Bladder Cancer
Conditions
Keywords
stage II bladder cancer, stage III bladder cancer, transitional cell carcinoma of the bladder
Brief summary
RATIONALE: Lymphadenectomy may remove tumor cells that have spread to nearby lymph nodes in patients with invasive bladder cancer. It is not yet known whether extended pelvic lymphadenectomy is more effective than standard pelvic lymphadenectomy during surgery. PURPOSE: This randomized phase II trial is studying standard pelvic lymphadenectomy to see how well it works compared to extended pelvic lymphadenectomy in treating patients undergoing surgery for invasive bladder cancer.
Detailed description
OBJECTIVES: Primary * To compare disease-free survival (DFS) of patients with muscle-invasive urothelial carcinoma of the bladder undergoing radical cystectomy with extended pelvic lymph node dissection (PLND) or standard pelvic lymphadenectomy. Secondary * To compare overall survival (OS) of patients randomized to extended PLND versus those randomized to standard pelvic lymphadenectomy. * To evaluate operative time; whether or not nerve sparing was performed, intraoperative, peri-operative and 90-day morbidity and mortality; length of hospital stay; histology (pure urothelial versus mixed); lymph node counts and lymph node density; adjuvant chemotherapy received; and local and retroperitoneal soft tissue recurrence in patients randomized to extended PLND versus those randomized to standard pelvic lymphadenectomy. * To collect peripheral blood and two paraffin-embedded blocks of the primary tumor for translational medicine studies, including circulating tumor cells (CTCs) and markers of epithelial and mesenchymal transition, and correlate these findings with pathologic T stage and node metastasis as well as DFS and OS. OUTLINE: This is a multicenter study. Patients are stratified according to prior neoadjuvant therapy (yes vs no), clinical stage (T2 vs T3 vs T4a), and Zubrod performance status (0-1 vs 2). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients undergo radical cystectomy and standard pelvic lymphadenectomy. * Arm II: Patients undergo radical cystectomy and extended pelvic lymphadenectomy. Blood and tumor specimens may be collected periodically for translational studies. After completion of study therapy, patients are followed up periodically for 6 years.
Interventions
PROCEDUREtherapeutic conventional surgery
Patients undergo radical cystectomy
PROCEDUREtherapeutic standard lymphadenectomy
Patients undergo standard pelvic lymphadenectomy.
PROCEDUREtherapeutic extended lymphadenectomy
Patients undergo extended pelvic lymphadenectomy
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed urothelial carcinoma of the bladder * Stage T2, T3, or T4a disease * No clinical stage consistent with a low-risk of node metastasis (CIS only, T1) * No T4b disease (fixed lesion) * Disease that requires primary radical cystectomy and lymph node dissection for definitive treatment * No laparoscopic surgery * Predominant urothelial carcinoma with any of the following elements allowed: * Adenocarcinoma * Squamous cell carcinoma * Micropapillary or minor components of other rare phenotype * No pure squamous cell carcinoma or adenocarcinoma * No visceral or nodal metastatic disease proximal to the common iliac bifurcation by 2-view chest x-ray and abdominal-pelvic imaging by computerized tomography or MRI of the abdomen and pelvis * No intra-operative pelvic lymph node involvement (confirmed by frozen section) at or above the bifurcation of the common iliac vessels in any of the extended template PATIENT CHARACTERISTICS: * Zubrod performance status 0-2 * ALT and AST ≤ upper limit of normal (ULN)\* * Alkaline phosphatase ≤ ULN\* * Not pregnant or nursing * Fertile patients must use an effective contraception * No other prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or stage I or II cancer from which the patient is in complete remission for the past 5 years * Medically suitable to undergo cystectomy, in the physician's opinion NOTE: \*Levels may be ≥ ULN provided metastatic disease is excluded using dedicated liver imaging, bone scan, or biopsy. PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior partial cystectomy for invasive bladder cancer * No prior pelvic surgery that would obviate a complete extended lymphadenectomy (e.g., aorto-femoral/iliac bypass) * Prior neoadjuvant chemotherapy for this cancer allowed provided it has been completed and patient has recovered * No prior pelvic irradiation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 5-year Disease-free Survival (DFS) | Duration of treatment and follow-up until death or 6 years after randomization | Comparing 5-year disease-free survival (DFS) in participants undergoing radical cystectomy for muscle-invasive urothelial carcinoma of the bladder (UCB) treated with radical cystectomy and extended pelvic lymph node dissection (PLND) compared to radical cystectomy and standard pelvic lymphadenectomy. Disease-free survival is defined as the time from the date of randomization to date of first documentation of relapse/recurrence or death due to any cause. Participants last known to be alive without report of relapse/recurrence are censored at date of last contact. Criteria for recurrence included measurable disease on cross-sectional imaging or plain radiography targeting lung, liver, and bone. If local pelvic recurrence was identified on digital rectal examination, biopsy was required for confirmation. Second primary tumors of the upper urinary tract or retained urethra were not considered to be recurrence. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Use of Nerve Preservation | Duration of surgery | Evaluating the frequency of nerve sparing surgery in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy. |
| 5-year Overall Survival (OS) | Duration of treatment and follow-up until death or 6 years after randomization | Comparing 5-year overall survival (OS) in participants randomized to extended PLND versus those randomized to standard pelvic lymphadenectomy. Overall survival is defined as the time from date of randomization to date of death from any cause. Participants known to be alive are censored at date of last contact. |
| Median Operative Time | Duration of surgery | Evaluating duration of surgery in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy. |
| Median Days in Hospital | From date of operation to 90 days post-operation | Evaluating duration of post-operative hospital stay in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy. |
| Receipt of Adjuvant Chemotherapy | From date of operation to 90 days post-operation | Evaluating the receipt of adjuvant chemotherapy in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy. Participants that reported plans to start adjuvant chemotherapy are included in these counts. |
| Frequency of Post-Operative Local Recurrence | From date of operation to 90 days post-operation | Evaluating the frequency of post-operative local and retroperitoneal soft-tissue recurrence in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy. |
| Post-Operative Morbidity | From date of operation to 90 days post-operation | Evaluating perioperative morbidity (death within 30 days of surgery) and post-operative morbidity (death within 90 days of surgery) in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy. |
| Lymph Node Counts | Duration of surgery | Evaluating the number of positive lymph nodes removed during surgery as well as the total number of lymph nodes removed in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy. |
Countries
Canada, United States
Participant flow
Pre-assignment details
658 participants were enrolled to Step 1 before surgery. 40 of participants did not undergo randomization primarily due to results of their intraoperative assessment. Thus, 618 participants were randomized to Step 2; 315 on the standard LND arm and 303 on the extended LND arm. 26 randomized participants were deemed ineligible. Which leaves a total of 592 randomized and eligible participants, 300 and 292 on the standard and extended LND, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Standard LND Active Comparator: Arm I Procedure/Surgery: therapeutic standard lymphadenectomy | 300 |
| Extended LND Experimental: Arm II Procedure/Surgery: therapeutic extended lymphadenectomy | 292 |
| Total | 592 |
Baseline characteristics
| Characteristic | Standard LND | Total | Extended LND |
|---|---|---|---|
| Age, Continuous | 68 years | 69 years | 69 years |
| Body Mass Index (BMI) | 27.3 kg/m^2 | 27.3 kg/m^2 | 27.3 kg/m^2 |
| Clinical T Stage T2 | 213 Participants | 421 Participants | 208 Participants |
| Clinical T Stage T3 or T4a | 87 Participants | 171 Participants | 84 Participants |
| Hydronephrosis | 74 Participants | 152 Participants | 78 Participants |
| Mixed Histologic Subtypes | 36 Participants | 48 Participants | 12 Participants |
| Neoadjuvant Chemotherapy Any neoadjuvant chemotherapy | 170 Participants | 336 Participants | 166 Participants |
| Neoadjuvant Chemotherapy Carboplatin-based | 10 Participants | 22 Participants | 12 Participants |
| Neoadjuvant Chemotherapy Cisplatin-based | 146 Participants | 293 Participants | 147 Participants |
| Neoadjuvant Chemotherapy None | 130 Participants | 256 Participants | 126 Participants |
| Neoadjuvant Chemotherapy Other neoadjuvant chemotherapy | 14 Participants | 21 Participants | 7 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 12 Participants | 5 Participants |
| Race/Ethnicity, Customized Black | 12 Participants | 22 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic | 6 Participants | 27 Participants | 21 Participants |
| Race/Ethnicity, Customized Other, Multiracial, Unknown | 10 Participants | 22 Participants | 12 Participants |
| Race/Ethnicity, Customized White | 271 Participants | 536 Participants | 265 Participants |
| Sex: Female, Male Female | 66 Participants | 122 Participants | 56 Participants |
| Sex: Female, Male Male | 234 Participants | 470 Participants | 236 Participants |
| Zubrod Performance Status of 0 or 1 0-1 | 295 Participants | 583 Participants | 288 Participants |
| Zubrod Performance Status of 0 or 1 2 | 5 Participants | 9 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 117 / 300 | 124 / 292 |
| other Total, other adverse events | 226 / 300 | 219 / 292 |
| serious Total, serious adverse events | 3 / 300 | 12 / 292 |
Outcome results
Primary
5-year Disease-free Survival (DFS)
Comparing 5-year disease-free survival (DFS) in participants undergoing radical cystectomy for muscle-invasive urothelial carcinoma of the bladder (UCB) treated with radical cystectomy and extended pelvic lymph node dissection (PLND) compared to radical cystectomy and standard pelvic lymphadenectomy. Disease-free survival is defined as the time from the date of randomization to date of first documentation of relapse/recurrence or death due to any cause. Participants last known to be alive without report of relapse/recurrence are censored at date of last contact. Criteria for recurrence included measurable disease on cross-sectional imaging or plain radiography targeting lung, liver, and bone. If local pelvic recurrence was identified on digital rectal examination, biopsy was required for confirmation. Second primary tumors of the upper urinary tract or retained urethra were not considered to be recurrence.
Time frame: Duration of treatment and follow-up until death or 6 years after randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard LND | 5-year Disease-free Survival (DFS) | 60 percentage of participants |
| Extended LND | 5-year Disease-free Survival (DFS) | 56 percentage of participants |
Comparison: 3-year DFS estimates of 55% among participants undergoing SLND and 65% undergoing ELND were used to estimate the target HR. Assuming exponential DFS distribution, 5 years of enrollment, 3 years of follow-up, and 564 eligible participants, the trial would have 85% power to detect a 28% lower risk of recurrence or death with ELND than SLND.p-value: 0.4595% CI: [0.86, 1.4]Log Rank
Secondary
5-year Overall Survival (OS)
Comparing 5-year overall survival (OS) in participants randomized to extended PLND versus those randomized to standard pelvic lymphadenectomy. Overall survival is defined as the time from date of randomization to date of death from any cause. Participants known to be alive are censored at date of last contact.
Time frame: Duration of treatment and follow-up until death or 6 years after randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard LND | 5-year Overall Survival (OS) | 63 percentage of participants |
| Extended LND | 5-year Overall Survival (OS) | 59 percentage of participants |
Comparison: We assumed that the standard lymphadenectomy arm has 5-year survival of 55%, so we had 83% statistical power to detect a hazard ratio of 0.72 (55% vs. 65% survival at 5 years).95% CI: [0.88, 1.45]
Secondary
Frequency of Post-Operative Local Recurrence
Evaluating the frequency of post-operative local and retroperitoneal soft-tissue recurrence in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.
Time frame: From date of operation to 90 days post-operation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard LND | Frequency of Post-Operative Local Recurrence | 9 percentage of participants |
| Extended LND | Frequency of Post-Operative Local Recurrence | 13 percentage of participants |
Secondary
Lymph Node Counts
Evaluating the number of positive lymph nodes removed during surgery as well as the total number of lymph nodes removed in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.
Time frame: Duration of surgery
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard LND | Lymph Node Counts | Total lymph nodes removed | 24 number of lymph nodes |
| Standard LND | Lymph Node Counts | Positive lymph nodes removed | 1 number of lymph nodes |
| Extended LND | Lymph Node Counts | Total lymph nodes removed | 39 number of lymph nodes |
| Extended LND | Lymph Node Counts | Positive lymph nodes removed | 2 number of lymph nodes |
Secondary
Median Days in Hospital
Evaluating duration of post-operative hospital stay in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.
Time frame: From date of operation to 90 days post-operation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard LND | Median Days in Hospital | 6 days |
| Extended LND | Median Days in Hospital | 7 days |
Secondary
Median Operative Time
Evaluating duration of surgery in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.
Time frame: Duration of surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard LND | Median Operative Time | 5.3 hours |
| Extended LND | Median Operative Time | 5.9 hours |
Secondary
Post-Operative Morbidity
Evaluating perioperative morbidity (death within 30 days of surgery) and post-operative morbidity (death within 90 days of surgery) in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.
Time frame: From date of operation to 90 days post-operation
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard LND | Post-Operative Morbidity | Death within 30 days | 1 Participants |
| Standard LND | Post-Operative Morbidity | Death within 90 days | 7 Participants |
| Extended LND | Post-Operative Morbidity | Death within 30 days | 8 Participants |
| Extended LND | Post-Operative Morbidity | Death within 90 days | 19 Participants |
Secondary
Receipt of Adjuvant Chemotherapy
Evaluating the receipt of adjuvant chemotherapy in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy. Participants that reported plans to start adjuvant chemotherapy are included in these counts.
Time frame: From date of operation to 90 days post-operation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard LND | Receipt of Adjuvant Chemotherapy | 11 percentage of participants |
| Extended LND | Receipt of Adjuvant Chemotherapy | 11 percentage of participants |
Secondary
Use of Nerve Preservation
Evaluating the frequency of nerve sparing surgery in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.
Time frame: Duration of surgery
Population: The overall number of nerve-sparing surgeries performed per arm is reported as well as the numbers for males and females on each arm. The standard LND arm has 234 male participants and 66 females, while the extended LND arm has 236 males and 56 females.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Standard LND | Use of Nerve Preservation | Male | No | 143 Participants |
| Standard LND | Use of Nerve Preservation | Male | Unilateral | 12 Participants |
| Standard LND | Use of Nerve Preservation | Male | Bilateral | 79 Participants |
| Standard LND | Use of Nerve Preservation | Female | No | 60 Participants |
| Standard LND | Use of Nerve Preservation | Female | Unilateral | 0 Participants |
| Standard LND | Use of Nerve Preservation | Female | Bilateral | 6 Participants |
| Standard LND | Use of Nerve Preservation | Overall | No | 203 Participants |
| Standard LND | Use of Nerve Preservation | Overall | Unilateral | 12 Participants |
| Standard LND | Use of Nerve Preservation | Overall | Bilateral | 85 Participants |
| Extended LND | Use of Nerve Preservation | Overall | Unilateral | 9 Participants |
| Extended LND | Use of Nerve Preservation | Male | No | 151 Participants |
| Extended LND | Use of Nerve Preservation | Female | Bilateral | 7 Participants |
| Extended LND | Use of Nerve Preservation | Male | Unilateral | 9 Participants |
| Extended LND | Use of Nerve Preservation | Female | Unilateral | 0 Participants |
| Extended LND | Use of Nerve Preservation | Male | Bilateral | 76 Participants |
| Extended LND | Use of Nerve Preservation | Overall | No | 200 Participants |
| Extended LND | Use of Nerve Preservation | Female | No | 49 Participants |
| Extended LND | Use of Nerve Preservation | Overall | Bilateral | 83 Participants |