Sergio Bracarda MD Head, Medical Oncology Department of Oncology AUSL-8 Istituto Toscano Tumori (ITT) San Donato Hospital Arezzo, Italy Ninth European International Kidney Cancer Symposium Dublin 25-26 April 2014
The problem.. RCC account for 2-3% of solid tumors About 15% of mrcc develop Brain Mets (BMs: 106/705): 44.3% at Clinical Presentation 55.7% in the following History Median characteristics at presentation: Cerebral (vs Cerebellar) site: 90% Neurological symptoms: 80% Median largest Size: 1.8cm (0.2-6.6) Median number: 1 (1-not measured) Vickers MM et Al. Clin Genitourin Cancer. 2013;11:311-5.
The problem.. Median Prognostic Score at presentation (Heng Score) Favorable 12% Intermediate 42% Poor 29% NB: KPS <80, DFI <1yr and BM number >4 associated with worse prognosis Treatment received (n= 106): Systemic Rx Local Rx Sunitinib 76 RT 81% Sorafenib 23 SRS 25% Bevacizumab 5 Surgery 25% Temsirolimus 1 Vickers MM et Al. Clin Genitourin Cancer. 2013;11:311-5.
Which data for available Targeted Agents in the BM subpopulation? A small prospective phase II Study of Sunitinib in pts with untreated BMs: 16 evaluable patients: No Local Response (with ORR as the 1 End Point) CNS disease stabilization in 5/16 cases (31%); 1 CR outside the CNS. Median TTP= 2.3 months, median OS= 6.3 months. Some data for Bevacizumab. More Data from the ARCCS and EAP Expanded Access Studies: ARCCS (Advanced Renal Cell Carcinoma Sorafenib exp. Acc. Trial) EAP (Sunitinib Global Expanded Access Program) Chevreau C. et Al. for the French Group on Renal Cancer. Clin Genitourin Cancer. 2014;12:50-4.
Is Bevacizumab Safe in patients with brain metastases? Patients with brain metastases been routinely excluded from bevacizumab trials, following a single case in 1997 of a 29-year-old patient with HCC who experienced a fatal cerebral hemorrhage from a previously undiagnosed brain met in a phase I study Gordon et al, J Clin Oncol 2001
Is Bevacizumab Safe in patients with brain metastases? In conclusion, in this selected patient population, pts with CNS mets are at a similar risk of developing a cerebral hemorrhage, independent of bevacizumab therapy... Treatment decisions should be driven by the benefit/risk assessment made by physicians for individual patients. Besse et al, Clin Cancer Res 2010
The Advanced RCC Sorafenib (ARCCS) expanded access trial: Subset analysis of pts with brain metastases (BM) - Pts with BM were required to have prior local therapy for their brain lesions, whether or not successful. - Pts who had surgery for BM also were eligible. Stadlet et al, Cancer 2010; Henderson et al, Eur Urol Suppl 2008
The Advanced RCC Sorafenib (ARCCS) expanded access trial: Subset analysis of pts with brain metastases (BM) - DCR in 72% of treated cases (n=50) - Drug related AEs were reported in 63% and 76% of pts with and without BM - Common AEs grade 3 were: HFSR (7% vs 10%), Fatigue (7% vs 4%), Diarrhoea (3% vs 2%) and Hypertension (0% vs 5%). - Seizure rates were 6% vs 0%. No CNS-related bleeding events.
In retrospective studies, median OS after diagnosis of Brain Mets ranged from 5 7 and 4 6 months in Pts treated with and without TKIs, respectively 2,3 The sunitinib RCC EAP, with >4,500 pts 3, remain the largest database to date for mrcc pts with brain mets treated with TKIs. 1 Lim ZD, et al. Am J Clin Oncol 2013; 2 Verma J, et al. Cancer 2011; 3 Gore ME, et al. Lancet Oncol 2009. 2 Verma J, et al. Cancer 2011; 3 Verma J, et al. Am J Clin Oncol 2012.
Baseline Characteristics (BMs n = 338) Characteristic Pts with brain mets (n=338) Overall population 1 (N=4,543) Median age (range), years 58 (21 81) 59 (19 89) ECOG PS, %* 0 1 2 3 4 MSKCC risk groups data, % * Favourable Intermediate Poor Missing 30 43 19 6 1 29 46 16 9 41 43 12 2 <1 20 33 26 21 *Missing data (pts with brain mets; total population) : ECOG PS (n=5; n=92); histology (n=0; n=1); prior nephrectomy status (n=12; n=199); prior antiangiogenic treatment (n=0; n=0) ; prior cytokine treatment (n=0; n=0) 1 Gore ME, et al. ESMO 2012 (820P).
RECIST-Defined Tumour Response and Clinical Benefit Pts with brain mets (n=324) Overall population 1 (N=4,219)* Number of evaluable pts, % 66 79 Objective response, % 9 16 Complete response 1 1 Partial response 8 14 Stable disease 3 months, % 33 45 Clinical benefit, % 42 61 *324 pts excluded from ITT population due to non-recist tumour assessment or data integrity issues Clinical benefit = objective response (complete or partial) + stable disease 3 months 1 Gore ME, et al. ESMO 2012 (820P).
Median PFs & OS Data in the BMs Sunitinib EAP Subset Pts with brain mets (n=324): Overall= 4,219. - Median PFS: 5.3 (95% CI: 4.3 5.6) vs 9.4 - Median OS: 8.2 (95% CI: 7.4 9.6) vs 18.7 Conclusions: limited but present activity 1 Gore ME, et al. ESMO 2012 (820P).
Should RT (or Neurosurgery) be performed for BMs in mrcc patients? Surely Yes, because of : Evidence of a Lower Local Control (and ORR) with use of antiangiogenic agents alone 1 Possible causes found in a a lower MVD and vascular phenotype 2 Evidence of an Increased Local Control (LC) with stereotactic radiosurgery (SRS), or surgery, with a possible Trend in OS when combined with TKIs: 3,4 median OS with SRS plus TKI: 6.7 vs 4.4m in a TKI vs never-tki group 3 1 Chevreau C. et Al. Clin Genitourin Cancer. 2014;12:50-4. 2 Barresi V et Al. Int J Mol Sci. 2014;15:5663-79. 3 Verma et Al. Am J Clin Oncol. 2013;36:620-4.
Evidence of «long term» improved Local Control with GKS or STS in Retrospective analyses Gamma Knife Surgery (GKS, 61 cases) 1 yr 2 yr 3yr OS 38% 17% 9% Local Control 74% 61% 40% Systemic Control 49% 21% 11% Median OS in pts receiving TKIs (n= 24) vs any TKI: 16.6 vs 7.2m (p=.04) 1 Well recognized Factors for OS: KPS 1, N of Brain Mets, GPA Score 2 Fig. 3. Kaplan-Meier plots. Left: OS comparing Pts treated or not with novel agents. Right: Time to Local Failure comparing Pts treated or not with novel agents. 1 Cochran DC et Al. J Neurosurg. 2012;116:978-83. 2 Seastone DJ et Al. Clin Genitourin Cancer. 2014;12:111-6.
GPA Score (Graded Prognostic Assessment): an accurate and facile diagnosis-specific tool to estimate OS for pts with brain metastases. METHODS: A multi-institutional retrospective (1985 to 2007) database of 3,940 pts with newly diagnosed brain metastases Univariate and multivariate analyses of prognostic factors (PF) associated with outcomes by primary site and treatment. Significant PF (in RCC: KPS score & number of Brain Mets) used to define Diagnosis-Specific GPA prognostic indices. A GPA of 4.0 relates with the best prognosis, whereas 0.0 corresponds with the worst. Fig.1. The sum of the points for each PF is the GPA for an individual patient. Sperduto PW et Al. J Clin Oncol. 2012;30:419-25.
Median Survival Time for Pts With Brain Mets by DS-GPA Score Diagnosis Overall DS-GPA Score 0-1.0 1.5-2.0 2.5-3.0 3.5-4.0 Survival Time (months) Survival Time No. of (months) Patients Survival Time (months) Patients Survival Time (months) Patients Survival Time (months) Patients Pts Median 95% CI Median 95% CI No. % Median 95% CI No. % Median 95% CI No. % Median 95% CI No. % P (log-rank) NSCLC 7.00 6.5 to 7.5 1,833 3.02 2.6 to 3.8 254 14 5.49 4.8 to 6.4 705 38 9.43 8.4 to 10.8 713 40 14.78 11.8 to 18.8 161 9 <.001 SCLC 4.90 4.3 to 6.2 281 2.79 1.8 to 3.1 65 23 4.90 4.0 to 6.5 119 42 7.67 6.3 to 9.1 84 30 17.05 4.7 to 27.4 13 5 <.001 Melanoma 6.74 5.9 to 7.5 481 3.38 2.5 to 4.3 84 17 4.70 4.1 to 5.4 150 31 8.77 6.7 to 10.8 135 28 13.23 9.1 to 15.6 112 23 <.001 RCC 9.63 7.6 to 10.9 286 3.27 2.0 to 5.1 43 15 7.29 3.7 to 10.9 76 27 11.27 8.8 to 14.8 104 36 14.77 9.7 to 19.8 63 22 <.001 Breast cancer 13.80 11.5 to 15.9 400 3.35 3.1 to 3.8 23 6 7.70 5.6 to 8.7 104 26 15.07 12.9 to 15.9 140 35 25.30 Kaplan-Meier curves for survival for six diagnoses by Graded Prognostic Assessment (GPA) group, showing excellent separation between groups (P <.001) for each diagnosis: 23.1 to 26.5 133 33 <.001 GI cancer 5.36 4.3 to 6.3 209 3.13 2.4 to 4.6 76 36 4.40 3.4 to 6.5 65 31 6.87 4.9 to 11.6 50 24 13.54 9.8 to 27.1 18 9 <.001 Other 6.37 5.2 to 7.5 450 (A) Breast cancer; (B) NSCLC; (C) SCLC; (D) Melanoma; (E) Renal Cell Carcinoma; (F) GI cancer. Total 7.16 6.8 to 7.5 3,940 3.10 2.8 to 3.4 545 16 5.40 4.9 to 5.9 1,219 35 9.63 8.7 to 10.6 1,226 35 16.73 14.6 to 18.8 500 14 <.001 Abbreviations: DS-GPA, diagnosis-specific Graded Prognostic Assessment; Sperduto PW et Al. J Clin Oncol. 2012;30:419-
Conclusions. - and Classified as Good/Intermediate Risk (Heng Score).