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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.

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.

Pegfilgrastim

Undergo nephroureterectomy and lymph node dissection

Nephroureterectomy

Vitaly Margulis

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.

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.

Chemotherapy Before Surgery in Treating Patients With High Grade Upper Urinary Tract Cancer

A Prospective Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery for Patients With High Grade Upper Tract Urothelial Carcinoma

Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

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.

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.

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 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.

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.

Renal insufficiency is defined as CrCl \< 60 ml/min.

National Cancer Institute (NCI)

ECOG-ACRIN Cancer Research Group

Serious adverse events are defined as treatment-related adverse events of grade 3 or higher. Other adverse events are treatment-related adverse events not included in the serious adverse events.

Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)

Arm B (Gemcitabine, Carboplatin)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Only eligible and treated patients are included in the analysis.

Study Statistician

Complete Pathologic Response Rate

Eligible and treated patients who underwent radical nephro-ureterectomy and were rendered disease-free

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Chemotherapy Before Surgery in Treating Patients With High Grade Upper Urinary Tract Cancer	NCT02412670	High Grade Uppe...	Methotrexate Vinblastine Doxorubicin Cisplatin Gemcitabine Carboplatin Pegfilgrastim Nephroureterect...	18 Years -	Eastern Cooperative Oncology Group
Chemotherapy Before Surgery in Treating Patients With High Grade Upper Urinary Tract Cancer	NCT02412670	High Grade Uppe...	Methotrexate Vinblastine Doxorubicin Cisplatin Gemcitabine Carboplatin Pegfilgrastim Nephroureterect...	18 Years -	Eastern Cooperative Oncology Group

Spots Global Cancer Trial Database for high grade upper tract urothelial carcinoma