Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

Objectives

I.  Determine, in a phase III randomized setting, whether neoadjuvant 
chemotherapy with MCV (methotrexate/cisplatin/vinblastine) significantly 
improves the rate of successful bladder preservation (tumor-free with good 
function) at 3 years.

II.  Determine whether, in the context of a potential bladder-preserving 
treatment regimen, neoadjuvant MCV chemotherapy reduces the rate of disease 
recurrence.

III.  Assess and compare the duration of disease-free survival, overall 
survival, and patterns of failure in patients receiving neoadjuvant MCV vs. no 
neoadjuvant chemotherapy (durability of local CR will be evaluated in patients 
with bladder preserved, and the frequency of subsequent development of 
metastases will be noted in all patients).

IV.  Evaluate the effects of neoadjuvant MCV chemotherapy on the sequelae from 
radiotherapy, surgery, or intravesical chemotherapy in these patients.

V.  Assess the value of cellular DNA analysis by flow cytometry in predicting 
patients whose tumors will achieve and maintain a CR to combined chemotherapy 
and radiotherapy.

Entry Criteria

Disease Characteristics:

Primary carcinoma of the bladder of any histology with histologic evidence of
muscle invasion
  Clinical Stage T2-4a, NX, M0

No nodal metastasis allowed
  Suspicious nodes must be histologically negative

Maximum tumor reduction (by TURB) required within 4 weeks of entry

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  No prior systemic chemotherapy

Endocrine therapy:
  Not specified

Radiotherapy:
  No prior pelvic radiotherapy

Surgery:
  Staging procedures and TURB with removal of as much of bladder tumor as
     possible required within 4 weeks of treatment
  Urinary diversion prior to treatment allowed

Other:
  No concurrent nephrotoxic or ototoxic drugs (e.g., aminoglycosides)

Patient Characteristics:

Age:
  At least 18

Performance status:
  Karnofsky 70%-100%

Hematopoietic:
  WBC at least 4,000
  Platelets at least 100,000
  Hemoglobin at least 10 g/dL

Hepatic:
  Bilirubin no greater than 2.0 mg/dL

Renal:
  Creatinine no greater than 1.7 mg/dL
  Creatinine clearance at least 60 mL/min

Other:
  Patient must be able to tolerate systemic chemotherapy, pelvic radiotherapy,
  and possible cystectomy

  No second malignancy within 5 years except:
     Nonmelanomatous skin cancer
     Stage T1a prostatic cancer
     In situ cervical carcinoma

Expected Enrollment

174 patients will be entered over about 2 years.

Outline

Randomized study.  Following treatment on Arm I or II, patients who achieve CR 
and those who achieve incomplete response but are unsuited for surgery receive 
Consolidation therapy, while those incomplete responders who are suited for 
surgery undergo radical cystectomy.

Arm I:  3-Drug Combination Chemotherapy followed by Radiotherapy plus 
Single-agent Chemotherapy.  MCV:  Methotrexate, MTX, NSC-740; Cisplatin, CDDP, 
NSC-119875; Vinblastine, VBL, NSC-49842; followed by small-field pelvic 
irradiation using external beam photons with energies of at least 4 MV (Co60 
equipment is not acceptable); plus CDDP.

Arm II:  Radiotherapy plus Single-agent Chemotherapy.  Small-field pelvic 
irradiation with equipment as in Arm I; plus CDDP.

Consolidation:  Radiotherapy plus Single-agent Chemotherapy.  Small-field 
pelvic irradiation followed by cone-down boost with equipment as in Arm I; 
plus CDDP.

Chakravarti A, Winter K, Wu CL, et al.: Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 62 (2): 309-17, 2005.[PUBMED Abstract]

Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 16 (11): 3576-83, 1998.[PUBMED Abstract]

Shipley W, Winter K, Kaufman D, et al.: An RTOG phase III trial (#89-03) of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A1197, 311a, 1998.

Efstathiou JA, Bae K, Shipley WU, et al.: Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol 27 (25): 4055-61, 2009.[PUBMED Abstract]

Shipley WU, Bae K, Efstathiou JA, et al.: Late pelvic toxicity following bladder-sparing therapy in patients with invasive bladder cancer: analysis of RTOG 89-03, 95-06, 97-06, 99-06. [Abstract] Int J Radiat Oncol Biol Phys 69 (3 Suppl): A-14, S8, 2007.

Chakravarti A, Winter K, Wu C, et al.: Expression of the epidermal growth factor receptor (EGFR) is associated with improved outcome in muscle-invading bladder cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-713, 2002.

Trial Contact Information

Trial Lead Organizations

Radiation Therapy Oncology Group

William Shipley, MD, FACR, Protocol chair		Ph: 617-726-8146; 877-726-5130 Email: wshipley@partners.org

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