Chemotherapy and Radiation Therapy in Treating Patients With Stage II or Stage III Bladder Cancer That Was Removed by Surgery

NCT ID: NCT00777491

Last Updated: 2022-06-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 70 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-12-31
• Study Completion Date: 2022-05-20

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.

Conditions

Bladder Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

5-FU and Cisplatin + BID Irradiation

Within 8 weeks following pre-study transurethral resection (TUR) patients receive 2.5 weeks of induction chemoradiotherapy (induction 5-fluorouracil, induction cisplatin, induction BID radiation therapy). Consolidation chemoradiotherapy begins 7-14 days following post-induction chemoradiotherapy endoscopic response evaluation. Patients achieving a complete response receive 1.5 weeks of consolidation chemoradiotherapy (consolidation 5-fluorouracil, consolidation cisplatin, consolidation BID radiation therapy). Patients without a complete response undergo radical cystectomy. Outpatient adjuvant chemotherapy (adjuvant gemcitabine, adjuvant cisplatin) begins 4-5 weeks following the post-consolidation endoscopic evaluation or 8-12 weeks following radical cystectomy, and continues for 12 weeks.

Group Type: EXPERIMENTAL

induction cisplatin

Intervention Type: DRUG

15 mg/m\^2 administered as a 60-minute infusion on days 1,2,3,8,9,10,15,16,17.

induction 5-fluorouracil

Intervention Type: DRUG

400mg/m\^2 administered as a 24-hour infusion on days 1,2,3, and 15,16,17.

Induction BID radiation therapy

Intervention Type: RADIATION

Twice daily (BID) on days 1-5,8-12,15-17. The first daily treatment consists of 1.6 Gy delivered to the pelvis. The second fraction consists of 1.5 Gy to the bladder for the first 5 treatment days. Then, 1.5 Gy is delivered to bladder tumor volume as the second treatment for the remaining 8 treatment days. The bladder tumor volume receives a total of 40.3 Gy.

Consolidation BID radiation therapy

Intervention Type: RADIATION

Twice daily (BID) for 8 days on days 1,2,3,4,5,8,9,10 of consolidation. 1.5 Gy per fraction for a total of 24 Gy delivered to the pelvis.

consolidation 5-fluorouracil

Intervention Type: DRUG

400 mg/m\^2 administered as a 24-hour infusion on days 1, 2, 3 and 8, 9, 10 of consolidation.

consolidation cisplatin

Intervention Type: DRUG

15 mg/m\^2 administered as a sixty-minute infusion on days 1, 2, 8, 9 of consolidation.

radical cystectomy

Intervention Type: PROCEDURE

Operable patients who have a pT1 or worse tumor response on re-evaluation following initial transurethral resection and induction chemoradiotherapy will have a radical cystectomy 3-8 weeks following the post-induction response evaluation.

Post-Induction Chemoradiotherapy Endoscopic Response Evaluation

Intervention Type: PROCEDURE

Urine cytology, cystoscopy, tumor site transurethral biopsy, and bimanual examination after biopsy.

adjuvant gemcitabine

Intervention Type: DRUG

1000 mg/m\^2 administered intravenously over 30-60 minutes (preferably 30 minutes) on days 1 and 8 of each 21-day cycle for four cycles.

adjuvant cisplatin

Intervention Type: DRUG

70 mg/m\^2 administered as a sixty-minute infusion on day 1 of each 21-day cycle for four cycles.

Gemcitabine + QD Irradiation

Within 8 weeks following pre-study transurethral resection (TUR) patients receive 2.5 weeks of induction chemoradiotherapy (induction gemcitabine and induction QD radiation therapy). Consolidation chemoradiotherapy begins 7-14 days following post-induction chemoradiotherapy endoscopic response evaluation. Patients achieving a complete response receive 1.5 weeks of consolidation chemoradiotherapy (consolidation gemcitabine and consolidation QD radiation therapy). Patients without a complete response undergo radical cystectomy. Outpatient adjuvant chemotherapy (adjuvant gemcitabine and adjuvant cisplatin) begins 4-5 weeks following the post-consolidation endoscopic evaluation or 8-12 weeks following radical cystectomy, and continues for 12 weeks.

Group Type: EXPERIMENTAL

induction gemcitabine

Intervention Type: DRUG

27 mg/m\^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15, 18, 22, 25.

Induction QD radiation therapy

Intervention Type: RADIATION

Once daily (QD) on days (1-5,8-12,15-19,22-26). For the first 10 treatment days, 2 Gy is delivered to the pelvis. Then, 2 Gy is delivered to the bladder for the next 4 treatment days, followed by 2 Gy to the bladder tumor volume for the remaining 6 treatment days. The bladder tumor volume receives a total of 40 Gy.

Consolidation QD radiation therapy

Intervention Type: RADIATION

Once daily (QD) pelvic radiation therapy for 12 days on days 1-5,8-12,15-16 of consolidation. 2 Gy per fraction for a total of 24 Gy delivered to the pelvis.

consolidation gemcitabine

Intervention Type: DRUG

27 mg/m\^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15 of consolidation.

radical cystectomy

Intervention Type: PROCEDURE

Operable patients who have a pT1 or worse tumor response on re-evaluation following initial transurethral resection and induction chemoradiotherapy will have a radical cystectomy 3-8 weeks following the post-induction response evaluation.

Post-Induction Chemoradiotherapy Endoscopic Response Evaluation

Intervention Type: PROCEDURE

Urine cytology, cystoscopy, tumor site transurethral biopsy, and bimanual examination after biopsy.

adjuvant gemcitabine

Intervention Type: DRUG

1000 mg/m\^2 administered intravenously over 30-60 minutes (preferably 30 minutes) on days 1 and 8 of each 21-day cycle for four cycles.

adjuvant cisplatin

Intervention Type: DRUG

70 mg/m\^2 administered as a sixty-minute infusion on day 1 of each 21-day cycle for four cycles.

Interventions

induction cisplatin

15 mg/m\^2 administered as a 60-minute infusion on days 1,2,3,8,9,10,15,16,17.

Intervention Type: DRUG

induction 5-fluorouracil

400mg/m\^2 administered as a 24-hour infusion on days 1,2,3, and 15,16,17.

Intervention Type: DRUG

induction gemcitabine

27 mg/m\^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15, 18, 22, 25.

Intervention Type: DRUG

Induction BID radiation therapy

Twice daily (BID) on days 1-5,8-12,15-17. The first daily treatment consists of 1.6 Gy delivered to the pelvis. The second fraction consists of 1.5 Gy to the bladder for the first 5 treatment days. Then, 1.5 Gy is delivered to bladder tumor volume as the second treatment for the remaining 8 treatment days. The bladder tumor volume receives a total of 40.3 Gy.

Intervention Type: RADIATION

Induction QD radiation therapy

Once daily (QD) on days (1-5,8-12,15-19,22-26). For the first 10 treatment days, 2 Gy is delivered to the pelvis. Then, 2 Gy is delivered to the bladder for the next 4 treatment days, followed by 2 Gy to the bladder tumor volume for the remaining 6 treatment days. The bladder tumor volume receives a total of 40 Gy.

Intervention Type: RADIATION

Consolidation BID radiation therapy

Twice daily (BID) for 8 days on days 1,2,3,4,5,8,9,10 of consolidation. 1.5 Gy per fraction for a total of 24 Gy delivered to the pelvis.

Intervention Type: RADIATION

Consolidation QD radiation therapy

Once daily (QD) pelvic radiation therapy for 12 days on days 1-5,8-12,15-16 of consolidation. 2 Gy per fraction for a total of 24 Gy delivered to the pelvis.

Intervention Type: RADIATION

consolidation gemcitabine

27 mg/m\^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15 of consolidation.

Intervention Type: DRUG

consolidation 5-fluorouracil

400 mg/m\^2 administered as a 24-hour infusion on days 1, 2, 3 and 8, 9, 10 of consolidation.

Intervention Type: DRUG

consolidation cisplatin

15 mg/m\^2 administered as a sixty-minute infusion on days 1, 2, 8, 9 of consolidation.

Intervention Type: DRUG

radical cystectomy

Operable patients who have a pT1 or worse tumor response on re-evaluation following initial transurethral resection and induction chemoradiotherapy will have a radical cystectomy 3-8 weeks following the post-induction response evaluation.

Intervention Type: PROCEDURE

Post-Induction Chemoradiotherapy Endoscopic Response Evaluation

Urine cytology, cystoscopy, tumor site transurethral biopsy, and bimanual examination after biopsy.

Intervention Type: PROCEDURE

adjuvant gemcitabine

1000 mg/m\^2 administered intravenously over 30-60 minutes (preferably 30 minutes) on days 1 and 8 of each 21-day cycle for four cycles.

Intervention Type: DRUG

adjuvant cisplatin

70 mg/m\^2 administered as a sixty-minute infusion on day 1 of each 21-day cycle for four cycles.

Intervention Type: DRUG

Other Intervention Names

fluorouracil; 5-FU; gemcitabine hydrochloride; gemcitabine hydrochloride; fluorouracil; 5-FU; cisplatin; TUR; gemcitabine hydrochloride

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Radiation Therapy Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John J. Coen, MD

Role: PRINCIPAL_INVESTIGATOR

GenesisCare USA

Philip J. Saylor, MD

Role: STUDY_CHAIR

Massachusetts General Hospital

Cheryl T. Lee, MD

Role: STUDY_CHAIR

University of Michigan Rogel Cancer Center

Chin-Lee Wu, MD, PhD

Role: STUDY_CHAIR

Massachusetts General Hospital

Locations

Georgia Cancer Center for Excellence at Grady Memorial Hospital

Atlanta, Georgia, United States

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States

Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center

Boise, Idaho, United States

Cancer Institute at St. John's Hospital

Springfield, Illinois, United States

Parkview Regional Cancer Center at Parkview Health

Fort Wayne, Indiana, United States

St. Agnes Hospital Cancer Center

Baltimore, Maryland, United States

Hudner Oncology Center at Saint Anne's Hospital - Fall River

Fall River, Massachusetts, United States

Saint Joseph Mercy Cancer Center

Ann Arbor, Michigan, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

West Michigan Cancer Center

Kalamazoo, Michigan, United States

McGill Cancer Centre at McGill University

Montreal, Quebec, Canada

Countries

United States; Canada

References

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.

Reference Type: RESULT

PMID: 21205754 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

CDR0000616858

Identifier Type: -

Identifier Source: secondary_id

RTOG-0712

Identifier Type: -

Identifier Source: org_study_id