High Grade Upper Tract Urothelial Carcinoma
Conditions
Keywords
carcinoma, drug therapy, nephroureterectomy, urinary tract, urothelium
Brief summary
This phase II trial studies how well giving chemotherapy before surgery works in treating patients with aggressive upper urinary tract cancer. Drugs used in chemotherapy, such as methotrexate, vinblastine, doxorubicin hydrochloride, cisplatin, gemcitabine hydrochloride, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Removing the affected upper urinary tract by surgery is the recommended treatment for upper urinary tract cancer, but can cause loss of kidney function and prevent patients from being able to receive chemotherapy after surgery. Giving chemotherapy before surgery, when the kidneys are working at their maximum, may allow less tissue to be removed during surgery and may be more effective in treating patients with high grade upper urinary tract cancer.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the rate of complete pathologic response (pCR = pT0pN0) as assessed by standard pathologic review attained by neoadjuvant systemic chemotherapy and nephroureterectomy. SECONDARY OBJECTIVES: I. To evaluate the safety of neoadjuvant systemic chemotherapy in patients with upper tract urothelial carcinoma preceding nephroureterectomy. II. To evaluate distant recurrence-free survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy. III. To evaluate event-free survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy. IV. To evaluate bladder cancer-free survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy. V. To evaluate cancer specific survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy. VI. To evaluate renal functional outcomes of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy. TERTIARY OBJECTIVES: I. To collect pre-treatment and post-treatment tumor tissue, peripheral blood mononuclear cell (PBMC), peripheral blood plasma, and urine specimens for potential evaluations of markers of chemotherapy response/resistance. OUTLINE: Patients are assigned to 1 of 2 treatment arms based on baseline renal function. ARM A (CREATININE CLEARANCE \[CRCL\] \> 50): Patients receive methotrexate intravenously (IV) over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy. ARM B (30 =\< CRCL \<= 50): Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Interventions
DRUGMethotrexate
Given IV
DRUGVinblastine
Given IV
DRUGDoxorubicin
Given IV
DRUGCisplatin
Given IV
DRUGGemcitabine
Given IV
DRUGCarboplatin
Given IV
DRUGPegfilgrastim
Administered subcutaneously
PROCEDURENephroureterectomy
Undergo nephroureterectomy and lymph node dissection
Sponsors
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have high grade upper tract urothelial carcinoma proven by one of the following: * Biopsy; * Urinary cytology with a 3-dimensional upper urinary tract mass on cross-sectional imaging; or * Urinary cytology and a mass visualized during upper urinary tract endoscopy * Patients must have a creatinine clearance \>= 30 ml/min as determined by Cockcroft-Gault calculation or 24-hour urine creatinine clearance measurement within 28 days of registration to be eligible for the study * Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Patients must have a left ventricular ejection fraction (LVEF) \>= 50% by (either multigated acquisition \[MUGA\] or 2-dimensional \[2-D\] echocardiogram) within 28 days of registration * Absolute neutrophil count (ANC) \>= 1500/mm\^3 * Platelets \>= 100,000/mm\^3 * Hemoglobin (HgB) \>= 9 * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) \< 2 X institutional upper limit of normal (ULN) * Bilirubin within institutional normal limits (or \< 2.5 X the ULN for patients with Gilbert's disease) * Patients with concomitant primaries of the bladder/urethra are allowed, as long as these sites are surgically resected and non-invasive cancers (\< cT1N0) * Patients may have a history of resectable urothelial cancer (including neoadjuvant chemotherapy) as long as patients meet one of the following: * pT0, Tis, or T1N0 and have no evidence of disease (NED) for more than 2 years from surgery or chemotherapy; * pT2-3aN0 and NED for more than 3 years from surgery or chemotherapy; or * \> pT3b, or N+ and NED for more than 5 years from surgery or chemotherapy * Women of childbearing potential and sexually active males must use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
Exclusion criteria
* Evidence of metastatic disease or clinically enlarged lymph nodes on computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis and CT chest obtained within 28 days of registration (a negative biopsy is required for lymph nodes \> 1 cm in size to confirm lack of involvement); patients with lymph nodes \> 1 cm in whom a biopsy is deemed not feasible are not eligible; patients with elevated alkaline phosphatase or suspicious bone pain should also undergo baseline bone scans to evaluate for bone metastasis * Any component of small cell carcinoma; other variant histologies are permitted provided the predominant (\>= 50%) subtype is urothelial carcinoma * Peripheral neuropathy \> grade 2 * History of allergy or hypersensitivity to methotrexate, vinblastine, doxorubicin (doxorubicin hydrochloride), cisplatin, gemcitabine (gemcitabine hydrochloride), carboplatin or filgrastim or pegfilgrastim * Another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer; patients that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment * Prior systemic doxorubicin for patients who have creatinine clearance that meets \>= 50 ml/min * Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, myocardial infarction in last 3 months, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Known to have human immunodeficiency virus (HIV) or are on combination antiretroviral therapy * Prior radiation therapy to \>= 25% of the bone marrow for other diseases or prior systemic anthracycline therapy; prior intravesical anthracycline therapy for non-muscle invasive urothelial carcinoma of the bladder is permitted * Pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Pathologic Response Rate | Assessed at nephroureterectomy or regional lymph node dissection (21-60 days from completion of chemotherapy; chemotherapy was administered for a total of 4 cycles; cycle length is 14 days and 21 days for arms A and B, respectively) | Complete pathologic response is defined as pT0pN0 (no evidence of disease) as assessed by pathologic evaluation of nephrectomy/ureterectomy and any identifiable regional lymph nodes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | Assessed every 3 months for 2 years, and every 6 months for 3-5 years | Event-free survival is defined as the time from registration to the earliest occurrence of recurrence of any type, disease progression, new invasive primary cancer, or death from any cause. Disease progression will be assessed using RECIST 1.1. Disease progression is defined as appearance of one or more new lesions, unequivocal progression of existing non-target lesions, or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Bladder Cancer-free Survival | Assessed every 3 months for 2 years, and every 6 months for 3-5 years | Bladder cancer-free survival was defined as the time from the date of surgery to the earlier of a return of bladder cancer or death from any cause. Patients alive without documented bladder cancer were censored at the date of last disease assessment. |
| Recurrence-free Survival | Assessed every 3 months for 2 years; and every 6 months for 3-5 years | Recurrence-free survival is defined as the time from the date of surgery to disease recurrence or death from any cause. Patients alive without documented recurrence will be censored at the date of last disease assessment. |
| Proportion of Patients With Renal Insufficiency at Completion of Chemotherapy | Assessed at completion of chemotherapy; at 8 weeks for Arm A and 12 weeks for Arm B | Renal insufficiency is defined as CrCl \< 60 ml/min. |
| Proportion of Patients With Renal Insufficiency at Completion of Surgery | Assessed at completion of surgery (21-60 days from completion of chemotherapy; chemotherapy was administered for a total of 4 cycles; cycle length is 14 days and 21 days for arms A and B, respectively) | Renal insufficiency is defined as CrCl \< 60 ml/min. |
| Cumulative Incidence of Cancer-specific Death at 24 Months | Assessed every 3 months for 2 years | Cancer-specific survival was defined as the time from registration to death due to cancer; deaths due to other causes are counted as competing events. Cancer-specific survival was analyzed using Gray's method and cumulative incidence of cancer-specific death at 24 months is reported. |
Countries
United States
Participant flow
Recruitment details
The study was activated on April 1, 2015 and accrued its first patient on August 27, 2015. Arm A reached its accrual and was closed on May 31, 2017. Arm B was closed due to slow accrual on January 5, 2018.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy. | 29 |
| Arm B (Gemcitabine, Carboplatin) Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy. | 6 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Ineligible | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm B (Gemcitabine, Carboplatin) | Total | Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) |
|---|---|---|---|
| Age, Continuous | 75 years | 66 years | 65 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 31 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 30 Participants | 26 Participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 27 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 30 | 1 / 6 |
| other Total, other adverse events | 30 / 30 | 6 / 6 |
| serious Total, serious adverse events | 7 / 30 | 3 / 6 |
Outcome results
Primary
Complete Pathologic Response Rate
Complete pathologic response is defined as pT0pN0 (no evidence of disease) as assessed by pathologic evaluation of nephrectomy/ureterectomy and any identifiable regional lymph nodes.
Time frame: Assessed at nephroureterectomy or regional lymph node dissection (21-60 days from completion of chemotherapy; chemotherapy was administered for a total of 4 cycles; cycle length is 14 days and 21 days for arms A and B, respectively)
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) | Complete Pathologic Response Rate | 0.103 proportion of participants |
| Arm B (Gemcitabine, Carboplatin) | Complete Pathologic Response Rate | 0.167 proportion of participants |
Secondary
Bladder Cancer-free Survival
Bladder cancer-free survival was defined as the time from the date of surgery to the earlier of a return of bladder cancer or death from any cause. Patients alive without documented bladder cancer were censored at the date of last disease assessment.
Time frame: Assessed every 3 months for 2 years, and every 6 months for 3-5 years
Population: Eligible and treated patients who underwent radical nephro-ureterectomy and were rendered disease-free
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) | Bladder Cancer-free Survival | NA months |
| Arm B (Gemcitabine, Carboplatin) | Bladder Cancer-free Survival | NA months |
Secondary
Cumulative Incidence of Cancer-specific Death at 24 Months
Cancer-specific survival was defined as the time from registration to death due to cancer; deaths due to other causes are counted as competing events. Cancer-specific survival was analyzed using Gray's method and cumulative incidence of cancer-specific death at 24 months is reported.
Time frame: Assessed every 3 months for 2 years
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) | Cumulative Incidence of Cancer-specific Death at 24 Months | 0.09 proportion of patients died of cancer |
| Arm B (Gemcitabine, Carboplatin) | Cumulative Incidence of Cancer-specific Death at 24 Months | 0.20 proportion of patients died of cancer |
Secondary
Event-free Survival
Event-free survival is defined as the time from registration to the earliest occurrence of recurrence of any type, disease progression, new invasive primary cancer, or death from any cause. Disease progression will be assessed using RECIST 1.1. Disease progression is defined as appearance of one or more new lesions, unequivocal progression of existing non-target lesions, or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Assessed every 3 months for 2 years, and every 6 months for 3-5 years
Population: Eligible and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) | Event-free Survival | NA months |
| Arm B (Gemcitabine, Carboplatin) | Event-free Survival | 10.2 months |
Secondary
Proportion of Patients With Renal Insufficiency at Completion of Chemotherapy
Renal insufficiency is defined as CrCl \< 60 ml/min.
Time frame: Assessed at completion of chemotherapy; at 8 weeks for Arm A and 12 weeks for Arm B
Population: All patients with chemotherapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) | Proportion of Patients With Renal Insufficiency at Completion of Chemotherapy | 0.2 proportion of participants |
| Arm B (Gemcitabine, Carboplatin) | Proportion of Patients With Renal Insufficiency at Completion of Chemotherapy | 0.833 proportion of participants |
Secondary
Proportion of Patients With Renal Insufficiency at Completion of Surgery
Renal insufficiency is defined as CrCl \< 60 ml/min.
Time frame: Assessed at completion of surgery (21-60 days from completion of chemotherapy; chemotherapy was administered for a total of 4 cycles; cycle length is 14 days and 21 days for arms A and B, respectively)
Population: All patients who underwent radical nephro-ureterectomy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) | Proportion of Patients With Renal Insufficiency at Completion of Surgery | 0.69 proportion of participants |
| Arm B (Gemcitabine, Carboplatin) | Proportion of Patients With Renal Insufficiency at Completion of Surgery | 0.833 proportion of participants |
Secondary
Recurrence-free Survival
Recurrence-free survival is defined as the time from the date of surgery to disease recurrence or death from any cause. Patients alive without documented recurrence will be censored at the date of last disease assessment.
Time frame: Assessed every 3 months for 2 years; and every 6 months for 3-5 years
Population: Eligible and treated patients who underwent radical nephro-ureterectomy and were rendered disease-free
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) | Recurrence-free Survival | NA months |
| Arm B (Gemcitabine, Carboplatin) | Recurrence-free Survival | 8.5 months |