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A Pilot Phase II Trial of Adjuvant Radiation Therapy "Sandwiched" Between Ifosfamide in Patients With Mixed Mesodermal Tumors

Phase 2
18 Years
Not Enrolling
Uterine Cancer

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Trial Information

A Pilot Phase II Trial of Adjuvant Radiation Therapy "Sandwiched" Between Ifosfamide in Patients With Mixed Mesodermal Tumors

Uterine sarcomas account for only 2-4% of uterine malignancies, yet they are responsible for
26% of uterine cancer deaths. Mixed mesodermal tumors (MMT), previously known as
carcinosarcoma, are the most common of the uterine sarcomas in the United States. Prognosis
for these patients is generally grim due to the propensity for early metastatic disease.
Patterns of spread are by both hematogenous and lymphatic dissemination. It has been noted
that 66% of patients with disease clinically confined to the uterus have nodal metastasis at
the time of diagnosis. The majority of patients will die with both wide spread
intra-abdominal and pelvic disease within two years of diagnosis.

Pelvic failure occurs in up to 50% of patients. Adjuvant pelvic radiation therapy has been
advantageous in controlling local recurrence. One study reports 26% local recurrence in
patients treated with surgery alone versus 14% recurrence in patients treated with surgery
and adjuvant pelvic radiation. Although adjuvant radiation shows a benefit in improving
local control, it has not been found to impact survival. This finding is likely attributed
to the high incidence of distant metastasis (85%) known to occur with disease recurrence.

Multiple chemotherapeutic agents have been evaluated in the management of advanced,
persistent or recurrent uterine MMT. Response to single agent therapy has been less than
35% with the most active agents identified being ifosfamide (response rate = 34.8%) and
cisplatin (response rate 17.9%. The use of chemotherapy in the adjuvant setting has been
explored as a means of attempting to impact the incidence of distant metastasis. The
Gynecologic Oncology Group (GOG) evaluated ifosfamide/cisplatin in the adjuvant setting in
patients with completely resected Stage I or II uterine MMT. At a minimum of two years
follow-up, 41 patients (53.1%) were progression free and 48 patients (73.8%) remained alive.
The authors concluded that this regimen suggests improved progression free interval and
perhaps even survival, as compared to historical controls. The results from this trial lead
to a randomization of ifosfamide vs. ifosfamide/cisplatin, in patients with advanced,
persistent or recurrent MMT with measurable disease. In this study patients were treated
with an Ifosfamide dose of 1.5 g/m2/day for five days every three weeks for eight courses.
This was administered with Cisplatin at a dose of 20 mg/m2/day. Unfortunately, this regimen
was associated with significant unanticipated toxicity and mortality necessitating a 20%
dose reduction of ifosfamide to 1.2 gm/m2 per day with the same dose of cisplatin. Results
from this study identified a statistically significant advantage in progression free
interval (P = .02) in the ifosfamide/cisplatin group (9 months) vs. the ifosfamide alone
group (4 months). There was not, however, a significant difference in survival (P = 0.07).

The optimal sequence and /or modality for adjuvant therapy in the management of MMT clearly
remains to be established. The rationale for this protocol is to "sandwich" pelvic
radiation with chemotherapy to decrease distant metastasis. A retrospective review of 10
patients treated at our institution with the sequential use of radiation "sandwiched"
between ifosfamide/platinum chemotherapy was recently performed. Along with cisplatin at a
dose of 20 mg/m2/day, the ifosfamide dose selected was based on the necessary dose reduction
from the GOG trial. An ifosfamide dose of 1.2 gm/m2/day prior to radiation, and further
decreased to 1.0 gm/m2/day following radiation for a total of 6 cycle, was administered. Of
the 8 patients who completed treatment, only 1 patient recurred at 17 months with a median
follow-up of 18 months (range 6-53 months). One of the two remaining patients had an
anterior abdominal wall recurrence between the 5th and 6th cycle of chemotherapy and the
other developed cerebral metastasis during her radiation therapy. Overall, the regimen was
well tolerated. Six of the 10 patients (60%) developed grade 3 neutropenia in the absence
of GCSF, two of which required a 1 week treatment delay. There were no cases of grade 3/4
thrombocytopenia noted. There was no febrile neutropenia and no hospital admissions for
toxicity. There were no observed grade 3 or 4 non-hematologic toxicities. With the median
follow-up of 18 months, we have not yet observed late toxicities.

The concept of sequential chemotherapy/radiation therapy/chemotherapy has been previously
reported. The chemotherapeutic agents employed in that trial were cisplatin and epirubicin
with a reported survival of 74% in patients with Stage I and II MMT with a median follow-up
period of 55 months. Toxicity was reported as tolerable and 98% of patients were able to
complete their therapy. Sequential chemotherapy/radiation/chemotherapy has also been
investigated in other high risk uterine tumors with a propensity for both distant and local
recurrence. A retrospective review of 23 patients treated with radiation "sandwiched"
between paclitaxel/platinum chemotherapy in patients with uterine papillary serous
carcinomas found 5/23 (22%) to have recurred with a median PFI of 16.6 months (range 12.1 -
23 months). The median follow-up was 21 months (range 10-45 months). Of the patients
remaining disease-free, the median PFI was 21.4 months (range 10-15 months). Toxicity was
acceptable and the regimen was well tolerated. A prospective trial of this regimen is
presently ongoing and without unexpected toxicity or morbidity.

The proposed study will sandwich radiation between the two most active chemotherapeutic
agents for MMT identified to date (ifosfamide/cisplatin). By doing so, we attempt to
decrease both local and distant recurrence, which may translate into an improved progression
free interval and possibly even extend survival.

Inclusion Criteria:

1. Histologically documented mixed mesodermal tumor (MMT) of uterus with no visible
residual disease.

2. Surgical staging to include total abdominal hysterectomy, bilateral
salpingo-oophorectomy, peritoneal washings, and lymph node sampling.

3. Surgical staging should be completed £ 6 weeks ± 7 days prior to enrollment.
Patients should have recovered from surgery and regained an ECOG performance status
of < 2, and have resumption of normal GI function. Patients with incompletely healed
incisions are eligible to participate.

4. Age >= 18 years.

5. ECOG performance status of <2.

6. Written voluntary informed consent.

Exclusion Criteria:

1. Patient has impairment of hepatic, renal or hematologic function as defined by the
following baseline laboratory values:

1. Serum SGOT and/or SGPT > 2.5 times the institutional upper limit of normal.

2. Total serum bilirubin >1.5mg/dl

3. History of chronic or active hepatitis

4. Serum creatinine >2.0 mg/dl

5. Platelets <100,000/mm3

6. Absolute neutrophil count (ANC) <1500/mm3

7. Hemoglobin <8.0 g/dl (the patient may be transfused prior to study entry)

2. Patient has severe or uncontrolled medical disease (eg. uncontrolled diabetes,
unstable angina, myocardial infarction within 6 months, congestive heart failure,

3. Patient has been treated with myelosuppressive chemotherapy within three weeks prior
to study entry.

4. Patients with any prior chemotherapy or radiotherapy for pelvic malignancy.

5. Patients with dementia or altered mental status that would prohibit the giving and
understanding of informed consent at time of study entry.

6. Patient has a uterine sarcoma other then mixed mesodermal tumor (MMT).

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the toxicity and tolerability of pelvic radiation "sandwiched" between cycles of chemotherapy in patients with MMT.

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Mark H Einstein, M.D., M.S.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Montefiore Medical Center and Albert Einstein College of Medicine


United States: Institutional Review Board

Study ID:




Start Date:

February 2003

Completion Date:

July 2011

Related Keywords:

  • Uterine Cancer
  • Mixed Mesodermal Tumor
  • MMT
  • Uterine Cancer
  • Radiation Therapy
  • Chemotherapy
  • Uterine Neoplasms
  • Mixed Tumor, Mesodermal



Montefiore Medical CenterBronx, New York  10467-2490