Bladder Cancer
Conditions
Keywords
stage I bladder cancer, transitional cell carcinoma of the bladder
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy 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, mitomycin C, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with cisplatin may kill more tumor cells. PURPOSE: This phase II trial is studying how well radiation therapy given together with chemotherapy works in treating patients with stage I bladder cancer.
Detailed description
After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and annually thereafter until termination of the study.
Interventions
DRUGcisplatin
60-minute intravenous (IV) infusion of 15 mg/m\^2 on days 1, 2, 3, 15, 16, 17, 29, 30, and 31 of radiation treatment.
DRUG5-fluorouracil
Continuous IV infusion of 500 mg/m\^2/24 hrs for 5 consecutive days during weeks 1 and 4 of radiation treatment.
DRUGMitomycin
IV bolus dose of 12 mg/m\^2 on day 1 of radiation treatment.
Total dose to the gross bladder volume of 61.2 Gy as 34 daily fractions 5 days/week, for approximately 7 weeks.
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
1. Pathologically proven diagnosis of carcinoma of the bladder within 105 days prior to registration. • Operable patients whose initial tumor is a primary high grade urothelial carcinoma of the bladder exhibiting histologic evidence of invasion into the lamina propria (disease clinical stage T1) or a high grade stage Ta urothelial carcinoma without hydronephrosis; patients who have involvement of the prostatic urethra with urothelial carcinoma and have no evidence of stromal invasion of the prostate remain eligible. If the patient's initial tumor was a high grade stage Ta urothelial carcinoma then his/her recurrent tumor must be a high grade stage T1 urothelial carcinoma to be eligible. 2. Patients must have a high grade urothelial carcinoma stage Ta or T1 that has recurred within 540 days after completion of the initial treatment \[TURBT and intravesical Bacillus Calmette Guerin (BCG) immunotherapy\] or on initial presentation with a T1 high grade tumor, the participating urologist judged BCG therapy is contraindicated or unsuitable because the patient is found to be intolerant of BCG therapy or because this patient may be immuno-compromised in ways other than that mentioned in
Exclusion criteria
2.8 or because the patient refuses BCG therapy. 3. With the presentations as described in Section 2, the participating urologist judges that the standard next therapy, based on present urologic guidelines for this patient, is radical cystectomy. 4. If radiologic evaluation of a lymph node is interpreted as positive, this must be evaluated further either by lymphadenectomy or by percutaneous needle biopsy. Patients with histologically or cytologically confirmed node metastases will not be eligible. 5. Patients must have an adequately functioning bladder as judged by the participating urologist and radiation oncologist and have undergone a re-staging TURBT by the participating urologist that showed (or was present in the outside pathology specimen) a high grade stage Ta or T1 tumor with uninvolved muscularis propria in the specimen and, if on prostatic urethral biopsy mucosal carcinoma is present, there is no evidence on biopsy in the prostatic stroma of tumor invasion. 6. Patient must be considered able to tolerate systemic chemotherapy combined with pelvic radiation therapy, and a radical cystectomy (if necessary) by the joint agreement of the participating urologist, radiation oncologist, and medical oncologist. 7. Appropriate stage for protocol entry, based upon the following minimum diagnostic workup within 60 days prior to registration: • History/physical examination including weight, performance data, body surface area 8. Zubrod Performance Status ≤ 1 9. Age ≥ 18 10. Complete blood count (CBC)/differential obtained no more than 30 days prior to registration on study, with adequate bone marrow function defined as follows: * White blood cell count (WBC) ≥ 4,000/ml * Absolute neutrophil count (ANC) ≥ 1,800 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.) 11. If the patient is to be treated with cisplatin, the serum creatinine should be ≤ 1.5 mg%; serum bilirubin of ≤ 2.0 mg% 12. Glomerular filtration rate (GFR) \> 25 ml/min \[For patients receiving cisplatin, GFR ≥ 60 ml/min\] 13. Serum pregnancy test for female patients of childbearing potential, ≤ 72 hours prior to study entry; women of childbearing potential and male participants must practice adequate contraception. 14. Patient must be able to provide study-specific informed consent prior to study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Free From Radical Cystectomy at 3 Years | Three years from registration | The number of participants who did not undergo a radical cystectomy within three years divided by the number of analyzed participants, presented with the 97.5% lower bound. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Distant Disease Progression at 3 Years | From registration to three years | Distant disease progression is defined as the first appearance of disease in a non-regional lymph node, solid organ or bone. Time to distant disease progression is defined as time from registration to the date of first distant disease progression, last known follow-up (censored), or death without distant disease progression (competing risk). Distant disease progression rate is estimated using the cumulative incidence method. |
| Percent of Participants With Distant Disease Progression at 5 Years | From registration to five years | Distant disease progression is defined as the first appearance of disease in a non-regional lymph node, solid organ or bone. Time to distant disease progression is defined as time from registration to the date of first distant disease progression, last known follow-up (censored), or death without distant disease progression (competing risk). Distant disease progression rate is estimated using the cumulative incidence method. |
| Percentage of Participants With Progression to Tumor Stage T2 or Greater at 3 Years | From registration to three years | Primary tumor stage T2 = tumor invades muscle; T3 = tumor invades perivesical tissue; T4 = tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall. Time to progression is defined as time from registration to the date of first progression, last known follow-up (censored), or death without tumor progression (competing risk). Tumor progression rates was to be estimated using the cumulative incidence method. |
| Percentage of Participants With Progression to Tumor Stage T2 or Greater at 5 Years | From registration to five years | Primary tumor stage T2 = tumor invades muscle; T3 = tumor invades perivesical tissue; T4 = tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall. Time to progression is defined as time from registration to the date of first progression, last known follow-up (censored), or death without tumor progression (competing risk). Tumor progression rate was to be estimated using the cumulative incidence method. |
| Percentage of Participants Who Have Died From Bladder Cancer at 5 Years (Disease-specific Survival) | From registration to five years | Time to death from bladder cancer is defined as time from registration to death from bladder cancer, last known follow-up (censored), or death from other cause (competing risk). More specifically, death absent a distant metastasis, death from non-bladder cancer, and death absent local recurrence comprise the competing risk. Death from bladder cancer rate is estimated using the cumulative incidence method. |
| Percentage of Participants Free From Radical Cystectomy at 5 Years | Five years from registration | The number of participants who did not undergo a radical cystectomy within five years divided by the number of analyzed participants. |
| Percentage of Participants Alive at 5 Years | From registration to five years | Overall survival time is defined as time from registration to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. |
| Distribution of Participants by Highest Grade Adverse Event | Adverse events are evaluated 8-10 weeks after end of study treatment (approximately 7 weeks), then every 3 months for one year, every 4 months for one year, every 6 months for 3 years, then annually. Maximum follow-up at time of reporting was 8.6 years. | Common Terminology Criteria for Adverse Events (CTCAE) version 4 grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. |
| Percentage of Participants With Local Recurrence at 3 Years | From registration to three years | Time to local recurrence is defined as time from registration to the date of first local recurrence, last known follow-up (censored), or death without local recurrence (competing risk). Local recurrence rate is estimated using the cumulative incidence method. |
| American Urological Association Total Symptom Score at Baseline and at 3 Years | Baseline and 3 years | The American Urological Association Total symptom score measures the severity of enlarged prostate symptoms. Possible scores range from 0 to 35, with higher scores indicating worse symptoms. |
| Percentage of Participants Alive at 3 Years | From registration to three years | Overall survival time is defined as time from registration to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 3DCRT + CT Concurrent three-dimensional conformal radiation therapy (3DCRT) and radiosensitizing chemotherapy (CT) consisting of either cisplatin alone or the combination of mitomycin and 5-fluorouracil. Protocol treatment must begin with 15 weeks after a transurethral resection of the tumor (TURBT). | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not start protocol treatment | 2 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | 3DCRT + CT |
|---|---|
| Age, Customized Years ≤ 59 | 4 Participants |
| Age, Customized Years 60-69 | 12 Participants |
| Age, Customized Years 70-79 | 14 Participants |
| Age, Customized Years ≥ 80 | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 32 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 31 Participants |
| Zubrod 0 | 29 Participants |
| Zubrod 1 | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 15 / 34 |
| other Total, other adverse events | 33 / 34 |
| serious Total, serious adverse events | 7 / 34 |
Outcome results
Primary
Percentage of Participants Free From Radical Cystectomy at 3 Years
The number of participants who did not undergo a radical cystectomy within three years divided by the number of analyzed participants, presented with the 97.5% lower bound.
Time frame: Three years from registration
Population: Eligible participants who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3DCRT + CT | Percentage of Participants Free From Radical Cystectomy at 3 Years | 88.2 percentage of participants |
Comparison: Null hypothesis = this treatment will result in 75% of participants free from radical cystectomy at 3 years. A lower confidence bound of 60% will be promising enough to pursue this regimen further. A sample size of 33 analyzable patients provides a one-sided 97.5% lower bound of 60% relative to the hypothesized 75%. In terms of type I error, this design provides a 2.5% chance of observing a 3-year percentage less than 60% if the true rate is 75%.
Secondary
American Urological Association Total Symptom Score at Baseline and at 3 Years
The American Urological Association Total symptom score measures the severity of enlarged prostate symptoms. Possible scores range from 0 to 35, with higher scores indicating worse symptoms.
Time frame: Baseline and 3 years
Population: Eligible participants who started study treatment and have baseline data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 3DCRT + CT | American Urological Association Total Symptom Score at Baseline and at 3 Years | Baseline | 9.84 units on a scale | Standard Deviation 6.47 |
| 3DCRT + CT | American Urological Association Total Symptom Score at Baseline and at 3 Years | Three years | 12.00 units on a scale | Standard Deviation 9.25 |
Secondary
Distribution of Participants by Highest Grade Adverse Event
Common Terminology Criteria for Adverse Events (CTCAE) version 4 grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: Adverse events are evaluated 8-10 weeks after end of study treatment (approximately 7 weeks), then every 3 months for one year, every 4 months for one year, every 6 months for 3 years, then annually. Maximum follow-up at time of reporting was 8.6 years.
Population: Eligible participants who started study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 3DCRT + CT | Distribution of Participants by Highest Grade Adverse Event | Grade 1 | 2 Participants |
| 3DCRT + CT | Distribution of Participants by Highest Grade Adverse Event | Grade 2 | 9 Participants |
| 3DCRT + CT | Distribution of Participants by Highest Grade Adverse Event | Grade 3 | 20 Participants |
| 3DCRT + CT | Distribution of Participants by Highest Grade Adverse Event | Grade 4 | 2 Participants |
| 3DCRT + CT | Distribution of Participants by Highest Grade Adverse Event | Grade 5 | 0 Participants |
Secondary
Percentage of Participants Alive at 3 Years
Overall survival time is defined as time from registration to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.
Time frame: From registration to three years
Population: Eligible participants who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3DCRT + CT | Percentage of Participants Alive at 3 Years | 69.2 percentage of participants |
Secondary
Percentage of Participants Alive at 5 Years
Overall survival time is defined as time from registration to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.
Time frame: From registration to five years
Population: Eligible participants who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3DCRT + CT | Percentage of Participants Alive at 5 Years | 56.4 percentage of participants |
Secondary
Percentage of Participants Free From Radical Cystectomy at 5 Years
The number of participants who did not undergo a radical cystectomy within five years divided by the number of analyzed participants.
Time frame: Five years from registration
Population: Eligible participants who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3DCRT + CT | Percentage of Participants Free From Radical Cystectomy at 5 Years | 88.2 percentage of participants |
Secondary
Percentage of Participants Who Have Died From Bladder Cancer at 5 Years (Disease-specific Survival)
Time to death from bladder cancer is defined as time from registration to death from bladder cancer, last known follow-up (censored), or death from other cause (competing risk). More specifically, death absent a distant metastasis, death from non-bladder cancer, and death absent local recurrence comprise the competing risk. Death from bladder cancer rate is estimated using the cumulative incidence method.
Time frame: From registration to five years
Population: Eligible participants who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3DCRT + CT | Percentage of Participants Who Have Died From Bladder Cancer at 5 Years (Disease-specific Survival) | 25.1 percentage of participants |
Secondary
Percentage of Participants With Local Recurrence at 3 Years
Time to local recurrence is defined as time from registration to the date of first local recurrence, last known follow-up (censored), or death without local recurrence (competing risk). Local recurrence rate is estimated using the cumulative incidence method.
Time frame: From registration to three years
Population: Eligible participants who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3DCRT + CT | Percentage of Participants With Local Recurrence at 3 Years | 32.5 percentage of participants |
Secondary
Percentage of Participants With Progression to Tumor Stage T2 or Greater at 3 Years
Primary tumor stage T2 = tumor invades muscle; T3 = tumor invades perivesical tissue; T4 = tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall. Time to progression is defined as time from registration to the date of first progression, last known follow-up (censored), or death without tumor progression (competing risk). Tumor progression rates was to be estimated using the cumulative incidence method.
Time frame: From registration to three years
Population: T-stage was not collected on follow-up forms and therefore this outcome measure could not be not analyzed.
Secondary
Percentage of Participants With Progression to Tumor Stage T2 or Greater at 5 Years
Primary tumor stage T2 = tumor invades muscle; T3 = tumor invades perivesical tissue; T4 = tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall. Time to progression is defined as time from registration to the date of first progression, last known follow-up (censored), or death without tumor progression (competing risk). Tumor progression rate was to be estimated using the cumulative incidence method.
Time frame: From registration to five years
Population: T-stage was not collected on follow-up forms and therefore this outcome measure cab not be not analyzed.
Secondary
Percent of Participants With Distant Disease Progression at 3 Years
Distant disease progression is defined as the first appearance of disease in a non-regional lymph node, solid organ or bone. Time to distant disease progression is defined as time from registration to the date of first distant disease progression, last known follow-up (censored), or death without distant disease progression (competing risk). Distant disease progression rate is estimated using the cumulative incidence method.
Time frame: From registration to three years
Population: Eligible participants who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3DCRT + CT | Percent of Participants With Distant Disease Progression at 3 Years | 12.3 percentage of participants |
Secondary
Percent of Participants With Distant Disease Progression at 5 Years
Distant disease progression is defined as the first appearance of disease in a non-regional lymph node, solid organ or bone. Time to distant disease progression is defined as time from registration to the date of first distant disease progression, last known follow-up (censored), or death without distant disease progression (competing risk). Distant disease progression rate is estimated using the cumulative incidence method.
Time frame: From registration to five years
Population: Eligible participants who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3DCRT + CT | Percent of Participants With Distant Disease Progression at 5 Years | 18.7 percentage of participants |