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Relatore:Dr.ssa ALKETA [email protected]
S.S. ONCOLOGIA MEDICA OSPEDALE SAN DONATO
AREZZO
ADJUVANT AND NEOADJUVANT APPROACHES IN RCC
RCC: Presentation at diagnosis
30% RecurrenceLocalizedLocally advancedMetastatic
Rationale of an adjuvant therapy approach in RCC
•Nearly 50% of all pts with RCC will have metastatic disease
upfront or during their disease course.
•Micrometastatic disease at the time of surgery in pts with recurrent
disease following nephrectomy
•Use of effective therapy may reduce the risk of relapse
Past Adjuvant Therapy Approaches Designed
• Radiation therapy• Hormonal therapy• Chemotherapy• Immunotherapy• Vaccines• Monoclonal antibody
Adjuvant randomized trials in RCC:Adjuvant randomized trials in RCC:
Treatment N Author (year) Outcome of the study
RT vs. observation 72 Kjaer (1987) negative
MPA vs. observation 136 Pizzocaro (1987) negative
Aut. tumor vaccine + BCG vs. observation
43 Adler (1987) negative
Aut. tumor vaccine ± BCG vs. observation
120 Galligioni (1996) negative
UFT vs. observation 71 Naito (1999) negative
IFN- vs. observation 247 Pizzocaro (2001) negative
IFN- NL vs. observation 283 Messing (2003) negative
HD IL-2 vs. observation 69 Clark (2003) negative
Aut. tumor vaccine vs. observation 553 Jocham (2004) positive in terms of PFS (p=0.02)
s.c. IL-2 + IFN- + 5-FU vs. observation 203 Atzpodien (2005) negative
Progress in recent years ...
• Better prognostic definition of the risk stratification
• Advances in knowledge of the molecular biology of RCC
• Availability of new target-based treatments, effective in metastatic disease and safe
Progress in recent years ...
• Better prognostic definition of the risk stratification
• Advances in knowledge of the molecular biology of RCC
• Availability of new target-based treatments, effective in metastatic disease and safe
Defining Risk
• Predicting the probability that a subject will experience a certain event in time
• Identifing patients at increased risk, which may benefit from adjuvant therapy and reducing toxicity in low-risk pts
Current Risk Stratification Algorithms
•Postoperative models:– Kattan’s nomogram, Memorial-Sloan-Kettering
Cancer Center (Kattan, J Urol 2001): RFS – SSIGN, Mayo Clinic (Frank, J Urol 2002): CSS– UISS (Zisman, J Clin Oncol, 2004): OS
•Preoperative models:– Yayciouglu (Urology 2001): RFS– Cindolo (Br J Urol Int 2003): RFS
Risk Group Stratification for patients with surgically resected
RCC
–SSIGN, Mayo Clinic (Frank, J Urol 2002): CSS–UISS (Zisman, J Clin Oncol, 2004): OS
Mayo Clinic Score for RCC (SSIGN)*
SSIGN Score 5-years C-SS
0-2 3-4 5-6 7-9 >10
100% 91% 64% 47% 0
Cancer- specific Survival rate
* Mayo Clinic Stage, Size, Grade and Necrosis score for ccRCC; Frank I, J Urol 2002
UCLA Integrated Staging System (UISS*):
* T stage, Grade, ECOG-PS
Pts with RCC undergone surgery
Non metastatic pts Metastatic pts
Low
Intermed
High risck
Low
Intermed
High risck
Zisman et al, JCO 2004
Downs TM et al. Crit Rev Oncol Hemato, 2009
UCLA Integrated Staging System (UISS): Nonmetastatic patients
OS 5 anni: 84%
OS 5 anni: 72% OS 5 anni: 44%
Zisman et al, JCO 2004
OS 5 anni: 30%
OS 5 anni: 19% OS 5 anni: 0%
Zisman et al, JCO 2004
UCLA Integrated Staging System (UISS): Metastatic patients
Kaplan–Meier survival analysis of the study population according to the formulated UISS categories separately for metastatic (M+) and nonmetastatic (M−) patients
UCLA Integrated Staging System (UISS): Survival Analysis
Downs TM et al. Crit Rev Oncol Hemato, 2009
Comparison of the SSIGN score and the UISS integrated models of risk stratification
Model Parameters Histologyvalidation
External Patients Limitations
SSIGN TNM stage, size, grade, necrosis
ccRCC yes 2656 Reliance upon subjective variable of necrosis.Useful only for ccRCCDoes not take into account a pt’s ECOG PS
UISS ECOG-PS, Fuhrman grade, TNM stage
RCC yes 8249 Reduced predictive power in non metastatic patients
Kapoor A. Urologic Oncology, 2009Downs TM. Crit Rev Oncol Hemato, 2009
Progress in recent years ...
• Better prognostic definition of the risk stratification
• Advances in knowledge of the molecular biology of RCC
• Availability of new target-based treatments, effective in metastatic disease and safe
New target-based treatments...
Brugarolas, NEJM 2007
TemsirolimusEverolimus
SunitinibSorafenibPazopanib
Axitinib
Bevacizumab
Ongoing Adjuvant Studies for RCC
Trial N Patient characteristicsTreatment arms
Study duration
Primary Endpoint
S-TRAC: Sunitinib Phase III TRial in Adjuvant Renal Cancer Treatment1
600 High-risk patients according to UISS Staging System*
Sunitinib Placebo
1 year Disease-free survival
ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavourable Renal Cell Cancer2
1,923 Non-metastatic RCC; disease stage II–IV
SunitinibSorafenibPlacebo
1 year (9 treatment cycles)
Disease-free survival
SORCE: Sorafenib in Patients with Resected Primary RCC at High/Intermediate Risk of Relapse3
1,656 Patients with high- and intermediate- risk resected RCC
SorafenibSorafenib/placeboPlacebo
3 years Disease-free survival
EVEREST: EVErolimus for Renal Cancer Ensuing Surgical Therapy, A Phase III Study4
1,218 Pathological stage intermediate or very high-risk patients with full or partial nephrectomy
EverolimusPlacebo
9 treatment cycles
Recurrence-free survival
PROTECT: Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma5
1,500 Patients with moderately high or high risk of relapse with nephrectomy of localised or locally advanced RCC
PazopanibPlacebo
1 year Disease-free survival
*T3 N0 or NX, M0, Fuhrman’s grade ≥2, ECOG ≥1 or T4 N0 or NX, M0, any Fuhrman grade, and any ECOG PS or any T, N1-2, M0, any Fuhrman’s grade, and any ECOG PS
1NCT00375674; 2NCT00326898; 3NCT004922584NCT01120249; 5NCT01235962
ASSURE (ECOG 2805)Adjuvant Sorafenib or Sunitinib for Unfavorable REnal Cell Carcinoma
Primary objective: disease-free survivalSecondary objective: OS, QoL, molecular & genetic predictors for DFS
Group ASunitinib 50mg (4 capsules)
orally q.d. 4 weeks followed by rest 2 weeks for nine cycles†
Group BSorafenib 400mg (2 tablets)
orally b.i.d. 6 weeks for nine cycles†
*Accrual goal = 1,332; †one cycle = 6 weeks
Stratification
Tumour: pT1b G3-4; pT2-T4 or any T with N+
Intermediate or high risk Very high risk
Histological sub-type Clear cell Non-clear cell
(except collecting ductor medullary)
ECOG PS 0 1
Surgery Laparoscopic Open
Group C
PlaceboR
and
om
isat
ion
Ran
do
mis
atio
n
Nep
hre
cto
my
Nep
hre
cto
my
Pre
reg
iste
r*P
rere
gis
ter*
N=290
*Crossover to sorafenib permitted
*
*
3:3:2
N=1656
PROTECT:A phase fase III randomised, double-blind controlled study, to evaluate efficacy and safety of Pazopanib adjuvant-therapy in pts with localized or locally advanced RCC
NEPHRECTOMY
Screening/ baseline
12 wks Tx 12 mo
OS
Pazopanib (800mg
QD)
Follow up
DFSN=750
N=750
1:1
Follow upMatching
Placebo
Primary objective: DFS N=1500
Secondary objective: OS, Safety, QoL, Biomarkers
RANDOMISATION
Neoadjuvant approaches in RCC
• Localized disease- What about neoadjuvant therapy to improve outcome?
- Neoadjuvant therapy to downsize and facilitate surgery?
• Metastatic disease (synchronous)
- Cytoriductive nephrectomy is still the standard of care in mRCC?
- Can pretreatment help to select pts who may not be cantidates for cytoreductive nephrectomy?
Localized disease: neoadjuvant therapy to improve outcome
Theoretical advantages to administer presurgical therapy:
•Downsizing Partial nephrectomy, Nephrone sparing surgery
•Assesment of tumor biology and proangiogenic factors•Decreasing circulating tumor cells•Provide tissue to study the mechanism of action of targeted agents
Localized disease: neoadjuvant therapy to improve outcome
Potential disadvantages of the presurgical approach:
• Increasing risk of perioperative morbidity and/or mortality
• Delay potentially curative surgery in nonresponding patients
Neoadjuvant therapy to downsize and facilitate surgery
• There is no universally accepted definition of resectability
• The decision of unresectability is often based on imaging
Does downsizing really improve
resectability ?Primary tumor downsizing in renal cell carcinoma is more prominent in smaller tumors enabling nephron sparing strategies
n= 85 primary tumors from 5 published studies, after pretreatment with sunitinib and sorafenib
Kroon et al., Urology 2012
Neoadjuvant therapy to downsize and facilitate surgery
Multiple Case Reports of effective downsizing of CVT
CVT = caval vein thrombus.Harshman et al, 2009; Karakiewicz et al, 2008; Kroeger et al, 2010.
Neoadjuvant approaches in metastatic RCC
Cytoriductive nephrectomy is still the standard of care in mRCC?
Cytoreductive Surgery in the Cytochines Era Combined Analysis
31% decrease in risk of death with nephrectomy
Flanigan RC, J Urol 2004
Choueiri TK, et al. 2011
Multivariate Analysis Demonstrated Better OS in Patients with CN
The advantage was mantained if adjusted by prognostic factors*
Choueiri TK, et al. J Urol 2011 *Heng DY, et al. J Clin Oncol 2009
Patients in poor risk group had a marginal benefit (p=0.06)
Overview of Targeted Therapy Pre-surgical Phase II Trials in Renal Cell Carcinoma
Trial Bevacizumab1 Sorafenib2 Sunitinib3 Sunitinib4 Sunitinib5
Number of patients 50 30 20 33 30
Number of nephrectomies 42 30 16 21 17
Days off prior to surgery 28 2–14 1 14 1
Median time of surgery (min)
168 185 180 195 NR
Median estimated blood loss
400 (0–7000) 950 (200–3000) 650 (80–3000) 750 (90–4700) NR
Duration in hospital (days) 5 (1–70) 6 (5–13) 8 (7–17) 7 (4–36) NR
Restart therapy (days) 28 28–42 28 21 28
Complications Clavien-Dindo
Grade I 9 (18%) 1 3 (15%) 2 1
Grade II 0 0 0 0 0
Grade III 2 0 0 1 0
Grade IV 0 1 0 2 0
Grade V 2 0 0 1 0
1Jonasch e et al, J Clin Oncol 2009; 27(25):4076–4081; 2 Cowey et al, J Clin Oncol 28, 2010 3 Bex A et al, ASCO GU 2010; 4 Powles T et al, ASCO GU 2010
5 Jonasch E et al, ASCO GU 2010 (personal communication)
1Jonasch e et al, J Clin Oncol 2009; 27(25):4076–4081; 2 Cowey et al, J Clin Oncol 28, 2010 3 Bex A et al, ASCO GU 2010; 4 Powles T et al, ASCO GU 2010
5 Jonasch E et al, ASCO GU 2010 (personal communication)
SURTIME: The SURgery and TIMe Phase III Study30073 of Sunitinib and Nephrectomy
• Primary endpoint: progression-free survival
• Secondary endpoint: OS, association with prognostic gene and protein expression profiles
EORTC-GU Group Study
NephrectomyNephrectomy
Sunitinib50 mg/day
(Schedule 4/2)
Sunitinib50 mg/day
(Schedule 4/2)
NephrectomyNephrectomy
Sunitinib50 mg/day
(Schedule 4/2)
Sunitinib50 mg/day
(Schedule 4/2)
Patients with synchronous
metastatic RCC and primary
tumour in situN=458
NCT01099423
RANDOMISATION
PI: Arnaud Mejean (CCAFU, HEGP, Paris, France)
CARMENA: Phase III Study of Sunitinib vs Nephrectomy + Sunitinib
NephrectomyNephrectomy
Sunitinib 50 mg/day
(Schedule 4/2)
Sunitinib 50 mg/day
(Schedule 4/2)
Sunitinib 50 mg/day
(Schedule 4/2)
Sunitinib 50 mg/day
(Schedule 4/2)N=576
Metastaticclear-cell
RCC
NCT00930033
Primary objective: Is sunitinib alone non-inferior to nephrectomy plus sunitinib in terms of overall survival?Primary objective: Is sunitinib alone non-inferior to nephrectomy plus sunitinib in terms of overall survival?
RANDOMISATION
Take home message
• Adjuvant therapy ?Yes… in high risk surgically resectable RCC
Given the risk/benefit profile, no adjuvant treatment is appropriate outside clinical trials
Take home message
• Neoadjuvant therapy ?
No published studies describing the use of neoadjuvant therapy in Nonmetastatic RCC
In metastatic RCC cytoreductive nephrectomy is currently used as a standard treatment for patients with good or intermediate risk Benefit less clear in patients with poor prognostic risk
Ongoing studies will clarifyThe value of surgery in the context of targeted therapy
The optimal timing of surgery in clinical practice
Thank you…