Urologic Cancer: Larry Weisenthal 1 Oct 2015 Ain’t going

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Urologic Cancer: Larry Weisenthal
1 Oct 2015
[email protected]
Ain’t going
here;
readily
available
for
reference
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Bladder
74,000 new cases
16,000 deaths
Mortality = 22%
Two flavors
No muscle invasion
Muscle invasion
Non-muscle invasion
TURBT + intravesical chemotherapy
Surveillance or maintenance intravesical or
maintenance BCG
Intravesical therapy is given by urologists;
it modestly reduces recurrence rates
Muscle invasion
Neoadjuvant platinum-based + radical
cystectomy ... or
Chemoradiotherapy
Muscle invasive
(continued)
50% recurrence
Neoadjuvant, platinum-based chemotherapy
reduces recurrences from 50% to 45%
Recurrent/Metastatic
Bladder
MVAC (MTX/VBL/Dox/CP) or Gem/Cis
Median overall survival about 12 months
Transitional Ca Renal
Pelvis and Ureter
7% of all kidney tumors
90% curable if superficial/localized. Role
for neoadj/adj chemotherapy not
established.
10% curable if deeply invasive
0% curable with penetration of urothelial
wall
Metastatic Renal Pelvis/
Ureter
Generally treated similarly to bladder, i.e.
MVAC or Gem/Cis
Metastatic bladder
immunotherapy
Atezolizumab (Roche PD-L1 checkpoint
inhibitor:
Response rate 15/311 (5%). With highest level of
PD-L1 expression, response rate was 27%.
This and similar agents work much better in lung,
melanoma, renal, etc.
Kidney Cancer
62,000 cases
14,000 deaths
23% mortality
Kidney Ca histopath
Clear Cell v Granular Cell, Prognosis not
all that different, but treatment of
advanced disease is somewhat different
Kidney Ca, Rx, Stg 1
7 cm or less, confined to kidney, N0
Partial, simply or radical nephrectomy
Cures > 50%
Kidney Ca, Stg II
> 7 cm tumor; confined to kidney, N0
Radical nephrectomy, -/+ RT
Kidney Ca, Stg III
T1,T2 N1 or T3 N0,N1 (where T3 -> renal vein
+/- vena cava extension or perinephric tissue
but confined within Gerota’s fascia)
Kidney Ca, Stg III Rx
Radical resection -/+ RT
Kidney Ca, Stg IV Rx
(cytokines)
Cytoreductive nephrectomy + Cytokine
therapy
Interferon alpha: 15% Resp rate; 2.5 mo
median survival advantage
High dose IL-2: 5% durable CR
Kidney Ca Rx:
“Targeted” 1. m-TOR
Everolimus -- PFS 4 months vs 2 months
placebo; No difference overall survival (clear
cells only; prior sunitinib or/and sorafenib)
Temsirolimus -- Hazard ratio for overall
survival 0.73 vs interferon alpha. Only agent
which has shown improved O.S. vs interferon
alpha in renal cell. (previously untreated; clear
and non-clear cells)
Kidney Ca Rx: “Targeted”
2. anti-VEGF (clear cell only)
Sunitinib: HR for death vs IFN- = 0.82, P = 0.051, 26
vs 22 months (compare to HR 0.73 for temsirolimus vs
IFN-). Approved on basis of PFS advantage vs IFN-).
Bevacizumab: Bev + IFN- better PFS than IFN-
alone. No improved OS.
Axitinib: Improved 2nd line PFS c.f. sorafenib
Pazopanib: Improved PFS c.f. placebo & non-inferior
c.f. sunitinib, /w better tolerance in 70% of pts.
Sorafenib: Improved PFS c.f. placebo; No improved
PFS c.f. IFN-
Kidney: Immune Checkpoint Inhibition
(Pts. previously Rxd /w angio inhibitor)
> 1% PD-L1
< 1% PD-L1
Prostate Cancer
221,000 New cases
27,500 Deaths
12% Mortality
Prostate Ca Grading
Prostate Ca Staging
Text
PSA
Screening (long discussion to follow)
Follow-up post surgery: 15% have PSA
“recurrence” s/p R.P., 35% of which have clinical
recurrence. 8 years avg between PSA
“recurrence” and clinical recurrence. Median time
to death 13 years after PSA “recurrence.”
Post-RT: As /w surgery, variable implications of
rising PSA level.
Post-hormonal Rx: Not helpful for monitoring
response, unless it falls to undetectable level.
PSA Screening
Screen 1,500 men -- Russian roulette chance
of doing multiple transrectal needle biopsies
Do transrectal needle biopsies -- Russian
roulette chance of discovering “actionable”
prostate cancer
Do “actionable” prostate cancer treatment -cure one additional patient of the 1,500
original men beyond those who would have
been cured absent PSA screening, while
producing horrendous unnecessary morbidity.
Prostate cancer comes in two “flavors,”
in the context of PSA screening,
generally speaking (explains why PSA
screening doesn’t work)
The “live with it” flavor: Don’t require
prostatic extirpation
The “die of it” flavor: Aren’t helped by
prostatic extirpation (i.e. micrometastases
already present at the time of the earliest
detectable elevation of PSA)
Therapeutic strategies
after Prostate Ca DX
Immediate definitive prostate extirpation
with curative intent
Watchful waiting
Active surveillance
Active surveillance
Regular check-up /w digital rectal exams
PSA monitoring
Transrectal ultrasound
Transrectal needle biopsies
Prosate Ca outcomes in pts diagnosed without
PSA screening
Watchful waiting: Gleason’s 2-7/Stg 1-2 ->
20 year mean f/u
90% die, but only 15% of prostate Ca.
Non-randomized observation Gleason’s 2-7,
Stg 1-2 -> 3.6% Ca deaths at 10 yrs for
watchful waiting/active surveillance; 2.4%
for RP; 3.3% for RT. But surveillance group
was objectively less “healthy” than RP group.
Extirpative therapy
Similar outcomes; differing toxicities
Radical prostatectomy
External beam RT (standard vs 3D conformal)
Brachytherapy/Interstitial implants (I125,
palladium, iridium)
Proton beam
Adjuvant/Neoadjuvant androgen deprivation therapy
In locally advanced (palpable) tumors, long term antiandrogen therapy (LH-RH agonist or orchiectomy)
improves overall survival as an adjuvant to EBRT (HR
0.63 on meta-analysis).
In locally advanced patient groups, adjuvant or
neoadjuvant (early) androgen deprivation improves OS,
in patients treated with RP, EBRT, or watchful waiting.
Take home message: consider early androgen
deprivation therapy in patients with locally advanced
tumors.
Note that the diagnosis of locally advanced tumors
does not require PSA screening.
Stage IV Prostate
Orchiectomy
LH-RH Agonists: histrelin, goserelin, leuprolide,
triptorelin (may “flare”)
LHRH antagonist (doesn’t “flare”): degarelix
Note: The end result of agonist or antagonist treatment
is the same—reduced testosterone production.
Antiandrogens
Antiandrogens: Used in combination with LHRH agonists to
prevent flare: bicalutamide, flutamide, nilutamide
Adrenal androgen blockers: aminoglutethimide, ketoconazole
Historical: Estrogens
Stage IV Prostate hormonal caveats
Early hormonal therapy in stage IV disease has
been beneficial in some studies, but not with
others, compared with deferred therapy. Watchful
waiting may be considered in individual cases, for
quality of life considerations.
Maximal androgen blockade (LH-RH agonist +
antiandrogen[s]) not clearly advantageous, but more
toxic
Advantage for continuous, rather than intermittent,
therapy remains unproven.
Bisphosphanates
(clodronate, zoledronic acid)
Survival advantage when combined with
hormonal therapy in patients with
documented bone mets.
No advantage in absence of bone mets
No advantage in hormone refractory disease
Hormone-refractory metastatic prostate cancer
Improved pain control but not survival or global QoL /w
mitoxantrone + prednisone vs prednisone alone
Improved OS (HR 0.8) for q. 3 wk docetaxel + prednisone
vs mitoxantrone + prednisone, but docetaxel arm also
received bolus high dose dexamethasone q 3 wk /w
docetaxel.
Improved OS (HR 0.8) for q. 3 wk estramustine + docetaxel
+ high dose dexamethasone vs mitoxantrone + prednisone.
q. 2 wk docetaxel appears better than q. 3 wk
After docetaxel failure, cabazitaxel + prednisone was
superior to mitoxantrone + prednisone (HR 0.7)
Very modest activity for other chemotherapy agents
Hormone refractory prostate: Immunotherapy
Active cellular immunotherapy: Sipuluecel-T
(autologous peripheral blood monocytes +
lymphocytes exposed in vitro to prostatic acid
phosphatase/GM-CSF fusion protein) -improved OS (HR 0.8), at cost of $100K per
month.
Immune checkpoint inhibitors have not to
date (to my knowledge) been reported to
produce notable results.
Hormone refractory prostate:
Radiopharmaceutical
Radium-223 (alpha emitter): selectively taken
up in areas of new bone formation (blastic
lesions)
Improved OS (HR 0.7) in hormone resistant
patients previously treated with, not eligible
for, or declining docetaxel.
Testicular Cancer
New cases 8,000
Deaths 400
5% mortality
Histologies
Seminoma
Non-seminoma (embryonal, teratoCa, yolk sac,
choriocarcinoma)
Testicular serum
markers
AFP: elevated in 50% of non-seminomas;
presence rules out seminoma
Beta-HCG: Elevated in 10% “localized”
seminoma and 50% of metastatic seminoma.
Elevated in 50% with non-seminomas.
LDH: Less specific; less useful
Testicular staging
Stage I: Testicle only
Stage II: Nodes positive
Stage III: Distant mets or positive nodes
plus greatly elevated serum markers
Seminoma prognosis
Good: No non-lung visceral mets; normal AFP
any beta-HCG, any LDH (90% of patients;
80% 5 yr PFS)
Intermediate: Presence of non-lung visceral
mets; normal AFP any beta-HCG, any LDH
(10% of patients; 70% 5 yr PFS)
Poor: None
Non-seminoma prognosis
Good: No non-lung visceral mets; Low
markers (60% of patients; 5 yr PFS 90%)
Intermediate: No non-lung visceral mets;
Intermediate markers (20% of patients; 5
year PFS 75%)
Poor: Mediastinal primary or non-lung
visceral mets or High markers (20% of
patients; 5 year PFS 40%)
Seminoma Rx
Stage I: radical orchiectomy + surveillance
CT scans. Overall recurrence is 20% at 10
years, but virtually all cured by RT or
chemotherapy. Alternative is primary
surgery + adjuvant RT or adjuvant
chemotherapy, with same excellent results.
Stage II (non-bulky): RT alone or
chemotherapy if RT contraindicated
Stage II (bulky): Chemotherapy alone
Stage III: Chemotherapy
Non-Seminoma Rx: Stg I
Alternative #1: radical orchiectomy +
surveillance CT scans. Overall recurrence is
30% at 10 years, but virtually all cured by
chemotherapy.
Alternative #2: orchiectomy +
retroperitoneal node dissection.
Alternative #3: orchiectomy + 1 or 2 courses
of BEP chemotherapy.
All 3 alternatives -> 99% cures.
Non-Seminoma Rx: Stg II
Scenario #1/Option #1: Radical orchiectomy
(R.O.) + retroperitoneal node dissection
(RPND). Normal markers post orchiectomy ->
surveillance with curative chemotherapy in
event of recurrence.
Scenario #1/Option #2: R.O. + RPND. Normal
markers post surgery -> 2 courses of
platinum based chemotherapy
Scenario #2: Abnormal markers post-surgery
-> BEP X 3 or EP X 4
Non-Seminoma Rx: Stg III
BEP X 3 for good risk
BEP X 4 for intermediate or poor
risk
Therapy of testicular cancer:
additional caveats
It’s a disease of young men and it’s largely
curable, therefore you don’t want to screw
up lives with overtreatment.
Long term problems: Contralateral 2nd
primaries (2%); Infertility; Leukemia; Renal
damage; Hearing loss; Restrictive lung
disease; solid tumors within radiation
portals; late cardiovascular events
Chemotherapy for Stage
III - IV Penile Cancer
Vincristine/Bleomycin/Methotrexate is a
mildly effective regimen; also Cisplatin/5FU
Other regimens are under clinical evaluation,
but it’s a rare disease in the USA (1,800 new
cases, most curable with surgery and/or RT;
only 300 deaths)
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