Should the primary be treated in patients with metastatic disease? Upper Tract Urothelial Cancer Seth P. Lerner, MD, FACS Professor, Scott Department of Urology Beth and Dave Swalm Chair in Urologic Oncology Baylor College of Medicine 4 th FOIU July 3-5, 2018
Financial and Other Disclosures Off-label use of drugs, devices, or other agents: None, Data from IRB-approved human research is presented I have the following financial interests or relationships to disclose: FKD Roche/Genentech JBL Viventia BioCancell, Nucleix, QED, UroGen UroGen, Vaxiion Disclosure code S S S S C C 2
Outline Upper urinary tract cancer unique biology Incidence and patterns of metastasis Efficacy of systemic chemotherapy Outcomes of post systemec treatment locoregional surgical consolidation NB: No high level evidence
Case 1 76 yo F Long history of recurrent multifocal TaLG bladder cancer MMC, BCG, BCG/Interferon, MMC/Gemcitabine Distal left ureter LG tumor Pyelonephritis - CTU Ureteroscopy LG Left NXU for large volume TaLGN0 cancer
Case 1 (cont) CT chest - bx proven TaG2 C1 Carbo/Taxol stopped after due to toxicity Atezo x 2 right nx bleeding URS HG (WHO G2); renal failure Right NXU - Path pt3n1 Atezo resumed after long break Progression in lung Gemcitabine single agent Alive 15 months after right NXU and anephric
Case 2 69 year old male CAD, CKD, hypertension, hyperlipidemia, Type II DM Primary left mid-ureteral urothelial carcinoma, T1 high grade with normal proximal ureter and renal pelvis No NAC due to renal insufficiency Subtotal left ureterectomy, left retroperitoneal lymphadenectomy (including para-aortic, common iliac and left pelvic lymph nodes), psoas hitch, left ileal ureter.
Case 2 (cont) Adjuvant chemotherapy: carboplatin/gemcitabine x 4 - Never recurred 2 years post op normal CT 3 yrs post op bladder T1Tis BCG 6+3 stopped due to toxicity NED x 4 years
RPLND for High Grade UTT Premise: LND utilization is low 27% in recent Canadian study 9 studies All retrospective LE:3 In patients T2 and clinically N0 13.3-40% have pathologic node metastasis LND improves CSS in patients with renal pelvis but not ureteral tumors
Upper Tract Genomics Upper tract cancers treated similar to bladder urothelial cancer But, genomic profiling suggests they are not twins Key findings FGFR3 (74%); 60% HG APOBEC predominant signature Novel: NPHS1 (11%);RHOB(11%) FGFR3-TACC3 fusion (1) Moss, et al Eur Urol 72:641, 2017
Comparison UTT and Bladder Cancer High grade urothelial cancer upper tract (n=52) and bladder (n=102) Somatic mutation and copy number variation 300 cancer gene panel Sfakianos, et al Eur Urol 68:970, 2015
pt0/ta/tis pt1 Low Grade pt2 High Grade pt3 pt4 Recurrence-Free Survival Probability + SE 3 Yr. 5 Yr. 10 Yr. pt0/ta/tis 94.4% + 1.5 91.8% + 1.9 90.0% + 2.3 pt1 88.6% + 2.1 88.0% + 2.2 81.0% + 3.5 pt2 75.3% + 2.9 71.4% + 3.2 70.1% + 3.4 pt3 51.5% + 2.6 48.0% + 2.7 41.6% + 3.3 pt4 15.7% + 5.3 4.7% + 4.1 4.7% + 4.1 Recurrence-Free Survival Probability + SE 3 Yr. 5 Yr. 10Yr. Low Grade 92% + 1.3 88% + 1.6 85% + 2 High Grade 60% + 1.8 57% + 1.9 52% + 3 Pathological tumor stage and grade most important prognostic factors in UTUC after RNU Margulis et al. Cancer 2009
Incidence of Metastasis 40-50% of patients have pta-t1 disease 50-60% of patients have pt2 25% these patients already have regional metastasis Incidence of regional disease increased by 2.6%, whereas the incidence of distant disease ( 8-9%) did not change over time ICUD UTT guidelines
Tumor Location and Distribution Frequency of renal pelvic tumors is about 1.5-2 times that of ureteral tumors (LE:3) Multifocal renal pelvis and ureter 7-24% (LE:2) No significant difference laterality (LE:3) Ureter tumors highest percentage in the distal ureter (LE:3) Prognosis (LE:3) Association of ureter location with worse outcomes may be stage specific T3 disease may have more favorable outcome in renal pelvis Bladder cancer risk may be higher with ureter tumors Multifocality and CIS associated with worse outcomes and higher bladder cancer risk should be mentioned in path reports ICUD UTT Guidelines Bassel Bachir and Wassim Kassouf
Progression and Metastasis Trends in stage 1973-2005 (SEER, NCDB) (LE:3) Increase in Ta,Tis; decrease in T1 Decrease in T2 T3 and metastases (8-9%) stable Surgical series 50% have muscle invasive disease (LE:2) Increase in high grade renal pelvis and ureter (LE:3) Sites of metastasis following surgical therapy (LE:3) Nodes (RP>mediastinal>pelvis), Lung, liver, bone Node metastasis follow expected lymphatic drainage Stage specific outcomes similar between bladder and UT but UT may have more aggressive pathology (LE:3) ICUD UTT Guidelines Bassel Bachir and Wassim Kassouf
EAU UTT Guidelines (2017) Radical nephroureterectomy There is no oncological benefit for RNU alone in patients with metastatic UTUC except for palliative considerations (LE: 3). Roupret, et al Eur Urol 73:111, 2018
Systemic Treatment ICUD Guidelines Cisplatin based chemotherapy MVAC Dose dense MVAC Gemcitabine/Cisplatin Many are unfit for cisplatin Performance status 2 CrCl < 60 ml/min Grade 2 hearing loss Grade 2 peripheral neuropathy NYHA class III heart failure Pham, et al World J Urol 35:367, 2017
Systemic Treatment ICUD Guidelines Treating primary prior to systemic treatment results in reduction of egfr Using egfr < 60 as a cutpoint N=388 49% cisplatin eligible prior to NXU 19% cisplatin eligible after NXU Pham, et al World J Urol 35:367, 2017 Kaag, et al Eur Urol 58:581, 2010
Surgical Consolidation 18 patients clinically N+ 1 Post chemotherapy Radical NXU + RPLND 5 year Ca specific survival 44% 28/59 cn+ post chemotherapy PLND or RPLND Improved PFS and OS 1 Youssef, et al BJUI 108:1286 2 Necchi, et al Clin GU Cancer13:80, 2015
RPLND and Visceral Metastasectomy N = 42 20 LND 12 Pulmonary 10 other 5-yr OS 31% Median OS 81 vs. 19 months for solitary vs. non-solitary A time from start of chemotherapy B time from metastasectomy C Time from resection solitary met Abe, et al J Urol 191:932, 2014
Percutaneous Surgery Options Usually reserved for low grade disease in solitary kidney Seeding is a risk
Conclusions Post chemotherapy surgical consolidation for patients with nodal and/or visceral metastatic disease may be beneficial in selected patients Nephron-sparing may make sense with ureter only tumors especially in solitary kidneys RPLND may provide long-term cancer control The decision to perform a nephroureterectomy may be based on palliation or residual high grade cancer with objective response in locoregional disease There is no high level evidence to support any particular approach