multidisciplinary approach for renal cell...

Multidisciplinary approach for renal cell

carcinoma

Axel Bex, MD, PhD

The Netherlands Cancer Institute

20 April, Antalya, Turkey

RCC –

European Union

• 60.000 new diagnoses/year

• 26.000 Cancer related deaths

• 30 % primary metastatic (with tumour in situ)

• 30 % develop metachronic metastasis

• 30.000 patients total with metastasis

• 7.000 with non-clear cell histology

• less than 25 % are estimated to be candidates for metastasectomy

Ferlay et al., 2006, Eggener et al., 2006 und Alt et al. 2011

Why is there a need for a multidisciplinary

approach ?

There is an increase in small renal masses with diverging treatment

options including urologists, radiologists, physicians

A substantial number of patients develops metachronous metastases:

Who follows the patient ? When to start systemic treatment ? Local

treatment of metastases or metastasectomy ?

In locally advanced or metastatic disease: Targeted therapies have

effectivity on primary tumours and metastases: When to use them in

combination with surgery ?

When and in whom to perform cytoreductive nephrectomy in

synchronous metastatic disease ?

There is an increasing number of trials and eligibility needs to be

discussed

DFS = disease-free survival.

Organisation of Follow Up and

Multidisciplinary Uro-oncology Panel

Full Panel members

•Urologist

•Medical Oncologist

•Radiologist

•Radiotherapist

Patient Urologist Follow-

Up

Neuro-

surgeon

Medical

Oncologist

Follow-Up

Radio-

therapist

Radio-

logist

Additional:

•Neurosurgeon

•General Surgeon

•Thoracic Surgeon

Nomogram evaluating 5-year competing risks of death in patients with localized renal cell carcinoma.

Kutikov A et al. JCO 2010;28:311-317

©2010 by American Society of Clinical Oncology

Kaplan-Meier survival analysis of 3119 patients based on

University of California Los Angeles Integrated Staging with

localized RCC

LR, low risk; IR, intermediate risk; HR, high risk.

Chin et al., Rev Urol. 2006 Winter; 8(1): 1–7.

Surveillance protocol following nephrectomy for localized RCC

using the University of California Los Angeles Integrated Staging

System.

Chin et al., Rev Urol. 2006 Winter; 8(1): 1–7.

Why is there no consensus on follow up ?

Many suggestions not validated

No prospective study data available

No evidence that timely detection of metastatic disease improves

outcome

Targeted therapy does not cure – how important is a delay in

diagnosis of progression ?

Probably only of value for a very small minority with local recurrence

or oligometastatic disease still open for local treatment with curative

intent with or without combination of targeted therapy


Current issues of combining targeted

therapy and surgery Is there an adjuvant treatment following nephrectomy to improve DFS

and outcome in high-risk disease?

What about neoadjuvant therapy to improve outcome?

Neoadjuvant/presurgical therapy to downsize and facilitate surgery?

Caval thrombus: Primary resection or neoadjuvant therapy?

Selection of candidates for cytoreductive nephrectomy ?


Ongoing Phase III Adjuvant Studies for RCC

Trial N Patient Characteristics Treatment

Arms

Treatment

Duration

Primary

End Point

S-TRAC: Sunitinib Trial in Adjuvant

Renal Cancer Treatment

600 High-risk patients according to

UISS

Sunitinib

Placebo

1 yr DFS

ASSURE: Adjuvant Sorafenib or

Sunitinib for Unfavorable RCC

1,923 Non-metastatic RCC; disease stage

II–IV

Sunitinib

Sorafenib

Placebo

1 yr

(9 treatment

cycles)

DFS

SORCE: Sorafenib in Patients with

Resected Primary RCC at

High/Intermediate Risk of Relapse

1,656 Patients with high- and

intermediate-risk resected RCC

Sorafenib

Sorafenib/

Placebo

Placebo

3 yrs DFS

EVEREST: Everolimus for Renal

Cancer Ensuing Surgical Therapy

1,218 Pathological stage intermediate or

very high-risk patients with full or

partial nephrectomy

Everolimus

Placebo

9 treatment

cycles

RFS

PROTECT: Pazopanib as an Adjuvant

Treatment for Localized RCC

1,500 Patients with moderately high or

high risk of relapse with

nephrectomy of localized or locally

advanced RCC

Pazopanib

Placebo

1 yr DFS

ATLAS: Adjuvant Axitinib Therapy of

Renal Cell Cancer in High Risk Patients

592 High-risk, non-metastatic RCC with

nephrectomy

Axitinib

Placebo

3 yrs DFS

UISS = UCLA integrated staging system.

US NIH, 2009, 2010a, 2010b, 2011a, 2011b.

What should neoadjuvant targeted therapy for localized RCC achieve ?

• Downsizing - locally confined renal masses for nephron sparing surgery that would

otherwise be candidates for nephrectomy

- locally advanced renal tumours to allow complete surgical resection

• Downstaging - reduce extent of locoregional disease and micrometastasis before

surgical resection

• Improve outcome parameters - prolong disease-free and overall survival in renal tumours with high-

risk of recurrence

Importance of biopsy prior to initiating medical

therapy for advanced or irresectible RCC

RCC = renal cell carcinoma.

Case of a 56 year old woman with B-cell lymphoma diagnosed as

‘classical’RCC on imaging

Primary Tumor Response to Targeted

Agents in 168 Patients With mRCC

Prior to sunitinib After 2 cycles of sunitinib

Primary tumor maximum overall response to

treatment with targeted agents Primary tumor response to a

targeted agent according to the

amount of response

mRCC = metastatic RCC.

Abel et al, 2011.

Largest Decrease of Primary Tumor

If Any Occurs in the First 2–4 Mos

Bex et al, 2009.

SLTS = surgery-limiting tumor site.

Case

October 2011:

• After 3 years FUP

Case

December 2011: 40 % reduction after two

cycles of sunitinib:

• Complete surgical resection with reconstruction of part of the

diaphragm

• Patient currently NED

Metastatic Disease

‘presurgical therapy’

Advantages in primary metastatic disease

– There is a need for systemic therapy

– Presurgical therapy may help to identify those who may not benefit

from cytoreductive nephrectomy

Metastases

– What is the role of metastasectomy after targeted therapy?

5-Year survival rates following complete resection of

solitary or oligometastasis

Bex et al, in P.N. Lara Jr. and E. Jonasch (eds.), Kidney Cancer,

DOI 10.1007/978-3-642-21858-3_8, © Springer-Verlag Berlin Heidelberg 2012

Case: Male patient, 67 years

March 2008:

• Left transabdominal nephrectomy owing to

pT2cN0M0 Fuhrman grade II clear cell RCC

Urologist Follow-Up

Case

June 2010:

• After more than 2 years FUP by Urologist with

CT scan every 6 months:

Case

Decision at MUP:

• Advanced retroperitoneal

lymphadenopathy

• Treat as systemic disease with first-line

sunitinib 50 mg/day 4/2

Medical

Oncologist

Follow-Up

Case

October 2010:

• After four cycles sunitinib

and FUP by

Medical

Oncologist with

CT scan after

every two cycles:

Case

Reason for MUP:

• Patient had adverse events

and Medical Oncologist saw an

opportunity to discuss RPLND and keep

patient out of toxicity if complete resection

would be feasible

Decision MUP:

• Complete RPLND technically feasible

• Perform surgery

Complete remission with TKI in RCC

only reported in those with previous

nephrectomy

n=64 with previous nephrectomy in all cases

61 % in CR after median FUP of 255d 48 % in CR after median FUP of 322d

Albiges et al., JCO 2012

October 2010:

• RPLND

• Vital clear cell metastasis,

completely resected

September 2011:

• Almost 1 year later without

any therapy and CT scans

at 3-monthly intervals

Medical

Oncologist

Follow-Up

Case

Case

Radiologist performed percutaneous RFA

Since then, FUP by Medical Oncologist with

NED

CN: IMT Planned CN: Targeted Therapy

Metastatic Burden Metastatic Burden

Symptomatic Primary Limited Extensive Limited Extensive

Good Risk Yes

No

Poor Risk Yes

No

Appropriate Appropriate

Uncertain

Uncertain

Uncertain

Inappropriate

RAND Appropriateness Panel on

cytoreductive nephrectomy

RAND = Research and Development; IMT = immunotherapy.

Halbert et al, 2006.

Potential Reasons Against Nephrectomy

Surgical morbidity/mortality may be significant

Benefit of nephrectomy only proven in combination with IFN-α

Short life expectancy spent mainly recovering from surgery

Significant PD during post-operative recovery period may preclude

systemic therapy

Delays initiation of systemic therapy to treat metastatic disease

IFN-α = interferon-alfa; PD = progressive disease.

Van der Veldt et al, 2008.

Arguments in Favor of Nephrectomy

Palliate local symptoms

Primary tumor has not responded to systemic therapy and progresses

Long interval between progression and death with potential progression of the

primary tumor if left in situ

Possibility of CR more likely in combination with nephrectomy

Benefit of pivotal phase III trials of targeted agents largely demonstrated in

nephrectomised patients

Adequate histology can be obtained

Removal of the source of metastases, growth factors, cytokines, etc…

CR = complete response.

Touijer et al, 2010.

Multidisciplinary decision on


Information required when planning cytoreductive

nephrectomy as part of a multimodality treatment in

patients with primary mRCC Age

Comorbidity

Performance

Symptoms of the disease at diagnosis including weight loss

Risk factor scores

Ability to receive systemic therapy

Metastatic burden and its relation to primary tumor volume

Resectability of primary tumor and metastasis

Likelihood to achieve complete surgical resection of all lesions

Histological subtype

Evaluation of resectability

Conditional survival of patients with mRCC

treated with VEGF-targeted therapy: a

population-based study

- 770 patients intermediate Heng risk

0

10

20

30

40

50

60

70

80

6

months

12

months

2 years another

2 years

% patients alive

% patients dead

45 % on targeted therapy

survive 2 years (n=346). Of

those 346 another 45 % live

another 2 years.

Harshman et al., Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a

population-based study. The Lancet Oncology Volume 13(9):927-935, 2012

Conditional survival of patients with mRCC

treated with VEGF-targeted therapy: a

population-based study

- 441 patients poor Heng risk

0

10

20

30

40

50

60

70

80

90

100

6

months

12

months

2 years another

2 years

% patients alive

% patients dead

11 % survive 2 years

(n=54). Of those 54

33 % live another 2 years

or 16 patients of 441

live 4 years

Harshman et al., Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a

population-based study. The Lancet Oncology Volume 13(9):927-935, 2012

Predictors of survival in advanced

RCC: Long-term results from SWOG

Trial S8949

Progression within first 90 days:

Yes vs. No HR 2.10 (1.50, 2.92) <0.0001

Lara P et al., J Urol 181(2):512-517, 2009

Multivariate proportional hazards model in 191patients, including earlyprogression

Survival HR

Variable Adjusted for Other Factors in Model (95% CI) p Value

Performance status (1 vs 0) 1.70 (1.26, 2.31) 0.0006

Lung metastasis (yes vs no) 0.81 (0.59, 1.11) 0.19

Randomized to nephrectomy 0.79 (0.58, 1.06) 0.12

Alkaline phosphatase (above vs below median) 1.24 (0.92, 1.68) 0.26

Hemoglobin (above vs below median) 0.84 (0.62, 1.14) 0.26

Progression by 90 days (yes vs no) 2.10 (1.50, 2.92) <0.0001

Survival was defined as starting 90 days after registration.

The Outcome of Patients Treated with Sunitinib Prior

to Planned Nephrectomy in Metastatic Clear Cell

Renal Cancer

Powles et al, European Urology 2011.

• Patients with MSKCC intermediate risk and absence of progression at metastatic

sites following pretreatment with sunitinib have the longest overall survival after


CARMENA Phase III Study of Sunitinib Only Vs.

Nephrectomy Followed by Sunitinib

Primary objective: Is sunitinib alone non-inferior to

nephrectomy plus sunitinib in terms of OS?

Nephrectomy

Sunitinib

50 mg/day

(schedule 4/2)

Sunitinib

50 mg/day

(schedule 4/2)

R

A

N

D

O

M

I

Z

A

T

I

O

N

N = 576

Metastatic

clear cell RCC

Biswas et al, 2009; US NIH, 2010c.

SURTIME, a EORTC-GU 30073 Phase III Study

Investigating the Sequence of Nephrectomy and

Sunitinib

Primary end point: PFS

Secondary end points: OS, association with prognostic gene

and protein expression profiles

Nephrectomy

Sunitinib

50 mg/day

(schedule 4/2)

Nephrectomy

Sunitinib

50 mg/day

(schedule 4/2)

Patients with

synchronous

mRCC and

primary tumor

in situ

R

A

N

D

O

M

I

Z

A

T

I

O

N

N = 458

Biswas et al, 2009; US NIH, 2010d.

Recommendations for a RCC multidisciplinary

tumour board

Presence of at least urologist, radiologist, medical oncologist,

pathologist and radiotherapist

Meet regularly and document decisions

Make use of prognostic nomograms for locally confined and

advanced disease to tailor follow up and therapy

Decisions on integrating surgery with targeted therapy are complex.

The team has to be aware of prognostic scores AND conditions

affecting surgery

Decisions should follow evidence whenever appropriate and available

Agree on and document transfer of care between specialists if

necessary or have physician assistants (nurse practitioners) keep

track of the patient


multidisciplinary approach for renal cell...

Documents