1. ADJUVANT AND NEOADJUVANT APPROACHES IN RCC
Relatore:
Dr.ssa ALKETA HAMZAJ
S.S. ONCOLOGIA MEDICA
OSPEDALE SAN DONATO
AREZZO

2. RCC: Presentation at diagnosis
Localized
Locally advanced
Metastatic
30% Recurrence

3. 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

4. Past Adjuvant Therapy Approaches Designed
Radiation therapy
Hormonal therapy
Chemotherapy
Immunotherapy
Vaccines
Monoclonal antibody

5. 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)
Aut. tumor vaccine + BCG vs. observation 43
Adler (1987)
Aut. tumor vaccine ± BCG vs. observation
120
Galligioni (1996)
UFT vs. observation 71
Naito (1999)
IFN- vs. observation
247
Pizzocaro (2001)
IFN- NL vs. observation
283
Messing (2003)
HD IL-2 vs. observation 69
Clark (2003)
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)

6. 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

7. 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

8. 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

9. 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

10. Risk Group Stratification for patients with surgically resected RCC
SSIGN, Mayo Clinic (Frank, J Urol 2002): CSS
UISS (Zisman, J Clin Oncol, 2004): OS

11. Mayo Clinic Score for RCC (SSIGN)*
Cancer- specific Survival rate
SSIGN Score years C-SS
0-2
3-4
5-6
7-9
>10
100%
91%
64%
47%
* Mayo Clinic Stage, Size, Grade and Necrosis score for ccRCC; Frank I, J Urol 2002

12. UCLA Integrated Staging System (UISS*):
Pts with RCC undergone surgery
Non metastatic pts
Metastatic pts
Low
Low
Intermed
Intermed
High risck
High risck
* T stage, Grade, ECOG-PS
Zisman et al, JCO 2004
Downs TM et al. Crit Rev Oncol Hemato, 2009

13. UCLA Integrated Staging System (UISS): Nonmetastatic patients
OS 5 anni: 84%
OS 5 anni: 72%
OS 5 anni: 44%
Zisman et al, JCO 2004

14. UCLA Integrated Staging System (UISS): Metastatic patients
OS 5 anni: 30%
OS 5 anni: 19%
OS 5 anni: 0%
Zisman et al, JCO 2004

15. UCLA Integrated Staging System (UISS): Survival Analysis
Kaplan–Meier survival analysis of the study population according to the formulated UISS categories separately for metastatic (M+) and nonmetastatic (M−) patients
Downs TM et al. Crit Rev Oncol Hemato, 2009

16. Comparison of the SSIGN score and the UISS integrated models of risk stratification
Parameters
Histology
validation
External
Patients
Limitations
SSIGN
TNM stage, size, grade, necrosis
ccRCC
yes
2656
Reliance upon subjective variable of necrosis.
Useful only for ccRCC
Does not take into account a pt’s ECOG PS
UISS
ECOG-PS, Fuhrman grade, TNM stage
RCC
8249
Reduced predictive power in non metastatic patients
Kapoor A. Urologic Oncology, 2009
Downs TM. Crit Rev Oncol Hemato, 2009

17. 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

18. New target-based treatments...
Bevacizumab
Temsirolimus
Everolimus
Sunitinib
Sorafenib
Pazopanib
Axitinib
Brugarolas, NEJM 2007

19. Ongoing Adjuvant Studies for RCC
Trial N
Patient characteristics
Treatment 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
Sunitinib
Sorafenib
Placebo
(9 treatment cycles)
SORCE: Sorafenib in Patients with Resected Primary RCC at High/Intermediate Risk of Relapse3
1,656
Patients with high- and intermediate- risk resected RCC
Sorafenib/ placebo
3 years
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
Everolimus
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
Pazopanib
*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
1NCT ; 2NCT ; 3NCT
4NCT ; 5NCT

20. ASSURE (ECOG 2805) Adjuvant Sorafenib or Sunitinib for Unfavorable REnal Cell Carcinoma
Group A
Sunitinib 50mg (4 capsules) orally q.d.  4 weeks followed by rest  2 weeks for nine cycles†
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 duct or medullary)
ECOG PS 1
Surgery
Laparoscopic
Open
Group B
Sorafenib 400mg (2 tablets) orally b.i.d.  6 weeks for nine cycles†
Preregister*
Nephrectomy
Randomisation
Group C
Placebo
Primary objective: disease-free survival
Secondary objective: OS, QoL, molecular & genetic predictors for DFS
*Accrual goal = 1,332; †one cycle = 6 weeks

21. N=290

22. *Crossover to sorafenib permitted
3:3:2
*Crossover to sorafenib permitted

23. 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
N E P H R E C T O M Y
Screening/ baseline
12 wks
Tx 12 mo OS
Pazopanib (800mg QD)
Follow up
DFS
N=750
1:1
Matching Placebo
R A N D O M I S A T I O N
Primary objective: DFS N=1500
Secondary objective: OS, Safety, QoL, Biomarkers

24. 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?

25. 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

26. 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

27. Neoadjuvant therapy to downsize and facilitate surgery
There is no universally accepted definition of resectability
The decision of unresectability is often based on imaging

28. 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

29. 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.

30. Neoadjuvant approaches in metastatic RCC
Cytoriductive nephrectomy is still the standard of care in mRCC?

31. Cytoreductive Surgery in the Cytochines Era Combined Analysis
31% decrease in risk of death with nephrectomy
Flanigan RC, J Urol 2004

32. Uno studio retrospettivo, condotto da 7 centri nel nord america , con l’obiettivo di studiare l’impatto della CN sulla sopravvivenza dei pz con mRCC trattati con VEGF targeted therapy.
Choueiri TK, et al. 2011

33. Multivariate Analysis Demonstrated Better OS in Patients with CN
The advantage was mantained if adjusted by prognostic factors*
Patients in poor risk group had a marginal benefit (p=0.06)
Choueiri TK, et al. J Urol 2011
*Heng DY, et al. J Clin Oncol 2009

34. Overview of Targeted Therapy Pre-surgical Phase II Trials in Renal Cell Carcinoma
Bevacizumab1
Sorafenib2
Sunitinib3
Sunitinib4
Sunitinib5
Number of patients 50 30 20 33
Number of nephrectomies 42 16 21 17
Days off prior to surgery 28
2–14 1 14
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)
Duration in hospital (days)
5 (1–70)
6 (5–13)
8 (7–17)
7 (4–36)
Restart therapy (days)
28–42
Complications Clavien-Dindo
Grade I
9 (18%)
3 (15%) 2
Grade II
Grade III
Grade IV
Grade V
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)

35. Patients with synchronous metastatic RCC and primary tumour in situ
SURTIME: The SURgery and TIMe Phase III Study30073 of Sunitinib and Nephrectomy
Nephrectomy
Sunitinib
50 mg/day (Schedule 4/2)
R A N D O M I S A T I O N
Patients with synchronous metastatic RCC and primary tumour in situ
N=458
Sunitinib
50 mg/day (Schedule 4/2)
Nephrectomy
Primary endpoint: progression-free survival
Secondary endpoint: OS, association with prognostic gene and protein expression profiles
EORTC-GU Group Study
NCT 35

36. CARMENA: Phase III Study of Sunitinib vs Nephrectomy + Sunitinib
R A N D O M I S A T I O N
Metastatic clear-cell RCC
Sunitinib 50 mg/day (Schedule 4/2)
N=576
Sunitinib 50 mg/day (Schedule 4/2)
The SURTIME study is designed to assess PFS in patients who receive post-surgical sunitinib versus pre-surgical sunitinib
The phase III CARMENA study is comparing sunitinib therapy alone with cytoreductive nephrectomy plus sunitinib
The aim of the study is to determine if sunitinib alone is 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?
PI: Arnaud Mejean (CCAFU, HEGP, Paris, France)
NCT 36

37. 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

38. 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 clarify
The value of surgery in the context of targeted therapy
The optimal timing of surgery in clinical practice

39. Thank you…