Cytoreductive nephrectomy in locally advanced renal tumors · 2016-11-30 · Cytoreductive nephrectomy in locally advanced renal tumors Why is this important? When tumors invade adjacent

Cytoreductive nephrectomy in locally advanced renal tumors

E. Jason Abel, MD, FACS

Associate Professor

Department of Urology

No disclosures

Cytoreductive nephrectomy in locally advanced renal tumors

Locally advanced renal tumors

Lymph node invasion

Tumors invading adjacent structures

Tumors invading major veins (thrombus)

Cytoreductive nephrectomy in locally advanced renal tumors

Why is this important?When tumors invade adjacent organs or major veins,

surgery becomes more complex

Increased risk for perioperative morbidity or death

Recovery more likely to be longer and systemic therapy delayed

Can we identify patients who are likely to benefit from cytoreductive surgery?

Adjacent organs/structures at risk

Adrenal gland

Posterior abdominal wall

Paraspinous muscles

Diaphragm

Liver

Spleen

Stomach

Duodenum

Pancreas

Colon/Mesentery

RCC invasion of adjacent organs is rare

T4 RCC

Less than 5 % of patients

Metastatic disease is common

RCC more likely to “compress” than invade

Multiple series demonstrate very poor

survival with pathologic T4 RCC

pT4 nephrectomy -Karellas et al, 2009

26 patients

median OS 11.7 months (includes M0)

pT4 Cytoreductive nephrectomy -Kassouf et al, 2007

23 mRCC patients

median OS 6.8 months

pT4 Cytoreductive nephrectomy -Takagi et al, 2014

14 mRCC patients

Median OS 4.5 months

Survival following CN for pT4 is very poor

Borregales et al, 2016

• M1 median CSS 8 months

• M0 median CSS 37 months

Can we predict adjacent organ invasion

preoperatively?

Margulis et al., 2007

30 patients with clinical T4NxM0 prompting adjacent organ resection

18 patients (60%) downstaged on final pathology

Very difficult to accurately predict pathologic T4 disease by preoperative or intraoperative findings

Should patients with clinical T4M1 RCC be offered pre-surgical targeted therapy?

Rini et al, J Urol 2012

30 patients – unresectable tumors

Median decrease in primary tumor ~ 1.2cm

45% of patients treated with nephrectomy

In patients with metastatic RCC and clinical T4 tumors, neoadjuvant therapy may allow selection of patients with favorable response to therapy

RCC with tumor thrombus

~10% of RCC tumors produce venous thrombus

Surgery for thrombus is more complex and risk of major complications/mortality is increased

Few studies evaluate CN in patients with thrombus

Majority of prior studies over long time period, include both met and non-met patients, single center analyses

What are the Risks?

Nephrectomy with thrombectomy

N=747, multi-institutional, 2000-2011

Includes non-metastatic and metastatic, all levels

Mortality ~ 5% in first 90days -Abel et al, J Urol 2013

For patients with IVC thrombus above hepatic veins Surgery may include cardiac bypass or hepatic ischemia

N=162, includes non-metastatic and metastatic

Mortality~10% in first 90days

34% major complications -Abel et al, Eur Urol 2014

Risks: Surgery for RCC with thrombus

Nephrectomy with thrombectomy

N=747, multi-institutional, 2000-2011

Includes non-metastatic and metastatic, all levels

Mortality ~ 5% in first 90days -Abel et al, J Urol 2013

For patients with IVC thrombus above hepatic veins Surgery may include cardiac bypass or hepatic ischemia

N=162, includes non-metastatic and metastatic

Mortality~10% in first 90days

34% major complications -Abel et al, Eur Urol 2014

NON- METASTATIC VS. METASTATIC

The rationale for surgery for complex surgery in non-metastatic RCC is simple ~50% patients are cured

Metastatic patients- are the risks of surgery justified for those patients with very limited life expectancies?

Cytoreductive nephrectomy in patients with tumor thrombus

Westesson et al , 2014

Cytoreductive nephrectomy in patients with tumor thrombus

Westesson et al , 2014

Cytoreductive nephrectomy in patients with tumor thrombus

Westesson et al , 2014

• 1990-2012, Single center

• 30 day mortality was 6.6%

• Median OS 12 months

• 26 patients with data for MSKCC risk grouping (4F,19I,3P)

• 33/76 patients received targeted agents

Cytoreductive nephrectomy

Cytoreductive surgery improves survival for many patients To benefit, patients must live longer than systemic therapy

alone

~9-10 months Culp et al. 2010, Richey et al. 2011

Not in poor risk patients by IMDC model Choueiri et al 2011, Heng et al. 2014

Cytoreductive Nephrectomy with Venous Tumor Thrombus: Study design

OBJECTIVE: To identify those mRCC patients with thrombus treated surgically who have very poor OS.

Consecutive mRCC patients with tumor thrombus treated with upfront CN from 2000-2015 at 5 centers University of Wisconsin, MDA Cancer Center, UT Southwestern Medical Center,

Moffitt Cancer Center, Emory hospital

Excluded patients who received neoadjuvant therapy

Evaluate the association of overall survival

Thrombus Level (Neves)

Risk models calculated preoperatively

MSKCC, IMDC, MDACC (Cancer 2010)

Abel et al, submitted

Patients: Thrombus Level

Overall n=427

n=130 (30%)

n=53 (12%)

n=145 (34%)

n=59 (14%)

n=40 (9%)

Abel et al, submitted

PATTERN OF MORTALITY WITHIN FIRST YEAR

• 3% DIED WITHIN 30 DAYS FOLLOWING SURGERY• vs 1-2% all cytoreductive nephrectomies- Jackson et al 2015

• 36% OF PATIENTS DIED WITHIN FIRST YEAR FOLLOWING SURGERY

11.9%

9.6%

7.8%

6.1%

DAYS FOLLOWING NEPHRECTOMY

PE

RC

EN

T M

OR

TA

LIT

Y

ASCO GU 2016

Survival according to thrombus level

• Overall median OS (IQR) was 18.9 (6.8-43.9) months.

Abel et al, submitted

Cytoreductive nephrectomy with IVC thrombus above hepatic veins

Abel et al, submitted

OS following surgery by thrombus level

RV only

Median OS 21.7 months (IQR 7.7-42.8).

IVC below diaphragm

Median OS 19.5 months (IQR 7.2-49.2)

IVC thrombus above diaphragm

Median OS 9.2 months (IQR 4.2-30.8)

Abel et al, submitted

Risk models for metastatic RCC

Developed to stratify patients into groups -OS from systemic treatment to death

MSKCC criteria

IMDC criteria

Developed to evaluate whether patients benefit from cytoreductive nephrectomy

MDACC model

Abel et al, submitted

MSKCC risk model

Survival by MSKCC Risk Group

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Pro

po

rtio

n s

urv

ivin

g

0 risk factors (median OS 30 months)

1 or 2 risk factors (median OS 14 months)

3, 4 or 5 risk factors (median OS 5 months)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Years following systemic therapy

Risk factors:

Time from nephrectomy-treatment < 1 year

KPS <80

Low hemoglobin

High corrected calcium

High LDH

Tick mark (I) indicates last follow-up

Motzer RJ, et al. J Clin Oncol 2002;17:2530–2540

MSKCC criteria predict poor outcomes

POOR

INTERMEDIATE

FAVORABLE

78% of patients

complete data

Abel et al, submitted

IMDC risk stratification model

Lancet Oncology, 2013

1028 consecutive patients from 13 centers

Using database consortium model* 17% favorable risk, median OS 43 months

52% intermediate risk, median OS 22.5 months

31% poor risk, median OS 7.8 months

*adapted from table 1

IMDC Criteria predictive of OS

POORINTERMEDIATE

FAVORABLE

90% patients

complete data

Abel et al, submitted

Median OS for thrombus below diaphragm is similar to large cytoreductive nephrectomy series

Favorable risk

Intermediate risk

Poor risk

43 months

22.5 months

7.8 months

Heng et al, Lancet Oncology 2013

65.5 months

24.5 months

13.4 months

Current series

Abel et al, submitted

MDACC Model

MDACC System Risk Stratification For Cytoreductive Nephrectomy

• 566 pts CN vs. 110 pts systemic therapy only

• Identified pre-operative variables that differed between groups based on survival

• Serum albumin < lower limit of normal

• Serum LDH > upper limit of normal

• Liver metastasis

• Symptoms due to metastatic disease

• Retroperitoneal lymph node involvement

• Supra-diaphragmatic lymph node involvement

• Clinical T stage 3 or 4

Culp, Tannir, Abel et al., Cancer, 2010

Pre-operative Assessment

Culp, Tannir, Abel et al., Cancer, 2010

Systemic therapy

without CN

median OS 8.5 mo

MDACC model predicts poor survival

FAVORABLE

UNFAVORABLE

88% of patients

complete data

Unfavorable group: median OS 9.2 months (IQR 4.8-42.8)

Abel et al, submitted

Can we identify patients with Early mortality (<270 days) following CN with thrombectomy

Multiple studies demonstrate OS ~9 months with systemic therapy alone Culp et al. 2010, Richey et al. 2011 Choueiri et al 2011, Heng et al. 2014

Univariable and multivariable models to evaluate associations with early mortality

Individual variables from three prognostic systems

Common variables including thrombus level

Abel et al, submitted

Independent predictors of early mortalityCharacteristic Hazard Ratio [95% CI] p-value

Systemic therapy < 1 year 1.65[0.8-3.2] 0.15

Serum hemoglobin <LLN 1.24[0.9-1.8] 0.12

Corrected serum calcium >10 mm/dL 1.20[0.8-1.7] 0.32

Serum lactate dehydrogenase > ULN 1.60[1.2-2.1] 0.005

Absolute platelet count >ULN 0.93[0.7-1.4] 0.92

Serum albumin <LLN 1.38[1.0-2.0] 0.07

Retroperitoneal lymphadenopathy 1.13[0.8-1.5] 0.42

Thrombus level

0 ref

1 0.92[0.6-1.5] 0.73

2 0.84[0.6-1.2] 0.35

3 1.00[0.6-1.6] 1.0

4 1.95[1.1-3.4] 0.02

Systemic symptoms present 1.57[1.2-2.1] 0.003

Independent predictors of early mortalityCharacteristic Hazard Ratio [95% CI] p-value

Systemic therapy < 1 year 1.65[0.8-3.2] 0.15

Serum hemoglobin <LLN 1.24[0.9-1.8] 0.12

Corrected serum calcium >10 mm/dL 1.20[0.8-1.7] 0.32

Serum lactate dehydrogenase > ULN 1.60[1.2-2.1] 0.005

Absolute platelet count >ULN 0.93[0.7-1.4] 0.92

Serum albumin <LLN 1.38[1.0-2.0] 0.07

Retroperitoneal lymphadenopathy 1.13[0.8-1.5] 0.42

Thrombus level

0 ref

1 0.92[0.6-1.5] 0.73

2 0.84[0.6-1.2] 0.35

3 1.00[0.6-1.6] 1.0

4 1.95[1.1-3.4] 0.02

Systemic symptoms present 1.57[1.2-2.1] 0.003

RCC patients with IVC thrombus treated with targeted therapies

Cost et al, Eur Urol 2011, 25 patients

Bigot et al, World J Urol 2013, 14 patients

few (<10%) where therapy changed surgical approach

Most patients had stable disease in thrombus

Must consider each patient individually

Palliative benefit of surgery (or systemic therapy)?

Conclusions

• OS for patients with IVC thrombus below diaphragm

similar to cytoreductive nephrectomy without

thrombus

• OS stratified by IMDC similar or better than expected

for non-thrombus patients

• Level 4 IVC thrombus, systemic symptoms, or poor

risk by predictive systems are high risk for early

mortality and upfront systemic therapy clinical trials

should be considered

THANK YOU