Lymphadenectomy in RCC: Yes, No, Clinical Trial?

Transcription

1 Lymphadenectomy in RCC: Yes, No, Clinical Trial? Viraj Master MD PhD FACS Professor Associate Chair for Clinical Affairs and Quality Director of Clinical Research Unit Department of Urology Emory University

2 None Disclosures

3 Outline Smaller volume (localized) Disease Larger volume (Locally Advanced) Disease Metastatic Disease NO defined templates are agreed upon

4 Take home messages All cancer surgeons think about this issue, for every single solid organ tumor Lymphadenectomy clearly has value in some disease states (penile, testis, melanoma, others) NO perfect answer whether to do a lymph node dissection Localized disease (smaller tumors) (ct1): not worth it Advanced disease (larger tumors): may make sense Metastatic disease: +/-

5 Importance Lymph node metastasis leads to a dramatic decrease in 5-year survival in RCC Positive lymph nodes are an independent prognostic factor for survival, even in the era of TKI therapy (IMDC data, Kroger et al, Eur Urol 2015) Therefore, knowing whether the patient has positive lymph nodes seems relevant for appropriate disease prognostication

6 Pros Provides valuable staging Large lymph nodes may actually not be cancerous Diagnose other diseases (e.g. lymphoma) May provide OS benefit Takes longer Cons More morbid May preclude minimally invasive surgical approaches No OS benefit

7 yo ECOG 0 Abdominal fullness, early satiety, leg swelling 8 cm renal tumor and multiple retroperitoneal nodes covering her IVC Right Nephrectomy + RPLND Papillary RCC + Multiple LN+ with extranodal extension Case

8 yo ECOG 0 Abdominal fullness, leg swelling 8 cm renal tumor and multiple retroperitoneal nodes Right Nephrectomy + RPLND Papillary RCC + Multiple LN+ with extranodal extension Case

9 yo ECOG 0 Abdominal fullness, leg swelling 8 cm renal tumor and multiple retroperitoneal nodes Right Nephrectomy + RPLND Papillary RCC + Multiple LN+ with extranodal extension Was this the right thing to do? Case

10 Randomized Trial Data Only 1 randomized study EORTC trial intent-to-treat analysis: to detect a benefit of 10% in the 5-yr survival rate for patients who underwent LN dissection 732 patients randomized 70% of patients low stage 4% had positive nodes 84 pts had enlarged LN, but only 17% of those nodes were actually positive for RCC Criticized However, even a lower difference in survival rate may be clinically significant and could have been shown in a study with a greater number of patients NO benefit on OS for node dissection Blom JH et al, Eur Urol 2009

11 Durable Disease-free Survival Achieved with Surgical Resection in patients with pathologically positive nodes T any N+M0 pts 68/2521 patients 22% disease free f/u 44 mo In patients who recurred, most did so quickly, widely DSS 5 yr survival 39% Predictors: >one node (HR=3.79), papillary histology (0.29), sarcomatoid features (3.39), PS >1 (3.74) Delacroix SE, J Urol 2011 DSS

12 Extent of LND affects survival in specific subcategories of RCC 1983 pts, retrospective, f/u 83 months 6.1% +ve lymph nodes Removal of each additional lymph node increased CSS 3-19% Identical findings for median PFS Lymph Node HR pt2a-b pnxm ( ) pt3c-pt4p NxMx cm1 only 0.89 ( ) pt2a-b pnxm ( ) pt3c-t4 pnxm ( ) Capitanio U BJUI 2014 Dissection p value <

13 SEER study: Yes, removing nodes helps , 9538 pts nonmetastastic RCC Med f/u 3.5 yrs No effect on DSS in patients with negative LN s, p=0.93 Pts with positive nodes had increased DSS with extensive LND (HR 0.8 per 10 LN s removed, p=0.04) Whitson JW, J Urol 2011 Increase of 10 LNs in a patient with 1 positive LN was associated with 10% absolute increase in DSS at 5 years p=0.004 Slide courtesy of J. Whitson

14 SEER study: No, removing nodes not associated with any survival advantage , 10,596 pts Multivariable Cox Regression analysis for CSM Performed 2 different additional analyses (censoring and missing indicator) HR for Node Positive Patients 0.83 ( ) p=0.1 Sun M, BJU I 2013

15 Depends on how you do the stats 2 years more data Grade not missing at random (high stages, large tumors missing grade) Inspection of the estimates of the impact of lymph node dissection (the hazard ratio) appear identical CI s show that the benefit to extent of lymphadenectomy may be as great as a 34% reduction in cancer-related death CI s provide extremely valuable information, particularly in the setting of marginally significant/non-significant p- values How to handle missing covariates Whitson JW, BJUI 2013

16 SEER Data Cox proportional hazards model extended (>9 nodes) vs. non-extended Covariate CSS OS HR (95% CI) HR (95% CI) Extended (vs. not extended) 0.88 ( )* 0.85 ( )** Covariates: Extended, vs non-extended, Gender, Age, Stage, Grade, Histology, Marital Status, Race/Ethnicity, Year of Surgery, malignant vs. non-malignant nodes *p=0.110; **p=0.039 Filson C, Laganosksy D, Patil D, Master V, unpublished data, 2016 AUA submission

17 LND in mrcc patients data Mayo Clinic, retrospective 305 pt, , 188 pt underwent LND Median f/u 8 years Propensity score matching LND not associated with improved survival using propensity score matching Supplemental tables very interesting: 6x more patients with papillary RCC had pn1 nodes cn1 does 4x more likely to have pn1 nodes pn1 patients 2.5x more likely to have 3 sites of metastatic disease Gershman B, J Urol 2016, available online

18 Case update 5 years later No disease on MRI until 2014 Single lung met, progressed thru multiple rounds of systemic therapy No abdominal recurrence

19 Outcome after cytoreductive nephrectomy for mrcc predicted by fractional % of tumor volume (FPTV) removed Retrospective, small numbers, single institution median DSS times 11.6 mos >90% FPTV 2.9 mos <90% FPTV removed (P = 0.002) HR for death 0.29 for patients with >90% FPTV removed (p=0.02), multivariable analysis Pierorazio P, BJUI 2007

20 Take home messages Localized disease (smaller tumors) (ct1): not worth it Advanced disease (larger tumors): may make sense Metastatic disease: +/- In the absence of a clinical trial assessing the role of LND in patients at high risk for lymph node metastases, it may be reasonable to use available retrospective data to guide clinical decision making We do need a clinical trial, or at least, additional wellorganized multicenter registry data (as a first step)

21 Thank you!

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24 CSS

25 OS

26 Meta-analysis of Complete RCC Metastases Removal Zaid HB, J Urol 2016

27 2014 Lung mets, progressed thru multiple rounds of systemic therapy No abdominal recurrence Cases

28 Outline Localized Disease Locally Advanced Disease Metastatic Disease La