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Roberto Sabbatini Azienda Ospedaliero Universitaria di Modena Policlicnico di Modena HOT TOPICS Controversie Oncologiche Indicazioni al Trattamento Locale.

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Presentazione sul tema: "Roberto Sabbatini Azienda Ospedaliero Universitaria di Modena Policlicnico di Modena HOT TOPICS Controversie Oncologiche Indicazioni al Trattamento Locale."— Transcript della presentazione:

1 Roberto Sabbatini Azienda Ospedaliero Universitaria di Modena Policlicnico di Modena HOT TOPICS Controversie Oncologiche Indicazioni al Trattamento Locale delle Metastasi Scuola di UrOncologia Tumore del rene Roma 23-24 maggio 2014

2 ESMO (Giugno 2012) NCCN (Gennaio 2013) EAU (Marzo 2013) AIOM (Luglio 2013) Terapia Adiuvante Non raccomandata al di fuori di studi clinici Nefrectomia in presenza di metastasi Solo se buon PS e grosso T. Oppure nei pazienti sintomatici Solo se anche le metastasi sono resecabili, buon PS (limitata ai casi a basso rischio) Sempre dove è possibile, prima del trattamento medico (Grado B) Resezione delle Metastasi Solo se: metastasi solitarie o multiple polmonari, lungo IL, buon PS, in risposta dopo terapia. Sempre se metastasi resecabili e buon PS Sempre se metastasi resecabili Courtesy of R. Passalacqua

3 RCC: metastasectomy as independent prognostic variable Eggener, J Urol 2008 Thomas, Curr Urol Rep 2009 Breau, Curr Opin Urol 2010 Median OS: 78 m. Median OS: 5 m.

4 Breau, Curr Opin Urol 2010 3711 pts Median OS overall: 17-41 m. Resected median OS: 44-55 m.

5  Median OS 80 m. Patients with 3 or 4 of these adverse prognostic factors had a worse prognosis. Prognostic Factors of Patients With Metastatic Renal Cell Carcinoma With Removed Metastases: A Multicenter Study of 556 Patients Naito, Urology 2013

6 Patients with only resected lung metastases have a longer survival Alt, Cancer 2011 Lung only mets Non Lung mets 887 pts nephrectomy 1976 – 2006 R0 predictive for CSS also for >3 mets and synchronous or asynchronous mets

7  417 pts (1986 – 2001) M1 lung (92 metastasectomy)  50% 1 or 2 mets; 37% > 5 mets.  63 pts (68%) R0  Incomplete resection  strongest risk factor for OS (5 yrs OS : 8% vs 45%) Murty, Ann Thorac Surg 2005 RISK FACTORS Larger nodule size Increasing n° of N+  Preoperative 1-second forced expiratory volume (FEV1) Shorter DFI (resected pts) If FEV1 is 60% to 70% of predicted normal, long- term survival decreases by about 33%. Conclusions Because pulmonary metastasectomy for renal cell carcinoma is safe, survival depends on complete resection of pulmonary disease and adequate pulmonary reserve.

8  good long-term results after metastasectomy  low morbidity and long-term efficacy  pulmonary surgery with systematic lymph node dissection is indicated Lung metastasis conclusions

9 The presence of bone metastases has been associated with poor outcome Hoffman, J Urol 2008 Woodward, Bone 2011 Beuselinck, Ann Oncol 2011 Motzer, BJC 2013 OS: 19.5 vs 38.5 months Predictive Factors: bone mets + PS N: 223 N: 1059 (30% bone mets) pts treated with SU Median OS 23.4 months Multivariate analysis of PFS and OS identified independent predictors: Ethnic origin, ECOG PS, including ethnic origin, time from diagnosis to treatment, prior cytokine use, HB. LDH, corrected Ca, neutrophils, PLTS and bone metastases (OS only).

10 Radical Surgery Can Lead to Durable Long Term Responses Retrospective analysis n=101 pts operatively treated for skeletal mets (1980 -2005) Predictors of longer survival Age younger than 65 No fractures Negative margins Fottner A et al., BMC musculoskeletal Dis 2010

11  RCC-subgroup analysis of a large randomized, placebo-controlled trial demonstrated significant benefits for ZA when compared to placebo 2,3 Development of anti-resorptive agents have revolutionized the management of bone disease 1.Lipton, Clin Cancer Res 2004; 2.Lipton, Cancer 2003 3.Rosen, JCO 2003; 4. Saad, BJU Int 2005 773 pts (46 RCC)  1 bone mets ECOG  2 352 days

12 Denosumab: Efficacy Overview Breast cancer 1,2 OST and MM 2,3 Prostate cancer 2,4 DmabZOLDmabZOLDmabZOL N1,0261,020886890950951 Pts with on-study SRE, %30.736.531.436.335.940.6 SRE breakdown, % RT Path Fx Surgery SCC 8.0 20.7 1.2 0.9 11.7 23.3 0.8 0.7 13.4 13.8 1.5 2.7 16.2 15.6 2.1 2.4 18.6 14.4 0.1 2.7 21.3 15.0 0.4 3.8 Median time to SRE, moNR26.420.516.320.717.1 HR P (non-inf.) P (superior.) 0.82 <.001.010 0.84 <.001.060 0.82 <.001 (0.0002).008 Abbreviations: Dmab, denosumab; HR, hazard ratio; Path Fx, pathologic fracture; RT, radiotherapy; SCC, spinal cord compression; SRE, skeletal-related event; ZOL, zoledronic acid. 1. Stopeck AT, et al. JCO. 2010;28(35):5132-5139; 2. Xgeva™ (denosumab) injection, for subcutaneous use [package insert]. Thousand Oaks, CA. Amgen Inc. 2010; 3. Henry D, et al. ECCO-ESMO 2009, abstract 20LBA; 4. Fizazi K, et al. ASCO 2010, abstract LBA4507. Dmab 120 mg SC* + placebo IV infusion q 4 wk ZOL 4 mg IV + placebo SC injection q 4 wk 155 RCC pts

13  Retrospective  76 pts with bone mets treated with SU or SO (49 BF + TKI - 27 TKI)  CAVEAT!!!!! ONJ 10% Concomitant use of BF and TKI in RCC pts with bone involvement probably improves treatment efficacy Beuselinck BJC 2012

14  1 st line setting – 30 pts randomized 1:1 EVE vs EVE +ZOL  EVE + ZOL significantly prolonged PFS and the time to 1 st SRE compared with EVE alone (P=0.03 for each) Concomitant use of ZA and EVE in RCC: RAZOR study (randomized phase II): PFS 1.0 0.8 0.6 0.4 0.2 0.0 Survival Probability 1212 1660 11 1582 20 0510 Time since randomisation (months) EVEEVE + ZOL + Censored Logrank P=0.0296 PFS mPFS (95% CI) EVE + ZOL: 7.5 mo (3.4-14.7 mo) EVE alone: 4.6 mo (3.2-6.3 mo) 1.0 0.8 0.6 0.4 0.2 0.0 Survival Probability 1212 1660 11 1582 20 0510 + Censored Logrank P=0.0296 Time to 1 st SRE Time since randomisation (months) Median time to 1 st SRE (95% CI) EVE + ZOL: 9.6 mo (4.3-15.5 mo) EVE alone: 5.2 mo (1.6-8.2 mo) EVEEVE + ZOL Broom RJ et al. ASCO-GU 2013. Poster #402

15 ♂ EM, ♂, 73 anni  Ipertensione arteriosa in trattamento farmacologico (Ramipril 5 mg/die)  Non altre comorbidità  PS 0 Luglio 2005  Dolore lombare non responsivo alla terapia con FANS Caso clinico

16 Luglio 2005 Rx rachide: ampia osteolisi del soma di L1, crollo di L2. TC rachide DL: osteolisi del soma di L1 e L2. Cuneizzazione di L2. Tessuto neoformato che impronta il sacco durale. RM rachide DL: bombatura del muro posteriore di L1 e L2 con tessuto neoformato che impronta il sacco durale.

17 Luglio 2005 Laminectomia decompressiva e stabilizzazione D11-L4 previa embolizzazione Radioterapia sul rachide D11-L4 30 Gy totali (3 Gy per frazione) Istologia compatibile con metastasi di carcinoma renale a cellule chiare

18  Re-treatment rates to same painful site  8% following 30 Gy in 10 fractions  20% following a single 8 Gy fractio  Convenience of single fraction treatment  Patient  Caregiver There is no evidence to suggest that a single 8 Gy fraction provides inferior pain relief to a more prolonged course of treatment in painful spine Radiotherapy for bone mets

19  Meta-analysis of reported randomized trials shows no significant difference in complete and overall pain relief between single and multifraction palliative RT for bone metastases. 16 studies: 5455 pts 2003

20 Brain metastases  The presence of brain metastases is a particularly important consideration when selecting treatment  Patients with brain metastases are often excluded from clinical trials due to their poor prognoses 2-4  Brain metastases occur in 4-17% of patients with RCC 5  RCC with brain metastases has been associated with a median survival of 7 months 3,4  Untreated brain metastases have a survival of around 3.2 months  Risk of developing spontaneous intracranial bleeding 1. Flanigan RC, et al. Curr Treat Options Oncol. 2003. 2. Gay PC, et al. J Neurooncol. 1987. 3. Decker DA, et al. J Clin Oncol. 1984. 4. Culine S, et al. Cancer. 1998. 5.Doh LS, et al. Oncology. 2006.

21 16.7% EAP EU Sorafenib: 3/1155 pts (28 brain mets)  0.3% US Sorafenib: 2502 pts (50 brain mets)  0% Global compassionate use Sunitinib: 2341 (182 brain mets)  <1% Shutz, Lancet 2009 Porta, Eur Urol 2008 Uncontrolled hypertension could probably justify the particularly high rate of intracerebral hemorrhage

22 A multi-institutional retrospective database of 3.940 pts Months 14.8 11.3 7.3 3.3

23 Seastone, Clinical Genitourinary Cancer 2013 166 RCC patients with brain metastases treated with SRS at the Cleveland Clinic between 1996 and 2010. Results: local control: 90% In 38% of patients there were additional distant CNS metastases at a median of 12.8 months. The median TTP (either local or distant) 9.9 m.

24  Median OS for pts treated with targeted agents (n = 24 vs 37) was 16.6 vs 7.2 mos  Freedom from local failure at 1 year: 93% vs 60%  Multivariate analysis  the use of targeted agents was the only factor that predicted for improved survival. Targeted agents appear to improve overall survival and local control in patients with brain metastases from RCC treated with GKS. Cochran, J Neurosurg 2012 61 pts 20 Gy

25  5-year actuarial rate of brain mets: 40% vs 17%, (P <.001).  TKI treatment  lower incidence of brain mets in Cox multivariate analysis  Lung mets increased the risk of brain mets Treatment with TKI agents reduces the incidence of brain metastasis in mRCC Verma, Cancer 2011 OS 338 pts: 154 TKI, 184 no : 25 vs 12.1 mos Brain mets incidence


27 Patients with metastatic renal cell carcinoma should be considered for multimodal therapy  A proportion of patients will achieve long-term survival with aggressive surgical resection  In the treatment of lung metastases, metastasectomy has a low morbidity and long-term efficacy  Sunitinib appeared more effective than sorafenib in delaying mean time to progression or onset of bone lesions  Concomitant use of antiresorptive agents and TKI or mTOR inhibitors probably improves efficacy of bone targeted therapy  Local treatments are in use to control symptoms in brain mets despite the low radiosensity  TKIs seems to be effective in the control of brain mets without high risk of bleeding Conclusions

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