Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

11. Urologic and Male Genital Cancers

Brendan D. Curti and 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.

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3. Advanced and metastatictumors. 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.

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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. Background

Carcinoma of the prostate is the second most common cancer in the United States after nonmelanoma skin cancer. An elevated prostate-specific antigen (PSA) is the most common finding leading to a diagnosis of prostate cancer. There are considerable controversies about the value of PSA screening because aggressive prostate cancer can be present with a normal PSA and, conversely, many men with an elevated PSA and biopsy-proven prostate cancer can have indolent disease that does not change life span. The number of new prostate cancer diagnoses is estimated at 192,000 in 2009 with over 27,000 deaths. However, the median survival of patients with early prostate cancer exceeds 10 years. The benefit of aggressive surgical or radiotherapeutic management of these patients may be largely dependent on individual patient comorbidities and the biology of the tumor.

B. Staging

Accurate staging in prostate cancer is often difficult before definitive surgery. There are many published prostate nomograms that can be helpful in predicting pathologic stage, determining patient outcome, and guiding treatment. These nomograms use PSA, clinical stage (based on physical exam including digital rectal exam), the Gleason score, and the number of positive biopsy cores to determine the probability of organ-confined disease, seminal vesicle invasion, and lymph node involvement. The 5-year progression-free and overall survival of radical prostatectomy or external beam radiation is also estimated by the nomogram.

Initial staging of prostate cancer may also include abdominal and pelvic CT scans, chest radiographs, bone scan, liver function tests, and acid phosphatase measurements depending on the initial PSA, the clinical suspicion for metastatic disease, and the patient's goals for therapy. The most commonly used staging is the TNM system shown in Table 11.3. The modified Whitmore-Jewett or American Urologic Association system is also used. In the American Urologic Association system, stages A, B, C, and D correspond closely to stages I, II, III, and IV in the TNM system.

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C. General considerations and goals of therapy

Selection of therapy for prostate cancer is complex and based on the extent of disease as well as the age and general medical condition of the patient. Although many biases exist, there are no prospective randomized trials comparing treatment modalities in patients with organ-confined disease.

With the possible exception of young patients (less than 65 years of age), T1a prostate cancer may be followed without further therapy because few patients will have disease progression. For other patients with organ-confined disease (T1b, T1c, T2), several treatment options exist. Radical prostatectomy (using the traditional perineal or retropubic approach, or using laparoscopy and/or robotic-assisted techniques) and external beam radiation therapy (using intensity-modulated radiation therapy [IMRT], proton beam or other modern image-guided treatment planning) probably offer equivalent disease-free and overall survival when PSA and Gleason score are taken into account. Observation or active surveillance should also be considered for patients with low-grade, organ-confined tumors. The choice of primary therapy should be based on the patient's performance status, goals for treatment, and toxicities of each modality. Toxicities of radical prostatectomy include the risks of anesthesia, bleeding, urinary leakage, and erectile dysfunction. Diarrhea, tenesmus, and rectal bleeding are more common with radiation. In general, younger men are more likely to receive radical prostatectomy whereas older men are more likely to receive radiation therapy. Lastly, brachytherapy and cryosurgery may also be alternatives for management of localized disease.

Patients with stage III tumors are often treated with radiation therapy. However, elderly patients or patients in poor general health may be followed with observation because the natural history of prostate cancer can be slow with progression over years rather than months. The addition of early hormonal therapy to radiation therapy may be considered in higher stage disease or in patients with Gleason grade 7 or greater. The addition of docetaxel-based chemotherapy in high-risk localized prostate cancer is being studied, but has not yet shown a survival benefit.

D. Treatment of metastatic disease

The initial treatment of choice in patients with metastatic disease is androgen ablation. Radiation for symptomatic localized metastasis may also be considered.

1. Androgen ablation. Surgical or medical castration is associated with an overall response of 75% of patients with metastatic prostate cancer, lasting a median of 18 months. Luteinizing hormone-releasing hormone (LHRH) analogs or orchiectomy are the primary initial treatment options and have equivalent PSA and radiographic response rates. Patient preference, existing medical conditions, and cost influence treatment choice. There are currently no good predictive markers for response in clinical practice although some data suggest circulating tumor cell (CTC) assays may be superior to PSA in assessing response and prognosis.

a. Orchiectomy is still a standard treatment for metastatic disease because it is relatively inexpensive and obviates the need for injections or daily medications. This procedure can often be done on an outpatient basis. However, most men choose a nonsurgical method of androgen ablation.

b. LHRH analogs are synthetic peptides administered byparenteral injection. These agents occupy the receptors for LHRH in the pituitary gland. Initially the release of LH is increased, causing a rise in the serum testosterone level (and possible tumor flare). The presence of super-physiologic LHRH analog blocks the physiologic pulsatile LH release from the pituitary, causing a fall in the serum testosterone to castration levels usually within 2 weeks. The most commonly used LHRH agonists are:,

bull Leuprolide 7.5 mg intramuscular (IM) depot monthly or 22.5 mg IM depot every 3 months or 30 mg IM depot every 4 months.

bull Goserelin 3.6 mg subcutaneous (SC) depot monthly or 10.8 mg SC every 3 months.

Tumor flare can usually be avoided by the concurrent use of antiandrogens. Disadvantages of LHRH agonists compared to surgical castration are the potential for poor patient compliance and the high cost of treatment. The possible benefit of intermittent hormonal therapy is currently being studied in randomized trials. Small studies suggest equivalent cancer outcomes and enhanced tolerance using intermittent dosing.

c. LHRH analogs and antiandrogens (total androgen blockade) have also been studied. Synthetic antiandrogens such as flutamide, bicalutamide, and nilutamide act by competing with testosterone at the level of the cellular receptor. A large randomized trial of flutamide given after orchiectomy did not show improvement in survival. Because of the lack of consistent evidence of benefit as well as added cost and toxicity, total androgen blockade is not considered standard initial treatment in patients with metastatic disease.

d. Estrogens. DES (diethylstilbestrol) is effective but not frequently used because of concern about potential cardiotoxicity and thrombophlebitis. Historically 3 to 5 mg/day of DES has been given; however, 1 mg/day produces fewer side effects without shortening survival. Painful gynecomastia can be prevented by superficial radiation (5 Gy) to the breast tissue before starting DES.

e. Second-line hormonal therapies have low response rates (less than 20%) and the median duration of response is 4 months. Initial hormone therapy should be continued to maintain castration levels of testosterone. Second-line therapies include addition of antiandrogens, estrogens, ketoconazole, and progestins. Patients who were initially treated with combined modality therapy occasionally respond to withdrawal of the antiandrogen. This should be considered before proceeding to more toxic therapies.

2. Cytotoxic chemotherapy. Patients who relapse from or fail to respond to androgen ablation can be considered for cytotoxic chemotherapy. Trials of chemotherapy before 2000 did not show any convincing benefit and induced significant toxicity in men who had impaired bone marrow reserve due to multiple courses of palliative radiation. More recent studies of mitoxantrone and docetaxel chemotherapy have shown some clinical benefit.

a. Mitoxantrone

bull Mitoxantrone 12 mg/m2 every 3 weeks and

bull Prednisone 5 mg twice a day.

This regimen demonstrated improved pain control and reduced need for analgesic medications compared to patients treated with prednisone alone in a randomized trial with no improvement in overall survival. This regimen is still used and has a relatively low toxicity profile.

b. Docetaxel chemotherapy. Two large randomized trials of docetaxel-based chemotherapy were the first to demonstrate a survival benefit over mitoxantrone and prednisone. The median survival benefit is modest (approximately 3 months); however, a greater proportion of patients are alive at 1, 2, and 3 years after docetaxel chemotherapy compared to mitoxantrone or best-supportive care.

bull Docetaxel 75 mg/m2 every 3 weeks and prednisone 5 mg twice a day or

bull Docetaxel 60 mg/m2 intravenously (IV) day 2 and estramustine 280 mg twice a day by mouth days 1 to 5 and prednisone 5 mg twice a day during 3 week cycles.

Docetaxel monotherapy is now the most common regimen for castration-resistant prostate cancer in men with good functional status. There are many phase II and III studies looking at docetaxel in combination with other biologic agents like atrasentan, dasatinib, and AT-101. There is no standard salvage regimen after docetaxel chemotherapy. Clinical trials should be offered to patients with good functional status.

3. Vaccine therapy. The U.S. Food and Drug Administration (FDA) has recently approved the first therapeutic vaccine in prostate cancer, sipuleucel-T. Sipuleucel-T is indicated in patients with symptomatic or minimally symptomatic metastatic hormone refractory prostate cancer. The drug is an autologous dendritic (DC) cell vaccine that is derived from the patient's own cells and pulsed with the prostatic acid phosphatase antigen in the presence of granulocyte-macrophage colony stimulating factor. It is administered at a dose that contains a minimum of 50 million pulsed DCs in 3 doses at approximately 2 weeks apart.

4. Evaluation of response. PSA, palliation of bone pain, and radiographic response can be used to assess treatment response. Care must be taken in the interpretation of bone scans to distinguish between healing bone (which can show increased radiotracer uptake) and progressive cancer.

5. Complications of therapy. All androgen ablation therapies will cause sexual dysfunction, including impotence and decreased libido. Orchiectomy can rarely be complicated by local infection or hematoma. LHRH analogs can cause an initial flare of the disease and are frequently associated with vasomotor symptoms (“hot flashes”). Androgen ablation can also cause diarrhea, osteoporosis, and hepatic dysfunction. Estrogens are associated with thromboembolic disease, fluid retention, and cardiac disease. Chemotherapy side effects include nausea and vomiting, mucositis, marrow suppression, peripheral neuropathy, integumentary changes, infusion reactions, and alopecia.

6. Follow-up. Patients treated with radical prostatectomy can be followed with PSA measurements every 3 to 6 months. Patients with a rising PSA level, evidence of local recurrence, and no evidence of metastatic disease can be considered for salvage radiation therapy to the prostatic bed. Some patients can be considered for bisphosphonate therapy. Osteoporosis is a complication of androgen deprivation therapy and may benefit from treatment. Monthly IV bisphosphonate therapy with zoledronic acid may decrease the incidence of skeletal related complications such as pathologic fractures in patients with bone metastases from prostate cancer.

III. TESTICULAR CANCER (GERM CELL TUMORS)

A. Overview

Although primary neoplasms of the testis can arise from Leydig or Sertoli cells, more than 95% of testicular cancers are of spermatogenic or germ cell origin. Germ cell tumors (GCTs) are rare, accounting for 1% of all malignancies in men. However, they are important malignancies because they represent the most common solid tumor in young men and because of their high degree of curability. With the advent of cisplatin-based chemotherapy, accurate tumor markers, and aggressive surgical approaches, overall cure rates for patients with disseminated disease exceed 90% and patients with early-stage disease are nearly always cured. GCT is also one of the few solid tumors for which salvage chemotherapy can be curative.

B. Histology

GCTs are categorized as either seminomatous or nonseminomatous (which includes a variety of other histologies such as embryonal cell carcinoma, choriocarcinoma, and yolk sac tumors). Pure seminoma accounts for 40% of patients with GCTs. Although mild elevations of the β-subunit of human chorionic gonadotropin (hCG) may be seen, pure seminoma is never associated with an elevation of α-fetoprotein (AFP). Nonseminomatous GCT can cause elevations of hCG, AFP, or both.

C. Staging

Pretreatment staging should include serum tumor markers (AFP, hCG) and CT of the abdomen and chest. Other radiographic procedures should be undertaken only if symptoms or physical examination dictate.

1. Stage I. Tumor confined to the testis with or without involvement of the spermatic cord or epididymis.

2. Stage II. Tumor with metastasis limited to retroperitoneal lymph nodes (IIA, 5 or fewer nodes, all ≤2 cm; IIB, more than 5 nodes or any node >2–5 cm; IIC, any node mass >5 cm).

3. Stage III. Tumor spread beyond retroperitoneal lymph nodes.

D. Treatment strategies and management of specific situations

The therapeutic approach to the patient with testicular cancer depends on the histology of the tumor and the clinical or pathologic stage of the disease.

1. Seminoma

a. Clinical stage I. Over 75% of patients with testicular seminoma present with early-stage disease and are often cured with orchiectomy alone. The former paradigm of adjuvant radiation therapy is rapidly being replaced by active surveillance for clinical stage I disease. Both the European and Canadian consensus guidelines list active surveillance as the primary option for clinical stage I disease and this practice is being rapidly adopted in the United States. Precise guidelines for surveillance imaging guidelines are in evolution, but current recommendations range to as low as two CTs over the first 2 years to much more intensive schedules that have frequent and prolonged imaging. The imaging schedules being developed in the Oregon/British Columbia Testicular Cancer Consortium include four CTs (6 months, 1 year, 18 months, and 30 months) based in part on the median time to relapse (13 months). Adjuvant radiation therapy or consideration of adjuvant carboplatin should be reserved for uncommon circumstances.

b. Stage II. Traditional management of the small fraction of patients with stage II disease has been allocated by tumor volumes. Patients with small volume retroperitoneal disease (stage II A disease) have often been given therapeutic radiation at doses slightly higher than the doses given as adjuvant therapy (3000–3500 cGy) and chemotherapy reserved for the 20% or so of patients who recurred after therapeutic radiation therapy. Patients with bulky disease (>5 cm) are given combination chemotherapy (usually bleomycin, etoposide, and cisplatin [BEP] × 3 or etoposide and cisplatin [EP] × 4 as described below for nonseminoma) with a very high expectation of cure.

2. Nonseminoma

a. Stage I disease. The currently preferred option for patients is surveillance without a retroperitoneal lymph node dissection (RPLND). Because 30% of these patients eventually experience relapse, they must be followed closely with serum markers, exam, and interspersed CT scans of the abdomen. Most patients who recur will do so within the first 2 years. Historically these patients had been pathologically staged and treated with a RPLND. Patients with pathologically confirmed stage I disease do not need any further therapy because only approximately 10% show relapse. In about 25% of patients, clinical stage I disease is found to be stage II pathologically at RPLND and treatment for these patients is discussed in the following section. The major complication of RPLND has been retrograde ejaculation with subsequent infertility, although this is rare in experienced centers using nerve-sparing procedures.

b. Stage II disease. Patients with clear-cut radiographic evidence of stage II disease and elevated serum markers should be treated primarily with chemotherapy. If the lymph nodes are equivocal and markers are negative, an RPLND can be considered or close observation with repeat CT to document growth. Patients with pathologically confirmed and completely resected stage II disease have a relapse rate of about 30%. Patients with fully resected pathologic stage II disease either can be treated with two cycles of adjuvant chemotherapy after RPLND or can be followed closely and treated with standard chemotherapy if they show relapse.

c. Stage III disease. About 30% of patients present with stage III disease. The most common site of involvement is the lungs, but liver, bone, and brain can also be involved with metastatic disease. These patients are further categorized as good, intermediate, or poor risk based on the primary site, level of marker elevation, and involvement of brain, liver, or bone. An international germ cell prognostic classification has been developed based on a retrospective analysis of more than 5,000 patients with metastatic GCTs. Poor risk (poor prognosis) patients according to the International Germ Cell Cancer Consensus Classification System include those with the following:

bull Mediastinal primary site or

bull Nonpulmonary visceral metastasis (e.g., liver, bone, and brain) or

bull Elevation of AFP > 10,000 ng/mL, hCG > 10,000 ng/mL, or LDH >10 × upper limit of normal (ULN)

Patients with nonseminoma without mediastinal primary or nonpulmonary visceral metastasis

bull Have a good prognosis with the AFP 1000 ng/mL, hCG 1000 ng/mL, and LDH 1.5 × UNL;

bull Have an intermediate prognosis if any of the markers is in the intermediate range (AFP 1000–10,000 ng/mL, hCG 1000–10,000 ng/mL, and LDH 1.5–10 × UNL).

d. Recommended therapy. All patients with stage II or III disease who require chemotherapy should receive cisplatin-based chemotherapy, as follows:

BEP

bull Cisplatin 20 mg/m2 IV over 30 minutes on days 1 to 5, and

bull Etoposide 100 mg/m2 IV on days 1 to 5, and

bull Bleomycin 30 U IV push weekly on days 1, 8, and 15

bull Repeat every 21 days regardless of blood cell counts for two (adjuvant therapy), three (good risk patients), or four (intermediate or poor risk) cycles.

If the patient has fever associated with granulocytopenia, give the next cycle at the same doses, followed by daily SC injections of granulocyte colony-stimulating factor (filgrastim) or a single dose of pegfilgrastim. Other chemotherapy regimens such as VIP (etoposide, ifosfamide, cisplatin) have not improved outcome and are more toxic. Substitution of carboplatin for cisplatin is inferior therapy and should not be used.

e. Surgery for residual disease. Patients who have a complete response with chemotherapy should be followed and do not require any further treatment. Patients whose marker levels normalize but who have not achieved a radiographic complete response should undergo complete surgical resection of residual disease. If the resected material reveals only teratoma, necrosis, or fibrosis, then no further therapy is necessary and the patient should be followed. If there is carcinoma in the resected specimen, the patient should receive two more cycles of cisplatin-based chemotherapy (cisplatin and etoposide).

f. Follow-up. Most patients who experience relapse do so within the first 2 years, although late relapses do occur. In general, patients should be followed with every 2 month physical examination, chest x-ray studies, and serum marker measurements during the first year and every 4 months during the second year. Patients should then be followed about every 6 months for the third and fourth year and yearly thereafter. Because tumors can arise in the contralateral testis, patients should be taught to do testicular self-examination.

E. Salvage chemotherapy

1. Standard-dose therapy. Patients who respond to first-line chemotherapy and then relapse are still curable with salvage regimens such as VIP or TIP:

VIP

bull Vinblastine 0.11 mg/kg (4.1 mg/m2) IV push on days 1 and 2, and

bull Ifosfamide 1.2 g/m2 IV over 30 minutes on days 1 to 5, and

bull Cisplatin 20 mg/m2 IV over 30 minutes on days 1 to 5

TIP

bull Paclitaxel 250 mg/m2 CI over 24 hours day 1

bull Ifosfamide 1.5 gm/m2 IV days 2 to 5

bull Cisplatin 25 mg/m2 IV days 2 to 5

Repeat every 21 days for four cycles. Any radiographic abnormalities that persist after salvage chemotherapy should be considered for surgical resection.

2. High-dose chemotherapy with autologous stem cell transplantation. High-dose chemotherapy with carboplatin and etoposide with or without cyclophosphamide or ifosfamide followed by autologous stem cell transplantation (ASCT) should be considered for patients requiring salvage chemotherapy. Overall, about 15% to 25% of these patients are long-term survivors. The role of ASCT in the initial salvage setting is still under evaluation. Patients with incomplete response, high markers, high disease volume, and late relapse may be best candidates for initial salvage ASCT.

F. Prognosis

With these strategies, the overall cure rate for patients with stage I disease is more than 98%, stage II disease more than 95%, and stage III disease more than 80%.

G. Complications of therapy

Because patients are cured, the short- and long-term toxicities are of considerable importance. The short-term toxicities of the described chemotherapy regimens include nausea and vomiting, myelosuppression, renal toxicity, and hemorrhagic cystitis. The major long-term morbidities include infertility, pulmonary fibrosis, and a small but definite risk of secondary leukemia.

H. Mediastinal and other midline germ cell tumors

GCTs can arise in several midline structures including the retroperitoneum, mediastinum, and pineal gland. All patients with GCTs at these sites should have a testicular ultrasound examination to exclude an occult primary tumor. Mediastinal nonseminomatous GCTs are associated with Klinefelter syndrome and with rare hematologic malignancies (particularly acute megakaryocytic leukemia). Small mediastinal seminomas can be treated with radiation therapy alone. Widespread tumors or nonseminomatous tumors should be treated with four cycles of BEP chemotherapy. Salvage chemotherapy (including autologous bone marrow transplantation) in patients with nonseminomatous mediastinal GCT is ineffective.

IV. CANCER OF THE PENIS

A. General considerations

Penile cancer is rare in North America but is a significant health problem in many developing countries. These tumors are nearly always squamous cell in origin and are associated with the presence of a foreskin and poor hygiene. Typically, these tumors present as a nonhealing ulcer or mass on the foreskin or glans. The most common treatment is wide surgical excision or penectomy, depending on the size and location of the lesion. Prophylactic inguinal lymph node dissection is indicated in certain subgroups of patients. Radiation therapy can also provide local control, especially with small tumors. However, local relapse may be up to 30% and surgery is still considered standard management, especially for larger tumors.

B. Chemotherapy for systemic disease

Active single agents include bleomycin, cisplatin, and methotrexate, with response rates of 20% to 50%. Combination chemotherapy results in high response rates, but whether survival is improved over that with single agents is unknown. A reasonable regimen is cisplatin 100 mg/m2 on day 1, with fluorouracil 1000 mg/m2/day given by continuous infusion on days 1 to 4. Cycles can be repeated every 21 days.

Selected Readings

Testis

Bhatia S, Abonour R, Porcu P, et al. High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol. 2000;18(19): 3346–3351.

Bosl GJ, Motzer RJ Testicular germ-cell cancer. N Engl J Med. 1997;337:242–254.

International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancer. J Clin Oncol. 1997;15:594–603.

Loehrer PJ Sr, Gonin R, Nichols CR, et al. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol. 1998;16: 2500–2504.

Saxman SB, Finch D, Gonin R, et al. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indiana University experience. J Clin Oncol. 1998;16(2): 702–706.

Williams SD, Birch R, Einhorn LH, et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med. 1987;316:1435–1440.

Bladder

Advanced Bladder Cancer Meta-analysis Collaboration: Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet. 2003;361:1927–1934.

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

Herr HW, Schwalb DM, Zhang ZF, et al. Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol.1995;13:1404–1408.

Lamm DL, Blumenstein BA, Crawford ED, et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med.1991;325:1205–1209.

Loehrer PJ Sr, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10:1066–1073.

Okeke AA, Probert JL, Gillatt DA, et al. Is intravesical chemotherapy for superficial bladder cancer still justified? BJUInt. 2005;96:763–767.

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. 2000;17:3068–3077.

Prostate

Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005;352:1977–1984.

Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med. 1998;339(15): 1036–1042.

Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341:1781–1788.

Partin AW, Kattan MW, Subong ENP, et al. Combination of PSA clinical stage and Gleason score to predict pathology in men with localized prostate cancer: a multiinstitutional update. JAMA. 997;277:1445–1451.

Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14:1756–1764.

Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Eng J Med. 2004;351:1502–1512.

Penile Cancer

Culkin DJ, Beer TM. Advanced penile carcinoma. J Urol. 2003;170:359–365.

Kroon BK, Horenblas S, Nieweg O. Contemporary management of penile squamous cell carcinoma. J Surg Oncol. 2005;89:43–50.