Radiation Oncology/Bladder

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[edit] Epidemiology

5th most common cancer. (4th in men, 8th in women)
Male:female = 3:1
63,210 cases/yr. 13,180 deaths/yr.
70% are superficial, 25% muscle invasive, 5% metastatic at presentation.

[edit] Risk factors

smoking - increases risk 2-3 X
occupational exposure - aromatic compounds, leather industry workers
schistosoma haematobium
cyclophosphamide

[edit] Pathology

98% transitional cell. Also adeno, squamous (Schistosoma), small cell.

[edit] Staging

Current, AJCC 6th ed. (2002):
Tumor:

  • Ta - non-invasive papillary carcinoma
  • Tis - carcinoma in situ, "flat tumor"
  • T1 - invades subepithelial connective tissue
  • T2 - invades muscle
    • T2a - invades superficial muscle (inner half)
    • T2b - invades deep muscle (outer half)
  • T3 - invades perivesical tissue
    • T3a - microscopically
    • T3b - macroscopically (extravesical mass)
  • T4 - invades other organs
    • T4a - invades prostate, uterus, vagina
    • T4b - invades pelvic wall, abdominal wall

Nodes:

  • N1 - single LN, 2 cm or less
  • N2 - single LN 2-5 cm; or multiple LN < 5 cm
  • N3 - LN > 5 cm

Regional nodes are the nodes of the true pelvis below the common iliac.

Overall stage:

  • Stage 0a - Ta N0M0
  • Stage 0is - Tis N0M0
  • Stage I - T1 N0
  • Stage II - T2 N0
  • Stage III - T3N0 or T4aN0
  • Stage IV - T4b or any N+ or M1

[edit] Older staging

AJCC - 5th and 6th editions the same

  • 4th edition (1992)
    • T1 (same), T2 (superficial muscle), T3a (deep muscle), T3b (perivesical fat), T4 (invades prostate, uterus, vagina, pelvic wall, abdominal wall)

UICC

  • 3rd edition (1978) - T3 is deep muscle invasion (similar to T2b)

[edit] Treatment of Superficial Bladder Cancer

80% of bladder cancers are superficial. Tis and Ta comprise this group.

  • Ta, low grade - TURBT with surveillance
Only 50-75% recur, but can be treated with repeat resection. Only in 5% of cases do they progress to T1 lesions, or in 1-3% of cases become high grade.
  • T1
high grade in 30-50%. Rarely low grade.

Risk factors for recurrence:

  • multiple tumors, tumors > 3-4 cm, positive urine cytology, tumors involving submucosa, dysplasia in multiple random biopsies

Treatment algorithm (from NCCN guidelines, v1.2005) Perform TURBT:

  • Tis: BCG
  • cTa, G1-2: may observe or consider single dose intravesical chemotherapy (not BCG)
  • cTa, G3 or cT1, G1-2: observe or intravesical BCG or mitomycin
  • cT1, G3: BCG or consider cystectomy. Re-resect if not completely resected.

Follow-up after treatment:

  • Cystoscopy + urine cytology every 3 months x 2 yrs, then q6m x 2 yrs, then annually

Treatment of recurrence: intravesical BCG (Bacillus Calmette-Guerin) or intravesical chemo


  • MRC T1 Bladder (1991-2003)
    • Randomized, 2 strata. 210 patients with pT1G3 TCC. Goal: prevention of progression to T2
      • Unifocal disease and no Tis: Arm 1) observation vs. Arm 2) RT 60/30
      • Multifocal disease and/or Tis: Arm 1) intravesical therapy (MMC or BCG) vs. Arm 2) RT 60/30
    • 2007 PMID 17631326 -- "A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder." (Harland SJ, J Urol. 2007 Sep;178(3 Pt 1):807-13; discussion 813. Epub 2007 Jul 16.)
      • Outcome: No difference in PFS, OS, or cystectomy rate
      • Conclusion: No evidence that RT is better than more conservative treatment; prognosis poor regardless

[edit] Cystectomy for Muscle-invasive Bladder Cancer

Distant mets are most common mode of treatment failure (30-45% at 5 years without chemo).

[edit] Recommended treatment

Per NCCN guidelines, v.2.2008
By clinical stage (based on exam and biopsy):

  • T2N0
    • Primary treatment: radical cystectomy, or segmental cystectomy (solitary lesion), or bladder sparing with chemo-RT. For poor performance status: TURBT alone, RT alone, or chemo alone. If remaining tumor after bladder conservation, proceed to cystectomy.
    • Adjuvant therapy: chemotherapy for poor risk patients (positive nodes, pT3)
  • T3N0
    • Primary treatment: neoadjuvant chemotherapy and radical cystecomy or bladder sparing with chemo-RT.
  • T4/N+
    • Primary treatment: chemotherapy or chemo-RT. Surgery only for select T4a pts.
  • Node-positive:
    • Primary treatment: chemotherapy or chemo-RT.

[edit] Surgical Management

  • Radical cystectomy with pelvic lymphadenectomy is considered the standard of care.
  • Radical cystectomy 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.
  • Dissection of presacral nodes is controversial and institution-dependent.
  • 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.
  • 50% will ultimately die of metastatic disease after radical cystectomy

[edit] Adjuvant Chemotherapy

To decrease DM but also improves local control.

  • PAC: cisplatin, doxorubicin, cyclophosphamide
  • MCV: Methotrexate, cisplatin, vinblastine
  • MVAC: adds Adriamycin to MCV


  • Skinner 1991 (1980-88) - adjuvant chemo after cystectomy for deep muscle invasive
    • 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.
    • 91 pts. 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

Meta-analysis:

  • PMID 16419069, 2006 — "Adjuvant chemotherapy in muscle-invasive bladder carcinoma: a pooled analysis from phase III studies." Ruggeri EM et al. Cancer. 2006 Feb 15;106(4):783-8.
    • 350 pts in 5 randomized trials. Benefit for OS (RR=0.74) and DFS (RR=0.65) for adjuvant chemotherapy.

[edit] 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) (46 months)
  • 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.

[edit] Preoperative Radiation

  • 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.


  • M.D.Anderson, 1977 - PMID 402205 - Miller et al.
    • 67 pts. T3 tumors. Randomized to 50 Gy RT+immediate cystectomy vs 60 Gy RT with cystectomy for salvage.
    • 5-year OS 45% (surgery) vs 22% (RT)
  • Danish National Bladder Cancer Group, DAVECA protocol 8201, 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 et al. Scand J Urol Nephrol Suppl. 1991;138:193-201.
    • 183 pts. T3. Pre-op RT 40 Gy + cystectomy vs radical RT 60 Gy with cystectomy for salvage. Median f/u 50 months.
    • No difference in OS (29% vs 23%). Local/pelvic recurrence lower (6.8% surgery vs 35% RT). No difference in DM.
  • 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)

[edit] Preoperative Chemoradiation

  • University of Paris, 1993 - PMID 8229129 — "Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study." Housset M et al. J Clin Oncol. 1993 Nov;11(11):2150-7.
    • 54 pts. T2-T4. TURBT followed by 5-FU/cisplatin + concomitant hyperfractionated split-course RT. Complete responders had either additional chemo/RT or cystectomy (not randomized).
    • 74% had pCR after biopsy. DFS better and DM rate less in responders vs non-responders.
    • Paved the road to bladder-conserving therapy with chemo/RT

[edit] Bladder preservation for muscle invasive disease (and medically inoperable)

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 - 71%

Estimated 5-year outcome with ChemoRT regimens:

  • OS - 50%
  • OS with intact bladder - 40%
  • % alive with intact bladder - 80%

No trials directly compare cystectomy and bladder-preservation.

[edit] Radiation alone for bladder preservation

  • Improved results with combined modality largely replaced RT only treatment.
  • Clinical CR after RT associated with improved survival.
  • PMID 2424878 (Quilty et al., 1986)
    • non-randomized trial
    • RT dose 50-57.5 Gy
    • Factors predicting improved reponse to RT alone:
      • Hemoglobin > 12 g/dl, Tumor < 7 cm, Urea < 7 mmol/l
      • cCR higher for Grade 3 (55.7%) vs grade 2 (30.6%) or grade 1 (16.7%)
    • Improved survival:
      • Hemoglobin > 13 g/dl, tumor < 7, AND urea < 10

Accelerated radiotherapy:

  • Cooperative Urological Oncology Group, UK (1988-1998)
    • Randomized. 229 patients with T2-T3 N0-N1 bladder cancer. Arm 1) AF split-course 60.8/32 BID (22.8/12 + 19/10 + 19/10) vs. Arm 2) Conventional CF 64/32. Primary endpoint local control
    • 2005 PMID 15878099 -- "A randomised trial of accelerated radiotherapy for localised invasive bladder cancer." (Horwich A, Radiother Oncol. 2005 Apr;75(1):34-43. Epub 2004 Nov 25.)
      • Outcome: LR AF 32% vs. CF 29% (NS); 3-year OS 47% vs. 54% (NS); 5-year OS 40% vs. 37% (NS)
      • Toxicity: Acute AF 44% vs. CF 26% (SS); Late toxicity (if FFR 2 years): Grade 2+ AHFX 44% vs. conventional 38% (NS). 2 treatment-related deaths on AHFX arm
      • Conclusion: No benefit for AHFX over conventional fractionation, worse acute GI toxicity

[edit] Medically inoperable patients

RT alone:

  • 50-75% local failure
  • 5-yr OS 20-39%
  • Shipley (1974-82)
    • PMID 4032570, 1985 — "Full-dose irradiation for patients with invasive bladder carcinoma: clinical and histological factors prognostic of improved survival." Shipley WU et al. J Urol. 1985 Oct;134(4):679-83.
      • 55 pts, T2-T4 (53% - T3).
      • 5-yr OS 28%, MS 2.3 yrs. Prognostic factors - extent or TURBT, ureteral obstruction.


Chemo + RT:

  • National Bladder Cancer Group (1980-85)
    • PMID 3613023, 1987 — 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.
      • cCR 77%. 4-yr OS 57% (for those with initial CR) vs 11% (non-responders).
    • PMID 6436510, 1984 — Cisplatin and full dose irradiation for patients with invasive bladder carcinoma: a preliminary report of tolerance and local response. (Shipley WU et al. J Urol. 1984 Nov;132(5):899-903.)

Non-Platinum Candidates:

  • Wayne State
    • PMID 16029789, 2005 — "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.)
      • 14 pt's, median age 80. Capecitabine (M-F) + RT (54-68 Gy)
      • cCR 77% with 27% relapse rate at median f/u 10.5 months

[edit] Selective bladder sparing approach

  • Based on pre-op chemo/RT data showing pathologic-CR (such as University of Paris study)
  • CR rate of ~70% with multi-agent chemotherapy + RT after TURBT.
  • Pioneering institutions have been Erlangen, Germany and MGH
  • 5-yr OS for bladder preservation 49-63% with 38-43% survival with an intact bladder. These OS survival rates are comparable to cystectomy 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 et al. Int J Radiat Oncol Biol Phys. 1993 Apr 2;25(5):783-90.
    • Phase II. 48 pts. Stage T2-4. Treated with RT to 40 Gy and cisplatin on days 1+22. Pts with CR were given additional 24 Gy boost + 3rd dose of cisplatin. Those with residual tumor after 40 Gy had radical cystectomy.
    • 67% achieved CR after induction therapy
  • 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 et al. J Clin Oncol. 1996 Jan;14(1):119-26.
    • Phase II. 91 pts. T2-T4aM0 suitable for radical cystectomy. Treated with 2 cycles of MCV followed by 39.6 Gy with concurrent cisplatin. Pts who achieved CR were treated with consolidation with 25.2 Gy RT + cisplatin.
    • 40% required cystectomy.
    • Conclusion: Bladder preservation achieved in the majority of pts.
  • NCI-Canada, 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 et al. J Clin Oncol. 1996 Nov;14(11):2901-7.
    • 99 pts. T2-T4b. Randomized to +/- chemotherapy concurrent with RT, either definitive RT or pre-cystectomy RT (selected by physician).
    • Decrease in pelvic recurrence with chemo/RT. No difference in OS or DM.
  • RTOG 89-03, 1998 (1990-93) - 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 et al. J Clin Oncol. 1998 Nov;16(11):3576-83.
    • Phase III. 123 pts. T2-T4a. Randomized to 1) 2 cycles of MCV before, or 2) no MCV before 39.6 Gy RT with 2 courses of cisplatin 100 mg/m2 q3w. Pts who achieved CR received additional 25.2 Gy (total of 64.8) with a 3rd course of cisplatin. Pts without CR underwent cystectomy.
    • Median f/u 60 months. 5-yr OS 48% vs 49%. Bladder preservation 36% vs 40% (N.S.). DM 33% vs 39% (N.S.). 5-yr survival with functioning bladder, 36% vs 40%.
    • Conclusion: 2 cycles of MCV did not increase CR rate, DM rate, or OS.
  • Erlangen (Germany)
    • PMID 9422567, 1998 (1982-96) — Efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer. (Sauer R et al. Int J Radiat Oncol Biol Phys. 1998 Jan 1;40(1):121-7.)
      • 415 patients treated prospectively
      • prior to 1986, patients received preoperative xrt. After 1986, patients received neoadjuvant chemoradiation.
      • patients received 45 Gy to pelvis; bladder was boosted to 54 Gy
      • if patients had CR, they were observed; otherwise, they had radical cystectomy
      • 36% 5yr OS with xrt alone, 61% OS when given cisplatin/xrt, 43% still had a bladder at 5 yrs
    • PMID 2211216, 1990 (1985-88) — Radiotherapy with and without cisplatin in bladder cancer. (Sauer R et al. Int J Radiat Oncol Biol Phys. 1990 Sep;19(3):687-91.) - all pts received chemo/RT.
      • 67 pts, T1-4. RT 50.4 Gy + cisplatin, days 1-5, weeks 1 & 5.
      • CR in 67-76%. 3-yr OS 68% (T2-T3). Noted high CR rates, even in pts with incomplete TURBT (76% compared to 45% historical control.)
  • MGH
    • PMID 9060542, 1997 (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.)
      • 106 patients with T2-T4a bladder CA
      • patients received neoadjuvant MCV, then cisplatin/xrt
      • 39.6 Gy to pelvis initially
      • if CR then bladder boosted to 54 Gy; otherwise, went onto radical cystectomy
      • 66% CR rate, 52% 5yr OS, 43% still had a bladder at 5 yrs
    • PMID 8413433, 1993 (? years) — "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.)
      • 53 pts. 2 cycles MCV, then RT with 2 courses of cispt.
      • Re-eval after 4000 cGy. RT dose 4500 to pelvis + 1980 boost to whole bladder = 6480 total dose.
      • Median f/u 48 mos. 45% DFS, 58% with functional bladder free of tumor.
  • SWOG, 2001 (1993-98) - 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 et al. J Urol. 2001 Jan;165(1):56-60.
    • Non-randomized. 56 pts. Locally advanced (N+, confined to the pelvis) or inoperable, T2-T4. TURBT followed by chemo/RT (5-FU + CDDP x 2 cycles). 50 Gy to CTV (including nodes) and 60 Gy to GTV(entire bladder and tumor).
  • RTOG 95-06 (1995-7)
    • Purpose: is this induction regimen tolerable?
    • 35 pts. Phase I/II. TURBT followed by induction chemo/RT (17 day course, weeks 1 & 3). Cisplatin + 5-FU given on days 1-3 and 15-17 with Pelvic XRT 3 Gy BID on days 1 and 3, 15 and 17 = 24 Gy. Evaluate response on week 8. For pts with CR and those without CR who are medically inoperable, proceed to consolidation chemo/RT (similar cisplatin + 5-FU schedule with bladder RT 2.5 Gy BID on days 1 and 3, 15 and 17) = 20 Gy. If less than CR and medically operable, proceed to radical cystectomy.
    • PMID 11110598, 2000 — "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 et al. Oncologist. 2000;5(6):471-6.
      • 97% completed induction therapy. 21% grade 3-4 hematologic toxicity is the most concerning side effect. CR 67%, 3 yr survival with intact bladder 66%, 3 yr OS 83%. No patient required cystectomy for radiation toxicity
  • RTOG 97-06 (1998-2000) Protocol (PDF)
    • 47 pts. Phase I/II trial. Operable muscle-invading. TURBT followed by cisplatin + BID RT followed by either selective bladder preservation or radical cystectomy and adjuvant chemotherapy.
    • BID schema based on encouraging results from University of Paris and MGH.
    • T2-T4a, NX or pN0.
    • Schema:
      TURBT -> induction chemo/RT (weeks 1-3) -> evaluate at week 6
      If CR: consolidation chemo/RT (weeks 7-8) -> 3 cycles MCV
      If less than CR: radical cystectomy (week 8) -> 3 cycles MCV
    • Induction: XRT BID x 12 days: 1.8 Gy/day to pelvis = 21.6 Gy, plus 1.6 Gy/day to bladder tumor = 40.8 Gy. Cisplatin 20 mg/m2 given on days 1-2 each week x 3 weeks.
    • Consolidation: XRT BID x 8 days: 1.5 Gy to pelvis and bladder= 24 Gy. Cisplatin 20 mg/m2 on days 1-2 each week x 2 weeks.
    • Total RT dose: 45.6 Gy to pelvis, 64.8 Gy to bladder tumor.
    • PMID 14529770, 2003 — "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 et al. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72.
      • 43 of 47 pts completed induction. CR to induction in 74%(32/43); 18%(8) had cystectomy due to residual dz. 79%(37/47) completed either consolidation chemo/RT or had cystectomy. Only 45%(21/47) completed all three phases of the bladder-preserving treatment.
      • Chemo/RT is well tolerated with minimal toxicity. Adjuvant MCV was poorly tolerated following induction+consolidation chemo/RT.
  • RTOG 99-06 - phase I/II. BID chemo/RT after TURBT. Taxol/cisplatin. Adjuvant Gemzar/cisplatin
    • 99-06 has same RT scheme as RTOG 02-33.
    • ASCO Abstract 2005 #4506 "Muscle-invading bladder cancer, RTOG Protocol 99-06: Initial report of a phase I/II trial of selective bladder-conservation employing TURBT, accelerated irrdiation sensitized with cisplatin and paclitaxel followed by adjuvant cisplatin and gemcitabine chemotherapy." Kaufman DS et al. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 4506.
      • 47 pts evaluable. Median f/u 30 mo.
      • 87% CR after induction. 72% completed all protocol treatment.

Ongoing:

  • 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)
  • 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).

[edit] Partial bladder irradiation

No chemoradiotherapy:

  • UK (Christie Hospital) (1993-99)
    • 149 pts. T2-T3N0M0, unifocal TCC <= 7cm. Randomized to whole bladder conformal RT (52.5 Gy, 20 fx, 2.63 Gy/fx) or partial bladder RT in 4 wks (57.5 Gy, 20 fx, 2.88 Gy/fx) or 3 wks (55 Gy, 16 fx, 3.44 Gy/fx)
    • 2004 PMID 15093917 — "Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy." (Cowan RA, Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):197-207.)
      • Median f/u 5.8 yrs for living pts. CR 75%, 5 yr LC 50%, 5 yr OS 58%, CSS 65%. Cystectomy-free survival (CFS) 47%; 85% of pts alive at 5 yrs retained their bladders. No stat.sig. difference between arms for CR, OS, or CFS. Treatment was well tolerated and there was no difference in treatment toxicity between the arms (although there was a trend for more severe acute urinary frequence in the 3 week arm).
    • Conclusion: Partial bladder treatment allowed an increase in delivered dose without an increase in toxicity.

[edit] 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%.

[edit] Radiation technique

Treat with an empty bladder

  • Small pelvic fields - includes all bladder, all prostate, lymph nodes adjacent to bladder. Simulate with air contrast in bladder; contrast in rectum. 4 fields. Superior: mid-sacrum (S2-3). Inferior: bottom of obturator foramen. Lateral: PTV 1 cm lateral to bony pelvis. Anterior: PTV 1cm anterior to bladder. Posterior: PTV at least 1.5 cm posterior to bladder. Shield femoral heads.
  • Whole bladder fields - PTV 0.5 cm margin around bladder + tumor
  • Tumor boost - PTV = GTV + 0.5.
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