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