Standard Versus Intensity-Modulated Pelvic Radiation Therapy in Treating Patients With Endometrial or Cervical Cancer

OBJECTIVES:

Primary

- To determine if pelvic intensity-modulated radiation therapy (IMRT) reduces acute
gastrointestinal toxicity in the 5th week (after 23-25 fractions) of pelvic radiation as
measured with the expanded prostate cancer index composite (EPIC) instrument.

Secondary

- To determine if grade 2+ gastrointestinal toxicity (Common Terminology Criteria for
Adverse Events version 4.0 [CTCAE v. 4.0]) is reduced with IMRT compared to conventional
whole-pelvis radiation therapy (WPRT).

- To determine if grade 2+ hematologic toxicity (CTCAE v. 4.0) is reduced with IMRT
compared to conventional WPRT.

- To determine if urinary toxicity is reduced with IMRT using the EPIC urinary domain.

- To validate EPIC bowel and urinary domains in women undergoing either IMRT pelvic
radiation treatment or four-field pelvic radiation treatment for endometrial or cervical
cancer.

- To assess the impact of pelvic IMRT on quality of life using the Functional Assessment
of Cancer Therapy-General (FACT-G) with cervix subscale.

- To determine if there is any difference in local-regional control, disease-free
survival, and overall survival between patients treated with IMRT as compared to
conventional WPRT.

- To perform a health-utilities analysis to measure the financial impact of pelvic IMRT
via the EQ-5D instrument.

- To identify molecular predictors of radiation toxicity and novel circulating cancer
biomarkers.

OUTLINE: This is a multicenter study. Patients are stratified according to type of cancer
(endometrial vs cervical), chemotherapy (none vs 5 courses of weekly cisplatin at 40 mg/m²),
and radiation dose (45 Gy vs 50.4 Gy). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients undergo standard (3-dimensional) radiation therapy 5 days a week for up
to 5-6 weeks.

- Arm II: Patients undergo intensity-modulated radiation therapy (IMRT) 5 days a week for
up to 5-6 weeks.

Some patients receive cisplatin IV over 1 hour on day 1. Treatment continues weekly for 5
weeks, concurrently with radiation therapy, in the absence of unacceptable toxicity or
disease progression.

Tissue and blood samples may be collected for biomarker and correlative analysis.

Quality of life may be assessed by questionnaires (including the Expanded Prostate Cancer
Index Composite [EPIC], the Functional Assessment of Cancer Therapy-General [FACT-G, Version
4], the EQ-5D, and the Common Toxicity Criteria Adverse Events - Patient-Reported Outcome
[PRO-CTCAE]) instruments at baseline and periodically during and after study therapy.

After completion of study therapy, patients are followed every 6 months for the first 2 years
and then annually for 5 years.

Inclusion criteria:

1. Pathologically proven diagnosis of endometrial or cervical cancer.

2. Patients must have undergone a hysterectomy (total abdominal hysterectomy, vaginal
hysterectomy or radical hysterectomy or total laparoscopic hysterectomy) for carcinoma
of the cervix or endometrium within 49 days prior to registration. Performance of a
bilateral salpingooophorectomy will be at the treating surgeon's discretion.

3. Appropriate stage for protocol entry, including no distant metastases, based upon the
following minimum diagnostic workup:

- 3.1 History/physical examination within 45 days prior to registration;

- 3.2 CT, MRI or positron emission tomography - computed tomography (PET-CT)
including the abdomen and pelvis should be performed for initial radiological
staging. This may be performed pre- or post-surgery within 90 days prior to
registration. Imaging performed post-operatively should show no evidence of
residual disease. Any evidence of malignancy identified on pre-operative imaging
should have been completely resected surgically prior to protocol treatment.

- 3.3 Chest CT or chest x-ray must be performed within 90 days prior to
registration (unless a PET-CT has been performed)

4. Zubrod Performance Status 0-2

5. Age ≥ 18;

6. Complete blood count (CBC)/differential obtained within 14 days prior to registration
on study, with adequate bone marrow function defined as follows:

- 6.1 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;

- 6.2 Platelets ≥ 100,000 cells/mm3;

- 6.3 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to
achieve Hgb ≥ 8.0 g/dl is acceptable.)

7. For patients receiving chemotherapy:

7.1 Within 14 days prior to registration, serum creatinine ≤ 1.5 mg/dL and calculated
creatinine clearance ≥ 50 cc/min. Both tests must be within these limits. The creatinine
clearance should be calculated using the Cockcroft-Gault formula: (See Section 7.3.1) 7.2
Aspartate aminotransferase (AST) ≤ 2 x upper limit of normal (ULN) 7.3 Bilirubin ≤ 2 x ULN
7.4 Alkaline phosphatase, Mg, blood urea nitrogen (BUN) and electrolytes must be obtained
and recorded 8 Endometrial Cancer: 8.1 Patients with the following histologic features are
eligible for pelvic radiation therapy without weekly cisplatin:

- <50% myometrial invasion, grade 3 adenocarcinoma without uterine serous carcinoma
(USC) or clear cell histology

- ≥50% myometrial invasion grade 1-2 adenocarcinoma without USC or clear cell histology
8.2 Patients with the following histologic features may be treated with pelvic
radiation with or without weekly cisplatin. The decision to add weekly cisplatin for
these patients is at the treating physician's discretion:

- ≥50% myometrial invasion, grade 3 including USC and clear cell carcinoma.

- International Federation of Gynecology and Obstetrics (FIGO) 2009 stage II endometrial
cancer of any grade including USC and clear cell carcinoma.

- FIGO 2009 IIIC1 (pelvic lymph node positive only, para-aortic nodes negative if
removed) including USC and clear cell carcinoma. Note: If para-aortic nodes are not
removed, CT abdomen or PET CT must demonstrate no evidence of lymphadenopathy. 9.
Cervical Cancer: 9.1 Patients with the following pathology findings may be treated
with pelvic radiation with or without weekly cisplatin at the treating physician's
discretion. The decision to add weekly cisplatin for these patients is at the treating
physician's discretion. 9.1.1 Patients with intermediate risk features including two
of the following histologic findings after radical hysterectomy:

- 1/3 or more stromal invasion

- Lymph-vascular space invasion

- Large clinical tumor diameter (> 4 cm) 9.1.2 Patients with cervical cancer treated
with a simple hysterectomy with negative margins 9.2 Patients with any of the
following criteria following radical hysterectomy are eligible for this study and must
receive weekly cisplatin:

- Positive resected pelvic nodes and para-aortic nodes negative if removed. Note: If
para-aortic nodes are not removed, CT abdomen or PET CT must demonstrate no evidence
of lymphadenopathy.

- Microscopic parametrial invasion with negative margins. 10. Patient must provide study
specific informed consent prior to study entry. 11. Willingness and ability to
complete the bowel and urinary domains of the EPIC prior to registration

Exclusion criteria:

1. Patients with para-aortic nodal disease or who require extended field radiotherapy
beyond the pelvis.

2. Patients with histology consisting of endometrial stromal sarcoma, leiomyosarcoma or
malignant mixed mullerian mixed tumor (MMMT or carcinosarcoma)

3. Patients who exceed the weight/size limits of the treatment table or CT scanner.

4. Mental status changes or bladder control problems that make the patient unable to
comply with bladder-filling instructions.

5. Patients with evidence of metastatic disease outside of the pelvis.

6. Patients with positive or close (< 3 mm) resection margins

7. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years.

8. Prior radiation therapy to the pelvis

9. Patients with active inflammatory bowel disease. 10 Severe, active co-morbidity,
defined as follows:

- 10.1 Unstable angina and/or congestive heart failure requiring hospitalization
within the last 6 months

- 10.2 Transmural myocardial infarction within the last 6 months

- 10.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration

- 10.4 Other major medical illness which requires hospitalization or precludes
study therapy at the time of registration

- 10.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation
defects; note, however,that laboratory test coagulation parameters are not
required for entry into this protocol

- 10.6 Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for
Disease Control and Prevention (CDC) definition; note, however, that HIV testing
is not required for entry into this protocol. The need to exclude patients with
AIDS from this protocol is necessary because the treatments involved in this
protocol may be significantly immunosuppressive. Protocol-specific requirements
may also exclude immunocompromised patients.

11. Patients with prior treatment with platinum-based chemotherapy 12. Women who are
breastfeeding