Relatore:Dr.ssa ALKETA HAMZAJalketa.hamzaj@usl8.toscana.it

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

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N=290

*Crossover to sorafenib permitted

*

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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…