Cervical Cancer, Endometrial Cancer
Conditions
Keywords
stage I endometrial carcinoma, stage II endometrial carcinoma, stage III endometrial carcinoma, endometrial adenoacanthoma, endometrial adenocarcinoma, endometrial adenosquamous cell carcinoma, stage IB cervical cancer, stage IIA cervical cancer, stage IIB cervical cancer, cervical adenocarcinoma, cervical adenosquamous cell carcinoma, cervical squamous cell carcinoma
Brief summary
RATIONALE: Specialized radiation therapy (RT), such as intensity-modulated radiation therapy (IMRT), that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving intensity-modulated radiation therapy to the pelvis with or without chemotherapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well intensity-modulated radiation therapy to the pelvis with or without chemotherapy works in treating patients with endometrial cancer or cervical cancer that has been removed by surgery.
Detailed description
OBJECTIVES: * Determine the transportability of intensity modulated radiotherapy (IMRT) to a multi-institutional setting in patients with resected endometrial or cervical cancer. * Compare the efficacy, in terms of reducing short-term bowel injury, of IMRT versus standard treatments. * Assess adverse events related to this regimen. * Estimate the rates of local-regional control, distant metastasis, and disease-free and overall survival. * Evaluate chemotherapy compliance with this regimen for patients with cervical carcinoma. OUTLINE: This is a multicenter study. Patients are stratified according to diagnosis (cervical vs endometrial cancer). All patients undergo intensity modulated radiotherapy (IMRT) once a day, 5 days a week, for 5.5 weeks. Patients with cervical cancer also receive cisplatin IV over 30-60 minutes on day 1 or 2. Treatment with cisplatin repeats every 7 days for 5 courses (during radiotherapy) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 6 weeks post-IMRT and then every 3 months for 2 years, every 6 months for years 3-5, and then annually for at least 3 years. PROJECTED ACCRUAL: A total of 92 patients will be accrued for this study.
Interventions
DRUGcisplatin
RADIATIONintensity-modulated radiation therapy
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Must have undergone a hysterectomy (total abdominal, vaginal, radical, or laparoscopic-assisted vaginal) within 7 weeks prior to study entry * Patients with endometrial cancer must have also undergone a bilateral salpingo-oophorectomy * Histologically confirmed diagnosis of 1 of the following: * Endometrial cancer meeting 1 of the following criteria: * Stage IB grade 3, IC grade 1-3, IIA, or IIB disease requiring postoperative pelvic radiotherapy * Unstaged (no lymph node dissection or sampling) stage IB grade 2 disease * Stage IIIC with all of the following: * Pelvic lymph node positive only * Para-aortic nodes sampled negative * Not receiving chemotherapy * Cervical cancer meeting 1 of the following criteria: * Post-radical hysterectomy and requires postoperative pelvic radiotherapy due to any of the following: * Positive pelvic nodes (negative para-aortic nodes) * Microscopic parametrial involvement and negative margins * Disease qualified by Sedlis criteria must have 2 of the following risk factors: * 1/3 or more stromal invasion * Lymph-vascular space invasion * Large clinical tumor diameter (≥ 4 cm) * Post-simple hysterectomy with negative margins and negative nodes by CT scan, MRI, or positron emission tomography-CT scan * No requirement for extended-field radiotherapy beyond the pelvis * No histologically confirmed papillary serous, clear cell, or neuroendocrine (either large or small cell) disease, endometrial stromal sarcoma, leiomyosarcoma, or malignant müllerian mixed tumor * No evidence of metastatic disease outside of the pelvis * No microscopic involvement of the resection margin (\< 3 mm) PATIENT CHARACTERISTICS: * Zubrod performance status 0-2 * WBC (white blood cell count) ≥ 4,000/mm³ (cervical cancer patients only) * Absolute neutrophil count ≥ 1,800/mm³ (cervical cancer patients only) * Platelet count ≥ 100,000/mm³ (cervical cancer patients only) * Hemoglobin ≥ 8.0 g/dL (transfusion allowed) * Serum creatinine ≤ 2.0 mg/dL (cervical cancer patients only) * Creatinine clearance ≥ 50 mL/min (cervical cancer patients only) * AST (aspartate aminotransferase) ≤ 2 times upper limit of normal * Bilirubin ≤ 2 times upper limit of normal * Patients must not exceed the weight and size limits of the treatment table or CT scanner * No mental status changes or bladder control problems that would preclude study compliance with bladder-filling instructions * No active inflammatory bowel disease * No severe, active, concurrent illness, defined as any of the following: * Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months * Transmural myocardial infarction within the past 6 months * Acute bacterial or fungal infection requiring IV antibiotics * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects * AIDS * No history of allergy to cisplatin (cervical cancer patients) * No prior invasive malignancy (except nonmelanoma skin cancer) unless disease-free for ≥ 3 years PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior radiotherapy to the pelvis that would result in overlap of radiotherapy fields * No prior platinum-based chemotherapy (cervical cancer patients) * No concurrent prophylactic growth factors (e.g., filgrastim \[G-CSF\], sargramostim \[GM-CSF\], or pegfilgrastim) * No concurrent prophylactic thrombopoietic agents * No concurrent amifostine or other protective agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reproducibility of Radiation Technique (Number of Unacceptable Deviations in Central IMRT Quality Assurance Review) | IMRT planning and dosing data is centrally reviewed for quality assurance after treatment delivery. | Central quality assurance review of the IMRT planning and dosing categorized unacceptable deviations (UD) from protocol compliance with the delineation of planning target volume for the vagina and pelvic lymph nodes. Each arm of this study is considered independently, they are not compared to each other. The study was designed such that, for each arm, 5 or more of 42 subjects scored as unacceptable would determine the respective treatment technique as not reproducible. For each arm this design provides 90% power with a 0.05 type I error to reject the null hypothesis that the true probability of concluding the given technique to be reproducible is \<= 80%. The alternative hypothesis is that the true probability is \>= 95%. For \[vagina / pelvic lymph nodes\]: UD is defined as: The 90% isodose surface covers \< 95% of \[internal target volume (ITV)/ planned target volume (PTV)\] 50.4 or \> 5% of the \[ITV/PTV\] 50.4 receives over 115%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Any Grade 3+ Treatment-related Adverse Events | From start of treatment to the end of follow-up. Maximum follow-up at time of analysis was 10.2 years for endometrium cancer patients and 9.5 years for cervical cancer patients. | Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. |
| Percentage of Patients With Any Late Grade 3+ Treatment-related Adverse Events | From 91 days after start of study treatment to the end of follow-up. Maximum follow-up at time of analysis was 10.2 years for endometrium cancer patients and 9.5 years for cervical cancer patients. | Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each adverse events (AE) based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Late is defined as more than 90 days after the start of radiation therapy. |
| Percentage of Cervical Carcinoma Patients That Were Chemotherapy Compliant | From start to end of chemotherapy, approximately five weeks from registration. | Chemotherapy treatment was centrally reviewed for quality assurance and compliance once complete chemotherapy treatment data was received from sites. |
| Percentage of Patients With Grade 2+ Bowel Adverse Events | From the start of treatment to 90 days. | Bowel adverse events are defined as any of the following adverse events: diarrhea; enteritis; fistula; ileus:gastrointestinal (GI); incontinence:anal; necrosis:GI; obstruction:GI; perforation:GI; proctitis; stricture/stenosis (including anastomotic):GI. Adverse events are graded using Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to adverse event. |
| Rate of Distant Metastases at Five Years | From registration to five years | Distant Metastases failure time is defined as time from registration to date of distant disease, death without distant metastases (competing risk), or last known follow-up (censored) and is estimated by the cumulative incidence method. Para-aortic nodal disease is considered to be distant disease for a cervical primary, but not for an endometrial primary. |
| Rate of Disease-free Survival at Five Years | From registration five years | Disease-free survival time is defined as time from registration to date of failure (any tumor recurrence, development of distant metastases or death from any cause) and is estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact. |
| Rate of Overall Survival at Five Years | From randomization to five years | Overall survival time is defined as time from randomization to the date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. |
| Rate of Local-regional Failure at Five Years | From registration to five years. | Local-regional failure time is defined as time from registration to date of local-regional failure (any failure in the treatment field, which will be the pelvis only), death without local-regional failure (competing risk), or last known follow-up (censored). Local-regional failure rates are estimated by the cumulative incidence method. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Endometrial Cancer: IMRT Endometrial Cancer patients receive Intensity Modulated Radiation Therapy (IMRT) | 58 |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) Cervical patients receive Intensity Modulated Radiation Therapy (IMRT) + Chemotherapy (cisplatin) | 48 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible / no protocol treatment | 15 | 8 |
Baseline characteristics
| Characteristic | Endometrial Cancer: IMRT | Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Total |
|---|---|---|---|
| Age, Continuous | 58 years | 43 years | 53 years |
| Sex: Female, Male Female | 58 Participants | 48 Participants | 106 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 42 / 43 | 39 / 40 |
| serious Total, serious adverse events | 2 / 43 | 3 / 40 |
Outcome results
Primary
Reproducibility of Radiation Technique (Number of Unacceptable Deviations in Central IMRT Quality Assurance Review)
Central quality assurance review of the IMRT planning and dosing categorized unacceptable deviations (UD) from protocol compliance with the delineation of planning target volume for the vagina and pelvic lymph nodes. Each arm of this study is considered independently, they are not compared to each other. The study was designed such that, for each arm, 5 or more of 42 subjects scored as unacceptable would determine the respective treatment technique as not reproducible. For each arm this design provides 90% power with a 0.05 type I error to reject the null hypothesis that the true probability of concluding the given technique to be reproducible is \<= 80%. The alternative hypothesis is that the true probability is \>= 95%. For \[vagina / pelvic lymph nodes\]: UD is defined as: The 90% isodose surface covers \< 95% of \[internal target volume (ITV)/ planned target volume (PTV)\] 50.4 or \> 5% of the \[ITV/PTV\] 50.4 receives over 115%.
Time frame: IMRT planning and dosing data is centrally reviewed for quality assurance after treatment delivery.
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Cancer: IMRT | Reproducibility of Radiation Technique (Number of Unacceptable Deviations in Central IMRT Quality Assurance Review) | 1 participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Reproducibility of Radiation Technique (Number of Unacceptable Deviations in Central IMRT Quality Assurance Review) | 0 participants |
Secondary
Percentage of Cervical Carcinoma Patients That Were Chemotherapy Compliant
Chemotherapy treatment was centrally reviewed for quality assurance and compliance once complete chemotherapy treatment data was received from sites.
Time frame: From start to end of chemotherapy, approximately five weeks from registration.
Population: Eligible patients in the chemotherapy group (cervical cancer patients) who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Cancer: IMRT | Percentage of Cervical Carcinoma Patients That Were Chemotherapy Compliant | 80 percentage of participants |
Secondary
Percentage of Patients With Any Grade 3+ Treatment-related Adverse Events
Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.
Time frame: From start of treatment to the end of follow-up. Maximum follow-up at time of analysis was 10.2 years for endometrium cancer patients and 9.5 years for cervical cancer patients.
Population: Eligible patients who started study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Endometrial Cancer: IMRT | Percentage of Patients With Any Grade 3+ Treatment-related Adverse Events | Non-hematologic | 19 percentage of participants |
| Endometrial Cancer: IMRT | Percentage of Patients With Any Grade 3+ Treatment-related Adverse Events | Overall | 30 percentage of participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Percentage of Patients With Any Grade 3+ Treatment-related Adverse Events | Non-hematologic | 30 percentage of participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Percentage of Patients With Any Grade 3+ Treatment-related Adverse Events | Overall | 48 percentage of participants |
Secondary
Percentage of Patients With Any Late Grade 3+ Treatment-related Adverse Events
Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each adverse events (AE) based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Late is defined as more than 90 days after the start of radiation therapy.
Time frame: From 91 days after start of study treatment to the end of follow-up. Maximum follow-up at time of analysis was 10.2 years for endometrium cancer patients and 9.5 years for cervical cancer patients.
Population: Eligible patients who started study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Endometrial Cancer: IMRT | Percentage of Patients With Any Late Grade 3+ Treatment-related Adverse Events | Non-hematologic | 12 percentage of participants |
| Endometrial Cancer: IMRT | Percentage of Patients With Any Late Grade 3+ Treatment-related Adverse Events | Overall | 12 percentage of participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Percentage of Patients With Any Late Grade 3+ Treatment-related Adverse Events | Non-hematologic | 10 percentage of participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Percentage of Patients With Any Late Grade 3+ Treatment-related Adverse Events | Overall | 10 percentage of participants |
Secondary
Percentage of Patients With Grade 2+ Bowel Adverse Events
Bowel adverse events are defined as any of the following adverse events: diarrhea; enteritis; fistula; ileus:gastrointestinal (GI); incontinence:anal; necrosis:GI; obstruction:GI; perforation:GI; proctitis; stricture/stenosis (including anastomotic):GI. Adverse events are graded using Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to adverse event.
Time frame: From the start of treatment to 90 days.
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Cancer: IMRT | Percentage of Patients With Grade 2+ Bowel Adverse Events | 27.9 percentage of participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Percentage of Patients With Grade 2+ Bowel Adverse Events | 22.5 percentage of participants |
Comparison: A sample size of 42 patients provides 64% power to detect a reduction in short-term grade 2 or higher bowel AEs from historical rate of 40% to 25%.p-value: 0.12Chi-squared
Comparison: A sample size of 42 patients provides 88% power to detect a reduction in short-term grade 2 or higher bowel AEs from historical rate of 40% to 20%.p-value: 0.043Chi-squared
Secondary
Rate of Disease-free Survival at Five Years
Disease-free survival time is defined as time from registration to date of failure (any tumor recurrence, development of distant metastases or death from any cause) and is estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact.
Time frame: From registration five years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Cancer: IMRT | Rate of Disease-free Survival at Five Years | 88 percentage of participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Rate of Disease-free Survival at Five Years | 84 percentage of participants |
Secondary
Rate of Distant Metastases at Five Years
Distant Metastases failure time is defined as time from registration to date of distant disease, death without distant metastases (competing risk), or last known follow-up (censored) and is estimated by the cumulative incidence method. Para-aortic nodal disease is considered to be distant disease for a cervical primary, but not for an endometrial primary.
Time frame: From registration to five years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Cancer: IMRT | Rate of Distant Metastases at Five Years | 7 percentage of participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Rate of Distant Metastases at Five Years | 14 percentage of participants |
Secondary
Rate of Local-regional Failure at Five Years
Local-regional failure time is defined as time from registration to date of local-regional failure (any failure in the treatment field, which will be the pelvis only), death without local-regional failure (competing risk), or last known follow-up (censored). Local-regional failure rates are estimated by the cumulative incidence method.
Time frame: From registration to five years.
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Cancer: IMRT | Rate of Local-regional Failure at Five Years | 5 percentage of participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Rate of Local-regional Failure at Five Years | 8 percentage of participants |
Secondary
Rate of Overall Survival at Five Years
Overall survival time is defined as time from randomization to the date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.
Time frame: From randomization to five years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Cancer: IMRT | Rate of Overall Survival at Five Years | 88 percentage of participants |
| Cervical Cancer: IMRT + Chemotherapy (Cisplatin) | Rate of Overall Survival at Five Years | 92 percentage of participants |