Urothelial and Kidney Cancers

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This management guide covers the treatment of urothelial cancers (carcinomas of the bladder, ureters, and renal pelvis) and kidney cancers (renal tumors).

Urothelial Cancer

In the United States in 2016, it is estimated that there will be 76,960 new diagnoses of bladder cancer, with approximately 16,390 deaths.

Urothelial cancers encompass carcinomas of the bladder, ureters, and renal pelvis, which 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 point 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), with 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

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

Occupational exposure to toxins 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 (eg, those with Lynch syndrome) with a higher risk of urothelial carcinoma of the urothelium, but the genetic basis for this familial clustering remains undefined.

Signs and Symptoms

Hematuria

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

Urinary voiding symptoms

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.

Bladder irritation without hematuria

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

Symptoms of advanced disease

Constitutional symptoms include night sweats, fever, weight loss, and anorexia. Pain can also be a symptom of more advanced disease, as is edema of the lower extremities secondary to lymphatic or venous obstruction.

Diagnosis

Initial workup

The initial evaluation of a patient in whom urothelial cancer is suspected consists of excretory urography (computed tomography [CT], magnetic resonance imaging [MRI], or intravenous pyelogram) followed by cystoscopy. Retrograde pyelography can better define the exact location of upper tract lesions. Definitive assessment of upper tract tumors by ureteroscopic examination and biopsy can be accomplished using either 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 compared with 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 select mucosal sites to detect possible concomitant carcinoma in situ. Biopsies of the primary lesion must include the muscularis propia to determine whether there is invasion of the muscle wall by the overlying carcinoma. A repeat biopsy must be performed if no muscle was identified in the original specimen, since significant upstaging occurs with the deeper biopsies.

CT/MRI

For urothelial cancers of the upper urinary tract or muscle-invasive bladder cancers, a CT or MRI scan of the abdomen/pelvis is performed to detect local extension of the cancer, involvement of the abdominal/pelvic lymph nodes, or systemic metastases. CT or MRI usually consists of an abdominal/pelvic CT scan with contrast (usually with delayed images, to assess the entire urinary tract).

Bone scan

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

Chest x-ray film

A chest x-ray film completes the staging evaluation. Any suspicious findings in a chest x-ray film must be followed by a CT scan of the chest.

Pathology

Transitional cell carcinomas (urothelial carcinomas)

These constitute 90% to 95% of urothelial tract cancers. In approximately 30% of newly diagnosed urothelial bladder tumors, 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 more advanced disease stages.

When carcinoma in situ is associated with superficial tumors, rates of recurrence and disease progression (development of muscle invasion) are higher (50% to 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 go on to develop muscle-invasive bladder cancers.

Squamous cell cancers

These malignancies account for 3% to 7% of urothelial carcinomas and are more common in the renal pelvis and ureters.

Adenocarcinomas

These tumors 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.

Staging and Prognosis

Staging system

Urothelial tract cancers are staged according to the American Joint Committee on Cancer 7th edition 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, and recurrences 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.

TABLE 1: TNM staging of urothelial tract cancers

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 was 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 or micropapillary features within the surgical specimen appears to be independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with node-negative bladder cancer at the time of cystectomy. As such, the presence of lymphovascular invasion and micropapillary features should be included in the pathologic assessment of bladder cancer.

Muscle-invasive carcinoma carries a 5-year disease-specific survival rate of 40% to 65%. When regional lymph nodes are involved, the 5-year survival rate is 0% to 30%. For patients with unresectable or metastatic bladder cancer, Karnofsky performance status of less than 80% and visceral disease (lung, liver, or bone) have also been shown to predict survival.

Treatment

Surgical approaches to superficial bladder cancer

Transurethral resection. Most patients with superficial bladder cancer can be treated adequately with transurethral resection (TUR). In patients with noninvasive, high-grade tumors, a repeated transurethral resection of a bladder tumor (TURBT) and post-resection examination under anesthesia are pivotal to rule out muscle-invasive bladder cancer (present in 30% to 50%) and similarly has been shown to improve treatment response/outcomes to intravesical induction BCG therapy. Such endoscopic procedures preserve bladder function, entail minimal morbidity, and can be performed repeatedly. Survival rates of more than 70% at 5 years are expected. Although TUR removes existing tumors, it does not prevent the development of new lesions. Patients should be monitored closely thereafter. Usually repeat cystoscopic evaluation is completed every 3 to 4 months.

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. Partial cystectomy is an infrequently used treatment option for patients whose tumors are not accessible or amenable to TUR but are solitary in location and away from the trigone.

Radical cystectomy. Radical cystectomy is generally not used for the treatment of superficial bladder tumors. A 2007 retrospective series of patients with no viable tumor at the time of radical cystectomy (pT0) would suggest that up to 9% of these patients may develop a recurrence following surgery. On multivariate analysis, the presence of lymphovascular invasion and concomitant carcinoma in situ on the transurethral bladder tumor resection specimen predicted poorer overall and recurrence-free survival, respectively. 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

• Non–muscle-invasive BCG-refractory high-grade disease

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

A 2007 analysis found that following radical cystectomy, patients remain at risk for upper tract recurrence, with a previous report estimating the incidence of upper tract recurrence at 2.5%. Only urethral tumor involvement was predictive of upper tract recurrence. Despite routine surveillance of the upper urinary tracts, 78% of these recurrences were detected only on development of symptoms, with the median survival following recurrence being only 1.7 years. Furthermore, the detection of asymptomatic upper tract recurrences via routine surveillance strategies did not predict lower pathologic stage, absence of nodal metastasis, or improved survival in patients at time of nephroureterectomy.

In the United States, four intravesical agents are commonly used: thiotepa, an alkylating agent; 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, particularly for high-grade disease. 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. Recently, in a phase III prospective trial, a full induction course of BCG and 3 years of maintenance therapy has been shown to provide a benefit in terms of recurrence-free survival for patients with high-risk non–muscle-invasive bladder cancer.

In a meta-analysis comparing intravesical BCG and chemotherapy (mitomycin, epirubicin, doxorubicin, or sequential mitomycin/doxorubicin), intravesical BCG was 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

The standardized treatment for invasive bladder cancer (stage II or higher) is radical cystectomy and extended pelvic lymph node dissection.

Radical cystectomy. Candidates for radical cystectomy include:

• Patients with muscle-invasive tumor

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

Partial cystectomy. Partial cystectomy is an infrequently used treatment option that 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. 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. Urinary reconstruction may involve any one of the following: intestinal conduits (eg, ileal, jejunal, or colonic), continent cutaneous diversion (eg, Indiana, Florida, 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 endoscopic or segmental resection. The tumor specifics that help determine which patients are best suited for radical surgical resection vs an endoscopic/segmental resection approach pertain to the anatomic location, multifocality, grade, and tumor extent within the upper tract.

Upper ureteral and renal pelvic tumors. These 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 and bladder cuff excision. 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, because multicentricity is more probable, and the risk of recurrence is greater than for lower ureteral lesions.

Lower ureteral lesions. These tumors may be managed by nephroureterectomy and bladder cuff excision, 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 adherence are indications to abandon conservative management and perform nephroureterectomy.

Radiation therapy for bladder cancer

Primary radiation or chemoradiation therapy. Radiation therapy, preferably with chemotherapy, may be used following a maximal TURBT in select curative-care patients for bladder preservation in place of cystectomy or for treatment of patients who not surgical candidates. James et al recently reported a phase III trial that confirmed improved locoregional disease-free survival and a trend toward improved overall survival with the addition of fluorouracil (5-FU) and mitomycin C to radiation for bladder preservation. Other trials have shown improved local control using cisplatin with or without 5-FU or paclitaxel with radiation compared with radiation alone. Efstathiou et al reported on a phase III study of bladder preservation with or without neoadjuvant chemotherapy following TUR, conducted by the Radiation Therapy Oncology Group, that 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. Several phase II trials and retrospective series have also shown a survival rate equivalent to that achieved with initial radical cystectomy while allowing for bladder preservation in approximately two-thirds of patients. Updates from institutions in Europe and the United States on more than 600 patients with long-term follow-up support the durability of outcomes previously reported. The extent of TUR and the absence of hydronephrosis are important prognostic factors in studies of bladder-conserving treatment.

Radiation dose and technique. Initially, a pelvic field is treated to 4,000 to 4,500 cGy using a three-dimensional conformal technique, with daily or twice-daily fractionation. Cystoscopy with bladder biopsies is performed. If a complete response is confirmed, the bladder tumor site is then boosted to a total dose approximating 6,480 cGy, using multifield techniques. Image-guided techniques including cone beam CT can be useful.

TABLE 2: Chemotherapy regimens for bladder carcinoma

The most frequently used systemic chemotherapy regimens for urothelial carcinoma are shown in Table 2.

Radiation therapy for renal pelvic and ureteral cancers

In patients with renal pelvic and ureteral lesions who have undergone nephroureterectomy and bladder cuff excision, 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 5,580 cGy is delivered using 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 vs 2,100 cGy in three hypofractionated treatments revealed high rates of relief of hematuria, frequency, dysuria, and nocturia in both regimens. In select 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 improve overall survival and reduce the risk of recurrence before or after cystectomy is a debated topic. Data from two randomized trials of cisplatin-based chemotherapy administered in the neoadjuvant setting provide evidence of a survival benefit. Despite these data, it appears that many, if not most, patients with muscle-invasive bladder cancer in the United States do not receive chemotherapy before surgery, or rather do so in the adjuvant setting.

Multiple underpowered randomized trials of different designs have given various chemotherapy regimens after cystectomy. Many of these trials had inadequate power or methodologic flaws that limited interpretation. Therefore, the role of adjuvant chemotherapy remains undefined. Despite this, the US bladder cancer community increasingly uses adjuvant chemotherapy by extrapolating a “perioperative” benefit from the neoadjuvant experience. Perioperative cisplatin-based chemotherapy should now be considered a standard of care. In the perioperative setting, carboplatin is inferior to cisplatin and should not be offered in this setting.

Chemotherapy for advanced disease

Treatment of advanced metastatic urothelial cancer is generally considered to be 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. This small subset of patients should be considered for post-chemotherapy retroperitoneal lymph node dissection, provided no additional sites of metastases are suspected on complete metastatic evaluation. A randomized trial showed an advantage for a regimen of M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) over cisplatin alone with regard to progression-free and overall survival, but with high rates of myelosuppression. In another randomized trial, the combination of gemcitabine and cisplatin exhibited survival equivalent to that with M-VAC in metastatic bladder cancer but was clinically better tolerated. Thus, cisplatin plus gemcitabine has become a common standard of care in this setting. Similar data do not exist for the perioperative setting. Although carboplatin is inferior to cisplatin in bladder cancer, this agent can be used if a contraindication to cisplatin exists (eg, neuropathy, poor renal function). Since many patients cannot receive cisplatin because of renal impairment, some nonrandomized studies (eg, a phase II study by Carles et al) have examined the subsitution of oxaliplatin, which can be given with creatinine levels up to six times the upper limit of normal.

Kidney Cancer

Approximately 62,700 new cases of renal tumors will be diagnosed in the United States in 2016, with an estimated 14.240 deaths from the disease. 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 (2%) 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

von Hippel-Lindau (VHL) disease. VHL disease, an autosomal-dominant disease, is associated with retinal angiomas, central nervous system 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 clear cell 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 abdominal imaging for various diagnostic reasons, renal cell carcinoma is being diagnosed more frequently as an incidental finding.

Asymptomatic

Today, most patients presenting with a renal cell carcinoma are asymptomatic at time of diagnosis and are detected incidentally in the evaluation or surveillance for other unrelated medical conditions.

Hematuria

Relatively infrequently, patients can present with gross or microscopic hematuria, particularly if a large renal mass extends into the renal collecting system or if a renal vein/inferior vena cava tumor thrombus is present. For central renal tumors, the presence of a transitional cell carcinoma (rather than a renal cell carcinoma) should be considered and ruled out.

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 (termed “Stauffer syndrome”), 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

Pre- and post-contrast–enhanced CT scanning

This technique 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

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. Transesophageal echocardiography is occasionally obtained preoperatively or intraoperatively to determine the proximal extent of the IVC thrombus, particularly in lesions suspected to be above the diaphragm.

Renal arteriography

Renal arteriography is not commonly used in the evaluation of suspected renal cell carcinoma. In patients with small, indeterminate lesions, arteriography may be helpful. It can also be used by the surgeon as part of the preoperative evaluation and management of a large renal neoplasm.

Evaluation of extra-abdominal disease sites

This includes a chest x-ray film 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.

Brain CT or MRI

A CT or MRI scan of the brain is indicated if neurologic signs or symptoms occur, or if it is needed for staging before systemic therapy is given.

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

TABLE 3: TNM staging of renal cell carcinoma

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 greater than 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 2 years.

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 and lactate dehydrogenase levels, and time interval to development of metastatic disease are important.

Treatment

Surgery

Surgical resection (open and laparoscopic radical or partial nephrectomy) is the established therapy for localized renal cell carcinoma. When performing a radical nephrectomy, the kidneys, adrenal gland, and perirenal fat (structures bound by Gerota fascia) are removed. Also, limited regional lymph node dissection can be performed for staging purposes. Partial nephrectomy is standard in patients with smaller tumors (eg, < 7 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 adjacent 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 before interferon-α immunotherapy, as compared with immunotherapy alone. However, patients must be carefully selected before the nephrectomy and should have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. It is also recommended that patients have a baseline CT or MRI of the brain before undergoing surgery. The ECOG performance status of a patient before treatment is an important determinant of disease-related outcome and should be considered in making treatment decisions. A number of biologics, such as everolimus, sunitinib, and sorafenib, are under study as adjuvant treatment for high-risk resected renal cancer.

Radiation therapy for renal cell carcinoma

Primary radiation therapy. Thermoablative therapies are increasingly used for patients who are not surgical candidates. Alternatively, radiation therapy may be considered for palliation as the primary therapy for renal cell carcinoma in patients whose clinical condition precludes definitive treatment, either because of extensive disease or poor overall condition. A dose of 4,500 cGy is delivered, with consideration of a boost up to 5,580 cGy. Early results with stereotactic body radiation therapy are encouraging; however, this approach remains strictly investigational.

Postoperative radiation therapy

This modality has not been shown to prevent recurrence.

Palliation

Radiation therapy is commonly used for palliation of metastatic disease, including that affecting the central nervous system.

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%.

There is no standard adjuvant therapy for renal cell carcinoma after surgical resection, regardless of recurrence risk. Multiple agents, including hormone therapy, radiation, immune therapy, and chemotherapy, have been tried, and none has produced benefit in the adjuvant setting. Thus, observation is the current standard of care. There are ongoing trials testing novel targeted agents in the adjuvant setting.

Interleukin-2 (IL-2, aldesleukin). The first US Food and Drug Administration (FDA)-approved treatment for metastatic renal cell carcinoma was high-dose IL-2 (Table 4).

TABLE 4: Therapeutic regimens for renal cell carcinoma

• High-dose regimen-High-dose IL-2 (720,000 IU/kg IV piggyback 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-α, have reported outcomes similar to those achieved with high-dose IL-2.

Biologic agents. Several oral multikinase inhibitors have been approved by the FDA for the treatment of advanced kidney cancer. In addition, a monoclonal antibody has been tested extensively in treating the disease and, in combination with interferon-α, was FDA-approved to treat metastatic renal cell carcinoma.

• Sorafenib-This agent targets several serine/threonine and receptor tyrosine kinases, especially vascular endothelial growth factor (VEGF), thought to be integral to the biology of renal cell carcinoma. 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 vs 2.8 months in the placebo group. Toxic effects associated with sorafenib included reversible 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-This agent targets several receptor tyrosine kinases. Initial phase II trials of sunitinib, given orally at 50 mg once daily for 4 weeks followed by 2 weeks off to 169 patients with metastatic renal cell cancer that failed to respond to prior cytokine-based therapy demonstrated an investigator-assessed objective response rate of 45%, a median duration of response of 11.9 months, and a median progression-free survival of 8.4 months. A phase III trial of sunitinib vs interferon-α in 750 patients with untreated metastatic renal cell cancer demonstrated a significant advantage with sunitinib, in terms of an independently assessed objective response rate (31%; 95% CI, 26%–36% vs 6%; P < .001) and progression-free survival (11 months vs 5 months). Sunitinib-treated patients had a median overall survival of 26.4 months, compared with 21.8 months for interferon-α–treated patients (P = .051).

• Temsirolimus-This agent and bevacizumab were added to the National Comprehensive Cancer Network Kidney Cancer Guidelines as options for first-line treatment of relapsed or medically unresectable stage IV renal cell carcinoma 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 of 626 patients (P = .0078) and received FDA approval for first-line as well subsequent treatment of advanced renal cell carcinoma.

• Bevacizumab-Two separate, multicenter, international studies have established bevacizumab-based therapy as robust in the front-line setting. One phase III trial randomized 649 untreated patients with metastatic renal cell carcinoma to treatment with interferon α-2a, recombinant plus placebo infusion or to interferon α-2a plus bevacizumab infusion at 10 mg/kg every 2 weeks. A significant advantage for bevacizumab plus interferon α-2a was observed for objective response rate (31% vs 13%, respectively; P < .0001) and progression-free survival (10.2 months vs 5.4 months; P < .0001). The hazard ratio (HR) for progression in the bevacizumab plus interferon α-2a arm was 0.63 (95% CI, 0.52–0.75; P = .0001).

A second multicenter phase III trial conducted in the United States and Canada through the Cancer and Leukemia Group B was nearly identical in design, except that it lacked a placebo infusion and did not require prior nephrectomy. The median progression-free survival was 8.5 months in patients receiving bevacizumab plus interferon α-2a (95% CI, 7.5–9.7) vs 5.2 months for patients using interferon α-2a monotherapy (95% CI, 3.1–5.6; P < .0001). The HR for progression for patients receiving bevacizumab plus interferon α-2a after adjusting for stratification factors was 0.71 (P < .0001). Also, among patients with measurable disease, the objective response rate was higher in patients treated with bevacizumab plus interferon α-2a (25.5%) than for those given interferon α-2a monotherapy (13.1%, P < .0001).

In the AVOREN (Avastin for Renal Cell Cancer) trial, bevacizumab significantly increased progression-free survival (10.2 months vs 5.4 months; P = .0001) of patients with metastatic renal cell carcinoma when administered in combination with interferon α-2a.

• Pazopanib-This agent, a multikinase angiogenesis inhibitor, has been used to treat advanced renal cell cancer. In a phase III study, 435 patients with advanced renal cell carcinoma were randomly assigned to treatment with pazopanib (800 mg/d orally) or placebo. Progression-free survival was significantly better in the pazopanib group than in the placebo group (HR = 0.46; P < .0000001). This benefit was observed for both treatment-naive patients (HR = 0.40; P < .00001) and for those who had previously received one cytokine-based treatment (HR = 0.54; P < .001). The response rate was 30% with pazopanib vs 3% with placebo, and the median duration of response was 58.7 weeks. Most of the adverse events associated with this therapy were grade 1 or 2. The most common laboratory abnormality was an elevation in alanine aminotransferase level. The FDA approved pazopanib for advanced renal cell carcinoma in October 2009. COMPARZ, a large phase III randomized trial, compared the efficacy and safety of pazopanib and sunitinib as first-line therapy in more than 1,100 patients with metastatic renal cell carcinoma. The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib vs sunitinib. Secondary end points included overall survival, safety, and quality of life. Pazopanib was noninferior to sunitinib with respect to progression-free survival (HR for progression of disease or death from any cause, 1.05; 95% CI, 0.90–1.22), meeting the predefined noninferiority margin (upper bound of the 95% CI, < 1.25). Overall survival was similar (HR for death with pazopanib, 0.91; 95% CI, 0.76–1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs 55%), hand-foot syndrome (50% vs 29%), and thrombocytopenia (78% vs 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60% vs 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P < .05 for all 11 comparisons).

• Everolimus-This agent is an oral inhibitor of mammalian target of rapamycin kinase that has shown activity in metastatic renal cell carcinoma in phase II studies. Motzer and colleagues presented results of a planned interim analysis of a phase III study assessing the clinical benefit of everolimus in patients who had progressive metastatic renal cell carcinoma after receiving sunitinib, sorafenib, or both. The primary end point was progression-free survival. A total of 410 patients were randomized in a 2:1 ratio to receive everolimus at 10 mg or placebo, respectively. Prior bevacizumab and/or cytokine treatment was allowed. The results showed a significant improvement in progression-free survival for everolimus compared with placebo (everolimus, 4 months; placebo, 1.9 months; P < .001)

• Axitinib-This agent is a potent, selective, second-generation inhibitor of VEGF receptors 1, 2, and 3 that blocks VEGF receptors at sub-nanomolar drug concentrations. The relative potency of axitinib is 50 to 450 times greater than that of the first-generation VEGF inhibitors. In addition, axitinib does not block other targets, including platelet-derived growth factor receptors, b-RAF, KIT, and FLT-3, thought to be responsible for some of the adverse events associated with other available oral VEGF inhibitors. The activity of axitinib in advanced renal cell cancer was initially demonstrated in two phase II clinical trials of patients with cytokine-refractory disease. The objective response rate and median progression-free survival were 44% and 15.7 months and 55% and 12 months, respectively. A subsequent randomized phase III trial reported by Rini et al, comparing axitinib with sorafenib, led to the regulatory approval of this compound in renal cancer. This trial included 723 patients with advanced renal cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. The median progression-free survival was 6.7 months with axitinib compared with 4.7 months with sorafenib (HR = 0.665; 95% CI, 0.544–0.812; one-sided P < .0001). The objective response rate as assessed by masked independent radiology review committee was 19% for axitinib and 9% for sorafenib (P = .0001), with a median duration of response of 11 months (95% CI, 7.4; not estimable) for axitinib and 10.6 months (8.8–11.5) for sorafenib. The most common adverse events were diarrhea, hypertension, and fatigue in the axitinib arm, and diarrhea, palmar-plantar erythrodysesthesia, and alopecia in the sorafenib arm.

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

Suggested Reading

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