Roberto SabbatiniAzienda Ospedaliero Universitaria di Modena

Policlicnico di Modena

HOT TOPICSHOT TOPICSControversie OncologicheControversie Oncologiche

Indicazioni al Trattamento Indicazioni al Trattamento Locale delle MetastasiLocale delle Metastasi

Scuola di UrOncologiaTumore del rene

Roma 23-24 maggio 2014

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

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.

Breau, Curr Opin Urol 2010

3711 pts Median OS overall: 17-41 m. Resected median OS: 44-55 m.

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 RemovedMetastases: A Multicenter Study of 556 Patients

Naito, Urology 2013

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

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%.

ConclusionsBecause pulmonary metastasectomy forrenal cell carcinoma is safe, survival depends on complete resection of pulmonary disease and adequate pulmonary reserve.

good long-term results after metastasectomy

low morbidity and long-term efficacy

pulmonary surgery with systematic lymph node dissection is indicated

Lung metastasis conclusions

The presence of bone metastases has been associated with poor outcome

Hoffman, J Urol 2008Woodward, Bone 2011Beuselinck, Ann Oncol 2011Motzer, 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 monthsMultivariate 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).

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

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

Denosumab: Efficacy Overview

Breast cancer1,2 OST and MM2,3 Prostate cancer2,4

Dmab ZOL Dmab ZOL Dmab ZOLN 1,026 1,020 886 890 950 951

Pts with on-study SRE, % 30.7 36.5 31.4 36.3 35.9 40.6

SRE breakdown, %RTPath FxSurgerySCC

8.020.71.20.9

11.723.30.80.7

13.413.81.52.7

16.215.62.12.4

18.614.40.12.7

21.315.00.43.8

Median time to SRE, mo NR 26.4 20.5 16.3 20.7 17.1

HRP (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

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

1st line setting – 30 pts randomized 1:1 EVE vs EVE +ZOL EVE + ZOL significantly prolonged PFS and the time to 1st 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

Surv

ival

Pro

babi

lity

12

16 6 01 115 8 2

15 200 5 10Time since randomisation (months)

EVE EVE + ZOL

+ CensoredLogrank 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

Surv

ival

Pro

babi

lity

12

16 6 01 115 8 2

15 200 5 10

+ CensoredLogrank P=0.0296

Time to 1st SRE

Time since randomisation (months)

Median time to 1st SRE (95% CI)EVE + ZOL: 9.6 mo (4.3-15.5 mo)EVE alone: 5.2 mo (1.6-8.2 mo)

EVE EVE + ZOL

Broom RJ et al. ASCO-GU 2013. Poster #402

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

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.

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

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

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

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 prognoses2-4

Brain metastases occur in 4-17% of patients with RCC5

RCC with brain metastases has been associated with a median survival of 7 months3,4

Untreated brain metastases have a survival of around 3.2 months

Risk of developing spontaneous intracranial bleeding1. 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.

16.7%

EAPEU Sorafenib: 3/1155 pts (28 brain mets) 0.3%US Sorafenib: 2502 pts (50 brain mets) 0%

Global compassionate useSunitinib: 2341 (182 brain mets) <1%

Shutz, Lancet 2009Porta, Eur Urol 2008

Uncontrolled hypertension could probably justify the

particularly high rate of intracerebral hemorrhage

A multi-institutional retrospective database of 3.940 pts

Months 14.811.3 7.33.3

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.

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 andlocal control in patients with brain metastases from RCC

treated with GKS.

Cochran, J Neurosurg 2012

61 pts20 Gy

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

OS338 pts: 154 TKI, 184 no

: 25 vs 12.1 mos

Brain mets incidence

Patients with metastatic renal cell carcinoma should be considered for multimodal therapy

A proportion of patients will achieve long-term survival with aggressive surgical resectionIn 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 lesionsConcomitant use of antiresorptive agents and TKI or mTOR inhibitors probably improves efficacy of bone targeted therapyLocal treatments are in use to control symptoms in brain mets despite the low radiosensityTKIs seems to be effective in the control of brain mets without high risk of bleeding

Conclusions