should the primary be treated in patients with metastatic disease? upper tract … ·...
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Should the primary be treated in patients with metastatic disease? Upper Tract Urothelial Cancer
4th FOIU July 3-5, 2018
Seth P. Lerner, MD, FACS Professor, Scott Department of Urology
Beth and Dave Swalm Chair in Urologic Oncology Baylor College of Medicine
Financial and Other Disclosures Off-label use of drugs, devices, or other agents: None,
Data from IRB-approved human research is presented
2
I have the following financial interests or
relationships to disclose: Disclosure code
FKD S
Roche/Genentech S
JBL S
Viventia S
BioCancell, Nucleix, QED, UroGen C
UroGen, Vaxiion C
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
• 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
• Premise: LND
utilization is low
• 27% in recent
Canadian study
• 9 studies
• All retrospective
• LE:3
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
pT2
pT3
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
pT4
Low Grade
High Grade
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
Margulis et al. Cancer 2009
Pathological tumor stage and grade most important prognostic factors in UTUC after RNU
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 loco-
regional disease
• There is no high level evidence to support any
particular approach