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MANEJO DEL PACIENTE “UNFIT” CON CARCINOMA DE VEJIGA AVANZADO Systemic treatment for the “unfit patient” with advanced bl

MANEJO DEL PACIENTE “UNFIT” CON CARCINOMA DE VEJIGA AVANZADO Systemic treatment for the “unfit patient” with advanced bladder cancer. Enrique Gallardo Institut Oncològic del Vallès Corporació Parc Taulí Sabadell. UNFIT PATIENTS.

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MANEJO DEL PACIENTE “UNFIT” CON CARCINOMA DE VEJIGA AVANZADO Systemic treatment for the “unfit patient” with advanced bl

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  1. MANEJO DEL PACIENTE “UNFIT” CON CARCINOMA DE VEJIGA AVANZADOSystemic treatment for the “unfit patient” with advanced bladder cancer Enrique Gallardo InstitutOncològic del Vallès CorporacióParcTaulí Sabadell

  2. UNFIT PATIENTS • Cancer patients not amenable with standard treatment and needing therefore a modified or attenuated treatment or also not deserving an active therapeutic approach (Monfardini, Cancer Treat Rev 2009) • Difficult to know how to treat unfit patients with metastatic urothelial cancer • There is no clear consensus on how to define “unfit” • On the other hand, it is an increasing population

  3. CANCER AND AGE From: Gillison, Oncology 2010;24

  4. HOW TO DEFINE A PATIENT AS UNFIT?

  5. HOW TO DEFINE A PATIENT AS UNFIT?

  6. Age Performance status Functional status Comorbidities Organ function  Renal function Social factors and cognitive status Prognostic classification HOW TO DEFINE A PATIENT AS UNFIT?Factors

  7. AGE AND CANCER Age alone is not enough to evaluate and decide treatment among older cancer patients. Age itself is not an independent risk factor Brunello, Cancer Treat Rev 2009;35 Several situations influencing Physiological changes Comorbid conditions Changes in performance s. Changes in functional status Cognitive changes Chen, Cancer 2003 Carreca, Cancer Treat Rev 2005 Trask, Cancer 2008 These are independent prognostic factors Maione, JCO 2005 Repetto Lancet Oncol 2002 (From: Yancik Cancer 1994)

  8. HOW TO DEFINE A PATIENT AS UNFIT?Scales

  9. COMPREHENSIVE GERIATRIC ASSESSMENT Rodin et al, JCO 2007

  10. UNFIT PATIENTS • Cancer patients not amenable with standard treatment and needing therefore a modified or attenuated treatment or also not deserving an active therapeutic approach.

  11. RENAL FUNCTION IMPAIRMENT • Cancer patients not amenable with standard treatment and needing therefore a modified or attenuated treatment or also not deserving an active therapeutic approach. • CisplatinGold-standard • Renal function is a major concern to decide chemo schedule • Usually measured by estimated creatinine clearance • CrCl correlated with age • Differences among formulae Dash, Cancer 2006

  12. Dash, Cancer 2006 Levey, Ann Intern Med 2009

  13. PROGNOSTIC FACTORS Bajorin et al, JCO 1999† Not only host factors, but tumor condition can define unfit patients Patients with poor prognosis (i.e., 2 factors) may not be eligible for chemotherapy See also De Santis, JCO 2009 *Lung, liver, bone †ValidatedbyBellmunt et al, Cancer 2002

  14. HOW TO DEFINE A PATIENT AS UNFIT?

  15. UNFIT PATIENTS • EORTC 30986 (MCaVi vs GCa) • Inclusion criteria & stratification factors • ECOG/WHO PS 2 • GFR < 60 mL/min • Differences in outcome depending on factors De Santis, JCO 2009

  16. EORTC 30986 De Santis, JCO 2009

  17. TREATMENT STRATEGIES

  18. TREATMENT STRATEGIES Results from randomized phase III ORR: 50-60% OS: 12-15 mo Modifiedfrom: Bellmunt et al, CritRevOncolHematol 2009

  19. TREATMENT STRATEGIES

  20. PLATINUM SUBSTITUTIONPhase II randomized trials 1.Bellmunt, Cancer 1997 2. Petrioli, Cancer 1996 3. Dogliotti, Eur Urol 2007

  21. PLATINUM SUBSTITUTIONPaclitaxel-Carboplatin • Several studies (n < 50) using paclitaxel and carboplatin combinations • Around 200 patients • ORR ~ 45% (13% CR) • OS ~ 9 mo • ECOG randomized phase III comparing MVAC vs PC, early closing for low recruitment

  22. PLATINUM SUBSTITUTIONGemcitabine-Oxaliplatin • Gemcitabine 1200 mg<7m2 d 1&8 + Oxaliplatin 100 mg/m2 d1 • ORR: 48% (3 CR/19 PR) • TTP: 5 mo • OS: 6.5 mo • n=46 Carles, Ann Ocol 2007;18

  23. PLATINUM SUBSTITUTION • Results from phase II, 1-arm, and phase II randomized studies, with carbo-based regimens, either for fit or unfit patients, show worse results than for cis-based ones. • ORR: 30-40% • OS: 8-10 mo • No data from phase III trials ORR: 50-60% OS: 12-15 mo Bellmunt, Cancer 1997 Petrioli, Cancer 1996 Dogliotti, Eur Urol 2007 Nogué, Cancer 2003, Bellmunt, Cancer 1992 Olivares, Proc ASCO 2004

  24. BIWEEKLY REGIMENS No big concerns on toxicity Bamias: Stratification following geriatric assessment

  25. MONOTHERAPY Pemetrexed. Vinflunine

  26. MONOTHERAPYPemetrexed • 1st line (Paz-Ares, 1998) • ORR 33% • OS 9.5mo (including some 2nd-line) • Toxic deaths (pre-vitamin era) • 2nd line (Sweeney, JCO 2006) • ORR: 28% • OS: 9.6 mo • Well tolerated

  27. MONOTHERAPY - Vinflunine “Vinflunine did not demonstrate any evidence of nephrotoxicity, even in the patient population with impaired renal function.” Vaughn, Cancer 2009

  28. PLATINUM-FREE DOUBLETS • Paclitaxel-gemcitabine combinations are the most widely used • ORR: 40-60% (naive or pretreated)* • Weekly schedule: ORR 69% and 42% CR+ • But… Toxic deaths due to pulmonary toxicity *Kaufman, Proc ASCO 2002 Li, JCO 2005 Meluch, JCO 2001 Sternberg, Cancer 2001 +Kaufman, Urol Oncol 2004

  29. EORTC 30986 Treatment A: M-CAVI: Methotrexate 30 mg/m2 d1, d15, d22 Carboplatin AUC 4.5 d1 Vinblastine 3 mg/m2 d1, d15, d22 q4wks N=119 R Treatment B: GC: Gemcitabine 1000 mg/m2 d1 and d8 Carboplatin AUC 4.5 d1 q3wks N=119 De Santis, ASCO 2010

  30. EORTC 30986 Results Median follow-up = 4.5 years From Wood, www.Oncology Education.ca

  31. Phase III EORTC 30986

  32. EORTC 30986 Toxicity From Wood, www.Oncology Education.ca

  33. TARGETED THERAPIESTrastuzumab • Previous phase II by Hussain et al with Carbo-Pac-Gem • Phase II using CPG + Trastuzumab in 44 HER2+ patients • ORR 70% (5 CR, 26 PR) • OS 14 mo Hussain et al, JCO 2007

  34. TARGETED THERAPIESSunitinib • Basedonpreclinicalactivity • 2nd line (Gallagher, JCO 2010) • ORR: 4/77 pts • Grade 3 toxicity in 47 pts, including 1 toxicdeath • 1st line, unfitforchemo (Bellmunt, ASCO GU 2008) • ORR: 17% • Role of biologicalmarkers

  35. ERCC1 • Predictive role in platinum-resistance in other tumors • Possible role in bladder cancer (Bellmunt, Ann Oncol 2007) • Validation in a cohort from EORTC 30987

  36. HOW TO DECIDE THE TREATMENT FOR AN UNFIT PATIENT?

  37. SUMMARY Consider objective of therapy Consider active life expectancy and functional status Make an adequate measurement of renal function to well classify patients’ status Growing population  Real health and cancer care problem Identify unfit patients suitable for therapy

  38. SUMMARY • Carboplatinisnot as good as cisplatinum BUT… Is a goodalternativeforunfitpatients • Otherregimens as analternative, includingtargetedtherapies in selectedpatients • Gem-Carboequally active as MCavi and lesstoxic • Prognosticfactorsusefulto define unfit • Needtodesignspecificclinicaltrialsforunfitpatients

  39. fitness

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