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

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00777491
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 70
• Locations: 11
• Arms: 2
• Duration (Months): 161.6
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bladder Cancer	Drug: induction cisplatin; Drug: induction 5-fluorouracil; Drug: induction gemcitabine; Radiation: Induction BID radiation therapy; Radiation: Induction QD radiation therapy; Radiation: Consolidation BID radiation therapy; Radiation: Consolidation QD radiation therapy; Drug: consolidation gemcitabine; Drug: consolidation 5-fluorouracil; Drug: consolidation cisplatin; Procedure: radical cystectomy; Procedure: Post-Induction Chemoradiotherapy Endoscopic Response Evaluation; Drug: adjuvant gemcitabine; Drug: adjuvant cisplatin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Dec 1, 2008
• Actual Primary Completion Date: Feb 18, 2018
• Actual Study Completion Date: May 20, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: induction cisplatin; 15 mg/m^2 administered as a 60-minute infusion on days 1,2,3,8,9,10,15,16,17.; Drug: induction 5-fluorouracil; 400mg/m^2 administered as a 24-hour infusion on days 1,2,3, and 15,16,17.; Other Names: fluorouracil 5-FU ; Radiation: 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.; 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.; 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.; Other Names: fluorouracil 5-FU ; Drug: consolidation cisplatin; 15 mg/m^2 administered as a sixty-minute infusion on days 1, 2, 8, 9 of consolidation.; Other Names: cisplatin ; Procedure: 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.; Procedure: Post-Induction Chemoradiotherapy Endoscopic Response Evaluation; Urine cytology, cystoscopy, tumor site transurethral biopsy, and bimanual examination after biopsy.; Other Names: TUR ; Drug: 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.; Other Names: gemcitabine hydrochloride ; Drug: adjuvant cisplatin; 70 mg/m^2 administered as a sixty-minute infusion on day 1 of each 21-day cycle for four cycles.
Experimental: 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.	Drug: induction gemcitabine; 27 mg/m^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15, 18, 22, 25.; Other Names: gemcitabine hydrochloride ; 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.; 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.; Drug: consolidation gemcitabine; 27 mg/m^2 administered as a 30-minute infusion on days 1, 4, 8, 11, 15 of consolidation.; Other Names: gemcitabine hydrochloride ; Procedure: 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.; Procedure: Post-Induction Chemoradiotherapy Endoscopic Response Evaluation; Urine cytology, cystoscopy, tumor site transurethral biopsy, and bimanual examination after biopsy.; Other Names: TUR ; Drug: 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.; Other Names: gemcitabine hydrochloride ; Drug: adjuvant cisplatin; 70 mg/m^2 administered as a sixty-minute infusion on day 1 of each 21-day cycle for four cycles.

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Without Distant Metastases by Three Years [From randomization to three years]

   Distant metastasis occurrence is defined as the first appearance of disease (with radiographic evidence) in a non-regional lymph node, solid organ or bone.

Secondary Outcome Measures

1. Percentage of Patients Who Completed Treatment Per Protocol [After each treatment component (induction, consolidation, adjuvant). Timing varies bases on arm, tumor response at multiple time points, and allowed time ranges.]

   Treatment administration data was centrally reviewed to determine if patients completed each treatment component per protocol.

2. Percentage of Patients With Grade 3 or Higher Genitourinary, Gastrointestinal, or Hematologic Adverse Events [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.]

   Highest grade adverse event (AE) per subject was counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. All adverse events are counted, regardless of reported relationship to protocol treatment.

3. Number of Patients Experiencing Complete Response of the Primary Tumor After Induction Therapy [3-4 weeks following induction therapy (approximately maximum 8 weeks from start of treatment depending on treatment arm and allowed time windows)]

   Patients will be considered as having a clinical complete response when all biopsies are negative at the site(s) of the pretreatment tumor(s).

4. Number of Participants With Progression or Removal of Bladder Five Years After Therapy [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.]

   Progression is defined as an increase of 50% or more in the largest diameter of the endoscopically appreciable tumor in the tumor-site biopsy specimen, the development of new bladder tumors, or the development of metastatic disease.

5. Change in American Urological Association Symptom Index (AUASI) Score at 3 Years [Baseline and 3 years]

   The AUASI is a validated 7-item measure used to assess urinary symptoms. A higher score indicates more severe symptoms for the individual questions and overall total. Six questions ask about frequency of symptoms over the past month with possible responses: 0= Not at all; 1 = Less than 1 time in 5; 2 = less than half the time, 3 = About half the time, 4 = More than half the time, 5 = Almost always. An additional question asks the number of times one gets up to urinate after going to bed, with response indicating the exact number of times ranging from 0 to 5. The total score is the sum of the questions and ranges from 0 to 35. Change is calculated as 3-year score - baseline score such that a negative change indicates improvement.

6. Determining Potentially Predictive Biomarkers for Acute and Late Toxicities [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]

7. Determining Potentially Predictive Biomarkers for Cystectomy-free Survival [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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.);

1. 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;

2. 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.

3. 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.

1. 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.

2. Prior allergic reaction to the study drug(s) involved in this protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Georgia Cancer Center for Excellence at Grady Memorial Hospital	Atlanta	Georgia	United States	30303
2	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
3	Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center	Boise	Idaho	United States	83706
4	Cancer Institute at St. John's Hospital	Springfield	Illinois	United States	62702
5	Parkview Regional Cancer Center at Parkview Health	Fort Wayne	Indiana	United States	46805
6	St. Agnes Hospital Cancer Center	Baltimore	Maryland	United States	21229
7	Hudner Oncology Center at Saint Anne's Hospital - Fall River	Fall River	Massachusetts	United States	02721
8	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan	United States	48106-0995
9	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109-0942
10	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
11	McGill Cancer Centre at McGill University	Montreal	Quebec	Canada	H2W 1S6

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: John J. Coen, MD, GenesisCare USA
• Study Chair: Philip J. Saylor, MD, Massachusetts General Hospital
• Study Chair: Cheryl T. Lee, MD, University of Michigan Rogel Cancer Center
• Study Chair: Chin-Lee Wu, MD, PhD, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Dec 18, 2014

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00777491
• Other Study ID Numbers: RTOG-0712; CDR0000616858
• First Posted: Oct 22, 2008
• Last Update Posted: Jun 15, 2022
• Last Verified: May 1, 2022

• Keywords provided by Radiation Therapy Oncology Group: stage II bladder cancer; stage III bladder cancer; transitional cell carcinoma of the bladder
• Additional relevant MeSH terms: Urinary Bladder Neoplasms; Gemcitabine; Cisplatin; Fluorouracil

Study Results

Participant Flow

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation
Arm/Group Description	Within 8 weeks following pre-study transurethral resection (TUR) patients receive 2.5 weeks of induction chemoradiotherapy (induction 5-fluorouracil, induction cisplatin, induction BID [twice daily] 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.	Within 8 weeks following pre-study transurethral resection (TUR) patients receive 2.5 weeks of induction chemoradiotherapy (induction gemcitabine and induction QD [once a day] 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.
Period Title: Overall Study
STARTED	35	35
Eligible	33	33
Has 3-year Efficacy Data	27	25
Started Induction Therapy	33	33
Started Consolidation Therapy	29	25
Started Adjuvant Therapy	32	31
Has Adverse Event Data (Treatment)	33	33
Has Adverse Event Data (Late)	32	31
Has 3 Year AUASI Data	6	6
COMPLETED	33	33
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	33	33	66
Age, Customized (Count of Participants)
<= 49 years	2 6.1%	0 0%	2 3%
50-59 years	5 15.2%	4 12.1%	9 13.6%
60-69 years	13 39.4%	20 60.6%	33 50%
>= 70 years	13 39.4%	9 27.3%	22 33.3%
Sex: Female, Male (Count of Participants)
Female	8 24.2%	8 24.2%	16 24.2%
Male	25 75.8%	25 75.8%	50 75.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3%	0 0%	1 1.5%
Not Hispanic or Latino	32 97%	33 100%	65 98.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 3%	1 1.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 9.1%	3 9.1%	6 9.1%
White	30 90.9%	29 87.9%	59 89.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Zubrod Performance Status (Count of Participants)
0	29 87.9%	32 97%	61 92.4%
1	4 12.1%	1 3%	5 7.6%
T Stage (Count of Participants)
cT2	32 97%	32 97%	64 97%
cT3-T4a	1 3%	1 3%	2 3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Without Distant Metastases by Three Years
Description	Distant metastasis occurrence is defined as the first appearance of disease (with radiographic evidence) in a non-regional lymph node, solid organ or bone.
Time Frame	From randomization to three years

Outcome Measure Data

Analysis Population Description

Eligible patients with 3-year data

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation
Arm/Group Description	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.	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.
Measure Participants	27	25
Number (90% Confidence Interval) [percentage of participants]	77.8 235.8%	84.0 254.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5-FU and Cisplatin + BID Irradiation, Gemcitabine + QD Irradiation
	Comments	The confidence interval of the rate was calculated by Clopper-Pearson's exact binomial confidence intervals methods with one-sided type I error of 0.1. The study required 32 analyzable patients in each arm, which would warrant a 10% chance of observing a percentage of patients without distant metastasis by 3 years of less than 75% if the true rate was 86%. With the actual number of evaluable patients, the study instead warrants a 13-14% chance.
	Type of Statistical Test	Other
	Comments	There was no formal comparison of the two treatment arms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		If the percentage of patients without distant metastasis by 3 years for either arm was greater than or equal to 75%, then it would be strongly considered as a potential arm in a subsequent phase III study, assuming treatment delivery and adverse events (AEs) were acceptable. If both arms met the criteria, then the treatment arm with less toxicity would be chosen.

2. Secondary Outcome

Title	Percentage of Patients Who Completed Treatment Per Protocol
Description	Treatment administration data was centrally reviewed to determine if patients completed each treatment component per protocol.
Time Frame	After each treatment component (induction, consolidation, adjuvant). Timing varies bases on arm, tumor response at multiple time points, and allowed time ranges.

Outcome Measure Data

Analysis Population Description

Eligible patients who started each treatment component (induction, consolidation, adjuvant)

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation
Arm/Group Description	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.	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.
Measure Participants	33	33
Induction Therapy	32 97%	31 93.9%
Consolidation Therapy	27 81.8%	23 69.7%
Adjuvant Therapy	18 54.5%	17 51.5%

3. Secondary Outcome

Title	Percentage of Patients With Grade 3 or Higher Genitourinary, Gastrointestinal, or Hematologic Adverse Events
Description	Highest grade adverse event (AE) per subject was counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. All adverse events are counted, regardless of reported relationship to protocol treatment.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Eligible patients with adverse event data for corresponding time period

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation
Arm/Group Description	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.	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.
Measure Participants	33	33
During Treatment	19 57.6%	18 54.5%
Between End of Treatment and 180 days after	8 24.2%	5 15.2%

4. Secondary Outcome

Title	Number of Patients Experiencing Complete Response of the Primary Tumor After Induction Therapy
Description	Patients will be considered as having a clinical complete response when all biopsies are negative at the site(s) of the pretreatment tumor(s).
Time Frame	3-4 weeks following induction therapy (approximately maximum 8 weeks from start of treatment depending on treatment arm and allowed time windows)

Outcome Measure Data

Analysis Population Description

Eligible patients who started induction therapy

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation
Arm/Group Description	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.	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.
Measure Participants	33	33
Count of Participants [Participants]	29 87.9%	25 75.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5-FU and Cisplatin + BID Irradiation, Gemcitabine + QD Irradiation
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments	Two-sided significance level of 0.05
	Method	Regression, Logistic
	Comments	Univariate analysis
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.493
	Confidence Interval	(2-Sided) 95%; 0.129 to 1.881
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference arm = 5-FU and Cisplatin + BID Irradiation

5. Secondary Outcome

Title	Number of Participants With Progression or Removal of Bladder Five Years After Therapy
Description	Progression is defined as an increase of 50% or more in the largest diameter of the endoscopically appreciable tumor in the tumor-site biopsy specimen, the development of new bladder tumors, or the development of metastatic disease.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Eligible participants with five-year data

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation
Arm/Group Description	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.	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.
Measure Participants	27	22
Count of Participants [Participants]	4 12.1%	5 15.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5-FU and Cisplatin + BID Irradiation, Gemcitabine + QD Irradiation
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments	Two-sided significance level of 0.05
	Method	Regression, Logistic
	Comments	Univariable analysis
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 0.426 to 5.277
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference arm = 5-FU and Cisplatin + BID irradiation

6. Secondary Outcome

Title	Change in American Urological Association Symptom Index (AUASI) Score at 3 Years
Description	The AUASI is a validated 7-item measure used to assess urinary symptoms. A higher score indicates more severe symptoms for the individual questions and overall total. Six questions ask about frequency of symptoms over the past month with possible responses: 0= Not at all; 1 = Less than 1 time in 5; 2 = less than half the time, 3 = About half the time, 4 = More than half the time, 5 = Almost always. An additional question asks the number of times one gets up to urinate after going to bed, with response indicating the exact number of times ranging from 0 to 5. The total score is the sum of the questions and ranges from 0 to 35. Change is calculated as 3-year score - baseline score such that a negative change indicates improvement.
Time Frame	Baseline and 3 years

Outcome Measure Data

Analysis Population Description

Eligible patients with baseline and 3-year scores

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation
Arm/Group Description	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.	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.
Measure Participants	6	6
Sensation of Not Emptying Bladder	-0.50	0.0
Urinate Again < 2 Hours After Urinating	-2.50	-1.0
Stopped and Started When Urinating	-1.00	0.00
Difficult to Postpone Urination	-3.00	-0.50
Weak Urinary Stream	-0.50	0.00
Push or Strain to Begin Urination	-0.50	0.00
How Often Get Up at Night to Urinate	-3.50	-1.50
AUA Total Symptom Score	-9.50	-3.50

7. Secondary Outcome

Title	Determining Potentially Predictive Biomarkers for Acute and Late Toxicities
Time Frame	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

Outcome Measure Data

Analysis Population Description

The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from our tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this outcome measure. Specimen use will require federal approval and funding separate from this trial.

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation
Arm/Group Description	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.	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.
Measure Participants	0	0

8. Secondary Outcome

Title	Determining Potentially Predictive Biomarkers for Cystectomy-free Survival
Time Frame	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

Outcome Measure Data

Analysis Population Description

The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from our tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this outcome measure. Specimen use will require federal approval and funding separate from this trial.

Arm/Group Title	5-FU and Cisplatin + BID Irradiation	Gemcitabine + QD Irradiation
Arm/Group Description	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.	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.
Measure Participants	0	0

Adverse Events

Time Frame	From randomization to last follow-up. Maximum follow-up was 11.4 years.
Adverse Event Reporting Description	Adverse event population = eligible patients who started protocol treatment.
Arm/Group Title	Arm I		Arm II
Arm/Group Description	Patients receive induction therapy comprising fluorouracil IV, cisplatin IV, and radiotherapy in weeks 1-4. Patients then undergo either radical cystectomy or receive consolidation therapy comprising fluorouracil IV, cisplatin IV, and radiotherapy in weeks 8-10.		Patients receive induction therapy comprising gemcitabine hydrochloride IV and radiotherapy in weeks 1-4. Patients then undergo either radical cystectomy or receive consolidation therapy comprising gemcitabine hydrochloride IV and radiotherapy in weeks 8-10.
All Cause Mortality
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/33 (48.5%)		11/33 (33.3%)
Serious Adverse Events
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/33 (33.3%)		8/33 (24.2%)
Blood and lymphatic system disorders
Febrile neutropenia	1/33 (3%)		0/33 (0%)
Cardiac disorders
Atrial fibrillation	1/33 (3%)		0/33 (0%)
Cardiac disorder	0/33 (0%)		1/33 (3%)
Gastrointestinal disorders
Abdominal pain	1/33 (3%)		0/33 (0%)
Colitis	0/33 (0%)		1/33 (3%)
Colonic perforation	0/33 (0%)		1/33 (3%)
Diarrhea	1/33 (3%)		2/33 (6.1%)
Dyspepsia	0/33 (0%)		1/33 (3%)
Gastrointestinal disorder	0/33 (0%)		1/33 (3%)
Mucositis oral	1/33 (3%)		0/33 (0%)
Nausea	0/33 (0%)		1/33 (3%)
Vomiting	0/33 (0%)		1/33 (3%)
General disorders
Fever	0/33 (0%)		1/33 (3%)
Pain [other]	1/33 (3%)		0/33 (0%)
Infections and infestations
Bladder infection [with normal or Grade 1-2 ANC]	0/33 (0%)		1/33 (3%)
Bladder infection [with unknown ANC]	1/33 (3%)		0/33 (0%)
Catheter related infection [with Grade 3-4 ANC]	0/33 (0%)		1/33 (3%)
Infection [other]	1/33 (3%)		0/33 (0%)
Pneumonia [with normal or Grade 1-2 ANC]	0/33 (0%)		1/33 (3%)
Urinary tract infection [with unknown ANC]	1/33 (3%)		0/33 (0%)
Injury, poisoning and procedural complications
Intraoperative complications	1/33 (3%)		0/33 (0%)
Investigations
Leukopenia	1/33 (3%)		0/33 (0%)
Neutrophil count decreased	1/33 (3%)		1/33 (3%)
Platelet count decreased	5/33 (15.2%)		0/33 (0%)
Metabolism and nutrition disorders
Dehydration	1/33 (3%)		0/33 (0%)
Hypokalemia	1/33 (3%)		1/33 (3%)
Nervous system disorders
Depressed level of consciousness	1/33 (3%)		0/33 (0%)
Intracranial hemorrhage	1/33 (3%)		0/33 (0%)
Ischemia cerebrovascular	1/33 (3%)		0/33 (0%)
Syncope	1/33 (3%)		0/33 (0%)
Psychiatric disorders
Confusion	1/33 (3%)		0/33 (0%)
Depression	1/33 (3%)		0/33 (0%)
Renal and urinary disorders
Renal failure	1/33 (3%)		0/33 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/33 (0%)		1/33 (3%)
Hemorrhage nasal	0/33 (0%)		1/33 (3%)
Vascular disorders
Thrombosis	1/33 (3%)		0/33 (0%)
Other (Not Including Serious) Adverse Events
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/33 (100%)		33/33 (100%)
Blood and lymphatic system disorders
Blood disorder	7/33 (21.2%)		6/33 (18.2%)
Hemoglobin decreased	28/33 (84.8%)		30/33 (90.9%)
Hemolysis	1/33 (3%)		2/33 (6.1%)
Cardiac disorders
Cardiac disorder	2/33 (6.1%)		0/33 (0%)
Ear and labyrinth disorders
Tinnitus	0/33 (0%)		2/33 (6.1%)
Eye disorders
Eye disorder	2/33 (6.1%)		2/33 (6.1%)
Vision blurred	2/33 (6.1%)		0/33 (0%)
Gastrointestinal disorders
Abdominal pain	10/33 (30.3%)		11/33 (33.3%)
Constipation	21/33 (63.6%)		14/33 (42.4%)
Diarrhea	23/33 (69.7%)		28/33 (84.8%)
Dry mouth	0/33 (0%)		4/33 (12.1%)
Dyspepsia	5/33 (15.2%)		7/33 (21.2%)
Flatulence	1/33 (3%)		2/33 (6.1%)
Gastrointestinal disorder	6/33 (18.2%)		11/33 (33.3%)
Hemorrhoids	2/33 (6.1%)		1/33 (3%)
Mucositis oral	2/33 (6.1%)		3/33 (9.1%)
Nausea	26/33 (78.8%)		24/33 (72.7%)
Proctitis	1/33 (3%)		5/33 (15.2%)
Rectal hemorrhage	2/33 (6.1%)		2/33 (6.1%)
Rectal pain	2/33 (6.1%)		0/33 (0%)
Stomach pain	2/33 (6.1%)		0/33 (0%)
Vomiting	12/33 (36.4%)		7/33 (21.2%)
General disorders
Chest pain	3/33 (9.1%)		2/33 (6.1%)
Chills	1/33 (3%)		6/33 (18.2%)
Edema limbs	6/33 (18.2%)		4/33 (12.1%)
Fatigue	29/33 (87.9%)		33/33 (100%)
Fever	4/33 (12.1%)		10/33 (30.3%)
General symptom	3/33 (9.1%)		1/33 (3%)
Irritability	0/33 (0%)		2/33 (6.1%)
Pain [other]	13/33 (39.4%)		8/33 (24.2%)
Infections and infestations
Bladder infection [with normal or Grade 1-2 ANC]	1/33 (3%)		2/33 (6.1%)
Bladder infection [with unknown ANC]	5/33 (15.2%)		1/33 (3%)
Urinary tract infection [with unknown ANC]	2/33 (6.1%)		1/33 (3%)
Injury, poisoning and procedural complications
Intraoperative complications	2/33 (6.1%)		0/33 (0%)
Investigations
Activated partial thromboplastin time prolonged	2/33 (6.1%)		0/33 (0%)
Alanine aminotransferase increased	7/33 (21.2%)		18/33 (54.5%)
Alkaline phosphatase increased	10/33 (30.3%)		8/33 (24.2%)
Aspartate aminotransferase increased	2/33 (6.1%)		15/33 (45.5%)
Creatinine increased	14/33 (42.4%)		7/33 (21.2%)
Hyperbilirubinemia	5/33 (15.2%)		3/33 (9.1%)
INR increased	2/33 (6.1%)		1/33 (3%)
Laboratory test abnormal	13/33 (39.4%)		7/33 (21.2%)
Leukopenia	22/33 (66.7%)		25/33 (75.8%)
Lymphopenia	19/33 (57.6%)		14/33 (42.4%)
Neutrophil count decreased	19/33 (57.6%)		16/33 (48.5%)
Platelet count decreased	20/33 (60.6%)		20/33 (60.6%)
Weight gain	2/33 (6.1%)		0/33 (0%)
Weight loss	8/33 (24.2%)		7/33 (21.2%)
Metabolism and nutrition disorders
Anorexia	12/33 (36.4%)		16/33 (48.5%)
Dehydration	11/33 (33.3%)		10/33 (30.3%)
Hypercalcemia	0/33 (0%)		3/33 (9.1%)
Hyperglycemia	25/33 (75.8%)		17/33 (51.5%)
Hyperkalemia	5/33 (15.2%)		3/33 (9.1%)
Hypermagnesemia	0/33 (0%)		2/33 (6.1%)
Hypoalbuminemia	8/33 (24.2%)		5/33 (15.2%)
Hypocalcemia	13/33 (39.4%)		8/33 (24.2%)
Hypokalemia	10/33 (30.3%)		9/33 (27.3%)
Hypomagnesemia	17/33 (51.5%)		13/33 (39.4%)
Hyponatremia	19/33 (57.6%)		15/33 (45.5%)
Hypophosphatemia	6/33 (18.2%)		4/33 (12.1%)
Musculoskeletal and connective tissue disorders
Back pain	8/33 (24.2%)		3/33 (9.1%)
Bone pain	3/33 (9.1%)		1/33 (3%)
Joint pain	4/33 (12.1%)		1/33 (3%)
Muscle weakness	6/33 (18.2%)		4/33 (12.1%)
Musculoskeletal disorder	6/33 (18.2%)		2/33 (6.1%)
Myalgia	4/33 (12.1%)		4/33 (12.1%)
Pain in extremity	3/33 (9.1%)		3/33 (9.1%)
Nervous system disorders
Dizziness	7/33 (21.2%)		7/33 (21.2%)
Headache	7/33 (21.2%)		9/33 (27.3%)
Memory impairment	2/33 (6.1%)		0/33 (0%)
Neurological disorder NOS	5/33 (15.2%)		3/33 (9.1%)
Peripheral motor neuropathy	2/33 (6.1%)		3/33 (9.1%)
Peripheral sensory neuropathy	12/33 (36.4%)		6/33 (18.2%)
Taste alteration	4/33 (12.1%)		5/33 (15.2%)
Psychiatric disorders
Agitation	2/33 (6.1%)		1/33 (3%)
Anxiety	2/33 (6.1%)		4/33 (12.1%)
Depression	7/33 (21.2%)		3/33 (9.1%)
Insomnia	17/33 (51.5%)		9/33 (27.3%)
Renal and urinary disorders
Bladder pain	2/33 (6.1%)		2/33 (6.1%)
Bladder spasm	4/33 (12.1%)		2/33 (6.1%)
Cystitis	6/33 (18.2%)		12/33 (36.4%)
Hemorrhage urinary tract	5/33 (15.2%)		3/33 (9.1%)
Urethral pain	1/33 (3%)		3/33 (9.1%)
Urinary frequency	24/33 (72.7%)		21/33 (63.6%)
Urinary incontinence	7/33 (21.2%)		5/33 (15.2%)
Urinary retention	4/33 (12.1%)		3/33 (9.1%)
Urogenital disorder	14/33 (42.4%)		9/33 (27.3%)
Reproductive system and breast disorders
Erectile dysfunction	2/33 (6.1%)		5/33 (15.2%)
Pelvic pain	1/33 (3%)		2/33 (6.1%)
Penile pain	2/33 (6.1%)		0/33 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	5/33 (15.2%)		5/33 (15.2%)
Dyspnea	6/33 (18.2%)		6/33 (18.2%)
Hiccough	4/33 (12.1%)		1/33 (3%)
Pharyngolaryngeal pain	2/33 (6.1%)		0/33 (0%)
Voice alteration	2/33 (6.1%)		0/33 (0%)
Skin and subcutaneous tissue disorders
Acne	2/33 (6.1%)		2/33 (6.1%)
Alopecia	4/33 (12.1%)		5/33 (15.2%)
Pruritus	2/33 (6.1%)		0/33 (0%)
Rash desquamating	2/33 (6.1%)		2/33 (6.1%)
Skin disorder	4/33 (12.1%)		3/33 (9.1%)
Sweating	0/33 (0%)		2/33 (6.1%)
Vascular disorders
Flushing	1/33 (3%)		2/33 (6.1%)
Hemorrhage	4/33 (12.1%)		1/33 (3%)
Hypertension	5/33 (15.2%)		0/33 (0%)
Hypotension	3/33 (9.1%)		1/33 (3%)
Phlebitis superficial	1/33 (3%)		3/33 (9.1%)

Limitations/Caveats

Adverse event data was updated when outcome measure 5 was entered.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.