Editors: Skeel, Roland T.
Title: Handbook of Cancer Chemotherapy, 7th Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 12 - Urologic and Male Genital Cancers
Urologic and Male Genital Cancers
Joseph S. Chan
Scott B. Saxman
Craig R. Nichols
I. Bladder cancer
A. General considerations and staging
Cancer arising in the bladder is usually transitional cell carcinoma (TCC), although occasionally squamous cell carcinoma, neuroendocrine carcinoma, and adenocarcinoma are seen. TCC falls into two major groups: superficial and invasive. The biology and natural history of these two groups differmarkedly. When planning treatment for bladder cancer, one must take into account the stage of the tumor (0 to IV), histologic grade (1 3), and location of the tumor within the bladder (related to surgical considerations of partial vs. total cystectomy).
The standard evaluation of a patient with invasive bladder cancer should include a computed tomography (CT) scan of the abdomen and pelvis, chest radiograph, complete blood cell count, and serum chemistry profile. In certain circumstances, urine cytology, chest CT, magnetic resonance imaging (MRI), and bone scan may also be helpful. The TNM staging system is summarized in Table 12.1.
B. General approach to therapy
Superficial-stage, low-grade tumors. Patients with stage 0 or I tumors are usually treated by transurethral resection (TUR) and fulguration, which may provide local control. However, most patients will have recurrence at other sites of the bladder. The risk of recurrence may be reduced by administration of intravesical therapy. Diffuse carcinoma in situ may also be treated with intravesicular therapy.
Deep-stage, high-grade tumors. Patients with larger stage II lesions or with stage III disease are usually managed by radical cystectomy. Partial cystectomymay be used in highly select patients with small and ideally located focal disease. The responsiveness of TCC to cisplatin-based combination chemotherapy suggests its potential in the neoadjuvant and adjuvant setting. With a significant rate of recurrence after surgery, the addition of chemotherapy to radical cystectomy, especially in a clinical trial, may be considered in patients with muscle-invasive bladder cancer. The addition of chemotherapy and radiation to local resection in bladder-sparing protocols is also under active investigation.
Advanced and metastatic tumors. Patients with locally advanced disease or local recurrences can be considered for radiation therapy. Patients with advanced or metastatic disease are candidates for systemic chemotherapy. There is evidence that chemotherapy can prolong
Table 12.1. TNM staging of bladder cancer
C. Treatment regimens and evaluation of response
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 periodic cystoscopy (initially every 3 months, then every 6 months, then annually) because even with intravesical therapy, an increased risk of new primary tumors persists. Patients being treated for diffuse carcinoma in situ should have biopsy confirmation of the return of normal mucosa after the instillation of therapy has been completed. These patients also require lifelong cystoscopic surveillance.
Selection of patients for intravesical therapy. Only patients with superficial or small, minimally invasive tumors (T1) should be treated. The grade of the tumor is also a significant predictor of progression. Patients with lesions at high risk for progression, especially those that persist or recur after initial intravesical
Prevention of relapse in patients with high-grade Ta and stage I lesions treated with TUR.
Prevention of new bladder tumors. Patients with two or more previously resected bladder tumors may be treated in an effort to prevent development of de novo malignancies.
Treatment of carcinoma in situ, which may involve the bladder diffusely and therefore not be amenable to TUR. 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 such as cystectomy.
Specific intravesical therapeutic regimens Bacillus Calmette-Guerin (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
Selection of 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 as compared to mitomycin. In addition, BCG demonstrates higher rates of response in treatment of carcinoma in situ. Therefore, BCG should be considered the agent of choice for intravesical therapy. The benefit of maintenance BCG therapy is controversial.
Response to therapy. In patients with Ta or T1 disease, intravesical BCG decreases tumor recurrence by approximately 50%. The complete response rate with BCG in carcinoma in situ is approximately 70% to 80%. However, the benefit of intravesical therapy in preventing progression to invasive or metastatic bladder cancer is still unclear.
Complications of therapy. All of the agents mentioned can cause symptoms of bladder irritation (pain, urgency, and 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 blood cell countsmonitored 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.
Adjuvant chemotherapy. With the encouraging response rates of cisplatin-based chemotherapy in advanced bladder cancer, there has been enthusiasm for using this therapy in the neoadjuvant and adjuvant setting. However, there are only a few select studies suggesting a survival benefit. The US Intergroup trial, which randomized patients to neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or radical cystectomy alone,
Bladder-sparing therapy. Reports of success with combination chemotherapy and radiotherapy as definitive treatment for muscle-invasive bladder cancer is compelling especially for patients who wish to keep their native bladder. However, there is no randomized trial directly comparing bladder preservation therapy with radical cystectomy. Bladder-sparing therapy does not avoid the possibility of newbladder tumors nor the distinct toxicities of chemotherapy and radiotherapy. Patients with favorable tumors and those who are unfit for radical cystectomy because comorbidities may be the best candidates for bladder-sparing protocols.
Systemic chemotherapy for advanced disease
Specific chemotherapy drugs and regimens. Drugs active against bladder cancer include cisplatin, doxorubicin, vinblastine, methotrexate, cyclophosphamide, gemcitabine, carboplatin, paclitaxel, and docetaxel. Of these, cisplatin is probably the most active drug as a single agent. The MVAC combination is the most standard therapy because of its significant survival advantage over single-agent cisplatin. However, the use of GC (gemcitabine and cisplatin) is increasing substantially due to similar response rates and survival data with fewer side effects. Specific regimens are shown in Table 12.2.
Response to therapy. MVAC may be expected to produce a complete response in approximately 15% of patients and a partial response in 35%, for an overall response rate of approximately 50% in patients with metastatic disease. The median survival time is approximately 14 months. The toxicity of the regimen is substantial and patient selection in regards to medical comorbidities and performance status is important. Response to any chemotherapy is monitored by periodic measurement of tumormasses with the expectation that most patients who will respond will do so within the first one to two cycles of treatment.
A trial comparing MVAC with GC demonstrated similar response rates and overall survival. An update of the trial's results demonstrated that these survival outcomes were maintained after long-term follow-up. However, the study was not powered statistically to prove equivalence of the two regimens. Despite this statistical argument, the GC regimen has entered common usage as first-line therapy in patients with advanced TCC.
Patients who will not tolerate cisplatin-based chemotherapy because of poor performance status or renal insufficiency may be considered for carboplatin or nonplatin-based therapy. Combinations containing
Table 12.2. Combination chemotherapy and active single agents for cancer of the bladder
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. Neuroendocrine tumors of the bladder are usually treated in a manner similar to small cell lung cancer with cisplatin/etoposide-based regimens and local radiation for those with disease confined to the bladder.
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 damage, but this can usually be prevented by vigorous hydration and saline diuresis. Nausea, vomiting and malaise are also commonly seen.
Follow-up. Patients with advanced disease can be followed up every few months for symptomatic progression. Serial x-ray studies or bone scans are costly and are of minimal value.
II. Prostate cancer
Carcinoma of the prostate is the most common cancer in the United States, with the exception of nonmelanoma skin cancer. Largely because of aggressive screening using prostate-specific antigen (PSA), the estimated number of new cases increased to more than 230,000 in 2006. However, the median survival of patients with early prostate cancer may be over 10 years. The benefit of aggressive surgical or radiotherapeutic management of these patients is largely dependant on individual patient comorbidities and the biology of the tumor.
Staging is usually done using a combination of clinical and pathologic indicators. Pathologic staging is necessary for a completely accurate staging of low-stage disease but it is often not needed, once the disease has become metastatic to the bones or visceral organs. Accurate determination of extension beyond the prostate capsule and into the lymph nodes may be difficult. Full assessment of stage may not be possible until after surgery and pathologic evaluation. Nomograms such as the ones published by Memorial Sloan Kettering Cancer Center are often helpful in predicting pathologic stage, determining patient outcome, and guiding treatment. These nomograms utilize the degree of elevation in PSA value and differentiation of the tumor using the Gleason score in determining prognostic information.
Full staging of prostate cancer may also include abdominal and pelvic CT scans, chest radiographs, bone scans, liver function tests, and acid phosphatase measurements. The most common staging system is the TNM system shown in Table 12.3. 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.
C. General considerations and goals of therapy
Selection of therapy for prostate cancer is complex and is based on the extent of disease as well as on the age and general medical condition of the patient. Although many biases exist, there are no good randomized trials comparing treatment modalities in patients with organ-confined disease.
With the possible exception of young patients less than 60 years of age, T1a prostate cancer may be followed up without further therapy as few patients will have disease progression. For other patients with organ-confined disease (T1b, T1c, T2), several treatment options exist. Radical prostatectomy and external beam radiation therapy are probably equivalent treatment modalities 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. However, there is no good direct comparison between these treatments and the choice of these options must take into account the patient's performance status and the toxicities of each modality. Toxicities of radical prostatectomy
Table 12.3. TNM staging of prostate cancer
Patients with stage III tumors are often treated with radiation therapy. However, very elderly patients or patients in poor general health may be followed up 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. Currently the addition of chemotherapy in high-risk, localized prostate cancer is being studied.
D. Treatment of metastatic disease
Patients with metastatic disease are usually treated initially with hormonal therapy. Radiation for symptomatic localized metastasis may also be considered.
Hormonal therapy. Hormonal therapy results in subjective response in approximately 75% of patients treated, lasting an average of 18 months. Most of these patients
Orchiectomy is still the standard modality of 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 hormonal therapy.
Luteinizing hormone releasing hormone (LHRH) analogs are synthetic peptides, which, when administered by parenteral injection, occupy the receptors for LHRH in the pituitary gland. Initially the release of luteinizing hormone (LH) is increased, causing a rise in the serum testosterone level. The continuous administration of therapeutic (super physiologic) doses of the LHRH analog blocks the physiologic pulsatile LH release from the pituitary, causing a fall in the serum testosterone to castrate levels. Currently used agents include the following:
Leuprolide 7.5 mg IM depot monthly or 22.5 mg IM depot every 3 months or 30 mg IM depot every 4 months.
Goserelin 3.6 mg SC depot monthly or 10.8 mg SC every 3 months
There is a potential for rapid worsening during the initial few weeks of therapy due to the paradoxical transient increase in testosterone production. This flare can usually be avoided by the concurrent use of antiandrogens. Another disadvantage is the potential for poor patient compliance and the high cost of treatment. The possible benefit of intermittent hormonal therapy is currently being studied.
LHRH analogs and antiandrogens (total androgen blockade) have been used in combination. Synthetic antiandrogens such as flutamide, bicalutamide, and nilutamide act by competing with testosterone at the level of the cellular receptor. However, 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.
Estrogens. Diethylstilbestrol (DES) 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
Second-line hormonal therapies have low response rates (<20%) and are of brief duration. Initial hormone therapy should be continued to maintain castrate 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.
Cytotoxic chemotherapy. Patients who relapse from or fail to respond to hormonal therapies can be considered for cytotoxic chemotherapy. Previous trials of chemotherapy were disappointing and the role of chemotherapy in treatment of hormone-refractory prostate cancer was unclear.
Mitoxantrone. A study of mitoxantrone 12 mg/m2 every three weeks and prednisone 5 mg b.i.d. demonstrated improved pain control and reduced need for analgesic medications as compared to patients treated with prednisone alone in a randomized trial with no improvement in overall survival. This regimen remains a possible treatment choice with a relatively low toxicity profile.
Docetaxel. Recently, two large randomized trials of docetaxel-based chemotherapy were the first to demonstrate a survival benefit over mitoxantrone and prednisone.
Docetaxel 75 mg/m2 every 3 weeks, and prednisone 5 mg b.i.d. or
Estramustine 280 mg t.i.d. PO on days 1 to 5 and docetaxel 60 mg/m2 IV on day 2 and prednisone 5 mg b.i.d. during 3-week cycles.
Owing to the survival benefit docetaxel-based chemotherapy is considered a standard treatment option for patients with hormone-refractory prostate cancer.
Evaluation of response. Evaluating the response is often difficult because many patients do not have measurable disease. However, the serum PSA is often elevated and can be serially measured as a marker for response. Bone scans are difficult to interpret because hot spots can reflect either the presence of disease or healing of bone in response to tumor regression.
Complications of therapy. All effective hormonal 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 hot flashes. Antiandrogens can cause diarrhea and hepatic dysfunction. Estrogens are associated with thromboembolic disease, fluid retention, and cardiac disease. Side effects of chemotherapy include nausea and vomiting, mucositis, marrow suppression, and alopecia.
Follow-up. Patients treated with radical prostatectomy can be followed up 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 hormone-refractory prostate cancer.
III. Testicular cancer (germ cell tumors [GCTs])
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. 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 cisplatinbased chemotherapy, accurate tumor markers, and aggressive surgical approaches, overall cure rates for patients with disseminated disease approach 80%, 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.
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 -subunit of human chorionic gonadotropin (hCG) may be seen, pure seminoma is never associated with an elevation of -fetoprotein (AFP). Nonseminomatous GCT can cause elevations of hCG, AFP, or both.
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.
Stage I: Tumor confined to the testis with or without involvement of the spermatic cord or epididymis
Stage II: Tumor with metastasis limited to retroperitoneal lymph nodes
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.
Seminoma. Most patients with seminoma present with early-stage disease and are nearly always cured with radiation therapy. Patients with stage I disease are treated with 2,500 cGy given to abdominal nodes in daily fractions over 3 to 4 weeks. Patients with lymph node involvement on lymphangiogram or CT scans receive a slightly higher dose of 3,000 to 3,500 cGy. The contralateral testis should be shielded to maintain fertility. Radiation to
Stage I disease. Historically, these patients have been pathologically staged and treated with a retroperitoneal lymph node dissection (RPLND). Patients with pathologically confirmed stage I disease do not need any further therapy because only approximately 10% show relapse. In approximately 25% of patients, clinical stage I disease is found to be stage II pathologically at RPLND, and the treatment for these patients is discussed in the following section. Themajor complication of RPLND has been retrograde ejaculation with subsequent infertility, although its occurrence is rare in experienced centers using nerve-sparing procedures. The other option for selected patients is surveillance without RPLND. These patients should be chosen carefully and must be committed to careful lengthy follow-up. Because 30% of these patients eventually experience relapse, they must be followed up closely with monthly measurements of serum markers and chest radiographs for the first year and every other month the year after that. Abdominal CT scans should also be performed every 2 months the first year, every 4 months the second year, and every 6 months thereafter. If patients are selected and followed up appropriately, overall survival appears to be the same as for patients undergoing RPLND.
Stage II disease. Patients with lymph nodes larger than 2 to 3 cm should be treated primarily with chemotherapy. If the lymph nodes measure less than 2 cm, an RPLND can be considered. Patients with pathologically confirmed and completely resected stage II disease have a relapse rate of approximately 30%. Patients with fully resected pathologic stage II disease can be either treated with two cycles of adjuvant chemotherapy after RPLND or followed up closely and treated with standard chemotherapy if they show relapse. Patients who choose to be under observation should receive monthly chest radiograph and serum marker evaluations and should be treated immediately if the disease recurs. Patients with stage II disease who have elevated markers after RPLND or whose disease is not completely resected should be treated in the same manner as patients with stage III disease.
Stage III disease. Approximately 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 on the basis of the primary site, level of
Mediastinal primary site or
Nonpulmonary visceral metastasis (e.g., liver, bone, and brain) or
Elevation of AFP (>10, 000 ng/mL), hCG (>10, 000 ng/mL), or lactate dehydrogenase (LDH) >10 upper limit of normal (ULN);
Patients with nonseminoma without mediastinal primary or nonpulmonary visceral metastasis have the following:
A good prognosis with the AFP <1,000 ng/mL, hCG <1,000 ng/mL, and LDH <1.5 ULN;
An intermediate prognosis if any of the markers is in the intermediate range (AFP 1,000 10,000 ng/mL, hCG 1,000 10,000 ng/mL, and LDH 1.5 10 (ULN).
Recommended therapy. All patients with stage II or III disease who require chemotherapy should receive cisplatin-based chemotherapy, BEP, as follows:
Cisplatin 20 mg/m2 IV over 30 minutes on days 1 to 5, and
Etoposide 100 mg/m2 IV on days 1 to 5, and
Bleomycin 30 U IV push weekly on days 1, 8, and 15
Repeat cycle every 21 days regardless of blood cell counts for two (adjuvant therapy), three (good-risk patients), or four (intermediate or poor risk patients) cycles.
If the patient has fever associated with granulocytopenia, we would give the next cycle at the same doses, followed by daily SC injections of granulocyte colonystimulating factor (filgrastim or 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.
Surgery for residual disease. Patients who have a complete response with chemotherapy should be followed up 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 up. If there is carcinoma in the resected specimen, the patient should receive two more cycles of cisplatin-based chemotherapy (cisplatin and etoposide).
Follow-up. Most patients who experience relapse do so within the first 2 years, although late relapses
E. Salvage chemotherapy
Standard-dose therapy. Patients who respond to first-line chemotherapy and then relapse are still curable with salvage regimens such as VIP:
Vinblastine 0.11 mg/kg (4.1 mg/m2) IV push on days 1 and 2,
Ifosfamide 1.2 g/m2 IV over 30 minutes on days 1 to 5, and
Cisplatin 20 mg/m2 IV over 30 minutes on days 1 to 5.
Repeat every 21 days for four cycles. Any radiographic abnormalities that persist after salvage chemotherapy should be considered for surgical resection.
High-dose chemotherapy with autologous stem cell transplantation (ASCT). High-dose chemotherapy with carboplatin and etoposide with or without cyclophosphamide/ifosfamide followed by ASCT should be considered for patients requiring salvage chemotherapy. Overall, approximately 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.
With these strategies, the overall cure rate for patients with stage I disease is more than 98%, that for stage II disease more than 95%, and that for 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 chemotherapy regimens described include nausea and vomiting, myelosuppression, renal toxicity, and hemorrhagic cystitis. Major long-term morbidities include infertility, pulmonary fibrosis, and a small but definite risk of secondary leukemia.
H. Mediastinal and other midline GCTs
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's 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 [ABMT]) 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 inmany developing countries. These tumors are nearly always of squamous cell 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 1,000 mg/m2/day given by continuous infusion on days 1 to 4. Cycles can be repeated every 21 days.
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