Prospettive future nel trattamento
chirurgico del mRCC
Alberto Lapini
The clinical challenge
Despite an increasing diagnosis of low-stage tumors
30% of patients are diagnosed with locally advanced or
metastatic disease at first presentation
A substantial number of patients develops systemic disease
progression regardless an initially organ confined tumor
Kidney Cancer
Metastatic disease
Treatment
“Surgery is the cornerstone of treatment for metastatic kidney cancer”
The advent of targeted therapies (TT) modified the therapeutic scenario of
metastatic disease introducing the possibility of medical therapy as single
treatment or in combination therapies (TT + surgery)
Surgery
Metastatic disease
Single metastatic
site
Multiple metastatic
sites
Primary tumor + metastatic disease
+
Bulky disease
+
Caval Thrombus
Target
therapies
Metastatic disease
Selection Criteria for surgery or
targeted therapies as first treatment
Potentially surgically resectable
Surgery
Surgically unresectable
Target
therapies
“Most patients who undergo resection of a solitary metastasis
experience recurrence but long –term progression-free survival has
been reported in these patients”
Chirurgia delle metastasi
Fattori prognostici favorevoli
Lesione solitaria
Sede polmonare
Sviluppo metacrono
Resection of metastatic renal cell carcinoma
JP Kavolius, DP Mastorakos, C Pavlovich, P Russo, ME Burt and MS Brady
Journal of Clinical Oncology, Vol 16, 2261-2266, 1998
Lesione solitaria: alcuni studi non evidenziano differenze significative tra
lesione solitaria e multipla , bensì tra asportazione completa e incompleta.
Sede- ossea vs polmonare : lesioni polmonari sono a miglior prognosi
Lesione metacrona- la differenza di sopravvivenza per metastasi a comparsa
oltre i 2 anni dipenderebbe dal fatto che le metastasi entro 2 anni sono più
frequentemente a sede ossea e quelle dopo i 2 anni a sede polmonare .
Considerando la stessa sede non sembra esserci una differenza significativa
di sopravvivenza per metastasi a comparsa < o > i 2 anni
Metastasectomy in renal cell carcinoma: a multicenter retrospective analysis.
Van der Poel HG, Roukema JA, Horemblas S, van geel AN, Debruyne FMJ
Eur.Urol. 35:197-203;1999
Cancer2011;117:2873-82.
La completa asportazione delle metastasi si associa ad un significativo aumento
della cancer-specific survival (CSS) mediana (4.8 years vs 1.3 years; P < .001).
Metastasi a sede esclusiva polmonare : Resezione completa - 5-year CSS pari al
73.6% vs Resezione Incompleta pari al 19% (P <.001).
Un miglioramento nella sopravvivenza si osserva anche nel gruppo di pazienti con
metastasi a sede extrapolmonare . Resezione completa 5-year CSS pari al32.5% vs
Resezione incompleta pari al 12.4% (P < .001).
La resezione completa rimane predittiva per incremento CSS per pazienti con ≥3
metastatic lesions (P < .001) ; metastasi sincrone (P < .001) o metacrone (P = .002)
All’analisi multivariata la resezione incompleta è un fattore di rischio significativo
per > rischio di morte cancro correlata
(hazard ratio, 2.91; 95% confidence interval, 2.17-3.90; P < .001).
to operate or not to operate
Variabili predittive :
Calcio serico > 10 mg/dL,
HGB < ai limiti
LDH > 1,5 il valore normale
Karnofsky < 80%
Inizio terapia sistemica <12 mesi
dalla diagnosi
Recidiva della patologia < 12 mesi
dalla nefrectomia
One point was assigned for each adverse
parameter met, up to a maximum of five points.
Each patient was assigned to a risk category :
favorable-risk (0 points),
intermediate-risk (1–2points)
poor-risk (3–5 points)
Metastatic disease
Selection Criteria for surgery
as first treatment
Elements in favor
Complete vs incomplete resection
Solitary lesion vs multiple lesions
Site : lung >backbone > other bones > visceral organs > CNS
Metachronous vs synchronous
Long disease -free interval following initial treatment (> 12 months)
Dicembre 1996
Maggio 2008
Ottobre 2011
Metastatic disease at first presentation
Primary tumor + metastases
Surgery VS Targeted Therapies
Timing of surgery in mRCC
Cytoreductive nephrectomy improves survival in mRCC
Now we have “better systemic therapies
Responses seen in primary tumor
We can identify reponder patients
Surgery first then systemic therapy or
systemic therapy first followed by surgery?
Metastatic RCC
Nefrectomy?
Jean B. deKernion. J.Urol. 130:2-7 1983
State of the Art
Treatment of advanced RCC-traditional methods and innovative approaches
“Complete surgical extirpation remains the only effective
management of this neoplasm ……. Based on the observation
that some patients have regression of metastases after removal of
the primary renal carcinoma the treatment of choice for patients
with concomitant metastases traditionally has been called
palliative or adjunctive nephrectomy.“
Jean B. deKernion
UCLA School of medicine and
The UCLA Jonsson Cancer Center
RCC accounts for the largest number of
patients with spontaneous regression
among solid tumours.
However, spontaneous regression of
metastatic RCC is rarely observed.
The site of the regression was most
commonly in the lung.
In a metanalysis of two randomized studies SWOG-8949 EORTC-30947,
comparing nephrectomy combined with immunotherapy versus
immunotherapy only, an increased long-term survival was found in patients
subjected to tumour nephrectomy.
Metastatic RCC
Today
Surgery + target therapy
Sunitinib better than IFN- α
irrespective of nephrectomy
Fractional percentage of
tumor volume removed
OBJECTIVE
To determine if the fractional percentage of tumour
volume (FPTV) removed at cytoreductive nephrectomy
predicts disease specific survival (DSS).
RESULTS
In all, 55 patients had their FPTV calculated exactly;
45 had a >90% FPTV. The median DSS times were
11.6 and 2.9 months for patients with > 90% and <
90% FPTV removed (P= 0.002).
The FPTV was defined as the volume of disease removed
at the time of cytoreductive nephrectomy, including
synchronously removed distant metastases, over the
total volume of cancer (removed and residual).
The evaluation of tumor volume
removal could be employed to choose
between cytoreductive nephrectomy
or presurgical target therapy
Factors that were identified as significant were:
1-serum albumin below the lower limit of normal
2-serum lactate dehydrogenase above the upper limit of normal
3-clinical T3 or T4 tumor classification
4-symptoms at presentation caused by a metastatic site
5- the presence of liver metastasis
6-retroperitoneal lymphadenopathy
7- supradiaphragmatic adenopathy (1 cm)
Surgical patients who had 4 risk factors did not appear to benefit from CN.
Nephrectomy+TKI vs TKI
CARMENA Trial
END POINT
OS
Presurgical target therapy
Presurgical target therapy
Potential benefits
the potential benefits of preoperative medical therapy include:
-downsizing of the primary tumor,
- More rapid initiation of systemic therapy may translate into decreased cancer related morbidity
before surgery,
- operate on “responding” patients (Litmus test)
-evaluation of the treated tumor tissue to better elucidate the action of these new drugs.
Downsizing of the primary tumor could facilitate the surgical extirpation of
unresectable masses, diminish thrombus extension within the inferior vena cava,
and, most controversially, allow imperative partial nephrectomy in patients who have
bilateral tumors or a single kidney.
Neoadjuvant target therapy
Efficacy
Autore
N. Casi
Farmaco
% Pazienti con
Riduzione T
primitivo
Decremento
Medio (range) del T
primitivo
Amin 2008
9
Suni/Sora
90%
12% (1-54%)
Veldt 2008
17
Sunitinib
76%
12%
Cowey 2010
30*
Sorafenib
82%
13% (1.40%)
Thomas 2009
19
Sunitinib
53%
9% (0-24%)
Bex 2009
10
Sunitinib
60%
14%
Jonash 2010
50
Beva/Beva+ Erl
52%
<10% (1-30%)
Trial: NCT01099423(SURTIME)
Randomized Phase III Trial Comparing Immediate Versus Deferred
Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma
458 patients
PS 0-1
No prior treatment
Primary End Point : PFS
Nefrectomy
Sunitinib
Sunitinib x 3
Nefrectomy
Downsizing of the primary tumor could facilitate the surgical extirpation of
unresectable masses, diminish thrombus extension within the inferior vena cava,
“When the Going Gets
Tough, the Tough Get Going”
Surgery is possible for almost everyone with
locally advanced disease without metastasis ,
even in presence of large tumors . But there
are very rare clinical situations , considered
“inoperable”
Inoperable tumor was considered to have “invasion of adjacent tissues or
organs with an associated confluent nodal mass involving
the great vessels…but not including the renal vein or IVC”
Bromwich E . BJU ;2002
Vena cava Involvement
Is presurgical Targeted therapy useful in all cases of caval thrombus?
Presence /absence of metastasis
Level : Surgical difficulty and complications
Median survival :
N0M0 51.7 mesi
N+M0 10.7 mesi
NxM+ 6.9 mesi
Hafercamp J.Urol 2007
Surgical Complications
To assess the cytoreductive effect of TMTs on inferior vena cava tumor thrombi.
One patient (4%) had an increase in the thrombus level (level II to III), 21 (84%)
had stable thrombi, and in 3 (12%) the thrombus level was decreased (1 level IV
to III, 1 level III to II, and 1 level II to no thrombus).
The median change in the volume of the primary tumor
was 0 cm3 (-2069 to 790.3); 12 patients (48%) had a
reduction in their primary mass, 3 (12%) had stable disease,
and 10 (40%) had an increase in the size of their primary tumor.
There was only one case (4%) where the surgical approach was potentially
affected by tumor thrombus regression (level IV to III).
Interestingly ,only patients treated with primary sunitinib had
measurable thrombus regression (no regression with bevacizumab or sorafenib)
Inoperable tumor was considered to have “invasion of adjacent
tissues or organs with an associated confluent nodal mass involving
the great vessels…but not including the renal vein or IVC”
Bromwich E . BJU ;2002
Large renal cell carcinoma with
possible extension into the liver
At surgery, the tumor did not invade
the liver. The pathologic stage was
T2 N0.
Sheth S. RadioGraphics 2001
Surgery-limiting tumour sites (SLTSs)
Surgically complex disease was defined as a primary tumour or retroperitoneal
locoregional metastases for which removal was deemed technically not feasible
or potentially associated with morbidity outweighing the benefit.
6/10 (60%) SLTSs revealed a reduction of tumour size with a median of 14%
(range -1/-20%) according to RECIST.
None of the ten SLTSs had a partial response (PR), whilst at distant
metastatic sites one complete remission and two PRs occurred.
May have presurgical target therapy impact on surgical management?
YES
Probably YES
Probably NO
Neoadjuvant targeted therapy before surgery is safe; however, degree of
cytoreduction is unpredictable and oncologic efficacy is not established (level of
evidence B) Margulis V. Eur Urol 2011
The reduction in tumor size was more profound in the
metastatic lesions than in the primary tumor
The effect of downsizing is most prominent in the
first 2–4 months of therapy
“None of the patients showed greater than 30% reduction in primary
tumor size, but 23% of patients showed at least 10% reduction by using
RECIST methodology after 8 weeks of therapy”.
“…… downsizing of large primary tumors to facilitate imperative nephron sparing
surgery, and avoid radical nephrectomy and dialysis.
……… potential use of preoperative targeted therapy with the aim of simplifying
(and reducing complications) for elective nephron sparing surgery.”
Ficarra V. Nature Reviews Urology 2010
Presurgical therapy and
perioperative complications
NO RISK ABOUT SIGNIFICANT COMPLICATIONS
Discontinuation of the drug's administration
When?
Consider half life drugs
Temsirolimus
Sorafenib
Sunitinib
Active metabolite
of Sunitinib
Bevacizumab
Pazopanib
17
hrs
24-48 hrs
40-60 hrs
80-110 hrs
14-21 days
30.9 hrs
We advocate a discontinuation of 2/3 times the
half life drug before and after surgery
Quanto tempo prima dell’intervento sospendere il farmaco?
CN + target therapy
When primary tumour bulk is
greater than metastases
Fractional percentage of tumour
volume (FPTV) : better cancer specific survival when > 90% of FPTV
is removed
Presurgical
target therapy
Multiple metastases involving single
or multiple organs not suitable for
surgery
RCC cases with thrombi in the
supradiaphragmatic caval vein
Surgically complex disease ( primary
Primary tumour and solitary
metastasis suitable for surgical
removal
tumor or retroperitoneal locoregional
metastases) for which removal was
deemed technically not feasible or
potentially associated with morbidity
outweighing the benefit.