Narrow networks expand, raising concern

Transcription

®
UrologyTimes.com
The Leading News Source for Urologists
MARCH 2015
VOL. 43, NO. 3
HEALTH POLICY
Study supports use of targeted
Bx, but key questions remain
A
C
B
A. Axial T2-weighted image of targetable prostate lesion suspicious for prostate
cancer. B. Coronal T2-weighted image of the same targetable lesion located at
the base of the prostate. C. Functional diffusion weighted image demonstrating
increased suspicion of the lesion for prostate cancer. (Photos courtesy of M. Minhaj Siddiqui, MD)
UT CONTRIBUTING EDITOR
U
Lisette Hilton
UT CORRESPONDENT
National Report—Narrow provider networks are
gaining ground among insurers and could impact
patient access to urologists. While insurers tout
the approach to care as a way to control costs and
preserve quality, urologists and others question
whether the payment model is all about cost.
Jeffrey Kaufman, MD, a urologist in Orange
County, CA and president of the AUA’s Western
Section, says that while he doesn’t have personal
experience with narrow networks, he’s aware that
urologists are unhappy and concerned that these
networks will disrupt doctor-patient relationships.
“The second concern is that a narrow network is going to be based primarily on cost.
Please see NARROW NETWORKS, page 16
Inside
Cheryl Guttman Krader
se of targeted magnetic resonance (MR)/
ultrasound fusion biopsy (“targeted biopsy”) resulted in the diagnosis of significantly more high-risk prostate cancers
and significantly fewer low-risk cancers compared with a standardized systematic biopsy
technique, reported the authors of a new study
from the National Cancer Institute (NCI).
The findings were published in JAMA
(2015; 313:390-7).
Given the strengths of the study, which
include the size and prospective enrollment
of its population (1,003 men), the research
Narrow networks
expand, raising
concern
lends significant support to the idea that
targeted biopsy is a promising technique for
minimizing the problems of prostate cancer
overdetection and overtreatment, according
to lead author M. Minhaj Siddiqui, MD, and
Samir Taneja, MD, a proponent of targeted
biopsy.
However, speaking to Urology Times,
both urologists pointed out that the potential impact of the study must be considered
in light of its limitations. As a bottom line,
more work needs to be done to determine
Please see BIOPSY, page 36
MARCH 2015
Q
VOL. 43, NO. 3
Ethics
Self-referral, live surgery
raise challenges 24
Patrick H. MCKenna, MD
M E N ’S H E A LT H
14 How
urology and primary care
can work together
CODING
30 Answers to
your questions on
papillotomy billing, biopsy codes
L E G I S L AT I O N
41 Congress,
White House pressing
for SGR repeal
Urethroplasty on
‘Y’ Tube: Watch three reconstructive urologists illustrate the
nuances of managing urethral strictures. UROLOGYTIMES.COM/TAG/YTUBE
NEW
INDICATION
XTANDI (enzalutamide) capsules is indicated for the treatment of
patients with metastatic castration-resistant prostate cancer (CRPC).
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Important Safety Information
Contraindications XTANDI (enzalutamide) capsules can cause
fetal harm when administered to a pregnant woman based on
its mechanism of action and findings in animals. XTANDI is not
indicated for use in women. XTANDI is contraindicated in women
who are or may become pregnant.
Warnings and PrecautionsIn Study 1, conducted in patients
with metastatic castration-resistant prostate cancer (CRPC) who
previously received docetaxel, seizure occurred in 0.9% of patients
who were treated with XTANDI and 0% treated with placebo. In
Study 2, conducted in patients with chemotherapy-naïve metastatic
CRPC, seizure occurred in 0.1% of patients who were treated with
XTANDI and 0.1% treated with placebo. Patients experiencing a
seizure were permanently discontinued from therapy and all seizure
events resolved. There is no clinical trial experience re-administering
XTANDI to patients who experienced a seizure, and limited clinical
trial experience in patients with predisposing factors for seizure.
Study 1 excluded the use of concomitant medications that may
lower threshold, whereas Study 2 permitted the use of these
medications. Because of the risk of seizure associated with XTANDI
use, patients should be advised of the risk of engaging in any activity
during which sudden loss of consciousness could cause serious
harm to themselves or others. Permanently discontinue XTANDI in
patients who develop a seizure during treatment.
Adverse ReactionsThe most common adverse reactions
(≥ 10%) reported from the two combined clinical trials
that occurred more commonly (≥ 2% over placebo) in the
XTANDI-treated patients were asthenia/fatigue, back pain,
decreased appetite, constipation, arthralgia, diarrhea, hot flush,
upper respiratory tract infection, peripheral edema, dyspnea,
musculoskeletal pain, weight decreased, headache, hypertension,
and dizziness/vertigo.
Other Adverse Reactions include:
A'(57'957>(4573'2/9/+849.+9<589:*/+87'*+
neutropenia occurred in 15% of patients treated with XTANDI
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patients and in Study 2, 1 patient in each treatment group
(0.1%) had an infection resulting in death.
Significantly improved overall survival†1
Significantly extended radiographic
progression-free survival†1
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Oral, once-daily dosing with no required
steroid coadministration1
Significantly delayed time to
chemotherapy initiation†1
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Visit XtandiHCP.com or snap
the QR code for more information
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receiving placebo. No patients experienced hypertensive crisis.
Medical history of hypertension was balanced between arms.
>6+79+48/542+*9589:*>*/8)549/4:'9/54/4
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or placebo treated patients.
Drug Interactions
AEffect of Other Drugs on XTANDI - Administration of strong
CYP2C8 inhibitors can increase the plasma exposure to
XTANDI. Co-administration of XTANDI with strong CYP2C8
inhibitors should be avoided if possible. If co-administration of
XTANDI cannot be avoided, reduce the dose of XTANDI. Co'*3/4/897'9/545,%$</9.89754-5735*+7'9+&!'4*
CYP2C8 inducers may alter the plasma exposure of XTANDI and
should be avoided if possible.
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inducer and a moderate CYP2C9 and CYP2C19 inducer in
.:3'48;5/*&!&!'4*&!
8:(897'9+8</9.
a narrow therapeutic index, as XTANDI may decrease the plasma
exposures of these drugs. If XTANDI is co-administered with
warfarin (CYP2C9 substrate), conduct additional INR monitoring.
Please see adjacent pages for Brief Summary of
Full Prescribing Information.
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A63=9/130</?:?3137C3259B1<1<?A71<72@4<?C/?F7;5?3/@<;@!;A63!'$A?7/9
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/?:?3137C3259B1<1<?A71<72@!'$D/@/=6/@3:B9A713;A3?=9/130<
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References:1.,)%!-=/18/537;@3?A.%<?A60?<<8!#@A399/@&6/?:/*(!;1
2.33?)$?:@A?<;5"'/A68<=43A/9;G/9BA/:7237;:3A/@A/A71=?<@A/A3
1/;13?034<?3163:<A63?/=FN Engl J Med
Table 1. Adverse Reactions in Study 1 (cont.)
Respiratory Disorders
XTANDI® (enzalutamide) capsules for oral use
Initial U.S. Approval: 2012
BRIEF SUMMARY OF PRESCRIBING INFORMATION
The following is a brief summary. Please see the package
insert for full prescribing information.
Grade 3 and higher adverse reactions were reported
among 47% of XTANDI-treated patients and 53% of
placebo-treated patients. Discontinuations due to adverse
events were reported for 16% of XTANDI-treated patients
and 18% of placebo-treated patients. The most common
adverse reaction leading to treatment discontinuation was
seizure, which occurred in 0.9% of the XTANDI-treated
patients compared to none (0%) of the placebo-treated
patients. Table 1 shows adverse reactions reported in Study
1 that occurred at a ≥ 2% higher frequency in the XTANDI
arm compared to the placebo arm.
INDICATIONS AND USAGE
Table 1. Adverse Reactions in Study 1
Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients
with metastatic CRPC who had not received prior cytotoxic
chemotherapy, of whom 1715 received at least one dose
of study drug. The median duration of treatment was 17.5
months with XTANDI and 4.6 months with placebo. Grade
3-4 adverse reactions were reported in 44% of XTANDItreated patients and 37% of placebo-treated patients.
Discontinuations due to adverse events were reported for
6% of XTANDI-treated patients and 6% of placebo-treated
patients. The most common adverse reaction leading to
treatment discontinuation was fatigue/asthenia, which
occurred in 1% of patients on each treatment arm. Table
2 includes adverse reactions reported in Study 2 that
occurred at a ≥ 2% higher frequency in the XTANDI arm
compared to the placebo arm.
XTANDI
N = 800
XTANDI is indicated for the treatment of patients with
metastatic castration-resistant prostate cancer (CRPC).
Grade
1-4a
(%)
CONTRAINDICATIONS
Pregnancy XTANDI can cause fetal harm when
administered to a pregnant woman based on its
mechanism of action and findings in animals. XTANDI is
not indicated for use in women. XTANDI is contraindicated
in women who are or may become pregnant. If this drug
is used during pregnancy, or if the patient becomes
pregnant while taking this drug, apprise the patient of
the potential hazard to the fetus and the potential risk for
pregnancy loss [see Use in Specific Populations (8.1)].
WARNINGS AND PRECAUTIONS
Seizure In Study 1, which enrolled patients who previously
received docetaxel, 7 of 800 (0.9%) patients treated with
XTANDI experienced a seizure and no patients treated with
placebo experienced a seizure. Seizure occurred from 31
to 603 days after initiation of XTANDI. In Study 2, 1 of
871 (0.1%) chemotherapy-naive patients treated with
XTANDI and 1 of 844 (0.1%) patients treated with placebo
experienced a seizure. Patients experiencing seizure were
permanently discontinued from therapy and all seizure
events resolved. There is no clinical trial experience readministering XTANDI to patients who experienced seizure.
Limited safety data are available in patients with
predisposing factors for seizure because these patients
were generally excluded from the trials. These exclusion
criteria included a history of seizure, underlying brain
injury with loss of consciousness, transient ischemic
attack within the past 12 months, cerebral vascular
accident, brain metastases, and brain arteriovenous
malformation. Study 1 excluded the use of concomitant
medications that may lower the seizure threshold,
whereas Study 2 permitted the use of these medications.
Because of the risk of seizure associated with XTANDI
use, patients should be advised of the risk of engaging
in any activity where sudden loss of consciousness could
cause serious harm to themselves or others. Permanently
discontinue XTANDI in patients who develop a seizure
during treatment.
ADVERSE REACTIONS
Clinical Trial Experience Because clinical trials are
conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed
in practice.
Two randomized clinical trials enrolled patients with
metastatic prostate cancer that has progressed on
androgen deprivation therapy (GnRH therapy or bilateral
orchiectomy), a disease setting that is also defined as
metastatic CRPC. In both studies, patients received
XTANDI 160 mg orally once daily in the active treatment
arm or placebo in the control arm. All patients continued
androgen deprivation therapy. Patients were allowed, but
not required, to take glucocorticoids.
The most common adverse reactions (≥ 10%) that
occurred more commonly (≥ 2% over placebo) in the
XTANDI-treated patients from the two randomized
clinical trials were asthenia/fatigue, back pain, decreased
appetite, constipation, arthralgia, diarrhea, hot flush, upper
respiratory tract infection, peripheral edema, dyspnea,
musculoskeletal pain, weight decreased, headache,
hypertension, and dizziness/vertigo.
Study 1: Metastatic Castration-Resistant Prostate
Cancer Following Chemotherapy Study 1 enrolled
1199 patients with metastatic CRPC who had previously
received docetaxel. The median duration of treatment
was 8.3 months with XTANDI and 3.0 months with
placebo. During the trial, 48% of patients on the XTANDI
arm and 46% of patients on the placebo arm received
glucocorticoids.
General Disorders
Asthenic
Conditionsb
Peripheral Edema
Placebo
N = 399
Grade Grade Grade
3-4
1-4
3-4
(%)
(%)
(%)
50.6
9.0
44.4
9.3
15.4
1.0
13.3
0.8
Musculoskeletal And Connective Tissue Disorders
Back Pain
26.4
5.3
24.3
4.0
Arthralgia
20.5
Musculoskeletal
15.0
Pain
Muscular
9.8
Weakness
Musculoskeletal
2.6
Stiffness
Gastrointestinal Disorders
2.5
17.3
1.8
1.3
11.5
0.3
1.5
6.8
1.8
0.3
0.3
0.0
21.8
1.1
17.5
0.3
Hot Flush
20.3
0.0
10.3
0.0
Hypertension
6.4
2.1
2.8
1.3
0.9
5.5
0.0
Diarrhea
Vascular Disorders
Nervous System Disorders
Headache
Dizzinessc
Spinal Cord
Compression and
Cauda Equina
Syndrome
Paresthesia
Mental
Impairment
Disordersd
Hypoesthesia
12.1
9.5
0.5
7.5
0.5
7.4
6.6
4.5
3.8
Epistaxis
3.3
0.1
1.3
0.3
a CTCAE v4
b Includes asthenia and fatigue.
c Includes dizziness and vertigo.
d Includes amnesia, memory impairment, cognitive disorder, and
disturbance in attention.
e Includes nasopharyngitis, upper respiratory tract infection, sinusitis,
rhinitis, pharyngitis, and laryngitis.
f Includes pneumonia, lower respiratory tract infection, bronchitis, and
lung infection.
Table 2. Adverse Reactions in Study 2
XTANDI
N = 871
Grade
1-4a
(%)
Grade
3-4
(%)
Placebo
N = 844
Grade
1-4
(%)
Grade
3-4
(%)
General Disorders
Asthenic
46.9
3.4
33.0
2.8
Conditionsb
Peripheral
11.5
0.2
8.2
0.4
Edema
Musculoskeletal And Connective Tissue Disorders
Back Pain
28.6
2.5
22.4
3.0
Arthralgia
21.4
1.6
16.1
1.1
Gastrointestinal Disorders
6.6
0.0
4.5
0.0
4.3
0.3
1.8
0.0
4.0
Infections And Infestations
Upper
Respiratory Tract 10.9
Infectione
Lower
Respiratory
8.5
Tract And Lung
Infectionf
Psychiatric Disorders
0.3
1.8
0.0
Constipation
23.2
0.7
17.3
0.4
Diarrhea
16.8
0.3
14.3
0.4
Vascular Disorders
Hot Flush
18.0
0.1
7.8
0.0
Hypertension
14.2
7.2
4.1
2.3
Nervous System Disorders
0.0
6.5
0.3
2.4
4.8
1.3
Insomnia
8.8
0.0
6.0
0.5
Anxiety
6.5
0.3
4.0
0.0
Renal And Urinary Disorders
Hematuria
6.9
1.8
4.5
1.0
Pollakiuria
4.8
0.0
2.5
0.0
Injury, Poisoning And Procedural Complications
Fall
4.6
0.3
1.3
Non-pathologic
4.0
1.4
0.8
Fractures
Skin And Subcutaneous Tissue Disorders
0.0
0.3
Pruritus
3.8
0.0
1.3
0.0
Dry Skin
3.5
0.0
1.3
0.0
Dizzinessc
11.3
0.3
7.1
0.0
Headache
11.0
0.2
7.0
0.4
Dysgeusia
7.6
0.1
3.7
0.0
5.7
0.0
1.3
0.1
2.1
0.1
0.4
0.0
0.6
8.5
0.6
0.0
10.5
0.0
1.5
4.7
1.1
0.1
5.7
0.0
Mental
Impairment
Disordersd
Restless Legs
Syndrome
Respiratory Disorders
Dyspneae
11.0
Infections And Infestations
Upper
Respiratory
16.4
Tract
Infectionf
Lower
Respiratory
Tract And
7.9
Lung
Infectiong
Psychiatric Disorders
Insomnia
8.2
Table 2. Adverse Reactions in Study 2 (cont.)
Renal And Urinary Disorders
Hematuria
8.8
1.3
5.8
1.3
Injury, Poisoning And Procedural Complications
Fall
12.7
1.6
NonPathological
8.8
2.1
Fracture
Metabolism and Nutrition Disorders
Decreased
18.9
0.3
Appetite
5.3
0.7
3.0
1.1
16.4
0.7
8.5
0.2
Investigations
Weight
Decreased
12.4
0.8
Reproductive System and Breast Disorders
Gynecomastia
3.4
0.0
1.4
0.0
a
b
c
d
CTCAE v4
Includes asthenia and fatigue.
Includes dizziness and vertigo.
Includes amnesia, memory impairment, cognitive disorder, and
disturbance in attention.
e Includes dyspnea, exertional dyspnea, and dyspnea at rest.
f Includes nasopharyngitis, upper respiratory tract infection, sinusitis,
rhinitis, pharyngitis, and laryngitis.
g Includes pneumonia, lower respiratory tract infection, bronchitis, and
lung infection.
Laboratory Abnormalities In the two randomized
clinical trials, Grade 1-4 neutropenia occurred in 15%
of patients treated with XTANDI (1% Grade 3-4) and in
6% of patients treated with placebo (0.5% Grade 3-4).
The incidence of Grade 1-4 thrombocytopenia was 6% of
patients treated with XTANDI (0.3% Grade 3-4) and 5% of
patients treated with placebo (0.5% Grade 3-4). Grade 1-4
elevations in ALT occurred in 10% of patients treated with
XTANDI (0.2% Grade 3-4) and 16% of patients treated
with placebo (0.2% Grade 3-4). Grade 1-4 elevations in
bilirubin occurred in 3% of patients treated with XTANDI
(0.1% Grade 3-4) and 2% of patients treated with placebo
(no Grade 3-4).
Infections In Study 1, 1% of patients treated with XTANDI
compared to 0.3% of patients treated with placebo died
from infections or sepsis. In Study 2, 1 patient in each
treatment group (0.1%) had an infection resulting in
death.
Falls and Fall-related Injuries In the two randomized
clinical trials, falls including fall-related injuries, occurred
in 9% of patients treated with XTANDI compared to 4% of
patients treated with placebo. Falls were not associated with
loss of consciousness or seizure. Fall-related injuries were
more severe in patients treated with XTANDI and included
non-pathologic fractures, joint injuries, and hematomas.
Hypertension In the two randomized trials, hypertension
was reported in 11% of patients receiving XTANDI and
4% of patients receiving placebo. No patients experienced
hypertensive crisis. Medical history of hypertension
was balanced between arms. Hypertension led to study
discontinuation in < 1% of patients in each arm.
DRUG INTERACTIONS
Drugs that Inhibit or Induce CYP2C8 Co-administration
of a strong CYP2C8 inhibitor (gemfibrozil) increased the
composite area under the plasma concentration-time curve
(AUC) of enzalutamide plus N-desmethyl enzalutamide
by 2.2-fold in healthy volunteers. Co-administration of
XTANDI with strong CYP2C8 inhibitors should be avoided
if possible. If co-administration of XTANDI with a strong
CYP2C8 inhibitor cannot be avoided, reduce the dose of
XTANDI [see Dosage and Administration (2.2) and Clinical
Pharmacology (12.3)].
The effects of CYP2C8 inducers on the pharmacokinetics
of enzalutamide have not been evaluated in vivo.
Co-administration of XTANDI with strong or moderate
CYP2C8 inducers (e.g., rifampin) may alter the plasma
exposure of XTANDI and should be avoided if possible.
Selection of a concomitant medication with no or minimal
CYP2C8 induction potential is recommended [see Clinical
Drugs that Inhibit or Induce CYP3A4 Co-administration
of a strong CYP3A4 inhibitor (itraconazole) increased
the composite AUC of enzalutamide plus N-desmethyl
enzalutamide by 1.3-fold in healthy volunteers [see
Clinical Pharmacology (12.3)].
The effects of CYP3A4 inducers on the pharmacokinetics
of enzalutamide have not been evaluated in vivo.
Co-administration of XTANDI with strong CYP3A4
inducers (e.g., carbamazepine, phenobarbital, phenytoin,
rifabutin, rifampin, rifapentine) may decrease the plasma
exposure of XTANDI and should be avoided if possible.
Selection of a concomitant medication with no or minimal
CYP3A4 induction potential is recommended. Moderate
CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine,
modafinil, nafcillin) and St. John’s Wort may also reduce
the plasma exposure of XTANDI and should be avoided if
possible [see Clinical Pharmacology (12.3)].
Effect of XTANDI on Drug Metabolizing Enzymes
Enzalutamide is a strong CYP3A4 inducer and a moderate
CYP2C9 and CYP2C19 inducer in humans. At steady
state, XTANDI reduced the plasma exposure to midazolam
(CYP3A4 substrate), warfarin (CYP2C9 substrate), and
omeprazole (CYP2C19 substrate). Concomitant use of
XTANDI with narrow therapeutic index drugs that are
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine,
dihydroergotamine, ergotamine, fentanyl, pimozide,
quinidine, sirolimus and tacrolimus), CYP2C9 (e.g.,
phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin)
should be avoided, as enzalutamide may decrease their
exposure. If co-administration with warfarin cannot be
avoided, conduct additional INR monitoring [see Clinical
USE IN SPECIFIC POPULATIONS
Pregnancy - Pregnancy Category X [see Contraindications
(4)].
Risk Summary
XTANDI can cause fetal harm when administered to a
pregnant woman based on its mechanism of action and
findings in animals. While there are no human data on the
use of XTANDI in pregnancy and XTANDI is not indicated
for use in women, it is important to know that maternal
use of an androgen receptor inhibitor could affect
development of the fetus. Enzalutamide caused embryofetal toxicity in mice at exposures that were lower than
in patients receiving the recommended dose. XTANDI
is contraindicated in women who are or may become
pregnant while receiving the drug. If this drug is used
during pregnancy, or if the patient becomes pregnant
while taking this drug, apprise the patient of the potential
hazard to the fetus and the potential risk for pregnancy
loss. Advise females of reproductive potential to avoid
becoming pregnant during treatment with XTANDI.
Animal Data
In an embryo-fetal developmental toxicity study in
mice, enzalutamide caused developmental toxicity
when administered at oral doses of 10 or 30 mg/kg/day
throughout the period of organogenesis (gestational days
6-15). Findings included embryo-fetal lethality (increased
post-implantation loss and resorptions) and decreased
anogenital distance at ≥ 10 mg/kg/day, and cleft palate
and absent palatine bone at 30 mg/kg/day. Doses of 30
mg/kg/day caused maternal toxicity. The doses tested
in mice (1, 10 and 30 mg/kg/day) resulted in systemic
exposures (AUC) approximately 0.04, 0.4 and 1.1 times,
respectively, the exposures in patients. Enzalutamide
did not cause developmental toxicity in rabbits when
administered throughout the period of organogenesis
(gestational days 6-18) at dose levels up to 10 mg/kg/day
(approximately 0.4 times the exposures in patients based
on AUC).
Nursing Mothers XTANDI is not indicated for use in
women. It is not known if enzalutamide is excreted
in human milk. Because many drugs are excreted in
human milk, and because of the potential for serious
adverse reactions in nursing infants from XTANDI, a
decision should be made to either discontinue nursing, or
discontinue the drug taking into account the importance
of the drug to the mother.
Pediatric Use Safety and effectiveness of XTANDI in
pediatric patients have not been established.
Geriatric Use Of 1671 patients who received XTANDI
in the two randomized clinical trials, 75% were 65 and
over, while 31% were 75 and over. No overall differences
in safety or effectiveness were observed between these
patients and younger patients. Other reported clinical
experience has not identified differences in responses
between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
Patients with Renal Impairment A dedicated renal
impairment trial for XTANDI has not been conducted.
Based on the population pharmacokinetic analysis
using data from clinical trials in patients with metastatic
CRPC and healthy volunteers, no significant difference
in enzalutamide clearance was observed in patients
with pre-existing mild to moderate renal impairment
(30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min)
compared to patients and volunteers with baseline
normal renal function (CrCL ≥ 90 mL/min). No initial
dosage adjustment is necessary for patients with mild
to moderate renal impairment. Severe renal impairment
(CrCL < 30 mL/min) and end-stage renal disease have not
been assessed [see Clinical Pharmacology (12.3)].
Patients with Hepatic Impairment A dedicated hepatic
impairment trial compared the composite systemic
exposure of enzalutamide plus N-desmethyl enzalutamide
in volunteers with baseline mild or moderate hepatic
impairment (Child-Pugh Class A and B, respectively)
versus healthy controls with normal hepatic function.
The composite AUC of enzalutamide plus N-desmethyl
enzalutamide was similar in volunteers with mild or
moderate baseline hepatic impairment compared to
volunteers with normal hepatic function. No initial dosage
adjustment is necessary for patients with baseline mild
or moderate hepatic impairment. Baseline severe hepatic
impairment (Child-Pugh Class C) has not been assessed
[see Clinical Pharmacology (12.3)].
OVERDOSAGE
In the event of an overdose, stop treatment with
XTANDI and initiate general supportive measures taking
into consideration the half-life of 5.8 days. In a dose
escalation study, no seizures were reported at < 240
mg daily, whereas 3 seizures were reported, 1 each at
360 mg, 480 mg, and 600 mg daily. Patients may be at
increased risk of seizure following an overdose.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been conducted to
evaluate the carcinogenic potential of enzalutamide.
Enzalutamide did not induce mutations in the bacterial
reverse mutation (Ames) assay and was not genotoxic in
either the in vitro mouse lymphoma thymidine kinase (Tk)
gene mutation assay or the in vivo mouse micronucleus
assay.
Based on nonclinical findings in repeat-dose toxicology
studies, which were consistent with the pharmacological
activity of enzalutamide, male fertility may be impaired
by treatment with XTANDI. In a 26-week study in rats,
atrophy of the prostate and seminal vesicles was observed
at ≥ 30 mg/kg/day (equal to the human exposure based
on AUC). In 4-, 13-, and 39-week studies in dogs,
hypospermatogenesis and atrophy of the prostate and
epididymides were observed at ≥ 4 mg/kg/day (0.3 times
the human exposure based on AUC).
Manufactured by: Catalent Pharma Solutions, LLC, St.
Petersburg, FL 33716
Manufactured for and Distributed by: Astellas Pharma
US, Inc., Northbrook, IL 60062
Marketed by:
Astellas Pharma US, Inc., Northbrook, IL 60062
Medivation, Inc., San Francisco, CA 94105
Revised: September 2014
14B006-XTA-BRFS
Rx Only
© 2014 Astellas Pharma US, Inc.
XTANDI® is a registered trademark of Astellas Pharma Inc.
076-0472-PM
6
❳Perspective❲
MARCH 2015 VOL. 43, NO. 3
UrologyTimes.com
❳Mission❲
New hope for treating
deep renal tumors?
T
his issue of Urology Times highlights interesting research by
University of Texas Southwestern Medical Center urologists on
the use of irreversible electroporation (IRE) in renal tumors.
IRE is a non-thermal tissue destruction technology that applies
short pulses of DC electric current to create cell membrane pores
and subsequent apoptosis. Morgan
and associates from UT Southwestern applied the treatment via two
to five percutaneous probes. The
potential advantages of IRE are that
the destructive mechanism is not
impacted by adjacent blood flow (ie,
large blood vessels) and that there
is sharp demarcation of treated and
untreated tissue.
However, probe placement must be
Dr. Wolf, a member of
very
exact, probes must be completethe Urology Times Editoly encased in tissue, and the patient
rial Council, is professor of
must be under complete neuromusurology at the University of
Michigan, Ann Arbor.
cular blockade. The authors report
one recurrence in eight patients at a
follow-up of 1 year, although this is
the first clinical study and it is reasonable to expect greater success as
experience is gained.
Current percutaneous ablation technologies (radiofrequency and
cryotherapy) are most effective for exophytic lesions less than 3 cm
in diameter. Treatment of larger
and deeper lesions, especially ones
that are close to large blood vesIt is for patients with
sels, are associated with a greater
larger and deeper lesions failure rate. Of course, the standard
that we are most in need nephron-sparing treatment—partial
nephrectomy—is more technically
of an alternative.
difficult (and complication prone) in
this same group of patients. It is for
these patients that we are most in need of an alternative.
Fortunately, IRE appears to be applicable to deep intra-renal lesions.
If further work with this technology refines its capacity for discrete tissue ablation deep within the kidney and adjacent to large blood vessels,
and especially if larger tumors can be addressed, then this would be a
major step forward in the minimally invasive treatment of localized
renal cancer.
J. Stuart Wolf, Jr., MD
Feedback
J. Stuart Wolf, Jr., MD
Send your comments to
Dr. Wolf c/o Urology Times, at
UT@advanstar.com
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❳Editorial Consultants❲
Leading urologic surgeons, with broad experience,
who help ensure the quality of our editorial
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ERECTILE DYSFUNCTION John Mulcahy, MD, PhD | Private Practice, Madison, AL
FEMALE UROLOGY Shlomo Raz, MD Professor of Surgery/Urology | University of California School of Medicine, Los Angeles
INFECTIONS Anthony Schaeffer, MD Professor and Chairman of Urology | Northwestern University Medical School, Chicago
MALE REPRODUCTIVE MEDICINE Craig S. Niederberger, MD Professor and Head of Urology | University of Illinois, Chicago
PEDIATRICS Howard Snyder, III, MD Professor of Surgery in Urology | University of Pennsylvania School of Medicine, Philadelphia
SOCIOECONOMICS William F. Gee, MD | Private Practice, Lexington, KY
STONES/ENDOUROLOGY Dean G. Assimos, MD Professor and Chair of Urology | University of Alabama, Birmingham
TRAUMA/RECONSTRUCTION Allen F. Morey, MD Professor of Urology | UT Southwestern Medical Center, Dallas
UROLOGIC CANCER Leonard G. Gomella, MD Professor and Chairman of Urology | Thomas Jefferson University, Philadelphia
UROLOGIC LAPAROSCOPY J. Stuart Wolf, Jr, MD Professor of Urology | University of Michigan, Ann Arbor
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7
BLOG
PSA testing: It’s not your
choice, it’s your patient’s
Henry Rosevear, MD, recently diagnosed his sixth patient with
metastatic prostate cancer, two of whom are in their fifties.
All had been told that rectal exams and PSA were useless. For
Dr. Rosevear, this raised two critical points: first, the difference
between screening someone for prostate cancer with PSA and
diagnosing someone with prostate cancer; and second, the
DR. ROSEVEAR
proper use of PSA as a screening tool. “This is the first time to my
knowledge that government institutions are actively telling the public to stop
using a test that has been credited with causing a huge stage migration,” he says
in his latest blog.
READ DR. ROSEVEAR’S OFFER TO PRIMARY CARE DOCS: urologytimes.com/PSA-choice
VIEW MORE CONTENT,
INCLUDING OUR OWN
VERSION OF
“THROWBACK THURSDAY,”
WHEN YOU LIKE US ON
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AACU LEGISLATIVE UPDATE
Work force proposals may endanger patient safety
From Arkansas to California, state legislators are stepping up efforts to address the
shortage of physicians. Not all of their proposals have patient safety and providers’
high professional standards as key components, writes Ross E. Weber of the AACU.
Measures include expanding nurse practitioners’ scope of practice, allowing NPs
to perform male sterilization, and the Interstate Medical Licensure Compact, a
Urology Times Resource Center
telemedicine proposal that could undermine the authority of state licensing boards.
THE LOWDOWN ON LOW T
Multiple resources—videos, articles, tools, and
CME—help you diagnose and treat low testosterone.
Learn how to determine whether testosterone
replacement therapy may be an option for your male
patientss. View all the resources here.
http://urologytimes.modernmedicine.com/
tag/lowdown-low-t
urologytimes.com/proposals
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TWITTER.COM/UROLOGYTIMES
Our followers tweet about the JAMA targeted Bx study
Matt Cooperberg, MD
@dr_coops
My soapbox view is it’s a reasonably well done paper
but nowhere near ready for prime time with community
radiologists. #urojc
Dr Rajiv K Singal
@DrRKSingal
@dr_coops Agree. Many MRIs in Toronto, Only Masoom
Haider at @Sunnybrook does/interprets ours. Too
much variability for general use #urojc
Matthew Wasco
@Gleason4plus5
@DrRKSingal @dr_coops Will be interesting to see
the max sensitivity/spec of MRI (90%?) with more
radiologist experience.
Matthew Hayn
@matthayn
Peter Pinto said exactly that at #suo14 - Community
urologists are disappointed with the MRI/fusion
results @dr_coops #urojc
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8
❳ Clinical Updates ❲
MARCH 2015
∣
Urology Times
IRE may offer safety, efficacy advantages
Nonthermal technique promising for small renal tumors
Dallas—Percutaneous irreversible electropora-
tion (IRE) is showing promise as a novel minimally invasive approach for treating small renal
tumors, according to the experience of urologists at the University of Texas Southwestern
Medical Center, Dallas.
❳ Kidney Cancer ❲
“To our knowledge, ours is the first clinical
study evaluating percutaneous IRE for treatment of small renal masses, and outcomes in
our patients indicate the procedure is feasible
and safe,” said first author Monica Morgan,
MD, who was a fellow in minimally invasive
surgery and endourology at the time of the study
and is currently assistant instructor in urology.
“Determination of its oncologic efficacy
will depend on longer follow-up in more
patients,” added Dr. Morgan, who worked on
the research with Jeffrey Cadeddu, MD, and
colleagues.
Findings from the retrospective study including 20 consecutive patients were presented at
the 2014 World Congress of Endourology and
SWL in Taipei, Taiwan.
The patients underwent the procedure
between April 2013 and March 2014. A total
number of 21 tumors were treated, with a median
size of 2.2 cm (1.2 to 3.6 cm). All patients underwent computed tomography with intravenous
contrast prior to the procedure to help delineate
the masses. The procedures were performed
under general anesthesia with cardiac synchronization, complete neuromuscular blockade, and
CT guidance using 15-cm monopolar probes
Clinical Updates
(NanoKnife, AngioDynamics). Median number of probes used was four (range, two to five).
Contrast-enhanced CT was performed
immediately after the procedure to evaluate
the area of ablation, and follow-up with contrast-enhanced CT scanning was scheduled at
6 weeks, 6 months, and 1 year postoperatively.
There were no intraoperative or postoperative
complications. Of 19 patients seen at 6 weeks,
two demonstrated contrast enhancement on
their 6-week follow-up CT and therefore were
considered treatment failures. Both patients
were treated early in the series and subsequently
underwent salvage radiofrequency ablation.
Seventeen patients were seen at 6 months,
and all seemed tumor-free, but recurrence was
seen in one of eight patients at 1 year. The latter
individual chose to undergo partial nephrectomy and was tumor-free with follow-up to 6
months, Dr. Morgan reported.
Technique avoids heat sink effect
IRE involves application of short pulses of DC
electric current that creates irreversible pores
in the cell membrane leading to apoptosis. Dr.
Morgan explained that as a nonthermal technique, IRE has the potential for greater efficacy
and safety than thermal ablative techniques (ie,
radiofrequency and cryotherapy), as it avoids
any heat sink effect that can occur when treating near large blood vessels as well as collateral
tissue damage.
“Histology studies show there is a sharp
demarcation around the edge of the measured
target tissue; therefore, we are able to calculate
and have the potential to ablate with great accuracy,” Dr. Morgan said.
However, IRE has some limitations and
drawbacks relative to the other techniques. The
patient must undergo a complete neuromuscular
blockade during the ablation portion of the procedure, and application of pulses must be timed
❳ UT Figure ❲
Percutaneous irreversible electroporation
was performed using 15-cm monopolar
probes. (Photo courtesy of AngioDynamics)
precisely to the myocardial refractory period to
prevent induction of arrhythmias.
In addition, probe placement is technically
challenging and the learning curve is steep. The
probes are placed to bracket the tumor, rather
than to violate it. Also, they must be completely
encased in tissue to prevent arcing, in parallel
to each other (<10 degrees deviation), and with
the tips on the same plane.
“Small deviations in probe placement can
lead to incomplete ablation,” Dr. Morgan
explained.
“Procedure times exceeded 3.5 hours in our
early cases, but were reduced to about 2 hours
later on in this series,” she added.
Based on characteristics of the failures and
recurrence, Dr. Morgan said that it appears IRE
may ablate better deeper in the kidney and less
well in the periphery, perhaps because fat acts
like an insulator. In addition, it may be more
effective for treating smaller tumors (<3 cm). UT
THIS ISSUE
InBrief❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯
Prostate Cancer
FDA approves cUTI agent
page 10
❯❯
BPH
page 13
For up-to-date news, visit
urologytimes.com/InBrief
FOR UP-TO-DATE NEWS, VISIT urologytimes.com/InBrief
The FDA has approved ceftazidimeavibactam (AVYCAZ) for the treatment of adult patients with complicated complicated urinary tract infections including
pyelonephritis caused by designated susceptible bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa.
The agent received a priority review based
on phase II data from manufacturer Actavis plc’s clinical development program and
supporting in vitro data, and thus should be
reserved for use in patients with limited or no
alternative treatment options, Actavis said.
Ceftazidime-avibactam is also approved
for the treatment of intra-abdominal infections (in combination with metronidazole).
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email: custserv@greenwaldsurgical.com
10
MARCH 2015
∣
Urology Times
Urologist experience may influence surveillance choice
High-volume surgeons more likely to recommend immediate treatment, data show
Mac Overmyer
Los Angeles—“The decision to initiate an [active
surveillance] protocol is complex and dependent
on multiple patient and provider factors.”
❳ Prostate Cancer ❲
That statement, taken from the introduction
to a recent study from researchers at Kaiser
Permanente Los Angeles Medical Center, Los
Angeles, sums up the issues surrounding the
implementation of active surveillance (AS) in
men with low-risk prostate cancer.
Physician experience appears to be one of
those factors. The study found that urologists
with higher surgical volumes, especially in
robotic procedures, are more likely to recommend immediate treatment (IT) than AS. The
study also found that urologists with fellowship
training in oncology and/or robotics are less
likely to advise patients to undergo intervention
and more likely to recommend AS.
Experience was not a subtle influence; the
authors found that surgeons with 50 or more
robotic procedures were seven times more
likely to recommend IT.
A ‘surprising’ finding
“We looked at many different factors, but the only
things that jumped out were experience and training. One of the surprising findings was that surgeons on fellowships receiving training in oncology and robotics were less likely to recommend
IT,” first author Gary W. Chien, MD, urology
program residency director at Kaiser Permanente
Los Angeles Medical Center, told Urology Times.
Dr. Chien had no definitive data showing
why physicians with additional training in
oncology and robotics were less likely to counsel for intervention.
“What we think is that it may be a referral
bias in that these doctors are seeing patients
who are more complex, and doctors with additional training are likely to be more stringent
in selecting patients to operate on,” he said.
“The take-home message is that we cannot
assume that patient clinical pathologic factors
are the driving influence in treating a patient
under active surveillance for low-risk prostate
cancer.”
Although confined to Kaiser Permanente
physicians on the West Coast, the study was
nevertheless broad based. Some 713 patients
managed by 87 urologists were enrolled in the
study. Patients had cT1-T2a stage prostate cancer, PSA <10.0 ng/mL, Gleason ≤6, <3 positive biopsy cores, and ≤50% cancer per core.
Respondents were all based in Southern California. All other demographics and baseline
characteristics were similar.
“We think that one of the strengths of the study
is the setting. It is a managed care setting, so every
patient has equal access to health care and sees
the physician they wish to. In addition, the physicians are salaried so there is no financial incentive influencing their decisions,” said Dr. Chien.
Urologist age, time in practice not factors
Factors such as urologist age and years in practice were examined but did not achieve statistical relevancy.
“What I would like to know is exactly what
kind of counseling is going on in consultations.
Who is making the decisions? Is it the physician? Is it the patient?” Dr. Chien asked.
He said he would like to see a prospective
study that focused on the content and dynamics
of counseling sessions, which would identify
the actions that influence patient decisions to
pursue or reject active surveillance.
The current study, presented at the 2014
World Congress of Endourology and SWL in
Taipei, Taiwan, appears to add one more factor to the list of factors that seem to influence
decision-making in the face of low-stage prostate cancer.
In June 2014, Urology Times reported on
a survey of 717 U.S. urologists’ and radiation
oncologists’ attitudes toward active surveillance (www.urologytimes.com/surveillancesurvey). That survey, published in Medical Care
(2014; 52:579-85), was conducted by 13 of the
nation’s leading urologists, who concluded:
“Most prostate cancer specialists in the United
States believe AS is effective and underused for
low-risk prostate cancer, yet continue to recommend the primary treatments their specialties
deliver.”
Urology Times also reported on a study presented at the 2012 American Society of Clinical
Oncology annual meeting in Chicago that
found that while nearly 75% of radiation oncologists and urologists responding to a survey
said that AS was effective, only 16% of oncologists and 28% of urologists would actually
choose AS in an appropriately representative
case (www.urologytimes.com/surveillanceefficacy). UT
Race a factor in prostate cancer risk reclassification
African-Americans found more likely to experience upgrading on serial biopsy
Baltimore—African-American men with very
low-risk prostate cancer being followed on
active surveillance are at significantly higher risk for disease upgrading on subsequent
biopsy compared to Caucasian men, according to analyses of prospectively collected data
from the Johns Hopkins Active Surveillance
registry.
The study was presented at the 2014 AUA
annual meeting in Orlando, FL, and more
recently published in the Journal of Urology (2015; 85:155-60). It included 39 AfricanAmerican men and 615 Caucasian men identified as meeting all National Comprehensive
Cancer Network criteria for very low-risk disease (clinical stage ≤T1, Gleason ≤6, PSA <10.0
ng/mL, PSA density <0.15 ng/mL/cc, positive
cores <3, percent cancer per core ≤50%). The
two racial cohorts were similar in age at entry
into active surveillance and in their findings
on initial biopsy.
Median follow-up duration for the AfricanAmerican and Caucasian men was also similar
(30.5 and 36.3 months, respectively), and there
was no significant difference between the two
groups in the proportion who showed progression on serial biopsy based on volume criteria
(48.7% vs. 52.4%, respectively).
However, a significantly higher proportion
of African-American men than Caucasians
experienced upgrading on serial biopsy overall (35.9% vs. 16.1%; p<.001) and in an analysis of the cumulative incidence of upgrading
(p=.002). On multivariable analysis adjusting
for PSA, prostate size, volume of cancer on
Please see PCA RISK, page 12
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12
MARCH 2015
∣
Urology Times
MRI plus biopsy could guide decision to treat
MRI may add value in monitoring men on surveillance
Vancouver, BC—Multiparametric MRI (mpMRI) of the prostate with subsequent targeted
biopsy shows promise for improving the
identification of men on active surveillance
(AS) for low-risk prostate cancer who require
definitive treatment, according to researchers
from the Vancouver Prostate Centre, Vancouver, BC.
The role of mpMRI in altering management
of patients on AS was investigated in a retrospective study led by Larry Goldenberg, MD,
and Peter Black, MD, both of the University of
British Columbia, Vancouver. It included 111
men who underwent the imaging technique as
part of their AS protocol.
During a median follow-up of about 2.5
years, mpMRI detected a total of 118 suspicious lesions (defined by a Prostate Imaging
Reporting and Data Systems [PIRADS] score
≥3) in 68 men. All 68 men underwent systematic and targeted biopsies; the targeted
biopsy was directed by transrectal ultrasoundmagnetic resonance fusion software in 39 men
and visually guided (“cognitive fusion”) in
29 men.
During follow-up, 27 (24.3%) of the 111
P C A RISK
continued from page 10
biopsy, and body mass index, African-American race was an independent predictor of grade
reclassification, with the likelihood of this event
being threefold higher in African-American
men compared to Caucasians (p=.002).
Information should be used in counseling
“We believe this information should be included
when counseling African-American men who
are considering active surveillance. If the goal
of active surveillance is to select and monitor
men with low-grade prostate cancer, our study
findings indicate that black men may benefit
from alternate enrollment criteria,” said lead
author Debasish Sundi, MD, resident at Johns
Hopkins’ Brady Urological Institute, Baltimore.
He noted that the motivation for the study
was derived in part from the fact that AfricanAmericans are under-represented in outcomes
studies of active surveillance cohorts and
because recent evidence shows that among men
with very low-risk prostate cancer who undergo
men stopped AS and went on to receive definitive treatment. The decision to stop AS was
based on the MRI findings in 17 men (15.3%)
and was independent of the MRI results in
the other 10 (9.0%). The MRI findings that
led to termination of AS included pathologic
disease progression in targeted biopsies (16
men) and lesion size increase on MRI (one
man). Among the 10 men who went on to
definitive treatment for reasons independent
of findings on mpMRI, the reasons included
pathologic disease progression in standard
biopsies (six men), patient choice (three), and
PSA rise (one), reported first author Hamidreza Abdi, MD, clinical fellow at Vancouver
Prostate Centre.
“Active surveillance is a way to address concerns pertaining to overdiagnosis and overtreatment of prostate cancer, but there remains a
risk for missing tumor progression due to the
limitations of biopsy sampling techniques,”
said Dr. Abdi.
“We believe our study shows mpMRI has
potential value for enhancing monitoring
of men on active surveillance. However, our
findings must be viewed as preliminary, and
it should be emphasized that subsequent targeted biopsy needs to be improved to minimize
errors.”
UTSTAT
Men with a PIRADS 4 or 5 lesion were
approximately sixfold more likely
than men with a PIRADS 3 lesion
to terminate active surveillance
(p=.0003).
The 118 lesions identified by mpMRI had a
median size of 12 mm. The radiologic grading
showed the majority (71 lesions, 60.2%) were
PIRADS 3, 37 lesions (31.4%) were PIRADS
4, and 10 (8.4%) were PIRADS 5.
Lesion score could predict AS termination
PIRADS score was examined as a possible
predictor of termination of AS in a multivariate analysis, and the results showed that men
with a PIRADS 4 or 5 lesion were approximately sixfold more likely than men with a
PIRADS 3 lesion to terminate active surveillance (p=.0003), Dr. Abdi reported.
Other variables investigated included PSA
density (≤0.15 vs. >0.15), number of lesions (1-2
vs. >2), apparent diffusion coefficient value
Please see MRI PLUS BIOPSY, page 13
largest African-American sample
size studied to date, we believe it is
“If the goal of active surveillance is to select a useful contribution to our understanding of associations between
and monitor men with low-grade prostate
race and outcomes of active surveilhe told Urology Times.
cancer, our study findings indicate that black lance,”
While the findings beg the question of what the alternate criteria
men may benefit from alternate enrollment
should be to select African-Americriteria.”
can men for active surveillance, the
answer is unknown.
DEBASISH SUNDI, MD
“The most important outcome is
prostate cancer-specific mortality. In
immediate surgery, African-Americans are
more likely than Caucasians to have adverse order to evaluate this rigorously in any cohort of
men having such benign disease features overpathologic features.
Dr. Sundi observed that the findings of this all, long-term follow-up is necessary,” said Dr.
study are consistent with analyses of active Sundi.
Senior author Edward M. Schaeffer, MD,
surveillance cohorts by investigators at Duke
University and the University of Miami. While PhD, professor of urology at Johns Hopkins,
the Johns Hopkins study includes more Afri- addressed the key point of the research. He told
can-American men than the two earlier reports, Urology Times, “While active surveillance
Dr. Sundi acknowledged that relatively small remains a viable option for African-American
sample size is a limitation of the Johns Hop- men, we need to ensure that we are not enrolling
black men who either have unrecognized highkins study.
“Nevertheless, because it is from a prospec- grade prostate cancer or who are at high risk for
tively followed cohort and considering it is the its development.” UT
UrologyTimes.com
∣
MARCH 2015
13
Transfusion rate high with prostatectomy for BPH
No difference in peri-op outcomes between open, minimally invasive surgery
San Diego—Analyses of data from the Nation-
wide Inpatient Sample of the Healthcare Cost
and Utilization Project are providing understanding on trends in utilization of simple prostatectomy for treatment of symptomatic BPH
and addressing the gap in information about
its outcomes.
❳ BPH ❲
In the retrospective study, researchers
analyzed data for the years 1998 to 2010 and
showed the frequency of simple prostatectomy
for BPH was low and decreased over the study
period from 3,150 cases in 1998 to 2,230 cases
in 2010. However, after reaching a low in 2008,
the number of procedures performed annually
steadily increased over the next 2 years.
Results from a comparative analysis focusing
on data from 2008 to 2010 found that whether
performed using an open technique or a minimally invasive approach, prostatectomy was
associated with a relatively high rate of perioperative transfusion, but low rates of patient
safety indicator (PSI) events. The perioperative
transfusion data seemed to favor the minimally
invasive procedure.
However, due in part to limited power, the
study found no statistically significant differences between the two approaches for any
perioperative outcomes, reported senior author
J. Kellogg Parsons, MD, MHS, associate pro-
MRI PLUS BIOP SY
(≤890 vs. >890), and lesion size (≤10 vs.
>10 mm), but with the chosen cut-offs,
none of those factors significantly predicted termination of AS.
“A prospective study with a larger
sample size and longer follow-up will
be needed to determine whether mpMRI
adds benefit in following men on active
surveillance and what role these other
features have in predicting progression,”
Dr. Abdi said.
Results from the study were presented at the 2014 AUA annual meeting in Orlando, FL. UT
fessor of urology
at the University
of California, San
Table Minimally invasive vs. open
prostatectomy for BPH
Diego.
“Simple prostaMinimally
invasive
Open
tectomy has been
prostatectomy prostatectomy
p value
recognized for a
long time as an
3.7 days
4.7 days
.19
Mean length of stay
appropriate interMean hospital
$47,423
$32,462
.15
vention for select
charges
men with symp10%
21%
.13
Transfusion rate
tomat ic BPH.
Source: J. Kellogg Parsons, MD, MHS
However, all published literature
on this procedure
describes small case series and represents Level that this protective effect approached statistical
3 evidence,” Dr. Parsons said.
significance (21% vs. 10%; p=.13).
“This report provides the first national data
“The transfusion rate for the open group
on validated patient safety indicators for simple is consistent with that reported in published
prostatectomy, and it addresses the dearth of series. In the future, as more data are collected
Level 1 and Level 2 evi- for the MISP group, we would expect to have
dence comparing mini- the power to identify a statistically significant
mally invasive and open difference in transfusion rate compared to OP,”
procedures.”
he said.
The study, presented
Dr. Parsons added that he and his colleagues
at the 2014 AUA annual at the University of California, San Diego have
meeting in Orlando, performed 25 cases of MISP without any patient
FL, identified 34,611 needing a transfusion, an observation that corpatients who underwent responds to other single-institution series.
simple prostatectomy
“We think the overall transfusion rate for
Dr. Parsons
between 1998 and 2010. the MISP group in the Nationwide Inpatient
Between 2008 and 2010, Sample sample is high,” he said. “It is important
there were 6,027 cases of open simple pros- to keep in mind that this rate represents nationtatectomy (OSP) and 182 cases of minimally wide outcomes in a nationwide database. We
invasive simple prostatectomy (MISP). The lack granularity in the data that would allow us
comparative analysis did not use earlier data to investigate whether this relatively high transbecause very few MISP cases were performed fusion rate represents a learning curve effect or
is explained by any other factors.”
prior to 2008.
There were no in-hospital deaths among men
There were no significant differences between
the OSP and MISP groups with respect to mean who underwent MISP. The in-hospital mortality
age (~70 years) or distributions of race, Charlson rate for OSP was 0.4%.
Discharge codes were used to identify data
comorbidity scores, insurance status, income
zip code, or hospital type (urban vs. rural and for the 16 PSI measures validated for surgery
teaching vs. non-teaching). However, about 95% patients. The rate of any PSI in the OSP group
of both procedures were done at urban centers, was 0.4%, and the PSI occurring at the highest
and the MISP procedures were predominantly frequency was failure to rescue (8.7%). There
were no statistically significant differences
done in teaching hospitals (~80%).
between groups in the rates for any PSI or for
Shorter stay for minimally invasive procedure any 16 individual PSIs.
Mean length of stay was 1 day shorter for the
On multivariate analysis comparing the two
men who had MISP compared to OSP (3.7 vs. procedures, there was no significant difference
4.7 days; p=.19), but the MISP group had higher in the adjusted probability of any PSI. The mulmean hospital charges ($47,423 vs. $32,462; tivariate analysis also showed that patient age,
p=.15).
Charlson comorbidity index (≤2 vs. 3+), and
Dr. Parsons reported that the transfusion rate type of institution (teaching vs. non-teaching)
was twofold higher in men who had the open did not predict the probability of experiencing
procedure compared with the MISP group, and any PSI. UT
❳ UT
❲
14
❳#LetsTalkMensHealth❲
Clinical Tips on the Care of Male Patients
MARCH 2015
∣
Urology Times
Men’s health: How urology and primary
care can work together
A cardiometabolic assessment is the focus of multifaceted treatment, prevention
Martin Miner, MD ● Joel Heidelbaugh, MD
W
hen asked to write about the
relationship between urology
and primary care, we realized
that the topic limited men’s
health to simply a working relationship between
these two disparate specialties. In our experience, men’s health is far more than the working
relationship between urology and primary care
centered around male-specific medical concerns, and includes
several different
and significant subspecialties. These
encompass and are
not limited to internal medicine, family
medicine, pulmonology, cardiology,
Dr. Miner
oncology, endocrinology, psychology,
psychiatry, and geriatrics (figure).
Men are referred
into a dedicated men’s
health center (MHC)
or a clinical program for a multifacDr. Heidelbaugh
eted evaluation that
includes a complete
Dr. Miner is co-director of
the Men’s Health Center at
medical and urologic
The Miriam Hospital and
assessment. The focus
clinical associate professor
is on a “cardiometaof family medicine and
urology at the Warren Alpert bolic” assessment,
given that the most
School of Medicine, Brown
University, Providence, RI.
significant causes of
Dr. Heidelbaugh is clinical
poor health in men
professor of family medicine
are adverse cardioand urology, University of
Michigan School of Medicine, vascular health habits
and obesity leading to
Ann Arbor.
metabolic syndrome
and ultimately, diabetes mellitus or coronary artery disease.
The subsequent referrals generated from
this comprehensive evaluation can be directed
toward other individualized medical subspe-
cialties or lifestyle and holistic health tutors
complementing the primary care clinician’s
goals of health surveillance and disease prevention. These subspecialties can then individualize referrals to the MHC for a comprehensive
urologic/medical assessment when indicated.
All of these evaluations and interventions are
viewed as extensions of and collaborations with
the patient’s own primary care clinician. These
evaluations are frequently triggered by one of
three conditions commonly encountered by
andrology/urology: erectile dysfunction, testosterone deficiency, and infertility.
These conditions are often complemented by
two urologic conditions managed most commonly by primary care and can serve as a focus
of an MHC:
O BPH/lower urinary tract symptoms
O PSA screening for prostate cancer.
These conditions are exclusive to men, or
rather the narrow lens of urologic male conditions. Together with those conditions that are
not necessarily exclusive to men but are common in both the male and female population,
they form the field of men’s health.
Men have unique and specific gender-based
medical and psychological concerns and needs.
These include depression, post-traumatic stress
disorder, stress management, and veteran’s
health needs; cardiovascular risk stratification; pulmonology, including obstructive sleep
apnea and insomnia or sleep medicine; cancer
screening, including prostate, bladder, lung,
and colorectal; exercise capacity and physiology; substance abuse; and metabolic issues of
obesity, including the spectrum of metabolic
syndrome, glucose intolerance, and dyslipidemia, hypertension, and proper diet.
Medical conditions not isolated to men often
present as male urologic conditions. It is the
presentation of the man through the preventive lens of male medical and urologic health
that becomes the foundation of an MHC. Such
a center of excellence must include the expertise of both the medical-focused men’s health
clinician and the astute urologist, who both
recognize the broad nature and comorbidities
associated with male urologic conditions.
The formation of an MHC program is not
an attempt to replace or take on the role of a
primary care clinician. Clearly, most urologists
do not have the knowledge or skill set to effi-
❳ UT Figure ❲ Men’s health: Multidisciplinary outreach
Internal medicine
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SECTION EDITOR
Dr. Kaplan is E. Darracott Vaughan Jr. Professor of
Urology at Weill Cornell Medical College and director
of the Iris Cantor Men’s Health Center, New York
Presbyterian Hospital, New York. Follow him on
Twitter at @MaleHealthDoc.
r5%BOEEFQSFTTJPO
r4FYVBMEZTGVODUJPO
Source: Martin Miner, MD
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In mCRPC therapy…
Is there more to the story?
INDICATION
ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic
castration-resistant prostate cancer (mCRPC).
IMPORTANT SAFETY INFORMATION
Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X)
when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.
Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema,
hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.
The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia,
lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.
Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten
for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.
Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of
abiraterone acetate was administered with a meal compared to a fasted state.
Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone,
after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms
and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences
unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid
excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages
of corticosteroids may be used before, during, and after stressful situations.
Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients
with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood
pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a
consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established
in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA
Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials.
Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum
potassium, and symptoms of fluid retention at least monthly.
mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.
Please see additional Important Safety Information on the next page.
Please see brief summary of full Prescribing Information on subsequent pages.
For men with mCRPC who progressed on ADT
In a clinical trial, patients had a median overall survival
on ZYTIGA® (abiraterone acetate) of…*
More than 1,000 days.
And every day tells a story.
35.3
5.2 MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL
MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone†
vs 30.1 MONTHS with placebo plus prednisone (active compound).‡
compared with placebo plus prednisone.
Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified
value for statistical significance not reached.
Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus
prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.
IMPORTANT SAFETY INFORMATION (cont)
Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten
for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.
Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose
of abiraterone acetate was administered with a meal compared to a fasted state.
Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see
Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior
to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter.
Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.
Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time
AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN,
interrupt ZYTIGA® treatment and closely monitor liver function.
*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients
with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously
treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients
received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic
progression-free survival.
ADT=androgen-deprivation therapy.
Janssen Biotech, Inc.
© Janssen Biotech, Inc. 2014 6/14 016819-140612
Please see brief summary of full Prescribing
Information on subsequent pages.
003307-130924
Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration
of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4
inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA®
dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug
interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on
the pharmacokinetics of abiraterone.
ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6
substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider
a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the
use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity
related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.
Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment
(Child-Pugh Class C).
†At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone
compared with 43% (234/542) of patients treated with placebo plus prednisone had died.
‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.
Learn more today at
www.zytigahcp.com.
Every day tells a story.
ZYTIGA® (abiraterone acetate) Tablets
Brief Summary of Prescribing Information.
ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the
treatment of patients with metastatic castration-resistant prostate cancer.
CONTRAINDICATIONS
Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant
woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in
women who are or may become pregnant. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking this drug, apprise the patient of
the potential hazard to the fetus and the potential risk for pregnancy loss [see
Use in Specific Populations].
WARNINGS AND PRECAUTIONS
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid
Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as
a consequence of increased mineralocorticoid levels resulting from CYP17
inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In
the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of
patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in
1% of patients treated with ZYTIGA [see Adverse Reactions].
Co-administration of a corticosteroid suppresses adrenocorticotropic hormone
(ACTH) drive, resulting in a reduction in the incidence and severity of these
adverse reactions. Use caution when treating patients whose underlying
medical conditions might be compromised by increases in blood pressure,
hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial
infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a
history of cardiovascular disease. The safety of ZYTIGA in patients with left
ventricular ejection fraction <50% or New York Heart Association (NYHA) Class
III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2)
was not established because these patients were excluded from these
randomized clinical trials [see Clinical Studies (14) in full Prescribing
Information]. Monitor patients for hypertension, hypokalemia, and fluid
retention at least once a month. Control hypertension and correct hypokalemia
before and during treatment with ZYTIGA.
Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two
randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of
patients taking placebo. Adrenocortical insufficiency was reported in patients
receiving ZYTIGA in combination with prednisone, following interruption of daily
steroids and/or with concurrent infection or stress. Use caution and monitor for
symptoms and signs of adrenocortical insufficiency, particularly if patients are
withdrawn from prednisone, have prednisone dose reductions, or experience
unusual stress. Symptoms and signs of adrenocortical insufficiency may be
masked by adverse reactions associated with mineralocorticoid excess seen in
patients treated with ZYTIGA. If clinically indicated, perform appropriate tests
to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of
corticosteroids may be indicated before, during and after stressful situations
[see Warnings and Precautions].
Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST
increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA,
typically during the first 3 months after starting treatment. Patients whose
baseline ALT or AST were elevated were more likely to experience liver test
elevation than those beginning with normal values. Treatment discontinuation
due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No
deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.
Measure serum transaminases (ALT and AST) and bilirubin levels prior to
starting treatment with ZYTIGA, every two weeks for the first three months of
treatment and monthly thereafter. In patients with baseline moderate hepatic
impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST,
and bilirubin prior to the start of treatment, every week for the first month,
every two weeks for the following two months of treatment and monthly
thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical
symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST,
ALT, or bilirubin from the patient’s baseline should prompt more frequent
monitoring. If at any time AST or ALT rise above five times the ULN, or the
bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and
closely monitor liver function.
Re-treatment with ZYTIGA at a reduced dose level may take place only after
return of liver function tests to the patient’s baseline or to AST and ALT less
than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see
Dosage and Administration (2.2) in full Prescribing Information].
The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater
than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN
is unknown.
Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty
stomach. No food should be consumed for at least two hours before the dose
of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken.
Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold
higher, respectively, when a single dose of abiraterone acetate was administered
with a meal compared to a fasted state. The safety of these increased exposures
when multiple doses of abiraterone acetate are taken with food has not been
assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)
in full Prescribing Information].
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid
Excess [see Warnings and Precautions].
Adrenocortical Insufficiency [see Warnings and Precautions].
Hepatotoxicity [see Warnings and Precautions].
Increased ZYTIGA Exposures with Food [see Warnings and Precautions].
Clinical Trial Experience: Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in clinical practice.
Two randomized placebo-controlled, multicenter clinical trials enrolled patients
who had metastatic castration-resistant prostate cancer who were using a
gonadotropin-releasing hormone (GnRH) agonist or were previously treated
with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a
dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the
active treatment arms. Placebo plus prednisone 5 mg twice daily was given to
control patients.
The most common adverse drug reactions (≥10%) reported in the two
randomized clinical trials that occurred more commonly (>2%) in the abiraterone
acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea,
vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.
The most common laboratory abnormalities (>20%) reported in the two
randomized clinical trials that occurred more commonly (≥2%) in the
abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated
AST, hypophosphatemia, elevated ALT and hypokalemia.
Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients
with metastatic CRPC who had received prior docetaxel chemotherapy. Patients
were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases.
Patients with liver metastases were excluded if AST and/or ALT >5X ULN.
Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred
with a ≥2% absolute increase in frequency compared to placebo or were events
of special interest. The median duration of treatment with ZYTIGA was 8 months.
Table 1: Adverse Reactions due to ZYTIGA in Study 1
ZYTIGA with
Prednisone (N=791)
System/Organ Class
Adverse reaction
Musculoskeletal and
connective tissue disorders
Joint swelling/discomfort2
Muscle discomfort3
General disorders
Edema4
Vascular disorders
Hot flush
Hypertension
Gastrointestinal disorders
Diarrhea
Dyspepsia
Infections and infestations
Urinary tract infection
Upper respiratory tract
infection
Respiratory, thoracic and
mediastinal disorders
Cough
Renal and urinary disorders
Urinary frequency
Nocturia
Injury, poisoning and
procedural complications
Fractures5
Cardiac disorders
Arrhythmia6
Chest pain or chest discomfort7
Cardiac failure8
Placebo with
Prednisone (N=394)
All
All Grades1 Grade 3-4 Grades Grade 3-4
%
%
%
%
29.5
26.2
4.2
3.0
23.4
23.1
4.1
2.3
26.7
1.9
18.3
0.8
19.0
8.5
0.3
1.3
16.8
6.9
0.3
0.3
17.6
6.1
0.6
0
13.5
3.3
1.3
0
11.5
5.4
2.1
7.1
0.5
0
2.5
0
10.6
0
7.6
0
7.2
6.2
0.3
0
5.1
4.1
0.3
0
5.9
1.4
2.3
0
7.2
3.8
2.3
1.1
0.5
1.9
4.6
2.8
1.0
1.0
0
0.3
1 Adverse
Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2
(continued)
ZYTIGA with
Placebo with
Prednisone (N=542)
Prednisone (N=540)
System/Organ Class
All Grades1 Grade 3-4 All Grades Grade 3-4
Adverse reaction
%
%
%
%
Renal and urinary disorders
Hematuria
10.3
1.3
5.6
0.6
Skin and subcutaneous
tissue disorders
Rash
8.1
0.0
3.7
0.0
1 Adverse events graded according to CTCAE version 3.0
2 Includes terms Edema peripheral, Pitting edema, and Generalized edema
3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness
events graded according to CTCAE version 3.0
terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness
3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,
Musculoskeletal discomfort, and Musculoskeletal stiffness
4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized
edema
5 Includes all fractures with the exception of pathological fracture
6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular
tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter,
Bradycardia, Atrioventricular block complete, Conduction disorder, and
Bradyarrhythmia
7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial
infarction or ischemia occurred more commonly in the placebo arm than in the
ZYTIGA arm (1.3% vs. 1.1% respectively).
8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular
dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection
fraction decreased
2 Includes
Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low
serum phosphorus (7%) and low potassium (5%) occurred at a greater than or
equal to 5% rate in the ZYTIGA arm.
Table 2: Laboratory Abnormalities of Interest in Study 1
Abiraterone (N=791)
Placebo (N=394)
Laboratory
All Grades Grade 3-4 All Grades Grade 3-4
Abnormality
(%)
(%)
(%)
(%)
Hypertriglyceridemia
62.5
0.4
53.0
0
High AST
30.6
2.1
36.3
1.5
Hypokalemia
28.3
5.3
19.8
1.0
Hypophosphatemia
23.8
7.2
15.7
5.8
High ALT
11.1
1.4
10.4
0.8
High Total Bilirubin
6.6
0.1
4.6
0
Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088
patients with metastatic CRPC who had not received prior cytotoxic
chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and
patients were excluded if they had liver metastases.
Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred
with a ≥2% absolute increase in frequency compared to placebo. The median
duration of treatment with ZYTIGA was 13.8 months.
Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2
System/Organ Class
Adverse reaction
General disorders
Fatigue
Edema2
Pyrexia
Musculoskeletal and
connective tissue disorders
Joint swelling/discomfort3
Groin pain
Gastrointestinal disorders
Constipation
Diarrhea
Dyspepsia
Vascular disorders
Hot flush
Hypertension
Respiratory, thoracic and
mediastinal disorders
Cough
Dyspnea
Psychiatric disorders
Insomnia
Injury, poisoning and
procedural complications
Contusion
Falls
Infections and infestations
Upper respiratory tract
infection
Nasopharyngitis
ZYTIGA with
Placebo with
Prednisone (N=542)
Prednisone (N=540)
All Grades1 Grade 3-4 All Grades Grade 3-4
%
%
%
%
39.1
25.1
8.7
2.2
0.4
0.6
34.3
20.7
5.9
1.7
1.1
0.2
30.3
6.6
2.0
0.4
25.2
4.1
2.0
0.7
23.1
21.6
11.1
0.4
0.9
0.0
19.1
17.8
5.0
0.6
0.9
0.2
22.3
21.6
0.2
3.9
18.1
13.1
0.0
3.0
17.3
11.8
0.0
2.4
13.5
9.6
0.2
0.9
13.5
0.2
11.3
0.0
13.3
5.9
0.0
0.0
9.1
3.3
0.0
0.0
12.7
10.7
0.0
0.0
8.0
8.1
0.0
0.0
Table 4 shows laboratory abnormalities that occurred in greater than 15% of
patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in
Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine
aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.
Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of
Study 2
Abiraterone (N=542)
Placebo (N=540)
Laboratory
Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4
Abnormality
%
%
%
%
Hematology
Lymphopenia
38.2
8.7
31.7
7.4
Chemistry
Hyperglycemia1
56.6
6.5
50.9
5.2
High ALT
41.9
6.1
29.1
0.7
High AST
37.3
3.1
28.7
1.1
Hypernatremia
32.8
0.4
25.0
0.2
Hypokalemia
17.2
2.8
10.2
1.7
1Based on non-fasting blood draws
Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2,
cardiac failure occurred more commonly in patients treated with ZYTIGA
compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4
cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to
5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred
in 0.2% of patients taking placebo. There were no treatment discontinuations
and one death due to cardiac failure in the placebo group.
In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one
death associated with arrhythmia and one patient with sudden death in the
ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths
due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in
the placebo arms. Myocardial ischemia or myocardial infarction led to death in
3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.
Post Marketing Experience
The following additional adverse reactions have been identified during post
approval use of ZYTIGA. Because these reactions are reported voluntarily from
a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.
DRUG INTERACTIONS
Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is
a substrate of CYP3A4.
In a dedicated drug interaction trial, co-administration of rifampin, a strong
CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid
concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong
CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing
frequency [see Dosage and Administration (2.3) and Clinical Pharmacology
(12.3) in full Prescribing Information].
In a dedicated drug interaction trial, co-administration of ketoconazole, a
strong inhibitor of CYP3A4, had no clinically meaningful effect on the
pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full
Prescribing Information].
Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an
inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6
drug-drug interaction trial, the Cmax and AUC of dextromethorphan
(CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when
dextromethorphan was given with abiraterone acetate 1,000 mg daily and
prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate
with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).
If alternative treatments cannot be used, exercise caution and consider a
dose reduction of the concomitant CYP2D6 substrate drug [see Clinical
Pharmacology (12.3) in full Prescribing Information].
In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of
ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be
monitored closely for signs of toxicity related to the CYP2C8 substrate if used
concomitantly with abiraterone acetate. OVERDOSAGE
Human experience of overdose with ZYTIGA is limited.
There is no specific antidote. In the event of an overdose, stop ZYTIGA,
undertake general supportive measures, including monitoring for arrhythmias
and cardiac failure and assess liver function.
Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions
permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled
room temperature].
Based on its mechanism of action, ZYTIGA may harm a developing fetus.
Therefore, women who are pregnant or women who may be pregnant should
not handle ZYTIGA without protection, e.g., gloves [see Use in Specific
Populations].
USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause
fetal harm when administered to a pregnant woman based on its mechanism of
action and findings in animals. While there are no adequate and well-controlled
studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use
in women, it is important to know that maternal use of a CYP17 inhibitor could
affect development of the fetus. Abiraterone acetate caused developmental
toxicity in pregnant rats at exposures that were lower than in patients receiving
the recommended dose. ZYTIGA is contraindicated in women who are or may
become pregnant while receiving the drug. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking this drug, apprise the patient of
the potential hazard to the fetus and the potential risk for pregnancy loss. Advise
females of reproductive potential to avoid becoming pregnant during treatment
with ZYTIGA.
In an embryo-fetal developmental toxicity study in rats, abiraterone acetate
caused developmental toxicity when administered at oral doses of 10, 30 or
100 mg/kg/day throughout the period of organogenesis (gestational days 6-17).
Findings included embryo-fetal lethality (increased post implantation loss and
resorptions and decreased number of live fetuses), fetal developmental delay
(skeletal effects) and urogenital effects (bilateral ureter dilation) at doses
≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and
decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused
maternal toxicity. The doses tested in rats resulted in systemic exposures
(AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.
Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known
if abiraterone acetate is excreted in human milk. Because many drugs are
excreted in human milk, and because of the potential for serious adverse
reactions in nursing infants from ZYTIGA, a decision should be made to either
discontinue nursing, or discontinue the drug taking into account the importance
of the drug to the mother.
Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not
been established.
Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials,
73% of patients were 65 years and over and 30% were 75 years and over. No
overall differences in safety or effectiveness were observed between these
elderly patients and younger patients. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.
Patients with Hepatic Impairment: The pharmacokinetics of abiraterone
were examined in subjects with baseline mild (n=8) or moderate (n=8)
hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy
control subjects with normal hepatic function. The systemic exposure
(AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased
by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate
baseline hepatic impairment, respectively compared to subjects with normal
hepatic function.
In another trial, the pharmacokinetics of abiraterone were examined in subjects
with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in
8 healthy control subjects with normal hepatic function. The systemic exposure
(AUC) of abiraterone increased by approximately 7-fold and the fraction of free
drug increased 2-fold in subjects with severe baseline hepatic impairment
compared to subjects with normal hepatic function.
No dosage adjustment is necessary for patients with baseline mild hepatic
impairment. In patients with baseline moderate hepatic impairment (Child-Pugh
Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do
not use ZYTIGA in patients with baseline severe hepatic impairment
(Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin
>3X ULN occur in patients with baseline moderate hepatic impairment,
discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and
Clinical Pharmacology (12.3) in full Prescribing Information].
For patients who develop hepatotoxicity during treatment, interruption of
treatment and dosage adjustment may be required [see Dosage and
Administration (2.2) in full Prescribing Information, Warnings and Precautions,
and Clinical Pharmacology (12.3)] in full Prescribing Information.
Patients with Renal Impairment: In a dedicated renal impairment trial, the mean
PK parameters were comparable between healthy subjects with normal renal
function (N=8) and those with end stage renal disease (ESRD) on hemodialysis
(N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is
necessary for patients with renal impairment [see Dosage and Administration (2.1)
and Clinical Pharmacology (12.3) in full Prescribing Information].
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information)
Patients should be informed that ZYTIGA and prednisone are used together
and that they should not interrupt or stop either of these medications without
consulting their physician.
Patients receiving GnRH agonists should be informed that they need to
maintain this treatment during the course of treatment with ZYTIGA and
prednisone.
Patients should be informed that ZYTIGA must not be taken with food and
that no food should be consumed for at least two hours before the dose of
ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken.
They should be informed that the tablets should be swallowed whole
with water without crushing or chewing. Patients should be informed that
taking ZYTIGA with food causes increased exposure and this may result in
adverse reactions.
Patients should be informed that ZYTIGA is taken once daily and prednisone
is taken twice daily according to their physician’s instructions.
Patients should be informed that in the event of a missed daily dose of
ZYTIGA or prednisone, they should take their normal dose the following day.
If more than one daily dose is skipped, patients should be told to inform
their physician.
Patients should be apprised of the common side effects associated with
ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated
liver function tests, and urinary tract infection. Direct the patient to a
complete list of adverse drug reactions in PATIENT INFORMATION.
Patients should be advised that their liver function will be monitored using
blood tests.
Patients should be informed that ZYTIGA may harm a developing fetus; thus,
women who are pregnant or women who may be pregnant should not
handle ZYTIGA without protection, e.g., gloves. Patients should also be
informed that it is not known whether abiraterone or its metabolites are
present in semen and they should use a condom if having sex with a
pregnant woman. The patient should use a condom and another effective
method of birth control if he is having sex with a woman of child-bearing
potential. These measures are required during and for one week after
treatment with ZYTIGA.
Manufactured by:
Patheon Inc.
Mississauga, Canada
Manufactured for:
Horsham, PA 19044
© Janssen Biotech, Inc. 2012
Revised: May 2014
015924-140528
www.urologytimes.com
∣
15
MARCH 2015
ciently evaluate men in the role of a primary care clinician. Yet urologists often
have the unique opportunity to initially
meet and monitor men as they enter the
medical infrastructure, and many men
do not yet have primary care clinicians.
For example, when these men present
for male-specific urologic concerns,
the urologist can connect the patient to
a knowledgeable primary care clinician
and seek a cardiovascular risk evaluation
as part of that individual’s presentation
of erectile dysfunction.
This does not exclude the urologist from
taking an active role in the medical comorbidities uncovered in these evaluations, but
often these are best served by evaluation
via the medical clinician and/or psychologist in a paired visit. This is an opportunity to take advantage of the presentation
of men who desire to “fix their urologic
problem” but also address the underlying
causes. This also aids the male patient who
is hesitant to visit the physician due to time
or psychological constraints.
❳ UT Table ❲ Cardiometabolic
workup in men
Vital signs
O
O
O
O
Height/weight
Pulse
Blood pressure
Body mass index
Abdominal waist circumference
>40 inches in Caucasian and African-American men and
>35 in Asian men determines presence of metabolic
syndrome
Lipid profile
O
O
O
O
O
Full lipid profile, including triglycerides
Total cholesterol/HDL ratio
Fasting serum glucose or non-fasting glycosylated
hemoglobin
Measurements determine degree of metabolic syndrome or diagnosis of type 2 diabetes mellitus
Risk stratification for atherosclerotic cardiovascular
disease risk (see tools.cardiosource.org/ASCVD-RiskEstimator)
calculator developed via the collaboration of the American College of Cardiology and American Heart Association in
2013, yet each has an evolving role in the
determination of cardiometabolic risk.
When cardiovascular risk is equivocal or
intermediate, the only risk marker with a
significant sensitivity and specificity is a
coronary artery CT calcium score (J Am
Coll Cardiol 2014; 63:2889-934).
When assessing cardiometabolic risk
in the male patient, it is also vital to assess
the presence of other health co-factors,
including diet; exercise capacity and habits; sleep (quantities and disorders) and
levels of stress; depression and anxiety;
and alcohol, tobacco, and illicit substance
abuse (AUA 2014 annual meeting course
by Carrion/Swierzewski). Validated
questionnaires can be used to gather the
symptomatic data to assist in assessing
each of these cofactors to determine risk.
$PODMVTJPO
We live in a time of great stress upon the
medical system and health care providOther biomarkers
5IFNFOTIFBMUIFWBMVBUJPO
ers. The adaptation of the patient-centered
High-sensitive or cardio-sensitive C-reactive protein
The basis of any men’s health evaluation
medical home model and electronic medito assess for underlying cardiometabolic risk
begins with the notation of the patient’s
cal records, as well as increasing scrutiny
apolipoprotein B*
vital signs: height, weight, pulse, blood
of testing and outcomes, all add to our
Urine microalbumin to serum creatinine ratio*
pressure, body mass index, and abdomburden of management of male patients.
25-hydroxy vitamin D level*
inal waist circumference (table). This
A men’s health program and concentraOther co-factors
measurement of visceral adiposity and
tion can allow those symptoms men see as
Diet
understanding of its predictive signifivital to a healthy life (eg, sexual function)
Exercise capacity and habits
cance for cardiometabolic disease by
and propel them into a softer landing for
Sleep habits and stress
the urologist, the men’s health general
a greater preventive focus and risk factor
Depression and anxiety
medical clinician, and patient serves as
analysis. This effort requires a urologist
Substance abuse
the first significant marker of the male
who acknowledges and seeks evaluation
patient’s cardiovascular risk. It also
of appropriate medical comorbidities cou*Not shown to be more effective at discriminating cardiovascular risk
allows the opportunity to identify men
pled with a productive partnership with
than traditional risk factors
with previously undiagnosed hypertenprimary care clinicians or focused within
Source: Martin Miner, MD, and Joel Heidelbaugh, MD
sion or monitor men previously diagthe context of a men’s health program or
nosed with hypertension. It allows for
center established to address these needs.
a quick classification of degree of obeA portion of the Affordable Care Act
sity in order to structure the appropriate
involves the implementation and use
C-reactive protein to assess for underlying carnutritional guidance and exercise program that diometabolic risk. Other biomarkers of cardio- of preventive services in the care of patients.
may follow.
metabolic risk can be individualized according Benchmarks will be set to track and validate
A waist circumference greater than 40 inches to each patient, but may include any of the fol- outcomes and the performance of health care
(measured at the umbilicus) allows a simple lowing: apolipoprotein B (a surrogate measure- providers, whether urologists or primary care
determination of the presence or absence of ment of small-particle LDL cholesterol), urine clinicians. Men’s health serves as a gendermetabolic syndrome. Further measurements microalbumin to serum creatinine ratio, and based opportunity to tailor these improved outof a man’s lipid profile, specifically targeting 25-hydroxy vitamin D level. It should be noted comes to the health-consuming habits of men
the total cholesterol/HDL cholesterol ratio and that none of these markers has been shown to be and improve preventive care. This is best done
triglyceride levels, together with a measurement highly effective at discrimination of cardiovas- in sync with the medical clinician, whether that
of a fasting serum glucose or a non-fasting gly- cular risk greater than traditional cardiovascu- individual is the patient’s primary care clinician
cosylated hemoglobin, allows the determina- lar risk factors such as the presence of tobacco or a trained men’s health clinician.
tion of the degree of metabolic syndrome or abuse, family history of premature heart attack,
We live in an age of women’s health, family
the diagnosis of type 2 diabetes mellitus. This and obesity.
health, and pediatric health. It is vital that we
construct is well understood to have a bidirecIn addition, none of the above factors has understand the factors and determinants of
tional relationship with testosterone deficiency. been shown to exceed the risk predictive improving men’s health and lessening the genTo complement this evaluation, a clinician capacity of traditional risk equations such as der gap as it pertains to both disease morbidity
may order a high-sensitive or cardio-sensitive the Framingham risk profile or the new risk and mortality.
O
O
O
O
O
O
O
O
O
16
❳ Special Report ❲
N A RROW N E T WORK S
The insurance companies are going to pay lip
service to the issue of value—quality divided
by cost. But we all understand cost is the driving
factor,” Dr. Kaufman said. “If equal or better
quality can be delivered, then we’re happy to do
MARCH 2015
health policy chair at the American Association
of Clinical Urologists (AACU) and a urologist
practicing in Seattle.
“Both limit access to providers to save cost
and tout improved quality, which has not been
established. Urologists need to be aware of
these models of care that may be established
in their communities,” Dr. Frankel said.
Having said that, it could
be to a urologist’s advantage to be part of a narrow
network, Dr. Frankel says.
Being part of a limited
number of providers could
increase a urologist’s or
group’s market share.
Dr. Frankel, who says
his group practice is part of
Medicare Advantage plans,
says these plans are narrow
networks in disguise. Medicare Advantage plans appear
to save money at first, but once seniors try to
make appointments with a specialist of their
choice or fill a prescription, the lack of choice
and sticker shock set in, Dr. Frankel says.
“The insurance companies are
going to pay lip service to the
issue of value—quality divided
by cost. But we all understand
cost is the driving factor.”
JEFFREY KAUFMAN, MD
it at a lower cost. But if companies are going to
sacrifice quality in favor of reducing the cost,
no one’s interests are better served.”
About narrow networks
Narrow networks are simply limited provider
networks, says Linda Cushman, executivein-residence, Cornell University’s master’s in
health administration program, and a human
resources professional with more than 30 years
of health care consulting experience.
The concept is nothing new.
Health maintenance organizations (HMOs)
were the original narrow network, Cushman
says. Today’s narrow networks are among the
payment models designed to rein in health care
costs, she says. Insurance companies have lost
the ability to risk adjust their premiums under
Obamacare.
“For individuals and small employers enrolling via the exchanges, Obamacare has eliminated most of the ways insurance companies have
traditionally used to control risk. The only way
that insurance companies think they have now
to control their costs is to eliminate higher cost
providers from their networks, because they
can’t eliminate higher cost people anymore.
That’s the crux of it,” Cushman said.
“Under Obamacare, they can’t protect themselves against bad risk, or what we used to call
adverse selection. So now, because they’re on
these exchanges and they’re competing, the best
way to compete is with a lower premium.”
Accountable care organizations (ACOs) are
different than narrow networks in that ACOs
focus on Medicare beneficiaries while narrow
networks can involve all patients. But ACOs
have important things in common with narrow
networks, according to Jeffrey Frankel, MD,
∣
Urology Times
according to a response by Aetna prepared for
Urology Times.
“As part of our provider performance evaluation, physicians are notified of their Aexcel
designation status, and all physicians have the
option of the reconsideration process,” according to the response. “Physicians may provide
additional information pertaining to their care
for Aetna members that might not be captured
in claims data. Physicians have this option after
they review member-level reports that we provide them in advance to a public display of their
status. This is done to ensure that our decisions
are made using the most comprehensive information and engage physicians as participants
in the process.”
But there appears to be confusion among
urologists about whether they belong to narrow networks or not. Urology Times reached
out to two urologists designated as being on
Aetna’s Aexcel network. One urologist’s assistant responded that the urologist knew nothing
about it. The other urologist responded, wanting
to remain anonymous, and said he didn’t know
he was a preferred provider on Aetna’s narrow
network.
Narrow networks, however, are a growing reality.
“What’s happening is
[most] insurance companies are picking hospitals
for these networks, initially.
That’s where it gets a little
dicey for the practicing urologist. If your hospital is not
part of the narrow network,
the odds are you’re not going
to be part of it,” Dr. Frankel
said.
Cushman, the consultant,
says most patients are still
covered by their employers.
And most employer health
plans are not going to narrow
networks. It’s patients who are on the exchanges, Medicare, and Medicaid that will be most
impacted, she says.
It’s true that the exchanges are pushing
narrowed products, according to a report by
the McKinsey Center for U.S. Health System
Reform. The McKinsey study looked at data
from 120 unique 2014 individual exchange
market products in the silver tier offered by 80
carriers and characterized networks as broad,
narrow, or ultra-narrow (defined by participating in the 20 largest local hospitals in a rating
area). The report found 70% of all networks
were narrow or ultra-narrow.
Narrow networks, however, are filtering in
the mainstream. In a Sept. 16, 2014 article, the
“The only way that insurance
companies think they have
now to control their costs is to
eliminate higher cost providers
from their networks, because they can’t
eliminate higher cost people anymore.”
LINDA CUSHMAN
Health care consultant
“Those are privatized Medicare patients, who
usually join a system of the hospital. They have
very low premiums for their supplement and the
network is very narrow. They have to go through
a primary care physician, get a referral; then, if
they want to see me, they have to pay $50. To
me, that’s quite a bit. It’s an economic disincentive to see a specialist,” Dr. Frankel said.
“Narrow networks [including Medicare
Advantage plans] are growing, and, politically, they’re going to continue to grow because
Republicans like those Medicare privatized
plans. It’s a way of limiting benefits.”
Are these networks in your community?
Aetna’s Aexcel narrow network is in 41 markets, and does not include tiering of hospitals,
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18
Los Angeles Times reported that “Anthem Blue
Cross is joining forces with several big-name
hospitals and their doctors to create an unusual
health plan option for employers in Southern
California. The joint venture… brings together
seven rival hospital groups in Los Angeles and
Orange counties, including well-known institutions Cedars-Sinai Medical Center and the
UCLA Health System.”
The California Public Employees’ Retirement System signed up and started with the
plan Jan. 1, 2015.
Narrow networks outside of exchanges are
most likely to pop up where insurers have more
options (in hospitals and providers) and more
clout, Cushman says. And they appear to be
more common in bigger cities, Dr. Frankel says,
where patients can get adequate coverage even
if their options for providers and hospitals are
limited.
Focus on cost
Granted, businesses in the for-profit health
industry can’t afford to ignore costs. Cost does
matter. And extreme variations in provider and
hospital costs do exist.
The McKinsey Center analysis found broad
networks tend to have higher premiums than
narrower networks of the same carrier, product
type (such as HMO or PPO), metal tier, and
rating area. Academic medical centers were
most often associated with broader networks.
For example, 35% of the ultra-narrow networks
in the analysis included an academic medical
center in network compared to 94% of broad
networks.
Insurance carriers also point to extreme variations in cost. A report released in January 2015
by the Blue Cross Blue Shield (BCBS) Association, based on independent BCBS companies’
claims data, found extreme cost variations for
MARCH 2015
knee and hip replacement surgeries among hospitals and markets.
The study shows that while the average cost
for a total knee replacement procedure was
$31,124 in 64 markets, it could cost as little
as $11,317 in Montgomery, AL and as much
as $69,654 in New York City. These extremes
exist even within markets. For example, in
Dallas, a total knee replacement could cost
between $16,772 and $61,585, depending on
the hospital.
In its statement prepared for Urology Times,
Aetna put it this way: “As the health care system
transforms from fee-for-service payment models to outcomes, value-based payment models
demonstrating clinical quality and efficiency
will be critical to increasing patient base and
optimizing revenue within urology.”
Urologists are among physicians in 12
medical specialty categories that are eligible
for Aexcel-designation within Aetna’s Specialist Performance Network. Urology, however, remains less exposed than some highcost specialty areas. On its website, the Blue
Cross Blue Shield Association says this about
its Blue Distinction program: “The Blue Distinction Centers for Specialty
Care program is evolving from
a quality-focused designation to
a more robust Total Value designation with the goal of further
differentiating Blue Distinction
Centers from other facilities.
True to its original commitment
as a quality-based program,
Blue Distinction is evolving to
become a value-based designation awarded to facilities that meet stringent
quality measures, focused on patient safety and
outcomes, as well as cost of care criteria.”
For now, BCBS is focusing on six specialty
areas: bariatric surgery, cardiac care, complex
and rare cancers, hip and knee joint replacements, spine surgery, and transplants.
Why the urologist shortfall matters
NARROW NETWORKS
BY THE NUMBERS
70
%
35
%
of all networks were narrow or ultranarrow in a study of 120 exchange
market products in the silver tier that
characterized networks as broad,
narrow, or ultra-narrow.
of ultra-narrow networks
included an academic medical
center in network vs. 94% of
broad networks.
Source: McKinsey Center for U.S. Health System Reform report (December 2013)
The shortage of urologists only adds to the complexity of how narrow networks might impact
the specialty.
“There are limited numbers of urologists.
We have 500 leaving practice per year through
attrition and about 260 to 270 graduating residency. So, we’re short,” Dr. Kaufman said. “And
there may be an unequal distribution of patients
in these networks. So you may have doctors
overwhelmed with patients or patients unable
to gain access to physicians.”
If there are too few urologists, insurance
companies deal with access, first. Access
trumps cost as an issue, according to Cushman.
Narrow network hospitals and providers are
based on cost, access, and quality indicators
∣
Urology Times
through the Affordable Care Act, according to
Cushman.
Aexcel-designated specialists, Aetna says,
have demonstrated effectiveness in the delivery
of care based on a balance of certain measures
that include volume, clinical performance, and
efficiency in the use of health care resources.
The National Committee for Quality Assurance
serves as an independent ratings examiner for
Aetna, according to the company’s statement.
Volume has to do with identifying urologists
and other specialists who have managed at least
20 episodes of care for Aetna members during
the past 3 years. Clinical performance indicators include: readmission rates, acute care complications, a doctor’s industry recognitions and
board certification, and whether the doctor uses
electronic prescribing or an electronic medical
record. Efficiency includes costs, resources to
treat patients, and number and types of services
performed, according to Aetna’s website.
Define quality
But good quality data for including urologists
in narrow networks isn’t available, Dr. Frankel
says.
“If your hospital is not part of
the narrow network, the odds are
you’re not going to be part of it.”
JEFFREY FRANKEL, MD
He speaks from experience. Dr. Frankel’s
practice was excluded from Aexcel a few years
ago, he says, and his patients received letters
indicating that the network is restricted to promote high-quality providers. But he discovered
his group’s exclusion had nothing to do with
quality.
“I met with the [insurer’s] medical director
in the Northwest who admitted that they did not
have urology-specific quality data, but the network was narrowed to the urologists who admitted at their preferred hospital,” Dr. Frankel said.
The industry’s metrics aren’t fine-tuned
enough for insurers to determine who is and is
not a high-quality urologist, Dr. Frankel says.
“So, their quality measures are based on
cost,” he said.
Dr. Frankel says the AACU’s message
regarding narrow networks is that they are not
a sign of quality.
“It’s a managed care model. It’s an economically based system,” Dr. Frankel said. “I can’t
say it’s not going to lower costs. It might. But
there are some significant disadvantages. We
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20
have a limited number of urologists and it’s very
difficult to get guaranteed coverage.”
Dr. Kaufman says he understands the motivation to provide value, and that’s a good thing.
“But I’m not sure narrow networks is the
best way to go. If there is an opportunity for
an insurance company or payer to identify
outliers—doctors who are providing less than
desirable quality or just are outrageous in their
costs—I have no problems with eliminating
them. Patients may choose to see a doctor
outside of network and that’s their right,” Dr.
Kaufman said. “We know there are some great
physicians and there are some lousy physicians,
but the majority of physicians are somewhere
in between, where they’re delivering reasonably good quality, abiding by the guidelines,
and they’re trying to watch costs.”
Specialists will be scrutinized
Urologists should take steps now to better
understand narrow networks and how they
MARCH 2015
might fit into the payment model.
They should understand that as more data
comes online, like the cost data on knee and
hip surgery, other specialties will be scrutinized for cost and quality indicators. Urolo-
“Value-based payment models
demonstrating clinical quality
and efficiency will be critical
to increasing patient base and
optimizing revenue within urology.”
AETNA STATEMENT
gists should know how their practices are
doing in relation to their peers’, Cushman
says.
“Specifically, [narrow networks] eliminate
the high-cost and/or low-quality providers,”
Cushman said.
“Too often, physicians are passive bystanders and cede control to payers. In the future
∣
Urology Times
as more data becomes available, the savvy
specialty groups will use that data to improve
the cost and quality profiles of their physician
members.”
Aetna recommends: “As inpatient and outpatient facility-based costs do impact efficiency,
specialty providers should consider the quality
and efficiency of facilities and ensure they are
informed about the most appropriate places to
provide services.”
To protect their market shares, urologists
should be proactive, analyzing whether narrow networks play a significant role in their
communities.
“I think you need to find out who is going to
be included in narrow networks and see if you
want to be part of it, if you want to stay viable,”
Dr. Frankel said. “It all comes down to referrals. If you’re not in a narrow network, you’re
not going to get referrals from the primary care
physicians.
“You have to be careful. You have to understand the business and politics of medicine. No
matter how well you do on board recertification, you may find yourself excluded if you
don’t keep up with this stuff.” UT
How network cancellations impact a practice: One specialist’s experience
In late 2013, James R. Pinke, MD, an ophthalmologist in
solo practice, received letters from a trio of insurance carriers outlining their plans to create special networks of
“five-star” physicians for 2014. Then came a letter in late
October with unexpected contents: Dr. Pinke would be
removed as an in-network provider for UnitedHealthcare’s
2014 Medicare Advantage (MA) network, effective Feb.
1. He was not alone: more than 2,000 other Connecticut
physicians also were being ousted.
Overnight, everything changed for Pinke Eye Center in
Shelton, CT, where he has practiced for 31 years. When he
started out, about 500 of his active patients were covered
by United’s MA plan. Medicare comprises fully 87% of Dr.
Pinke’s practice—and United’s MA plan is second only to
traditional fee-for-service Medicare plus supplemental
insurance for his patients.
“Effectively, we would have had to shut our doors.
That’s how many United Medicare Advantage patients
we had,” said Tina Pinke, the practice administrator who
is also the ophthalmologist’s wife.
According to Tina Pinke, the practice received no
explanation from United concerning her husband’s initial
exclusion from its 2014 MA network.
“It’s very threatening to any practice to be removed
from a very large Medicare Advantage network with no
feedback,” she said, noting that her husband has performed more than 30,000 cataract procedures “with no
problems, no ‘black letters,’ nothing.”
United spokesperson Betsy Chin says the company’s
decisions regarding network inclusion “are influenced
by multiple factors, but they are locally driven and based
on a combination of geography, quality, and efficiency.
When making decisions about our network, we focus
on ensuring that our members will have ready access to
care and also consider providers’ relative performance
on industry quality metrics and their ability to deliver
high-quality care for the most members in the most costefficient manner.”
Initially, Dr. Pinke stayed on United’s 2014 online provider directory. Brokers knew of insurers’ narrowing networks, but they had been given directories and still saw Dr.
Pinke among listed network physicians. So did patients.
“There was mass confusion about who was in and
who was out,” Tina Pinke said, explaining her husband’s
name was on and off the list for a while. After 2 weeks,
a United provider services representative returned the
practice’s phone calls and confirmed that Dr. Pinke would
be removed from the MA network.
Subsequently, the practice tried phoning 500 patients
to alert them that Dr. Pinke wouldn’t be in-network,
explaining that meant he couldn’t take United’s MA
patients—most of them elderly and coming to him for
30 years with active eye diseases such as glaucoma—
after Feb. 1, 2014.
The town’s only other ophthalmologist also had been
removed from United’s 2014 MA network, leaving no
ophthalmologists in-network at the local hospital, Tina
Pinke recalls. Two local medical societies, along with Dr.
Pinke and several other physicians, became vocal about
the matter and hundreds of people attended a town hall
meeting. On Dec. 4, days before the MA open enrollment
period ended, Pinke received a letter from United saying
he was back in its 2014 MA network.
“None of our patients were notified, though,” Tina
Pinke said. “It caused a lot of animosity—patients blaming us, thinking Dr. Pinke did something wrong. It puts
you totally on the defensive.” She said it caused a “tremendous amount of disruption” to the practice, lengthening office visits because of explanations to patients at
check-in and again by the ophthalmologist during exams.
United’s initial letter to Dr. Pinke in fall 2013 “said you
could appeal, and we immediately sent a certified letter,
but we never received acknowledgment of the appeal,”
and United’s follow-up letter in December didn’t mention it, Tina Pinke said. “It just said, ‘After further review
of our network, we decided to include you.’ ” She isn’t
sure whether the Fairfield and Hartford county medical societies’ legal involvement on behalf of members
played a role.
Read this article in its entirety online at
www.modernmedicine.com/cancellation-impact.
UrologyTimes.com
∣
Speak Out
Has the current state
of medicine affected
your retirement plans?
“I
t’s affected my plans because the distribution of reimbursement favors the
technology component in compensation. The
professional side is dwarfed by people providing technology, but it’s not minimizing the physician’s role. Even though technicians provide
the service, urologists bear the responsibility.
If there’s a problem during a ureteroscopy,
you never see the ureteroscope manufacturer
blamed; the physician takes the brunt.
The urology establishment also tends to promote technology. There’s an attitude that if you
do an open nephrectomy, you should be driving a horse and buggy. There’s nothing wrong
with it; it’s a good operation. Technology is
glorified rather than craftsmanship.
Urology should take a stand and say, ‘The
king has no clothes.’ We’ve seen technologies
come and go. Balloon dilation of the prostate
went by the wayside because it wasn’t effective. The urology establishment has to be more
assertive that the craftsmanship of urology is as
important as the technology.
Most likely, I will retire earlier than I originally
planned. At one time, I thought I’d work until I
was 70, but I don’t see that now. You can’t just
close a solo practice; you have to phase it out
or hand it over to somebody else. If you’re in a
group, you can decide one day to retire and a
partner will take care of your patients. If you’re
an employee, the company will find someone,
but if you’re a solo practitioner your ultimate
responsibility is to the patient.”
Abraham Steinberg, MD
Geneva, IL
“T
21
MARCH 2015
he Golden Age of medicine, where reimbursement was much higher, is no longer
here, but I went into medicine partly because of
my own passion and because of my family’s legacy. My great-great-great grandfather emigrated
from China in 1850 looking for gold and settled in
a small town in gold country called Fiddletown,
CA. He was also an herbalist. Because he wasn’t
successful at finding gold, he treated Chinese
miners and later those building the transcontinental railroad. Since he helped establish the
family tradition, a lot of our family has entered
medicine and dentistry through the generations.
Even with the changes in the health care system, I still love what I’m doing. Coming into medi-
I still get satisfaction from practicing urology.
cine, I knew it would not
The problem is finding glimmers of sunshine
be as lucrative as it was
in the past. I came in with through clouds. Hospitals would like to vertically integrate everyone and say, ‘Work as an
my eyes open.
employee and we’ll take care of all these aggraThat’s the nice thing
vations,’ but I don’t know anyone who works as
about physicians coman employee who doesn’t still have to deal with
ing into medicine now.
those issues. If anyone thinks they’ve found the
They’re
here
for
the
Dr. Yee
perfect solution, call me.”
right reasons. I’m not
happy about all the
Andrew B. Sher, MD
changes, but I also have a Masters in Public
Leesburg, FL
Health studying health policy and management. As an
individual physician, I hope
to help effect change so we
can improve health care for
all Americans.
I know there’s more concern about finances after
you retire, but that’s part
of being a medical doctor
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Molecular pathways: next-generation immunotherapy––inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587.
3. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.
24
❳ Q&A ❲
MARCH 2015
∣
Urology Times
PATRICK H. MCKENNA, MD
Dr. McKenna was interviewed by Urology Times Editorial
Consultant Philip M. Hanno, MD, MPH, professor of urology
at the University of Pennsylvania, Philadelphia.
ETHICS IN UROLOGY
Self-referral, live surgery
raise ethical challenges
Urologist self-referral of services such as intensity-modulated radiation
therapy and pathology has raised ethical questions that continue to be
debated. In this interview, Patrick H. McKenna, MD, former chairman
of the AUA’s Judicial & Ethics Committee, discusses self-referral as
well as the AUA expert witness program, conflicts of interest, and live
surgical demonstrations. Dr. McKenna is professor of urology at the
University of Wisconsin, Madison.
Q: Please discuss the AUA Judicial
& Ethics Committee’s duties.
A: This committee has broad responsibilities in matters related to controversy with the
association and its members, ethics of medical practice, education, and research. It serves
in an advisory capacity to the AUA Board,
allowing active membership input at the highest levels on these matters. Every section has
two representatives that sit on the committee,
along with senior leadership from the administrative side of the AUA and the AUA’s legal
counsel.
The main areas of focus are monitoring the
organization’s conflict of interest policy, the
expert witness policy and, more recently, the
development of the expert witness voluntary
registry. It covers a tremendous number of ethical issues and is also involved in writing and
updating policy on these issues.
I strongly recommend members to check out
the policy statements on the AUA web site. The
work of this committee is often not recognized
but represents one of the best member benefits.
Q: How often does the committee meet?
A: Normally, we meet twice a year face to
face, and then by phone in between when necessary. There is an executive committee of the
Judicial & Ethics Committee that meets more
frequently.
Q: Please discuss the expert
witness program.
A: Over the last decade, the committee has
developed one of the best expert witness programs of any medical organization.
All members agree to abide by the expert
witness affirmation statement (http://www.
auanet.org/about/policy-statements/testimony-in-medical-liability-cases.cfm). There are
key elements that our members agree to abide
by that go above most state requirements for
expert witnesses. Some of these areas include:
only testifying on matters the members have
recent and relevant substantive clinical experience, allowing the Judicial & Ethics committee
Please discuss the AUA expert
witness program.
PHILIP M. HANNO, MD, MPH
The goal of the voluntary
Expert Witness Registry
is to provide good expert
witnesses in the hope that
the number of cases that go
to trial is diminished.
to review any testimony, and being willing to
provide testimony for both plaintiff and defendants. You must be at least 5 years out of training to testify and have been clinically active in
the area under question within at least 5 years.
Recently, the AUA Board approved the
establishment of a voluntary Expert Witness
Registry. Most urology malpractice cases result
in upholding the defendant’s position, but even
the process of a trial can be very disruptive
to a urologist’s practice. The goal of the registry is to provide good expert witnesses in the
hope that the number of cases that go to trial
is diminished.
Q: What can the committee do if it believes
somebody acted inappropriately?
A: The committee follows a step-by-step policy
when referred a malpractice case to review.
That provides fair review for our members.
Usually, two members who are not from the
same section review the case, as does the entire
executive committee.
The case is scored on a sheet that is based on
the expert witness affirmation statement. The
case and review are presented to the entire committee. The committee can decide to provide
feedback to the member and have them review
the affirmation statement or may recommend
to the board that disciplinary action be taken
against the member.
Q: What is the most severe action that
can be taken against a member?
A: The committee itself cannot take action, but
we can recommend to the board that there be
a formal rebuke of a member. The most severe
action would be a recommendation for member
expulsion from the AUA.
There have been rebukes and expulsions
in the past; members can view rebukes and
expulsions on the AUA members-only website.
Q: Let’s discuss a study published in the
New England Journal of Medicine (2013;
369:1629-37). Among self-referring
urologists, the number of intensitymodulated radiation therapy procedures
for prostate cancer rose from 80,000
to 366,000 from 2006 to 2010, and the
article concluded that financial incentives
for self-referring providers were likely
a major factor driving the increase.
Should we be surprised by these findings,
especially given the cost of equipment
and the higher reimbursements for
IMRT? Isn’t this just human nature?
Please see ETHICS, page 26
DOCUMENT Results: Mulvariate Analysis of
Known Risk Factors and Assay Performance1
Odds
Rao 3.00
2.50
2.00
1.50
1.00
0.50
0.00
Age
(0.0563)
PSA
(0.2593)
HGPIN
(0.7546)
Atypia ConfirmMDx
(p-value)
(0.0465)
(<0.0018)
26
❳ Q&A ❲
E T HIC S
A: First, let me say that this is not an area of
urology where I am an expert. I serve on the
board of the American Association of Clinical
Urologists and on other health policy committees, so I have participated in discussions about
this article. As a pediatric urologist, I’m not
involved with prostate cancer treatment, which
may be an advantage in giving a fair evaluation
of the current information.
Shouldn’t the burden of proof
rest with those doing the selfreferrals, because your gut
instinct is that ownership is
obviously going to make a
difference?
I agree some may have that
gut instinct, but the data
does not exist to support
that finding.
The AUA has responded to this article, as
has the AACU and the Large Urology Group
Practice Association. There are specific problems with the study that have been pointed out
by these organizations; specifically, the study
design and patient selection. Several publications, including the AUA News, have also
identified problems with this study. A recent
OncLive summary by Drs. Judd Moul and
Deepak Kapoor succinctly summarizes that
urology practices are prescribing IMRT appropriately (www.onclive.com/.../at-issue-imrtself-referral/2). In addition, two other articles
(J Urol 2011; 186:860-4, Brachytherapy 2014;
13:157-62) pointed out that three-dimensional
conformal radiation therapy decreased during
the time that IMRT saw an increase and the
pattern of IMRT use saw similar increases in
physician office and hospital facilities.
We need good data to know whether any of
these accusations are true. I’m not sure we have
all of the necessary data, but the two articles
suggest that new technologies such as robotics
and IMRT are rising more rapidly, as some of
the previous treatments are declining because
people are gravitating toward new technology.
Q: Shouldn’t the burden of proof rest with
those doing the self-referrals, because
your gut instinct is that ownership is
MARCH 2015
obviously going to make a difference?
A: I agree some may have that gut instinct, but
the data does not exist to support that finding.
The AUA has good guiding principles for selfreferral. You need to follow state and federal
regulations pertaining to care. For example,
with standard radiology, you have to provide
patients with information on alternative sites.
The most important thing is to have a complete discussion with the patient about what
their disease process is and what the options are
for their treatment. They should be advised that
they are entitled to seek a second opinion, and
treatment should be based on objective, medically acceptable and supported recommendations. Provision of ancillary services should be
transparent and in the patient’s best interest.
Patients’ urologic care should not be disrupted
if they obtain their ancillary services from a
different supplier.
Something else to note when talking about
these services is that they are integrated, giving patients, particularly older patients, the
ability to get these services in one place. It’s
important to point out the benefits of integrated
services. In addition to obtaining the services
in one center, patients also benefit from close
interaction between specialists. Close interaction between specialists may limit the number
of studies done and allows close working relationships; for example, urologists and radiation
oncologists can determine the boundaries of
radiation treatment together.
Q: I can see advantages to this if it were
a competitive market where people were
setting their own prices and it wasn’t
mandated by insurance companies,
but when it’s the same price no matter
where you do it, it doesn’t seem like there
is any major advantage to the patient
being treated in the same center.
A: It’s important to be procedure specific
when discussing this. For example, there are
significant differences with outpatient surgery
reimbursement. Hospital-connected outpatient
surgery centers receive significantly higher
reimbursement than freestanding centers.
IMRT is one of those exceptions where there
isn’t a significant difference in reimbursement.
We have two journal articles that come to different conclusions. The New England Journal
study has significant flaws, and the Journal of
Urology article suggests that use of IMRT is
increasing at a similar rate in physician offices
and at hospitals.
Last year, I was invited as visiting professor to a large urology group practice and saw
how these integrated services worked. I was
quite impressed. I saw in action some of the
benefits of having a large integrated group; for
example, having a single EMR is a big advantage when studying patient care. Not only can
∣
Urology Times
the guidelines be implemented throughout the
whole practice very quickly, but the practice has
a fairly robust EMR, so they can document that
the guidelines are being followed.
I saw urologists talk to their robotic surgeon
about a case and then go downstairs and talk
to their radiation oncologist. It is clearly an
advantage to have the different specialists in
the same building.
Having served on the Judicial & Ethics Committee for over a decade, it is clear to me that
we have a highly ethical membership that is
focused on improving patient care. I feel confident that integrated independent practices bring
added value to patient care and may decrease
costs in some areas.
One way the AUA will help us make these
decisions is the new realignment that’s happening in the areas of health policy and quality.
At the 2014 AUA annual meeting, we voted
on moving health policy and quality into two
separate groups, and the new Science & Quality Council will oversee guidelines, a new
data center, and patient safety issues. I think
the development of the AUA Quality Registry
(AQUA), our new quality patient database, will
allow better patient data collection to evaluate treatment decisions. I think it will support
my belief that we are providing good patientfocused care in our practices.
Q: Do you think that disclosure of
conflict of interest sufficiently mitigates
the problem for the patient?
A: I’m not sure. The patient makes a connection with the physician and facility. My guess
is the patient is more likely to stay there than
go somewhere else no matter what disclosure
is given. What we need is to confirm whether
the treatment follows guidelines and to confirm
a good outcome from treatment. This is why
the AUA approach is on target by providing a
resource to obtain that data.
UT EXCLUSIVE VIDEO
urologytimes.com/McKenna-videos
In three videos, Dr. McKenna discusses
urologist self-referral of intensitymodulated radiation therapy and
imaging and pathology services, as
well as live surgery demonstrations.
UrologyTimes.com
∣
❳ Q&A ❲
MARCH 2015
Q: The practice of physician self-referral
for imaging and pathology services has
been criticized, because it can lead to
increased use and escalating health care
expenditures with little or no benefit
to the patient. Jean M. Mitchell, PhD,
looked at Medicare claims for men to
determine how the in-office ancillary
services exception affected the use of
surgical pathology services and cancer
detection rates associated with prostate
biopsies (Health Affairs 2012; 31:741-9).
Self-referring urologists billed Medicare
for 4.3 more specimens per prostate
biopsy than the adjusted mean of six
specimens per biopsy than non-selfreferring urologists sent to independent
pathology providers, a 72% difference.
The regression-adjusted cancer detection
rate in 2007 was 12 percentage points
higher for men treated by urologists who
did not self-refer, indicating unnecessary
biopsies. What is the AUA position on this?
is consulting with a pharmaceutical
or device manufacturer be a principal
investigator on one of their studies, or
is this an inherent conflict of interest?
How does the AUA view this issue?
A: The AUA doesn’t have a specific guideline
related to pharmaceutical research, but our
Code of Ethics specifically states that research
needs to be in the patient’s best interest. There
needs to be full disclosure of any conflicts of
interest that you have as a researcher. If you are
Q: What is the AUA’s position regarding
the in-office ancillary services exception?
A: The AUA’s position on this was one of the
key points taken up at the 2014 Joint Advocacy
Conference in Washington. The AUA policy
states that there is benefit in having integrated
services and providing care in one site for the
patient where there is interaction among specialists, as long as urologists follow the guidelines we talked about earlier.
Q: Should an academic physician who
the chairman or on the board of a pharmaceutical company making urologic medications,
you couldn’t serve as a guideline chairman in
an area that the company has a product or hold
other key positions for the AUA. Speaking personally, if a paper were published about a drug
in which one of the physician authors serves
on the board for the drug’s developer, I would
scrutinize the paper closely and certainly that
relationship should be disclosed.
Please see ETHICS, page 28
Equip yourself for lithotripsy.
A: The AUA has responded to this article, and
interestingly, Dr. Mitchell was also the author
of the New England Journal article we discussed earlier. Funding for the pathology study
is from the group that stands to gain the most by
her allegations—similar to the previous article.
When this paper came out, I asked an oncologist at my institution how many biopsy samples
he routinely does, and his answer was 12.
This paper covered a period of time when
there was transition between six and 10-12
cores. The mean of six specimens reported in
this paper is probably wrong, and subsequent to
this article, two papers were published that supported the fact that a higher number of biopsy
samples will have a higher detection rate (J Urol
2013; 189:2039-46, Rev Urol 2013; 15:137-44).
I think most urologists are following the AUA
guidelines, which recommend 10 to 12 samples.
At our institution, we recently standardized
the whole prostate biopsy process. This is a
high-volume procedure with easy-to-monitor
complications. We have decided on a standardized process, determined what antibiotic we
will utilize, decided against rectal swabs for
bacterial culture, and agreed to the number of
biopsies and how to manage the specimens.
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28
❳ Q&A ❲
MARCH 2015
E T HIC S
Q: Let’s talk about live surgical
demonstrations at meetings like the
AUA. What’s the advantage of a live
demonstration versus a recorded
demonstration with the surgeon taking
real-time questions from the audience?
Are there ethical or patient safety issues
with live surgical demonstrations?
A: That’s a great question. When I was secretary of the North Central Section, I advocated
strongly for live surgical presentations and
expanded its use at our annual meeting. There
are strong opinions about this held by prominent members of our organization. The AUA
has specific standard operating practices for
live surgery.
If live surgery is utilized as a teaching method, it needs to be well organized and follow
specific guidelines. To begin with, the patient
who is having the surgery needs to know that
they are going to be a part of a live surgical
performance. The facility where the patient is
being treated also needs to be aware. The decision to do a procedure must meet acceptable
indications. I believe the person overseeing the
planned educational event should review the
case in advance. It is very important to have
a sophisticated company handling the broadcast, because you need to be able to control
the live feed and stop it immediately if any
issues arise. I like to sit right at the control
table. I like having more than one facility when
doing these so we can switch between cases
if necessary.
I also believe the surgery should not be any
different than if the patient was not participating in a demonstration. I don’t like the idea of
the physician stopping at key points and waiting
until we come back to the scene. If we miss a
key point, we miss a key point. The surgery
should proceed as it normally would. I believe
it is wrong for an urologist to do a live case from
another institution. It should be done at their
home institution with their own team.
There are some other key components. The
audience shouldn’t be able to call in questions.
They need to go through a moderator. I prepare the moderator beforehand to make sure
that they are comfortable with the case.
From a learning point of view, a live surgery
case results in better attention by participants.
There seems to be higher retention and more
interest in a case when it is done live. Some
people refer to this as a “crash” mentality; the
audience is wondering what the next step is and
if something will go wrong. This is the same
reason why some argue against live surgery.
If the above steps are followed, there should
not be a higher complication rate. If there is
a problem, the person overseeing the course
should discontinue the transmission.
Q: Should the AUA get away from
lobbying on economic issues and leave
that to other urology organizations
and restrict itself to issues related to
research, patient safety and well-being,
and optimal care? It seems like a potential
tube
∣
Urology Times
ethical conflict for one organization
to have both of those functions.
A: Medicine has changed significantly, and
the direction is to connect reimbursement with
quality outcomes, patient safety, and costs.
Even tort reform on a national level incorporates the concept of patient quality with the
recommendation of safe havens provided if
physicians follow established guidelines. The
government is looking at specific monitors of
quality in discussions about reimbursement. As
we go forward, more and more reimbursement
is not going to be based just on the volume of
what we do, but on the quality of outcomes.
The AUA has taken the correct stance, particularly by putting a lot of emphasis on guidelines. Guidelines are going to be important not
only for reimbursement and patient safety, but
also for tort reform. In the future, if you follow
guidelines, you will likely be in a safe haven as
far as tort litigation. All these things are coming together, and the AUA’s readjustment of its
quality and health policy is right in line with
what the future has to bring. We can’t disconnect from the economic part, because the government is connecting economics to quality.
Q: I understand. It just seems like the
AUA shouldn’t be the organization
that’s protecting the economic interest
of urologists; that should be handled
by a different organization. The AUA
should be more concerned with quality
of care, outcomes, and guidelines.
A: I think we really are focused primarily on
patient-related factors. I don’t think our orga-
‘Y’tube is a video resource for urologists and other physicians who
focus on men’s health. Videos cover surgical aspects of a variety of men’s
health issues, with the goal of providing clinicians a current reference.
UROLOGYTIMES.COM/TAG/YTUBE
THIS MONTH’S INSTALLMENT
James M. Hotaling, MD, MS, | Section Editor
Reconstructive urologists illustrate nuances of managing urethral strictures
Sean P. Elliott, MD, MS,
Alex Vanni, MD,
Jeremy Myers, MD,
demonstrates one of the
most simple and
reliable urethroplasty
techniques: excision
and primary
anastomosis of
the urethra.
shows buccal mucosa graft urethroplasty
for lengthy bulbar urethral strictures
that are not amenable to excision
and primary anastomotic
urethroplasty.
demonstrates, in two videos, creation
of a definitive perineal urethrostomy
for severe urethral strictures and
a posterior urethroplasty for pelvic
fracture urethral injury.
UrologyTimes.com
∣
❳ Q&A ❲
MARCH 2015
Are there ethical or patient
safety issues with live surgical
demonstrations?
The AUA doesn’t have a
specific guideline related to
pharmaceutical research,
but our Code of Ethics
specifically states that
research needs to be in the
patient’s best interest.
gists, I did not think there was any need to be
involved in health policy issues. I have come
to understand that academic urologists need
to be more involved in this area. More and
more educational programs are being driven
and supported by clinical dollars. This cannot be sustained. We need to rethink how the
costs of graduate medical education are being
covered.
There was a recent report from the Institute
of Medicine recommending major changes in
29
how graduate medical education will be funded in the future. There are work force issues
and research support issues. These are areas
where academic urologists need to become
involved. Our academic institutions are often
the largest employers in a region and carry significant weight with local and national political
leaders. I encourage more academic urologists
to become active in this area because as an
organized group, we can have a significant
impact. UT
nization is focused on the economic part of
practice, but those elements are connected.
Our focus really is on education, quality, and
ethics, but the government is connecting all of
this, so that reimbursement is going to be tied to
quality. The AUA is in the best position to help
urologists learn how to practice medicine in a
quality-conscious way. We also need to work
and maintain our specialty by helping to define
our areas of expertise. In many of the areas that
we manage patients, other specialties overlap or
compete. This clearly has an economic aspect,
but it is important to maintain the integrity of
our specialty.
I think there is going to be a total change
in how we think about quality. Separate physician/nurse quality committees will give
way to institutional quality committees that
incorporate all aspects of the institution. For
example, right now, we focus on central line
infections, catheter-related urinary tract infections, ventilator-associated infections, and C.
difficile infections. These are really measures
of effective hand washing, type of equipment,
education, room cleaning, etc. What is the best
hand washing solution to use? What is the cost?
Where are the hand washing stations placed?
What is the best cleaning solution for hospital
cleaning staff to use?
In the future, we need to connect the entire
facility to the quality initiatives and understand
the cost along with the most effective methods to improve patient care. Future committees need to be broad based. It’s going to be an
exciting time, but we have to rethink how we
function. It’s not going to be the typical quality
of the old days.
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References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic
prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Schulze
H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced
testosterone surge in patients with metastatic carcinoma of the prostate. J Urol. 1990;144(4):934-941. 3. Loblaw DA, Virgo
KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer:
2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.
Q: Is there anything else
you’d like to discuss?
A: Yes. Three years ago, I did not understand
completely the importance of being involved
in health policy. Like many academic urolo-
30
❳Business of Urology❲
MARCH 2015
∣
Urology Times
Papillotomy billing:
Two pathways to choose
Either report increased effort, risk involved or use unlisted code 53899
Q I have a coding question that I
just cannot find an answer for. The
physician stated he did a papillotomy
of kidney stones, and I’m not able to
find a code for it.
The operative report indicated
that physician obtained a flexible
ureteroscope and did a renoscopy.
The patient was noted to have
intraparenchymal calculi throughout
the lower middle upper pole and
a posteriorly located lower pole.
Capsulotomy was started on the lower
pole calices, and multiple stones were
released during the process. “We then
addressed the middle pole calices and
performed papillotomy throughout the
middle pole,” the report said. “Finally,
we performed papillotomies in the
upper pole in standard fashion. Multiple
renal calculi were extracted during that
process. We then obtained a 1.9 caliceal
basket and extracted all loose calculi.”
I asked exactly how the papillotomy
was performed. He stated that he
went up to the kidney with the scope.
Once stones were identified, he
lasered/cut the kidney to extract the
stone. He also left the slit open to
drain. Then once he got to the stones,
he took them out with a basket.
Please help.
A
Good question. Unfortunately, as
you suggested, there is no code that specifically describes the procedure performed.
In reading the operative note above, it
appears that the capsulotomy and papillotomy were used
to free stones. We
agree that the procedure note clearly
THIS ISSUE
indicates a significant amount of
❯❯THE BOTTOM LINE
extra work from that
How to evaluate patient
which is normally
safety in your practice
performed during
a basket extraction
❯❯MONEY MATTERS
of a stone or stones.
Life insurance: Selecting the
Accordingly, we see
owner of your policy
two pathways, nei-
Business of
Urology
32
34
Coding Q&A
Ray Painter, MD, Mark Painter
Urologist Ray Painter, MD, is president of Physician Reimbursement Systems, Inc., in Denver and
is also publisher of Urology Coding and Reimbursement Sourcebook. Mark Painter is CEO of PRS
Urology SC in Denver.
ther of which will sidestep the need for a
manual review prior to payment.
Pathway 1: You might consider adding
the –22 modifier to code 52352 (Cystourethroscopy, with ureteroscopy and/or
pyeloscopy; with removal or manipulation of calculus [ureteral catheterization
is included]). Argue that the procedure
required a significant increased effort and
was more risky due the approach to the
stones. You may wish to create an addendum to the operative note indicating the
amount of time spent to accomplish the
procedure and provide a relative reference
to a standard stone extraction (ie, “The
operation took 1 hour; 133% of the time
required to perform a typical stone extraction.”). Future operative notes of this type
should also include a relative time reference. If an indwelling stent is left, also
report 52332 (Cystourethroscopy, with
insertion of indwelling ureteral stent [eg,
Gibbons or double-J type]).
Pathway 2: Use an unlisted code 53899
(Unlisted procedure, urinary system)
with guidance for the payer on how to
pay for the service as an additional note
to the payer in the form of a letter. We
would recommend that you reference
codes 52352 and 52346 (Cystourethroscopy with ureteroscopy; with treatment of
intra-renal stricture [eg, balloon dilation,
laser, electrocautery, and incision]) as a
combined value upon which to base the
reimbursement.
Q
I am considering making an
investment in a small company that
provides outsourced urodynamic
studies whereby the company sends
a nurse and urodynamic equipment
to the physician’s premises, the
study is conducted, the results are
loaded into the company’s proprietary
software, and the results are
delivered to the physician—usually an
obstetrician/gynecologist, urologist,
or urogynecologist.
This company takes advantage of
split billing and appears to deliver
very high-quality services using the
best equipment. The company bills
the physician directly and in turn the
physician bills Medicare/Medicaid/
insurance directly using split billing,
with over 100 clinics/practices using
this process.
However, in some of my due
diligence, some physicians I have
spoken with raised a concern that
Medicare/Medicaid might do away
with such split billing that allows for
such a study to be outsourced to the
company. Is this a valid concern? Are
there any caveats of urodynamic split
billing to look out for as it relates to
this outsourcing arrangement?
A
If the physician has a contract with
Correction
Our December 2014 column (“2015 final
rule reflects shift from fee for service”) contained the following incorrect statement:
“Medicare has decided to eliminate all the
G codes for prostate biopsies and revise code
G0416 to be reported for all biopsies over 10
specimens.” It should have read: “Medicare
has decided to combine reporting of prostate
biopsies regardless of number of specimens
under revised code G0416. 88305 should not
be used for the analyses of prostate biopsies
for Medicare patients with dates of service
on or after Jan. 1, 2015.” We apologize for
any confusion this may have caused.
UrologyTimes.com
∣
31
MARCH 2015
an outside entity to perform urodynamics in their
office, the physician can legally charge for the
test.
If the test is performed on one day and the
physician reads the test on another day, the
technical component of the test is billed on the
date performed and the professional component
should be billed on the day the test is read by
the physician. Both components should be paid
by Medicare.
Some private payers do not pay for “split
billing” (billing for the technical component
on a different day than reporting the professional component), insisting that the physician
charge for the complete test without splitting
into technical and professional components.
For those payers, the test, without modifiers, should be charged on the day it was
performed.
Note: At this point there is not a payment
differential for billing the services separately
for the majority of payers.
We are not aware of any attempt by Medicare to change these rules. However, we have
heard talk of overutilization of these tests and
caution you to be certain that you have clear,
documented pathways to determine medical
necessity for each test.
We will further caution you to make sure
that you are compliant with anti-kickback laws.
for all prostate needle biopsies regardless of
the number of biopsies/cores. The new definition of G0416 (Surgical pathology, gross and
microscopic examinations, for prostate needle biopsy, any method) reflects this change.
We mistakenly added to the confusion in
our December 2014 column (“2015 final rule
reflects shift from fee for service,” page 28),
where we wrote: “Medicare has decided to
eliminate all the G codes for prostate biopsies
and revise code G0416 to be reported for all
biopsies over 10 specimens.”
The correct statement should have been:
“Medicare has decided to combine reporting
of prostate biopsies regardless of number of
specimens under revised code G0416. 88305
should not be used for the analyses of prostate
biopsies for Medicare patients with dates of
service on or after Jan. 1, 2015.” We apologize
for this error. UT
Q
My physician performed a prostatic
needle biopsy recently in which he only
took nine specimens instead of the usual
12. How should I bill for these specimens?
A friend tells me that I should be using
G0416. However, I thought this code
was for more than 10 specimens. Also,
the CPT code 88305, the code for a
single specimen, still shows that it is an
active paying code when I looked it up on
AUACodingToday.com I am confused.
A
Your friend is correct. Prostate biopsies
were “separated” from other surgical specimens listed in 88305, even though they are
still listed in the CPT code for 2015. Medicare no longer pays 88305 for prostate needle
biopsies. G0416 is now the appropriate code
Send coding and reimbursement questions to Ray
Painter, MD, and Mark Painter c/o Urology Times,
at UT@advanstar.com.
Questions of general interest will be chosen
for publication. The information in this
column is designed to be authoritative, and
every effort has been made to ensure its
accuracy at the time it was written. However,
readers are encouraged to check with
their individual carrier or private payers for
updates and to confirm that this information
conforms to their specific rules.
Androgen levels may impact antiandrogen therapy.1-3
Learn more at inhibitandrogen.com/excess
References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castrationresistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen.
Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical
studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH
agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New
York, NY: Plenum Press; 1986:627-644.
32
MARCH 2015
∣
Urology Times
FIRST IN A SERIES
How to evaluate patient
safety in your practice
Tools, processes are available to measure safety culture
and analyze/mitigate risks
A
lmost 12 years have passed since
the National Quality Forum
(NQF) released its 2003 consensus recommendations entitled,
“Safe Practices for Better Healthcare.” The initial release was primarily driven
by the Institute of Medicine’s sentinel report
on medical errors (“To Err is Human: Building a Better Health System”) and was aimed at
inpatient hospital environments. NQF updated
its Safe Practices recommendations in January
2014.
Many of the 34 safe practices remain
unchanged from their original issue, are generalizable to the office setting, and incorporate
strong evidence of reducing harm to patients.
Yet the penetration of these practices and principles in community urology practice remains
uncertain and unmeasured. How much safer are
patients than they were 10 years ago?
According to the report, “Every day, patients
are still harmed, or nearly harmed, in healthcare institutions across the country. This harm
is not intentional; however, it usually can be
avoided. The errors that create harm often stem
back to organizational system failures, leadership shortfalls, and predictable human behavioral factors.”
In a series of articles, I will review aspects of
this important report that are relevant to quality
and safety in urologic practice. After reading
these articles, urologists should reflect honestly
on their own opportunities to improve the safety
of care in their own practices.
Barriers to creating culture of safety
Health care is a highly complex, error-prone
activity where many barriers exist to creating
and sustaining a culture of safety. These barriers include expectations that physicians will
perform perfectly and errors are caused only
by negligence or incompetence; lack of open
communication when errors do occur; lack
of awareness about the prevalence of risks,
errors, and adverse outcomes; a lack of systems thinking; and a lack of safety-oriented
leadership.
NQF’s Safe Practice 1 addresses these barriers with recommendations for structures and
systems that raise awareness of the problem,
implement measurement and accountability for
safe practices, and lead to actions and investments. In a urology practice, these practices
could involve incorporating safety in a mission statement, appointing a physician or staff
member as the patient safety officer, creating a
patient safety committee (in a larger practice),
encouraging reports of errors and near misses
Recommended reading, tools
Visit www.urologytimes.com/safety-reading for these recommended articles and tools
related to patient safety.
O
O
O
O
O
O
O
Safe Practices for Better Healthcare (National Quality Forum)
Dowling, RA and Baum, NH. Ensuring patient safety: Culture and communication
(Urology Times, December 2007, page 30)
Dowling, RA and Baum, NH. Ensuring patient safety: Practical steps to take now
(Urology Times, January 2008, page 27)
Medical Office Survey on Patient Safety Culture (Agency for Healthcare Research and
Quality)
Global Trigger Tool (Institute for Healthcare Improvement)
Failure Mode and Effects Analysis Tool (Institute for Healthcare Improvement)
White Paper on the Incidence, Prevention and Treatment of Complications Related to
Prostate Needle Biopsy (AUA/SUNA)
The Bottom Line
Robert A. Dowling, MD
Dr. Dowling is an independent
consultant, the former medical
director of a large metropolitan
urology practice, and the
consulting medical director for
Healthtronics IT Solutions. He
resides in Fort Worth, TX.
without fear of consequences, patient safety
education for all staff members, and communication strategies by leadership to the other
physicians and staff.
In a closely related recommendation, Safe
Practice 2 reads: “Healthcare organizations
must measure their culture, provide feedback
to the leadership and staff, and undertake interventions that will reduce patient safety risk.”
This recommendation is very easy for the urology practice to implement, and if for the first
time, should probably be done before addressing the leadership issues of Safe Practice 1.
Health care is a highly complex,
error-prone activity where many
barriers exist to creating and
sustaining a culture of safety.
The Agency for Healthcare Research and
Quality has developed the Medical Office
Survey on Patient Safety Culture, a free,
easy-to-implement validated instrument
complete with Spanish version, implementation webinar and user guides, a data entry
tool (for large practices), and a comparative
database that is even broken down by specialty to allow benchmarking. Survey domains
include questions about teamwork; patient
follow-up; overall perceptions; organizational learning; staff training; communications about errors; support from leadership
regarding safety, office practices, and standardization; and work pressure and pace. All
members of the health care team, including
physicians, are surveyed.
In 2014, there were 27,103 survey responses from 935 office practices, including 109
responses from urology. These results are critical context for understanding the responses
from your own practice, analyzing the results,
and developing actions based upon this knowledge.
Safe Practice 4 is the effective identification
(and then mitigation) of risks and hazards in
the health care setting. In hospital settings, one
UrologyTimes.com
∣
33
MARCH 2015
common approach to identifying risks involves
the analysis of adverse events; for example, the
Institute for Healthcare Improvement’s (IHI)
Global Trigger Tool.
Analyzing, mitigating risks
A more proactive approach includes the IHI’s
Failure Mode and Effects Analysis Tool, where
processes with risk are taken apart into steps,
the possible things that could go wrong are
identified, and the causes and effects of those
failures are identified with the purpose of
addressing the causes before they result in a
“failure.” Most urology practices do not have
the resources to conduct these formal studies,
but can borrow from the principles to conduct
their own risk assessment. For example, consider this simple series of steps:
Identify five procedures in your office
that involve risks to patient safety (examples:
prostate biopsy, vasectomy, cystoscopy, bacillus
Calmette-Guérin instillation, office injections/
implantations).
For each procedure, identify five things
(failure modes) that could go wrong (examples:
wrong patient, wrong procedure, wrong or broken equipment, infection/contamination, anaphylactic reaction).
For each failure mode, identify five possible causes (example for infection: equipment not properly sterilized, antibiotics not
taken, cross contamination from lubricating
jelly, patient colonized with resistant organism because of recent antibiotic use, break in
sterile technique).
For each possible cause, identify all
prevention strategies and opportunities for
improvement (example: “AUA/SUNA White
Paper on the Incidence, Prevention and Treatment of Complications Related to Prostate
Needle Biopsy”).
Another approach might involve hiring a
consultant to conduct a formal risk assessment
based upon a site visit and/or personal observation. An outsider may bring a level of distance
and objectivity to the process that avoids any
bias introduced by members of the staff who
may be inured to some of the potential risks
they have failed to recognize in their busy daily
routines.
Bottom line: Safety is an unspoken yet fundamental expectation of all patients, and health
care delivery—even in the office—is a complicated and error-prone business. Creating and
maintaining a culture that improves the safety
of patients requires active steps by practice
leaders. Simple tools and procedures are available and can be used in urology practices of all
sizes and shapes. UT
r
r
r
r
❳t Practice Pointers ❲
The National Quality Foundation recently updated
its recommendations “Safe Practices for Better
Healthcare,” but penetration of these practices
and principles in community urology practice
remains uncertain and unmeasured.
t The Agency for Healthcare Research and Quality’s
Medical Office Survey on Patient Safety Culture
is a free, validated instrument that measures a
practice’s patient safety culture.
t The Institute for Healthcare Improvement’s
Failure Mode and Effects Analysis takes apart
processes with risk into steps, identifies the possible things that could go wrong, and identifies
the causes and effects of those failures with the
purpose of addressing the causes before they
result in a “failure.”
t Another approach to evaluating risk might
involve hiring a consultant to conduct a formal
risk assessment based upon a site visit and/or
personal observation.
Learn more at inhibitandrogen.com/sequence
*Currently in the absence of published, randomized, prospective clinical study data on treatment
sequencing in mCRPC.
mCRPC=metastatic castration-resistant prostate cancer.
References: 1. Sartor AO, Tangen CM, Hussain MHA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest
Oncology Group trial (SWOG 9426). Cancer. 2008;112(11):2393-2400. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management
of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology
practice guideline. J Clin Oncol. 2007;25(12):1596-1605.
34
MARCH 2015
Life insurance: Selecting
the owner of your policy
selecting the owner of a life insurance
policy?
A
Many physicians recognize the benefits
of an overall financial plan to meet their longterm objectives such as retirement planning,
education planning, and investment planning.
However, planning for the unexpected, via life
insurance, is certainly less pleasant, and also
quite difficult. Understandably, no one likes to
contemplate their own demise, and there are so
many other important issues that seem to take
precedence over the life insurance decisionmaking process.
Whatever the reason, delaying this important
part of the planning process can result in expensive and unintended tragic consequences. When
planning for survivor income needs, you will
need to consider the ongoing income needs of
your survivors, as well as any immediate lumpsum needs. Once you have defined the qualitative and quantitative need for life insurance, you
can begin to determine which specific product
in the life insurance marketplace best meets
your objectives.
The work, however, does not end there. Time
also needs to be spent on the intricacies of how
those death benefits pass to the intended heirs,
and how your estate is impacted, prior to making the purchase.
Prior to purchasing a life insurance policy,
give careful consideration to who the owner of
❳t Financial Tips ❲
While life insurance proceeds aren’t subject to
income taxes, the proceeds can be subject to
estate taxes.
t The four most common ways to own a life
insurance policy include: by the insured, by the
insured’s spouse, by a person other than the
insured’s spouse, and by a trust.
t In 2015, if you want to pay the insurance premiums, premiums in excess of $14,000 (unchanged
from 2014) may be considered taxable gifts.
t If you are in line to inherit from a relative but
would rather have the funds go to someone else,
you must use a disclaimer.
the policy should be. While insurance proceeds
aren’t subject to income taxes, the proceeds
can be subject to estate taxes. The four most
common ways to own a life insurance policy
include:
By the insured. If you own the policy, the
insurance proceeds will be considered part of
your taxable estate and may be subject to estate
taxes if your estate is large enough.
By the insured’s spouse. The insurance proceeds won’t be included in your taxable estate
if your spouse both owns the policy and is the
Minor children can’t own insurance
policies in most states, so you may
have to set up a custodial account if
the owners are minors.
beneficiary of the policy, unless you inherit the
policy under the terms of your spouse’s will.
However, if someone else is named as beneficiary, such as a child, the proceeds will be considered a gift and may be subject to gift taxes.
By a person other than the insured’s spouse. In
this situation, the insurance proceeds won’t be
included in your taxable estate. However, in
2015 keep in mind that if you want to pay the
insurance premiums, premiums in excess of
$14,000 (unchanged from 2014) may be considered taxable gifts. In situations where you have
two or more beneficiaries, you will have to gift
the money for the premiums to the beneficiaries
in order to qualify for the gift tax exclusion.
Minor children can’t own insurance policies
in most states, so you may have to set up a custodial account if the owners are minors. Care
must be taken if you are transferring an existing
policy. This is considered a gift, which may
trigger gift taxes if the cash value is in excess
of $14,000. Also, if you die within 3 years of
transferring a policy, the proceeds will still be
included in your taxable estate.
By a trust. When a trust owns the policy, the
proceeds are not considered part of your taxable estate if the trust is irrevocable and you
are not the beneficiary, meaning that you can’t
change the terms or terminate the trust. The
same tax rules apply to trusts as those applicable to a person other than your spouse, but
Urology Times
Money Matters
Joel M. Blau, CFP,
Ronald J. Paprocki,
JD, CFP, CHBC
Careful consideration of ownership is crucial, as proceeds
can be included in taxable estate
Q What are the best options when
∣
Joel M. Blau, CFP, (top)
is president and Ronald J. Paprocki, JD, CFP, CHBC, is chief
executive officer of MEDIQUS
Asset Advisors, Inc. in Chicago.
They can be reached at 800-8838555 or blau@mediqus.com or
paprocki@mediqus.com.
you often can structure more flexibility into a
trust arrangement.
While it may seem easiest to simply own the
policy and have a spouse be the beneficiary, as
you can see, other options may be more favorable. Spend some time with your financial
planner to determine the most efficient way to
structure your life insurance policies. Only in
this manner will your insurance plan be properly coordinated with your overall financial
plan in an effort to minimize or reduce estate
taxation.
Q I am in line to inherit from a relative,
but would prefer the funds go to other
family members instead. Is that possible?
A
You will need to use a disclaimer, which
must meet certain requirements:
The disclaimer must be in writing and be
irrevocable.
You must disclaim the gift within a certain
amount of time—generally 9 months after the
date of death or taxable transfer.
You must take action before you receive any
benefits from the gift.
You must not have already benefited from
the inheritance.
Under the law, you cannot direct or control
who specifically receives the gift you’re refusing. But unless an alternate beneficiary is
named in the will, the assets are generally
treated as if you had also died. In other words,
they pass to the decedent’s next-in-line beneficiary.
r
r
r
r
Send us your questions
Send your questions about estate planning,
retirement, and investing to Joel M. Blau, CFP,
c/o Urology Times, at UT@advanstar.com.
Questions of general interest will be chosen for publication.
The information in this column is designed to be authoritative. The publisher is not engaged in rendering legal advice.
2
18
e
us b
i t um
V is o t h n
bo
at
Connection
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r
9
Your Constant
36
❳ Clinical Spotlight ❲
BIOP S Y
the role of targeted biopsy in prostate cancer
detection.
Dr. Siddiqui, assistant professor of surgeryurology at the University of Maryland School
of Medicine, Baltimore, was involved in the
MARCH 2015
study as a urologic oncology fellow at the
NCI.
“The findings of our study are consistent
with the idea that findings on multiparametric
prostate MRI better reflect the real disease in
the prostate and therefore guide a biopsy that
provides better risk stratification,” he said.
“However, our study was not randomized; it
looked at pathology results rather than clini-
∣
Urology Times
cal outcomes; and most of the men had undergone prior standard biopsy, often with negative
results.
“Ideally, prospective, randomized trials
should be conducted to establish that targeted
biopsy reduces risk of disease recurrence or
prostate cancer-specific mortality, and we look
to leading centers implementing this technique
to design clinical trials that will give us the type
of information needed to advance the field.”
Not ready for clinical practice
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t6SPMPHZ4QFDJöD$PEFT
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t$SPTTXBMLPGUPQVSPMPHZDPEFT
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“This is an important paper strengthening the
idea that targeted biopsy has a role in prostate
cancer detection for allowing more accurate
assessment of disease and better detection of
high-risk cancer,” said Dr. Taneja, professor
of urology and radiology at the NYU Langone
Medical Center, New York. “However, we
cannot use this study to define how urologists
might use targeted biopsy in clinical practice.”
“Ideally, prospective,
randomized trials
should be conducted
to establish
that targeted
biopsy reduces risk of disease
recurrence or prostate cancerspecific mortality, and we look
to leading centers implementing
this technique to design clinical
trials that will give us the type of
information needed to advance the
field.”
M. MINHAJ SIDDIQUI, MD
There will be 2, 3 month
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Coding, Reimbursement, and Practice Management Solutions
The study analyzed data from men referred to
the NCI between 2007 and 2014 with elevated
PSA or an abnormal digital rectal examination.
Eighty percent of the men had a prior biopsy,
of which about 54% were negative. All of the
men were found to have areas of prostate cancer suspicion on multiparametric prostate MRI
and then underwent concurrent targeted biopsy
(mean cores per patient, 5.3) and extended-sextant biopsy (“standard biopsy”; mean cores per
patient, 12.3). None of the men had received any
treatment for prostate cancer, but 170 went on
to prostatectomy.
The targeted and standard biopsy techniques
UrologyTimes.com
∣
❳ Clinical Spotlight ❲
MARCH 2015
identified cancer in nearly the same number of
men: 461 and 469 cases, respectively. However,
the targeted biopsy performed significantly
better than the standard technique or even the
combination of the two in detecting high-risk
disease.
Compared with the standard biopsy, targeted biopsy diagnosed 30% more high-risk
cancers (p<.001) and 17% fewer low-risk cancers (p=.002). In addition, although 22% more
cases of prostate cancer were identified using
both techniques versus targeted biopsy alone,
83% of the additional cancers were low risk and
only 5% were high risk.
Based on those data, it was determined that
200 men would need to have the combined
biopsy in order to diagnose one additional highrisk cancer, but at the same time, 17 additional
low-risk cancers would be found.
Other analyses focusing on the 170 men who
underwent prostatectomy also favored targeted
biopsy. Compared with both standard biopsy
and the combination of the two techniques,
the findings from the targeted biopsy better
reflected the pathology in the whole prostate
gland. Using the technique of decision curve
analysis, the investigators found the targeted
biopsy was superior to the standard technique
or combination approach for guiding the recommendation for surgery.
“It turned out that when combining the two
techniques, the standard biopsy led to enough
bad decisions that it undermined the value of
the targeted biopsy,” Dr. Siddiqui said.
Prior biopsy an ‘important limitation’
Dr. Siddiqui and co-authors acknowledged that
the predominance of men with a prior biopsy in
the study population is an important limitation.
Considering the potential for bias, subcohort
analyses were undertaken in men with and
without prior biopsy, and the results showed
risk distribution for the targeted biopsy was
similar in the two groups.
“The findings are reassuring that targeted
biopsy has a benefit in biopsy-naïve men, but
they are just subgroup analyses, and it will be
important to see if the outcomes are validated
as other centers investigate biopsy-naïve populations,” Dr. Siddiqui said.
Commenting on the population characteristics, Dr. Taneja explained that the performance
of targeted biopsy differs depending on the
indication.
“Among biopsy-naïve men, systematic biopsy tends to identify a lot of low-grade, low-risk
cancers that are small in volume, whereas the
targeted approach tends to avoid detection
of those lesions and maintain or increase the
detection of high-grade disease. However,
among men who had a previous standard biopsy
“This is an important paper
strengthening the idea that
targeted biopsy has a role in
prostate cancer detection
for allowing more accurate
assessment of disease and better detection
of high-risk cancer. However, we cannot use
this study to define how urologists might use
targeted biopsy in clinical practice.”
SAMIR TANEJA, MD
with a negative result, both the systematic and
targeted biopsy do not find much low-risk cancer due to a lower prevalence of disease, but the
targeted biopsy tends to find more high-grade
disease,” he explained.
“Due to the different underlying prevalence
of disease in men with and without prior biopsy,
it really cannot be concluded based on findings from the whole NCI study cohort whether
targeted biopsy reduced prostate cancer overdetection.”
High-grade misses: A red flag?
Dr. Taneja also observed that the number of
high-grade cancers missed by the targeted biopsy may raise a red flag for urologists, considering that appears to be a common community
concern about targeted biopsy. Illustrating his
point, Dr. Taneja noted that results of an audience poll at the Society of Urologic Oncology
2014 winter meeting in Bethesda, MD showed
that 99% of attendees who listened to a debate
about targeted biopsy said they would not use
multiparametric MRI to guide the procedure.
Their main reason was that it misses high-grade
disease.
He suggested that targeting error might
account for the high-grade cancers missed
by the targeted biopsy in the NCI study and
in the majority of studies published to date,
noting that in the NYU series, which will be
presented at the 2015 AUA annual meeting in
New Orleans, the rate of missed high-grade
cancer is lower, perhaps due to improved targeting techniques with the evolution of coregistration devices.
“The NCI cohort was studied over a 7-year
period beginning in 2007, and certainly the
imaging, its interpretation, and methods for
biopsy have evolved and are improved,” Dr.
Taneja said. “The reality is that systematic
biopsy misses more high-grade disease than
the targeted approach.”
37
Technology, learning curve
hurdles remain
Dr. Taneja’s remarks are a
reminder of certain pragmatic
issues affecting the dissemination of targeted biopsy. Dr.
Siddiqui pointed out that the
3T technology used for multiparametric prostate MRI is
currently not widely available,
and even at centers where it is
installed, there may not be a
radiologist with the necessary
expertise to interpret the scan.
“In our study, all of the
scans were read by two highly experienced genitourinary
radiologists. However, there is
a learning curve to reading the
prostate multiparametric MRI, and it is easy for
radiologists who are new to the interpretation
to overcall suspicious areas,” Dr. Siddiqui said.
Dr. Taneja added that experience with the
technique of targeted biopsy is another hurdle
that must be cleared by urologists prior to
implementation of MR-targeted biopsy in the
community.
“While commercially available co-registration platforms may help in reducing the learning curve, we have learned from community
feedback that there is great variability in the
ease of use for such platforms, and the learning
curve with certain devices may be considerable,” Dr. Taneja said.
Based on their belief that multiparametric
MRI provides more reliable imaging of the
prostate, Dr. Siddiqui and colleagues at the University of Maryland are initiating studies investigating its use with targeted fusion biopsy in
men undergoing active surveillance and to
guide focal brachytherapy in appropriate candidates. UT
More about this topic
Visit www.urologytimes.com/targeted-biopsy for
these additional articles on MRI-guided prostate
biopsy:
t.3*HVJEJOHGVUVSFPGQSPTUBUFDBODFSEJBHOPTJT
t.3HVJEBODFNBZPGGFSCFOFGJUJONVMUJQMF
scenarios
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focus (an interview with Samir S. Taneja, MD)
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damental benefits
t.3*NBZBEEWBMVFJONPOJUPSJOHNFOPOBDUJWF
surveillance
38
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UrologyTimes.com
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❳Washington and You❲
MARCH 2015
Congress, White House
pressing for SGR repeal
Debate continues over how to finance permanent reform
Washington —Have the stars finally become
aligned in such a way that Congress resolves the
perennial Medicare physician fee fiasco? The
signs seem to point that way, and that certainly
would be good news for urologists.
In fact, by the time you read this, it may
already have happened. But then, haven’t we
said that before?
Just in case it does, though, let’s put into perspective some of the developments that have
taken place over the last few months.
Support gaining for repeal bill
First, key House and Senate committees late
last year agreed on legislation to repeal the sustainable growth rate (SGR) formula, but they
could not agree on a way to pay the estimated
$144 billion 10-year cost. However, the bill was
endorsed by much of the medical community
and has since gained increased support.
Then, after the new Republican-controlled
Congress was sworn in, the first hearing of the
114th Congress by the House Energy & Commerce Health Subcommittee, held Jan. 21 and
22, focused on “A Permanent Solution to the
SGR: The Time is Now.”
Once again, there was universal agreement by
witnesses and both Republican and Democratic
lawmakers that the SGR must be repealed and
that another “doc fix” patch should be avoided.
That patch would be required by March 31 to
avoid a 21% Medicare payment cut.
But, once again, there was less-than-universal agreement on how to pay for it, with some
committee members (Democrats) even suggesting that it could be done without specifically
enacting “pay-fors.”
“If members are serious about seizing this
historic moment to pass SGR reform, as a purely
practical matter, for the bill to pass the House of
Representatives and Senate, it must include sensible offsets,” declared Subcommittee Chairman Joseph Pitts (R-PA).
It was only a couple weeks after that hearing
that President Obama submitted his fiscal year
2016 federal budget to Congress, a document
that was quickly dismissed by GOP congresUROLOGY TIMES (ISSN 0093-9722 PRINT), (ISSN 2150-7384 DIGITAL) is published 13 times a year:
monthly with 2 issues in April by UBM Advanstar 131 W First St., Duluth MN 55802-2065. Subscription rates:
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POSTMASTER: Address changes, P.O. returns, etc. should be forwarded to Urology Times, c/o UBM
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sional leaders. However, in that budget was a
call for Congress to repeal the SGR and reform
Medicare physician payments “in a manner
consistent with the reforms included in recent
bipartisan, bicameral legislation.”
The administration’s budget includes numerous initiatives to generate Medicare savings by
more than $415 billion over the next decade.
“If members are serious about
seizing this historic moment to pass
SGR reform, as a purely practical
matter, for the bill to pass the House
of Representatives and Senate, it
must include sensible offsets.”
REP. JOSEPH PITTS (R-PA)
Plus, he called for the end of sequestration, cuts
triggered by the Budget Control Act of 2011 that
slashed Medicare rates by 2% through 2021.
To encourage health care providers who
deliver better care and better outcomes for
patients, the administration set a goal for 2016
of making 30% of Medicare payments through
alternative payment models that link payment to
delivery of efficient, high-quality, coordinated
health care rather than for volume of health
care services. The goal by 2018 would be 50%.
Reforming the SGR would help achieve that,
the president said.
Bill reflects emphasis on quality
Last year’s legislation would have provided
positive payment updates of 0.5% for the first 5
years, and then would have frozen payments for
an additional 5 years to allow for the development and adoption of new, innovative payment
and delivery models. Then, payments would be
determined by many factors, including performance in the newly created Merit-Based Incentive Payment System (MIPS) for those who
remain in the fee-for-service payment system.
Physicians in qualifying alternative payment
models would receive a 5% bonus for 5 years.
In addition, the MIPS program would harmonize the various Medicare quality reporting programs, noted Barbara L. McAneny, MD, chair
of the American Medical Association Board of
41
Bob Gatty
UT Washington
Correspondent
Bob Gatty, a former
congressional aide, covers
news from Washington
for Urology Times.
Trustees. These would include the Physician
Quality Reporting System, Electronic Health
Record Incentive Programs/Meaningful Use,
and the Value-Based Payment Modifier.
The requirements of these individual programs, Dr. McAneny told the Health Subcommittee Jan. 22, are often contradictory and
duplicative, and impose “an unreasonably
high burden and unduly high penalties on physicians, without clear evidence that they actually improve the quality of care.”
“Under the current Medicare payment system, physicians lose revenue if they perform
fewer procedures or lower cost procedures,
even if their patients are healthier as a result.
Most fundamentally, under Medicare, physicians are not paid at all when their patients stay
well,” she said.
She pointed out that many high-value services are not reimbursed by Medicare.
“Medicare will not pay primary care physicians and specialists to coordinate care by
telephone or email, yet it will pay for duplicate
tests and the problems caused by conflicting
medications,” she said.
The bottom line, warned Dr. McAneny, is
that physicians can’t continue the way things
are today, pointing out that from 2001 to 2015
the cost of caring for patients, according to the
government, has gone up 27%, while the average annual Medicare physician payment update
has been only about 0.3% per year. Adjusted for
inflation, it’s actually fallen by 18%.
So the politicians in Washington, both in
Congress and at the White House, say now is
the time to act.
Let’s see if they do.
Fast Facts
Sustainable growth rate repeal:
❯❯ was the subject of legislation last year for
which Republicans and Democrats could not
agree on funding
❯❯ was addressed in a January 2015 hearing of
the House Energy & Commerce Health Subcommittee
❯❯ was included in President Obama’s fiscal year
2016 federal budget
42
MARCH 2015
IN THE
PUBLIC
∣
Urology Times
“We still advise our patients to use PDE-5 inhibitors on demand,” he
explained. “PDE-5 inhibitors are effective in treating ED following nervesparing radical prostatectomy, assuming that there are still some spontaneous but insufficient erections.”
WHAT YOUR PATIENTS ARE READING IN PRINT, ONLINE
M E DSC A P E
H E A LT H D AY N E W S
Is ageism contributing to underuse
of RT in older men with high-risk PCa?
Pediatric lower urinary tract
symptoms linked to bullying
ELDERLY MEN with high-risk prostate cancer have been undertreated since
BULLYING is associated with lower urinary tract symptoms in 8- to 11-year-olds,
the mid-1990s because of “prevalent age bias against the use of radiation
say researchers from Vanderbilt University Medical Center, Nashville, TN.
therapy,” according to commentary published online in the Journal of CliniThe authors, who published their findings in the Journal of Urology (2015;
cal Oncology (Jan. 5, 2015).
193:650-4), examined the correlation between pediatric lower urinary tract
Co-authors Dean Shumway, MD, and Daniel Hamstra, MD, PhD, of the
symptoms and exposure to
University of Michigan, Ann Arbor, published their combullying among this age group.
ments in an invited commentary on a recent study on
Christina B. Ching, MD,
the use of androgen deprivation therapy and radiation
and colleagues looked at a
therapy in older men with high-risk prostate cancer
bullying questionnaire at a
that was also published online in the Journal of Clinical
pediatric urology clinic. Data
Oncology.
were included for 113 children
The authors write that they endorse the approach of
at the clinic and 63 children in
geriatric oncologists who advocate for the assessment
the primary care setting.
In a urology setting, symptom scores of "physiologic age" in making treatment decisions. They
The authors observed sigconclude by recommending that "careful consideration
were significantly associated with
nificant differences between
should be given to also treating with radiation therapy"
victimization scores.
the two populations, with more
because the modality is associated with "substantial
perpetrators of bullying in the
improvements in disease-specific and [overall survival]."
primary care group. Within the urology clinic group, Vancouver Symptom Score
was significantly associated with self- and peer-perceived victimization scores.
W I R E D.COM
PDE-5 inhibitor use associated with
prostate cancer recurrence after RP
GERMAN RESEARCHERS have identified a surprising association between
the use of phosphodiesterase type-5 inhibitors after radical prostatectomy
and biochemical recurrence, they reported in the Journal of Urology (2015;
193:479-83).
“We were astonished. We expected opposite results,” said lead researcher Uwe Michl, MD, of Martini-Klinik Prostate Cancer Center in Hamburg.
Dr. Michl added that the study's findings should not change practice.
RESEARCH continues on a male contraception solution, according to a
report on Wired.com.
The report discussed two compounds, H2-gamendazole and JQ1.
H2-gamendazole prevents premature sperm cells from growing a tail and
head in the testis. The unfinished sperm fragments are then reabsorbed
into the testis. The compound is currently in animal testing.
JQ1 obstructs a testicle-specific bromodomain called BRDT, “making the
sex cells that would otherwise produce sperm draw a blank about their own
behavior,” according to the Wired report. The compound is currently in the
chemical optimization stage of research.
NEWS ODDITIES
'Ordinary' man found to have female organs
AFTER UNDERGOING SCANS for suspected
bladder cancer, a UK man is preparing for
a hysterectomy because doctors found a
womb and a full set of female reproductive organs, according to a report in The
Telegraph.
Physicians believe the patient has a rare
condition called persistent Mullerian duct
syndrome (PMDS), which results in men
developing external male genitalia and
internal female reproductive organs.
Usually discovered at birth or puberty,
this man’s PMDS was not discovered until
recently and he has always considered
himself an “ordinary” guy. It was when he
noticed blood in his urine that he went to
get tested for bladder cancer and the condition was revealed.
“I was shocked when the consultant said
I had a fully functioning set of women’s
reproductive organs, and I was even having
periods,” he said.
“It appears I could even potentially get
pregnant,” he added. His upcoming hysterectomy could possibly lead to menopause.
He said: “It’s possible tests will show I’m
both male and female, but I feel completely
right living life as a guy. Even if tests showed
that I was mostly a woman, I would still continue living as a man.”
PHOTO: GETTY IMAGES/ CULTURA
Male contraception: Two compounds show promise
M E DSC A P E
GLYDO (lidocaine HCl jelly USP, 2%)
Brief Summary of Prescribing Information
GLYDO (lidocaine HCl jelly USP, 2%) is indicated for prevention and control of pain in procedures involving the
male and female urethra, for topical treatment of painful urethritis, and as an anesthetic lubricant for endotracheal
intubation (oral and nasal).
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, this drug should be used during pregnancy only if clearly
needed.
CONTRAINDICATIONS
Lidocaine is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide
type or to other components of GLYDO.
Labor and Delivery
Lidocaine is not contraindicated in labor and delivery. Should GLYDO be used concomitantly with other products
containing lidocaine, the total dose contributed by all formulations must be kept in mind.
WARNINGS
EXCESSIVE DOSAGE, OR SHORT INTERVALS BETWEEN DOSES, CAN RESULT IN HIGH PLASMA LEVELS AND
SERIOUS ADVERSE EFFECTS. PATIENTS SHOULD BE INSTRUCTED TO STRICTLY ADHERE TO THE RECOMMENDED
DOSAGE AND ADMINISTRATION GUIDELINES AS SET FORTH IN THIS PACKAGE INSERT.
THE MANAGEMENT OF SERIOUS ADVERSE REACTIONS MAY REQUIRE THE USE OF RESUSCITATIVE EQUIPMENT,
OXYGEN, AND OTHER RESUSCITATIVE DRUGS.
GLYDO should be used with extreme caution in the presence of sepsis or severely traumatized mucosa in the area of
application, since under such conditions there is the potential for rapid systemic absorption.
When used for endotracheal tube lubrication care should be taken to avoid introducing the product into the lumen
of the tube. Do not use the jelly to lubricate the endotracheal stylettes. If allowed into the inner lumen, the jelly
may dry on the inner surface leaving a residue which tends to clump with flexion, narrowing the lumen. There have
been rare reports in which this residue has caused the lumen to occlude. (See also ADVERSE REACTIONS and
DOSAGE AND ADMINISTRATION.)
Nursing Mothers
Lidocaine is secreted in human milk. The clinical significance of this observation is unknown. Caution should be
exercised when lidocaine is administered to a nursing woman.
PRECAUTIONS
General
The safety and effectiveness of lidocaine depend on proper dosage, correct technique, adequate precautions, and
readiness for emergencies. (See WARNINGS and ADVERSE REACTIONS.) The lowest dosage that results in
effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Repeated doses of
lidocaine may cause significant increases in blood levels with each repeated dose because of slow accumulation
of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated,
elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and
physical status. Lidocaine should also be used with caution in patients with severe shock or heart block.
GLYDO should be used with caution in patients with known drug sensitivities. Patients allergic to paraaminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine.
Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant
hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the
need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol
for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure,
and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis,
prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy,
indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before
using).
Information for Patients
When topical anesthetics are used in the mouth, the patient should be aware that the production of topical
anesthesia may impair swallowing and thus enhance the danger of aspiration. For this reason, food should not
be ingested for 60 minutes following use of local anesthetic preparations in the mouth or throat area. This is
particularly important in children because of their frequency of eating.
Numbness of the tongue or buccal mucosa may enhance the danger of unintentional biting trauma. Food and
chewing gum should not be taken while the mouth or throat area is anesthetized.
Carcinogenesis—Long-term studies in animals have not been performed to evaluate the carcinogenic potential of
lidocaine.
Mutagenesis—The mutagenic potential of lidocaine has been tested in the Ames Salmonella reverse mutation
assay, an in vitro chromosome aberrations assay in human lymphocytes and in an in vivo mouse micronucleus
assay. There was no indication of any mutagenic effect in these studies.
Impairment of Fertility: The effect of lidocaine on fertility was examined in the rat model.
Administration of 30 mg/kg, s.c. (180 mg/m2) to the mating pair did not produce alterations in fertility or general
reproductive performance of rats. There are no studies that examine the effect of lidocaine on sperm parameters.
There was no evidence of altered fertility.
Use in Pregnancy
Teratogenic Effects: Pregnancy Category B
Reproduction studies for lidocaine have been performed in both rats and rabbits. There was no evidence of harm
to the fetus at subcutaneous doses of up to 50 mg/kg lidocaine (300 mg/m2 on a body surface area basis) in the rat
model. In the rabbit model, there was no evidence of harm to the fetus at a dose of 5 mg/kg, s.c. (60 mg/m2 on a
body surface area basis). Treatment of rabbits with 25 mg/kg (300 mg/m2) produced evidence of maternal toxicity
and evidence of delayed fetal development, including a non-significant decrease in fetal weight (7%) and an
increase in minor skeletal anomalies (skull and sternebral defect, reduced ossification of the phalanges). The effect
of lidocaine on post-natal development was examined in rats by treating pregnant female rats daily subcutaneously
at doses of 2, 10, and 50 mg/kg (12, 60, and 300 mg/m2) from day 15 of pregnancy and up to 20 days post partum.
No signs of adverse effects were seen either in dams or in the pups up to and including the dose of 10 mg/kg (60
mg/m2); however, the number of surviving pups was reduced at 50 mg/kg (300 mg/m2), both at birth and the
duration of lactation period, the effect most likely being secondary to maternal toxicity. No other effects on litter
size, litter weight, abnormalities in the pups and physical developments of the pups were seen in this study.
A second study examined the effects of lidocaine on post-natal development in the rat that included assessment of
the pups from weaning to sexual maturity.
Rats were treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine (60 mg/m2 and 180 mg/m2 on a body surface
area basis, respectively). This time period encompassed 3 mating periods. There was no evidence of altered postnatal development in any offspring; however, both doses of lidocaine significantly reduced the average number of
pups per litter surviving until weaning of offspring from the first 2 mating periods.
Pediatric Use
Although, the safety and effectiveness of GLYDO in pediatric patients have not been established, a study of 19
premature neonates (gestational age <33 weeks) found no correlation between the plasma concentration of
lidocaine or monoethylglycinexylidide and infant body weight when moderate amounts of lidocaine (i.e. 0.3 mL/
kg of lidocaine gel 20 mg/mL) were used for lubricating both intranasal and endotracheal tubes. No neonate had
plasma levels of lidocaine above 750 mcg/L. Dosages in children should be reduced, commensurate with age, body
weight, and physical condition. (See DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse experiences following the administration of lidocaine are similar in nature to those observed with other
amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high
plasma levels caused by excessive dosage or rapid absorption, or may result from a hypersensitivity, idiosyncrasy, or
diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The
following types are those most commonly reported:
There have been rare reports of endotracheal tube occlusion associated with the presence of dried jelly residue in
the inner lumen of the tube. (See also WARNINGS and DOSAGE AND ADMINISTRATION.)
Central Nervous System
CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness,
apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of
heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression, and arrest. The
excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity
may be drowsiness merging into unconsciousness and respiratory arrest.
Drowsiness following the administration of lidocaine is usually an early sign of a high blood level of the drug and
may occur as a consequence of rapid absorption.
Cardiovascular System
Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and
cardiovascular collapse, which may lead to cardiac arrest.
Allergic
Allergic reactions are characterized by cutaneous lesions, urticaria, edema, or anaphylactoid reactions. Allergic
reactions may occur as a result of sensitivity either to the local anesthetic agent or to other components in the
formulation. Allergic reactions as a result of sensitivity to lidocaine are extremely rare and, if they occur, should be
managed by conventional means. The detection of sensitivity by skin testing is of doubtful value.
OVERDOSAGE
Acute emergencies from local anesthetics are generally related to high plasma levels encountered during
therapeutic use of local anesthetics. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.)
Management of Local Anesthetic Emergencies
The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and
respiratory vital signs and the patient’s state of consciousness after each local anesthetic administration. At the
first sign of change, oxygen should be administered.
The first step in the management of convulsions consists of immediate attention to the maintenance of a patent
airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate
positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of
the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the
circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and
if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental
or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be
familiar, prior to use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory
depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by
the clinical situation (e.g., ephedrine).
If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis,
bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative
measures should be instituted.
Dialysis is of negligible value in the treatment of acute overdosage with lidocaine.
The oral LD50 of lidocaine HCl in non-fasted female rats is 459 (346 to 773) mg/kg (as the salt) and 214 (159 to 324)
mg/kg (as the salt) in fasted female rats.
Mfd. for SAGENT Pharmaceuticals
Schaumburg, IL 60195 (USA)
Mfd. by Klosterfrau Berlin GmbH
Made in Germany
©2014 Sagent Pharmaceuticals, Inc.
March 2014
You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.
Please see full prescribing information for GLYDO (lidocaine HCl jelly USP, 2%).
FEATURING
PreventIV Measures
Packaging and Labeling
SM
All trademarks herein are the property of Sagent Pharmaceuticals, Inc.
PreventIV Measures is a service mark of Sagent Pharmaceuticals, Inc.
©2014 Sagent Pharmaceuticals, Inc. Printed in USA 1932
www.SagentPharma.com | www.glydo.com
smooth sailing
FOR YOUR URETHRAL PROCEDURES
Prefilled. Preassembled. Preferred by 80%1 of polled U.S urologists and urology nurses.
SAGENT Pharmaceuticals is proud to offer GLYDO
(lidocaine HCl jelly USP, 2%), a sterile and prefilled
urological anesthetic lubricant. GLYDO is filled in
a novel syringe used in 40 countries, with over 500
million applications and 40 years of experience.2
GLYDO is available in both 11 mL and 6 mL
preassembled, ready-to-use, disposable syringes
in sterile individual packs.
1
A description of GLYDO was preferred by 159/193
clinicians in a June 2014 survey.
2
Data on file, Sagent Pharmaceuticals, Inc., 2014.
Visit www.glydo.com for more details and ordering information.
Please see a brief summary of prescribing information for GLYDO (lidocaine HCl jelly USP, 2%) on the next page.
FEATURING
PreventIV Measures
Packaging and Labeling
SM
All trademarks herein are the property of Sagent Pharmaceuticals, Inc.
PreventIV Measures is a service mark of Sagent Pharmaceuticals, Inc.
©2014 Sagent Pharmaceuticals, Inc. Printed in USA 1932

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