Treatment and Surveillance of Non- Muscle Invasive Bladder Cancer David Josephson, MD FACS Fellowship Director, Urologic Oncology and Robotic Surgery Program
Staging Most important in risk assessment and management Ta confined to mucosa, 70% of non-muscle invasive TCC T1-30% TNM 2002
Low grade Ta Rarely progress only 2% Frequently recur 70% need repeat resections Multiplicity Recurrence at first cystoscopy Previous recurrence Tumor size > 3 cm
High Grade Ta Low incidence: 2-9% of all non-muscle invasive TCC Mandate repeat TUR to assure accurate staging Intravesical treatment 50% recur 25% progress Potentially lethal 20% may die
T1 High incidence of progression 35-48% progress to muscle invasive dz within 3 years when treated by TUR alone Mandate repeat TUR to assure accurate staging and removal of residual tumor burden Frequently understaged or misclassified EORTC 1400 patients: 10% upstaged to T2 on review of path. Lack of muscle in initial specimen 50% have residual dz or are muscle invasive
T1 Substaging T1A: invasion superficial to the level of muscularis mucosae (MM) T1B: invasion into MM T1C: invasion through MM but superficial to muscularis propia Worse prognosis with increasing invasion Opponents argue inconsistency, lack of orientation
CIS Can increase recurrence rate from 43% to 73% when concomitant Half progress to muscle invasive dz 20% will ultimately die of metastatic dz even with intravesical BCG LIFETIME surveillance especially upper tracts and prostatic urethra
Important Factors for Recurrence & Progression Progression and recurrence characteristic Nearly 60-90% with non-muscle invasive dx will recur if treated by TUR alone Factors Grade : better predict progression and mortality Depth: Ta vs T1 Multiplicity Tumor size LVI Recurrence at 3 Months Presence of CIS Sylvester et al Eur Urol 2006
RISK GROUP CLASSIFICATION BASED ON STAGE/GRADE Risk Group Recurrence Progression Mortality Low risk: Grade 1 stage Ta Grade 1 stage T1, single tumor 37% 0% 0% Intermediate risk: Grade 1 stage T1, multiple tumors Grade 2 stage Ta Grade 2 stage T1, single tumor 45% 1.8% 0.7% High risk: Grade 2 stage T1, multiple tumors Grade 3 stage Ta Grade 3 stage T1 CIS association 54% 15% 9.5% Overall 48% 7.5% 4.6% Josephson, Expert Rev. Anticancer Ther. 7(4), 567 581 (2007)
Initial TUR or Biopsy preferred histopathological assessment Rule out muscle invasion Laser (Neo/yag) No difference in recurrence Lack of tissue for staging or grading Good for low grade Management
Role of Re-resection for T1 TCC Persistent tumor in 27% ta, 37% t1 Even if normal cysto, 17% with residual CA Only 23% of high grade Ta confirmed on review 30% of T1 upstaged if no muscle in initial TUR Critical to further recommendations Schips Urology 59(2), 220 223 (2002).
Intravesical Therapy Not for all patients Traditional indications Multiple and large tumors (> 3 cm) Early recurrence High Grade Ta Any T1 Cis or Lymphovascular invasion Positive cytology after resection of all visible tumor
Available agents Chemotherapy: Mitomycin, thiotepa, doxorubicin, epirubicin, Gemcitabine, Valrubicin BCG Immunotherapy Interferon Vitamins A, C, E, selenium Bropiramine
Bladder Cancer: Immediate Post-op Chemo Given Peri-Op Single dose Low Morbidity Only for 1 st Tumors Reduces tumor Implants and potentially recurrence in up to 40% Better results in low risk tumors Gudjonsson, Eur Urol 55 (2009), pp. 773 780; Ayres, BJU Int, 2010, p 14-7
Low Risk Patients: Intravesical Chemotherapy Meta-analysis 4 EORTC Trials 2 MRC Trials Numerous regimens Recurrence 20% risk reduction Progression No impact Pawinski, J Urol 1996, 156;1934-41. Huncharek, J Clin Epid 2000, 676-680
BCG vs Chemotherapy BCG superior to thiotepa, epirubicin, adriamycin BCG vs mitomycin mixed results but favor BCG Meta-analysis 1 11 trials 2 year recurrence 38% vs 46% Maintenance had bigger impact 10 yr RFS 2 30% with BCG, no impact of chemo Bohle, J. Urol. 169(1), 90 95 (2003). Herr, J. Urol. 147, 1020 1023 (1992).
Intravesical BCG Impacts recurrence & progression 6 wks vs 6 wks + maintenance for 3 years Maintenance regimens differ RFS 5yrs: 41% vs 60% Significant side effects Fever, chills, hematuria Urinary side effects Only 16% for 3 years? If 1/3 dose is equal
Carcinoma in Situ (CIS) Up to 50% progress to T2 10% metastasize BCG mainstay of therapy Up to 70% response BCG failure Repeat BCG +/-IFN-a Valrubicin (valstar) 20% response rate Good for poor surgical candidatesd Experimental agents Early Cystectomy Sylvester RJ, Urology 66(6 Suppl. 1), 90 107 (2005).
Intravesical treatment Failures If chemo given, can benefit from BCG If BCG given, considered failure if: higher number of recurrence, increased grade/stage, CIS Muscle invasive disease High grade at both 3 and 6 mo Additional course at 3 mo can provoke response in 50% at 6 mo
Surveillance Plan Vigilant follow-up Life long regardless of grade/stage Cystoscopy and Cytology Every 3 months x 2 years Every 6 months x 2 years Annually thereafter Annual CT Urogram to check ureters/kidneys (5% risk) Role of urine based markers uncertain
Urine Based Markers FDA APPROVED Stat BTA TRAK Nuclear matrix protein NMP22 FISH :fluorscence in situ hybridization Investigational Hyaluronic acid Cytokeratins BLCA-4
Non-Invasive Bladder Cancer Conclusions Two Diseases Low grade Ta: bothersome but treatable T1 and CIS: Can be life threatening Needs Less invasive follow up Better interventions for high risk patients
1-800-826-HOPE djosephson@coh.org