Latest On IVC Tumor Thrombus Sarah P. Psutka MD Fellow in Urologic Oncology Mayo Clinic, Rochester, MN

Thirteenth International Kidney Cancer Symposium October 24-25, 2014 Chicago, Illinois, USA

Classification & Prognostication

2012 ISUP Conference Recommendations: Handling and Staging of Renal Cell Carcinoma 1. The thrombus length should not be included in the measurement of the main tumor mass 2. Positive vein margin: only when there is adherent tumor visible at the actual margin, confirmed microscopically

3. Analysis of separate “caval thrombus” specimen: •

Recommendation: sample 2 or more sections to assess for adherent caval wall tissue Trpkov K et al., Am J Surg Pathol 2013: 37 (10): 1505

Impact of Vascular Margin Status (1) • N = 256 N0M0 (1993 – 2009) • Median follow-up 36.7 months • Excluded patients with grossly incomplete resection

• Positive vascular margin (def): • Microscopic tumor present at the margin of resection, invading the vein wall • Prevalence = 47/256 (18.4%)

Abel et al., BJU Int 2014, doi:10.1111/bju.12515

Impact of Vascular Margin Status (2) Local Recurrence-Free Survival

Metastasis-Free Metastasis-FreeSurvival Survival

• Multivariable analysis: • Positive vascular margins predictive of Local Recurrence: HR 2.96 (95% CI: 1 – 8.7, p=0.04) • Not predictive of systemic recurrence: HR 1.32, (95% CI: 0.8 – 2.5, p=0.25) Abel et al., BJU Int 2014, doi:10.1111/bju.12515

Impact of Vascular Margin Status (3) • N = 304 (2000 – 2009)

• Median follow-up: 76.8 months

• Positive vascular margins associated with more aggressive pathologic features 100

80

Local Recurrence-Free Survival Negative

60

100

40

20

20

Negative

60

Negative

40

Positive

20

Positive

P = 0.026 1

P < 0.001

P = 0.004 2

3

4

5

0

Cancer-Specific Survival

80

60

Positive

0

100

80

40

0

Distant Metastasis-Free Survival

0

1

2

3

4

5

0

0

1

2

3

4

5

• Positive vascular margins associated with increased Cancer-Specific Mortality (HR 1.49, p = 0.05) after adjusting for presence of fat invasion, tumor thrombus level > 2, pN1, M1, coagulative tumor necrosis, sarcomatoid differentiation Psutka SP et al., NCS, 2014

Impact of Histologic Subtype on Cancer-Specific Survival (1) Cancer-Specific Survival (%) Whole Population: n = 807

ccRCC Non-ccRCC

P = 0.03

• Patients with non-ccRCC: presented with larger tumor size, higher nuclear grade, higher frequency of sarcomatoid differentiation Kaushik D et al., Urology 2013; 82; 136

Impact of Histologic Subtype on Cancer-Specific Survival (1) Cancer-Specific Survival (%) Matched Cohort N = 56 non-ccRCC: 112 ccRCC

Cancer-Specific Survival (%) Whole Population: n = 807

ccRCC ccRCC Non-ccRCC Non-ccRCC

P = 0.03

P = 0.95

• Multivariable analysis: • Noncc-RCC: HR 1.2 (p = 0.43) • Non-clear-cell histology is not independently associated with inferior cancer-specific survival Kaushik D et al., Urology 2013; 82: 136

Impact of Histologic Subtype on Cancer-Specific Survival (2) Prevalence

• Multicenter cohort study (n=1774) • Predictors of Cancer-Specific Mortality • Tumor thrombus level II – IV (HR 1.8 - 2.3, p < 0.01) • N0 (HR 0.45, p < 0.001) • M0 (HR 0.42, p < 0.001) • Fat Invasion (HR 1.49, p < 0.01) • Histology (vs. ccRCC) • Papillary RCC (HR 1.62, p < 0.05)

• Conclusion: papillary histology associated with increased cancerspecific mortality

Overall (n = 1774)

5-Year CSS 63.4%

Clear Cell RCC (n = 1594)

89.9%

54.8%

Papillary RCC (n = 151)

8.5%

36.8%

Chromophobe RCC (n = 29)

1.6%

59.5%

Cancer-Specific Survival

Chromophobe Clear Cell Papillary

Tilki D et al., Eur Urol 2014; 66: 577

Impact of Tumor Thrombus Level (1): Thrombus height • Debate regarding the prognostic value of tumor thrombus level • Implications for tumor staging (pT3a vs. pT3b vs. pT3c) Cancer-Specific Survival, by Tumor Thrombus Level Mayo Clinic, N = 845 1971 - 2009

p I

Cancer-Specific Survival, by Tumor Thrombus Level III vs. > IV

Mayo Clinic, N = 845 1971 - 2009

Multicenter Cohort, N = 162 2000 - 2012

Level III

Level IV P = 0.63 p 1

• Preoperative systemic symptoms • Level 4 tumor thrombus

• 90 day mortality in 17/162 (10.5%) • Associated with

• ECOG Performance Status • Low Serum Albumin

Normal Serum Albumin Serum Albumin < LLN

• Complications and perioperative mortality stable across centers and over time • No association with use of cardiopulmonary bypass or deep hypothermic circulatory arrest Abel EJ et al., Eur Urology 2014; 66 :584 Haddad AQ et al., J Urology 2014; 192: 1050

Proposed Preoperative Risk Stratification: Level III – IV Tumor Thrombi RCC with IVC Thrombus Above the Hepatic Veins

NO RISK FACTORS

RISK STRATIFICATION CONSIDERING • ECOG PS > 1 • Serum Albumin below < LLN • Systemic Symptoms • IVC Thrombus above the diaphragm

RISK FACTORS PRESENT

Metastatic Disease? NO

YES

SURGERY AT EXPERIENCED CENTER

Evaluate for Potential Benefit from Cytoreductive Nephrectomy considering Risks of Deferring Surgery GOOD RISK

POOR RISK

(1) Discussion re: increased risk of surgery (2) Evaluation to optimize preoperative care ALTERNATIVE Medical Oncology Consultation Neoadjuvant Clinical Trial Abel EJ et al., Eur Urology 2014; 66: 584

Proposed Preoperative Risk Stratification: Level III – IV Tumor Thrombi RCC with IVC Thrombus Above the Hepatic Veins

NO RISK FACTORS

RISK STRATIFICATION CONSIDERING • ECOG PS > 1 • Serum Albumin below < LLN • Systemic Symptoms • IVC Thrombus above the diaphragm

RISK FACTORS PRESENT

Metastatic Disease? NO

YES

SURGERY AT EXPERIENCED CENTER

Evaluate for Potential Benefit from Cytoreductive Nephrectomy considering Risks of Deferring Surgery GOOD RISK

POOR RISK

(1) Discussion re: increased risk of surgery (2) Evaluation to optimize preoperative care ALTERNATIVE Medical Oncology Consultation Neoadjuvant Clinical Trial Abel EJ et al., Eur Urology 2014; 66: 584

What is the role of Neoadjuvant Targeted Therapy in the management of RCC with IVC Tumor Thrombus? • No level one evidence to-date to guide integration of targeted medical therapy into the treatment of RCC with venous tumor thrombus • Multiple case reports/case series with variable outcomes: Cost et al., 2011 (n=25)

Kwon et al., 2014 (n = 22)

Bigot et al., 2014 (n = 14)

Decrease in Tumor Thrombus

44%

4.6%

43%

Stable Disease

28%

90.8%

43%

Thrombus Progression

28%

4.6%

14%

• Neoadjuvant systemic therapy in patients with RCC and VTT remains experimental • Unclear role in altering surgical approach/outcomes • Recommend enrollment in clinical trials

Cost et al., Eur Urol 2014; 59: 912 Sassa N et al., Jpn J Clin Oncol 2014; 44(4): 370 Bigot P et al., World J Urol 2014; 32 (1): 109

Preoperative Planning: Prediction of Requirement for Extensive Vascular Resection during IVC Tumor Thrombectomy • Predicting the need for extensive IVC resection and complex vascular reconstruction (N = 172, 2000 – 2010) • En bloc circumferential resection, Patch graft, Tube-interposition graft (22%) Optimal Radiographic Features to Predict need for IVC-R Odds

P-value

Predicted Probability of IVC-R

Ratio Right Sided Tumor

2.81

0.02

27%

Maximal AP diameter of the IVC > 34 mm

5.54

< 0.001

42%

AP diameter of the IVC at the Renal Vein Ostium (RVo) > 24 mm 8.37

15.5 mm

5.5

0.002

31%

Coronal diameter of the renal vein at the RVo > 19 mm

3.86

0.009

31%

Complete occlusion of the IVC at the RVo

8.71

5 mm

6.91