Cervical Cancer
Conditions
Keywords
Cervical, Carcinoma, Cisplatin, IMRT, Radiation, INTERTECC, International, External Beam, Brachytherapy, LDR, HDR, IGRT, CBCT
Brief summary
The purpose of this study is to find out whether patients with cervical cancer treated with PET-guided Bone Marrow Sparing IMRT have less side effects with equal cancer control compared to standard radiation techniques (IMRT). The hypothesis is that PET-guided Bone Marrow Sparing IMRT will reduce acute hematologic and gastrointestinal toxicity and increase chemotherapy tolerance for cervical cancer patients treated with concurrent cisplatin.
Detailed description
Multiple randomized controlled trials have established concurrent cisplatin-based chemoradiotherapy as the standard of care for locally advanced cervical cancer \[3-8\]. The addition of concurrent cisplatin to radiotherapy (RT) increases pelvic control, disease-free survival (DFS) and overall survival; however, 5-year DFS and overall survival are still only approximately 60% and 5-year pelvic failure is approximately 30%. Moreover, acute gastrointestinal (GI) and hematologic toxicity are increased. Approximately 30% of patients will experience acute grade ≥ 3 toxicity, predominantly GI and hematologic. Methods to reduce toxicity during chemoradiotherapy, particularly gastrointestinal and hematologic, could mitigate this toxicity and take advantage of the therapeutic benefits of intensive concurrent chemotherapy. Intensity modulated radiation therapy (IMRT) is a modern RT technique that differs from conventional techniques in many ways. First, patients undergo computed tomography (CT) simulation so that customized target volumes can be defined 3-dimensionally. IMRT treatment planning involves multiple beam angles and uses computerized inverse treatment planning optimization algorithms to identify dose distributions and intensity patterns that conform dose to the target, reducing radiation dose to surrounding tissues. IMRT delivery is typically accomplished with the use of multileaf collimators, which involve small motorized leaflets (collimators) that move in and out of the beam path, modulating the dose intensity. PET-guided Bone Marrow Sparing IMRT is designed to spare hematopoietically active subregions of the pelvic bone marrow using quantitative image segmentation. Previous studies indicate this approach can reduce toxicity and improve chemotherapy tolerance, which may improve outcomes and help optimized delivery of cytotoxic chemotherapy.
Interventions
RADIATIONPET-guided Bone Marrow-Sparing Intensity Modulated Radiation Therapy (IMRT)
IMRT 45.0 Gy (intact) or 50.4 Gy (postoperative high-risk) in 1.8 Gy daily fractions over 5-5.5 weeks with PET-guided Bone Marrow-Sparing
DRUGCisplatin
Weekly infusion of 40 mg/m2 (80 mg max) x 5 weeks
RADIATIONIMRT
IMRT 45.0 Gy (intact) or 50.4 Gy (postoperative high-risk) in 1.8 Gy daily fractions over 5-5.5 weeks
Sponsors
National Cancer Institute (NCI)
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase II: IMRT (standard) vs. PET-guided Bone Marrow-Sparing IMRT (experimental), non-randomized Phase III: IMRT (standard) vs. PET-guided Bone Marrow-Sparing IMRT (experimental), randomized
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Biopsy-proven, invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix * Biopsy result positive for carcinoma within 60 days prior to registration * FIGO clinical stage I-IVA disease, based on standard diagnostic workup, including:History/physical examination and/or Examination under anesthesia (if indicated) * If the patient is status post hysterectomy, one or more of the following conditions must be present: positive lymph nodes, positive margins, parametrial invasion, or non-radical surgery (i.e., simple hysterectomy). * If the patient is inoperable, one or more of the following conditions must be present: clinical stage IB2-IVA, positive lymph nodes on nodal sampling or frozen section, and/or parametrial invasion * Within 42 days prior to registration, the patient must have any of the following, if clinically indicated: examination under anesthesia, cystoscopy, sigmoidoscopy, rigid proctoscopy, or colonoscopy. * X-ray (PA and lateral), CT scan, or PET/CT scan of the chest within 42 days prior to registration; * CT scan, MRI, or PET/CT of the pelvis within 42 days prior to registration; * Karnofsky Performance Status 60-100 * Absolute neutrophil count (ANC) ≥ 1500 cells/mm3; Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable); Creatinine clearance ≥ 50 mg/dl; Bilirubin \< 1.5 mg/dl; WBC ≥ 3,000/μl; ALT/AST \< 3 x ULN; INR ≤ 1.5 * Negative serum pregnancy test for women of child-bearing potential
Exclusion criteria
* Prior invasive malignancy (except non-melanomatous skin cancer), unless disease free for a minimum of 3 years; * Prior systemic chemotherapy within the past three years * Prior radiotherapy to the pelvis or abdomen that would result in overlap of radiation therapy fields; * Para-aortic, inguinal, or gross (unresected) pelvic nodal metastasis. Gross pelvic nodal metastasis is defined as either: Radiographic evidence of nodal metastasis on CT or MRI (node having short axis diameter \> 1 cm)OR Radiographic evidence of nodal metastasis on diagnostic FDG-PET or PET/CT scan (abnormally increased FDG uptake as determined and documented by the radiologist)OR Biopsy-proven metastasis (e.g. needle biopsy) in undissected node * Distant metastasis * Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects * Uncontrolled diabetes, defined as diabetes mellitus, which in the opinion of any of the patient's physicians requires an immediate change in management; * Uncompensated heart disease or uncontrolled high blood pressure * Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Event (Acute Hematologic or GI Toxicity) | Up to 30 days post radiation, about one month | Acute grade \>= 3 neutropenia or clinically significant \>=2 diarrhea or any grade \>=3 GI toxicity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Up to 36 Months post treatment, a total of about 38 months | Time from registration to first recurrence of disease or death from any cause |
| Acute Adverse Events | Up to 30 days post-treatment, about one month | Acute grade 2 and 3 Adverse Events occurring Up to 30 days post-treatment |
Countries
China, Czechia, India, Poland, Thailand, United States
Participant flow
Pre-assignment details
7 participants determined to be ineligible. 1 participant withdrew before protocol therapy due to an emergency
Participants by arm
| Arm | Count |
|---|---|
| IMRT All patients receive IMRT with concurrent cisplatin 40 mg/m2
Intensity Modulated Radiation Therapy (IMRT): 45.0 Gy (intact) or 50.4 Gy (postoperative high-risk) in 1.8 Gy daily fractions over 5-5.5 weeks
Cisplatin: Weekly infusion of 40 mg/m2 (80 mg max) x 5 weeks | 55 |
| PET-Guided Bone Marrow-Sparing IMRT PET-Guided Bone Marrow-Sparing IMRT with concurrent cisplatin 40 mg/m2 Intensity Modulated Radiation Therapy (IMRT): 45.0 Gy (intact) or 50.4 Gy (postoperative high-risk) in 1.8 Gy daily fractions over 5-5.5 weeks Cisplatin: Weekly infusion of 40 mg/m2 (80 mg max) x 5 weeks | 46 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible | 7 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | PET-Guided Bone Marrow-Sparing IMRT | Total | IMRT |
|---|---|---|---|
| Age, Continuous | 46 years STANDARD_DEVIATION 51.2 | 52.8 years STANDARD_DEVIATION 12.6 | 54.1 years STANDARD_DEVIATION 12.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 12 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 82 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 7 Participants | 3 Participants |
| Figo Stage IB1 | 3 Participants | 4 Participants | 1 Participants |
| Figo Stage IB2 | 7 Participants | 12 Participants | 5 Participants |
| Figo Stage IIA1 | 1 Participants | 4 Participants | 3 Participants |
| Figo Stage IIB | 25 Participants | 66 Participants | 41 Participants |
| Figo Stage IIIB | 10 Participants | 13 Participants | 3 Participants |
| Figo Stage IVA | 0 Participants | 2 Participants | 2 Participants |
| Grade 1 | 1 Participants | 4 Participants | 3 Participants |
| Grade 2 | 16 Participants | 44 Participants | 28 Participants |
| Grade 3 | 16 Participants | 34 Participants | 18 Participants |
| Grade Not graded | 13 Participants | 19 Participants | 6 Participants |
| Histologic Status Adenocarcinoma | 10 Participants | 18 Participants | 8 Participants |
| Histologic Status Squamous cell Carcinoma | 36 Participants | 83 Participants | 47 Participants |
| Kamofsky Status 100 | 27 Participants | 56 Participants | 29 Participants |
| Kamofsky Status 70 | 1 Participants | 1 Participants | 0 Participants |
| Kamofsky Status 80 | 1 Participants | 5 Participants | 4 Participants |
| Kamofsky Status 90 | 17 Participants | 39 Participants | 22 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 18 Participants | 11 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Latina/Hispanic | 9 Participants | 12 Participants | 3 Participants |
| Race/Ethnicity, Customized Other/unknown | 4 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized White, non-Hispanic | 26 Participants | 64 Participants | 38 Participants |
| Sex: Female, Male Female | 46 Participants | 101 Participants | 55 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 | 0 / 55 | 0 / 46 |
| other Total, other adverse events | 55 / 55 | 46 / 46 |
| serious Total, serious adverse events | 0 / 55 | 0 / 46 |
Outcome results
Primary
Primary Event (Acute Hematologic or GI Toxicity)
Acute grade \>= 3 neutropenia or clinically significant \>=2 diarrhea or any grade \>=3 GI toxicity
Time frame: Up to 30 days post radiation, about one month
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMRT Arm (Phase II) | Primary Event (Acute Hematologic or GI Toxicity) | 55 Participants |
| PET-Guided BMS-IMRT (Phase II) | Primary Event (Acute Hematologic or GI Toxicity) | 46 Participants |
Secondary
Acute Adverse Events
Acute grade 2 and 3 Adverse Events occurring Up to 30 days post-treatment
Time frame: Up to 30 days post-treatment, about one month
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT Arm (Phase II) | Acute Adverse Events | Grade 2 or higher GI toxicity | 17 participants |
| IMRT Arm (Phase II) | Acute Adverse Events | Grade 3 or higher GI toxicity | 2 participants |
| IMRT Arm (Phase II) | Acute Adverse Events | Grade 3 or higher hematologic toxicity | 17 participants |
| PET-Guided BMS-IMRT (Phase II) | Acute Adverse Events | Grade 2 or higher GI toxicity | 17 participants |
| PET-Guided BMS-IMRT (Phase II) | Acute Adverse Events | Grade 3 or higher GI toxicity | 1 participants |
| PET-Guided BMS-IMRT (Phase II) | Acute Adverse Events | Grade 3 or higher hematologic toxicity | 25 participants |
Secondary
Progression-free Survival
Time from registration to first recurrence of disease or death from any cause
Time frame: Up to 36 Months post treatment, a total of about 38 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMRT Arm (Phase II) | Progression-free Survival | 46 Participants |
| PET-Guided BMS-IMRT (Phase II) | Progression-free Survival | 55 Participants |