Urothelial and Kidney Cancers

April 17, 2009
Mark Hurwitz, MD

,
Philippe E. Spiess, MD

,
Brian Rini, MD

,
Louis L. Pisters, MD

,
Bruce G. Redman, DO

In the year 2008, an estimated 68,810 new cases of bladder cancer will be diagnosed in the United States, and approximately 14,100 patients will die of this disease.

UROTHELIAL CANCER

In the year 2008, an estimated 68,810 new cases of bladder cancer will be diagnosed in the United States, and approximately 14,100 patients will die of this disease.

Urothelial cancers encompass carcinomas of the bladder, ureters, and renal pelvis; these cancers occur at a ratio of 50:3:1, respectively. Cancer of the urothelium is a multifocal process. Patients with cancer of the upper urinary tract have a 30% to 50% chance of developing cancer of the bladder at some time in their lives. On the other hand, patients with bladder cancer have a 2% to 3% chance of developing cancer of the upper urinary tract. The incidence of renal pelvis tumors is decreasing.

Epidemiology

Gender Urothelial cancers occur more commonly in men than in women (3:1) and have a peak incidence in the seventh decade of life.

Race Cancers of the urothelial tract are also more common in whites than in blacks (2:1).

Etiology and risk factors

Cigarette smoking The major cause of urothelial cancer is cigarette smoking. A strong correlation exists between the duration and amount of cigarette smoking and cancers at all levels of the urothelial tract. This association holds for both transitional cell and squamous cell carcinomas.

Analgesic abuse Abuse of compound analgesics, especially those containing phenacetin, has been associated with an increased risk of cancers of the urothelial tract. This risk appears to be greatest for the renal pelvis, and cancer at this site is usually preceded by renal papillary necrosis. The risk associated with analgesic abuse is seen after the consumption of excessive amounts (5 kg).

Chronic urinary tract inflammation also has been associated with urothelial cancers. Upper urinary tract stones are associated with renal pelvis cancers. Chronic bladder infections can predispose patients to cancer of the bladder, usually squamous cell cancer.

Occupational exposure has been associated with an increased risk of urothelial cancers. Workers exposed to arylamines in the organic chemical, rubber, and paint and dye industries have an increased risk of urothelial cancer similar to that originally reported for aniline dye workers.

Balkan nephropathy An increased risk of cancer of the renal pelvis and ureters occurs in patients with Balkan nephropathy. This disorder is a familial nephropathy of unknown cause that results in progressive inflammation of the renal parenchyma, leading to renal failure and multifocal, superficial, low-grade cancers of the renal pelvis and ureters.

Genetic factors There are reports of families with a higher risk of transitional cell cancers of the urothelium, but the genetic basis for this familial clustering remains undefined.

Signs and symptoms

Hematuria is the most common symptom in patients presenting with urothelial tract cancer. It is most often painless, unless obstruction due to a clot or tumor and/or deeper levels of tumor invasion have already occurred.

Urinary voiding symptoms of urgency, frequency, and/or dysuria are also seen in patients with cancers of the bladder or ureters but are uncommon in patients with cancers of the renal pelvis.

Vesical irritation without hematuria can be seen, especially in patients with carcinoma in situ of the urinary bladder.

Symptoms of advanced disease Pain is usually a symptom of more advanced disease, as is edema of the lower extremities secondary to lymphatic obstruction.

Diagnosis

Initial work-up The initial evaluation of a patient suspected of having urothelial cancer consists of excretory urography, followed by cystoscopy. In patients with upper tract lesions, retrograde pyelography can better define the exact location of lesions. Definitive urethroscopic examination and biopsy can be accomplished utilizing rigid or flexible instrumentation.

At the time of cystoscopy, urine is obtained from both ureters for cytology, and brush biopsy is obtained from suspicious lesions of the ureter. Brush biopsies significantly increase the diagnostic yield over urine cytology alone. Also, at the time of cystoscopy, a bimanual examination is performed to determine whether a palpable mass is present and whether the bladder is mobile or fixed.

Evaluation of a primary bladder tumor In addition to biopsy of suspicious lesions, evaluation of a bladder primary tumor includes biopsy of selected mucosal sites to detect possible concomitant carcinoma in situ. Biopsies of the primary lesion must include bladder wall muscle to determine whether there is invasion of muscle by the overlying carcinoma.

CT For urothelial cancers of the upper tract or muscle invasive bladder cancers, a CT scan of the abdomen/pelvis is performed to detect local extension of the cancer and involvement of the abdominal lymph nodes.

Bone scan For patients with bone pain or an elevated alkaline phosphatase level, a radioisotope bone scan is performed.

A chest x-ray completes the staging evaluation.

Pathology

Transitional cell carcinomas constitute 90% to 95% of urothelial tract cancers.

Squamous cell cancers account for 3% to 7% of urothelial carcinomas and are more common in the renal pelvis and ureters.

Adenocarcinomas account for a small percentage (< 3%) of bladder malignancies and are predominantly located in the trigone region. Adenocarcinomas of the bladder that arise from the dome are thought to be urachal in origin.

Carcinoma in situ In approximately 30% of newly diagnosed bladder cancers, there are multiple sites of bladder involvement, most commonly with carcinoma in situ. Although carcinoma in situ can occur without macroscopic cancer, it most commonly accompanies higher disease stages.

When carcinoma in situ is associated with superficial tumors, rates of recurrence and disease progression (development of muscle invasion) are higher (50%–80%) than when no such association is present (10%). Carcinoma in situ involving the bladder diffusely without an associated superficial tumor is also considered an aggressive disease. Most patients with this type of cancer will develop invasive cancers of the bladder.

Staging and prognosis

Staging system Urothelial tract cancers are staged according to the American Joint Committee on Cancer (AJCC) TNM classification system (Table 1). Superficial bladder cancer includes papillary tumors that involve only the mucosa (Ta) or submucosa (T1) and flat carcinoma in situ (Tis). The natural history of superficial bladder cancer is unpredictable, andrecurrences are common. Most tumors recur within 6 to 12 months and are of the same stage and grade, but 10% to 15% of patients with superficial cancer will develop invasive or metastatic disease.

Prognostic factors For carcinomas confined to the bladder, ureters, or renal pelvis, the most important prognostic factors are T stage and differentiation pattern. The impact of associated carcinoma in situ on Ta and T1 lesions is discussed previously (see section on “Pathology”). Less-differentiated Ta–T1 lesions also are associated with higher recurrence and disease progression rates. Patients with well-differentiated Ta lesions without carcinoma in situ have a 95% survival rate, whereas those with high-grade T1 lesions have a 10-year survival rate of 50%. The presence of lymphovascular invasion within the surgical specimen appears to be independently associated with overall survival, cause-specific survival, as well as local and distant recurrence in patients with node-negative bladder cancer at the time of cystectomy. As such, the presence of lymphovascular invasion should be included in the pathologic assessment of bladder cancer.

Muscle invasive carcinoma carries a 5-year survival rate of 20% to 50%. When regional lymph nodes are involved, the 5-year survival rate is 0% to 20%.

Treatment

TREATMENT OF LOCALIZED DISEASE

Surgical approaches to superficial bladder cancer

Transurethral resection Most patients with superficial bladder cancer can be treated adequately with transurethral resection (TUR). Such procedures preserve bladder function, entail minimal morbidity, and can be performed repeatedly. Survival rates > 70% at 5 years are expected. Although TUR removes existing tumors, it does not prevent the development of new lesions. Patients should be followed closely.

Laser The neodymium:yttrium-aluminum-garnet (Nd:YAG) laser has achieved good local tumor control when used in the treatment of superficial bladder tumors. However, it has not been adopted for general use because of its limitations in obtaining material for staging and grading of tumors.

Partial cystectomy is an infrequently utilized treatment option for patients whose tumors are not accessible or amenable to TUR.

Radical cystectomy is generally not used for the treatment of superficial bladder tumors. The indications for radical cystectomy include:

• Unusually large tumors that are not amenable to complete TUR, even on repeated occasions

• Some high-grade tumors

• Multiple tumors or frequent recurrences that make TUR impractical

• Symptomatic diffuse carcinoma in situ (Tis) that proves unresponsive to intravesical therapy

• Prostatic stromal involvement.

Intravesical therapy The indications for intravesical therapy include:

• Stage T1 tumors, especially if multiple

• Multifocal papillary Ta lesions, especially grade 2 or 3

• Diffuse Tis

• Rapidly recurring Ta, T1, or Tis disease.

In the United States, four intravesical agents are commonly used: thiotepa, an alkylating agent; bacillus Calmette-Gurin (BCG), an immune modulator/stimulator; and mitomycin and doxorubicin, both antibiotic chemotherapeutic agents. The dose of BCG varies with the strain (50 mg [Tice] or 60 mg [Connaught]). Mitomycin doses range from 20 to 40 mg. Although all four agents reduce the tumor recurrence rate, BCG is the most effective. For the treatment of papillary Ta and T1 lesions, BCG and mitomycin have the greatest efficacy (complete response rate, approximately 50%). For the treatment of Tis, BCG is extremely effective.

In a recent meta-analysis, comparing intravesical BCG and chemotherapy (mitomycin, epirubicin, doxorubicin, or sequential mitomycin/doxorubicin), intravesical BCG was shown to be superior in reducing the risk of short- and long-term treatment failure for Tis. Therefore, intravesical BCG appears to be the agent of choice for Tis.

Surgical approaches to invasive bladder cancer

Radical cystectomy Invasive bladder cancer (stage II or higher) is best treated by radical cystectomy. Candidates for radical cystectomy include:

• Patients with muscle-invasive tumor (depth of invasion is not important, merely its presence), regardless of grade

• Patients with high-grade, invasive, lamina propria tumors with evidence of lymphovascular invasion, with or without Tis

• Patients with diffuse Tis or recurrent superficial cancer who do not respond to intravesical therapy.

In men, radical cystectomy includes en bloc pelvic lymph node dissection and removal of the bladder, seminal vesicles, and prostate. In women, radical cystectomy entails en bloc pelvic lymph node dissection and anterior exenteration, including both ovaries, fallopian tubes, uterus, cervix, anterior vaginal wall, bladder, and urethra.

Partial cystectomy is an infrequently utilized treatment option and should only be considered when there is a solitary lesion in the dome of the bladder and when random biopsy results from remote areas of the bladder and prostatic urethra are negative.

Urethrectomy is routinely included in the anterior exenteration performed in female patients. Urethrectomy in male patients is performed if the tumor grossly involves the prostatic urethra or if prior TUR biopsy results of the prostatic stroma are positive. Delayed urethrectomy for positive urethral cytology or biopsy is required in about 10% of male patients.

Urinary reconstruction may involve any one of the following: intestinal conduits (eg, ileal, jejunal, or colonic), continent cutaneous diversion (eg, Indiana or Kock pouch), or orthotopic reconstruction (in both male and female patients).

Surgical approaches to ureteral and renal pelvic tumors

Optimal surgical management of urothelial malignancies of the ureter and renal pelvis consists of nephroureterectomy with excision of a bladder cuff. Some tumors may respond well to local resection, and tumor specifics may allow for a more conservative intervention.

Upper ureteral and renal pelvic tumors (because of similar tumor behavior and anatomic aspects) may be considered as a group, whereas lower ureteral tumors may be considered as a separate group.

Upper ureteral and renal pelvic tumors are best treated with nephroureterectomy. Solitary, low-grade upper tract tumors may be considered for segmental excision or ureteroscopic surgery if close surveillance is feasible. Care should be exercised, however, as multicentricity is more probable and the risk of recurrence is greater than for lower ureteral lesions.

Lower ureteral lesions may be managed by nephroureterectomy, segmental resection, and neovesical reimplantation or by endoscopic resection. A 15% recurrence rate is seen after segmental resection or endoscopic excision. Careful follow-up is mandatory. Disease progression, the development of a ureteral stricture precluding periodic surveillance, and poor patient compliance are indications to abandon conservative management and perform nephroureterectomy.

ROLE OF RADIATION THERAPY

Radiation therapy for bladder cancer

Primary radiation or chemoradiation therapy Radiation therapy, either alone or in conjunction with chemotherapy, is the modality of choice for patients whose clinical condition precludes surgery, either because of extensive disease or poor overall status. Trials have shown that patients treated with irradiation and cisplatin with or without fluorouracil (5-FU) have improved local control, as compared with patients treated with irradiation alone.

The most frequently utilized systemic chemotherapy regimens for urothelial carcinoma are shown in Table 2. Other studies suggest that TUR followed by radiation therapy combined

with cisplatin or 5-FU chemotherapy, with cystectomy reserved for salvage, provides a survival equivalent to that achieved with initial radical cystectomy while allowing for bladder preservation in many patients. The extent of TUR and the absence of hydronephrosis are important prognostic factors in studies of bladder-conserving treatment. Updates from institutions in Europe and the United States on over 600 patients with long-term follow-up support the durability of outcomes previously reported.

A randomized phase III study of bladder preservation with or without neoadjuvant chemotherapy following TUR, conducted by the Radiation Treatment Oncology Group (RTOG), revealed no advantage to the use of MCV (methotrexate, cisplatin, and vinblastine) before radiation therapy and concurrent cisplatin. The favorable outcome without neoadjuvant chemotherapy may make bladder preservation a more acceptable option for a wider range of patients.

Preoperative irradiation may improve survival in patients undergoing radical cystectomy. Its use is limited due to concern over complications occurring with the urinary diversions currently utilized.

Radiation dose and technique Initially, a pelvic field is treated to approximately 4,500 cGy utilizing a multifield box technique, with 180 cGy delivered daily. The bladder tumor is then boosted to a total dose of 6,480 cGy utilizing multifield techniques, with 180 cGy delivered daily. Alternatively, twice daily treatment may be considered.

Radiation therapy for renal pelvic and ureteral cancers

In patients with renal pelvic and ureteral lesions who have undergone nephroureterectomy, postoperative local-field irradiation is offered if there is periureteral, perirenal, or peripelvic extension or lymph node involvement. A dose of approximately 4,500 to 5,040 cGy is delivered utilizing multifield techniques.

Palliative irradiation

Palliative radiation therapy is effective in controlling pain from local and metastatic disease and in providing hemostatic control. A randomized study comparing 3,500 cGy in 10 fractions and 2,100 cGy in 3 hypofractionated treatments revealed high rates of relief of hematuria, frequency, dysuria, and nocturia with either regimen. In selected cases of bladder cancer, aggressive palliation to approximately 6,000 cGy may be warranted to provide long-term local tumor control. Concurrent chemotherapy should be considered.

NEOADJUVANT/ADJUVANT CHEMOTHERAPY

Perioperative chemotherapy to reduce the risk of recurrence before or after cystectomy is a debated topic. Multiple randomized trials of different designs have given various chemotherapy regimens before and/or after cystectomy. Many of these trials had inadequate power or methodologic flaws that limit interpretation. In general, there is likely a small (5% to 10%) reduction in the risk of recurrence for perioperative chemotherapy given to high-risk (T3 and/or N+) patients, with an uncertain effect on overall survival.

CHEMOTHERAPY FOR ADVANCED DISEASE

Treatment of advanced metastatic urothelial cancer is generally considered palliative. Response rates are high with cisplatin-containing regimens (50% to 60%), but the duration of response is short, and median survival is 12 to 14 months. A small subset of patients (5% to 10%; usually with only lymph node metastases) can have a complete response to chemotherapy. A randomized trial showed an advantage for a regimen of M-VAC (methotrexate, vinblastine, Adriamycin [doxorubicin], and cisplatin) over cisplatin alone with regard to disease progression-free and overall survival. In another randomized trial, the combination of gemcitabine (Gemzar) and cisplatin exhibited equivalent survival to M-VAC in metastatic bladder cancer but was clinically better tolerated. Thus, cisplatin plus gemcitabine is the standard of care. Carboplatin can be substituted if a contraindication to cisplatin exists (eg, neuropathy, poor renal function). The role of combination chemotherapy in the adjuvant treatment of resected urothelial cancer remains undetermined and an area of clinical research. A randomized trial of neoadjuvant M-VAC in locally advanced resectable bladder cancer showed a trend in survival favoring M-VAC over surgery alone, but it was not statistically significant.

KIDNEY CANCER

Approximately 54,390 new cases of renal cell carcinoma will be diagnosed in the year 2008 in the United States, with an associated 13,010 deaths. There has been a steady increase in the incidence of renal cell carcinoma that is not explained by the increased use of diagnostic imaging procedures. Mortality rates have also shown a steady increase over the past 2 decades.

Epidemiology

Gender and age This malignancy is twice as common in men as in women. Most cases of renal cell carcinoma are diagnosed in the fourth to sixth decades of life, but the disease has been reported in all age groups.

Ethnicity Renal cell carcinoma is more common in persons of northern European ancestry than in those of African or Asian descent.

Etiology and risk factors

Renal cell carcinoma occurs most commonly as a sporadic form and rarely as a familial form. The exact etiology of sporadic renal cell carcinoma has not been determined. However, smoking, obesity, and renal dialysis have been associated with an increased incidence of the disease.

Genetic factors More recently, a genetic basis has been sought for this disease.

von Hippel-Lindau disease (VHL), an autosomal-dominant disease, is associated with retinal angiomas, CNS hemangioblastomas, and renal cell carcinoma.

Chromosomal abnormalities Deletions of the short arm of chromosome 3 (3p) occur commonly in renal cell carcinoma associated with VHL disease. In the rare familial forms of renal cell carcinoma, translocations affecting chromosome 3p can be present. Sporadic renal cell carcinoma of the nonpapillary type is also associated with VHL-gene silencing.

Associated malignancy Two studies from large patient databases have reported a higher-than-expected incidence of both renal cell cancer and lymphoma. No explanation for this association has been found.

Signs and symptoms

Renal cell carcinoma has been associated with a wide array of signs and symptoms. The classic triad of hematuria, flank mass, and flank pain occurs in only 10% of patients and is usually associated with a poor prognosis. With the routine use of CT scanning for various diagnostic reasons, renal cell carcinoma is being diagnosed more frequently as an incidental finding.

Hematuria More than half of patients with renal cell carcinoma present with hematuria, either gross or microscopic.

Other common signs/symptoms Other commonly associated signs and symptoms of renal cell carcinoma include normocytic/normochromic anemia, fever, and weight loss.

Less common signs/symptoms Less frequently occurring, but often described, signs and symptoms include polycythemia, hepatic dysfunction not associated with hepatic metastasis, and hypercalcemia. Although not a common finding at the time of diagnosis of renal cell carcinoma, hypercalcemia ultimately occurs in up to 25% of patients with metastatic disease.

Diagnosis

Contrast-enhanced CT scanning has virtually replaced excretory urography and renal ultrasonography in the evaluation of suspected renal cell carcinoma. In most cases, CT imaging can differentiate cystic from solid masses and also supplies information about lymph nodes and renal vein/inferior vena cava (IVC) involvement.

Ultrasonography is useful in evaluating questionable cystic renal lesions if CT imaging is inconclusive.

Venography and MRI When IVC involvement by tumor is suspected, either IVC venography or MRI is needed to evaluate its extent. MRI is currently the preferred imaging technique for assessing IVC involvement at most centers.

Renal arteriography is not used as frequently now as it was in the past in the evaluation of suspected renal cell carcinoma. In patients with small, indeterminate lesions, arteriography may be helpful. It is also used by the surgeon as part of the preoperative evaluation of a large renal neoplasm.

Percutaneous cyst puncture is used in the evaluation of cystic renal lesions that are thought to be potentially malignant on the basis of ultrasonography or CT imaging. Percutaneous cyst puncture permits the collection of cyst fluid for analysis, as well as the evaluation of cyst structure via instillation of contrast medium after fluid removal. Benign cyst fluid is usually clear to straw-colored and low in protein, fat, and lactic dehydrogenase (LDH) content, whereas malignant fluid is usually bloody with high protein, fat, and LDH content.

Evaluation of extra-abdominal disease sites includes a chest x-ray or CT imaging of the chest. A bone scan is required if a patient has symptoms suggestive of bone metastasis and/or an elevated alkaline phosphatase level.

Pathology

Renal cell carcinoma arises from the proximal renal tubular epithelium. Histologically, renal cell carcinoma can be of various cellular types: clear cell (70% to 80%), papillary (10% to 15%), and chromophobe (5%). Oncocytoma is a benign renal tumor. Approximately 10% to 20% of renal cell carcinomas have sarcomatoid features (spindled cells that can occur in any subtype), which is a more aggressive malignancy with a worse prognosis.

Staging and prognosis

Staging system The preferred staging system for renal cell carcinoma is the TNM classification (Table 3).

Prognostic factors The natural history of renal cell carcinoma is highly variable. However, approximately 30% of patients present with metastatic disease at diagnosis, and one-third of the remainder will develop metastasis during follow-up.

Five-year survival rates after nephrectomy for tumors confined to the renal parenchyma (T1/2) are > 80%. Renal vein involvement without nodal involvement does not affect survival. Lymph node involvement and/or extracapsular spread is associated with a 5-year survival of 10% to 25%. Patients with metastatic disease have a median survival of 1 year and a 5-year survival of 0% to 20%.

Several prognostic schemes have been developed for both localized and metastatic renal cell carcinomas. In general, factors such as tumor stage and grade, performance status, hemoglobin value, calcium, LDH level, and time interval to development of metastatic disease are important.

Treatment

Surgery

Radical nephrectomy is the established therapy for localized renal cell carcinoma. At surgery, the kidneys, adrenal gland, and perirenal fat (structures bound by Gerota’s fascia) are removed. Also, limited regional lymph node dissection is often performed for staging purposes. Partial nephrectomy is standard in patients with smaller tumors (eg, < 4 cm) or in whom radical nephrectomy would unacceptably compromise overall renal function.

Because complete resection is the only known cure for renal cell carcinoma, even in locally advanced disease, surgery is considered if the involved structures can be safely removed. In patients with metastatic renal cell carcinoma, two randomized, controlled trials have shown a survival benefit of 6 months (combined analysis) with a debulking nephrectomy prior to interferon-alpha immunotherapy, as compared with immunotherapy alone. However, patients must be carefully selected prior to the nephrectomy and should have a performance status of 0 to 1 according to the World Health Organization criteria. The performance status of a patient prior to treatment is an important determinant of disease-related outcome and should be considered in making treatment decisions.

Radiation therapy for renal cell carcinoma

Primary radiation therapy Radiation therapy may be considered for palliation as the primary therapy for renal cell carcinoma in patients whose clinical condition precludes surgery, either because of extensive disease or poor overall condition. A dose of 4,500 cGy is delivered, with consideration of a boost up to 5,500 cGy.

Postoperative radiation therapy has not been shown to prevent recurrence.

Palliation Radiation therapy is commonly used for palliation for metastatic and local disease.

Systemic therapy for advanced disease

Metastatic renal cell carcinoma is resistant to chemotherapeutic agents. An extensive review of currently available agents concluded that the overall response rate to chemotherapy is 6%.

Interleukin-2 The first US Food and Drug Administration (FDA)-approved treatment for metastatic renal cell carcinoma was high-dose interleukin-2 (IL-2, aldesleukin [Proleukin];

Table 4).

High-dose regimen High-dose IL-2 (720,000 IU/kg IV piggy back every 8 hours for 14 doses, repeated once after a 9-day rest) results in a 15% remission rate (7% complete responses, 8% partial responses). The majority of responses to IL-2 are durable, with a median response duration of 54 months.

The major toxicity of high-dose IL-2 is a sepsis-like syndrome, which includes a progressive decrease in systemic vascular resistance and an associated decrease in intravascular volume due to a “capillary leak.” Management includes judicious use of fluids and vasopressor support to maintain blood pressure and intravascular volume and at the same time to avoid pulmonary toxicity due to noncardiogenic pulmonary edema from the capillary leak. This syndrome is totally reversible.

Other doses and schedules Because of the toxicity of high-dose IL-2, other doses and schedules have been and are being evaluated. Several trials of low-dose IL-2 (3–18 × 106 IU/d), either alone or combined with interferon-alpha, have reported outcomes similar to those achieved with high-dose IL-2.

Multikinase inhibitors Three oral multikinase inhibitors have been approved by the FDA for the treatment of advanced kidney cancer.

Sorafenib (Nexavar) targets several serine/threonine and receptor tyrosine kinases thought to be integral to the biology of renal cell carcinoma, especially vascular endothelial growth factor (VEGF). A phase III placebo-controlled trial was conducted in 769 patients with advanced renal cell carcinoma who had received prior systemic treatment. The recommended oral dose of sorafenib (400 mg twice daily) was used. The median progression-free survival was 5.5 months in the sorafenib group versus 2.8 months in the placebo group. Toxic effects associated with sorafenib included reversible skin rashes in 40% and hand-foot skin reactions in 30% of patients. Notably, the incidence of treatment-emergent cardiac ischemia/infarction events was higher with sorafenib (2.9% vs 0.4%).

Sunitinib (Sutent) targets several receptor tyrosine kinases. In a single-arm, multicenter phase II trial of patients with metastatic renal cell disease, the overall response rate with sunitinib was nearly 40% (all partial responses), with a median time to disease progression of 8.7 months. Diarrhea, skin discoloration, and mucositis/stomatitis were the most common adverse events occurring more frequently with sunitinib. Decreases in left ventricular ejection fraction were noted with sunitinib, and dose reductions and/or antihypertensive or diuretic medications may be required.

Temsirolimus (Torisel) and bevacizumab (Avastin) were added to the NCCN Kidney Cancer Guidelines as options for first-line treatment of relapsed or medically unresectable stage IV renal cancer (RCC) with predominant clear cell histology and in the case of temsirolimus, non-clear cell histology. The recommendations were based on the results of large randomized trials. Temsirolimus significantly prolonged median overall survival in a phase III trial in 626 patients (P = .0078) and received FDA approval for first-line as well subsequent treatment (clear cell histology only) of advanced RCC. In the AVOREN trial, bevacizumab significantly increased progression-free survival (10.2 months vs 5.4 months; P = .0001) of patients with metastatic RCC when administered in combination with interferon-a2a.

As always, patients should be encouraged to participate in ongoing clinical trials of metastatic renal cell cancer.

SUGGESTED READING

ON UROTHELIAL CANCER

Barton Grossman H, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859–866, 2003.

Duchesne GM, Bolger JJ, Griffiths GD, et al: A randomized trial of hypofractionated schedules of palliative radiotherapy in the management of bladder carcinoma: Results of Medical Research Council Trial BA09. Int J Radiat Oncol Biol Phys 47:379–388, 2000.

Hudson MA, Herr HW: Carcinoma in situ of the bladder. J Urol 153:564–572, 1995.

Hussain MH, Glass TR, Forman J, et al: Combination cisplatin, 5-fluorouracil, and radiation therapy for locally advanced unresectable or medically unfit bladder cancer cases: A Southwest Oncology Group study. J Urol 165:56–60, 2001.

Lotan Y, Gupta A, Shariat SF, et al: Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. J Clin Oncol 23:6533–6539, 2005.

Milosevic M, Gospodarowicz M, Zietman A, et al: Radiotherapy for bladder cancer. Urology 69:80–92, 2007.

Sylvester RJ, van der Meijden AP, Witjes JA, et al: Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: A meta-analysis of the published results of randomized clinical trials. J Urol 174:86–92, 2005.

Von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 17:3068–3077, 2000.

ON KIDNEY CANCER

Dutcher JP, Szczylik C, Tannir N, et al: Correlation of survival with tumor histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma (adv RCC) receiving temsirolimus (TEMSR) or interferon-alpha (IFN). J Clin Oncol 25:5033, 2007.

Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134, 2007.

Escudier B, Koralewski P, Pluzanska A, et al: A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon-α2a as first-line therapy in metastatic renal cell carcinoma. J Clin Oncol 25:3, 2007.

Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal cell cancer. N Engl J Med 345:1655–1659, 2001.

Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281, 2007.

Mickisch GH, Garin A, van Poppel H, et al: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alone in metastatic renal-cell carcinoma: A randomized trial. Lancet 358:966–970, 2001.

Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124, 2007.

Parkinson DR, Sznol M: High-dose interleukin-2 in the therapy of metastatic renal cell carcinoma. Semin Oncol 22:61–66, 1995.

Rabinovitch RA, Zelefsky MJ, Gaynor JJ, et al: Patterns of failure following surgical resection of renal cell carcinoma: Implications for adjuvant local and systemic therapy. J Clin Oncol 12:206–212, 1994.

Stodlen WM, Vogelzang NJ: Low-dose interleukin-2 in the treatment of metastatic renal cell carcinoma. Semin Oncol 22:67–73, 1995.

Zisman A, Pantuck AJ, Dorey F, et al: Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 19:1649–1657, 2001.

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