RCC: Gestione delle metastasi Cinzia Ortega - Special … · Cinzia Ortega Per gentile concessione...
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ssa C. Ortega Cinzia Ortega Dipartimento di Oncologia Medica Fondazione del Piemonte per l’Oncologia I.R.C.C.S. Candiolo RCC: Gestione delle metastasi Per gentile concessione della Dott.s
Transcript of RCC: Gestione delle metastasi Cinzia Ortega - Special … · Cinzia Ortega Per gentile concessione...
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Cinzia OrtegaDipartimento di Oncologia Medica
Fondazione del Piemonte per l’Oncologia
I.R.C.C.S. Candiolo
RCC: Gestione delle metastasi
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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)
Solo se : Sempre se Sempre se
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Divisione di Oncologia Medica, IRCCS Candiolo
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
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RCC: metastasectomy as independent prognostic variable
Median OS: 78 m.
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Divisione di Oncologia Medica, IRCCS Candiolo
Eggener, J Urol 2008
Thomas, Curr Urol Rep 2009
Breau, Curr Opin Urol 2010
Median OS: 5 m.
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3711 pts Median OS overall: 17-41 m.
Resected median OS: 44-55 m.
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Divisione di Oncologia Medica, IRCCS Candiolo
Breau, Curr Opin Urol 2010
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� Median OS 80 m.
Prognostic Factors of Patients With Metastatic Renal Cell Carcinoma With Removed Metastases:
A Multicenter Study of 556 Patients
Divisione di Oncologia Medica, IRCCS Candiolo
Patients with 3 or 4 of these adverse prognostic factors had a worse prognosis.
Naito, Urology 2013
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Patients with only resected lung metastases have a longer survival
Lung only mets887 pts nephrectomy
1976 – 2006
R0 predictive for
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Divisione di Oncologia Medica, IRCCS Candiolo Alt, Cancer 2011
Non Lung mets
R0 predictive for
CSS also for >3
mets and
synchronous or
asynchronous mets
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� Collaborative retrospective project: 5206 cases of lung
metastasectomy
�Pts with single metastases had 5 yrs survival of 43%; 2-3 mets:
34%; >4 mets: 27%
International Registry of Lung Metastases
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� RESECTABILITY : determinant of survival
�RO: Overall 5 yrs survival 36%; median OS: 35 m.
�R1 (incomplete): Overall 5 yrs survival 13%; median OS: 15 m.
Pastorino, J Thorac Cardiovasc Surg 1997
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� 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%)
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Divisione di Oncologia Medica, IRCCS Candiolo 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.
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� good long-term results after metastasectomy
� low morbidity and long-term efficacy
Lung metastasis conclusions
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low morbidity and long-term efficacy
� pulmonary surgery with systematic lymph node
dissection is indicated
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The presence of bone metastases has been associated with poor outcome
N: 223 N: 1059 (30% bone mets)
pts treated with SU
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Divisione di Oncologia Medica, IRCCS Candiolo
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
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).
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Radical Surgery Can Lead to Durable Long Term Responses
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Divisione di Oncologia Medica, IRCCS Candiolo
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
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� Sunitinib significantly prevented the growth of metastastic bone lesions in
mouse model in vivo
� The number of osteoclasts in sunitinib-treated mice was significantly less than
that in control mice
� In 16 pts with mRCC: both serum and urinary levels of NTX significantly
declined during the first 4 wks of treatment with sunitinib
Sunitinib is a potent anticancer agent for RCC bone metastases
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Divisione di Oncologia Medica, IRCCS CandioloMaita, IJC 2012
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Sorafenib in bone mets
58 pts enrolled in sorafenib EAP
Median PFS 11.2 m. vs 4.7 m.
(no bone M1 vs bone M1)
Pts. with bone mets progressed earlier than pts without bone
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Divisione di Oncologia Medica, IRCCS Candiolo Riechelmann, Am J Clin Oncol 2008
� Pts. with bone mets progressed earlier than pts without bone
mets during sorafenib treatment.
� Bone is known to be a rich reservoir of growth factors and their receptors
including TGFbeta and EGFR � pathways stimulated by these growth factors are
not inhibited by sorafenib.
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Sunitinib appeared more effective than sorafenib or IFN-alfa at extending mean time to progression or onset of
bone lesions292 pts
107 SU
147 SO
82 M1
23 new
lesions
TTP of pre-existing
SU
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TTP of pre-existing
bone lesions
TTP of occurence
of new lesions
SU
Zolnierek, J Cancer Res Clin Oncol 2010
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� 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
•773 pts (46 RCC)
• ≥ 1 bone mets
• ECOG ≤ 2
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Divisione di Oncologia Medica, IRCCS Candiolo 1.Lipton , Clin Cancer Res 2004; 2.Lipton , Cancer 2003 3.Rosen , JCO 2003; 4. Saad, BJU Int 2005
352 days
Denosumab: Efficacy Overview
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, %
Dmab 120 mg SC* + placebo IV infusion q 4 wk
ZOL 4 mg IV + placebo SC injection q 4 wk
155 RCC pts
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Divisione di Oncologia Medica, IRCCS Candiolo
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.
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� 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
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Divisione di Oncologia Medica, IRCCS Candiolo Beuselinck BJC 2012
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� Retrospective (209 pts)
� 76 pts with bone mets treated with
SU
� (35 BF + SU - 41 SU)
� RESULTS:
disease control: 86% vs 71%
median PFS 15 vs 5 mNS
Divisione di Oncologia Medica, IRCCS Candiolo
median PFS 15 vs 5 m
median OS: NR vs 14 m.
In multivariate analysis:
factors associated with PFS� BF use and pre-
treatment neutrophil to lymphocyte ratio >3
factors associated with OS ���� BF use and
elevated pre-treatment ALP and SU induced
HTN
Keizman, EJC 2012Per gentile concessione della Dott.ssa C. Ortega
� 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 + Censored
Logrank P=0.0296
PFS
1.0 + Censored
Logrank P=0.0296
Time to 1st SRE
Divisione di Oncologia Medica, IRCCS Candiolo
0.8
0.6
0.4
0.2
0.0
Su
rviv
al
Pro
ba
bil
ity
1
2
16 6 01 115 8 2
15 200 5 10
Time since randomisation (months)
EVE EVE + ZOL
mPFS (95% CI)
EVE + ZOL: 7.5 mo (3.4-14.7 mo)
EVE alone: 4.6 mo (3.2-6.3 mo)
0.8
0.6
0.4
0.2
0.0S
urv
iva
l P
rob
ab
ilit
y1
2
16 6 01 115 8 2
15 200 5 10Time 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 #402Per gentile concessione della Dott.ssa C. Ortega
Fractionation schemes effective for the treatment of
painful bone mets and/or prevention of SRE
� Pain relief equivalency
Radiotherapy for bone mets
�30 Gy in 10 fractions
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�30 Gy in 10 fractions
�24 Gy in 6 fractions
�20 Gy in 5 fractions
�8 Gy in a single fraction Pe
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Comparative Advantages
� 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
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� 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
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� Meta-analysis of
reported randomized
trials shows no
significant difference
in complete and
overall pain relief
between single and
16 studies: 5455 pts
2003
Divisione di Oncologia Medica, IRCCS Candiolo
between single and
multifraction
palliative RT for bone
metastases.
Per gentile concessione della Dott.ssa C. Ortega
a total of 265 pts:
131 pts: 1x8 Gy/4x4 Gy
vs
134 pts: 10x3Gy/15x2.5Gy/20x2Gy
IJROBP 2011
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Brain metastases
� The presence of brain metastases is a particularly important consideration when selecting treatment
� Patients with brain metastases are often excluded f rom clinical trials due to their poor prognoses 2-4
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Divisione di Oncologia Medica, IRCCS Candiolo
� 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.
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16.7%
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Divisione di Oncologia Medica, IRCCS Candiolo
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
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PROGNOSTIC FACTORS
RPA classes
1200 patients from three consecutive
RTOG trials treated with radiosurgery or
stereotactic surgery
Class 1: patients with KPS ≥ 70,
< 65 years , controlled primary and
no extracranial metastases;
Class 3: KPS < 70;
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Class 3: KPS < 70;
Class 2: all others.
Int. J. Radiation Oncology Biol. Phys. 1997
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A multi-institutional retrospective database of 3.940 pts
Months
14.8
11.3
7.3
3.3
Divisione di Oncologia Medica, IRCCS CandioloPer gentile concessione della Dott.ssa C. Ortega
� median OS ���� 3-7 mos
� 60-90% Neurological symptoms responders (median duration of
improvement 10-12 wks)
� Meyners, BMC Cancer 2010 (220 pts):
Results of Radiotherapy: WBRT alone
Wronsky, 1997
Culine 1998
Cannady 2004
Divisione di Oncologia Medica, IRCCS Candiolo
� Meyners, BMC Cancer 2010 (220 pts):
� Improved outcomes were associated with WBI doses >30 Gy, better
performance status, fewer brain mets, lack of extracerebral metastases,
and lower RPA class.
� Patients receiving WBI alone appear to benefit from WBI doses >30 Gy.
However, such a benefit is limited to RPA class 1 or 2 patients.
� median OS for the RPA classes 1, 2, and 3� 7.1 m, 4.2 m, and 2.3 m.
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Adjuvant WBRT after surgery or radiosurgery: intracranial progression, not OS improvement
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Divisione di Oncologia Medica, IRCCS Candiolo Kocher, JCO 2011
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Divisione di Oncologia Medica, IRCCS Candiolo
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.
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database of all brain metastases treated with Gamma Knife SRS
103 brain metastases patients (41 RCC; 62 melanoma)
34 lesions received adjuvant chemotherapy and 56 received pre-SRS whole brain RT
Local control at 12 months was 91 % for RCC
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Divisione di Oncologia Medica, IRCCS Candiolo
� Kawabe J Neurosurg 2012 –
2553 pts - GKS is effective in
the treatment of brainstem
metastases, particularly from
the viewpoint of maintaining
a good neurological
condition in the patient
Smaller tumor volume (P=0.007) and RCC pathology (P=0.04) were found to be
positive predictors of response.
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� 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.
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Divisione di Oncologia Medica, IRCCS Candiolo Cochran, J Neurosurg 2012
61 pts
20 Gy
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Treatment with TKI agents reduces the incidence of brain metastasis in mRCC
OS
338 pts: 154 TKI, 184 no
: 25 vs 12.1 mos
Brain mets incidence
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� 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
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Sorafenib provides a clinical benefit and reduces the incidence of brain metastases
� (EU-ARCCS trial)Comparable efficacy irrespective of metastases and metastatic site
� No cerebral haemorrhageoccurred in patients with brain mets
*DCR = CR + PR + SD ≥8 weeks; †For 1,031 evaluable patients
Metastatic site
Overall population(n=1,155)
Lung(n=748)
Liver(n=277)
Bone(n=363)
Brain(n=28)
DCR,* % 72.8† 73.0 64.3 69.2 60.7
Median PFS, months
6.8† 6.8 5.3 6.0 7.4
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*DCR = CR + PR + SD ≥8 weeks; For 1,031 evaluable patients
Beck J, et al. ECCO 2007
Massard, Ann Oncol 2009.
� Retrospective analysis of data from two centres involved in TARGET
� Five-fold reduction in the 2-year incidence of brain metastases with sorafenib compared with placebo (4 vs 20%)
3 6 9 12 15 18 21 24 27
Inci
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00
10
20
30 Placebo (n=66)sorafenib (n=73)
Time from randomisation (months)
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� Karnofsky performance status at the start of therapy <80%
� diagnosis to treatment time < 1yr
� number of brain metastases >4
Retrospective series of 106 patients with mRCC and brain mets treated with TT: prognostic factors for OS
77 SU
23 SO
5 BEVA
1 TEMT
Local disease treatment
:81% WBRT
25% SRS
25% Surgery
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Divisione di Oncologia Medica, IRCCS Candiolo Vickers, Clinical Genitourinary Cancer, 2013
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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
Conclusions
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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
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