration 
 
ECOG CTC Flow Sheet (#466R) 
Baseline within one week of registration. 
 
 
 
 
 
 
On Treatment:  Every month 
 
 
 
 
 
 
 
 
Off Treatment:  See Follow-up 
 
 
 
 
 
 
 
 
 
 
12.0  PATIENT CONSENT AND PEER JUDGEMENT 
 
All institutional, state, and national guidelines concerning informed consent and peer 
review will be observed. 
 
 
13.0  MINORITIES AND WOMEN STATEMENT 
 
This study will be initially open to patients undergoing treatment at Montefiore 
Medical Center.   
 
Although distributions may vary by disease type, our recruitment procedures have 
been developed to enroll patients who are representative of the target population. 
 
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14.0  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 Montefiore IRB. 
 
 
15.0      ELIGIBILITY CHECKLIST 
 
 
 
 
 
 
 
 
 
Yes 
 
No 
Histologically documented uterine carcinosarcoma 
 with no visible residual disease 
 
Surgical staging to include total abdominal 
hysterectomy, bilateral salpingo-oophorectomy, 
peritoneal washings, and lymph node sampling. 
 
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 does not have severe or uncontrolled 
concurrent medical disease (eg. Uncontrolled 
diabetes, unstable angina, myocardial infarction 
within 6 months, congestive heart failure, etc.) 
 
Patient has not had any prior chemotherapy 
or radiotherapy for pelvic malignancy. 
 
Patients has no dementia or altered mental  
status that would prohibit the giving and  
understanding of informed consent at the  
time of study entry. 
 
Patient Name____________________________________ 
 
Patient MR#_____________________________________ 
 
Treating Physician________________________________ 
 
Principal Investigator______________________________ 
  (Signature) 
 
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16.0  REFERENCES 
 
1. 
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. 
2. 
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. 
3. 
Rose, P.G., et al., Patterns of metastasis in uterine sarcoma. An autopsy study. 
Cancer, 1989. 63(5): p. 935-8. 
4. 
Chi, D.S., et al., The role of whole-pelvic irradiation in the treatment of early-stage 
uterine carcinosarcoma. Gynecol Oncol, 1997. 65(3): p. 493-8. 
5. 
Le, T., Adjuvant pelvic radiotherapy for uterine carcinosarcoma in a high risk 
population. Eur J Surg Oncol, 2001. 27(3): p. 282-5. 
6. 
Omura, G.A., et al., A randomized study of adriamycin with and without dimethyl 
triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer, 1983. 52(4): 
p. 626-32. 
7. 
Thigpen, J.T., et al., Phase II trial of cisplatin in the treatment of patients with 
advanced or recurrent mixed mesodermal sarcomas of the uterus: a Gynecologic 
Oncology Group Study. Cancer Treat Rep, 1986. 70(2): p. 271-4. 
8. 
Sutton, G.P., et al., Phase II trial of ifosfamide and mesna in mixed mesodermal 
tumors of the uterus (a Gynecologic Oncology Group study). Am J Obstet Gynecol, 
1989. 161(2): p. 309-12. 
9. 
Curtin, J.P., et al., Paclitaxel in the treatment of carcinosarcoma of the uterus: a 
gynecologic oncology group study. Gynecol Oncol, 2001. 83(2): p. 268-70. 
10. 
Sutton, G., et al., A phase III trial of ifosfamide with or without cisplatin in 
carcinosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol, 
2000. 79(2): p. 147-53. 
11. 
Homesley, H.D., et al., Phase III trial of ifosfamide with or without paclitaxel in 
advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin 
Oncol, 2007. 25(5): p. 526-31. 
12. 
Toyoshima, M., et al., Clinical experience with combination paclitaxel and 
carboplatin therapy for advanced or recurrent carcinosarcoma of the uterus. Gynecol 
Oncol, 2004. 94(3): p. 774-8. 
13. 
Ramondetta, L., et al.,, A phase II multicenter trial of paclitaxel and carboplatin in 
women with advanced or recurrent malignant mixed müllerian tumors (MMMT) of 
the uterus. J Clin Oncol, 2007. 25(18S ). 
14. 
Hoskins, P.J., et al., Carboplatin plus paclitaxel for advanced or recurrent uterine 
malignant mixed mullerian tumors. The British Columbia Cancer Agency experience. 
Gynecol Oncol, 2008. 108(1): p. 58-62. 
15. 
Powell, M.A., et al., Phase II evaluation of paclitaxel and carboplatin in the 
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treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group study. J 
Clin Oncol, 2010. 28(16): p. 2727-31. 
16. 
Callister, M., et al., Malignant mixed Mullerian tumors of the uterus: analysis of 
patterns of failure, prognostic factors, and treatment outcome. Int J Radiat Oncol Biol 
Phys, 2004. 58(3): p. 786-96. 
17. 
Gerszten, K., et al., The impact of adjuvant radiotherapy on carcinosarcoma of the 
uterus. Gynecol Oncol, 1998. 68(1): p. 8-13. 
18. 
Gonzalez Bosquet, J., et al., The impact of multi-modal therapy on survival for uterine 
carcinosarcomas. Gynecol Oncol. 116(3): p. 419-23. 
19. 
Fields, A.L., et al., Pilot phase II trial of radiation "sandwiched" between 
combination paclitaxel/platinum chemotherapy in patients with uterine papillary 
serous carcinoma (UPSC). Gynecol Oncol, 2008. 108(1): p. 201-6. 
20. 
Einstein M.H., e.a., Phase II efficacy and toxicity of sequential ifosfamide or 
ifosfamide plus cisplatin 'sandwiched' with radiation therapy as adjuvant therapy for 
patients with surgically-staged carcinosarcoma. Poster presentation to 2010 Society 
of Gynecologic Oncologists Annual Meeting.  San Francisco, CA. 
21. 
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. 
22. 
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. 
23. 
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. 
24. 
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. 
 
 
               
 
 
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APPENDIX 1:  STUDY SCHEDULE 
 
 
Parameter 
Pre-
treatment 
Day 13-15 
(Cycles 1-6) 
 
Each 
Cycle 
Completion 
of  Study 
Follow-up 
Visit 
History & Physical 
Exam 
X 
 
X 
X 
X 
Pelvic Exam 
X 
 
 
X 
 
Weight, Performance, 
Status 
X 
 
X 
X 
X 
CBC with differential, 
platelets 
X 
X 
X 
X 
X 
Electrolytes, Mg, BUN, 
Cr 
X 
 
X 
X 
X 
SGOT, Bili 
X 
 
X 
X 
X 
Urinalysis  
X 
 
 
X 
X 
CA-125, CA19-9 
X 
 
X 
X 
X 
EKG 
X3 
 
 
 
 
CXR 
X 
 
 
 
X1 
CT chest/abd/pelvis 
X4 
 
 
X 
X2,1 
p53 
X 
 
 
 
 
ER/PR 
X 
 
 
 
 
HER2neu 
X 
 
 
 
 
1.  If clinically indicated. 
2.  Annually 
3.  With in 4 months of therapy 
4.  With in 28 days of therapy 
 
  
 
  
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