Clinical trial NCT00777491: Chemotherapy and Radiation Therapy in Treating Patients With Stage II or Stage III Bladder Cancer That Was Removed by Surgery
Official title: A Phase II Randomized Study For Patients With Muscle-Invasive Bladder Cancer Evaluating Transurethral Surgery And Concomitant Chemoradiation By Either BID Irradiation Plus 5-Fluorouracil And Cisplatin Or QD Irradiation Plus Gemcitabine Followed By Selective Bladder Preservation And Gemcitabine/Cisplatin Adjuvant Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bladder Cancer
Keywords: stage II bladder cancer
stage III bladder cancer
transitional cell carcinoma of the bladder
Lead sponsor: Radiation Therapy Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-10-22
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as fluorouracil, cisplatin, and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy together with radiation therapy may kill more tumor cells.

PURPOSE: This randomized phase II trial is studying two different chemotherapy and radiation therapy regimens to see how they work in treating patients with stage II or stage III bladder cancer that was removed by surgery.

Detailed description: OBJECTIVES:

Primary

* To estimate the rate of distant metastasis at 3 years in patients who have undergone transurethral resection of the bladder tumor for stage II or III muscle-invasive bladder cancer treated with chemoradiotherapy comprising fluorouracil, cisplatin, and radiotherapy vs gemcitabine hydrochloride and radiotherapy followed by selective bladder preservation and adjuvant chemotherapy comprising gemcitabine hydrochloride and cisplatin.

Secondary

* To estimate the treatment completion rate in these patients.
* To estimate acute and late grade toxicities (≥ grade 3 genitourinary, gastrointestinal, and hematologic toxicities) of these regimens in these patients.
* To estimate the efficacy of these regimens, in terms of achieving complete response of the primary tumor, in these patients.
* To estimate the efficacy of these regimens, in terms of preserving the native, tumor-free bladder 5 years after completion of therapy, in these patients.
* To estimate the value of tumor histopathologic, molecular genetic, DNA content, metabolomic, and proteomic parameters as possible significant prognostic factors for initial tumor response and recurrence-free survival.
* To analyze for American Urological Association (AUA) Symptom scores at baseline and at 3 years from patients on both arms.
* To find potentially predictive biomarkers for cystectomy-free survival.
* To find potentially predictive biomarkers for acute and late toxicities.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor stage (T2 vs T3-4a). Patients are randomized to 1 of 2 treatment arms.

Eligibility criteria: Inclusion criteria:

1. Pathologically (histologically or cytologically) proven diagnosis of primary carcinoma of the bladder (transitional cell cancer) within 8 weeks of registration. Operable patients whose tumors are primary carcinomas of the bladder and exhibit histologic evidence of muscularis propria invasion and are American Joint Committee on Cancer (AJCC) clinical stages T2-T4a, Nx or N0, M0 (Appendix IV) without hydronephrosis; patients who have involvement of the prostatic urethra with transitional cell cancer (TCC) that was visibly completely resected and no evidence of stromal invasion of the prostate remain eligible. T2a, T2b, T3a, T3b -substages‖ are not usually able to be determined with clinical (TURBT) staging.
2. If radiologic evaluation of a lymph node is interpreted as "positive", this must be evaluated further either by lymphadenectomy or percutaneous needle biopsy. Patients with histologically or cytologically confirmed node metastases will not be eligible.
3. Patients must have an adequately functioning bladder after thorough evaluation by an urologist and have undergone as thorough a transurethral resection of the bladder tumor as is judged safely possible.
4. Patients must be considered able to tolerate systemic chemotherapy combined with pelvic radiation therapy, and a radical cystectomy by the joint agreement of the participating Urologist, Radiation Oncologist, and Medical Oncologist.
5. History and physical examination including weight, performance status, and body surface area within 8 weeks prior to study registration
6. Zubrod Performance Status ≤ 1
7. Age ≥ 18
8. Complete blood count (CBC)/differential obtained no more than 4 weeks prior to registration on study, with adequate bone marrow function defined as follows:

   * 8.1 White blood cell count (WBC) ≥ 4000/ml
   * 8.2 Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3;
   * 8.3 Platelets ≥ 100,000 cells/mm3;
   * 8.4 Hemoglobin (hgb) ≥ 10.0 mg/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable.);
9. Serum creatinine of 1.5 mg% or less; serum bilirubin of 2.0 mg% or less; creatinine clearance of 60 ml/min or greater no more than 4 weeks prior to registration; Note: Calculated creatinine clearance is permissible. If the creatinine clearance is \> 60 ml/min, then a serum creatinine of up to 1.8 mg% is allowable at the discretion of the study chair;
10. Serum pregnancy test for female patients of childbearing potential, ≤ 72 hours prior to study entry; women of childbearing potential and male participants must practice adequate contraception.
11. Patient must be able to provide study-specific informed consent prior to study entry.

Exclusion criteria:

1. Evidence of tumor-related hydronephrosis
2. Evidence of distant metastases or histologically or cytologically proven lymph node metastases
3. Previous systemic chemotherapy (for any cancer) or pelvic radiation therapy
4. A prior or concurrent malignancy of any other site or histology unless the patient has been disease-free for ≥ 5 years except for non-melanoma skin cancer and/or stage T1a prostate cancer or carcinoma in situ of the uterine cervix
5. Patients judged not to be candidates for radical cystectomy; patients with pN+ or T4b disease are considered to have unresectable disease
6. Patients receiving any drugs that have potential nephrotoxicity or ototoxicity (such as an aminoglycoside)
7. Severe, active co-morbidity, defined as follows:

   * 7.1 Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months;
   * 7.2 Transmural myocardial infarction within the last 6 months;
   * 7.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
   * 7.4 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration;
   * 7.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol.
   * 7.6 Acquired Immune Deficiency Syndrome (AIDS) based upon current Center for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients.
8. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
9. Prior allergic reaction to the study drug(s) involved in this protocol

Primary outcomes:
measure: Percentage of Patients Without Distant Metastases by Three Years
timeFrame: From randomization to three years
Secondary outcomes:
measure: Percentage of Patients Who Completed Treatment Per Protocol
timeFrame: After each treatment component (induction, consolidation, adjuvant). Timing varies bases on arm, tumor response at multiple time points, and allowed time ranges.
measure: Percentage of Patients With Grade 3 or Higher Genitourinary, Gastrointestinal, or Hematologic Adverse Events
timeFrame: From start of treatment to 180 days after the end of treatment. Treatment could last up to 40 weeks depending on arm, tumor response, and allowed time ranges.
measure: Number of Patients Experiencing Complete Response of the Primary Tumor After Induction Therapy
timeFrame: 3-4 weeks following induction therapy (approximately maximum 8 weeks from start of treatment depending on treatment arm and allowed time windows)
measure: Number of Participants With Progression or Removal of Bladder Five Years After Therapy
timeFrame: From start of treatment to five years after the end of therapy. Treatment could last up to 40 weeks depending on arm, tumor response, and allowed time ranges.
measure: Change in American Urological Association Symptom Index (AUASI) Score at 3 Years
timeFrame: Baseline and 3 years
measure: Determining Potentially Predictive Biomarkers for Acute and Late Toxicities
timeFrame: The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from the NRG tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this out
measure: Determining Potentially Predictive Biomarkers for Cystectomy-free Survival
timeFrame: The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from the NRG tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this out
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Georgia Cancer Center for Excellence at Grady Memorial Hospital
state: Georgia
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center
state: Idaho
city: Springfield
country: United States
facility: Cancer Institute at St. John's Hospital
state: Illinois
city: Fort Wayne
country: United States
facility: Parkview Regional Cancer Center at Parkview Health
state: Indiana
city: Baltimore
country: United States
facility: St. Agnes Hospital Cancer Center
state: Maryland
city: Fall River
country: United States
facility: Hudner Oncology Center at Saint Anne's Hospital - Fall River
state: Massachusetts
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Cancer Center
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Montreal
country: Canada
facility: McGill Cancer Centre at McGill University
state: Quebec
Study officials:
affiliation: GenesisCare USA
name: John J. Coen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Philip J. Saylor, MD
role: STUDY_CHAIR
affiliation: University of Michigan Rogel Cancer Center
name: Cheryl T. Lee, MD
role: STUDY_CHAIR
affiliation: Massachusetts General Hospital
name: Chin-Lee Wu, MD, PhD
role: STUDY_CHAIR
References:
citation: Choudhury A, Swindell R, Logue JP, Elliott PA, Livsey JE, Wise M, Symonds P, Wylie JP, Ramani V, Sangar V, Lyons J, Bottomley I, McCaul D, Clarke NW, Kiltie AE, Cowan RA. Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer. J Clin Oncol. 2011 Feb 20;29(6):733-8. doi: 10.1200/JCO.2010.31.5721. Epub 2011 Jan 4.