HOT TOPICS
Controversie Oncologiche
Indicazioni al Trattamento
Locale delle Metastasi
Roberto Sabbatini
Azienda Ospedaliero Universitaria di Modena
Policlicnico di Modena
Scuola di UrOncologia
Tumore del rene
Roma 23-24 maggio 2014
ESMO
(Giugno 2012)
Terapia
Adiuvante
Nefrectomia
in presenza
di metastasi
Resezione
delle
Metastasi
NCCN
(Gennaio 2013)
EAU
(Marzo 2013)
AIOM
(Luglio 2013)
Non raccomandata al di fuori di studi clinici
Solo se buon
PS e grosso T.
Oppure nei
pazienti
sintomatici
Solo se:
metastasi
solitarie o
multiple
polmonari, lungo
IL, buon PS, in
risposta dopo
terapia.
Solo se anche le metastasi sono
resecabili,
buon PS (limitata ai casi a basso
rischio)
Sempre se
metastasi
resecabili e buon
PS
Sempre dove è
possibile, prima
del trattamento
medico (Grado B)
Sempre se
metastasi
resecabili
Courtesy of R. Passalacqua
RCC: metastasectomy as independent
prognostic variable
Median OS: 78 m.
Median OS: 5 m.
Eggener, J Urol 2008
Thomas, Curr Urol Rep 2009
Breau, Curr Opin Urol 2010
3711 pts
Median OS overall: 17-41 m.
Resected median OS: 44-55 m.
Breau, Curr Opin Urol 2010
Prognostic Factors of Patients With
Metastatic Renal Cell Carcinoma With Removed
Metastases: A Multicenter Study of 556 Patients

Median OS 80 m.
Patients with 3 or 4 of these adverse prognostic factors had a worse prognosis.
Naito, Urology 2013
Patients with only resected lung
metastases have a longer survival
887 pts nephrectomy
1976 – 2006
R0 predictive for
CSS also for >3
mets and
synchronous or
asynchronous mets
Lung only mets
Non Lung mets
Alt, Cancer 2011




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%)
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, longterm 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.
Murty, Ann Thorac Surg 2005
Lung metastasis conclusions
 good
 low
long-term results after metastasectomy
morbidity and long-term efficacy
 pulmonary
surgery with systematic lymph node
dissection is indicated
The presence of bone metastases
has been associated with poor outcome
pts treated with SU
N: 223
OS: 19.5 vs 38.5 months
Predictive Factors: bone mets + PS
N: 1059 (30% bone mets)
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).
Hoffman, J Urol 2008
Woodward, Bone 2011
Beuselinck, Ann Oncol 2011
Motzer, BJC 2013
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
Development of anti-resorptive agents have
revolutionized the management of bone disease

RCC-subgroup analysis of a large
randomized, placebo-controlled trial
demonstrated significant benefits for ZA
when compared to placebo 2,3
•773 pts (46 RCC)
•  1 bone mets
• ECOG  2
352 days
1.Lipton , Clin Cancer Res 2004;
2.Lipton , Cancer 2003
3.Rosen , JCO 2003;
4. Saad, BJU Int 2005
Dmab 120 mg SC* +
placebo IV infusion q 4 wk
Denosumab:
Efficacy Overview
ZOL 4 mg IV +
placebo SC injection q 4 wk
155 RCC pts
Breast cancer1,2
OST and MM2,3
Prostate cancer2,4
Dmab
ZOL
Dmab
ZOL
Dmab
ZOL
N
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, %
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, mo
NR
26.4
20.5
16.3
20.7
17.1
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.
Concomitant use of BF and TKI in RCC pts with bone
involvement probably improves treatment efficacy



Retrospective
76 pts with bone mets treated with SU or SO (49 BF + TKI - 27 TKI)
CAVEAT!!!!! ONJ 10%
Beuselinck BJC 2012
Concomitant use of ZA and EVE in RCC:
RAZOR study (randomized phase II): PFS
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)


Time to 1st SRE
PFS
1.0
mPFS (95% CI)
EVE + ZOL: 7.5 mo (3.4-14.7 mo)
EVE alone:
4.6 mo (3.2-6.3 mo)
0.6
0.4
0.2
+ Censored
Logrank P=0.0296
0.8
Survival Probability
Survival Probability
0.8
0.0
1
2
1.0
+ Censored
Logrank P=0.0296
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)
0.6
0.4
0.2
0
2
0.0
16
15
6
8
0
15
5
10
Time since randomisation (months)
EVE
1
1
EVE + ZOL
20
1 16
2 15
0
6
8
0
2
1
15
5
10
Time since randomisation (months)
EVE
Broom RJ et al. ASCO-GU 2013. Poster #402
EVE + ZOL
1
20
Caso clinico
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
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
Istologia compatibile con
metastasi di carcinoma renale
a cellule chiare
Radioterapia sul rachide D11-L4
30 Gy totali (3 Gy per frazione)
Radiotherapy for bone mets

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
2003

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
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 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.
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
A multi-institutional retrospective database of 3.940 pts
Months
14.8
11.3
7.3
3.3
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.
Seastone, Clinical Genitourinary Cancer 2013
Targeted agents appear to improve overall survival and
local control in patients with brain metastases from RCC
treated with GKS.



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.
61 pts
20 Gy
Cochran, J Neurosurg 2012
Treatment with TKI agents reduces
the incidence of brain metastasis in mRCC
338 pts: 154 TKI, 184 no
OS : 25 vs 12.1 mos
Brain mets incidence



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
Verma, Cancer 2011
Conclusions
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