Issues in Managing Urogenital Cancer

Educational Objectives

The goal of this program is to improve the management of bladder and kidney cancers. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe second-look transurethral bladder resection and radiation therapy for patients with bladder cancer.

2.   Discuss bladder-sparing treatment options with eligible patients.

3.   Assess the effects of radical cystectomy on disease management and quality of life.

4.   Evaluate whether a patient with kidney cancer is likely to benefit from cytoreductive nephrectomy.

5.   Explain new targeted therapies intended to shrink tumors and slow the progression of kidney cancer.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee 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. Figlin is an investigator for Amgen, Argos Therapeutics, Keryx Biopharmaceuticals, Novartis, Pfizer, and Wyeth, and provides consulting for Pfizer and Wyeth. Dr. Inman and the planning committee reported nothing to disclose. In their lectures, Drs. Inman and Figlin present in­formation related to the off-label or investigational use of a therapy, product, or device.

Acknowledgments

Dr. Inman was recorded at 41st Annual Duke Urologic Assembly, held March 7-10, 2009, in Las Vegas, NV, and sponsored by the Division of Urologic Surgery, Duke University Medical Center. Dr. Figlin was recorded at 2008 Urology Symposium, held September 19-20, 2008, in Carlsbad, CA, and sponsored by Kaiser Permanente. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Cystectomy: When is it Necessary? When Can it Be Avoided?

Brant A. Inman, MD, Assistant Professor of Urology, Duke University Medical Center, Durham, NC

Background on bladder cancer: epidemiology  —  ninth most common malignant tumor; two-thirds of cases occur in developed countries; tobacco use most significant risk factor (directly attributable cause in 65% of men and 30% of women; dose-response curves peak at »10 cigarettes per day; typically 30-yr delay between start of smoking and development of malignancy); incidence and mortality rates  —  incidence significantly higher than mortality; »70% of cases occur as superficial or nonmuscle-invasive disease (»25% invasive, »5% metastatic; patients may transi­tion between stages); risk for progression of superficial disease  —  calculated from risk factors (eg, carcinoma in situ, high-grade disease, T1 tumors); risk for progression with single low-grade tumor <5%; bacillus Calmette-Guérin (BCG) vaccine recommended only for patients with multiple recurrences or high risk for progression; rate of unfavorable outcomes increases with age

Resection: second-look transurethral bladder resection of bladder tumor (TURBT)  —  second resection procedures at 4 to 6 wk find malignancies in one-third of patients with stage Ta high-grade tumors; 5% of malignancies muscle-invasive; findings during second look TURBT strongly predict prognosis; Ta disease or carcinoma in situ often suc­cessfully managed with TURBT; consider cystectomy in patients with repeat or recurrent T1 disease; studies of pa­tients with positive second-look TURBT found long-term outcomes of transurethral resection (TUR) comparable to those of cystectomy; TUR alone may successfully manage most bladder malignancies (including those in high-risk populations); radical TUR  —  advocated for ill patients with T2 disease; patients undergo 3 successive resections; long-term data indicate favorable outcomes; 20% risk for progression from T2 disease to T3 disease found at 10-yr follow-up; most patients receiving radiation as salvage option died; patients undergoing cystectomy as salvage op­tion typically survived; TURBT with chemotherapy  —  speaker recommends for patients too ill for cystectomy or in­eligible for combined regimens; TURBT plus chemotherapy associated with better outcomes than TURBT alone

Radiation therapy (RT) and chemotherapy: randomized trial of neoadjuvant radiation  —  stopped due to lack of efficacy; no benefit from adding RT to cystectomy; RT vs TUR for high-grade T1 disease  —  study found high rate of late failures (3-5 yr after RT) in RT arm; recurrence of disease several years later frequently reported with RT; retrospective data study  —  found similar outcomes with all treatments; variations in quality of RT or cystectomy may explain contradictory data; collected data  —  bladder cancer associated with overall long-term survival rate of »20%; sicker patients more likely to receive RT (possibly skewing outcomes); patients with recurrent cancer after RT experience poor cystectomy outcomes (<50% successful); less efficacious with higher stages of disease; RT plus chemotherapy plus TURBT  —patients without prevalent disease on second look TURBT receive 40 gy RT and chemotherapy (5-fluorouracil [5-FU] or cisplatin [both radiosensitizing]); third TURBT performed at 7 wk from start of treatment; patients undergo cystectomy if tumors remain detectable (one-third of patients); patients without tumors complete RT regimen (40 to 65 gy) and complete chemotherapy; fourth TUR performed, at which point »60% cancer-free, but 15% have invasive cancer and 25% superficial cancer (cystectomy indicated); bladder-spar­ing regimens  —  many protocols and no standardization; “clumping” of survival end points  —  overall and disease-specific survival end points should not overlap (may indicate problems with data); greater numbers of patients should die in overall survival curves than recurrence-free curves; large series data for bladder-sparing options  —  50% to 60% of patients survive with cancer at 5 yr (40% to 50% at 10 yr); one-third to one-half of patients retain bladder at 10 yr; toxicity  —20% of patients have bladder-related toxicity; 10% report bowel problems; prospective evaluation by Japanese National Health Service  —  compared quality of life [QOL]) in standard population to pa­tients receiving cystectomy or chemotherapy and RT; chemotherapy and RT group reported lowest QOL across multiple indicators; attempting to spare bladder does not always yield superior outcomes (patients may be left with extremely poor bladder function); nocturia  —  common manifestation of bladder toxicity; chemotherapy plus RT plus TUR vs chemotherapy plus TUR  —highly similar outcomes; speaker speculates RT may have no effect beyond stiffening bladder (benefits undetermined)

Radical cystectomy: recommendations favor removal of extended pelvic lymph nodes; extended lymphadenectomy  —removes internal and external iliac nodes and obturator nodes; follows common iliac artery up to aorta on left side (some groups recommend continuing to inferior mesenteric artery [IMA]); follows vena cava on right side (up to presacral nodes); standard pelvic lymph node resections typically remove »15 nodes (extended resections typically remove »25; speaker reports average of 30-60 nodes); Baylor study  —  analyzed lymph nodes removed from different sites in patients with T2 disease; presacral nodes tested positive in 5% of patients; majority of positive nodes found below bifurcation of aorta; skip tumors  —nodes below bifurcation of common iliac artery may test negative, while nodes between bifurcation of common iliac artery and bifurcation of aorta test positive; re­moving nodes up to area between bifurcation of common iliac artery and bifurcation of aorta typically sufficient for identifying patients with positive lymph nodes; isolated positive nodes rarely occur above bifurcation of aorta; T3 disease  —  26% of patients have positive pelvic nodes; lymph node dissection  —  takes 1.0 to 1.5 hr; robotic cystec­tomies commonly remove »6 nodes (possibly insufficient); increases in T stage increase probability of malignant nodes; 25% of total cystectomy patients have positive nodes (corresponds directly with survival rates); multiple studies found removal of greater numbers of nodes improved outcomes (even when nodes tested negative); cystec­tomy and pelvic lymphadenectomy alone  —  study found »25% of patients with positive nodes remained disease-free at 5 yr; may indicate therapeutic benefit of lymphadenectomy; macroscopic nodes  —  data supports surgically removing nodes ³2 cm (10-yr survival possible with adjuvant chemotherapy); node quantity  —  patients with >20% of nodes positive experienced poorer outcomes; neobladder  —  improvement in QOL equal to or less than standards achieved with ileal conduit urinary diversion; patient eligibility should receive strong consideration; excellent re­sults in young patients or healthy patients »60 yr of age; may compromise QOL in unsuitable recipients; counseling patients  —  advise patients of high risk for complications; patients typically ill, with high incidence of comorbidi­ties; studies report complication rates of 20% to 50% (speaker thinks rates greatly underestimated); frequent com­plications include digestive issues, (prolonged ileus [20%]; bowel obstruction [2%]), and wound complications

Managing T2 and high-grade T3 disease: consider patient’s age, comorbidities, and symptoms; “bladder cripples” may benefit from cystectomy, even with Ta disease; speaker recommends providing patients accurate predictive scores (eg, for recurrence and progression); second-look TURBT may prevent understaging; variant histologies (eg, micropapillary, adenocarcinoma, squamous cell carcinoma, nested signet-ring cell carcinoma) do not typically re­spond well to chemotherapy (immediate cystectomy recommended)

Questions and Answers

Gender differences: elderly women with bladder cancer typically have extremely thin bladder walls; majority of studies focus on men; benefits of repeated TURBT uncertain in women; TURs performed in women do not delve deep and typically serve diagnostic purposes

Cytology: RT induces changes in cytology; speaker does not recommend as basis for treatment; data support using fluorescence in situ hybridization (FISH) for monitoring response to BCG

Partial cystectomy: controversial; usually reserved for urachal tumors (in dome of bladder; typically mucinous ade­nocarcinoma; transitional cell carcinoma also possible); potentially applicable to unifocal small tumors without carcinoma in situ; should not be performed on patients with carcinoma in situ (due to high risk for recurrence) or multifocal disease; T2 or T3 disease remains eligible; 4% to 5% of patients with bladder cancer considered candi­dates; tumor must be in upper region of bladder (well above trigone); speaker recommends catheterization and che­motherapy of bladder (with mytomycin C or thiotepa) before surgical opening (prevents spilling of urine containing cancer cells into peritoneum); tumor location should be assessed via cystoscopy; analysis of frozen sections of re­sected tissue recommended; patients with recurrence after partial cystectomy typically develop severe disease (due to altered lymphatic drainage)

Cytoreductive Nephrectomy for
Metastatic Renal Cell Cancer

Robert A. Figlin, MD, Chair, Medical Oncology & Therapeutics Research; Arthur and Rosalie Kaplan Chair in Medical Oncology; Director, Kidney Cancer Program; and Interim Director, City of Hope Comprehensive Can­cer Center, Duarte, CA

Background: standard of care in properly selected patients; treatment rationale  —  palliates local symptoms; primary tumor rarely responds to systemic therapy (targeted or otherwise); delays time to progression; improves survival rates; rate of spontaneous regression only 0.6%; arguments against cytoreductive nephrectomy  —  significant mor­bidity and mortality; majority of benefits proven in era of immune-based therapy (eg, interferon, interleukin-2 [IL-2]); patients may experience disease progression during extended postoperative recovery period (potentially delays start of systemic therapy); systemic immune-based therapies  —  show no efficacy in treating primary tumors; peri­operative mortality  —  typically low; speaker reports rate of 0% after 30 days; majority of patients become eligible for systemic therapy

Studies: randomized controlled trials  —  in Mickisch trial (Lancet, 2001) patients with metastatic disease received ne­phrectomy followed by interferon, or interferon alone; patients properly selected for cytoreductive nephrectomy showed greater improvements in time-to-progression and overall survival; larger series by Southwest Oncology Group reported similar findings; combined findings established cytoreductive nephrectomy as standard of care (for patients with favorable risk for morbidity and mortality); speaker recommends cytoreductive nephrectomy with IL-2 as preferred regimen for achieving durable remission; cytoreductive nephrectomy in elderly patients  —  incidence of kidney cancer peaks at 60 to 65 yr of age; incidence of advanced kidney cancer increasing; male-to-female ratio of 2 or 2.5:1 (renal cell carcinoma); MD Anderson Cancer Center study  —  average stage, size, and grade of tumors found similar between age groups; perioperative mortality rates »20% in elderly patients (1% in patients <75 yr of age); no difference in survival time between age groups (median 13-14 mo); Kassouf study (2008)  —  included 23 patients (median age 55 yr) with large tumors and widely metastatic disease; length of stay and time to systemic treatment after nephrectomy comparable to lower stage disease (but with significantly greater blood loss); poor sur­vival rates reported (median survival 5 mo with T4 disease); ineligibility for systemic therapy decreased median survival to 2 mo (7 mo with systemic therapy); nodal metastases  —  N-positive disease associated with poorer ulti­mate survival rates; relationship between nodal disease and metastasis unclear with clear cell carcinoma (75%-80% of kidney cancers); papillary subtype of renal cell carcinoma (occurs in 10%-15% of patients) driven by nodal me­tastases; cytoreductive surgery before systemic therapy  —  speaker recommends aggressive resection of all intra-ab­dominal disease appropriate; majority of clinical data based on clear cell histology (role in other histologies unproven)

Targeted agents: antivascular endothelial growth factor (anti-VEGF) agents  —  eg, sorafenib and sunitinib; profound effect on progression-free survival and ultimate survival; infrequently produce response in primary tumor; potential for use to reduce tumor volume before nephrectomy; efficacy difficult to validate in trials (ongoing); paradigm of choice  —  speaker continues to recommend cytoreductive nephrectomy; majority of patients in trials of VEGF-tar­geted agents previously underwent nephrectomy (few complete responses); waiting for tumors to downstage not advised (uncommon phenomenon); residual tumors potential sources of morbidity or metastatic disease (justifies cytoreductive nephrectomy); speaker recommends multidisciplinary approach to kidney cancer (coordinated be­tween medical oncologist and urologic oncologist); neo-adjuvant therapy  —  systemic therapy given before defini­tive surgical resection; allows selection for surgery based on response to treatment; possibility of downstaging; avoids exposing patients with rapid progression to elevated risks associated with resection; therapy may increase morbidity and mortality associated with resection or decondition patients for surgery; no proven benefit; VEGF-tar­geted agents may promote wound dehiscence by inhibiting angiogenesis necessary for healing; monoclonal anti­bodies (eg, bevacizumab [Avastin]) have long half-life (2-3 wk) compared to small molecule inhibitors (measured in hours)

Treatment paradigms: example paradigm  —  check patients with untreated metastatic kidney cancer and favorable performance status plus favorable surgical prognosis for clear cell histology without sarcomatoid variant (poor prognosis); patients with predominant clear cell histology receive cytoreductive nephrectomy and targeted therapy; patients with non-clear cell disease may receive targeted therapy, plus cytoreductive nephrectomy after showing benefit (allows time to gauge rate of progression and associated surgical risks); patients with non-clear cell histol­ogy eligible for clinical trials or alternative management (nephrectomy considered only on individual basis); stan­dardization of targeted therapy  —  speaker recommends delaying surgery 1 mo after bevacizumab; 1-day wait sufficient after oral targeted therapy with half-life of 4 to 8 hr; proper cessation of targeted agents should be ar­ranged with medical oncologist before surgery (prevents wound complications); duration of targeted therapy before surgery remains undefined; clinically evident lymph node metastases  —  confirmed and suspected metastases ideally removed at time of surgery; conclusions  —  surgery should be relegated to centers with significant track record; complete removal of all intra-abdominal and retroperitoneal disease should be attempted

Suggested Reading

Burkowski RM et al: Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol 25:4536, 2007; Freeman JA et al: Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 76:833, 2006; Herr HW, Donat SM: A re-staging transure­thral resection predicts early progression of superficial bladder cancer. BJU Int  97:1194, 2006; Johannes V et al: The role of pelvic lymphadenectomy and radical cystectomy for lymph node positive bladder cancer. Cancer 73:3020, 2006; Margulis V et al: Surgical morbidity associated with administration of targeted molecular therapies before cytoreductive nephrectomy or resection of locally re­current renal cell carcinoma. J Urol 180:94, 2008; Merseburger AS et al: Bladder preserving strategies for muscle-invasive bladder cancer. Curr Opin Urol 18:513, 2008; Mickisch et al: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 358:966, 2001; Motzer RJ et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115, 2007; Pantuck AJ et al: Cytoreductive nephrectomy for metastatic renal cell carcinoma: is it still imperative in the era of targeted therapy? Clin Cancer Res 13:693S, 2007; Schwaibold SE et al: 357 long-term results of TUR and radiochemotherapy of invasive bladder cancer. Eur Urol Suppl 6:12, 2007; Tan LB et al: Clinical and epidemiological features of patients with genitourinary tract tumour in a blackfoot disease endemic area of Taiwan. BJU Int 102:48, 2008; Wilby D et al: Bladder cancer: new TUR techniques. World J Urol 27:309, 2008.