Targeted therapies in renal cell carcinoma

Transcription

1 Targeted therapies in renal cell carcinoma Geriatric Oncology: Cancer in Senior Adults Stéphane OUDARD Stéphane OUDARD, Service de Cancérologie Médicale Hôpital Georges Pompidou, Paris Université René Descartes, Paris 5, France

2 Introduction Renal cancer occurs mostly between age 62 and 67 in Europe (IARC 2007). Metastatic renal cancer is observed in 25% of these patients and median age is slightly higher. mrcc patients are often > 65 and 1/3 to ½ are > mrcc patients are often > 65 and 1/3 to ½ are > 70.

3 Efficacy of targeted agents, results of randomized d trials Agent Nber Range of benefit Median age Patients > 70 years, pts ( PFS results) (years) % Sunitinib [27-87] NR Sorafenib [19-86] 16 Bevacizumab 649 & [30-82] NR and IFN 3, [56-70] Temsirolimus * 58 [32-81] NR Everolimus [27-85] NR Pazopanib [25-85] 35 (> 65y) Not reported 1 Motzer RJ, et al. New Engl J Med 2007; 2 Escudier B, et al. New Engl J Med 2007; 3 Escudier B et al, Lancet 2007 ; 4 Rini B et al, J Clin Oncol Hudes G et al, New Engl J Med 6 Motzer B et al, Lancet Sternberg C et al, J Clin Oncol 2010

4 Prospective clinical trials : inclusion of older patients? Patients t older than 70 represent only a limited subgroup in Phase III trials. Information f on these patients t is limited. it Subgroup analyses as well as results of compassionate programs seem to indicate the same range of efficacy in elderly l and younger patients 1 Stadler Cancer 2010, Gore Lancet 2009, Eisen T et al, JNCI 2008, vol 100:

5 Efficacy of different targeted therapies based on the pivotal trials in metastatic renal cell carcinoma of 65-year-old patients <65 years sunitinib >65 years sunitinib <65 years sorafenib >65 years sorafenib <65 years bevacizumab + IFN >65 years bevacizumab + IFN <65 years temsirolimus >65 years temsirolimus <65 years everolimus >65 years everolimus <65 years pazopanib >65 years pazopanib Targeted therapy better Alternative therapy better

6 Analysis of sorafenib in older population from the TARGET trial Retrospective analysis from TARGET trial Safety and efficacy of sorafenib N= 115 > 70 years old vs 787 younger pts < 70 PFS : 26.3 weeks older pts vs 23.9 younger pts Clinical benefit = 84.3 % vs 83.5% Maintenance of health status PS: 121 d vs 85 days Eisen T et al, JNCI 2008, vol 100:

7 Analysis of sorafenib in older population from the TARGET trial Time to self-reported health status deterioration (FACT G PWB)* Patients > 70 years Patients < 70 years function 0.75 function 0.75 Surviva al distribution Surviva al distribution Time (days) Time (days) Sorafenib Placebo Eisen T Censored et al, JNCI data 2008, vol 100: *Physical Well-Being domain of the Functional Assessment of Cancer Therapy General Eisen T et al, JNCI 2008, vol 100:

8 Toxic effects of targeted agents in older patients t according to subgroup analyses: Sunitinib ib : more frequent fatigue Beva/IFN : more grade ¾ events (66 vs 58%) Sorafenib : no difference in trial Fatigue and cutaneous symptoms more frequent in Access program Temsirolimus : Everolimus : No major differences But! Most comorbidities were exclusion criteria in controlled trials. Toxicity in older patients may be underestimated

9 Which toxicities are you waiting for in the era of antiangiogenic drugs? Bellmunt J et al, Critical Rev Oncol Hematol 2009 vol 69:64-72

10 Main toxicities of antiangiogenic therapies that represent risks ik for older patients # 1 cardio-vascular effects Hypertension - Edema with a certain degree of water retention - Arterial thrombosis (heart infarct) - Venous thrombo-embolism - Cardiac failure - Cardiac rhythm troubles.

11 Main toxicities of antiangiogenic therapies that represent risks ik for older patients # 2 renal effects Renal insuffisiency - Hypertension - Glomerular thrombotic microangiopathy - Anemia (decrease secretion EPO) Launay Vacher V et al, Anti-Cancer Drugs 2009, 20:81 82

12 Main toxicities of antiangiogenic therapies that represent risks ik for older patients # 3 Digestive symptoms: - Nausea-vomiting - Mucositis - Diarrhea Decreased food intake # 4 General symptoms: - Fatigue - Hand and foot syndrome Decreased mobility

13 Main toxicities of antiangiogenic therapies that represent risks ik for older patients # 5 Biologic disturbances: - Hyperglycemia - Hypercholesterolemia - Anemia - Neutropenia - Thrombopenia - Hypothyroidism

14 Factors to consider in the ederly mrcc population Bellmunt J et al, Critical Rev Oncol Hematol 2009 vol 69:64-72

15 Absorption and Metabolism change in the elderly population Physiological Changes from Aging: Decreased gastric motility Decreased secretions Decreased absorptive surface Consequence on Drug Absorption: May lead to slower absorption and delayed onset of effect Physiological i l Changes from Aging: Consequence on Drug Metabolism: Decreased Liver Size (Between 18 44%) Decreased Hepatic Blood Flow Antiangiogenic drugs that undergo Phase 1 Metabolism will result in higher concentrations from decreased metabolism

16 How can we manage potential risks in the geriatric i population? Geriatric appraisal To help making a decision on whether to treat cancer in ederly patients Geriatric assessment scores based on: - Functionality (self ability) - Cognitive status and mood - Social situation (familial help?) - Comorbidities and their treatments. t t

17 To help making a decision on whether to treat cancer in elderly l patients Geriatric algorithm (Balducci-Extermann) 3 categories Healthy Frail Too sick Treat as usual Evaluate ate life expectancy without cancer versus with treated cancer (oncogeriatric assessment) Limited interventions, supportive care

18 Survival probability correlates with individual health hstatus Independent Vulnerable val ratio Survi Independent Incontinent Vulnerable* Frail** Fragile 5 years Higher vulnerability and frailty are associated with increased risk of death Survival (months) Rockwood K et al. Lancet 1999, 353,

19 Incidence of comorbidities in «frail» elderly patients (>70) in France (2006) Cardiovascular Type of comorbity % Cardiac failure 29 Coronaropathy 22 Hypertension 47 Cardiac rhythm 23 Thrombo-embolism 15 Digestive system 18 Denutrition 10 Osteoarticular syndrome with impact on mobility 43 Metabolic disturbances Diabetes 12 Dehydration 9 Thyroid disease 9

20 Toxic effects of treatments targeted therapies for mrcc in patients with comorbidities Type of comorbity Treatment Toxicity Cardiovascular HTA,. Digestive system Digestive symptoms Denutrition Weight loss Osteoarticular with mobility impact Hand and foot Syndome, fatigue Metabolic disturbances hypothyroidism Renal insufficiency MAT, proteinuria Diabetes Normalization of glycemia (SU) 1 1 Billemont B and Medioni J et al, Br J Cancer Nov 4;99(9):1380-2

21 Example from our institution regarding older patients t treated t with TKI Clinical Case of a women, 78 years old Kidney cancer, lung metastasis HTA, well controlled with 3 medications Sunitinib given at 37.5 mg 4w/6 After 1 cycle, PRES syndome with coma, ocular vision disturbance, epilepsia and HTA - sunitinib ib stop - complete recovery in 7 days - need to manage HTA especially in ederly population Medioni J et al, Targeted Oncol 2007

22 Example from our institution regarding older patients treated with TKI Clinical Case of a man, 70 years old Left nephrectomy, clear cell carcinoma, F gr 4 residual GFR = 41 ml/min lung metastasis Bevacizumab (B) & IFN After second injection (B) HTA, nephrotic syndrom, haemolytic-uraemic syndrome - B stop - biopsy: glomerular thrombotic microangiopathy - Response: normalization blood pressure, return to renal function to previous baseline levels Frangie C et al. Lancet Oncol 2007, 8:177-78

23 If an elderly patient appears to be a candidate for targeted therapies Consider situations at risk: - Comorbidities >2 = risk ++ - Polypharmacy y >3 = risk ++ - Familial status (alone or with an elderly spouse) Think that these risks have potential synergistic effects: comorbidities x polypharmacy x familial status = Very high risk of complications!

24 Adjusting targeted therapies in elderly patients t means Estimate the risk of complications Reinforce information to general practitioner and dfamily Close management with frequent visits & calls Hold or decrease treatment doses before occurrence of severe toxicities iti!!!!