RENAL REVIEW
Renal Cancer
| IMMUNOTHERAPY AND PATIENT SELECTION IN ADVANCED DISEASE —Michael B. Atkins, MD, Professor of
Medicine, Harvard Medical School, and Deputy Chief, Division of Hematology/Oncology, Beth Israel Deaconess Medical
Center, Boston, MA
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| Meta-analysis data: interferon therapy achieves—≈13% overall and ≈3% complete response rates; ≈3.8-mo survival advantage;
use limited to—control arm of phase 3 trials; component of empiric combination therapy based on mechanisms
of action, tolerability, and availability; bottom line—continued use of interferon as single therapeutic agent unlikely
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| High-dose interleukin-2 (IL-2) therapy: approval by Food and Drug Administration (FDA) based on quality of therapeutic
response (eg, ≈40% of all responders recurrence free at >10 yr); cost and toxicity limit clinical application
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 | Phase 3 trial data: suggest high-dose IL-2—achieves higher and more durable and complete response rates than low-
dose IL-2 and interferon (as patients develop more side effects or immunosuppression, lower doses of IL-2 and interferon
become less effective); may be particularly useful (relative to low-dose IL-2 therapy) for treating tumors in more
immune-sequestered locations; point—efforts to improve selection criteria warranted
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| Factors affecting response to immunotherapy
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| Circulating tumor-associated myeloid (TAM) cells (CD11b+ , CD14- , and CD15+ ): levels increase in patients with renal
cancer; produce arginase that reduces local arginine concentrations and T-cell receptor (TCR) zeta-chain expression on
surface of T cells; point—increase in TAM cell concentration and loss of TCR zeta-chain expression associated with
poor response to IL-2 therapy
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| Therapeutic implications: arginase expression—induced by prostaglandins and inhibited by cyclooxygenase-2 (COX-2)
inhibitors; administration of celecoxib (Celebrex) can enhance efficacy of interferon therapy in patients with high levels
of COX-2 inhibition; production of TAM cells—induced by vascular endothelial growth factor (VEGF); potentially
blocked by administration of bevacizumab (provides rationale for combination therapy)
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| Tumor-related features that may identify candidates for therapy: features associated with favorable response to IL-2
therapy include—presence of clear cell histology and alveolar features; absence of papillary or granular features
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| Carbonic anhydrase 9 (CA9): data suggest primary IL-2 immunotherapy achieves good response and survival rates in patients
with high CA9 expression and good pathology; hypothetically, beneficial effect of CA9 expression linked to—expression
of other von Hippel-Lindau/hypoxia-inducible factor (VHL/HIF)-driven proteins (ie, glucose transport,
protein type 1 [GLUT-1], or erythropoietin); absence of molecular abnormalities that may be associated with immune
suppression (eg, p10 methylation, Akt activation, B7-H1 expression)
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| Additional factors: high phospho-Akt expression associated with poor response to IL-2 therapy; B7-H1 in primary
tumors—immunosuppressive molecule surrounds tumor; associated with decline in overall survival; lack of expression
associated with 2-fold increase in response to high-dose IL-2; DQ1-α—histocompatibility complex class 2 antigen;
high expression of molecule found in most patients who responded to high-dose IL-2 therapy
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| Additional observations: potential exists to identify predictors of response and limit therapy to individuals most likely to
benefit; candidates for immunotherapy have—clear cell, alveolar, HIF-driven, CA9-expressing tumors; good prognosis
based on clinical features; poor candidates for immunotherapy have immunosuppressive tumors that—are Akt-driven,
granular, and papillary; express B7-H1 and COX-2; have low CA9 expression and poor prognosis; immunotherapy—
first-line therapy in select patients; considered part of clinical trial whenever possible
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| Selection with targeted agents: CA9 with temsirolimus—25% response rate associated with high or low CA9 expression;
high tumor phosphatase-6 or phospho-Akt expression seem necessary for response to target of rapamycin (TOR) inhibitor;
VEGF pathway blockade—VHL mutations associated with improved progression-free survival; randomized or controlled
studies necessary to evaluate progression-free survival (property of tumor or property of therapy?)
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| Conclusions: cytokine-based immunotherapy continues to play role in management of stage IV disease; high-dose IL-2
reasonable option for select patients; interferon and IL-2 may be combined with targeted anti-VEGF pathway agents;
overcoming tumor-induced immunosuppression research priority (immune response probably necessary for durable complete
therapeutic response); selection opportunities may exist for other targeted therapies
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| LAPAROSCOPY IN RENAL CELL CANCER —Benjamin R. Lee, MD, Associate Professor of Urology, Albert Einstein
College of Medicine of Yeshiva University, Bronx, NY
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| Renal cell cancer (RCC): detection increasing; pathologic staging—single most important prognostic factor; T1 (≤7-cm
tumors; 5-yr survival, 80%-90%); T2 (>7-cm tumors confined to kidney; 5-yr survival, 50%-60%); T3 (tumor extending
into major veins and perinephric tissues; 40%-50% survival); T4 (disease invading beyond Gerota’s fascia; 10%-14%
survival); local recurrence—1% to 2% for developing tumor in contralateral kidney; 2% to 4% for tumors <3 cm
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| Nephrectomy: standard of care for renal masses; laparoscopic radical nephrectomy—achieves good specimens; effectively
manages renal masses ≤12 cm in diameter and some lesions ≤22 cm in diameter; oncologically equivalent to open
radical nephrectomy for achieving 10-yr disease-free, cancer-specific, and actuarial survival rates
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| Laparoscopic partial nephrectomy: used by—less experienced surgeons to remove exophytic lesions located <4 cm
from collecting system; experienced surgeons may remove more endophytic lesions located closer to collecting system
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| Technique: intraoperative ultrasonography helps localize mass; excise lesion with 1-cm margin; hemostasis—placing
bulldog clamp on artery and vein allows dissection in relatively bloodless field; Surgicel bolster (oxidized cellulose)
provides second degree of compression and hemostasis; argon laser cauterizes 1 to 2 mm on surface of kidney; gelatin
matrix thrombin sealant (FloSeal) decreases postoperative hemorrhaging and leakage; pointers—vent trocars when
using argon laser (without ventilation, high flow of argon gas can cause rapid increase in pneumoperitoneal pressures);
once FloSeal delivered to base of lesion, reconstruct renal capsule over Surgicel bolsters; place Lapra-Ty clip to cinch
capsule; remove bulldog clamp to restore perfusion to kidney; concerns with partial nephrectomy—ischemia time;
ability to achieve hemostasis; surgical margins
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| Data: when compared to open partial nephrectomy, laparoscopic approach reduced operating time (ischemia time slightly
longer), blood loss, need for postoperative pain medication, duration of hospitalization, and degree of convalesence;
assessment of partial nephrectomy data show—mean tumor size 2.9 cm (31% of resected tumors >3 cm); 5% of tumors
located in solitary kidney; with experience, surgeon can manage lesions in central or hilar areas
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| Radiofrequency ablation of lesion: allows treatment of high-risk individuals; delivery of heat energy solubilizes lipid
component of cell membrane; mechanisms of action include coagulative necrosis and vascular infarct of renal end arteries;
generally indicated for managing patients with—<4-cm exophytic solid renal masses located away from collecting
system; older patients with multiple medical problems, eg, cardiac disease, requiring warfarin (Coumadin); at high risk
during laparoscopic partial nephrectomy; technique—insert needle and extend tines to cover area of interest; use saline-
infused radiofrequency ablation to manage patient with marked cardiovascular disease and left lower pole lesion; histochemical
nicotinamide adenine dinucleotide stain provides adjunct for assessing cellular viability and confirming 100%
cell death; technical aspects—impedance-based feedback system monitors resistance; thermocouples monitor temperature
to determine when treatment completed (>100°C)
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| Take-home message for RCC: laparoscopic nephrectomy—standard of care; 10-yr disease-specific survival equivalent to
open surgery; not associated with increased risk for port-site metastases; indicated for managing any renal mass without
inferior vena cava (IVC) involvement; partial nephrectomy—indicated for lesions ≤4 cm; optimizes preservation of renal
function; radiofrequency ablation—allows treatment of high-risk patients
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| Additional considerations: intraoperative biopsy—ensures negative margins; sent for frozen sections; should be performed
in lateral, medial, and superior aspects; overview of options—laparoscopic partial nephrectomy indicated for patient
without significant comorbidity; cryosurgery (surgeon can visualize ice ball and limits of area treated; to avoid
hemorrhaging, ensure thaw cycle completed before removing probe); radiofrequency ablation (indicated when patient
has comorbidity; achieves effective hemostasis by cauterizing entire area being treated); saline infused radiofrequency
ablation (disburses heat energy; reaches target temperatures more quickly); robotic surgery (less useful for managing mobile
organs such as kidney)
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| RADICAL NEPHRECTOMY FOR RENAL MASSES —Donald L. Lamm, MD, Clinical Professor of Urology, University
of Arizona College of Medicine, Tucson, and Director, Bladder Cancer-Genitourinary (BCG) Oncology, Phoenix, AZ
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| Introduction: observation or partial nephrectomy may be appropriate for some small lesions; determining aggressiveness
of management—<3% of patients with <3-cm lesions have metastatic disease; on average, enhancing renal masses grow
3 mm/yr; factors predicting survival—tumor size and grade; understaging; lesions 3 to 4 cm in size—associated with
marked decline in favorable prognosis; incidence of metastatic disease <3% at 3-cm cutoff (11% of lesions located outside
renal capsule) and 8.4% for 3.1- to 4-cm lesions (36% of lesions outside renal capsule)
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| Partial nephrectomy: results excellent for small tumors
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| Data from matched series comparing partial nephrectomy to radical nephrectomy (328 patients, 15-yr comparison):
cause-specific survival rates 91% for partial nephrectomy and 96% for radical surgery; postoperative creatinine levels
1.3 mg/dL for partial nephrectomy and 1.6 mg/dL for radical surgery; points—more thorough operation may provide
some clinical benefit but can cause problems, eg, lower creatinine levels; 5-yr survival rate with partial
nephrectomy—96% for ≤4-cm tumors; 83% for 4- to 7-cm tumors; 59% for pT3A tumors
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| Additional observations: goal—remove all cancer with adequate margins; nodal excision—did not increase survival in
randomized trials; may benefit ≈5% of patients; prolongs surgery, but complication rate relatively low; radical
nephrectomy—may be option for patients with larger tumors that have been upstaged (unless upstaging has occurred,
radical and partial nephrectomies achieve similar disease-specific survival rates in patients with <4-cm tumors; 36% of
patients with >3-cm tumors had disease that was upstaged); preferred option when surgeon lacks experience performing
partial nephrectomies
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Stone Disease
| CURRENT OPTIONS FOR MANAGING LOWER POLE RENAL STONES —Fernando Coste-Delvecchio, MD, Urologic
Surgeon, James A. Haley Veterans’ Hospital, Tampa, FL
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| Lower pole renal stones: more common; increasingly managed by shock-wave lithotripsy (SWL); noninfectious clinically
insignificant stone fragments produced by lithotripsy—may be responsible for changes in stone distribution; gravitate
into lower renal poles; serve as nidus for further stone growth; intervention necessary as stones grow and produce symptomatic
episodes; factors that must be investigated to achieve consistent, reliable, and reproducible results—stone size
and hardness (or fragility); intrarenal anatomy where stone located (key when planning SWL)
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| Stone hardness (ie, fragility): certain calcareous and some cystine stones do not fragment easily with SWL
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| Computed tomography (CT): attenuation values—distinguish between uric acid and calcium stones; used alone, result
in considerable overlap; knowing stone composition—insufficient for predicting stone fragility; range of fragility for
calcareous and cystine stones varies dramatically even when accounting for size of stones; internal structure of
stones—varies widely within stones of same crystallographic composition, eg, homogeneous calcium oxalate stones
harder to fragment than heterogeneous calcium oxalate stones; micro-CT imaging may eventually facilitate patient selection
by correlating internal structure of stone with known fragility (for current technology to work, patient must consistently
pass similar stones with similar levels of fragility); SWL contraindicated in patients who have—stones with
CT attenuation values >700 Hounsfield units (stones likely too hard for lithotriptor); renal tubular acidosis or hyperparathyroidism
(patients at increased risk of forming calcium phosphate stones)
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| Other cases in which endoscopic approach preferred: obesity—risk factor for recurrent nephrolithiasis; patient may be
too heavy for lithotripter, or it may be impossible to target stone; even when accounting for stone size and location, ureteroscopic
stone therapy achieves equivalent success rates without increasing morbidity in obese patients; presence of uncorrected
coagulopathy—studies show no increased risk for bleeding when lithotripsy performed with holmium:
yttrium aluminum garnet (Ho:YAG) laser; after failed SWL or percutaneous nephrolithotomy (PNL)—ureteroscopy can
be used as salvage procedure; to reduce number of accesses required to render renal unit stone-free—combine with percutaneous
approach; can displace stone into trajectory of rigid nephroscope; pregnancy—most stones pass before delivery;
even though ureteroscopy has been used successfully in pregnant women, other time-proven techniques (ie, JJ
stenting or nephrostomy tube placement) available
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| Intracorporeal lithotrites that can be used through flexible endoscopes: Ho:YAG laser—preferred lithotrite; fragments
all stone types, with broad safety margin; fragments pass on their own; expensive; loss of endoscopic flexion may prevent
device from reaching lower pole stones in situ (to circumvent problem, use Nitinol basket to displace stone from lower
pole into more accessible location); electrohydraulic lithotriptor (EHL)—less expensive than Ho:YAG laser; lower pole
stones can be reached in situ by placing 1.4 French probes through fully deflected endoscope; associated with narrow
safety margin and cannot fragment calcium oxalate monohydrate stones; produces stone fragments that must be removed
manually or by further fragmentation; frequency-doubled double-pulse neodymium (Nd):YAG (FREDDY) laser—
ineffective for monohydrate and cystine stones and for managing tumors and strictures; however, still has role in endourologic
management because of lower cost
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| Conclusions: when managing—>1-cm stones, use percutaneous approach (higher stone-free rates; no increase in morbidity);
<1-cm stones, ureteroscopy and SWL comparable (ureteroscopy preferred for managing obese patients, or patients
who have uncorrected coagulopathy or hard renal stones); technique—modern ureteroscopic stone management favors
use of access sheath, Ho:YAG laser, and, when necessary, stone displacement to more accessible location; in future, expect
increase in number of retrograde intrarenal surgeries performed
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Suggested Reading
Albaquami N, Janetschek G: Indications and contraindications for the use of laparoscopic surgery for renal call carcinoma.
Nat Clin Pract Urol 3:32, 2006; Al-Qudah HS et al: Laparoscopic management of kidney cancer: updated review.
Cancer Control 14:218, 2007; Atkins MB et al: Interleukin-2 therapy of metastatic renal cell carcinoma: uptake of phase
III trials. Clin Genitourin Cancer 5:114, 2006; Lee BR: Laparoscopic total and partial nephrectomy—the new standard?
Rev Urol 5:9, 2003; McDermott DF, Atkins MB: Interleukin-2 therapy of metastatic renal cell carcinoma: predictors of
response. Semin Oncol 33:583, 2006; Miller DC et al: Partial nephrectomy for small renal masses: an emerging quality of
care concern? J Urol 175:853, 2006; Pantuck AJ et al: Renal cell carcinoma with retroperitoneal lymph nodes: role of
lymph node dissection. J Urol 169:2076, 2003; Preminger GM: Management of lower pole renal calculi: shock wave
lithotripsy versus percutaneous nephrolithotomy versus flexible ureteroscopy. Urol Res 34:108, 2006; Thompson RH: radical
nephrectomy: too radical for small renal masses? Lancet 36B:823, 2006.
Educational Objectives
| The goal of this program is to improve management of renal cancer and of lower pole renal stones. After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Assess the clinical efficacy of immunotherapeutic options for managing renal cancer.
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| 2. Describe tumor-related factors that may help identify candidates for renal cancer immunotherapy.
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| 3. Investigate the role of laparoscopy in the management of renal cell cancer.
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| 4. Discuss the role of radical nephrectomy in the management of renal masses.
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| 5. Analyze the clinical advantages and disadvantages of current techniques for eliminating lower pole renal stones.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts
were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial
interest. For this program, the following has been disclosed: Dr. Lamm is affiliated with Mission Pharmacal Company,
Organon, and Sanofi-Pasteur; Dr. Lee is affiliated with RITA Medical Systems.
Acknowledgments
Dr. Atkins gave his scientific lecture at the 7th Annual Society of Urologic Oncology (SUO) Meeting to Discuss Current
Topics and Strategies in Urologic Oncology, held December 1-6, 2006, in Bethesda, MD, and sponsored by the SUO and
the National Cancer Institute; Dr. Coste-Delvecchio gave his scientific lecture at the 2007 Florida Urological Society (FUS)
Annual Meeting held August 30 to September 2, 2007, in Miami Beach, FL; Drs. Lamm and Lee gave their scientific lectures
at Perspectives in Urology: Point/Counterpoint presented November 9-11, 2006, in Scottsdale, AZ, by Grant/Downing
Education. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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