Urologic and Male Genital Cancers
Brendan D. Curti
Craig R. Nichols
I. BLADDER CANCER
A. General considerations and staging
More than 90% of patients with bladder cancer have transitional cell carcinoma (TCC). Other histologies include squamous cell neuroendocrine and adenocarcinoma. TCC falls into two major groups: superficial and invasive. The biology and natural history of these two groups differ markedly. The major factors that influence treatment choice and prognosis in bladder cancer are stage (0 to IV), histological grade (1 to 3), and location of the tumor within the bladder. Nuclear over expression of the tumor suppressor gene p53 and the Lewis-x blood group are associated with poorer prognosis in TCC.
The standard evaluation of a patient with invasive bladder cancer should include cystoscopy under anesthesia, computed tomography (CT) imaging of the abdomen and pelvis, chest radiograph, complete blood cell count (CBC), and serum chemistry profile. Chest CT and bone scan may also be helpful when stage IV disease is suspected. The TNM staging system is summarized in Table 11.1.
B. General approach to therapy
1. Superficial-stage, low-grade tumors. Patients with stage 0 or I tumors are usually treated by transurethral resection (TUR) and fulguration to achieve local control. Over 80% of patients will have recurrent bladder cancer despite initial complete resection. The risk of local recurrence may be reduced by administration of intravesical therapy, with the strongest benefit conferred by Bacillus Calmette-Guérin (BCG) vaccine. Diffuse carcinoma in situ may also be treated with intravesical therapy or cystectomy.
2. Deep-stage, high-grade tumors. Patients with muscle-invasive disease (stage II or III) are usually managed by radical cystectomy. Partial cystectomy may be used in highly selected patients with small and ideally located focal disease. Definitive radiation therapy can also be considered, although there has never been a direct comparison of the outcomes of radical cystectomy to radiation. Several randomized studies have shown a survival
benefit with platinum-containing combination administered before radical cystectomy. A meta-analysis of 10 randomized studies also showed a statistically significant 5-year survival benefit for platinum-containing combinations, but not for cisplatin monotherapy. Several smaller studies suggest a benefit of postsurgical adjuvant therapy comparable to neoadjuvant treatment, but there are no randomized comparisons to determine the optimal timing for chemotherapy.
TABLE 11.1 TNM Staging of Bladder Cancer
TX: Primary tumor cannot be assessed
TO: No evidence of primary tumor
Ta: Noninvasive papillary carcinoma
Tis: Carcinoma in situ
T1: Tumor invades subepithelial connective tissue
T2: Tumor invades muscle
T2a: Superficial (inner half)
T2b: Deep (outer half)
T3: Tumor invades perivesical fat
T3a: Microscopically
T3b: Macroscopically (extravesical mass)
T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall
T4a: Tumor invades the prostate, uterus, or vagina
T4b: Tumor invades the pelvic wall or abdominal wall
Stage groupings are as follows:
Stage 0: Ta or Tis, N0, M0
Stage I: T1, N0, M0
Stage II: T2, N0, M0
Stage III: T3 or T4a, N0, M0
Stage IV: T4b, N0, M0; any T, N1 to 3, M0 to 1
Modified from Edge SB, Byrd DR, Compton CC, et al (Eds.). AJCC cancer staging manual (7th ed.). New York: Springer; 2010.
3. Advanced and metastatic tumors. The prognosis for locally advanced and metastatic disease is poor. Patients with locally advanced disease or local recurrences can be considered for radiation therapy. Patients with advanced or metastatic disease can be offered systemic chemotherapy or clinical trial participation. There is evidence that chemotherapy can prolong survival and that combination chemotherapy is superior to single agents.
C. Treatment regimens and evaluation of response
1. Intravesical chemotherapy
a. Method of administration and follow-up. Intravesical therapy is usually administered in a volume of 40 to 60 mL through a Foley catheter. The catheter is then clamped and the agent
retained for 2 hours. This procedure delivers a high local concentration to the tumor area while usually avoiding systemic effects. Patients with superficial bladder cancers require lifelong surveillance with cystoscopy (initially every 3 months, then every 6 months, then annually) because of the high probability of recurrence even with intravesical therapy. Patients with diffuse carcinoma in situ should have biopsy confirmation of response after intravesical therapy and lifelong cystoscopic surveillance. Patients with persistent or recurrent cancer may require cystectomy.
b. Selection of patients for intravesical therapy. The indications for intravesical therapy are as follows:
(1) Prevention of relapse in patients with high grade Ta and stage I lesions after TUR.
(2) Prevent recurrence or progression in patients with two or more previously resected bladder tumors.
(3) Treatment of carcinoma in situ. A course of instillation therapy is usually given, followed by repeat biopsies. Persistence of carcinoma in situ is an indication for more aggressive local management with cystectomy or definitive radiation.
Intravesical therapy is not indicated for muscle-invasive TCC.
c. Specific intravesical therapeutic regimens
BCG 120 mg weekly for 6 to 8 weeks, or
Thiotepa 30 to 60 mg weekly for 4 to 6 weeks, or
Mitomycin 20 to 40 mg weekly for 6 to 8 weeks, or
Doxorubicin 50 to 60 mg weekly for 6 to 8 weeks
d. Selection of therapy. BCG is the agent of choice for intravesical therapy. Two separate studies have shown BCG to be superior to thiotepa and doxorubicin in preventing recurrence. Two published meta-analyses suggest significantly less tumor recurrence with BCG compared to mitomycin. In addition, BCG demonstrates higher rates of response in carcinoma in situ.
e. Response to therapy. Intravesical BCG decreases tumor recurrence by approximately 50% in patients with Ta or T1 disease. The complete response rate with BCG in carcinoma in situ is approximately 70% to 80%. Despite these favorable response rates, the benefit of maintenance BCG therapy is controversial and the benefit of intravesical therapy in preventing progression to invasive or metastatic bladder cancer is still unclear.
f. Complications of therapy. All of the agents mentioned can cause symptoms of bladder irritation (pain, urgency, hematuria) and allergic reactions. Thiotepa is systemically absorbed and can occasionally cause myelosuppression. This is rare with mitomycin and doxorubicin. Patients receiving thiotepa
should have their CBC monitored closely. Mitomycin can cause dermatitis in the perineal area and hands. BCG is occasionally associated with systemic symptoms including fever, chills, malaise, arthralgias, and skin rash. Septic reactions and disseminated BCG infections are rare.
2. Neoadjuvant chemotherapy. Platinum-containing neoadjuvant combination chemotherapy can increase resectability and can confer a survival benefit compared to radical cystectomy in patients with muscle-invasive TCC. Adjuvant chemotherapy is preferred at some centers because it does not delay possible curative surgery. There are few prospective randomized studies of adjuvant chemotherapy after cystectomy and no large studies comparing neoadjuvant with adjuvant chemotherapy.
3. Bladder-sparing therapy. Combination chemotherapy and radiation can be offered to patients with muscle-invasive bladder cancer who desire bladder preservation or are not candidates for radical cystectomy. Cisplatin chemotherapy concurrent with radiation increases local control. Approximately 30% of patients are free of recurrence 5 years after combined modality therapy for muscle-invasive disease. Salvage cystectomy has been used in some patients who do not achieve a complete response or recur after a bladder-sparing approach. There have been no randomized trials comparing bladder preservation therapy with radical cystectomy. Local symptoms from radiation including urinary frequency, incontinence, and proctitis usually resolve, but can persist in some patients. Candidates for a bladder-sparing approach are patients with favorable tumors (e.g., no involvement of the trigone or ureter) or patients who are unfit for radical cystectomy due to comorbidities.
4. Systemic chemotherapy for advanced disease.
a. Specific chemotherapy drugs and regimens. Drugs active against bladder cancer include cisplatin, gemcitabine, doxorubicin, vinblastine, methotrexate, pemetrexed cyclophosphamide, ifosfamide, carboplatin, paclitaxel, and docetaxel. Cisplatin is the most active drug single agent in TCC. The MVAC regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) is considered by many genitourinary oncologists to be a “gold standard” in advanced bladder cancer because of the number of studies confirming response. A study comparing gemcitabine and cisplatin (GC) to MVAC showed comparable efficacy, duration of response, and less toxicity with GC. Specific regimens are shown in Table 11.2.
b. Response to therapy. MVAC induces complete response in approximately 15% of patients and partial response in 35%, for an overall response rate of 50% in patients with metastatic disease. The median survival is 14 months. The toxicity of
the regimen is substantial and patient selection in regard to medical comorbidities and performance status is important. Response to chemotherapy is monitored by periodic measurement of tumor masses with the expectation that most patients who will respond will do so within the first one or two cycles of treatment.
TABLE 11.2 Combination Chemotherapy and Active Single Agents for Cancer of the Bladder
Regimen or Single Agent
Doses and Schedules
Methotrexate/vinblastine/doxorubicin/cisplatin
Methotrexate 30 mg/m2 IV on day 1
Vinblastine 3 mg/m2 IV on day 2
Doxorubicin 30 mg/m2 IV on day 2
Cisplatin 70 mg/m2 IV on day 2 (with adequate pre- and posthydration)
Repeat methotrexate and vinblastine on day 15 and 22 if white blood cell count >2000/µL and platelet count >50,000/µL.
Cycles should be repeated every 28 days.
Gemcitabine/cisplatin
Gemcitabine 1000 mg/m2 day 1
Cisplatin 70 mg/m2 on day 2
Repeat gemcitabine on day 8 and 15 if white blood cell count >2000/µL and platelet count >50,000/µL. Cycles should be repeated every 28 days.
Carboplatin/gemcitabine
Carboplatin AUC 5 day 1
Gemcitabine 1000 mg/m2 day 1 and day 8
Cycles repeated every 21 days
Carboplatin/paclitaxel
Carboplatin AUC 6
Paclitaxel 225 mg/m2
Cycles repeated every 21 days
Paclitaxel
250 mg/m2 IV over 24 hours every 21 days
AUC, area under the curve; IV, intravenously.
Patients who cannot tolerate cisplatin-based chemotherapy because of poor performance status or renal insufficiency may be considered for carboplatin-based therapy. Combinations containing carboplatin, gemcitabine, docetaxel, or paclitaxel have all shown activity.
Management of the non-TCC histologies arising from the bladder is difficult. Local therapies should be identical to TCC, but the role of chemotherapy is limited. Non-TCC histologies respond poorly to chemotherapy with the exception of neuroendocrine tumors. Neuroendocrine tumors of the bladder are usually treated similarly to small-cell lung cancer with cisplatin and etoposide chemotherapy and local radiation for those with bladder-confined disease. Although the initial response rate is high with neuroendocrine histology,
the incidence of recurrence and death from metastatic disease is also high.
c. Complications of systemic therapy. The major dose-limiting toxicity of MVAC is myelosuppression, which often precludes the administration of chemotherapy on days 15 and 22. GC produces significantly less neutropenia and mucositis but more thrombocytopenia. Cisplatin can cause renal tubular injury, but this can usually be prevented by vigorous hydration and repletion of electrolytes. Cisplatin is also highly emetogenic and requires aggressive management to minimize nausea and vomiting.
d. Follow-up. Patients with advanced disease can be followed every few months for symptomatic progression. Serial x-ray studies or bone scans are costly and are of minimal value.
II. PROSTATE CANCER
A. BackgroundRelated posts:
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