ADVANCES IN INTERNAL MEDICINE/UPDATE ON PROSTATE CANCER
| SIGNIFICANT ADVANCES IN INTERNAL MEDICINE —Laurence B. Gardner, MD, Professor and Chair, Department
of Medicine, University of Miami Miller School of Medicine, Miami, FL
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| Trastuzumab (Herceptin): recombinant monoclonal antibody directed at HER-2 receptor; study found overexpression
of HER-2 receptor in some breast cancers associated with poorer prognosis, compared to those not associated with
HER-2–receptor amplification; another study found trastuzumab improved disease-free survival in patients with HER-2–
positive tumors and node-negative or node-positive disease; patients experience minimal toxic effects (eg, neutropenia,
alopecia); outcomes analyses concluded trastuzumab had beneficial effect in metastatic and nonmetastatic HER-2–positive
disease; however, health insurance companies objected to implication that widespread availability and use warranted;
insurers cite high cost, premature conclusions of outcomes analyses, overestimation of prevalence of HER-2–
positive disease, and inflated benefit in efficacy studies
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| Patient safety: Institute for Healthcare Improvement—works with medical community to ensure patient safety and
prevent medical errors; performed literature survey and found hospitals in which likelihood of surgical infections lowest,
ventilator-associated pneumonia virually eliminated, and intravenous (IV) catheter sepsis almost entirely avoided
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| Central line infection: Allegheny General Hospital (AGH) in Pittsburgh, PA, has implemented real-time error management
in intensive care unit (ICU) to decrease incidence of central line infections; laboratory gets positive blood culture
for central line-associated bacteremia (CLAB) and alerts nurse manager and infection control; infection control sends
email message to central-line response team (physician project leader, infectious disease specialist, and IC nurse manager);
response team meets with care team at bedside to ascertain cause of infection and recommend countermeasures; response
team has recommended limited use of prone femoral central lines because of high rate of associated bacteremia;
stickers used to notify caregivers when to change line; red lines on floor of patient’s room to remind personnel to wash
hands; response team recommendations resulted in decrease in deaths from CLAB from 19 to 1, resulting in significant
decrease in cost to hospital
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| Beta-blockers: study data—in hospitalized patients with identified cardiac risk factors undergoing noncardiac surgery,
atenolol reduced number of coronary-related deaths during 6 to 8 mo after discharge, decreased average mortality by
5.1% per year, reduced out-of-hospital mortality by 3.6% per year, while overall incidence of myocardial infarction (MI)
remained unchanged; 4 subsequent studies suggested significant improvement in perioperative mortality from short-term
use of β-blockers, but 2 did not; retrospective analysis—looked at claims and mortality data from 329 hospitals to identify
subgroups that might benefit from therapy with β-blockers; revised cardiac risk index (RCRI), with scores ranging
from 0 to 4, stratified patients according to known cardiac risk factors; β-blocker use in patients ≤65 yr age 14.1%; β-
blocker use in patients >65 yr age 23.6%; odds ratio for perioperative treatment with atenolol increased with age of patient
and RCRI, eg, 14.2% in patients with RCRI of 0 and 43.7% in patients with RCRI >4; β-blockers associated with
decreased risk for mortality among patients in highest cardiac risk group and apparent increased risk in patients in lowest
cardiac risk group; number needed to treat (NNT) to show benefit in high-risk group 33, and NNT to cause harm in low-
risk group 8; recommendations—consider short-term use of β-blockers only in patients at high risk for cardiac complications
undergoing noncardiac surgery
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| Vitamin E: meta-analysis involving 19 clinical trials and 136,000 participants; 9 of 11 trials found high-dose vitamin E
(>400 IU/day) increased all-cause mortality; some benefit found in taking <33 IU/day, but data suggest increase in risk
for mortality associated with high-dose vitamin E; data came from cohort study, not randomized controlled trial; do not
recommend high-dose vitamin E therapy; vitamin E at doses <400 IU per day not harmful
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| Angiotension-converting enzyme (ACE) inhibitors: avoid ACE inhibitors in patients with—unilateral renal
stenosis; renal insufficiency based on ischemia; mineralocorticoid deficiency (eg, type 4 renal tubular acidosis [RTA])
because of hyperkalemia; used to—treat hypertension; treat and prevent diabetic kidney disease and various types of
cardiac disease; diabetic patients—do not develop renal failure without first developing microalbuminuria (marker for
diabetic nephropathy); study looked at diabetic patients with hypertension but without microalbuminuria for 3 yr; patients
received either ACE inhibitor (trandolapril) and calcium channel blocker (CCB; verapamil), CCB alone, or ACE
inhibitor alone; rate of progression to microalbuminuria analyzed; ACE inhibitor slowed progression; concluded hypertensive
patients with diabetes should receive ACE inhibitor (standard of practice); beneficial effects independent of blood
pressure (BP) control; cardiovascular disease—ACE inhibitors reduce risk for worsening heart failure (HF), MI, and
death from cardiovascular causes in patients with HF or left ventricular dysfunction; study looked at patients with preserved
left ventricular function and stable coronary disease on intensive medical management (eg, aspirin, β-blockers, statins,
diuretics if needed), except for ACE inhibitor therapy, to see if ACE inhibitor (trandolapril) might benefit this
patient population; no significant difference in mortality rate found in patients with preserved left ventricular function
and stable coronary disease; study refutes conclusions drawn from previous study using ACE inhibitor (ramipril) that
found benefit in this patient population; concluded that, in absence of significant coronary or left ventricular disease,
ACE inhibitors do not protect against complications of cardiac disease
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| Blacks and HF: study looked at fixed dose of isosorbide dinitrate/hydralazine (BiDil) to treat congestive heart failure
(CHF) in blacks; study terminated when placebo group showed excess of adverse outcomes and treatment group showed
benefit for points being measured; major side effects common and severe, eg, headache in 47% of patients and dizziness
in 29.3%; advise patients about decrease in mortality risk and in readmission for CHF, but warn about side effects
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| Herpes zoster (shingles): risk for shingles and its painful complications increase with age; herpes zoster not serious
unless ophthalmic nerve affected; sequelae, ie, postherpetic neuralgia (PHN), serious complication; data recently released
about live attenuated vaccine tested in susceptible patient population; data strongly suggest vaccine decreases incidence
and morbidity of PHN; currently, glucocorticoids used to prevent PHN, and antiviral agents used to treat herpes
zoster; vaccine prevents herpes zoster and its complications
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| UPDATE ON PROSTATE CANCER —H. Ballentine Carter, MD, Professor of Urology and Oncology, Johns Hopkins
School of Medicine, Baltimore, MD
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| Prostate cancer: mortality rates and prostate-specific antigen (PSA) testing—mortality rate since 1995 below that
of 1986 when PSA test rarely performed; mortality rate dropped 27% from 1992 to 2001, mostly because of decrease in
incidence of distant disease (PSA testing resulted in earlier detection of disease; new diagnosis with distant disease now
relatively rare); incidence of distant disease decreased 50% to 70% between 1986 and 1999, possibly because of more
frequent PSA testing; less likely that decline in mortality rate due to improved survival among men with distant disease;
population screening—age-adjusted incidence of prostate cancer 49% higher in 2001 than in 1986 when screening uncommon;
lifetime risk for diagnosis 5 to 6 times risk for death, resulting in overdiagnosis and overtreatment in some patients;
false positive tests, unnecessary biopsies, and unwanted side effects of treatment occur in some patients; to justify
cost of screening, early detection should improve health outcomes
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| Screening options: primary testing involves serial digital rectal examinations (DRE) and PSA testing; based on outcome
of these tests, if risk for prostate cancer high, perform secondary testing with transrectal ultrasonography (TRUS)-
directed needle biospy; PSA—highest predictive value for cancer, compared to other tests (DRE and TRUS); detects
early-stage cancers; pathologic features of PSA-detected cancers more favorable, compared to DRE-detected cancers;
limited by inability to distinguish life-threatening from indolent disease
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| PSA secretion and isoforms: zymogen or pro-PSA (pPSA) secreted by prostatic luminal epithelial cell; pPSA acted
on by protease to form active PSA that liquefies seminal plasma; in serum, most PSA molecules bound to antiproteases,
but small proportion exists freely as fPSA fraction; fPSA sub-fractionates into pPSA and BPSA (marker for benign prostatic
hyperplasia [BPH])
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| Factors affecting PSA level: PSA level increases with age or presence of benign or malignant disease (eg, prostate
cancer, BPH, inflammation; BPH most common cause of PSA elevation); in general, Asians have lower PSA levels
than whites, and whites have lower levels than blacks; DRE can elevate PSA levels; prostate biopsy dramatically increases
PSA levels, but return to baseline occurs within 3 mo; ejaculation can increase PSA levels (recommend abstinence
from sexual activity for 3 days before PSA test); treatment for malignant or benign disease can lower PSA levels
by reducing production of PSA (5-α-reductase inhibitors [finasteride and dutasteride] reduce PSA by ≈50%; suspect
prostate cancer if PSA does not decrease or if while on medication, PSA begins to increase); ≈15% biological variability
from measurement to measurement (repeat test if abnormal)
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 | Interpretation of PSA levels: young age and small prostate increase risk for prostate cancer, even if PSA 2 to 2.5 ng/mL;
in men with small prostates without BPH, any rise in PSA level may indicate cancer; men who have PSA levels >10%
to 15% of prostate volume at greater risk for prostate cancer (PSA density); if PSA >4.0 ng/mL, increase >1.5 ng/mL
over 2 yr indicates increased risk for prostate cancer, as does fPSA level below 15% to 20%
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| PSA screening in clinical practice: age to start—prostate cancer relatively common in high-risk men (ie, blacks
and patients with family history) in their 40s; study found abnormal PSA test in 8% of black men, 7% of men with family
history, and 20% of black men with family history; if test abnormal, ≥50% have prostate cancer; recommend screening
patients at high risk at 40 yr of age; speaker recommends beginning routine screening at 40 yr of age for all men (54/100
000 men 50-64 yr of age die of prostate cancer each year; most could have been detected before 50 yr of age); younger
men more likely to have curable disease; PSA more specific test in younger men; frequency of testing—recommend 2-
yr testing interval for men with PSA <2.0 ng/mL (majority of men); >95% of cancers detected during second round of
screening after 4-yr interval had curable features at surgery; ≈80% of men have PSA <2.5 ng/mL; 8% to 12% have PSA
2.6 to 4.0 ng/mL and 4.0 to 10.0 ng/mL; 2% have PSA >10.0 ng/mL; no PSA level excludes diagnosis of prostate cancer;
cancer yield on biopsy 12% in men with PSA of 0 to 2 ng/mL, 15% to 25% in men with PSA of 2 to 4 ng/mL, and 17%
to 32% in men with PSA of 4 to 10 ng/mL; PSA level not dichotomous marker (normal or abnormal) but continuum;
keep suspicion high for cancer in young men with low PSA levels and increasing PSA levels; when to stop testing—not
likely to extend life for most men >70 yr of age if small cancer detected; guidelines—recommend PSA test and DRE at
40 yr of age and again at 45 yr of age; recommend testing every other year in patients 50 to 70 yr of age if PSA <2.0 ng/
mL and annual testing if PSA >2.0 ng/mL; perform prostate biopsy in patient with abnormal DRE or if PSA >2.5 ng/mL
in men 40 to 49 yr of age (look for rising PSA levels); biopsy if PSA >4 ng/mL in men 50 to 70 yr of age; rise in PSA
level >1.5 ng/mL during 2-yr interval suggests prostate cancer (refer for biopsy)
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| Risk assessment after diagnosis: Gleason score strongest predictor of disease progression; today, most biopsy-detected
cancers have score >5; score of 5 to 6 considered low-risk disease, 7 equals intermediate risk, and 8 to 10 indicates
high risk; use Gleason score and other predictors of disease extent to assess recurrence risk; recurrence risk over 10 yr
≈15% in men with low-risk disease (nonpalpable disease, PSA <10 ng/mL, and Gleason score ≤6); in men with moderate-
to high-risk disease (palpable lesion, or PSA level ≥10 ng/mL, or Gleason score ≥7) recurrence risk 50% to 75%
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| Management options: local (regional) disease—low risk; all options reasonable, ie, expectant management, external
beam radiotherapy, brachytherapy, and surgery; base decisions on eg, comorbidities, age of patient, patient’s interpretation
of cure or eradication of disease, quality of life (QOL) issues; intermediate risk—surgery and external beam radiotherapy;
high risk—androgen deprivation therapy plus external beam radiotherapy (preferred; superior to radiotherapy
alone); surgery for younger men who prefer it
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| Survival rates: in patients with intermediate- and high-risk disease not detected by screening, surgery reduced deaths
from prostate cancer by 50% at 8 yr, compared to no treatment; no data on screening-detected disease; PSA-based definitions
of cure have overestimated cure rates with radiation therapy; QOL outcomes—study comparing surgery, pelvic irradiation
and observation found no differences in general health-related QOL scores; long-term sexual function similar
for surgery and irradiation; urinary irritative symptoms worsen after irradiation but urinary control better; metastatic
disease—focus on palliation; androgen ablation results in symptomatic improvement and PSA reductions in 80% of patients;
hormone-responsive disease eventually becomes hormone refractory; consider lutenizing hormone-releasing hormone
(LHRH) analogues in men with metastatic disease; consider androgen receptor blockers (eg, casodex, flutamide) in
refractory disease; use PSA level to check for efficacy of hormonal therapy; after disease progresses, consider mitoxantrone
and corticosteroids or docetaxel
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Educational Objectives
| The goal of this program is to educate the listener about significant advances in internal medicine and in the diagnosis and
treatment of prostate cancer. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss use of trastuzumab for HER-2 receptor-positive breast cancer.
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| 2. Discuss patient safety issues, including methods to decrease the incidence of central line infection.
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| 3. Evaluate current recommendations for the use of β-blockers, vitamin E, and angiotension-converting enzyme (ACE)
inhibitors.
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| 4. Review the role of prostate-specific antigen (PSA) testing in screening for and monitoring prostate cancer.
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| 5. Describe management options for patients with prostate cancer based on risk group.
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Discussed on This Program
Atenolol [Tenormin]
Bicalutamide [Casodex]
Docetaxel [Taxotere]
Dutasteride [Avodart]
Finasteride [Propecia, Proscar]
Flutamide [Eulexin]
Isosorbide dinitrate and hydralazine hydrochloride [BiDil]
Mitoxantrone HCl [Novantrone]
Trandolapril [Mavik]
Trastuzumab [Herceptin]
Verapamil HCl [Calan, Calan SR, Covera-HS, Isoptin SR, Verelan, Verelan PM]
Suggested Reading
Allaf ME et al: Update on watchful waiting for prostate cancer. Curr Opin Urol. 14:171, 2004; Arvin AM et al:
New viral vaccines. Virology. 344:240, 2006; Carter HB: PSA scores: should we use a lower threshold? Johns Hopkins
Med Lett Health After 50. 17:6, 2004; Carter HB et al: Improved biomarkers for prostate cancer: a definite need. J
Natl Cancer Inst. 96:813, 2004; Carter HB: Prostate cancers in men with low PSA levels--must we find them? N Engl
J Med. 350:2292, 2004; Carter HB et al: Prostate-specific antigen and all-cause mortality: results from the Baltimore
Longitudinal Study On Aging. J Natl Cancer Inst. 96:557, 2004; Remuzzi G et al: Prevention and Treatment of Diabetic
Renal Disease in Type 2 Diabetes: The BENEDICT Study. J Am Soc Nephrol. 17:S90, 2006; Roy A et al: Using
beta-blockers to cut perioperative risk in CAD. Cardioprotective strategies for noncardiac surgery. Postgrad Med.
118:34,2005; Schouten O et al: A meta-analysis of safety and effectiveness of perioperative beta-blocker use for the
prevention of cardiac events in different types of noncardiac surgery. Coron Artery Dis. 17:173, 2006; Thompson CA:
New heart-failure therapy takes race into account. Am J Health Syst Pharm. 62:1745, 2005; Warlick CA et al: Expectant
treatment with curative intent in the prostate-specific antigen era: triggers for definitive therapy. Urol Oncol. 24:51,
2006; Wesorick DH et al: The preoperative cardiovascular evaluation of the intermediate-risk patient: new data, changing
strategies. Am J Med. 118:1413,2005;
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Gardner was recorded in Miami, FL, January 22-27, 2006, at Internal Medicine Update 2006, sponsored by the University
of Miami Miller School of Medicine. Dr. Carter was recorded in Baltimore, MD, May 2-6, 2005, at Topics in Clinical
Medicine, sponsored by the Johns Hopkins School of Medicine. The Audio-Digest Foundation thanks the speakers and
the sponsors for their cooperation in the production of this program.
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