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
DFS = disease-free survival.
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 ?
DFS = disease-free survival.
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
cytoreductive nephrectomy
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
cytoreductive nephrectomy
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
DFS = disease-free survival.