Neoadjuvant Chemotherapy With Methotrexate, Vinblastine, Adriamycin and Cisplatin (M-VAC) Plus Avastin in Patients With Urothelial Cancer

Inclusion Criteria:

1. Patients must have histologic proof of urothelial cancer. Patients with all histologic subtypes are eligible as long as transitional cell carcinoma predominant, with 2 exceptions:

   * More than a few clusters of small cell carcinoma are treated with different chemotherapy and are ineligible for this study
   * Patients with micropapillary tumor will be allowed irrespective of the extent of transitional cell carcinoma. A transitional cell component is not required in the setting of pure or extensive micropapillary tumors. Note that minor histologic components are acceptable.
2. Patients with primary tumors arising in the bladder or urethra are eligible if they demonstrate any of the following features:

   * A 3-dimensional mass on examination under anesthesia (EUA); ie: cT3b disease
   * Direct invasion of prostatic stroma or the vaginal wall: ie:cT4a disease
   * Lymphovascular invasion on the specimen with \>/= cT1 disease
   * Hydronephrosis present on CT scan or on renal ultrasound
   * Tumor involving bladder diverticulum.
3. Patients with more than a few areas of micropapillary histology are eligible, even if they do not meet the anatomic criteria for locally advanced disease enumerated above. Patients with micropapillary histology will be analyzed as a separate cohort.
4. Patients with primary tumors arising in the ureter or renal pelvis are eligible they have either grade 3 tumor, or a radiographic abnormality large enough to recognize as an abnormal mass by CT or MRI imaging. These patients may also be analyzed separately, since we do not have benchmark data for upper tract disease.
5. Patients must have an evaluation in the department of urology, and be deemed an acceptable surgical candidate.
6. Patients must have adequate physiologic reserves as by:

   * Zubrod performance status (PS) of \</= 1; or 2 if of recent onset and due entirely to the cancer and not due to comorbidity (especially if the compromised performance status is related to uncontrolled pain which is expected to be rapidly reversible when therapy starts)
   * Normal WBC, ANC \>/= 1,800, and platelet count \>/= 150,000. Supranormal values judged to be of benign or inconsequential etiology are acceptable
   * Transaminase (AST or ALT) \</= 3 \* the ULN
   * Conjugated bilirubin \</= 1.5 mg/dl (or total bilirubin \</= 2.5 mg/dl)
   * Normal Serum Creatinine or Creatinine clearance (either measured or by Cockcroft-Gault formula) of \>/= 50 ml/min.Cockcroft-Gault: CLcr = \[(140-age) \* wt(kg)\]/\[72 \* Cr(mg/dL)\] (For females, multiply by 0.85)
7. Patients (Pts) must NOT have clinical evidence of disease beyond the involved organ by either CT or MRI of the abdomen and pelvis, and chest X-ray. Pts with lymph node involvement are not eligible. In absence of a bone scan, pts should be free of bone pain and have an alk. phos. \< 150% of the ULN, or a normal bone fraction of alk. phos. If these features are present, pts should have a bone scan and this should be interpreted as showing no evidence of metastatic disease to be eligible. In case of bladder tumors, cancer invading local organs (pT4a) but not pelvis sidewall (pT4b) are allowed.
8. Patients must have a determination of LV function with an EF \>/= 50% to participate.
9. Women of child-bearing potential (i.e., who has had menses at any time in the preceding 24 consecutive months) must have a negative pregnancy test. Elevations of BHCG which are related to tumor (and not the rapid escalation associated with pregnancy, i.e. doubling time of 3-5 days) are acceptable.
10. Patients of child-bearing or child-fathering potential must agree to use an acceptable form of birth control while on the study, i.e. condoms.
11. Patients with second malignancies are eligible provided that the expected outcome from the second cancer is such that this will not interfere in the delivery of this therapy, or the assessment of response in the cystectomy specimen. The expected survival from the prior malignancy should reliably be \> 4 years to be eligible for this study.
12. Patients must be \>/= 18 years of age.

Exclusion Criteria:

1. Patients must not have current, recent (within 3 weeks), or planned participation with other experimental medication clinical trials.
2. Prior systemic cytoreductive chemotherapy for bladder cancer. Please note, that prior intra-vesical therapy is allowed.
3. Blood pressure of \> 140/90 mmHg. Patients whose blood pressure is controlled with oral medication are eligible, as long as the blood pressure is \</= 140/90 mmHg.
4. Any prior history of hypertensive crisis or hypertensive encephalopathy.
5. New York Heart Association (NYHA) Grade II or greater congestive heart failure.
6. History of myocardial infarction or unstable angina within 6 months prior to study enrollment.
7. History of stroke or transient ischemic attack within 6 months prior to study enrollment.
8. Clinically significant peripheral vascular disease (e.g., aortic aneurysm, aortic dissection).
9. Symptomatic peripheral vascular disease.
10. Evidence of bleeding diathesis or coagulopathy.
11. Known history of central nervous system or brain metastases.
12. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study. For the purpose of this study, Cystoscopy and ureteroscopy is not included as a major surgical procedure.
13. Lactating women.
14. Proteinuria at screening as demonstrated by either:

    * Urine protein:creatinine (UPC) ratio \>/= 1.0 at screening OR
    * Urine dipstick for proteinuria \> 2+ (or \> 100 protein on urinalysis) Patients discovered to have \>2+ proteinuria on dipstick urinalysis or \>100 on urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate \<= 1g of protein in 24 hours to be eligible.
15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to therapy. Patients with Crohn's disease will be excluded.
16. Serious, non-healing wound, ulcer, or bone fracture.
17. Lung carcinoma of squamous cell histology or any histology in close proximity to a major vessel, cavitation, or history of hemoptysis (bright red blood of 1/2 teaspoon or more; non-small cell lung cancer trials only).
18. Inability to comply with study and/or follow-up procedures, or sign informed consent.
19. Patients who are not candidates for surgery, or are unwilling to undergo surgery.
20. Patients with fluid collections (such as ascites, or pleural effusions) are not eligible for therapy as such collections may serve as a reservoir for methotrexate.
21. Know hypersensitivity to any component of Avastin.