# Radiation Oncology/Bladder/Muscle Invasive

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Muscle-Invasive Bladder Cancer

## Treatment Overview

Per NCCN guidelines (v.1.2010), stage based on TURBT
* cT2N0
** Radical cystectomy with neoadjuvant chemo
** Segmental cystectomy (highly selected patients with a solitary lesion in a suitable location, no Tis)
** Selective bladder-sparing with chemo-RT
* T3N0
** Radical cystectomy with neoadjuvant chemo
** Selective bladder-sparing with chemo-RT
* T4/N+
** Chemotherapy
** Chemo-RT

## Surgical Management

* Radical cystectomy with pelvic lymphadenectomy is considered the standard of care.
** Includes perivesicular fat and urethra
** In women, the anterior wall of the vagina, the ovary and the uterus are also taken
** In men, the prostate and seminal vesicles are taken. Prostate-sparing radical cystectomy is controversial, as up to 40% may have urothelial cancer or prostate cancer found in the prostate
* Dissection of presacral nodes is controversial and institution-dependent
* Bladder reconstruction includes incontinent versus continent urinary tract
** Incontinent urinary tract is when urine drains from ureters through segment of ilium to skin surface
** Two types of continent urinary tracts include cutaneous reservoir versus orthotopic ileal reservoir. A cutaneous reservoir is made from bowel with a valve to maintain continence. An orthotopic ileal reservoir is an ileal conduit which is anastomosed to the urethra and has improved the quality of life after radical cystectomy.
* Operative mortality rate is generally cited at 2-5%, but tends to be lower in high volume institutions.
* Outcomes depend on pathologic extent of disease
** Local control is 90-95%
** Overall 5-year OS after surgery alone is ~50%, primarily because ~50% will die of metastatic disease after radical cystectomy
** Localized disease pTis-T2N0 (50-60%): 5-year OS 75-85%
** Locally advanced disease pT3-T4aN0 (20-30%): 45-55%
** Regional lymph node mets pN1-3 (20-30%): 25-35%

### Delay To Therapy

* McGill; 2006 (1965-2006) PMID 16846680 -- "Delay in the surgical treatment of bladder cancer and survival: systematic review of the literature." (Fahmy NM, Eur Urol. 2006 Dec;50(6):1176-82. Epub 2006 Jun 13.)
** Systematic review. 13 studies, 7700 patients. Effect of treatment interval on survival. Due to heterogeneity, meta-analysis could not be performed.
** Outcome: No correlation in 3 papers (23%), trend to worse survival in 2 papers (15%), significant impact on survival 8 papers (62%)
** Conclusion: Delays to treatment appear associated with worse outcome; window of opportunity <12 weeks from diagnosis to radical cystectomy

### Adjuvant Chemotherapy

To decrease DM but also improves local control.
* PAC: cisplatin, doxorubicin, cyclophosphamide
* MCV: Methotrexate, cisplatin, vinblastine
* MVAC: adds Adriamycin to MCV
Meta-analysis
* Rome; 2006 PMID 16419069 — "Adjuvant chemotherapy in muscle-invasive bladder carcinoma: a pooled analysis from phase III studies." (Ruggeri EM, Cancer. 2006 Feb 15;106(4):783-8.)
** Meta-analysis. 5 RCTs, 350 patients. Benefit of adjuvant chemotherapy in addition to radical cystectomy
** Outcome: Benefit for adjuvant chemo for both DFS (RR 0.65, SS) and OS (RR 0.74, SS). No significant heterogeneity
** Conclusion: Results of analysis favor use of adjuvant chemotherapy
Randomized
* University of Southern California; 1991 PMID 1997689 - "The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial." (Skinner DG et al. J Urol. 1991 Mar;145(3):459-64; discussion 464-7.)
** Retrospective. 91 patients, s/p cystectomy + LN dissection. TCC with pathologic stage (3rd edition TNM, i.e. deep muscle invasion) T3-4 or N+. Randomized to 4 courses of cisplatin, doxorubicin, cyclophosphamide (PAC) qmonth vs no further tx.
** At 3 years, disease recurrence in 30% (chemo) vs 54%, death from bladder cancer 29% vs 50%. Difference in death from any cause (34% vs 50%) was N.S. Benefit of chemotherapy on survival and NED for all stratified nodal groups (0 LN, 1 LN, 2+ LN), but prognosis for 2+ LN was poor.
** Conclusion: Adjuvant chemo improves survival for muscle-invasive bladder cancer

### Neoadjuvant Chemotherapy

* Advantage of neoadjuvant chemotherapy is the prognostic value of seeing a response to chemo.
* Patients with a good response can potentially be triaged towards a bladder sparing approach.
* Patients who achieve complete response (cT0) after neoadjuvant chemo still require cystectomy based on early results from SWOG 0129 ASCO 2008
* SWOG 8710, 2003 - PMID 12944571 — "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer." Grossman HB et al. NEJM 2003 Aug 28;349(9):859-66.
** Randomized prospective trial comparing surgery alone to neoadjvuant MVAC
** 317 patients with T2-T4a disease
** Median survival 77 months (MVAC arm) vs 46 months (surgery alone) (p=0.06)
* Nordic study, 2004 (1985-97) - PMID 15036674 — "Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies." Sherif A et al. Eur Urol. 2004 Mar;45(3):297-303.
** Retrospective. 620 in two consecutive trials. T1G3, T2-T4a.
** HR of 0.80 for survival in favor of neoadjuvant chemotherapy. OS 56% vs 48%.
** Conclusion: survival benefit for neoadjuvant cisplatin-based chemotherapy.
* Meta-analysis: Ontario, 2004 (1984-2002) - PMID 14713760 — "Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis." Winquist E et al. J Urol. 2004 Feb;171(2 Pt 1):561-9.
** Absolute survival benefit of 6.5% for neoadj chemotherapy.

### Neoadjuvant RT

* Preoperative radiation was popularized in the early 1980's with the theoretical advantage of making cells less viable and potentially decreasing dissemination of tumor cells after surgical manipulation.
* Original data out of M.D. Anderson suggested a survival benefit with preoperative radiation therapy, but only when compared to historical controls using outdated surgical techniques.
* Preoperative radiation fell out of favor with the advent of ileal conduits to radical cystectomy as irradiated bowel makes for a poor anastomosis and conduit.
Meta-Analysis
* Georgia; 1998 PMID 9677446 -- "Planned preoperative radiation therapy in muscle invasive bladder cancer; results of a meta-analysis." (Huncharek M, Anticancer Res. 1998 May-Jun;18(3B):1931-4.)
** Meta-analysis. 5 RCTs comparing preop RT with cystectomy alone.
** Outcome: Unadjusted analysis benefit of RT (OR 0.7, SS), however, after correction for design deficiencies, no benefit (OR 0.9, NS)
** Conclusion: Available clinical trial data do not support role for routine preop RT
Randomized
* SWOG/Intergroup Preoperative Radiation Trial PMID 9072571, Journal of Urology, 1997
** 140 patients.
** 20 Gy preoperative radiation vs cystectomy alone
** Radiation delivered 400 cGy x 5 fractions
** Survival equivalent 53% (surgery alone) vs 43% (xrt)

## Bladder Preservation Overview

Success rate of bladder preservation:
* TURBT alone - 20% free of invasive bladder recurrence
* RT alone - 41%
* Chemo alone - 19%
Complete response rate:
* RT alone - 45%
* Chemo alone - 27%
* TURBT + chemo - 51%
* TURBT + chemo-RT - 70-80%
Estimated 5-year outcome with ChemoRT regimens:
* OS - 50-60%
* OS with intact bladder - 40%
* % alive with intact bladder - 80%
No trials directly compare cystectomy and bladder-preservation.
There are 2 main concerns about bladder preservation compared with radical cystectomy:
* Toxicity of radiation therapy on bladder function, which thus far appears to be reasonable
* Field cancerization effect, whereby 30-50% of patients experience a local recurrence (~50% invasive and ~50% superficial), either in the area of tumor or in a different part of bladder. If bladder preservation is selected, close surveillance is critical

## Definitive RT vs Surgery

* Yorkshire, UK; 2010 (1993-1996) PMID 19665319 -- "A 10-year retrospective review of a nonrandomized cohort of 458 patients undergoing radical radiotherapy or cystectomy in Yorkshire, UK." (Munro NP, Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):119-24. Epub 2009 Aug 6.)
** Retrospective. 458 patients in Northern and Yorkshire Cancer Registry
** Outcome: 10-year OS RT 22% vs radical cystectomy 24% (NS)
** Conclusion: No significant difference in all-cause survival between surgery and radiotherapy

## Definitive RT vs Preop RT And Surgery

* Danish National Bladder Cancer Group, DAVECA 8201 (1983-1986) -- Definitive RT vs Preop RT + cystectomy
** Randomized. 183 patients. cT2-T4a. Arm 1) Pre-op RT 40 Gy + cystectomy vs Arm 2) Radical RT 60 Gy with cystectomy for salvage.
** 1991 PMID 1785004 — "Treatment of advanced bladder cancer category T2 T3 and T4a. A randomized multicenter study of preoperative irradiation and cystectomy versus radical irradiation and early salvage cystectomy for residual tumor. DAVECA protocol 8201. Danish Vesical Cancer Group." (Sell A, Scand J Urol Nephrol Suppl. 1991;138:193-201.) Median F/U 4.2 years
*** Outcome: Salvage cystectomy 28%. Local/pelvic failure Cystectomy 7% vs RT 35%, no difference in DM. No difference in OS (29% vs 23%)
*** Conclusion: Improved pelvic control with surgery, but no difference in survival
* Institute of Urology; 1982 PMID 7044462 -- "Treatment of T3 bladder cancer: controlled trial of pre-operative radiotherapy and radical cystectomy versus radical radiotherapy." (Bloom HJ, Br J Urol. 1982 Apr;54(2):136-51.)
* MD Anderson (1964-1970) -- Definitive RT vs Preop RT + cystectomy
** Randomized. 67 patients, Stage B2-C (T3). Arm 1) definitive RT 60 Gy vs Arm 2) Preoperative RT 50 Gy followed by cystectomy
** 1977 PMID 402205 -- "Bladder cancer: superiority of preoperative irradiation and cystectomy in clinical stages B2 and C." (Miller LS, Cancer. 1977 Feb;39(2 Suppl):973-80.)
*** Outcome: 5-year OS RT 16% vs preop RT + cystectomy 46% (SS)
*** Conclusion: Institutional policy has changed to preoperative RT with planned cystectomy, except for patients declining or medically unfit for surgery

## Definitive RT

* Initially a common treatment approach to bladder cancer, particularly for older patients and larger tumors
* 5-year OS for that patient population was ~30%, with local failure in ~50%; clinical CR after RT associated with improved survival
* Dose and fractionation not clearly established, Perez recommends 60-66 Gy in 1.8-2 Gy/fx. Please see Radiation Technique
* Definitive RT no longer used, due to both advances in radical cystectomy and development of orthotopic ileal reconstruction (for patients who get surgery) and due to benefit of concurrent chemo-RT (for patients who get bladder preservation)
* Edinburgh; 1986 (1971-1982) PMID 2424878 -- "Primary radical radiotherapy for T3 transitional cell cancer of the bladder: an analysis of survival and control." (Quilty PM, Int J Radiat Oncol Biol Phys. 1986 Jun;12(6):853-60.)
** Retrospective. 333 patients, T3 tumors <10cm, treated with radical RT, prior TUR in 23%. Median dose 55/20, majority treated with 3 field technique
** Outcome: pCR 41%. 5-year local control 24%. 5-year OS 26%, 10-year OS 15%. Predictors for local control: Hgb >13 g/dl, tumor <7cm, urea <7 mmol/l, Grade 3 tumor
** Conclusion: Patients should be selected for primary RT on the basis of tumor size, grade, and plasma urea level
* Harvard; 1985 (1974-1982) PMID 4032570 — "Full-dose irradiation for patients with invasive bladder carcinoma: clinical and histological factors prognostic of improved survival." (Shipley WU, J Urol. 1985 Oct;134(4):679-83.)
** Retrospective. 55 patients, T2-T4 (T2 14%, T3 53%, T4 33%). RT alone 64-68 Gy
** Outcome: 5-year OS 28% (T2-T3 45% vs T4 9%, SS). Papillary 63% vs solid/flat pattern 20% (SS). Complete TUR 54% vs incomplete 17% (SS). Urethral obstruction none 47% vs present 14% (SS)
** Conclusion: Full dose RT can be offered, with relatively high probability of success in select subsets

## RT Alone or Chemo-RT
### Randomized

* International BA06 30894 (1989-1995) -- definitive therapy +/- neoadjuvant CMV x3
** Randomized. 976 patients from 106 institutions, muscle invasive urothelial carcinoma (T2G3-T4 N0-Nx). Arm 1) definitive therapy (surgery 50%, RT 43%, surgery + RT 8%) vs Arm 2) neoadjuvant chemotherapy cisplatin 100 mg/m2 + MTX 30 mg/m2 + vinblastine 4 mg/m2 Q3W x 3 cycles. Choice of definitive therapy based on patient/physician preference; RT patients primarily older, Nx, and T3-T4
** 2011 PMID 21502557 -- "International Phase III Trial Assessing Neoadjuvant Cisplatin, Methotrexate, and Vinblastine Chemotherapy for Muscle-Invasive Bladder Cancer: Long-Term Results of the BA06 30894 Trial." (International Collaboration of Trialists, J Clin Oncol. 2011 Jun 1;29(16):2171-7. Epub 2011 Apr 18.)
*** Outcome: 10-year locoregional relapse CMV- 39% vs CMV+ 40% (NS), mets-free survival 23% vs 33% (SS), overall survival 30% vs 36% (SS). Cause of death bladder cancer in CMV- 72% vs CMV+ 70%. Benefit comparable for surgery (26% reduction in risk of death) and radiation (20% reduction)
*** Toxicity: chemo-related mortality 1%, operative mortality 3.7%
*** Conclusion: Neoadjuvant CMV improves survival and should be considered state of the art. No impact on locoregional control
* NCI Canada (1985-1989) -- RT vs RT + concurrent cisplatin
** Randomized. 99 patients. cT2-T4b, either definitive therapy or pre-cystectomy (selected a priori). Arm 1) RT 40/20 or 60/30 vs Arm 2) Same RT with concurrent cisplatin 100 mg/m2 Q2W x3 cycles
** 1996 PMID 8918486 — "Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group." (Coppin CM, J Clin Oncol. 1996 Nov;14(11):2901-7.) Median F/U 6.5 years
*** Outcome: 5-year pelvic failure RT 59% vs chemo-RT 40% (SS), first site pelvic failure 52% vs chemo-RT 29% (SS), held in both definitive and preop groups. No difference in DM. 3-year OS 47% vs 33% (NS). If definitive treatment, bladder preservation RT 36% vs chemo-RT 70% (NS)
*** Conclusion: Concurrent cisplatin may improve pelvic control and bladder preservation, but not (with a trend) overall survival.
* BC2001 (2001-2008) -- RT vs RT+ concurrent fluorouracil and mitomycin C (also randomized to whole bladder vs. more localized)
** Randomized. 360 patients from 45 UK centers. T2-T4a N0 (could have neoadjuvant cisplatin). Arm 1) radiation alone 55/20 or 64/32 (per center)with no pelvic LN RT vs. Arm 2) same RT with CI 5FU (500 mg/m2) fractions 1-5 & 16-20 + mitomycin C 12mg/m2 day 1
** 2012 PMID 22512481 -- "Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer" (James, N. D. et al. N Engl J Med 366, 1477–1488 (2012)) Median follow up: 70 mo
*** Outcome:
**** 2 year recurrence free rate 67% vs. 54% (HR 0.68; 95%CI: 0.48-0.96; p=0.03) favoring chemoradiotherapy.
**** Locoregional relapse at 2 years 18% vs. 32% (HR 0.57).
*****  Primarily due to decreased recurrent muscle-invasive bladder cancer (11% vs 19%), not non-muscle invasive bladder CA (14% vs 17%) or pelvic LN relapse (5% vs 7%). The low incidence of isolated pelvic relapse is notable given that patients were treated without pelvic LN RT.
**** Overall survival not significantly improved at 5 years 48% vs. 35% (HR 0.82; 95% CI: 0.63-1.09; P=0.16), but curves diverge after 2 years.
**** Chemotherapy associated with significantly more Grade 3-5 GI toxicity by CTCAE, primarily due to GI toxicity, but no difference in late toxicity by RTOG or LENT/SOM scales.
*** Conclusion: Concurrent 5FU and mitomycin C improves locoregional recurrence free survival and reduces local failure.

### Retrospective

* Naples, Italy; 2008 (1994-2002) PMID 18008364 -- "Bladder-sparing, combined-modality approach for muscle-invasive bladder cancer: a multi-institutional, long-term experience." (Perdona S, Cancer. 2008 Jan 1;112(1):75-83.)
** Retrospective. 121 patients, TURBT and cT2-T4 bladder cancer (typically younger, T2, no hydronephrosis, no comorbidities). Neoadjuvant MCV x2, then definitive RT 65 Gy (n=43) or same RT with concurrent cisplatin or carboplatin (n=78). Restaging TUR 6 weeks later. Median F/U 5.5 years
** Outcome: pCR 86%. Local recurrence 34% (invasive 18%). 5-year OS 68% (if TURBT R0 70%, if R1 56%), 5-year bladder preservation 51%. 5-year DSS after salvage cystectomy (overall in 20% patients) 50%
** Toxicity: Cystectomy for shrinking bladder <1%, Grade 4 2%, urgency with nocturia 24%. Good overall bladder function
** Conclusion: Conservative combined treatment is a reasonable alternative to radical cystectomy
* Erlangen, Germany
** Initial chemo-RT; 1990 (1985-1988) PMID 2211216 — "Radiotherapy with and without cisplatin in bladder cancer." (Sauer R, Int J Radiat Oncol Biol Phys. 1990 Sep;19(3):687-91.)
*** Retrospective. 67 patients, cT1-T4 on TURBT. RT 50.4/28 with concurrent cisplatin 25 mg/m2 D1-5, W1 and W5. Cystoscopy 6 weeks. Compared to historical and contemporaneous RT-only cohorts
*** Outcome: pCR 72% (including 70% in R2 TURBT). If pCR, local recurrence 18%; if pPR, local recurrence 9% (1/11). 3-year OS 66% (though T4 only 25%). Historical comparison of pCR: if complete TUR RT 78% vs chemo-RT 67% (NS), if incomplete TUR 45% vs 76%
*** Toxicity: Worsening of bladder function by chemo-RT not observed
*** Conclusion: Addition of concurrent cisplatin improves control rated, particularly if suboptimal TURBT performed, but has no impact on survival
** Update; 1998 (1982-1996) PMID 9422567 — "Efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer." (Sauer R, Int J Radiat Oncol Biol Phys. 1998 Jan 1;40(1):121-7.)
*** Retrospective. 282 patients, TURBT, cT2-T4 or high risk T1. Prior to 1986, primary RT (n=98) to 54-56 Gy, after concurrent chemo-RT with cisplatin (n=115) or carboplatin (n=69), RT 59.4 Gy. Cystoscopy 4-12 weeks later. If no pCR, salvage cystectomy. Median F/U 7.5 years
*** Outcome: pCR RT 57% vs cis-RT 85% vs carbo-RT 70% (cis vs carbo SS). 5-year OS 36% vs 61% vs 47%. 5-year bladder preservation 38% vs 47% vs 41% (79% of surviving patients maintained their bladder)
*** Toxicity: Grade 3 30%, Grade 4 1%
*** Conclusion: Addition of cisplatin improves bladder preservation and survival. Cystectomy should be reserved for those who fail chemo-RT
** Update; 2002 (1982-2000) PMID 12118019 -- "Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results." (Rodel C, J Clin Oncol. 2002 Jul 15;20(14):3061-71.)
*** Retrospective. 415 patients, TURBT, cT2-T4 (79%) or high risk T1 (21%). Primary RT (30%) or chemo-RT (70%), cystoscopy ~6 weeks later. If pCR, observation, otherwise several treatment options (observation 36%, local treatment 26%, radical cystectomy 37%). Median F/U 5 years
*** Outcome: Overall pCR 72%, cisplatin-RT pCR 82% (extent of TUR strong predictor). After CR, 10-year local control 64%, DM 35%, bladder preservation 80%. Salvage cystectomy (20% overall) 10-year DSS 45%; time-to-cystectomy nonresponders 6 months, responders with local failure 26 months
*** Toxicity: cystectomy for contracted bladder in 2%
*** Conclusion: Complete TUR with chemo-RT a reasonable alternative to radical cystectomy

## Definitive Chemo-RT

* Please see the RT Alone or Chemo-RT section above for more studies
* Please see the Selective Bladder-Sparing Approach section below for further discussion of bladder preservation options
* SWOG 9312; 2001 (1993-1998) - PMID 11125363 — "Combination cisplatin, 5-fluorouracil and radiation therapy for locally advanced unresectable or medically unfit bladder cancer cases: a Southwest Oncology Group Study." (Hussain MH, J Urol. 2001 Jan;165(1):56-60.
** Phase II. 56 patients. Locally advanced T2-T4N+ (34%) or inoperable (21%) or refused cystectomy (45%). TURBT followed by RT 60 Gy with concurrent cisplatin 75 mg/m2 and 5-FU 1000 mg/m2 Q4 weeks. Treatment completed as planned in 57%, response not determined in 18%
** Outcome: CR 49%. 5-year OS 32%, for patients who refused surgery 5-year OS 45%
** Conclusion: Concurrent 5-FU/cisplatin with RT is feasible, may be alternative for cystectomy
* National Bladder Cancer Group; 1987 (1980-85) PMID 3613023 — Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. (Shipley WU et al. JAMA. 1987 Aug 21;258(7):931-5.)
** 70 pts, T2-T4. Cisplatin + RT. RT 45 Gy + boost to total of 64.8 Gy. Cisplatin q3w x 8 courses, beginning day before RT.
** Outcome: cCR 77%. 4-yr OS 57% (for those with initial CR) vs 11% (non-responders).
** Conclusion: Results are encouraging
Non-Platinum Candidates
* Wayne State; 2005 PMID 16029789 — "A single institution experience with concurrent capecitabine and radiation therapy in weak and/or elderly patients with urothelial cancer." (Patel B et al. IJROBP 2005 Aug 1;62(5):1332-8.)
** Retrospective. 14 patients, median age 80. RT 54-68.4 Gy with concurrent capecitabine 1600 mg/m2. Median F/U 10 months
** Outcome: cCR 77%, local relapse 27%
** Toxicity: Fatigue 43%, dehydration 43%, Grade 3 diarrhea 29%
** Conclusion: Concurrent capecitabine and RT well tolerated in elderly patients

## Selective Bladder-Sparing Approach

* Operable patients, for whom the goal is to spare bladder but with planned cystectomy if no complete response to early induction
* Initial favorable reports from MGH, RTOG, Paris, and Erlangen in early 1990's
* Conceptual approach: Induction chemo-RT to ~45 Gy, then cystoscopy ~3 weeks later. Split-course consolidation chemo-RT to ~65 Gy if pathologic complete response (pCR), else planned radical cystectomy. This way, RT dose to bowel is kept in range to allow construction of conduit
** The main difference between definitive chemo-RT and selective bladder-sparing approach is timing of salvage cystectomy (after ~45 Gy vs ~65 Gy).
** It is not well documented whether delivering full chemo-RT dose improves pCR and ultimately bladder preservation rates
** The incremental benefit of adding consolidative chemo-RT after induction is also not well established (e.g Erlangen chemo-RT 50.4 Gy outcomes)
** Conversely, it is not well documented whether delaying radical cystectomy impacts outcomes in this setting. If performed alone, radical cystectomy should be performed within 12 weeks of diagnosis (see above)
** The toxicity impact of irradiating bowel that might serve as a conduit to higher dose with definitive chemo-RT is also not well documented, particularly if partial bladder RT is used
** The QoL in patients with post-therapy native bladder vs reconstructed neobladder has not been well evaluated
* Current RTOG protocols use fundamentally the same approach as RTOG 85-12, with more modern chemo
* CR rate of 70-80% with multi-agent chemotherapy + RT after radical TURBT. Extent of TURBT critical predictor of success, while multifocal disease, extensive CIS, and presence of hydronephrosis are a detriment
* 5-yr OS for bladder preservation 50-60%, majority with an intact bladder. These OS survival rates are comparable to cystectomy series
* Please also see the section on Quality of Life evaluations below

### Ongoing

* RTOG 05-24 (ongoing) - A Phase I/II Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation Following Transurethral Surgery for Non-Cystectomy Candidates With Muscle-Invasive Bladder Cancer.
** T2-T4a, N0-1 or T1 grade 3. Medically inoperable. 1.8 Gy for 39.6 Gy (small pelvic fields) then 14.4 Gy (whole bladder to 54 Gy) then 10.8 Gy (boost) for total 64.8 Gy. Weekly Taxol +/- Herceptin x 6 cycles. Herceptin given only for pts with her-2-neu overexpression (2-3+ by IHC).

### Randomized

* RTOG 02-33 - Concomitant boost. TURBT followed by induction chemo/RT (BID RT and randomized to Taxol + cisplatin vs 5-FU and cisplatin), evaluate tumor response, then consolidation chemo/RT (BID RT and randomized to same arm as above), then 4 cycles adjuvant chemo (Gemzar, Taxol, Cisplatin). Cystectomy for those who fail induction.
** Purpose is to compare efficacy and morbidity of taxol vs 5-FU combined with cisplatin (comparing trials 95-06 and 99-06).
** Radiation — Induction:40.3 Gy: BID RT x 13 days, 1.6 Gy small pelvic fields, 1.5 Gy boost to whole bladder (days 1-5) or 1.5 Gy boost to bladder tumor (8 days; days 8-17). Consolidation: 24 Gy: 1.5 Gy BID small pelvic fields x 8 days. Total: 64.3 Gy (44.8 small pelvic, 7.5 whole bladder, 12 tumor)
** 2010 ASTRO Abstract -- "Preliminary Results of RTOG 0233: A Phase II Randomized Trial for Muscle-invading Bladder Cancer Treated by Transurethral Resection and Radiotherapy Comparing Two Forms of Concurrent Induction Chemotherapy" (Zietman AL, IJROBP Volume 78, Issue 3, Supplement , Pages S31-S32, 1 November 2010)
*** 93 pts. Median F/U 3 yrs. 98% completed induction in TC arm vs 96% FC. Adj chemo completed in 67% of pts with TC and 53% for FC. Response (T0, Ta, or Tcis) after induction: 87% TC vs 79% FC. CR (T0) 72% and 62%. Alive with bladder intact at 4 yrs: 73% vs 69%.
*** Toxicity: grade 4 tox during induction: 4 in TC vs 1 in FC; during adj chemo: 11 in TC vs 15 in FC. Most toxicities were renal or heme. No GI grade 3+ tox in either arm during induction, but 3 seen during consolidation with FC. Late gr 3+ RT toxicity 9% TC and 4% FC, mostly bladder.
*** Conclusion: "Both induction regimens had high rates of completion, response, and bladder preservation. The completion rate for subsequent adjuvant chemotherapy was, however, lower for both arms. This study provides a useful benchmark for the evaluation of novel chemo-radiotherapy combinations in bladder cancer."
* RTOG 89-03 (1990-93) -- Selective chemo-RT bladder sparing +/- induction MCV x2 cycles
** Phase III. Stopped prematurely due to severe neutropenia and sepsis. 123 of 174 patients. cT2-T4a. Randomized to Arm 1) 2 cycles of MCV before, or Arm 2) no MCV before RT 39.6/22 with concurrent cisplatin 100 mg/m2 q3w x2 courses (per RTOG 88-02), cystoscopy 4 weeks later. If CR, consolidative RT 25.2/14 with concurrent cisplatin 100 mg/m2, else radical cystectomy. Total RT dose 64.8/36
** 1998 PMID 9817278 — "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." (Shipley WU, J Clin Oncol. 1998 Nov;16(11):3576-83.) Median F/U 5 years
*** Outcome: pCR MCV+ 61% vs MCV- 55%. r-year bladder preservation 36% vs 40% (NS). DM 33% vs 39% (NS). 5-year OS 48% vs 49% (NS) Predictors for worse outcome hydronephrosis and incomplete TURBT
*** Conclusion: 2 cycles of MCV did not increase CR rate, change DM rate, or impact OS. High toxicity.

### Non-Randomized

* Combined analysis, RTOG 9906 & 0233
** 2014 Abstract: ASCO Genitourinary Cancers Symposium -- "Long-term outcomes among patients who achieve complete or near-complete responses after the induction phase of bladder-preserving combined modality therapy for muscle-invasive bladder cancer: A pooled analysis of RTOG 9906 and 0233." (Mitin T, J Clin Oncol 32, 2014 (suppl 4; abstr 284))
*** Both trials allowed pts with near-complete response (Ta or Tis) after induction to proceed with consolidation therapy.
*** 119 pts had either a CR (n=101;85%) or near-CR (n=18;15%).
*** Median f/u 5.9 yr. Bladder recurrence in 36% of T0 pts vs. 28% of Ta/Tis pts (NS). DSS, OS, and survival with intact bladder were not significantly different.
*** Conclusion: "There is no apparent difference in the bladder recurrence and salvage cystectomy rates between complete and near-complete responders as judged at the time of cystoscopic evaluation after induction phase of bladder preserving CMT. It is appropriate to recommend that patients with Ta or Tis after induction chemo-RT continue with bladder-sparing therapy."
* RTOG 99-06; 2009 (1999-2002) PMID 19100600 -- "Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy." (Kaufman DS, Urology. 2009 Apr;73(4):833-7. Epub 2008 Dec 18.)
** Phase I/II. 80 patients, cT2-T4a on full TURBT. Induction chemo-RT, RT 40.3/26 BID over 3 weeks with concurrent cisplatin 120 mg/m2 + taxol 150 mg/2. Cystoscopy/urine cytology 3 weeks later. If CR, consolidation with chemo-RT, RT 24/16 BID with concurrent cisplatin/taxol. Total RT dose split-course 64.3/42 BID. Adjuvant cisplatin/gemcitabine x4 cycles. Median F/U 4.2 years
** Outcome: pCR 81%. After full course, 5-year local recurrence 28%, regional failure 11%, DM 31%. 5-year DSS 71%, and OS 56%
** Toxicity: Acute G3-4 26% (mainly GI) during induction, 8% during consolidation. Late toxicity 6% but resolved in all
** Conclusion: Favorable tumor response; deserves further study
* RTOG 97-06; 2003 (1998-2000) PMID 14529770 — "RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy." (Hagan MP, Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72.)
** Phase I/II. 47 patients, cT2-T4aN0 on aggressive TURBT, operable. Induction RT 40.8/24 BID with concurrent cisplatin 20 mg/m2 QW, cystoscopy in 3 weeks. If CR, consolidative RT 24/16 BID with concurrent cisplatin 20 mg/m2 QW, followed by MCV x3 cycles. If less than CR, radicarl cystectomy + MCV x3 cycles. Total RT dose 64.8/40
** Outcome: pCR 74%. After full course, local recurrence 18% (invasive 12%). 3-year OS 61%, 3-year bladder preservation 48%
** Toxicity: Grade 3 in 20%; adjuvant chemo Grade 3-4 toxicty 77%
** Conclusion: Accelerated chemo-RT well tolerated, with results comparable to prior studies. Adjuvant chemo poorly tolerated
* RTOG 95-06; 2000 (1995-1997) PMID 11110598 — "The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response." (Kaufman DS, Oncologist. 2000;5(6):471-6.)
** Phase I/II. 34 patients. cT2-T4aNx on aggressive TURBT. Used Paris regimen: Induction RT hyperfractionated split-course RT 24/8 over 3 weeks (D1, D3, D15, D17 BID) with concurrent cisplatin 15 mg/m2 + 5-FU 500 mg/m2, cystoscopy in 3-4 weeks. If CR, consolidative RT 20/8 (D1, D3, D15, D17 BID) with concurrent 5-FU/cisplatin, else radical cystectomy. Total RT dose 44/16. Median F/U 2.4 years
** Outcome: pCR 67%. After full course, local recurrence 45% (invasive 15%), DM 26%. 3-year OS 86%, 3-year bladder preservation 66%
** Toxicity: Grade 3-4 hematologic toxicity 21%
** Conclusion: Concern about local recurrence and toxicity, until data matures, plan to go ahead with conventional BID RT
* Harvard
** Initial MGH report; 1993 PMID 8413433 — "Selective bladder preservation by combination treatment of invasive bladder cancer." (Kaufman DS et al. N Engl J Med. 1993 Nov 4;329(19):1377-82.)
*** Retrospective. 53 patients, cT2-T4 on TURBT. Initial 2 cycles MCV, then RT 39.6/22 with concurret cisplatin 70 mg/m2 Q3W. Response assessed after 40 Gy. If CR, continued with 25.2/14. Total RT dose 64.8/36. Median F/U 4 year
*** Outcome: pCR 77%. 5-year OS 48%, 5-year bladder preservation 58% (89% bladder preservation in those in pCR). Hydronephrosis poor prognostic factor
*** Conclusion: Conservative treatment may be an acceptable alternative
** Update; 1997 PMID 9060542 (1986-93) — "Bladder preservation by combined modality therapy for invasive bladder cancer." (Kachnic LA et al. J Clin Oncol. 1997 Mar;15(3):1022-9.)
*** Retrospective. 106 patients, T2-T4a on maximal TURBT. Treatment approach as above
*** Outcome: pCR 66%. 5-year OS 52%, 5-year bladder preservation 43% (79% bladder preservation in those in pCR)
*** Conclusion: Results similar to cystectomy in these patients; majority of long-term survivors retain their bladder
* RTOG 88-02; 1996 (1988-90) - PMID 8558186 — "Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802." (Tester W, J Clin Oncol. 1996 Jan;14(1):119-26.
** Phase II. 85 patientss. cT2-T4aM0 suitable for radical cystectomy. Induction with 2 cycles of MCV alone (MTX 30 mg/m2, cisplatin 70 mg/m2, vinblastine 2mg/m2), followed by RT 39.6/22 with concurrent cisplatin 70 mg/m2 Q3W, cystoscopy 2 weeks later. If CR, consolidative RT 25.2/14 with concurrent cisplatin 70 mg/m2, else radical cystectomy. Total RT dose 64.8/36
** Outcome: pCR 80%. After full course, local recurrence 54% (invasive 26%), DM 22%. Cystectomy in 40% (induction 15%, invasive recurrence 18%, extensive noninvasive recurrence 7%). 4-year OS 62%, 4-year bladder preservation 44% (60% in patients with full course)
** Toxicity: Worse toxicity compared with RTOG 85-12
** Conclusion: Bladder preservation achieved in the majority of patients, and survival similar to surgical series
* RTOG 85-12; 1993 (1986-88) - PMID 8478228 — "Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12." (Tester W, Int J Radiat Oncol Biol Phys. 1993 Apr 2;25(5):783-90. )
** Phase II. 48 patients, stage cT2-4N0-2. Induction RT 40/20 with concurrent cisplatin 100 mg/m2 Q3W, cystoscopy 2 weeks later. If CR, consolidative RT 24/12 with concurrent cisplatin 100 mg/m2, else radical cystectomy. Median F/U of surviving patients 3 years
** Outcome: pCR 67%. After full course, local recurrence 40%, regional recurrence 11%, DM 29%. 3-year OS 64%
** Toxicity: late Grade 3+ in 7%
** Conclusion: Need better patient selection to achieve disease control and bladder preservation
* Universite Paris; 1993 (1988-1991) PMID 8229129 — "Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study." (Housset M, J Clin Oncol. 1993 Nov;11(11):2150-7.)
** Prospective. 54 patients, T2-T4. TURBT followed by 5-FU/cisplatin + concomitant hyperfractionated split-course RT. RT given 24/8 over 3 weeks (D1, D3, D15, D17 BID). Cystoscopy after 6 weeks. If CR (74%), either chemo-RT (55%) or cystectomy (45%), not randomized. Boost RT 20/8 (D64, D66, D78, D80 BID) with concurrent 5-FU/cisplatin. Median F/U 2.2 years
** Outcome: pCR 74% on cystoscopy. In CR patients, local control 90% (3/22 in chemo-RT vs 1/18 in cystectomy arms), DM rate 30%. 3-year OS 59%, no difference between cystectomy and chemo-RT
** Conclusion: Neoadjuvant chemo-RT treatment may be proposed as the conservative approach
| Trial | Induction RT | Induction chemo | Planned break | Consolidative RT | Consolidative chemo | Total RT dose | pCR | Survival |
| RTOG 99-06 | 40.3/26 | cisplatin/taxol | 3 weeks | 24/16 | cis/taxol, cis/gem x4 | 64.3/42 | 81% | 5y: 56% |
| RTOG 97-06 | 40.8/24 | cisplatin | 3 weeks | 24/16 | cisplatin | 64.8/40 | 74% | 3y: 61% |
| RTOG 95-06 | 24/8 | cisplatin/5-FU | 3-4 weeks | 20/8 | cisplatin/5-FU | 44/16 | 67% | 3y: 86% |
| RTOG 89-03 | 39.6/22 | ±MCV x2 alone, then cisplatin | 4 weeks | 25.2/14 | cispaltin | 64.8/36 | 61% | 5y: 48% |
| RTOG 88-02 | 39.6/22 | MCV x2 alone, then cisplatin | 2 weeks | 25.2/14 | cispaltin | 64.8/36 | 80% | 4y: 62% |
| RTOG 85-12 | 40/20 | cisplatin | 2 weeks | 24/12 | cisplatin | 64/32 | 74% | 3y: 59% |
| Harvard; 1993 | 39.6/22 | MCV x2 alone, then cisplatin | 2 weeks? | 25.2/14 | cispaltin | 64.8/36 | 77% | 5y: 48% |
| Paris; 1993 | 24/8 | cisplatin/5-FU | 6 weeks | 20/8 | cisplatin/5-FU | 44/16 | 67% | 3y: 64% |

## Quality of Life Evaluations
### Bladder Sparing Approaches

* GETUG 97-015; 2010 (1999-2001) PMID 20385453 -- "Quality of Life Assessment After Concurrent Chemoradiation for Invasive Bladder Cancer: Results of a Multicenter Prospective Study (GETUG 97-015)." (Lagrange JL, Int J Radiat Oncol Biol Phys. 2010 Apr 10. [Epub ahead of print])
** Phase II. 51 patients. cT2-T4. TURBT R0 66% (included patients who were not surgical candidates). Induction RT 45/25 with concurrent cisplatin/5-FU Q3W, cystoscopy 2 weeks later. If pCR, consolidative RT 18/10 with concurrent cisplatin/5-FU. EORTC QLQ-C30 questionnaire and LENT-SOMA scale used at 0.5, 1, 2, and 3 years after treatment. Median F/U 8 years
** Outcome: 8-year OS 36% (for surgical candidates 45%), 8-year bladder preservation 66%
** QoL: Satisfactory bladder function by LENT-SOMA in 100% of preserved bladders at 3 years. Patient satisfaction with bladder fuction satisfactory prior to therapy 35%, at 6 months 43%, at 18 months 57%, and at 3 years 29%. Sexual function preserved in 79%
** Conclusion: Overall bladder preservation in 67% of patients at 8 years, with satisfactory QoL and bladder function in those who had preserved bladder
* Harvard; 2003 (1986-2000) PMID 14532773 -- "Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors." (Zietman AL, J Urol. 2003 Nov;170(5):1772-6.)
** Retrospective. 49 patients (out of 71 alive in 2001), native bladders, disease-free after chemo-RT therapy. Urodynamic evaluation and questionnaire. Median F/U 6.3 years
** Outcome: Normal urodynamic function 67%, decreased compliance 22%. Bladder hypersensitivity and incontinence 6%. On questionnaire, control problems 19%, urgency 15%, flow symptoms 6%. Pads worn by 11% of women. Bowel symptoms 22%. Majority of men retained sexual function. Global HRQoL high
** Conclusion: Majority of patients retain good bladder function

### Comparison With Surgery

* Karolinska Institute; 2002 PMID 11937249 -- "Distressful symptoms after radical radiotherapy for urinary bladder cancer." (Henningsohn L, Radiother Oncol. 2002 Feb;62(2):215-25.)
** Retrospective. 58 patients treated with radical RT before 1995 (63-68 Gy split course), compared with 251 patients with radical cystectomy, and 310 general population patients.
** Outcome: GU moderate distress: RT 25% vs general population 9%, surgery not evaluated. GI moderate distress: RT 32% vs surgery 24% vs general population 9%. Sexual life dissatisfaction: 36% vs 67% vs 28%
** Conclusion: Approximately three quarters of long-terms survivors after radical RT had functioning urinary bladder with little or no distress from urinary tract. Prevalence of sexual dysfunction was lower than after surgery, with comparable GI dysfunction
* Trento, Italy; 1996 (1981-1994) PMID 8780548 -- "Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma. A survey by a self-administered questionnaire." (Caffo O, Cancer. 1996 Sep 1;78(5):1089-97.)
** Retrospective study. 59 patients, treated conservatively (49%) or with cystectomy (51%), who returned questionnaire (~65% rate in both)
** Outcome: QoL in conservative group better than in surgical group. Lower QoL after surgery due to stoma presence, lack of sexual activity, and worse physical condition. Little impact on social and recreational life
** Conclusion: Quality of life is better after conservative therapy than after cystectomy

## Palliative Radiotherapy

Short course:
* Medical Research Council BA-09, 2000 - PMID 10802363 (Duchesne GM et al.)
** 272 pts, multicenter. Randomized. 21 Gy / 3 fx as effective as 35 Gy / 10 fx
* Helsinki, Finland, 1992 - PMID 1378746 (Salminen E et al.)
** 94 pts. 30 Gy / 6 fx (twice a week)
* UK, 1994 (1982-89) - PMID 7513538 (Srinivasan V et al.)
** Non-randomized (short course vs std fractionation). Compare 1) 17 Gy / 2 fx (over 3 days) vs. 2) 45 Gy / 12 fx (375 cGy/fx)
** 41 pts with hematuria or pain. Clearing of hematuria in 59% (2 fraction) vs 16% (long course); improvement in pain in 73% vs 37%.

## Treatment of Uncommon Histologies

Small Cell Carcinoma:
* SEER (1991-2005)
** 2012 PMID 22019246 -- "Treatment trends and outcomes of small-cell carcinoma of the bladder." (Koay EJ, Int J Radiat Oncol Biol Phys. 2012 May 1;83(1):64-70.)
*** 533 pts. No significant difference in outcomes between pts treated with TURBT+RT/Chemo vs Cystectomy+Chemo. However, <20% of pts treated with RT or cystectomy. Majority of pts treated with TURBT alone.
*** Conclusion: "Relatively few patients with small-cell carcinoma of the bladder receive potentially curative therapies. Chemotherapy should be a major component of treatment. Cystectomy and bladder-sparing approaches represent two viable strategies and deserve further investigation to identify the patients who may benefit from organ preservation or not."
* CAGMO Consensus Guidelines
** 2013 PMID 23671508 -- "Management of small cell carcinoma of the bladder: Consensus guidelines from the Canadian Association of Genitourinary Medical Oncologists (CAGMO)."
Radiation Technique:
* MSKCC; 2014 No PMID yet Abstract (Article in Press) "External beam radiation therapy for small cell carcinoma of the urinary bladder" (Mattes MD, Pract Radiat Oncol, Published online: May 27, 2014)