Carcinoma of the bladder

C a r c i n o m a of the B l a d d e r Elizabeth Hossan and Anne Striegel

VERY 10 minutes someone in the United States is diagnosed with bladder cancer. It is the fourth most common cause of cancer death in men over 75 years of age. Carcinoma of the urinary bladder accounts for approximately 2% of all malignant tumors. It is estimated that there will be 52,300 new cases of bladder cancer diagnosed in 1993, with 9,900 individuals dying of this disease. i Over the past 20 years, several advances in health care have positively altered the overall survival of patients with bladder cancer. Progress in the knowledge of tumor biology has facilitated recognition of disease-related prognostic factors and, in turn, influenced therapeutic decisions. Advances in patient selection, surgical technique, and stoma management have affected the quantity and quality of survival for patients who are treated surgically. Integration of therapeutic modalities has increased treatment options for a broader spectrum of patients with bladder cancer. Regardless of these advancements, patients with bladder cancer continue to be faced with treatment options that affect their physical, sexual, and psychosocial well-being. Both recurrent disease and premature death remain as threatening consequences of this disease. The purpose of this article, is to present to the reader an overview of recent information concerning diagnosis, treatment, rehabilitation, and survival for patients with bladder cancer.

E

INCIDENCE

The incidence of bladder cancer is highest among white men over 50 years of age who live in areas of industrialized countries. Bladder cancer From the Department of Genitourinary Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Elizabeth Hossan, RN, MS: Clinical Nurse Specialist, Department of Genitourinary Oncology, The University of Texas M.D. Anderson Cancer Center; AnneStriegel, RN, MS, OCN: Clinical Nurse Specialist, Department of Genitourinary Oncology, The University of Texas M.D. Anderson Cancer Center. Address reprint requests to Elizabeth Hossan, RN, MS, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 13, Houston, TX 77030. Copyright 9 1993 by W.B. Saunders Company 0749-2081/93/0904-000555.00/0 252

occurs more frequently in men than in women by a ratio of 3:1. The incidence in black men is one half that of white men and is even lower among men of Asian or Hispanic race. The age-adjusted incidence of bladder malignancies has been shown to increase steadily after 50 years of age, with the highest incidence occurring in the 7th decade of life. z The vast majority of bladder tumors are epithelial in origin. In the United States, transitional cell carcinoma (TCC) comprises 90% of all cases of bladder cancer. The remaining 10% consist of squamous cell carcinoma (SCC), adenocarcinoma, sarcomatoid variant, or any combination of these histological variations. RISK FACTORS

Environmental factors associated with an increased risk for bladder cancer are numerous. These include occupational chemical exposure, cigarette smoking, history of chronic urinary tract infections, chronic use of analgesics, and exposure to cytotoxic drugs and radiation. As early as 1895 the association between occupational factors and bladder cancer was first described in aniline dye workers in Germany. In 1954, Case and colleagues showed that dye workers in Britain had a 10- to 50-fold increased risk of death from bladder cancer. Since then, studies have identified benzidine, 1 naphthylamine, and 2 naphthylamine as the primary causative agents. Kimono painters, many of whom ingested benzidine-based dyes by licking their brushes, had seven times the expected rate of bladder cancer. Other occupational risk groups associated with bladder cancer include truck drivers and workers exposed to dye, rubber, leather, paint, aromatic amines, aluminum, and organic chemicals. The etiology for the increased risk in truck drivers is unknown. However, chronic exposure to exhaust fumes may be the influencing factor. The average length between exposure to carcinogenic agents and development of bladder cancer is between 16 and 22 years. 3 Tobacco use has been shown to be a contributing factor in more than one in six deaths in the United States. Smoking accounts for 30% of all cancer deaths, including deaths from bladder can-

Seminars in Oncology Nursing, Vol 9, No 4 (Novemberl, 1993: pp 252-266

BLADDER CARCINOMA

cer. It is responsible for almost half of the cancer deaths among men and one third among women. Cigarette smokers who inhale deeply may have a greater risk then those who do not. The different classes of carcinogens in tobacco have been identified as polycyclicaromatic hydrocarbons, nitrosamines, and aromatic amines. Bladder infections caused by the parasitic flatworm Schistosoma Haematobium, prevalent in Africa and Egypt, increase the risk of SCC. After penetrating the skin, the worms develop in the portal and pelvic veins, and the ova lodge in the bladder urothelium. Chronic irritation of the bladder mucosa caused by the parasite eggs may increase the rate of urothelial regeneration and act as a promoter of tumor development. Other urinary infections also may increase the risk of SCC of the bladder. 3 Long-term use of analgesics containing phenacetin has been linked to cancers of the bladder, renal pelvis, and ureter. Influenced by this association, the US Food and Drug Administration (FDA) banned the sale of phenacetin. 4 The risk of developing TCC of the bladder also increases after long-term exposure to cyclophosphamide and pelvic irradiation. According to a Danish study, 5 patients treated with cyclophosphamide for nonHodgkin's lymphoma experienced a sevenfold risk of bladder cancer. Follow-up of atomic bomb survivors in Hiroshima and Nagasaki showed a dosedependent relationship between radiation exposure and bladder cancer mortality.3 The relationship between bladder cancer and the artificial sweetners saccharin and sodium cyclamate is unclear. Early studies showed that cyclamates caused bladder cancer in laboratory animals. These findings suggested that artificial sweetners containing cyclamates may increase the risk of bladder cancer in humans. Influenced by these findings, the FDA banned the use of cyclamates in 1969. 4 Based on current population studies, there seems to be no increase in the risk of bladder cancer for most people who use artificial sweeteners. A larger study by the National Cancer Institute and FDA in 1978, found some evidence of an increased risk for the small number of heavy users of cyclamates. However, subsequent studies have not confirmed this finding. 4 SCREENING AND PREVENTION

There is currently no reliable screening procedure for diagnosing bladder cancer. Urine cytology

253

can be used as a screening tool, with a sensitivity of about 75% and specificity greater than 95%. Unfortunately, the incidence of preclinical bladder cancers in the general population is considered to be too low to make large-scale screening programs cost-effective.6 Cessation of cigarette and pipe smoking leads to an estimated 30% to 60% reduction in the risk of bladder cancer within the first 2 through 4 years after stopping, but the risk does not return to the level of nonsmokers. 4 Curtailment of hazardous occupational exposures is another preventive measure. DIAGNOSIS AND STAGING

Hematuria is the most common presenting symptom of bladder cancer. The patient often describes an episode of gross painless hematuria that may or may not have been associated with symptoms of urgency, frequency, or painful micturition. In 20% of newly diagnosed cases of bladder cancer, the patient has been asymptomatic. Symptoms associated with more advanced disease include flank, rectal, or pelvic pain, changes in bowel habits, or lower extremity edema. Regardless of the patient's symptoms at initial evaluation, a comprehensive diagnostic workup is recommended. The diagnostic workup allows the urologist to define the clinical and pathological characteristics of the patient's tumor. Staging of the tumor facilitates decisions regarding appropriate therapy, tumor response, patient follow-up, and disease-related prognosis (Fig 1).

Diagnostic Evaluation The first step in establishing a diagnosis of urothelial malignancy is the intravenous pyelogram (IVP). This radiographic study outlines the architecture and filling patterns within the structures of the upper urinary tract. Abnormalities in uniformity of flow and evidence of hydronephrosis or obstruction alert the urologist to the possibility of tumor within the renal pelvis or ureters. An excretory urogram delineates the pattern of distensibility of the bladder wall as the bladder is filled with contrast material. Papillary tumor cells that rise above the urothelial surface can be easily visualized. This study is less definitive if the tumor cells are flat or sessile. Neither the IVP nor the excretory urogram define the degree of mucosal invasion by the tumor. 2

HOSSAN AND STRIEGEL

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The cystoscopic examination provides both clinical and pathological confirmation of the presence of tumor within the bladder. Visual inspection of the urothelial tissue of the urethra, prostate, bladder, and ureters can be easily accomplished during this procedure. The morphology of the tumor can be described (Fig 2). Bladder washings are obtained for cytology and flow cytometry. Positive bladder washings confirm the presence of malignant cells. Flow cytometry provides information about the DNA histograms and nuclear structures of the malignant cells. This data is helpful in determining the biologic potential of the patient's tumor. A bimanual examination of the bladder provides

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the urologist with clinical information regarding the size, location, and mobility of the bladder mass. Induration of the bladder wall suggests tumor invasion below the mucosal layer. Adjacent organs such as the prostate, rectum, and uterus can be evaluated for local extension of the tumor. 2'7 During the cystoscopy, tumors confined to the bladder mucosa are resected. Random biopsies of mucosal areas adjacent to the tumor and throughout the bladder are obtained to determine the presence of carcinoma in situ. The trigone area of the bladder, ureteral orifices, and prostatic urethra also are biopsied. The biopsied specimens must be sufficient to determine the presence and depth of tumor invasion below the basement membrane. The computed tomography (CT) scan is used to evaluate bladder wall thickening or induration and pelvic adenopathy. The exact cause of these architectural abnormalities cannot be determined by this scan only. As yet, these radiographic imaging studies cannot detect the presence of microscopic disease in the lymph nodes or early invasion of tumor within the bladder wall. s'9 Distant metastases can be easily identified with a CT of the abdomen and pelvis, and a chest x-ray. A bone scan may be recommended if the patient is symptomatic with bone pain.

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255

Tumor Staging The goals of tumor staging are threefold. First, the clinical and pathological characteristics of the tumor are assigned to predetermined categories within an established framework. Second, decisions regarding therapy, response to treatment, and overall survival can be made in a logical manner. Third, the system establishes a frame of reference with which to communicate among clinical settings. At present, the framework for staging bladder cancer is shared by the Jewett-Strong-Marshall system and the TNM (tumor, node, metastases) system developed by the Union International Contra Cancer (UICC) and the American Joint Committee on Cancer Staging (Fig 3; Table 1). 8-12 Both systems define staging categories based on the depth of tumor infiltration, the presence of nodal involvement, and evidence of distant metastases. The TNM system delineates further by including the morphological appearance of the tumor, papillary versus sessile. Skinner 11 describes the present staging systems to be inadequate as a framework from which to direct clinical management of the patient with bladder cancer. He emphasizes the importance of consistency and accuracy in determining the presence of muscle invasion. The histological grade of the tumor is not clearly accounted for in the present staging system but has been shown to be an important indicator of tumor growth potential. The presence of carcinoma in situ is another important prognostic factor for tumor recurrence with potential invasion that is not well described in the present staging system. Therefore, Skinner has recommended aggressive therapy for patients with any level of tumor infiltration regardless of clinical and pathological stage at diagnosis. Close followup for patients with carcinoma in situ is essential s'rA~a~s

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The goal of bladder cancer treatment is to cure with minimal treatment-related morbidity. In the past 20 years, survival rates for cancer of the bladder have improved steadily. Presently, treatment recommendations are dictated by the stage, grade, and histology of the tumor, the patient's overall medical condition, and the likelihood of recurrence. 13 Less than a decade ago, the preferred treatment for invasive bladder cancer was a combination of preoperative radiotherapy followed by radical cystectomy. Today, the primary treatment for this stage of bladder cancer is a radical cystectomy with a pelvic lymph node dissection. The 5-year survival rate for patients presenting with highgrade, high-stage (T3a to T4) bladder cancer after radical cystectomy, with or without radiation therapy, is approximately 30% to 50%. 14'15 SUPERFICIAL DISEASE

Survival and response to therapy for patients with bladder cancer are influenced by the stage of the tumor at diagnosis. Patients with localized disease have a far better prognosis than those with invasive or distant disease. Tumor confined to the mucosa is considered superficial (Fig 3). The initial treatment is transurethral resection (TUR) with the intent of complete removal of all tumor. Once superficial disease has been diagnosed, it is important to identify those patients at risk for developing recurrent disease. Forty percent to 60% of patients with superficial papillary tumors and 80% to 100% of those with carcinoma in situ will develop tumor recurrence within 2 years after initial diagnosis of bladder cancer. Soloway ts listed important predictive factors that influence tumor recurrence and progression. These include high-grade tumor; invasion of the lamina propria; a positive cytology after resection; the presence of multifocal lesions, dysplasia, or carcinoma in situ from mucosal biopsies of normal-appearing urothelium; and a prior history of bladder cancer. The prognostic factor most often associated with tumor recurrence is the number of tumors present at diagnosis. Only 46% of patients present with solitary superficial tumor at the time of diagnosis.15

16,17

256

HOSSAN AND STRIEGEL Table 1. Staging Systems of Bladder Cancer American Joint Committeeand UICC(1974)

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p0 pis pA pl p2 p3a p3b p4 N1-3 N4 M1

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The second most significant prognostic factor for recurrence is chronology. After the initial diagnosis of bladder cancer, the patient has a 45% risk of developing a subsequent recurrence. With the development of a second recurrence, the risk of further recurrence is 84%.14 As many as 30% of the patients with superficial bladder tumors go on to develop muscle invasive disease. Factors associated with increased risk for invasion include rate of recurrence, tumor size, grade, and stage.15 The goals of intravesical chemotherapy after therapeutic cystoscopy with complete resection of all visible tumor are twofold. First, prophylactic therapy may prevent tumor recurrence. Second, intravesical therapy is used to eradicate residual TCC when there is pathological evidence of incomplete tumor resection. Drugs that have demonstrated activity include thiotepa, mitomycin C (MMC), doxorubicin, and Bacillus CalmetteGutrin (BCG). is Thiotepa, an alkylating agent, is usually instilled into the bladder in a dose of 30 to 60 mg, as a concentration of 1 mg/mL. The schedule of administration is variable. When used for prophylaxis, it is usually delivered weekly for 4 weeks, followed by reevaluation of the patient at 12 weeks. Successfully treated patients receive monthly maintenance instillations for 1 year. Thiotepa may cause systemic (myelosuppression) or local toxicities. Chemical cystitis occurs in 20% to 40% of patients but rarely requires discontinuation of treatment. 18 MMC, an antitumor antibiotic, is poorly absorbed by the bladder mucosa. Toxicity is primarily local, and myelosuppression due to MMC in-

stillation is rare. Irritative symptoms occur in 10% to 30% of patients and may occasionally require termination of therapy. A rash on the palms or genitalia is frequently seen. The recommended treatment using MMC is 20 mg intravesically every other week, then monthly. Is Doxorubicin hydrochloride is an anthracycline antibiotic that has antineoplastic activity against a broad spectrum of tumors. Most of the studies using doxorubicin delivered intravesically have been performed in Europe and Japan. The dosage used varied widely among studies.IS BCG is a mycobacterium bacillus also used for the treatment or prophylaxis of superficial bladder tumors. The instillation of the bacterium is believed to stimulate macrophages that are in contact with the tumor cells. Presumably, a host response to the tumor cells is induced. Endogenous interleukins may play a part in the antitumor benefit related to intravesical instillation of BCG. The dose of BCG is 5 • 10 6 organisms given weekly for 6 weeks. Toxicities associated with BCG therapy are common. The most frequent side effect is lower urinary tract irritative symptoms. Hematuria, fever and lethargy, or malaise also have been reported. 18 The potential for systemic side effects may be greater with BCG than with other intravesical agents. Systemic dissemination of BCG and subsequent clinical infection may occur. Pneumonia and hepatitis have been seen with this therapy. 19 In randomized controlled trials, the use of prophylactic intravesical chemotherapy with any of the agents just mentioned has reduced the relapse rate by approximately 50%. Other inflammatory mediators such as tumor necrosis factor and inter-

BLADDER CARCINOMA

257

leukin-2 are currently being used in trials for superficial disease. Carcinoma In Situ

Carcinoma in situ (CIS) refers to a lesion that is noninvasive but has a high potential for invasion. It is multifocal and diffuse and reflects the potential for the entire urothelial surface to undergo malignant changes. Intravesical BCG is the treatment of choice for patients with CIS. Intravesical thiotepa or doxorubicin also may be used to treat this pathological variant of superficial bladder cancer. Follow-up evaluation includes cystoscopy, and urinary cytologies at 2- and 3-month intervals for the first year, 4-month intervals for the second year, and 6-month intervals thereafter. If the CIS lesion does not respond to BCG therapy, cystoprostatectomy with urinary diversion is recommended. 2 SURGERY

There are four primary roles for surgery in the treatment of bladder cancer. These include diagnostic, definitive, integrative, and palliative. The selection of the appropriate surgical role is based on factors such as degree of tumor invasion, prognosis for recurrence, recognition of early tumor progression, survival, and the patient's ability to maintain self-care with regard to surgical outcome. The different types of surgical interventions include transurethral resection of bladder tumor (TURBT), partial cystectomy, and radical cystectomy. The advantages and disadvantages of each approach will be discussed. TURBT is the primary surgical modality for treatment of patients with superficial bladder cancer (Tis, Ta, T1, T2). This procedure provides a method for eradicating the entire burden of tumor, provided the depth of invasion does not preclude complete resection of the tumor. TURBT can be repeated as definitive therapy in the event of tumor recurrence. It can also be combined with intravesical chemotherapy to treat patients with multifocal or persistently recurring tumors, or carcinoma in situ. The major limitation of TURBT is the fact that, as a single modality, it does not prevent disease recurrence or progression. A second limitation of TURBT is incomplete resection because of tumor location and multifocality. Lesions in the area of the bladder neck, ureteral orifice, or pros-

tatic urethra are difficult to resect. 17'18'20 Complications of TURBT include local hemorrhage, incomplete resection, and tumor seeding. 2~ Partial cystectomy is reserved for a few patients who meet the following criteria. The primary lesion is solitary in nature. It may be high-grade but the degree of invasion is limited to the superficial level (stages T1 or T2). The histology is restricted to TCC or adenocarcinoma. The tumor may be located in areas that are difficult to resect with TURBT, but the preferred location is on the posterior wall of the upper hemisphere. The procedure itself is preceeded by extensive clinical staging, followed by preoperative radiation therapy that is proposed to reduce the incidence of tumor seeding at the time of the resection. Partial cystectomy is performed immediately after the completion of radiation therapy. A bilateral pelvic lymph node dissection is performed during the surgery. Advantages of a partial cystectomy include bladder preservation and maintenance of the normal male erectile function. Surgical morbidity is less, and patient acceptance of the procedure is high. Disadvantages of this surgical procedure include risk of tumor seeding, failure to recognize and remove occult areas of tumor, and high incidence of local recurrence. 7'2~ Radical cystectomy with urinary diversion (Fig 4) is the treatment of choice for patients with invasive bladder cancer. As straightforward as this may seem, a number of considerations must be addressed before this surgery is performed. The goals of this treatment are consistent with providing the patient with a cure for the disease coupled with low morbidity, prolonged disease-free survival, and optimum quality of life. The patient's ability to live with the physical and psychosocial changes imposed by this surgery must be assessed. Decisions regarding the role of surgery as a therapeutic modality must be made. Will the patient be able to accept the physiological and anatomical changes created by the surgery? With regard to timing of cystectomy, when is conservative therapy no longer beneficial? What benefit does preoperative therapy offer the patient? Should a regional lymph node dissection be included with the radical cystectomy? If so, how will it affect surgical morbidity and overall survival? Finally, what type of urinary diversion would be most appropriate for this patient?22 Patient education, physical and psychosocial as-

HOSSAN AND STRIEGEL

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sessment, and rehabilitation begin in the preoperative phase of preparation for surgery. Education begins with assisting the patient to develop a positive attitude toward managing the urinary diver-

sion. The urinary diversion must be adapted to the patient. Physical limitations in providing self-care must be assessed to ensure that the urinary conduit or continent diversion is compatible with the patient's life-style. Selection of the site for the urinary stoma is important to ensure success with maintaining a healthy stoma and a secure drainage system. If the patient has been exposed to previous abdominal/pelvic irradiation or surgery, alterations in the selection of the stomal site will be necessary to ensure adequate healing and proper circulation to the new stoma. Areas of bony protuberance, skin folds, and unevenness in subcutaneous tissue must be avoided when selecting the stomal site. This will ensure a secure, intact drainage system that will not leak but will maintain skin integrity. 22,23 The physiological changes in the anatomy as a result of the surgery will affect the psychosocial and sexual behaviors of the individual (Fig 5). These aspects of imposed change must be addressed with the patient and significant other in the preoperative phase of surgical preparation. 23'24 Radical cystectomy with urinary diversion for patients with invasive bladder cancer was developed by Bricker in the early 1950s. 25 Since that time, this procedure has undergone few modifications with regard to technique. The low surgical mortality rates reported today, 1.3% to 3.4% are attributed to better patient selection for surgery, improved perioperative care, and advances in technical aspects of external drainage appliances. 26'27 The surgical procedure itself results in an en bloc removal of the anterior pelvic organs with reanastomosis of the ureters to a segment of resected bowel. This resected bowel is brought forward, with circulation intact, to the surface of the anterior abdominal wall for the purposes of collecting and draining the patient's urine (Fig 4). In men, the prostate, seminal vesicles, and bladder, along with the visceral peritoneum and the perivesicle fat, are removed. A routine urethrectomy is not performed in men unless tumor cells have been found along the urethral membrane or the prostatic urethra. In women, the urethra is resected along with the bladder, cervix, anterior vaginal wall, vaginal cuff, uterus, ovaries, fallopian tubes, and anterior pelvic peritoneum (Fig 5). When a pelvic lymph node dissection is included as part of the radical cystectomy, resection of the bilateral nodes from the iliac bifurcation to the femoral canal and

259

BLADDER CARCINOMA

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from the genitofemoral nerve to the bladder pedicle is performed. 7'26'28 The construction of the conduit diversion may vary depending on the health of the bowel segment selected for use as the continent diversion. Patients who have received preoperative radiation therapy to the abdomen/pelvis of more than 5000 cGys may have sustained injury to the distal ileal segment or surrounding mesentary. Additional segments to consider for conduit formation include the j e j u n u m or the transverse colon. A wellestablished blood supply from the mesenteric branches to the conduit must be maintained, and the reanastomosis of the ureter to the new conduit

must be secure without risk of obstruction or leakage (Fig 4). 28 Postoperative mortality is defined as any death that occurs during the hospitalization for cystectomy or within 30 days of surgery. The most frequently reported causes of surgical mortality include sepsis, pneumonia, and cardiac arrest. 26 Acute complications related to the surgery include bowel obstruction or fistula formation at the site of the bowel reanastomosis, pyelonephritis, urine leakage from the site of anastomosis, vascular infarction and necrosis of the conduit or stoma, wound infection or dehiscence of the peristomal skin from the stoma, or retraction of the stoma. Many of the late complications associated with the urinary diversion usually occur within 2 years of the surgery. These complications include strictures or narrowing of the stoma, ureterointestinal stenosis or obstruction, frequent urinary tract infections, urinary calculi formation, or peristomal hernia, z6 Many of these complications can be successfully avoided with patient education, early diagnosis, and prompt treatment. As patient survival increases, these potential complications will need to be addressed at a preventive level. The timing of the decision to change from conservative therapy to radical ablative surgery has become more important with regard to cure and survival. Advances in knowledge of tumor behavior have influenced the decision to recommend radical surgery at an earlier stage of tumor migration. This approach has resulted in subsequent improvement in overall survival. However, indicators for radical surgery vary among surgeons with regard to timing of surgery. According to Skinner, ll any overt high-grade tumor associated with muscosal atypia or CIS, or any recurrence after initial conservative therapy of a unifocal highgrade lesion warrants radical cystectomy. Patients with superficial tumors that are endoscopically unresectable should undergo radical cystectomy. Several authors have consistently demonstrated an inverse relationship between the degree of tumor invasion and the length of disease-free survival for patients with invasive bladder cancer (stages A, B, and C). According to Whitmore, 29 the term "invasion" includes any level of infiltration of tumor beyond the in situ phase. The pathological behavior of the tumor changes with the invasion of the lamina propria. The line of demarcation between superficial and deep muscle

HOSSAN AND STRIEGEL

260

invasion is arbitrary. It may not be optimal to determine therapy based on this determination of tumor stage exclusively. Pagano et alz~ presented a series of 200 patients who had been treated with standard therapy for superficial disease. Twenty-three percent progressed to T1 invasion. Those patients who agreed to radical cystectomy early in their progression maintained an 85% survival rate of 5 years. Patients who delayed surgery beyond 6 months after progression from Ta to T1 lesions had a significantly higher mortality rate of 75%. Within the 6-month period of time from initial progression to surgery, the pathological stage of these tumors advanced further. Wishnow and coUeagues27 reported no difference in the overall survival for surgically treated patients with superficial (p2) or deep muscle (p3) invasion. Survival and recurrence rates were adversely affected in patients with grade III tumors. The presence of vascular or lymphatic invasion in the surgical specimen also correlated with a lower survival rate. In the study by Malkowicz and colleagues,3~ the presence of vascular invasion in patients with p2 lesions was associated with an increase in the incidence of death resulting from metastatic disease. The presence of CIS varied without regard for disease stage (pl or p2) and did not adversely affect the 5-year survival rate. It is interesting to note that, although only 5% of the patients with clinical stage T2 disease were known to have CIS at the time of surgery, pathological staging of these cystectomy specimens demonstrated the presence of CIS in 61% of the resected bladders. 3~ RADIATION THERAPY

Radiation therapy (XRT) has been used as a single modality or in combination with chemotherapy to treat patients with invasive disease who are not surgical candidates because of poor health or poor performance status. 31"32 Several studies have demonstrated correlations between the variables of radiation dose and successful local tumor contro1. 33-35 Curative responses to radiation therapy exclusively have been reported to be as high as 68%, but overall survival has been short. 33 The inclusion of pelvic lymph nodes in the field of radiation has not influenced survival. 35 As has been demonstrated with other therapeutic deci-

sions, patient selection, the degree of tumor differentiation, and the level of tumor invasion correlate with response to therapy and length of survival. 34,35

The benefits of XRT as a single modality include palliation of local tumor symptoms, temporary control of local tumor growth with possible downstaging, bladder preservation, and limited interference with sexual potency. Disadvantages of XRT include increased frequency of local recurrence and decreased survival when compared with combined or more aggressive therapies. Treatment-related toxicities are frequent and may be severe enough to warrant a delay in treatment. 32'35 Acute toxicities have included bleeding, diarrhea, and painful micturition that may last several months. Late toxicities of radiation therapy have been reported to include bowel and bladder obstructions severe enough to require surgical interventions. 34 Preoperative radiation therapy is no longer routinely recommended for patients with invasive bladder cancer. Recent studies comparing presurgical XRT with surgery alone demonstrated no differences in overall survival or tumor recurrence rates. 36 High doses of preoperative radiation have contributed to surgical morbidity as a result of radiation-induced desmoplastic pelvic fibrosis, delayed wound healing, and potential instability of the ureteral anastomoses. Initially, preoperative radiation therapy was intended to enhance survival for patients with invasive disease by downstaging the primary tumor, decreasing the metastatic potential of circulating microscopic tumor cells, and decreasing the rate of local recurrence. However, studies have shown that preoperative XRT does not prevent distant metastasis or pelvic recurrence with greater efficacy than radical cystectomy as a single modality for patients with high-stage invasive disease. 17'36'37 BLADDER PRESERVATION

Complete remission of the primary tumor with maintenance of an intact functioning bladder, surrounding viscera, and sexual function are certainly attractive end points for patients with bladder cancer. The bladder can be successfully preserved when the disease is superficial and amenable to TURBT with or without intravesical therapy or partial cystectomy. For patients with locally inva-

BLADDER CARCINOMA

sive disease (T2 to T4), bladder preservation remains a controversial consideration still under investigation. Therapeutic trials must guarantee the patient complete remission of the local tumor in conjunction with sterilization of any micrometastases. In addition to these demands, long-term disease-free survival and quality of life must be comparable or better than standard cystectomy with systemic therapy. Several trials have been conducted with these goals in mind. 32'38"4~ Combination radiation therapy plus chemotherapy have positively influenced both tumor regression and overall survival for patients with invasive bladder cancer. Shipley et a132 used single agent cisplatin in combination with concurrent radiation therapy to treat a group of patients with unresectable tumors. Seventy percent of these patients achieved an endoscopically proven complete remission. At 42 months, 73% of the initial responders were disease-free with intact bladders. During the treatment program, 18% of the patients experienced acute toxicities that included diarrhea, urinary frequency, and dysuria severe enough to delay treatment. Late toxicities for five patients included intestinal obstruction, hematuria severe enough to require palliative cystectomy, and aseptic necrosis of adjacent bone structures. In a subsequent program, Shipley et a138 combined maximum TUR plus systemic chemotherapy with methotrexate, cisplatin, vinblastine, followed by local XRT plus concurrent cisplatin (CDDP). Two thirds of the patients responded to this program with complete regression (CR) of local tumor and were given consolidation XRT to the area of the tumor, along with additional cisplatin. Patients who failed to achieve an initial CR were offered radical cystectomy with no further systemic therapy. More than 50% of the responding patients were in CR after the chemotherapy only. Five patients achieved a CR after the completion of XRT and concurrent CDDP. Seventy-four percent of the CR patients were disease-free with functioning bladders at a median of 20 months. Treatment-related acute toxicities were severe, and 21% of the patients were unable to complete the treatment program as a result of these toxicities. Farah et al4~ used a treatment strategy that included TUR, systemic therapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), and local XRT. The patients were endoscopically

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evaluated at baseline, after four cycles of systemic MVAC, and after XRT. Eight patients achieved a CR with MVAC only. Three more patients were in CR after XRT. Sixty-three percent of the responders were disease-free with functioning bladders at a median of 31 months. Radiation-induced toxicities were few. Toxicities to MVAC and protocol tolerance were not described. Salvage cystectomy was recommended for incomplete local control or for recurrent disease. Patients with T4 disease did not benefit from this program. 4~ In summary, bladder preservation may be a cautious alternative for patients with locally invasive bladder cancer if combination therapy can provide complete local tumor regression and sterilization of systemic micrometastases. Patient selection is again emphasized. Tumor stage inversely correlates with local tumor regression and predicts for overall response. 41 Acute treatment-related toxicities may be more severe with combined modalities. More time is needed to fairly evaluate duration of response and quality of life for this group of patients. ADVANCED DISEASE

Advanced bladder cancer is defined as locally invasive (stage C) or metastatic (stage D) disease. For these patients, the prognosis is poor and survival is compromised. Therapeutic demands for patients with locally invasive disease include both local and systemic therapies designed to control the primary or recurrent tumor and to prevent or delay the development of metastatic disease. For patients with metastatic disease, systemic chemotherapy is necessary and has resulted in tumor regression with increased survival. NEOADJUVANT CHEMOTHERAPY

The primary manifestation of failure in the treatment of invasive bladder cancer is the establishment of widespread metastatic disease after successful treatment of the primary tumor with radical surgery or radiation therapy. In the past, treatment for patients with distant metastases (stage D2) has been limited to palliative management of local recurrence, with little benefit to any metastatic sites. The addition of some form of systemic therapy in a neoadjuvant or adjuvant setting for high-risk patients may be an alternative approach to improve c u r e r a t e s . 42

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Many phase II trials that now employ neoadjuvant and adjuvant chemotherapy have been designed based on the increased efficacy found with combination regimens used to treat patients with metastatic bladder cancer. Patients with clinically staged high-grade, high-stage (T3b and T4) bladder lesions are frequently found to have lymph node involvement at the time of cystectomy. The risk of developing metastatic disease in these patients treated with surgery only is high. These findings further justify the rationale for considering the administration of systemic chemotherapy before or after radical surgery. Primary or neoadjuvant chemotherapy has recently become a preferred approach in the treatment of adult solid tumors. If the neoadjuvant chemotherapy is effective, the bulk and extent of the local tumors are reduced. This would render tumors previously considered inoperable or marginally operable to be completely resectable after initial chemotherapy. Support for this hypothesis has been described in a series of neoadjuvant trials for patients with locally advanced bladder cancer. In these studies, neoadjuvant therapy resulted in successful downstaging to p0 noninvasive bladder cancer for approximately 50% of the patients treated in this manner. 43 Other benefits of neoadjuvant therapy include enhanced curability of operative tumors, identification of tumor sensitivity to selected chemotherapy agents, and prevention or delay of potential metastatic disease. One disadvantage of neoadjuvant therapy includes the development of resistant tumor ceils to future chemotherapy. A second disadvantage for patients who fail to respond to initial chemotherapy is the delay in time from diagnosis to the potentially curative surgical procedure. Finally, postcystectomy morbidity may be higher in patients who have received neoadjuvant chemotherapy because of delayed recovery from treatment-induced toxicities. Recently, clinical trials have supported the therapeutic benefits of neoadjuvant chemotherapy for treatment of patients with locally invasive bladder cancer. Many of these trials have used MVAC chemotherapy followed by surgical cystectomy. A phase I/II study of neoadjuvant MVAC was conducted at Memorial Sloan-Kettering Cancer Center. The investigators of this study concluded that MVAC in this setting did induce regression of the primary bladder tumor. Pathological complete re-

missions occurred in a frequency similar to that seen with MVAC in the treatment of metastatic bladder cancer. Toxicities with this chemotherapy regimen were described as significant but were considered to be acceptable in the neoadjuvant setting. 44 Long-term randomized trials are ongoing with the goal of demonstrating a survival benefit for patients receiving neoadjuvant therapy. ADJUVANT CHEMOTHERAPY

Adjuvant chemotherapy involves the systemic administration of chemotherapy agents after removal of the primary tumor with no evidence of residual disease. To date, the benefits of adjuvant therapy for patients with bladder cancer remain controversial. Logothetis and colleagues45 demonstrated a survival benefit for patients with pathological stage C and stage DI bladder cancer who were treated with combination chemotherapy in the adjuvant setting. All patients with locally invasive bladder cancer who were treated with radical cystectomy between 1981 and 1986 were included in the nonrandomized study. The control group consisted of low-risk patients with favorable pathological findings at cystectomy. This group did not receive adjuvant chemotherapy. The second group of patients were described as high-risk for relapse (Table 2) based on pathological findings at the time of surgery. These patients did not receive adjuvant therapy because they refused systemic treatment, were ineligible for medical reasons, or were not offered therapy. The third group of patients also was considered to be high-risk for relapse. These patients were treated with at least one course of adjuvant chemotherapy in the postoperative setting. Sixtytwo percent of the patients treated with adjuvant chemotherapy sustained a significantly longer disease-free interval than the high-risk patients who did not receive chemotherapy after cystectomy.45 Table 2. Pathological Risk Factors for Tumor Recurrence After Cystectomy in Patients ~rrth Invasive Bladder Cancer (p2, p3, p4) 9 Vascular invasion in the primary tumor 9 Invasion of perivesicle fat by tumor cells 9 Extension of tumor into pelvic viscera (prostate, uterus,

vagina) 9 Tumor cells present in regional lymph nodes Data from references 27, 30, and 45.

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Over the past 2 decades, many clinical trials using chemotherapy only or in combination with other modalities have had a positive impact on the overall survival of patients with metastatic bladder cancer (stage D2). Early studies were plagued with problems of patient noncompliance and poor tolerance associated with treatment-related toxicities. The introduction of cisplatin for treatment of patients with urothelial tumors increased survival rates for patients with metastatic TCC, but complete remissions were not achieved with singleagent therapy only. 46'47 Building on the response rate to single-agent therapy, Tannock et alas found systemic therapy, using a combination of methotrexate, doxorubicin, and cyclophosphamide, to be as effective as cisplatin alone with regard to survival for treatment of patients with metastatic TCC. Tumor regressions with this program were still incomplete. Chemotherapy programs that have demonstrated complete remissions in both the primary tumor and metastatic lesions have included drug combinations with cisplatin, doxorubicin, cyclophosphamide (CISCA), or MVAC. Other variations of these programs that have been considered for treatment of patients with advanced disease include cisplatin, methotrexate, vinblastine (CMV), and methotrexate, vinblastine, epirubicin, cisplatin (MVEV). 42,48,49 The efficacy of MVAC chemotherapy for treatment of patients with urothelial tumors was first studied at Memorial Sloan-Kettering Cancer Center in the early 1980s. It has subsequently become the most widely applied treatment regimen for patients with advanced bladder cancer. Two reasons for the expanded use of this chemotherapy regimen include evidence of responses in resistant metastatic sites such as liver and bone, and increased survival for patients who achieve a complete remission with this program. 5~ A randomized trial at M.D. Anderson Cancer Center compared MVAC with CISCA chemotherapy for patients with metastatic bladder cancer. Results of this study demonstrated a survival advantage for patients with metastatic disease who were treated with the MVAC regimen. The overall response rate in this study was significant. Sixty percent of the patients treated with MVAC and

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46% of the patients treated with CISCA demonstrated a response to systemic therapy. Unfortunately, neither of these therapies has proven to be effective for the treatment of nontransitional cell bladder tumors nor have they been effective for prevention of second primaries that may occur elsewhere in the urothelium. 51 For patients with metastatic TCC (stage D2) who have failed to respond to frontline chemotherapy regimens using methotrexate/cisplatin combinations, alternative salvage regimens have not been found to be effective. Recently, fluorouracil (5FU) has been shown to be an active agent in the treatment of urothelial tumors. As yet, no complete remissions have been reported with 5FU as a single-agent therapy. Interferon (IFN) has not been investigated for use as a systemic agent in the treatment of metastatic bladder cancer, but preliminary reports have suggested that a clinical significant synergy exists with the combination of 5FU and IFN. 52 Based on this premise, Logothetis et a152 studied the use of 5FU plus IFN in patients with advanced bladder cancer who had relapsed after definitive therapy or were refractory to standard protocols. A 28% response rate was achieved in a group of heavily pretreated patients. To improve on the overall response rate of the initial trial, cisplatin was added to the 5FU, alfa IFN regimen (FAP). A 61% response rate was obtained using this new treatment scheme. 53 Current studies are underway to compare the response rates for patients with MVAC versus those treated with FAP (Table 3). MANAGEMENT OF SIDE EFFECTS

The professional nurse is provided with a wide spectrum of challenges when caring for a patient with bladder cancer. Patient education is a critical component of nursing care throughout all phases of the patient's diagnosis, therapy, and rehabilitation. During the initial phase of diagnosis, the nurse is often in a position to establish an environment in which the patient and family members can receive information and ask questions. Very often, interventions at this phase of the illness can effectively prevent problems of therapeutic intolerance or noncompliance in the future. Once the diagnosis and therapeutic options have been described, the nurse is instrumental in providing reinforcement or

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Table 3. Combination Chemotherapy in Metastatic Bladder Cancer FAP CI daily, days 1-5 and 28-33 subcutaneous days 1-5, MWF, then 28-33 70 mg/m 2 IV days 1, 7, 14, 21 Two-week rest, then repeat above.

5-Fluorouracil IFN-(~

Cisplatin

500 mg/m z 5 mu/m 2

MVAC Methotrexate

Vinblastine Adriamycin Cisplatin

30 mg/m z 3 mg/m 2 30 mg/m 2 70 mg/m 2

IV days 1, 15, 22 IV days 2, 15, 22 IV day 2 IV day 2

Repeat every 28 days. Abbreviations: el, continuous infusion; MWF, Monday, Wednesday, Friday; IV, intravenous. Data from references 53 and 54.

clarification of information that will prepare the patient for the recommended therapy. Before any treatment begins, the nurse must assess the patient's physical condition, emotional well-being, understanding of the status of the disease, and concerns about the proposed treatment. Any physical or psychosocial limitations that would interfere with the patient's ability to actively participate in the proposed plan of care must be considered before chemotherapy is started or surgery is performed. The surgical or enterostomal therapy nurse works closely with the preoperative patient and the patient's partner to familiarize them with the anatomical and physiological changes that will be imposed by the surgery. The location of the patient's stoma will be marked before surgery. The postoperative care of the patient undergoing a radical cystectomy with urinary diversion is similar to the care required by any patient who has undergone abdominal surgery with general anesthesia. The patient with a new urinary diversion will need ongoing encouragement and reinforcement in order to gain skills of self-care and reestablish confidence and self-esteem. The patient who will receive intravesical, neeadjuvant, or adjuvant chemotherapy will need information regarding how the chemotherapy will be administered, what side effects can be expected, and how this treatment may affect normal activities of daily living. Systemic therapy for treatment of patients with bladder cancer usually includes combinations of agents that generate a variety of both acute and

delayed toxicities. The hematologic, gastrointestinal, renal, neurological, and cardiovascular systems are at greatest risk for chemotherapy-induced toxicities. The management of drug-induced myelosuppression involves patient education regarding signs and symptoms of granulocytopenia and thrombocytopenia. Hematopoietic growth factors such as filgrastim and sargramostrim promote granulocyte regeneration and reduce the patient's risk for infection. 55 Muco-esophagitis, often associated with 5FU and methotrexate, can be managed with a program of oral hygiene. A variety of mouth rinses and coating agents can be used prophylactically to protect and maintain the mucosal integrity. Several topical medications may be used to treat both bacterial and fungal oral abrasions. Leucovorin rescue may be used to promote timely excretion of methotrexate and its metabolites, thereby decreasing the severity of the gastrointestinal toxicities. Antiemetic therapy with HT3 antagonists, such as ondansetron, has significantly reduced both acute and delayed nausea and vomiting associated with cisplatin. Aggressive hydration with appropriate electrolyte replacement remains the most important intervention against cisplatin-induced nephrotoxicity. An appropriate interval between the administration of methotrexate and cisplatin will reduce the risk of renal toxicity when both agents are included in the treatment protocol. 43 The biologic agent interferon has recently been introduced as an effective agent in combination with 5FU and cisplatin for the treatment of patients with metastic TCC. 53 Acute side effects associated with interferon include fever, chills, malaise, and headaches. Fatigue and anorexia are common sequelae described by patients treated with interferon on a long-term basis. 43 The combination of interferon with 5FU has been shown to increase many of the chemotherapy side effects. Patients with coronary artery disease, past history of myocardial infarction, thrombotic stroke, or pulmonary embolism are at increased risk for developing cardiovascular toxicities associated with 5FU. 43 Neuropathy, constipation, and ileus are acute toxicities of vinblastine that resolve as the patient recovers from the side effects of therapy. Extravasation with local tissue ulceration is a concern with both vinblastine and doxorubicin. This is a

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serious p r o b l e m that can be successfully avoided by using a well-established intravenous access and by m o n i t o r i n g the site o f infusion frequently.

CONCLUSION The future for patients with bladder cancer is not as dismal today as it was in the early 1970s. O v e r the past 20 years, a d v a n c e s in t u m o r staging and t h e r a p e u t i c m a n a g e m e n t h a v e p o s i t i v e l y influenced both cure rates and overall survival. E v e n patients with metastatic disease are beginning to h a v e m o r e treatment options with potential for increased survival. A variety o f e n v i r o n m e n t a l factors h a v e been targeted as risk factors for bladder cancer. U n f o r -

tunately, only limited efforts h a v e b e e n d e e m e d appropriate for p r e v e n t i o n and early detection o f bladder cancer a m o n g populations at greatest risk. Professional nurses are c h a l l e n g e d to m e e t a variety o f physiological and p s y c h o l o g i c a l needs in each phase o f the patient's illness. Patient education is critical in assisting the patient to return to the highest level of wellness possible.

ACKNOWLEDGMENT The authors wish to thank Thomas J. Striegel for his professional expertise and enthusiasm with our illustrations, Chris Logothetis, MD, for his encouragement with this project and review for content, and the secretaries of our department for their skillful preparation of this paper.

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