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Prof. Enrico Cortesi

Current strategies in the treatment of invasive and non-invasive disease. Prof. Enrico Cortesi. Department of Radiology oncology and human pathology; Oncology Unit B. “ Sapienza ” University of Rome. Rome, March 22 th 2013. Bladder Cancer: an unmeet medical need.

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Prof. Enrico Cortesi

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  1. Current strategies in the treatment of invasive and non-invasive disease Prof. Enrico Cortesi Department of Radiology oncology and human pathology; Oncology Unit B. “Sapienza” University of Rome Rome, March 22th 2013

  2. Bladder Cancer: an unmeet medical need. In 2012 bladder cancer was: The 4th cause for incidence The 8th cause of death in men Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  3. Bladder Cancer: from enthusiasm to depression Items found in PubMed for advanced tumors and clinical trials from 2000 to Jan 2013. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  4. Bladder Cancer: epidemiology 25% 30% 30% 70% 45% Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  5. Tumori dell’urotelio: profilo ricorrente e a rapida evoluzione • Profilo del paziente avanzato o metastatico • Fragile, frequenti co-morbidità • Insufficienza renale in più del 50% dei pazienti • Coinvolgimento viscerale in più del 75% dei pazienti Rischio stimato di ricaduta: 100% Dopofallimentodiplatino? Rischio stimato di sviluppare metastasi a distanza: 30%-40%(1) 1a Linea Metastatica Chemioterapia con regimi a base diplatino Vinfluvina, primo farmaco registrato dopo il fallimento di terapia a base di platino Taxani, Nav, altro…? E dopo…? Malattiainvasiva Trattamentilocaliassociati a chemioterapia con regimi a base diplatino (1) Guidelines on Bladder Cancer: Muscle-invasive and Metastatic. European Association of Urology. 2008. (2) Bellmunt J, Théodore C, Demkov T et al. J Clin Oncol 27: 4454-4461, 2009.

  6. Controversies in bladder tumors (BTs): cT1 G3 : any best strategy ? cT2 cN0 : any chance for bladder saving ? cT3-4 cN+ : does cystectomy save more lives? The present role of neo/adjuvant chemotherapy ? M+: there is only one standard first line?Any room for triplets? M+: the role for a second line therapy ? Any standard? Any biological therapy? Sorry…..NONE ! Controversies in usual and rare tumors of the bladder EnricoCortesi

  7. Treatment of Bladder Cancer • Non-invavise disease • Role of cistectomy and pre-operative imaging • Neoadjuvant chemotherapy • Adjuvant chemotherapy • Bladder Sparing Approach • First line therapy Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  8. Treatment of Bladder Cancer • Non-invasive disease • Role of cistectomy and pre-operative imaging • Neoadjuvant chemotherapy • Adjuvant chemotherapy • Bladder Sparing Approach • First line therapy Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  9. Non invasive disease: cT1, G3 Risk and Current Option: NCCN Guidelines v1.2013 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  10. Non invasive disease: pT1, G3 Kulkarni GS et al. Eur Urol. 2010 Jan;57(1):60-70. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  11. Non invasive disease: pT1, G3 Kulkarni GS et al. Eur Urol. 2010 Jan;57(1):60-70. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  12. The current study has analysed the presence and number of CTC through CellSearch in a group of 44 patients with primary diagnosis of NMIBC.

  13. 44 patients were enrolled (38 males, 6 females), mean age 62 years (range 51-78) all with histopathological diagnosis of NMIBC. All tumors were diagnosed as transitional cell carcinomas. A population of 20 healthy donors was included as negative control

  14. Patient characteristics and histopathology

  15. CTC were detectable in 8/44 patients (18%) and in 0/20 healthy volunteers.

  16. Presence of CTC was found significantly associated to shorter TFR (follow up: 24 months) In the group of CTC+ patients, 7/8 (87.5%) experienced a local recurrence in the 24 months of follow up, while in the group of CTC- only 13/36 (36%) local relapses were observed.

  17. All CTC+ patients with local recurrence of disease experienced a progression to muscle invasive disease as well Progression to muscle invasive disease occurred in 7/8 CTC+ and in 0/36 CTC- patients

  18. Correlationbetween CTC and T CTC were found in 8/26 (31%) patients with T1 tumors, and in 0/18 patients with Ta. This difference was found statistically significant (p= 0.0275).

  19. Correlationbetween CTC and G Association between CTC presence and tumor grading was found not statistically significant. (G1-2 vs G3, p=0.1133).

  20. Correlationbetween CTC and CIS CTC presence was also found associated to concomitant presence of CIS; in the group of patients with CIS, CTC were found in 5/8 (62.5%) compared to 3/36 (8.3%) found in the group without CIS (p= 0.00228).

  21. To our knowledge, our study for the first time reports about CTC prognostic significance in a homogeneous population of T1 bladder cancer patients using CellSearch. The detection of CTC in this setting of disease may allow to identify patients with high risk of progression and candidate for adjuvant treatment.

  22. Non invasive disease: pT1, G3 Both bladder preservation and RC are appropriate options for T1G3 BCa. Risk stratification of patients based on pathologic features at initial TUR or at recurrence can select those most appropriate for bladder preservation compared to those for whom cystectomy should be strongly considered. Kulkarni GS et al. Eur Urol. 2010 Jan;57(1):60-70. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  23. Non invasive disease: pT1, G3 Cost-effectiveness analysis of immediate radical cystectomy versus intravesical Bacillus Calmette-Guerin therapy for high-risk, high-grade (T1G3) bladder cancer. “The results of the current study indicated that, for healthy patients aged 60 years with T1G3 bladder cancer, immediate radical cystectomy would provide improved survival and quality-adjusted survival at lower cost. However, for patients aged 70 years, the most cost-effective therapy is initial conservative treatment with intravesical BCG. Proper risk stratification can help optimize patient outcomes while decreasing costs to the healthcare system”. Kulkarni GS,et al. Cancer. 2009 Dec 1;115(23):5450-9. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  24. Treatment of Bladder Cancer • Non-invasive disease • Role of cistectomy and pre-operative imaging • Neoadjuvant chemotherapy • Adjuvant chemotherapy • Bladder Sparing Approach • First line therapy Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  25. Role of cystectomy Results of radical cystectomy Stage Recurrence-Free Overall Survival 5 y. 10y. 5 y. 10y. T2 N- 89 87 77 57 N+ 50 50 52 52 T3a N- 78 76 64 44 N+ 41 37 40 26 T3b N- 62 61 49 29 N+ 29 29 24 12 T4a N- 50 45 44 23 N+ 33 33 26 20 Stein et al JCO 2001;19:666 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  26. Role of cystectomy Results of radical cystectomy Stage Recurrence-Free /Overall Survival 5 years Organ-confined (<pT2pNo) 73% 62% non-organ-confined (>pT2pNo) 56% 49% Positiv lymph nodes (pT1-4, pN+) 33% 24% Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  27. Discrepancies beetween clinical and pathological stage Data was collected from nine centers and 3,393 patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy and pelvic lymphadenectomy without neo-adjuvant chemotherapy Clinical and pathological stage was similar for 1076 (31.7%) patients. Down-staging was observed in 607 (17.9%) patients and clinicalunder-staging was observed in 1710 (50.4%) patients. BJU International 2011; 107:898-904 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  28. Improving imaging: the role of MRI and TC • Imaging parameters required for staging MIBC are: • the extent of local tumour invasion; • tumour spread to lymph nodes; • tumour spread to the upper urinary tract and other distant organs. • The accuracy of MRI for T-staging varies from 73% to 96%.These values were 10-33% higher than those obtained with CT. The sensitivity for detection of LN metastases is low, ranging from 48-87%. Overall, CT and MRI show similar results in the detection of lymph node metastases. Eur Radiol 1996;6(2):129-33. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  29. The role of DW-MRI in staging T DW is superior to T2-weighted MRI in staging of organconfined tumours (≤T2) and both techniques are comparable in the evaluation of higher-stage tumours. Waiting for definitive data Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  30. The role of PET/TC in staging N and M • FDG and C11-met positron emission tomography is avidly taken up by TCC and may be of value for diagnosis and staging • The urinary excretion of 18FDG prevents distinction of the primary tumor from the surrounding tracer use of 11C-methionine J Clin Oncol 2010; 28:3973-3978 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  31. Treatment of Bladder Cancer • Non-invasive disease • Role of cistectomy and pre-operative imaging • Neoadjuvant chemotherapy • Adjuvant chemotherapy • Bladder Sparing Approach • First line therapy Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  32. Meta-analysis: Results How to read this meta-analysis? Monotherapy is ineffective as neoadjuvant treatment But … how great is the benefit? Neoadjuvant treatment decrease the risk of death of 13%! Combination therapy is effective as neoadjuvant treatment Vale et al. Lancet, 361 (2003), pp. 1927–1934 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  33. Meta-analysis. 5% absolute benefit at 5 years (45% to 50%) Vale et al. Lancet, 361 (2003), pp. 1927–1934 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  34. Meta-analysis: efficacy by type of local therapy. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  35. Meta-analysis synthesis. • Treatment with cisplatin monotherapy has only a trend for increased survival in neoadjuvant setting. • Platinum based combination therapy is effective to increase survival. • The magnitude of benefit of neoadjuvant therapy is to decrease the risk of death of 13%. • Benefit mainly in patients with p0 disease • Effect irrespective of type of local therapy Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  36. Neoadjuvant CHT: BA06 30894 trial Surgery/RT 976 pts CHT Surgery/RT JCO 2011;29:2171-7  Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  37. Neoadjuvant CHT: BA06 30894 trial No increase in cystectomy related death were found in patients treated with CMV JCO 2011;29:2171-7  Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  38. Targets ant target therapies in urothelial carcinoma Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  39. Target therapies in urothelial carcinoma Is there a role for target therapies in neoadjuvant therapy? Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  40. Phase II trial of neoadjuvant CIS-GEM + Sunitinb Cisplatin-eligible pts with cT2-4aN0 bladder cancer received G 1000 mg/m2 and C 35 mg/m2 on day (D) 1 and D8 with S 25 mg orally daily D1-14 of a 21D cycle for 4 cycles. ASCO 2012, Abstr 4581 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  41. Phase II trial of neoadjuvantDDMVAC+bevacizumab (60 patients ) 61%  38%  33%  13%  2%  85% completed 4 cycles, 56/60 had cistectomy. Although bevacizumab did not impact down-staging based upon historical expectations, determining the effect on recurrence requires longer follow-up. ASCO 2012, Abstr 4523 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  42. Neoadjuvant CHT and pathologic downstaging 449 patients from the randomised prospective Nordic Cystectomy Trials 1 and 2 were analysed retrospectively. Eligible patients were defined as T2-T4aNXM0 preoperatively and pT0-pT4aN0-N+M0 postoperatively. The median follow-up time was 5 yr. Survival benefits of NAC are reflected in downstaging of the primary tumour. Chemo-induced downstaging might be a potential surrogate marker for OS. Rosenblatt R et al. Eur Urol. 2011 Dec 13. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  43. Treatment of Bladder Cancer • Non-invasive disease • Role of cistectomy and pre-operative imaging • Neoadjuvant chemotherapy • Adjuvant chemotherapy • Bladder Sparing Approach • First line therapy Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  44. Adjuvant therapy Adjuvant chemotherapy for invasive bladder cancer (individual patient data) (Review) Cochrane Database Syst Rev. 2006;(2):CD006018.  Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  45. Adjuvant therapy Adjuvant chemotherapy for invasive bladder cancer (individual patient data) (Review) The overall hazard ratio of 0.75 (95% CI 0.60 to 0.96) represents a 25% relative decrease in the risk of death on chemotherapy compared with that on control.This is conventionally significant (P = 0.019), and is equivalent to an absolute improvement in survival of 9% (95%CI 1%to 16%) at three years. Cochrane Database Syst Rev. 2006;(2):CD006018.  Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  46. Adjuvant therapy Adjuvant Chemotherapy in Muscle-Invasive Bladder Carcinoma. A Pooled Analysis from Phase III Studies Relative risk ratio forest plot for overall survival. Relative risk ratio forest plot for disease-free survival. Ruggeri et al. Cancer. 2006;106(4):783-8. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  47. Adjuvant therapy Adjuvant Chemotherapy in Muscle-Invasive Bladder Carcinoma. A Pooled Analysis from Phase III Studies “The results obtained with our analysis demonstrated statistical significance for both OS (P 0.001) and DFS (P 0.001) in favor of radical cystectomy followed by AC. …the number of patients enrolled in them, were too low to sustain this treatment modality as a standard practice”. Ruggeri et al. Cancer. 2006;106(4):783-8. Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  48. Adjuvant therapy: the Spanish Study Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. PGC x 4 q21 days; (Paclitaxel 80 mg/m2 d1 and 8, Gemcitabine 1000 mg/m2 d1 and 8 and Cisplatin 70 mg/m2 d1) • pT3-4 bladder cancer, pN0/pN+, • ECOG PS 0-1, • adequate renal function • ≤ 8 weeks post-cystectomy, • no relevant co-morbidities, • signed informed consent R Observation Primary objective was overall survival (OS). Results: The study was open in July 2000 and prematurely closed due to poor recruitment in July 2007, with 142 patients randomized. OS (ITT population) was significantly prolonged in the PCG arm (median NR; 5yr OS: 60%) compared to observation (median 26m; 5yr OS: 31%) (p<0.0009). DFS (p<0.0001), TTP (p<0.0001) and disease specific survival (p<0.0002) were also superior in the PGC arm. This study strongly suggest that adjuvant PGC improves OS and DFS. But…“The power for firm conclusions is however limited”. Paz-Ares ASCO 2010 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  49. Adjuvant therapy: the Spanish Study Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

  50. Adjuvant vs.Neoadjuvant Optimal delivery of perioperative chemotherapy: Preliminary results of a randomized, prospective comparative trial of preoperative and postoperative chemotherapy for invasive bladder cancer Logothetis et al. J Urol 155: 1241, 1996 Current strategies in the treatment of invasive and non-invasive disease Enrico Cortesi

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