Section 4: Cancer of the Bladder, Ureter, and Renal Pelvis

Section 4: Cancer of the Bladder, Ureter, and Renal Pelvis

W. Scott McDougal

William U. Shipley

Donald S. Kaufman

Douglas M. Dahl

M. Dror Michaelson

Anthony L. Zietman

This chapter details the incidence, epidemiology, pathology, and treatment of cancers of the bladder, ureter, and renal pelvis. Transitional cell carcinomas (TCCs) constitute 90% to 95% of all the urothelial tumors diagnosed in North America and Europe. TCCs occur throughout the lining of urinary tract from the renal calyceal system to the proximal two thirds of the urethra, at which point squamous epithelium predominates. In this eighth edition, cancers of the renal pelvis and ureter are grouped with bladder cancer rather than with cancers of the kidney. This is a natural fit as approximately 90% of the urothelial cancers of the renal pelvis, ureter, and bladder are transitional cell cancers, all of which share similarities in epidemiology, pathology, biology, patterns of spread, molecular tumor markers, and treatment. We present the common characteristics of urothelial cancers in an initial section and then deal in subsequent sections with the separate characteristics of these organs. The multidisciplinary treatment of this chapter reflects the current approach to patients with these diseases.

Cancers of the Bladder, Renal Pelvis, and Ureter

Epidemiology

Bladder cancer is two and one-half times more common in males than in females and more common in whites than in blacks. There are approximately 53,000 new cases per year, which is a 20% increase from 20 years ago. The incidence increases with age and peaks in the sixth, seventh, and eighth decades of life.

Simultaneous or subsequent development of transitional cell cancer of the urethra in patients with transitional cell cancer of the bladder occurs with an incidence of 6% to 16%. Indeed, in one study, 16% of female patients with deeply invasive bladder cancer developed urethral cancer. The most predictive risk factor for urethral involvement in the female is the presence of concomitant vaginal extension of the bladder cancer.1 Other risk factors that make urethral involvement more likely in both males and females are recurrent multifocal bladder cancers and bladder neck involvement. Carcinoma in situ (CIS) involving the bladder neck and trigonal involvement extending to the bladder neck are associated with an increased incidence of urethral involvement.2

The incidence of ureteral TCC is 0.7 per 100,000, whereas renal pelvic TCCs have an incidence of 1 per 100,000.3 Renal pelvic tumors constitute 5% of all renal tumors, and 90% of them are TCCs. Squamous cell carcinoma and adenocarcinoma constitute the majority of the remainder. Renal pelvic transitional cell cancers constitute 5% of all TCCs of the urinary tract. Patients who have primary TCCs of the renal pelvis and/or ureter have a 20% to 40% incidence of either synchronous or metachronous bladder cancer. Conversely, patients with bladder cancer have a 1% to 4% incidence of synchronous or metachronous upper tract urothelial tumors.4,5 However, if the bladder cancer is grade III, there is associated CIS, or the patient has failed intravesical chemotherapy, some reports suggest a doubling of the incidence of upper tract tumors.6 Patients with Balkan nephropathy have an increased incidence of upper tract tumors; these tumors are usually low grade and multiple.7 There are specific areas of Taiwan where TCC of the renal pelvis accounts for 40% of all renal tumors, while in other nonendemic areas, the upper tract tumors account for only 1% or 2% of renal tumors.8 The etiologic factor in the Taiwanese endemic region is still unknown.

Risk factors for urothelial cancer may be classified into one of three categories: (1) gene abnormalities resulting in perturbations in cell cycle regulatory processes, (2) chemical exposure, and (3) chronic irritation. Those risk factors involving genetic abnormalities include protooncogene expression, tumor suppressor gene mutation, and abnormalities of specific cell cycle regulatory proteins. Protooncogenes that have been implicated in bladder cancer include the Ras p21 proteins.9The tumor suppressor genes that have been associated with P.1359


an altered biology of the disease include p53, p21, p27, and the retinoblastoma gene (Rb).10 Loss of heterozygosity of chromosome 9 has been implicated in superficial bladder cancer. Abnormalities in specific cell cycle regulatory proteins such as CABLES, Ki-67, and cyclin D1 have also been implicated.10,11,12,13,14 At this time there is no single molecular marker that is capable of predicting the tumor with a high degree of accuracy, which may result in muscularis propria invasion or distant metastases.

Chemical exposure has perhaps the most epidemiologic evidence to support it as an inciting agent. Aromatic amines, aniline dyes, and nitrites and nitrates have all been implicated. Tobacco use carries with it, for those who continue to smoke, a threefold increased risk of developing bladder cancer, and even exsmokers have a twofold increased risk.15 Analgesic abuse, particularly phenacetin, results in an increased risk of renal pelvic cancers. Numerous reports have shown strong associations between the development of both bladder and upper tract TCCs with industrial contact to chemicals, plastics, coal, tar, and asphalt. Cyclophosphamide administration over the long term, particularly in patients who have upper tract or bladder outlet obstructions, results in an increased risk of bladder cancer. These cancers when discovered tend to be particularly aggressive. Coffee, tea, and artificial sweeteners have not been shown to act as independent risk factors.

Chronic irritants include catheters, Schistosoma haematobium, and irradiation. Chronic irritation due to indwelling catheters associated with chronic infection increases the risk for the development of squamous cell carcinoma; S. haematobium infestation results in an increased risk of squamous cell and TCCs; pelvic irradiation also carries with it an increased risk of developing a squamous cell cancer.

There are many studies that suggest high water consumption, vitamin intake, and various diets as beneficial in preventing bladder cancer. However, none of these have shown any clear benefit with respect to prevention. When drugs such as cyclophosphamide are given, careful attention to hydration and relieving obstruction may be helpful in preventing the development of urothelial cancers.

Screening and Early Detection

Screening has not been particularly useful in the detection of bladder cancer. There have been a number of reports of the outcome of screening for urothelial neoplasms. The only test of proven usefulness is a urinalysis to detect microhematuria. If significant microhematuria is detected, then specific diagnostic studies are performed. When individuals are screened, 4% to 20% are found to have microhematuria. Of those with microhematuria, 0.1% to 6.6% have bladder tumors. This translates into a discovery rate of bladder cancer in the population at large varying from 0.005% to 0.2%. None of the patients who had bladder tumors incidentally discovered in these particular studies had invasive disease. In follow-up, no patient who had grade I, stage Ta tumors discovered by disease screening progressed at 7 years of follow-up. Only those with CIS, T1, or high-grade tumors developed progressive disease and that occurred only after 4 years of follow-up. However, some studies have suggested that routine screening results in a reduced mortality from bladder cancer. Although the concept is appealing, the data are not convincing as the studies are not randomized and the control arm consists of patients not comparable with those of the study population.16 On the other hand, others have suggested that screening in high-risk populations increases the early detection rate of high-grade cancers. Early treatment of these would be expected to be associated with an increased survival, although this hypothesis in this group of patients has not been substantiated. Screening does not generally improve the detection rate of low-grade tumors because the methods used for screening have a large number of false-negative findings for low-grade tumors. When urothelial cancer is suspected, noninvasive screening may be performed using cytology, nuclear matrix protein, telomerase, or fluorescence in situhybridization analysis, but the definitive diagnosis is made only by cystoscopy and biopsy.

Cytology has been regarded as the gold standard for noninvasive screening of urine for bladder cancer. It has a sensitivity of 40% to 60% with a specificity in excess of 90%. Nuclear matrix protein17 fibrin/fibrinogen degradation products,18 urinary bladder cancer antigen,19 and basic fetoprotein20 have all been compared with cytology in bladder cancer screening studies. Other methods used include fluorescence in situ hybridization,21 microsatellite analysis of free DNA,22 and telomerase reverse transcriptase determination.23 Unfortunately, all of these tests have a sensitivity that ranges from only 40% to 75% with a specificity of 50% to 90%, thus not making it possible to eliminate the need for cystoscopy by the use of these tests.24 These urinary biomarkers have not been studied yet for sensitivity and specificity in detecting upper tract TCC.

Cytology is illustrative of the problems of noninvasive screening. Poorly differentiated tumors have a 20% false-negative detection rate, whereas well-differentiated tumors have up to an 80% false-negative detection rate. Most of the other noninvasive screening tests have similar levels of false-positive and false-negative rates but have the benefit of lack of subjectivity by the person reading the test. Cytology remains the preferred bladder tumor marker for specificity25; however, many of the other bladder tumor markers have a better sensitivity than does cytology.26

Pathology

More than 90% of the TCCs throughout the lining of the urinary tract occur in the urinary bladder, and of the remaining 10%, most are in the renal pelvis and fewer than 2% are in the ureter and urethra. Squamous cell carcinomas, defined by the presence of keratinization, account for 5% of bladder tumors. Other even less-common bladder tumors include adenocarcinoma and undifferentiated carcinoma variants such as small cell carcinoma, giant cell carcinoma, and lymphoepitheliomas.27,28,29 Tumors of mixed origin are quite common and consist of TCC; within which squamous and adenocarcinomatous elements are also identified. These are considered variants of TCC and they do not portend a worse prognosis. Adenocarcinoma may arise in the embryonal remnant of the urachus on or above the bladder dome. Other adenocarcinomas may closely resemble intestinal adenocarcinoma and must be distinguished from direct spread to the bladder from an intestinal primary by careful clinical evaluation. Rarely, these demonstrate a signet ring cell or clear cell histology.

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Primary Tumors of the Bladder

The differential diagnosis of TCC usually does not pose a diagnostic difficulty for experienced pathologists, but tumors that are grade I and invasive are occasionally difficult to distinguish from von Brunn's nests.30 Also rarely, an invasive TCC may be overdiagnosed when the glandular component of a nephrogenic adenoma is mistaken for TCC with glandular differentiation or for a pure adenocarcinoma. When invasion of the lamina propria has occurred, the pathologist must report whether muscularis propria is present in the submitted tissue and whether there is invasion of the muscularis propria. If muscularis propria is not present in the submitted tissue, this should be noted by the pathologist. Identification of invasion of the muscularis propria by tumor may occasionally be difficult, as it may be confused with involvement of the muscularis mucosa, which is in the lamina propria.31 More than two thirds of newly diagnosed cases of bladder tumors are exophytic papillary TCCs that are confined to the epithelium (stage Ta) or invade only into the lamina propria (stage T1). These tumors are generally managed endoscopically and, in some cases, by intravesical therapy (see 鈥�Superficial Bladder Cancer [Ta, Tis, T1]鈥�). Approximately one half to two thirds of patients with such tumors have a recurrence or a new TCC in the bladder within 5 years.

Bladder tumors are also classified by their cytologic characteristics as low grade (G1) or high grade (G2, G3).29 Tumor grade is clinically more significant for noninvasive tumors because nearly all of the invasive neoplasms are high grade at diagnosis. Papillary carcinomas of low grade are considered to be relatively benign tumors that histologically resemble the normal urothelium. They show only very slight pleomorphism or loss of polarity and rarely progress to a higher stage. Primary CIS (stage Tis) that presents without a concurrent exophytic tumor constitutes only 1% to 2% of newly detected cases of bladder cancer, but CIS is found accompanying more than half of bladders presenting with multiple papillary tumors. CIS in this instance is either adjacent to or involving mucosal sites remote from papillary lesions.32 CIS is believed to be an important precursor of invasive cancer, and if untreated, will develop into muscularis propria鈥搃nvasive disease within 5 years from the initial diagnosis in more than 50% of patients.

Upper Tract Tumors

Like bladder tumors, 90% of upper tract tumors are TCCs with similar morphology.33 Squamous cell carcinomas account for most of the remaining carcinomas, with adenocarcinoma representing at most 1% of upper tract malignancies. The cytologic characteristics for classification of TCC by grade are the same for upper tract TCC and those in the bladder.

Molecular Tumor Markers

As the natural history of superficial urothelial tumors is that of recurrence, an area of controversy is whether tumors that occur at separate sites or at separate times in the urothelial tract are derived from the same clone or are polyclonal in origin. A report by Sidransky et al.34 demonstrated the clonality of multiple bladder tumors from different sites. Miyao et al.35 showed concordant genetic alterations in asynchronous tumors from individual patients. These studies suggest that urothelial TCCs appearing at different times and sites can be derived from the same neoplastic clone. Moreover, many studies have reported an increasing frequency of specific genetic abnormalities in bladder tumors of more advanced stages.36,37,38 Many tumor suppressor gene modifications, including those of p53, pRB, p16, p21, thrombospondin-1, glutathione, and factors controlling the expression and function of the epidermal growth factor receptor (EGFR), have been shown in retrospective analyses to be adverse prognostic factors in patients with TCC after various treatments.39,40,41,42,43 However, even in the most intensively studied tumor suppressor gene in advanced TCC, the p53 gene, retrospective analyses give conflicting data on whether a mutation of p53 confers an increased responsiveness or an increased resistance to chemotherapy or radiation.40,41 Fortunately, this conflict in the predictability of the responsiveness to adjunctive chemotherapy of TCCs with a p53 mutation is now being tested by a prospective phase III trial of postcystectomy methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy, funded by the National Cancer Institute.44

The enthusiasm engendered by the development of novel biologic agents targeted against tumor-specific growth factor pathways or against angiogenesis has been fortified by positive studies in a variety of solid tumors. Two classes of agents that have received great attention are inhibitors of EGFR, including EGFR1 and EGFR2 (or HER2/neu), and inhibitors of vascular endothelial growth factor (VEGF) or its receptors. Ample preclinical evidence has shown that (1) many, if not most, bladder tumors express products of the EGFR family, (2) overexpression correlates with an unfavorable outcome, and (3) inhibition of these pathways may have an antitumor effect.45,46,47,48,49,50

A number of cooperative groups, including Cancer and Leukemia Group B (CALGB), Radiation Therapy Oncology Group (RTOG), and Southwest Oncology Group (SWOG), have or are planning to study inhibitors of EGFR1 and HER2/neu in the treatment of advanced bladder cancer. The RTOG has evaluated the outcomes of 73 patients treated on four of the RTOG bladder-preserving protocols and have found in these patients treated with transurethral surgery and concurrent chemotherapy and radiation that p53, p16, and pRB altered expression had no prognostic significance, but that overexpression of HER2 correlated with a reduced complete response rate that was significant (50% vs. 81%; P =.026). EGFR overexpression, which occurred in only 19% of the patients, was significantly associated with improved disease-specific survival in this group. These findings have led to the opening of a new protocol within the RTOG for patients with muscle-invading bladder cancer who are not fit for cystectomy. This phase I/II protocol, RTOG-0524, the combination of paclitaxel and daily radiation therapy, plus trastuzumab (Herceptin) given only to those patients overexpressing HER2. To our knowledge, this is the first example of molecular targeted therapy being combined with radiation in 17 patients with muscle-invading bladder cancer.51

Another avenue for potential selective increase in tumor cytotoxicity relative to normal tissues is the inhibition of angiogenic inducers, which are frequently present in bladder tumors. Several studies have correlated elevated VEGF levels or cyclooxygenase-2 expression with disease recurrence or progression, often as an independent prognostic factor by multivariate analysis.52 This is the basis for combining anti-VEGF P.1361


therapy or various cyclooxygenase-2 inhibitors, with other forms of cytotoxic therapy in prospective clinical trials. For instance, the CALGB is proposing to evaluate the benefit of combining bevacizumab (Avastin) with cisplatin and gemcitabine to improve survival in patients with metastatic TCCs; and the RTOG is evaluating whether high expression of VEGF receptors on immunochemistry staining of the primary tumor is an unfavorable predictor of tumor response to patients with muscle-invading TCCs treated with radiation concurrent with radiosensitizing chemotherapy.

The major challenge for clinical and translational investigators is to design appropriate prospective trials that will identify which molecular tumor markers will be prognostic of outcome and also be predictive of whether a patient will do better treated by surgery, radiation, chemotherapy, molecular targeted therapy, or a combination of these. Only then can molecular tumor markers be incorporated into clinical decision-making and allow physicians to make better treatment choices on behalf of their patients.

Cancer of the Bladder

Cancers of the bladder can be grouped into three general categories by their stages at presentation: superficial cancers, muscularis propria鈥搃nvasive cancers, and metastatic cancers. Each differs in clinical behavior, primary management, and outcome. When treating superficial tumors, the aim is to prevent recurrences and progression to a stage that is life-threatening. With muscularis propria鈥搃nvasive disease, the main issue is to determine which tumors require cystectomy; which can be successfully managed by bladder preservation, using combined modality therapy; and which tumors, by virtue of a high metastatic potential, require an integrated systemic chemotherapeutic approach from the outset. Combination chemotherapy is the standard for treating metastatic disease. Despite reports of complete responses (CRs) in more than 40% of cases, the duration of response and overall cure rates remain low. Nonetheless, newer therapies with improved chemotherapeutic regimens, possibly including rationally targeted agents against tumor-specific growth factor pathways, offer the hope that these response rates, long-term control rates, and survival may improve in the future.

Clinical Presentations and Staging

Bladder cancer is rarely incidentally discovered at autopsy. Indeed, almost all cases show symptoms in the premortem period. The most common presentation is gross painless hematuria. Unexplained frequency and irritative voiding symptoms should alert one to the possibility of CIS of the bladder or, less commonly, muscularis propria鈥搃nvasive cancer.

Workup

The workup of suspected bladder cancer should include cytology, a cystoscopy, and an upper tract study. The preference for the upper tract study is a renal computed tomography (CT) scan as both ureter and renal pelvis can be particularly well visualized as well as the relevant lymph nodes and the kidney parenchyma.

Careful staging is important, as treatment depends on the initial stage of the disease. The clinical stage of the primary tumor is determined by transurethral resection of the bladder tumor (TURBT). This resection should include a sample of the muscularis propria for appropriate diagnosis, particularly if the tumor appears sessile or high grade. Once the specimen has been resected, the base of the resected area should be separately biopsied. Any suspicious areas in the remainder of the bladder should be biopsied, and many advocate additional selected biopsies of the bladder mucosa and a prostatic urethral biopsy as well. Urethral biopsies are clearly indicated in patients with risk factors for urethral involvement as previously discussed and in those who have persistent positive cytologies in the absence of a demonstrated bladder lesion. Alpha amino levulinic acid installation and the utilization of specific wavelengths to visualize the bladder tumor have been recommended to increase the yield of positive biopsies, but in our experience it is extremely difficult to differentiate inflammatory lesions from urothelial carcinomas using this technique.

Staging

The primary bladder cancer is staged according to the depth of invasion into the bladder wall or beyond (Table 40.4.1).53 The urothelial basement membrane separates superficial bladder cancers into Ta (noninvasive) and T1 (invasive) tumors. The P.1362


muscularis propria separates superficial disease from deeply (muscularis propria) invasive disease. Stage T2 and higher T stage tumors invade the muscularis propria, the true muscle of the bladder wall. If the tumor extends through the muscle to involve the full thickness of the bladder and into the serosa, it is classified as T3. If the tumor involves contiguous structures such as the prostate, the vagina, the uterus, or the pelvic sidewall, the tumor is classified as stage T4. In a TURBT specimen, in contrast to a cystectomy specimen, it is relatively infrequent for the pathologist to be able to make an accurate assessment as to the depth of invasion of the tumor into the muscularis propria. In some well-oriented pieces of tissue, one can discern that the involvement is only superficial, whereas in other similarly well-oriented specimens one can see that invasion is deep. However, the fragmentary nature of many TURBT specimens precludes a definitive interpretation of the depth of involvement of the muscularis propria in many instances. Thus the primary pathologic substages of the TNM staging system shown in Table 40.4.1, such as pT2a and pT2b, cannot be determined from TURBT specimens. CT scans or magnetic resonance images (MRIs), even those done prior to the TURBT, are not reliable for staging of the primary tumor. Neither scan can differentiate a Ta/T1 tumor from a T2/T3 tumor because neither can visualize the depth of invasion of the primary tumor into the bladder wall. However, these scans are helpful in staging of the primary tumor when they show unequivocal tumor extension outside the bladder (stage T3, Fig. 40.4.1). CT scans or MRIs following a TURBT also are not reliable for staging of the primary tumor because either surgically induced edema in the resected portion of the bladder wall or postsurgical extravesical inflammatory stranding may be confused with extravesical tumor extension.

Table 40.4.1 American Joint Committee on Cancer 2002 TNM Bladder Cancer Staging

Primary tumor (T)
Tis Carcinoma in situ
Ta Noninvasive papillary tumor
T1 Tumor invades the lamina propria, but not beyond
T2 Tumor invades the muscularis propria
pT2a Tumor invades superficial muscle (inner half)
pT2b Tumor invades deep muscle (outer half)
T3 Tumor invades perivesical tissue
pT3a Microscopically
pT3b Macroscopically (extravesical mass)
T4 Tumor invades any of the following: prostate, uterus, vagina, pelvis or abdominal wall
T4a Tumor invades prostate, uterus, vagina
T4b Tumor invades pelvis or abdominal wall
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node, 2 cm or less in greatest dimension
N2 Metastasis in a single lymph node more than 2 cm but less than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension
Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
(From ref. 53, with permission.)

Patients who have documented muscularis propria鈥搃nvasive bladder cancer require an additional set of studies: chest x-ray, liver function studies, creatinine, and electrolytes and an evaluation of the pelvic and retroperitoneal lymph nodes on CT scan. Bimanual examination is also performed at the time the tumor is transurethrally resected to evaluate for possible extravesical extension of tumor and to determine mobility of the pelvic contents. An exciting new advance in staging bladder cancers involves MRI lymphangiography.54 With this technology we have found that nodes that appear to be enlarged on CT may be differentiated as to whether or not they are inflammatory or malignant. The sensitivity and specificity of the test is quite high. Having this information preoperatively allows for either neoadjuvant chemotherapy followed by cystectomy and/or identifies involved lymph nodes in areas not commonly accessed at cystectomy. If there is a history of functional bowel abnormality, a barium study of the segment of bowel to be used for the diversion should be performed. It is our practice when using colon in the reconstruction of the urinary tract to obtain a barium enema and/or colonoscopy so that there are no surprises at the time of surgery. Finally, patients with muscularis propria鈥搃nvasive bladder cancer must have a prostatic urethral and bulbous urethral biopsy to determine whether or not an orthotopic bladder may be placed or whether the procedure should encompass the urethra: that is, a cystoprostatourethrectomy in males or a cystourethrectomy and anterior exenteration in females.

Treatment of Superficial Bladder Cancer (Ta, Tis, T1)

Seventy percent of patients with bladder cancer have superficial disease at presentation. Approximately 15% to 20% of these patients will progress to stage T2 disease or greater over time. Fifty percent to 70% of those presenting with Ta or T1 disease will have a recurrence following initial therapy. Low-grade tumors (grade I or II) and low-stage (Ta) disease tend to have a lower recurrence rate at about 50% and a 5% progression rate, whereas high-risk disease (grade III, T1 associated with CIS, and multifocal disease) has a 70% recurrence rate and a 30% progression rate to stage T2 disease or greater disease. Less than 5% of patients with superficial bladder cancer will develop metastatic disease without developing evidence of muscularis propria invasion (stage T2 disease or greater) of the primary lesion.

Patients who are at significant risk for development of progressive disease or recurrent disease following TURBT are generally considered candidates for adjuvant intravesical drug therapy. For practical purposes this would include those with multifocal CIS, CIS associated with Ta or T1 tumors, any grade III tumor, multifocal tumors, and those whose tumors rapidly recur following TURBT of the initial bladder tumor. A number of drugs have been used intravesically, including bacillus Calmette-Gu茅rin (BCG), interferon and BCG, thiotepa, mitomycin C, doxorubicin, and gemcitabine. Complications generally include frequency, dysuria, and irritative voiding symptoms. Over the long term, bladder contracture may occur with these agents. Other complications, which are specific for each drug, are as follows: BCG administration may result in fever, joint pain, granulomatous prostatitis, sinus formation, disseminated tuberculosis, and death; thiotepa may cause myelosuppression; mitomycin C may cause skin desquamation and rash; and doxorubicin may cause gastrointestinal upset and allergic reactions. The proposed benefit of intravesical chemotherapy is to lessen the rate of recurrences and reduce the incidence of progression. Unfortunately, it cannot be clearly stated that any of these P.1363


drugs accomplish these goals over the long term. Many studies have demonstrated that over the short term there is a reduction in the recurrence rate of superficial tumors. Unfortunately, in many of these studies the follow-up is less than 2 years.

 Computed tomography scan of a patient with a muscularis propria
Figure 40.4.1. Computed tomography scan of a patient with a muscularis propria鈥搃nvasive bladder cancer performed before a transurethral tumor resection showing unequivocally an extravesical extension of tumor (stage T3). Tumor projecting into the bladder lumen (black arrow); portion of the tumor extending into the ureter outside the bladder (white arrow).

A number of studies have compared one intravesical chemotherapeutic agent with another. For the most part, BCG in these comparisons has a slight advantage in reducing recurrences.55 However, when the follow-up is more than 5 years, it appears that there is minimal overall effect in reducing the recurrence rate when compared with no treatment. Approximately 70% of patients with high-grade disease will experience recurrence whether or not they are treated with intravesical therapy. Moreover, there is no well-documented evidence that the use of these agents prevents disease progression, that is, from stage Ta/T1 disease to stage T2 or greater disease. Indeed, about one third of patients who are at high risk for disease progression (those with grade III, T1 disease) will progress to stage T2 or greater disease whether or not they are treated with BCG.56 One third of patients at 5 years who have disease progression and undergo a cystectomy die of metastatic disease. Thus, approximately 15% of patients with superficial disease at high risk for disease progression (CIS with associated Ta or T1 disease, rapidly recurrent disease, and/or grade III disease), irrespective of treatment modality, will die of their disease.57 If definitive therapy (cystectomy) is performed when the disease is found to progress into the muscularis propria (T2 or greater), there is no difference in cure rate when these patients are compared with those who present with T2 or greater disease primarily. These statistics have encouraged some to perform a pre-emptive cystectomy in those patients at high risk for progression before muscularis propria invasion is documented. Ten-year cancer-specific survivals of 80% are given as justification for this approach as compared with 50% in patients in whom the cystectomy is performed when the disease progresses to involve the muscularis propria.58 Unfortunately, this approach subjects approximately two thirds of these patients who are included in the 80% cancer-specific survival figure to a needless cystectomy, making it questionable as to whether there is in fact any survival advantage whatsoever.

Treatment of Muscularis Propria鈥揑nvasive Disease

Surgical Approaches

The standard of care for squamous cell carcinoma, adenocarcinoma, TCC, and spindle cell carcinoma invading the muscularis propria of the bladder is a bilateral pelvic lymph node dissection and a cystoprostatectomy, with or without a urethrectomy in the male. In the female an anterior exenteration is performed, which includes the bladder and urethra (the urethra may be spared if uninvolved and an orthotopic bladder reconstruction is performed), the ventral vaginal wall, and the uterus. A radical cystectomy may be indicated in non鈥搈uscularis propria鈥搃nvasive bladder cancers when grade III disease is multifocal and/or associated with CIS or when bladder tumors rapidly recur, particularly in multifocal areas following intravesical drug therapy. When the prostate stroma is involved with TCC or when there is concomitant CIS of the urethra, a cystoprostatourethrectomy is the treatment of choice. The authors have described a method of doing this procedure en bloc, which allows for removal of the entire bladder, prostate, and urethra as a single specimen.59 If the urethra needs to be removed, the type of urinary reconstruction is limited to an abdominal urinary diversion. In selected circumstances in the male, the neurovascular bundles coursing along the lateral side of the prostate caudally and adjacent to the rectum more cephalad may be preserved, sometimes preserving potency. Partial cystectomies may rarely be performed in selected patients, thus preserving bladder function and affording in the properly selected patient the same cure rate as a radical cystectomy. Patients who are candidates for such procedures must have focal disease located far enough away from the ureteral orifices and bladder neck to achieve at least a 2-cm margin around the tumor and a margin sufficient around the ureteral orifices and bladder neck to reconstruct the bladder. Practically, this limits partial cystectomies to those patients who have small tumors located in the dome of the bladder and in whom random bladder biopsies show no evidence of CIS or other bladder tumors.

Survival

The probability of survival from bladder cancer following cystectomy is determined by the pathologic stage of the disease. Survival is markedly influenced by the presence or absence of positive lymph nodes. Some have argued that the number of positive nodes impacts survival in that when resected, there is a potential for cure provided there are less than four to eight positive nodes.60,61 Others are not in complete agreement with this. It is clear, however, that positive perivesical nodes have a less ominous prognosis when compared with involvement of iliac or para-aortic nodes. Pathologic type may also impact outcome, but in most series survival is more dependent on pathologic stage than on the cell type of the cancer. Most large series of survival statistics following treatment include all patients regardless of cell type. These series are generally constituted as to histologic type as follows: TCC, 85% to 90%; combination of TCC and either squamous cell or adenocarcinoma, 6%; pure squamous cell carcinoma, 3%; pure adenocarcinoma, 3%; small cell and spindle cell carcinoma, 2% (Table 40.4.2).

Table 40.4.2 Survival after Radical Cystectomy According to Pathologic Stage at 10 Years

Pathologic Stage Disease-Specific Survival (%) Overall Survival (%)
pTa, Tis, T1 with high risk of progression 82 鈥�
Organ confined, negative nodes (pT2, pN0) 73 49
Nonorgan confined (pT3鈥�4a or pN1鈥�2) 33 23
Lymph node-positive (any T, pN1鈥�2) 28, 34 21
(Data derived from refs. 60, 61, 88, 89, 90.)

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Types of Urinary Diversion

Urinary diversions may be divided into continent and noncontinent. Noncontinent urinary diversions or conduits involve the use of a segment of ileum or colon and, less commonly, a segment of jejunum. The distal end is brought to the skin and the ureters are implanted into the proximal end. The patient wears a urinary collection appliance. The advantages of a conduit (ileal or colonic) are its simplicity and the reduced number of immediate and long-term postoperative complications. In most series, the complication rate is about 13%; that is, 13% of patients who undergo a cystectomy and urinary diversion of this type will have a significant complication, which impacts on hospital stay or recovery. Generally, the distal ileum is used for the urinary conduit or reservoir, however, if it has been irradiated or is otherwise involved, one may select the right colon or a short segment of jejunum. The latter is the least desirable choice as electrolyte problems may be significant. On occasion during exenterative surgery when an end colostomy is created, a segment of distal bowel is used, thus obviating the need for an intestinal anastomosis.

Continent diversions may be divided into two types: abdominal and orthotopic. Abdominal diversions require a continence valve, whereas an orthotopic neobladder depends on the urethral sphincter for continence. The reservoir is made of bowel that is fashioned into a globular configuration. In the abdominal type of continent diversion, the stoma is brought through the abdominal wall to the skin. The patient catheterizes the pouch every 4 hours. Orthotopic urinary diversions entail the use of bowel brought to the urethra, thus allowing the patient to void by Valsalva (Fig. 40.4.2). Patients must have the facility to catheterize themselves, as it is mandatory in the abdominal continent diversion and occasionally necessary in the orthotopic reconstruction. Another type of continent diversion, the ureterosigmoidostomy, is rarely used at this time because of excessive long-term complications. The advantage of continent diversions is the avoidance of a collection device. The advantage of an orthotopic bladder over all other types of continent diversions is that it rehabilitates the patient to normal voiding through the urethra, often without the need for intermittent catheterization or the need to wear a collection device. Postoperative and long-term complications of continent diversion are increased over the conduit types of diversions. Indeed, in some series postoperative complications range from 13% to 30%. Long-term metabolic complications are also increased.

. Intravenous urogram of a patient with an orthotopic bladder after radical cystoprostatectomy. The orthotopic bladder was constructed of the right colon and distal ileum.
Figure 40.4.2. Intravenous urogram of a patient with an orthotopic bladder after radical cystoprostatectomy. The orthotopic bladder was constructed of the right colon and distal ileum.

Complications of Cystectomy and Urinary Diversion

The complications of all types of urinary diversion may be divided into three; metabolic, neuromechanical, and surgical (Table 40.4.3).

Metabolic Complications of Urinary Intestinal Diversion

When intestine is interposed in the urinary tract there is the potential for a number of metabolic complications.62 These may involve electrolyte abnormalities and altered drug metabolism, which may result in altered sensorium, infection, osteomalacia, growth retardation, calculi both within the reservoir as well as in the kidney, short bowel syndrome, cancer, and altered bile metabolism.

P.1365


Table 40.4.3 Complications of Cystectomy and Urinary Diversion

Metabolic
   Electrolyte abnormalities
   Abnormal sensorium/drug metabolism
   Infection
   Osteomalacia
   Growth retardation
   Calculi
   Short bowel syndrome
   Cancer
Neuromechanical
   Atonic segment
   Intestinal contractions
   Failure of continence mechanism
Surgical
   Urine leak
   Bowel obstruction
   Fecal leak
   Pyelonephritis
   Sepsis
   Ureteral intestinal obstruction
   Renal failure
   Stoma problems
   Death
   Postoperative complications of any major surgical procedure

Perhaps the most significant metabolic complication is an alteration in electrolytes. These abnormalities often have far-reaching consequences. Depending on the segment used, a specific electrolyte abnormality may occur. Thus, when ileum and colon are used, hyperchloremic metabolic acidosis may occur. When the jejunum is the segment of choice, a hypochloremic, hyperkalemic metabolic acidosis may result.

Specific electrolyte abnormalities are more common with certain segments. Thus, hypokalemia is more common when colon is used, hypocalcemia is more common when ileum and colon are used, and hypomagnesemia is more common when ileum and colon are used.

The most pervasive detrimental effect created by urinary intestinal diversion in all likelihood is due to the acidosis. It occurs in general when jejunum, ileum, or colon is interposed in the urinary tract. Acidosis may result in electrolyte abnormalities, osteomalacia, growth retardation, altered sensorium, altered hepatic metabolism, renal calculi, and abnormal drug metabolism. Because jejunum is rarely used, the following discussion relates only to colon and ileum. Moreover, because acidosis is the prime contributor to many metabolic complications, it is of some importance to understand the mechanism of the acidosis. In general, patients with normal renal function as well as normal hepatic function are less prone to acidosis and its complications.

Treatment for the metabolic acidosis is rather straightforward and can be accomplished with bicarbonate, which has the potential to cause gas, or with Bicitra solution, which is sodium citrate and citric acid. Polycitra, which is a combination of potassium citrate, sodium citrate, and citric acid, may also be employed. It has the advantage of supplying potassium, which on occasion is deficient. Chlorpromazine and nicotinic acid have been used to block the chloride bicarbonate exchanger and thus lessen the potential for the acidosis. They may be used to ameliorate the acidosis in patients who have difficulty taking Polycitra or bicarbonate.

Patients with conduits may have 3% to 4% incidence of renal calculi over the long term. Those with reservoirs have up to a 20% incidence of calculi within the reservoir. The pathogenesis may be a metabolic alteration and/or infection, whereas reservoir stones are most commonly due to a surgical foreign body and/or mucus serving as a nidus.

There is an increased incidence of bacteriuria in patients with either conduits or pouches. The incidence of sepsis is 13% and the etiology is thought to be transmucosal translocation of bacteria. In addition, there appears to be a diminished antibacterial activity of the intestinal mucosa. Thus, the immunoglobulins, which are normally secreted by intestinal mucosa, are altered. In addition to this, when the bowel is distended there can be a translocation of bacteria from the lumen into the blood stream.

Because the intestine is interposed in the urinary tract, drugs that are eliminated from the body through the kidney unchanged and have the potential to be reabsorbed by the gut can in fact result in significant alterations in metabolism of that drug. This is particularly true for Dilantin and for cyclophosphamide. Patients with a urinary diversion, when given systemic chemotherapy, have a higher incidence of complications and are more likely to have their chemotherapy limited when compared with patients without diversion receiving the same drugs and dose.63

Table 40.4.4 Short-Term Complications after Cystectomy and Urinary Diversion

Complication Percent
Acute acidosis requiring therapy 16
Urine leak 3鈥�16
Bowel obstruction 5
Fecal leak 5
Pyelonephritis 5鈥�15
Sepsis 5鈥�15

Removing a segment of bowel from the intestinal tract may result in untoward complications. The loss of the distal ileum may result in vitamin B12 malabsorption and then manifest itself as anemia and neurologic abnormalities. Bile salt malabsorption may occur and result in diarrhea. Loss of the ileocecal valve may result in diarrhea with bacterial overgrowth of the ileum and malabsorption of the vitamin B12 and fat-soluble vitamins A, D, E, and K. Loss of the colon may result in diarrhea and bicarbonate loss.

Neuromechanical Complications

Neuromechanical complications may be of two types: atonic, resulting in an atonic segment with urinary retention, and upper tract deterioration or hyperperistaltic contractions. The latter is relevant in continent diversions as this may result in incontinence and a low-capacity reservoir.

Surgical Complications

There are a number of surgical complications that occur and these may be divided into short-term and long-term complications.64,65 There are a number of complications that occur following any major surgical procedure, which include thrombophlebitis, pulmonary embolus, wound dehiscence, pneumonia, atelectasis, myocardial infarction, and death. Complications specific to cystectomy and urinary diversion are detailed in Tables 40.4.4 and 40.4.5.

Selective Bladder-Preserving Approaches

The treatment options for muscularis propria鈥搃nvasive bladder tumors can broadly be divided into those that spare the bladder and those that involve removing it. In the United P.1366


States, radical cystectomy with pelvic lymph node dissection is the standard method used to treat patients with this tumor, but conservative management with organ preservation is now the standard of care in numerous malignancies, including carcinomas of the breast, the anus, and the head and neck region, where radical surgery can be avoided in the majority of patients. Several reports from North America and Europe have described long-term results using multimodality treatment of muscularis propria鈥搃nvading bladder cancer, with appropriate safeguards for early cystectomy should this treatment fail. For bladder-conserving therapy to be more widely accepted, this treatment approach must have a high likelihood of eradicating the primary tumor, must preserve good organ function, and must not result in compromised patient survival.

Table 40.4.5 Long-Term Complications after Cystectomy and Urinary Diversion

Complication Percent
Ureteral intestinal obstruction 15
Renal deterioration 15
Renal failure 7
Stoma problems 15
Intestinal stricture 10
Bowel obstruction 5

Successful bladder-preserving approaches have evolved during the last 2 decades, with added efficacy reported when cisplatin is given concurrently with radiation. From 1981 to 1985, the National Bladder Cancer Group first used cisplatin as a radiation sensitizer in 68 patients with muscularis propria鈥搃nvading bladder cancer that was unsuitable for cystectomy. In a multicenter protocol this approach was shown to be feasible and safe.66 Furthermore, the long-term survival rate with stage T2 tumors (64%) and stage T3 to T4 tumors (22%) was encouraging. This early result with concurrent cisplatin and pelvic irradiation was validated by the National Cancer Institute鈥揅anada randomized trial of radiation (either definitive or precystectomy) with or without concurrent cisplatin for patients with T3 bladder cancer. The Canadian study showed a significant improvement in pelvic tumor control (67% vs. 47%) in the patients who were assigned cisplatin.67 Additionally, single-institution studies showed that the combination of a visibly complete TURBT followed by radiation therapy or radiation therapy concurrent with chemotherapy safely improved local control.68,69 These findings led single institutions and the RTOG to develop the algorithm for bladder preservation of an initial TURBT of as much of the bladder tumor as is safely possible, followed by the combination of radiation with concurrent radiosensitizing chemotherapy. One key to the success of such a program is the selection of patients for bladder preservation on the basis of the initial response of each individual patient's tumor to therapy. Thus, bladder conservation is reserved for those patients who have a clinical CR to concurrent chemotherapy and radiation. Prompt cystectomy is recommended for those patients whose tumors respond only incompletely or who subsequently develop an invasive tumor (Fig. 40.4.3). All of the protocols developed at the Massachusetts General Hospital (MGH) or within the RTOG since 1986 explicitly direct discontinuation of the bladder-sparing effort in favor of radical cystectomy at the earliest sign of failure of local control. These protocols require that the patients be medically fit and willing to undergo cystectomy should the initial treatment fail. One third of the patients entering a potential bladder-preserving protocol with trimodality therapy (initial TURBT followed by concurrent chemotherapy and radiation) will require radical cystectomy.

For almost 2 decades, the MGH and the RTOG have evaluated in phase II and III protocols concurrent radiochemotherapy plus neoadjuvant or adjuvant chemotherapy. Two large centers in Europe (Erlangen, Germany, and Paris, France) have evaluated concurrent radiochemotherapy without neoadjuvant or adjuvant chemotherapy (Table 40.4.6). Radiosensitizing drugs studied in these series, either singly or in various combinations, include cisplatin, carboplatin, paclitaxel, and 5-fluorouracil (5-FU). In addition to these drugs, gemcitabine has been shown to have radiosensitizing properties so intense as to, when used concurrently with bladder radiation, require marked gemcitabine dose reduction to avoid damaging pelvic organs.70 Preliminary results indicate that in very low gemcitabine doses (33 mg/m2 twice weekly) treatment is well tolerated and therefore worthy of further study.

 Schema for trimodality treatment of muscularis propria鈥搃nvasive bladder cancer with selective bladder preservation. TURBT, transurethral resection of the bladder tumor; XRT, radiation therapy.
Figure 40.4.3. Schema for trimodality treatment of muscularis propria鈥搃nvasive bladder cancer with selective bladder preservation. TURBT, transurethral resection of the bladder tumor; XRT, radiation therapy.

Phase II and phase III protocols with concurrent radiochemotherapy are listed in Table 40.4.6 and are described here. The first RTOG study, RTOG 8512, included 42 patients treated with once-daily radiation treatment and concurrent cisplatin, yielding a 5-year survival of 52%.71 This treatment was well tolerated and resulted in 42% of the patients achieving long-term survival with an intact bladder. RTOG studies 8802 and 8903 used MCV (methotrexate, cisplatin, and vinblastine) chemotherapy as neoadjuvant treatment.72 In the latter study patients were treated on a phase III trial with or without two cycles of MCV before the combination of cisplatin and once-a-day radiation.73 No improvement was seen in survival or in local tumor eradication as a result of neoadjuvant therapy. With a median follow-up of 5 years, the overall survival was 48% in patients treated with MCV and 49% in those who received no neoadjuvant treatment. The cystoscopic CR rate was 61% in the MCV arm and 55% in the control arm, not statistically significant. At 5 years, metastases were present in 35% of the patients who received MCV and 42% of those who were given no neoadjuvant chemotherapy. This difference was not statistically significant. The toxicity of the MCV arm was considerable, with only 67% of patients able to complete the planned treatment. This phase III study was not sufficiently powered to settle the question P.1367


of the place of neoadjuvant chemotherapy in patients undergoing bladder-preserving therapy, but neither the RTOG nor the MGH has revisited the question of the effectiveness of neoadjuvant chemotherapy.

Table 40.4.6 Results of Multimodality Treatment for Muscle-Invading Bladder Cancer

Series (Reference) Multimodality Therapy Used No. of Patients 5-Year Overall Survival (%) 5-Year Survival with Intact Bladder (%)
RTOG 8512, 1993 (ref. 71) External-beam radiation + cisplatin 42 52 42
RTOG 8802, 1996 (ref. 72) TURBT, MCV, external-beam radiation + cisplatin 91 51 44 (4 y)
RTOG 8903, 1998 (ref. 73) TURBT 卤 MCV, external-beam radiation + cisplatin 123 49 38
U. Paris, 1997 (ref. 74) TURBT, 5-FU, external-beam radiation + cisplatin 120 63 NA
Erlangen, 2002 (ref. 75) TURBT, external-beam radiation, cisplatin, carboplatin, or cisplatin and 5-FU 415 (cisplatin, 82; carboplatin, 61; 5-FU/cisplatin, 87) 50 42
MGH, 2003 (ref. 78) TURBT 卤 MCV, external-beam radiation + cisplatin 190 54 45
RTOG, Radiation Therapy Oncology Group; TURBT, transurethral resection of bladder tumor; MCV, methotrexate, cisplatin, vinblastine; 5-FU, 5-fluorouracil; NA, not available; MGH, Massachusetts General Hospital.

Housset et al.74 from the University of Paris reported on 120 patients with stage T2 to T4a bladder cancer. The treatment consisted of TURBT followed by cisplatin and 5-FU given concurrently with twice-a-day hypofractionated radiation. The authors reported a 63% overall survival.

The University of Erlangen has updated the largest bladder-sparing study to date, 415 patients treated from 1982 to 2000.75 This report included 126 patients who received radiation without any chemotherapy and 89 patients who were not clinical stage T2 to T4 but classified as 鈥渉igh-risk T1.鈥� The CR rate of all 415 patients was 72%, and local control of the bladder tumor after the CR without a muscle-invasive relapse was maintained in 64% of the patients at 10 years. The 10-year disease-specific survival was 42%, and more than 80% of these survivors preserved their bladder. This series, not randomized, reported sequential use of radiation with no chemotherapy (126 patients), followed by concurrent cisplatin (145 patients), concurrent carboplatin (95 patients), and concurrent cisplatin with 5-FU (49 patients). The CR rates in these four sequential treatment protocols were 51%, 81%, 64%, and 87%, respectively.76,77 The 5-year actuarial survival with an intact bladder from these four sequential protocols was 38%, 47%, 41%, and 54%. These results suggest strongly that radiochemotherapy, when given concurrently, is superior to radiation therapy alone, that carboplatin is less radiosensitizing than cisplatin, and that cisplatin plus 5-FU may be superior to cisplatin alone. The authors recognized that this conclusion is compromised by the absence of any randomized trial data from their institution.

From 1994 to 1998, twice-daily radiation therapy was introduced into RTOG protocols with concurrent cisplatin or with cisplatin plus 5-FU as radiosensitizers.78From 1999 to 2002, twice-a-day radiation concurrent with cisplatin and paclitaxel as radiosensitizers along with adjuvant cisplatin and gemcitabine was evaluated. The initial reports of this protocol (RTOG 99-06) are of a 73% completion rate with acceptable toxicity and an 87% CR rate. The second innovation in that protocol was to use as adjuvant chemotherapy the regimen cisplatin (70 mg/m2 on day 1) and gemcitabine (1,000 mg/m2 on days 1, 8, and 15). The initial outcomes report of RTOG 96-06 report a 73% completion rate with acceptable toxicity and 87% CR rate.79 The latest North American protocol for bladder-sparing treatment (RTOG 0233) has opened. This is a randomized phase II study comparing two combinations of radiosensitizing chemotherapy (cisplatin plus paclitaxel vs. cisplatin plus 5-FU), each given concurrently with an induction course of twice-daily radiation treatment. This is followed in patients whose tumors initially respond completely by consolidation chemoradiation and in those with incompletely responding tumors by radical cystectomy. All patients then undergo a three-drug adjuvant treatment with cisplatin, gemcitabine, and paclitaxel. Because cisplatin is not an ideal drug for bladder cancer patients because of significant percentage have impaired renal function, a British group examined in a phase I/II study the combination of 5-FU and mitomycin C with pelvic radiotherapy in bladder cancer. They reported a CR rate of 70 % in those receiving mitomycin C 12 mg/m2 day 1 and 5-FU 500 mg/m2 given days 1 to 5 on weeks 1 and 4 in combination with external-beam radiation to 55 Gy and 20 fractions.80 The British group are now testing by a phase III trial this chemoradiotherapy regimen compared with radiation therapy alone. This trial incorporates the quality of life and bladder capacity measurements as well as cancer control end points.81

Predictors of Outcome

The update from the MGH includes all 190 patients with muscularis propria鈥搃nvading bladder cancer clinical stages T2 to T4a on successive, prospective, selective bladder-preserving protocols from 1986 to 1997.82 Eighty-one patients had been followed for 5 years or more and 28 patients for 10 or more years. The 5- and 20-year overall survival rates are 54% and 36%, respectively. The 5- and 20-year disease-specific survival rates are P.1368


63% and 59%. The 5- and 20-year disease-specific survival rates with an intact bladder are 46% and 45%. The disease-specific survival rate stratified by clinical stage is shown in Figure 40.4.4. Clinical stage also significantly influences the CR rate, which is 71% for stage T2 and 57% for stage T3 to T4a. The presence of hydronephrosis, however, significantly reduced the CR rate from 68% to 37% and likely reduces disease-specific survival. As a result of this finding, patients with tumor-associated hydronephrosis are now excluded from our bladder-preserving protocols. The lack of efficacy of neoadjuvant MCV, albeit in one small and poorly powered study, has directed our attention to evaluating the usefulness of adjuvant chemotherapy.

Disease-specific survival with bladder preservation for all 190 patients treated on protocol at the Massachusetts General Hospital from 1986 to 1997.
Figure 40.4.4. Disease-specific survival with bladder preservation for all 190 patients treated on protocol at the Massachusetts General Hospital from 1986 to 1997.

The current schema for trimodality treatment of muscle-invading bladder cancer is provided in Figure 40.4.3. The 5- and 10-year disease-specific survival rate for the 66 patients undergoing cystectomy is 48% and 41%, respectively. This indicates the very important contribution of prompt salvage cystectomy for disease control in the 66 patients who required salvage cystectomy.

Of the 121 patients who were complete responders after induction therapy, 73 developed no further bladder tumors, 32 subsequently developed a superficial occurrence, and 16 developed an invasive tumor.83 Twenty-nine patients with superficial recurrence were treated conservatively by TURBT and intravesical chemotherapy, and three underwent immediate cystectomy. However, 7 of the 29 patients required subsequent cystectomy for additional superficial (4 patients) or invasive (3 patients) recurrence. For these individuals the overall survival was comparable to that of the 73 who had no failure. However, one third of these patients required a salvage cystectomy.

The pelvic recurrence rate of all 190 patients was 8.4%. This includes 6 of the 41 patients who underwent immediate cystectomy and 6.7% of the remainder, with a median follow-up of 7.3 years.

Radiation Treatment

The most common approach with external-beam irradiation reported from North America and Europe involves the treatment of the whole small pelvis to include the external and internal iliac lymph nodes in the target volume for a total dose of 40 to 45 Gy in 1.8- to 2.0-Gy fractions during 4 to 5 weeks. Subsequently, the target volume is reduced to deliver a final boost dose of 20 to 25 Gy in 15 fractions to the primary bladder tumor. Some protocols call for partial bladder radiation as the boost volume if the location of the tumor in the bladder can be satisfactorily identified by the use of cystoscopic mapping, selected mucosal biopsies, and imaging information from CT or MRI. Plans using conventional fractionation that result in a whole bladder dose of 50 to 55 Gy and a bladder tumor volume dose of 65 Gy in combination with concurrent cisplatin-containing chemotherapy have been widely used. In the United Kingdom, a dose of 50 to 55 Gy at 2.5 to 2.75 Gy per fraction in 4 weeks is common. The available information suggests that the higher dose per fraction may lead to a higher rate of serious late complications. Data from urodynamic and quality-of-life studies indicate that lower dose per fraction irradiation given once or twice a day concurrent with chemotherapy results in excellent long-term bladder function. Twice-a-day fractionation schedules when given as radiation alone have not been shown to be more effective in long-term local tumor control than that achieved with once-per-day schedules.84

Because the bladder is not a fixed organ, its location and volume can vary considerably from day to day. This results in a number of logistic problems to ensure adequate coverage of the bladder. Studies have identified substantial movement of the bladder during the course of external-beam radiation therapy, and as a result of these findings, the bladder must be empty when simulated and always emptied just prior to each treatment. A minimum margin of 2.5 cm superiorly around the target to the edge at the light field is necessary for two-dimensional plans.85 For three-dimensional planning a clinical target volume or planning target volume expansion of 2.5 cm is advised superiorly and 1.0 cm at the other borders. Bladder tumor doses of higher than 65 Gy seem attractive, especially in light of the higher doses used now in CT-planned prostate cancer patients. Because of increased problems with organ motion and with the fact that the majority of patients are now treated with concurrent cisplatin-containing chemoradiation, P.1369


escalation in doses above 65 Gy should be done only under the umbrella of phase I-II protocols.

Interstitial radiation therapy does make it possible to deliver a higher biologic dose of radiation to a limited area of the bladder within a short period. This approach has been reported from institutions in The Netherlands, Belgium, and France. It is reserved for patients with solitary bladder tumors and as part of combined modality therapy with transurethral resection and external-beam radiation therapy as well as interstitial radiation therapy. External-beam doses of 30 Gy are used in combination with an implant tumor dose of 40 Gy. These groups report that for patients with solitary clinical stage T2 to T3a tumors less than 5 cm in diameter, local control rates at 5 years range from 72% to 84% with disease-specific survivals of approximately 80%.86

Comparison of Treatment Outcomes of Contemporary Cystectomy Series with Contemporary Selective Bladder-Preserving Series

Comparing the results of selective bladder-preserving approaches with those of radical cystectomy series is confounded by the discordance between clinical (TURBT) staging and pathologic (cystectomy) staging. Clinical staging is more likely to understage the extent of disease with regard to penetration into the muscularis propria or beyond than is pathologic staging.87 Thus, if any favorable outcome bias exists it is in favor of the pathologically reported radical cystectomy series. Also, most cystectomy series do not report by 鈥渋ntention to treat鈥� and exclude reporting those patients in whom a cystectomy is found to be inappropriate because of advanced disease. In addition, many patients in cystectomy series do not have preoperative proof of a muscle-invading tumor and include 25% to 40% of patients who have tumors of less than pathologic stage T2, in contrast to bladder preservation reports, in which nearly all patients are stage T2 or greater. The University of Southern California reported on 633 patients with pathologic stage T2 to T4a undergoing contemporary radical cystectomy, with an overall survival rate at 5 years of 48% and at 10 years of 32%.88 Similarly, the report from Memorial Sloan-Kettering Cancer Center contemporary radical cystectomy series reported a 5-year overall survival rate of 36% in patients with tumors of pathologic stage T2 to T4.89 Also, in a national phase III protocol by SWOG, Eastern Cooperative Oncology Group, and CALGB for patients with clinical stage T2 to T4a bladder tumors, in whom the intention to treat was randomly assigned and reported, the 5- and 10-year overall survival rates for all 307 eligible patients were 50% and 34%, respectively.90 These overall survival rates from contemporary cystectomy series are comparable to those reported from single-institution and cooperative group results using contemporary selective bladder-preserving approaches with trimodality therapy (Table 40.4.7).

Table 40.4.7 Muscle-Invasive Bladder Cancer: Survival Outcomes in Contemporary Series

Series (Reference) Stages No. of Patients Overall Survival (%)
5 Year 10 Year
Cystectomy
   U. Southern California, 2001 (ref. 88) pT2-pT4a 633 48 32
   Memorial Sloan-Kettering, 2001 (ref. 89) pT2-pT4a 181 36 27
   SWOG/ECOG/CALGB,a,b 2003 (ref. 90) cT2-cT4a 307 50 34
Selective Bladder Preservation
   U. Erlangena (2002) (ref. 75) cT2-cT4a 326 45 29
   MGHa (2003) (ref. 78) cT2-cT4a 190 54 36
   RTOGa (1998) (ref. 79) cT2-cT4a 123 49 鈥�
SWOG, Southwest Oncology Group; ECOG, Eastern Cooperative Oncology Group; CALGB, Cancer and Leukemia Group B; MGH, Massachusetts General Hospital; RTOG, Radiation Therapy Oncology Group.
aThese series include all patients by their intention to treat.
bFifty percent of patients were randomly assigned to receive three cycles of neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, cisplatin).

Concerns often expressed by urologists are that trimodality therapy is complex, hard to administer, and costly. Although it is correct that trimodality therapy requires close cooperation of urologic, medical, and radiation oncologists, multimodality cancer clinics are now becoming commonplace in North America and provide an ideal setting for ensuring the best treatment.

Bladder-Preservation Treatments with Less Than Trimodality Therapy

It has been argued that trimodality therapy might represent excessive treatment for many patients with invasive bladder cancer and that comparable results could be obtained by TURBT, either alone or with chemotherapy. Herr91 reported the outcome of 432 patients initially evaluated by repeat TURBT for muscle-invasive bladder tumors. In that series, 99 patients (23% of the original 432 patients) initially treated conservatively without immediate cystectomy had a 34% rate of progression to a recurrent muscle-invading tumor at 20 years. In series combining TURBT and MVAC chemotherapy, only 50% of those found to have a clinical CR proved to be tumor-free at cystectomy.92 By comparison one of the clearest examples of the improved success of trimodality treatment was reported in the study from the University of Paris.93 TURBT followed by concurrent cisplatin, 5-FU, and accelerated radiation was used by this group initially as a precystectomy regimen. In the first 18 patients, all of whom demonstrated no residual tumor on P.1370


cystoscopic evaluation and rebiopsy (a CR) but who all underwent a cystectomy, none had any tumor in the cystectomy specimen (100% had a pathologic CR). Comparing approaches by TURBT plus MVAC chemotherapy alone with trimodality therapy, the 5-year survival rates are comparable (50%), but the preserved bladder rate for all patients studied ranged from 20% to 33% when radiation therapy was not used and from 41% to 45% when radiation therapy was used.81 Thus, trimodality therapy increases the probability of surviving with an intact bladder by 30% to 40% compared with the results reported with TURBT and chemotherapy alone.

Selective bladder-sparing by trimodality therapy should be one of the approaches considered in the treatment of patients with muscle-invading bladder cancer. Although it is not suggested that it will replace radical cystectomy, sufficient data now exist from many national and international prospective studies to demonstrate that it represents a valid alternative. This contribution to the quality of life of patients so treated represents a unique opportunity for urologic surgeons, radiation oncologists, and medical oncologists to work hand-in-hand. It must be understood, however, that lifelong bladder surveillance is essential because only prompt salvage cystectomy can prevent the focus of a new or a recurrent bladder cancer from disseminating

Systemic Chemotherapy with Radical Therapy

Neoadjuvant Chemotherapy

The most important initial decisions, once muscularis propria (T2) bladder cancer has been diagnosed, are (1) whether radical cystectomy should be performed immediately or whether bladder-preserving strategies should be employed, using limited surgery (i.e., TURBT), irradiation and chemotherapy, and (2) whether neoadjuvant chemotherapy should be used, or adjuvant chemotherapy following cystectomy or following bladder preservation with radiation and chemotherapy.

The advantages of neoadjuvant chemotherapy are the good responses achieved with cisplatin-containing regimens and a possible improvement in survival in patients with micrometastatic disease. The disadvantages are equally obvious. They include, principally, the inherent difficulties in assessing response, the fact that clinical rather than pathologic criteria must be relied on, and the delay in cystectomy associated with neoadjuvant chemotherapy.

Black et al.94 summarized the rationale in 2006 for neoadjuvant chemotherapy, pointing to the well-established 30% to 45% failure rate after radical cystectomy as the basis for the argument that surgery alone is inadequate treatment for muscle-invasive bladder cancer. The principal advantage of neoadjuvant chemotherapy is that the drugs are delivered at the earliest possible time to occult micrometastatic disease.

There is abundant evidence that muscularis propria invasive transitional cell cancer of the bladder is associated with occult metastases, with the likelihood that micrometastases are present, in many cases, at the time of initial discovery of the bladder tumor. Although down-staging of the primary tumor has been demonstrated, randomized studies using single-agent neoadjuvant chemotherapy have failed to demonstrate a survival benefit or a reduction in the development of distant metastases.

Despite more than 2 decades of clinical experience and investigation with neoadjuvant chemotherapy, followed either by radiochemotherapy as part of bladder-sparing or radical cystectomy, there is still uncertainty as to whether treatment, timed in this way, affects survival. There were, in fact, some hopeful results from early-phase I-II trials of single-agent chemotherapy but important background data from studies in patients with measurable metastatic disease clearly showed the superiority of MVAC over single-agent cisplatin on survival.95 Several phase II studies done subsequently, using multiagent chemotherapy, as well as several randomized studies, and a meta-analysis all failed to demonstrate a survival benefit. Although the published randomized trials have given conflicting results, there are now several studies that have shown a survival benefit from neoadjuvant combination chemotherapy, at least in certain subsets of patients (vide infra). Do these results, however, as interesting and important as they are, effectively make the case for neoadjuvant chemotherapy as a new standard of treatment in muscularis propria鈥搃nvasive bladder cancer?

The study by Grossman et al.96 evaluated neoadjuvant chemo-therapy in improving survival in patients with locally advanced bladder cancer treated with radical cystectomy. Patients with muscularis propria鈥搃nvasive bladder cancer (stage T2 to T4a) were randomly assigned to radical cystectomy alone or three cycles of MVAC followed by radical cystectomy. 317 patients were enrolled during an 11-year period. Patients assigned to neoadjuvant chemotherapy were given three 28-day cycles of MVAC as follows: methotrexate (30 mg/m2 on days 1, 15, and 22), vinblastine (3 mg/m2 on days 2, 15, and 22), doxorubicin (30 mg/m2 on day 2), and cisplatin (70 mg/m2 on day 2). The authors reported that MVAC can be given safely before radical cystectomy, but not without significant side effects. One third of patients had severe hematologic or gastrointestinal reactions, but, on the positive side, there were no drug-related deaths, nor did the chemotherapy adversely affect the performance of surgery.

The conclusions by Grossman et al.96 were as follow. (1) The survival benefit associated with MVAC appeared to be strongly related to down-staging of the tumor to pTo. Thirty-eight percent of the chemotherapy-treated patients had no evidence of cancer at cystectomy as compared with 15% of patients in the cystectomy-only group (P <.001). In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen. (2) The median survival was 77 months for the chemotherapy-treated patients compared with 46 months for the cystectomy-only group. (3) The 5-year actuarial survival was 43% in the cystectomy group, which was not significantly different from 57% in the chemotherapy-treated group (P=.06). The authors point out that their study is different from seven previous negative studies that used either single-agent cisplatin (demonstrated to be inferior to MVAC in measurable metastatic disease) or a two-drug combination.

It should be noted that it took 11 years to accrue 317 cases in 120 institutions, and during that lengthy time, diagnostic standards, patient care, including supportive care during chemotherapy, and surgery have all changed. Furthermore, some of the problems associated with large cooperative studies are evident. The authors state that central pathologic review was not possible in 46 cases because slides were not available, and that muscle invasion could not be confirmed in central review in 17 patients. Another concern is the wide 95% confidence P.1371


interval, 25 to 60 in the median survival of 46 months in the cystectomy group and 55 to 104 in the 77-month survival in the chemotherapy plus cystectomy group.

This clinical trial favors MVAC neoadjuvant chemotherapy over cystectomy only, but although this study alone does not yet make the case convincingly for neoadjuvant MVAC to be the declared standard treatment precystectomy in muscularis propria鈥搃nvasive bladder cancer, it would be reasonable on the basis of these data for urologists and medical oncologists to discuss the pros and cons of neoadjuvant MVAC with their patients precystectomy.

The Medical Research Council and the European Organization for the Research and Treatment of Cancer (EORTC), with Dr. R. R. Hall as coordinator, began in 1989 a prospective randomized trial of neoadjuvant cisplatin, methotrexate and vinblastine in patients undergoing cystectomy or full-dose external-beam radiotherapy for muscularis propria bladder cancer.97

It is important, in assessing the results of this study, to note that in 6 years 976 patients were recruited from more than 100 institutions in 20 countries. Further, of 491 patients assigned chemotherapy, 99 did not receive all three cycles for a variety of reasons, and 26% of patients required dose decreases or delay. Seventy-six of 561 patients did not undergo a planned cystectomy. 32.4% of patients underwent (optional) cystoscopy and biopsy after chemotherapy, and the biopsy confirmed endoscopic CR in 44%.

This represented the largest randomized trial of neoadjuvant cisplatin-based chemotherapy for muscularis propria鈥搃nvasive bladder cancer. The study was powered to detect a 10% improvement in survival, but the study results showed only a possible 5% difference in 3-year survival, and to confirm this benefit statistically would require 3,500 patients. They concluded, therefore, that although they observed a possible improvement in 3-year survival, 鈥渢his conclusion is not certain because this very large multicenter trial had sufficient power to detect only a larger survival benefit.鈥� We cannot conclude from this study鈥攁nd the authors do not suggest鈥攖hat neoadjuvant chemotherapy should be considered the new standard of care in the treatment of muscularis propria bladder cancer based on these data.

This Medical Research Council/EORTC study was updated in 2002 with a median follow-up of 7.4 years.98 The difference in 5-year survival between those who received chemotherapy (50%) and those who did not (44%) just reached clinical significance with a probability value of .048. The 7-year survival rates were 43% versus 37%. There was also an improved disease-free survival (P=.012). Based on their interpretation of the data as presented, Sharma and Bajorin99 stated that a significantly improved survival was seen in all patients receiving chemotherapy. Overall survival was superior for patients who received chemotherapy at 3 years (55% vs. 50%), 5 years (50% vs. 44%), and 8 years (43% vs. 37%), with a median follow-up of 7 years. There was also an improved disease-free survival (P=.012) and locoregional progression-free survival (P=.003).

A third randomized trial, the Nordic Cystectomy Trial 1, provides support for the value of neoadjuvant chemotherapy.100 Patients were treated with two cycles of neoadjuvant doxorubicin and cisplatin. All patients received 5 days of radiation followed by cystectomy. A subgroup analysis was performed and showed a 20% difference in disease-specific survival at 5 years in patients with T3 and T4 disease, but there was no difference in stages T1 and T2, nor a difference when all entered patients were compared.

The Nordic Cystectomy Trial 2 included only stage T3鈥揟4a patients in an attempt to confirm the positive results in Nordic I in this subgroup of patients.101 This trial eliminated radiation therapy and substituted methotrexate for doxorubicin in order to lower toxicity. In 317 patients studied, no survival benefit was noted in the chemotherapy arm. The authors concluded that despite substantial downstaging, no survival benefit was seen with the neoadjuvant chemotherapy after 5 years of follow-up.

Raghavan et al.102 published a meta-analysis of all completed randomized trials. of neoadjuvant chemotherapy for invasive bladder cancer. Their analysis, comprising 2,688 patients, led the authors to the following conclusions: single-agent neoadjuvant chemotherapy is ineffective and should not be used; current combination chemotherapy regimens improve the 5-year survival by 5%, which reduces the risk of death by 13% compared with the use of definitive local treatment alone (i.e., from 43% to 38%). Although each of the studies cited here were adequately designed and sufficiently powered to settle the question as to whether neoadjuvant chemotherapy should be considered the new standard of care in invasive bladder cancer, a careful review of all of the published material on this subject suggests the following conclusion: Although the published data on neoadjuvant chemotherapy do not meet the required standard to declare neoadjuvant chemotherapy the new standard of care in muscularis propria bladder cancer, the data in support of benefit are sufficiently compelling that patients should be informed of the potential benefits versus the risks of neoadjuvant chemotherapy as part of the discussion leading to a decision to proceed with cystectomy.

Two additional meta-analyses have been published.103,104 Both of these showed a 4% to 6% absolute increase in 5-year survival, and Black et al.94 stated that when 鈥渋ncluding only studies employing combination chemotherapy, the effect increased to a 5% to 7% improvement in survival.鈥�

Black et al.94 make the case for risk-adapted neoadjuvant chemotherapy, that is, offering neoadjuvant chemotherapy to patients who are at highest risk and most likely to respond to treatment. In this context, risk is determined by 鈥渢he anatomic extent of disease, the tumor biology, the tumor grade, the histologic subtype and biomarkers 鈥� The extent of disease includes size, clinical TNM stage, location in the bladder, ureteral obstruction 鈥� and extravesical extension.鈥� A surrogate end point of major importance is the achieving of a complete pathologic response to neoadjuvant chemotherapy (pTo). Pathologic CR has been assessed in several trials with cisplatin-based combinations showing pTo rates of 14% to 38%. In a meta-analysis by Winquist et al.,105 pTo status was the only factor independently predictive of overall survival in multivariate analyses of four trials (786 patients).

The question to be answered by future studies is whether a regimen that produces high rates of pTo in the neoadjuvant setting will result in higher rates of long-term cure postcystectomy.

Molecular Markers in Neoadjuvant Chemotherapy

Takata et al.106 studied gene expression profiles from biopsies prior to neoadjuvant MVAC and identified 14 genes that were expressed differently in responders and nonresponders. The P.1372


p53 gene, angiogenesis factor expression (VEGF), EGFR, HER-2/new protein, and lymphovascular invasion have all been examined retrospectively, but the true significance of these and other factors must await results from large prospective studies.

Adjuvant Chemotherapy

The obvious advantage of adjuvant, as opposed to neoadjuvant chemotherapy, is that pathologic staging allows for a more accurate selection of patients. This approach facilitates the separation of patients in stage pT2 from those in stages pT3 or pT4 or node-positive disease, all at a high risk for metastatic progression. The major disadvantage is the delay in systemic therapy for occult metastases while the primary tumor is being treated. It is not possible to assess response to treatment, as there is no clinical end point except for clinically detectable disease progression. Pathologic staging has been used to advantage in breast cancer and colon cancer, two diseases in which adjuvant chemotherapy has been demonstrated to increase disease-free survival. The parallel continues in that in breast cancer, colon cancer, and bladder cancer, drugs for use in the adjuvant setting have been selected on the basis of their demonstrated activity in advanced, measurable metastatic disease.

Adjuvant chemotherapy has been studied in two major clinical settings: (1) following bladder-sparing chemo-irradiation, and (2) following radical cystectomy. In the former case, it became clear in our early bladder-sparing studies that bladder cancer is a systemic disease, and simply rendering the bladder free of invasive cancer is not sufficient to prevent death from metastatic disease in the majority of patients whose bladders are sterilized by chemoirradiation.107 In our earlier studies, which used cisplatin alone as the radiosensitizing drug, the combination of methotrexate, vinblastine, and cisplatin (MCV), a total of three 28-day cycles was used as the treatment of choice for the adjuvant phase of treatment. The adjuvant regimen of choice in our later studies has consisted of four cycles of cisplatin plus gemcitabine. In our current study, the adjuvant regimen of choice consists of four cycles of cisplatin, gemcitabine, and paclitaxel, a potent and well-tolerated regimen in the treatment of metastatic disease.108

The results thus far of the contribution of adjuvant chemo-therapy in affecting survival in patients undergoing bladder-sparing treatment are uncertain.

The place of adjuvant chemotherapy postcystectomy has been studied, but the results are not clear, as several of the reported studies were small phase II studies using a variety of chemotherapeutic regimens. Many of the early studies used drug combinations now little-used as combinations of newer drugs have come to the forefront. Investigators generally agree that in the face of positive nodes and even with negative nodes and high pathologic stage of the primary tumor, adjuvant chemotherapy is likely to be important in improving survival. In reviewing existing reports of adjuvant trials in bladder cancer, there are five randomized trials using adjuvant chemotherapy.109,110,111,112,113

As reviewed by Sharma and Bajorin,99 three studies found no difference between adjuvant chemotherapy and cystectomy alone, but all three were seriously flawed in design and/or accrual. Two of the five studies112,113 showed a survival benefit for cystectomy and adjuvant chemotherapy over cystectomy alone, but the first is subject to criticism for both method considerations and small accrual. Unfortunately, method and accrual issues bear on the second study's validity as well.

Nonetheless, in a follow-up report by Stockle et al.114 an analysis of 166 patients including the 49 initially randomized patients, difference was noted in the 80 patients who received adjuvant chemotherapy as compared with 86 patients who underwent cystectomy alone. The extent of nodal involvement proved important, and when patients were stratified by the number of nodes involved, adjuvant chemotherapy was most effective in patients with N-1 disease.

The group at M. D. Anderson Cancer Center conducted a trial comparing two cycles of neoadjuvant MVAC and three cycles of postcystectomy MVAC versus five cycles of adjuvant MVAC.115 No difference in survival was noted, but 40% of patients given two cycles of neoadjuvant MVAC had no evidence of muscularis propria disease (pTo). The overall cancer-free survival rate was 58% with a follow-up of 6.8 years. This trial had the largest fraction of truly poor risk patients, as patients with clinical stage T2 were excluded. By the study design, this clinical investigation does not provide a comparison between neoadjuvant and adjuvant treatment, as all patients received some adjuvant chemotherapy.

Several phase III trials of adjuvant chemotherapy have been reported during the past decade. The first randomized trial,112 reported first in 1991, concluded that there was a modest disease-free survival in node-positive patients following cystectomy treated with the combination of cyclophosphamide, doxorubicin, and cisplatin. As with several other reported adjuvant studies, including those by Stockle et al.113 and Freiha et al.,111 reported adjuvant studies have been hampered by small numbers of patients. The vital question of the usefulness of adjuvant chemotherapy is now being tested in an EORTC/intergroup trial appropriately designed and powered to settle the issue. In this trial, patients will be randomized to receive adjuvant chemotherapy, standard-dose MVAC, high-dose MVAC, or gemcitabine/cisplatin, after cystectomy for muscularis propria鈥搃nvasive bladder cancer versus observation. This study, to accrue more than 1,300 patients, will evaluate four cycles of immediate chemotherapy versus therapy at the time of relapse in patients with pT3鈥攑T4 tumors or with node-positive disease. The chemotherapy regimens will be used at the choice of the individual investigator.

Another important adjuvant trial is underway, which is an example of the convergence of biologic predictors and chemotherapy in the search for improved treatment of bladder cancer. This is a multi-institutional SWOG phase III trial, sponsored by the National Cancer Institute and led by the University of Southern California.116 The purpose of the study is to evaluate the therapeutic and prognostic significance of altered p53 expression by the tumor p53 following radical cystectomy in patients whose tumors are pT1 or pT2 and assessed for p53 status. For patients with p53-negative tumors, the treatment is observation. For those with p53-positive tumors, the patients are randomized to MVAC or observation. The possible significance of other genes, including p21, pRB, c-erb, Bcl-2, and others may prove to be important as relates to prognosis and possible benefit for chemotherapy following cystectomy.

In an important review of the current status of adjuvant chemotherapy in muscle-invasive bladder cancer, the Advanced Bladder Cancer Meta-analysis Collaboration examined 491 patients from six trials, representing 90% of all patients randomized in cisplatin-based combination chemotherapy trials. They concluded that there is insufficient evidence on which to base reliable treatment decisions, and they recommended further P.1373


research.117 The EORTC-30994 is large enough and appropriately designed to lead to valid conclusions and the results of that study are awaited. The authors recommend 鈥渆xtensive participation of urologists in ongoing and future randomized trials [of adjuvant chemotherapy].鈥�

Until the completion of a well-designed and well-executed clinical trial(s), sufficiently powered to settle the question, the place of adjuvant chemotherapy will necessarily remain uncertain. The place of newer drug combinations, already determined to be active in advanced bladder cancer, remains to be determined.

Combined Modality Treatment of Locoregionally Advanced Disease

The place of combined modality therapy for advanced disease has not been settled. Dodd et al.118 presented data demonstrating an improvement in long-term survival in selected patients undergoing resection of persistent cancer deposits after MVAC or CMV (cisplatin, methotrexate, and vinblastine). In their original series, the Memorial Group reported that 13 patients who had complete resection of viable tumor postchemotherapy had a median survival of 25 months, and some of those patients survived longer than 5 years. Other investigators have reported similar results.119

In our experience, carefully selected patients with locally advanced unresectable bladder cancer, including some patients with pelvic nodal masses, may experience long-term survival with the combination of chemotherapy and radiation. To be selected for this combined modality treatment patients had to have (1) an excellent performance status, (2) locally advanced measurable disease, (3) a normal hemogram and kidney function tests, and (4) no evidence of distant metastases beyond the common iliac lymph nodes. The initial treatment consisted of four to six cycles of combination chemotherapy, usually MCV, and less commonly gemcitabine-cisplatin. If significant regression of tumor was achieved, radiation treatment was administered in combination with radiosensitizing chemotherapy, usually cisplatin-paclitaxel. Gemcitabine was not generally used in the program because of the problems associated with the exquisite radiosensitizing properties of gemcitabine, with severe reactions seen with the usual therapeutic doses of gemcitabine when administered concurrently with radiation. When gemcitabine was used in the neoadjuvant part of the program, we avoided gemcitabine-radiation interactions by using a waiting period of at least 2 months from the completion of gemcitabine treatment to the start of radiation.

These patients were carefully selected, but in the majority of patients so treated, excellent tumor shrinkage and long-term survival was achieved in patients who would otherwise have been expected to succumb within a median time of 24 months if treatment had consisted of chemotherapy alone. These results must now be subjected to phase II and phase III studies if they are to merit wider usage.

Quality of Life After Cystectomy or Bladder Preservation

Evaluating the quality of life in long-term survivors of bladder cancer has been difficult and only recently have attempts been made to assess this in an objective and quantitative fashion.120鈥�130. A number of problems arise in the interpretation of the published studies. Tools to assess quality-of-life variables were developed early for common prostate and gynecologic cancers but no such instruments exist for bladder cancer. The instruments now used in bladder cancer are thus adaptations of uncertain validity. The published studies are all cross-sectional and patients have follow-up of varying lengths. This may matter in a surgical series in which functional outcome improves with time and a radiation series in which it may deteriorate. All studies are hampered by incomplete accrual of all potential participants. It is never clear whether the nonparticipants are those who have had a worse outcome or are the most satisfied. Despite these limitations, some conclusions can now be drawn.

Radical cystectomy causes changes in many areas of quality of life, including urinary, sexual, and social function, daily living activities, and satisfaction with body image.120,121,122,123,124,125,126 Sexual function has been particularly emphasized because of the high prevalence of erectile dysfunction. Researchers have, during the last decade, concentrated on the relative merits of continent and noncontinent diversions. Available data have been mixed with some groups, surprisingly, reporting few differences between the quality of life of those with an ileal conduit and those with continent diversions. Until recently, little comparative data have been available on those who have neobladders. Hart et al.124 have compared outcome in cystectomy patients who have either ileal conduits, cutaneous Koch pouches, or urethral Koch pouches. Of 1,074 patients undergoing cystectomy for bladder cancer at the University of Southern California, 368 were eligible for study because they were alive, spoke English, and had no major health issues that could affect global quality of life. Sixty-one percent of these completed self-reporting questionnaires. Regardless of the type of urinary diversion, the majority of patients reported good overall quality of life, little emotional distress, and few problems with social, physical, or functional activities. Problems with their diversions and with sexual function were the most commonly reported. After controlling for age, no significant differences were seen among urinary diversion subgroups in any quality-of-life area. It might be anticipated that those receiving the urethral Koch diversions would be the most satisfied and the explanation why this is not so is unclear. It may be that the subgroups were too small to detect differences, but perhaps it is more likely that each group adapts in time to the specific difficulties presented by that type of diversion.

More recently Porter and Penson125 attempted a systematic review of the literature testing the premise that continent diversions result in improved health-related quality-of-life outcomes. Of 378 articles on this subject published in English during 3 decades, only 15 employed appropriate instruments and had sufficient follow-up of these, and only 1 evaluated outcome in a prospective fashion. They concluded that, whatever our assumptions, there is no literature to support the use of one urinary diversion over another. A second review by Gerharz et al.126 of the world's literature came to the same conclusion.

Zietman et al.127 have performed a study on patients treated with TURBT, chemotherapy, and radiation for muscularis propria鈥搃nvasive bladder cancer at the MGH. Of 221 patients with clinical stages T2-4a cancer of the bladder treated at the MGH from 1986 to 2000, 71 were alive with their native bladders and disease-free in 2001. These patients were asked to undergo a urodynamic study and to complete a P.1374


quality-of-life questionnaire. Sixty-nine percent participated in some component of this study with a median time from trimodality therapy of 6.3 years. This long follow-up is sufficient to capture the majority of late radiation effects. Seventy-five percent of patients had normally functioning bladders by urodynamic studies. Reduced bladder compliance, a recognized complication of radiation, was seen in 22% but in only one third of these was it reflected in distressing symptoms. The urodynamic study in 2 of 12 women showed bladder hypersensitivity, involuntary detrusor contractions, and incontinence. The questionnaire showed that bladder symptoms were uncommon, especially among men, with the exception of control problems. These were reported by 19%, with 11% wearing pads (all women). Distress from urinary symptoms was half as common as their prevalence. Bowel symptoms occurred in 22% with only 14% recording any level of distress. The majority of men retained sexual function. Global health-related quality of life was high. The great majority of patients treated by trimodality therapy therefore retain good bladder function. It was concluded that there is a small but detectable level of lasting bowel dysfunction and distress and that this might be judged the additional price that these patients have had to pay to retain their bladders for a higher chance of sexual potency.

A recent study reported by Herman et al.128 showed that when low doses of gemcitabine are used as an alternative radiation-sensitizer to cisplatin, then treatment is very tolerable as measured by protocol completion and by the prospective use of the Functional Assessment of Cancer Therapy鈥揃ladder (FACT-BL) questionnaire. This may be important as a significant proportion of patients will subsequently need cystectomy despite an attempt at organ-conservation and need to be in the best possible physical shape for this.

Two cross-sectional questionnaire studies, one from Sweden and one from Italy, have compared the outcome following radiation with the outcome following cystectomy.129,130 The questionnaire results for urinary function following radiation were very similar to those recorded in the MGH study. More than 74% of patients reported good urinary function. Both studies compared bowel function in irradiated patients with that seen in patients undergoing cystectomy. In both, the bowel symptoms were greater for those receiving radiation than for those receiving cystectomy (10% vs, 3% and 32% vs, 24%, respectively) but in neither was this statistically significant.

In the assessment of sexual function, most women in the MGH study preferred not to answer the questions and no data were therefore available for them. Almost all men, however, did. In contrast to patients who have been irradiated for prostate cancer, the majority of male bladder-sparing patients reported adequate erectile function (full or sufficient for intercourse), and only 8% reported dissatisfaction with their sex lives. These findings are in line with those obtained in the Swedish and Italian series in which 38% and 25% of men retained useful erections as compared with 13% and 8% of cystectomized controls. The MGH series allowed the use of sildenafil, which probably contributed to the better outcome.

Metastatic Bladder Cancer

An estimated 12,500 deaths per year in the United States are due to metastatic bladder cancer.131 Initial spread of bladder cancer most typically is to pelvic lymph nodes. Through lymphatic and hematogenous means, bladder cancer can then metastasize to distant organs, most commonly the lungs, bone, liver, and brain. The prognosis of metastatic bladder cancer, as with other metastatic solid tumors, is poor, with a median survival on the order of only 12 months. Nevertheless, since the discovery that platinum-containing agents have significant antitumor effect in bladder cancer, there has been great interest in the use of chemotherapy for advanced disease.

Compared with other solid-tumor malignancies, transitional cell cancer is particularly chemosensitive. In phase II clinical trials, radiographic response rates may be as high as 70% to 80%, and in phase III clinical trials, response rates are often on the order of 50%. This compares favorably to other solid malignancies, such as lung, prostate, or breast cancer, which typically have much lower response rates in phase III studies. Moreover, a small but substantial minority of responding patients manifest a CR, and among these patients some long-term, durable responses are observed. Overall, however, the duration of response in TCC is short, with a median of 4 to 6 months, and therefore the impact of chemotherapy on survival has been disappointing. As newer targeted agents come into clinical practice, the hope is that their incorporation into treatment regimens will lengthen duration of response and ultimately translate into a real change in survival among patients with advanced TCC.

Cisplatin

In 1976, a series of 24 patients with bladder cancer treated with single-agent cisplatin was reported.132 The investigators observed eight partial responses in addition to four minor responses. Fourteen of the subjects were chemonaive patients, and all eight responders were in this group. Subsequent studies confirmed the activity of cisplatin in TCC, although the response rate to single-agent cisplatin has been lower than that of cisplatin-containing combination therapy.133,134Thus, most subsequent studies have explored combination regimens.

Cisplatin-Based Combination Chemotherapy

The standard chemotherapy regimen for advanced bladder cancer for more than a decade was methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).135,136 MVAC is administered in 28-day cycles, with starting doses of methotrexate 30 mg/m2 (days 1, 15, and 22), vinblastine 3 mg/m2 (days 2, 15, and 22), doxorubicin 30 mg/m2 (day 2), and cisplatin 70 mg/m2 (day 2). Another commonly used regimen has been CMV, which omits the doxorubicin and has somewhat less toxicity.137 The MVAC regimen has superior activity to cisplatin alone,133,134 and to other cisplatin-containing regimens.138 The response rate to MVAC is 40% to 65%,134,135,139 and there is improved progression-free and overall survival compared with either single-agent cisplatin or cisplatin, cyclophosphamide, and doxorubicin. Complete response is seen in 15% to 25% of patients, with an expected median survival of 12 months.133,134,135,136,137,138(Table 40.4.8).

Table 40.4.8 Standard Cisplatin-Containing Regimens for Transitional Cell Carcinoma

Regimen Response
Agents (References)   Schedule Composite No. of Assessable Patients CR (%) RR (%) Median Survival (Mo)
MVAC (134,135,137) Methotrexate
Vinblastine
Doxorubicin
Cisplatin
30 mg/m2 d 1, 15, 22
3 mg/m2 d 2, 15, 22
30 mg/m2 d 2
70 mg/m2 d 2
374 12鈥�35 39鈥�65 12.5鈥�14.8
CMV (ref. 142) Cisplatin
Methotrexate
Vinblastine
70 mg/m2 d 2
30 mg/m2 d 1, 8
4 mg/m2 d 1, 8
104 10 36 7
GC (ref. 143) Gemcitabine
Cisplatin
1000 mg/m2 d 1, 8, 15
70 mg/m2 d 2
203 12 49 13.8
CR, complete response; RR, response rate.

On the negative side, MVAC is associated with substantial toxicity. This is a difficult chemotherapy regimen, and most P.1375


patients require dose adjustment at some point in their treatment. Toxic effects of MVAC in notable numbers of patients include neutropenia, anemia, thrombocytopenia, stomatitis, nausea, and fatigue.96,98,139 The majority of patients will experience grade 3 or 4 myelosuppression, and grade 3 or 4 gastrointestinal toxicity occurs in one third of patients. The rate of chemotherapy-induced fatality among patients with metastatic disease may be as high as 3%, most often due to neutropenic sepsis.139

Phase II studies have explored the use of gemcitabine and cisplatin together (GC) in metastatic bladder cancer.140,141 Gemcitabine (1,000 mg/m2) was administered on days 1, 8, and 15 every 4 weeks. Cisplatin was administered once every 4 weeks, either on day 1 or 2 (70 to 75 mg/m2), or weekly on days 1, 8, and 15 (35 mg/m2). In total, 116 patients were treated in the three studies with this doublet, with a response rate of 42% to 66% and a CR rate of 18% to 28%. Primary toxicity was hematologic, and was generally easily managed, with rare hospitalizations for febrile neutropenia and no toxic deaths.

Based on these encouraging results, GC was compared with standard MVAC in a multicenter phase III study.139,143 MVAC was administered as previously described, and GC was administered in 28-day cycles with gemcitabine 1,000 mg/m2 (days 1, 8, and15) and cisplatin 70 mg/m2 (day 2). Four hundred five patients were randomized to one of the two treatment arms, and the two groups exhibited similar characteristics, with slightly more adverse factors on the GC arm. Median survival was 14.0 months with GC and 15.2 months with MVAC, which were statistically comparable. Median progression-free survivals were 7.7 and 8.3 months with GC and MVAC, respectively. Adjusted for prognostic factors, the hazard ratios were 0.99 for overall survival and 1.01 for progression-free survival.143

Table 40.4.9 Phase II Trials of Taxane-Containing Chemotherapy Regimens

Regimen Composite No. of Patients Response Rate (%) Median Survival (Mo) Reference(s).
Carboplatin/paclitaxel 104 21鈥�65 8.5鈥�9.5 148,149,151
Cisplatin/paclitaxel 52 50 10.6 146
Cisplatin/docetaxel 129 52鈥�60 8.0鈥�13.6 144,145,147
Cisplatin/gemcitabine/paclitaxel 61 78 15.8 157,162
Carboplatin/gemcitabine/paclitaxel 49 68 14.7 160
Cisplatin/gemcitabine/docetaxel 35 66 15.5 159
Gemcitabine/paclitaxel 94 54鈥�60 14.4 152鈥�154

In contrast, patients treated with GC had significantly less toxicity and improved tolerability. Toxic deaths (1% vs. 3%), neutropenic fevers (2% vs. 14%), grade 3/4 neutropenia (71% vs. 82%), grade 3/4 mucositis (1% vs. 22%), and alopecia (11% vs. 55%), were all lower in the GC group. Patients receiving GC gained more weight, reported less fatigue, and had better performance status than patients receiving MVAC. As a result of this study, GC is generally considered the current standard of care for metastatic bladder cancer.

Taxane- and Platinum-Containing Regimens

The addition of taxanes to cisplatin-based regimens has been the subject of numerous phase II trials in bladder cancer (Table 40.4.9). The doublets of cisplatin/paclitaxel and cisplatin/docetaxel appear to have response rates comparable to that of GC.144,145,146,147 Trials with carboplatin suggest that this agent has good activity, although likely not the same level of activity as cisplatin. P.1376


In a study of 33 patients treated with carboplatin/paclitaxel, the response rate was 57%, with median survival of 12 months.149 When the same doublet was studied in the second line in 54 patients previously treated with cisplatin-containing regimens, the overall response rate was 16% and median survival was 6 months. A randomized phase II study treated 110 previously untreated patients with either GC or carboplatin/gemcitabine.150 The response rate was 49% for GC versus 40% for carboplatin/gemcitabine, and median survival was 12.8 months for GC versus 9.8 months for carboplatin/gemcitabine. Safety and tolerability were comparable.

A phase III trial compared MVAC with carboplatin and paclitaxel.151 Unfortunately the study failed to reach its accrual goal, and a total of 85 patients were randomized. No significant differences in efficacy were seen in the underpowered analysis, but the MVAC group compared with the carboplatin/paclitaxel group exhibited a trend toward higher response rate (36% vs. 28%), progression-free survival (8.7 vs. 5.2 months), and overall survival (15.4 vs. 13.8 months). Quality-of-life measures were the same in the two groups.

Omission of platinum completely has been studied as well. The doublet of gemcitabine and paclitaxel appears to have good activity, with phase II studies suggesting that this regimen has response rates and survival comparable to GC, with minimal toxicity.152,153,154 We have also seen instances of long-term durable CRs with this doublet.155 Gemcitabine/paclitaxel may be a reasonable regimen to consider in patients unfit for platinum therapy. Gemcitabine and docetaxel has been studied as well, with early results demonstrating a response rate of 33% and median survival of 12 months in a trial of 27 patients with advanced TCC.156

Triplet Chemotherapy

Because of the activity of each of these agents in TCC, investigators have asked whether triplet combinations of platinum, taxanes, and gemcitabine might have increased activity. Three such studies, with cisplatin/gemcitabine/paclitaxel,157 carboplatin/gemcitabine/paclitaxel,158 and cisplatin/gemcitabine/docetaxel,159demonstrated high CR rates of 28% to 32%, and overall response rates of 66% to 78%. A majority of patients in these studies did not have visceral metastases. A second study of carboplatin/gemcitabine/paclitaxel showed a more modest response rate of 43% and overall survival of 11 months in a more typical population of metastatic TCC.160 Because 5-FU is also an active agent in TCC, a triplet of paclitaxel, cisplatin, and infusional high-dose 5-FU with leucovorin was studied in 44 patients. The response rate was 75%, with 28% CRs, and the median overall survival was 17 months. Significant toxicity included frequent myelosuppression, gastrointestinal disturbances, infections, and two treatment-related deaths.161

A randomized phase II study among 85 patients has studied GC versus cisplatin/gemcitabine/paclitaxel, with comparable response rates of 43% and 44%, and overall survival of 12 versus 14 months.162 Experience from larger studies will be required to determine whether addition of paclitaxel to GC has a substantial impact on overall survival.

Biologic Agents

The enthusiasm engendered by development of novel biologic agents targeted against tumor-specific growth factor pathways or angiogenesis has been fortified in recent years by positive studies in a variety of solid tumors. Two classes of agents that may be of interest in TCC are inhibitors of epidermal growth factor receptors (EGFR), including EGFR1 and EGFR2 (HER2/neu), and inhibitors of vascular endothelial growth factor (VEGF) or its receptors. There is ample preclinical evidence that many bladder tumors express members of the EGFR family, that overexpression may correlate inversely with prognosis, and that inhibition of these pathways may have an antitumor effect.45,46,47,48,49,50,51 A number of groups are conducting studies with inhibitors of EGFR1 and/or HER2/neu in the treatment of advanced bladder cancer. Similarly, the utility of angiogenesis inhibitors in TCC will be explored in upcoming years.

Section Summary

Our understanding of cancer of the urinary bladder is in a state of evolution, with important advances in our appreciation of multiple risk factors, strategies of prevention, and possibly earlier detection through screening. Superficial bladder cancer accounts for the majority of patients at presentation, and although it uncommonly progresses to muscularis propria鈥搃nvasive disease, it is difficult to eradicate by local treatment. The mainstay of treatment following TURBT is the by intravesical route, either by one of several chemotherapeutic agents, or BCG, with BCG the initial treatment of choice of most urologists with or without alpha interferon. For muscularis propria鈥搃nvasive disease, there have been improvements in surgical techniques, including continent diversions and neobladders, which have the potential of improving quality of life for patients. Bladder-preservation approaches, while still under study in the interest of improving results and limiting side effects, are now moving into the mainstream of treatment with results in comparable patients equal to those achieved by radical cystectomy, and with increasing numbers of patients expressing an interest in organ-sparing treatment. Quality-of-life considerations have come to the forefront in the care of patients with bladder cancer, much as they have in other cancers, and there are now some important scientific data documenting the quality of life following cystectomy as well as with bladder-sparing treatment.

Whether bladder-sparing or cystectomy is used as local treatment, combined modality approaches are essential if treatment is to be optimal. Neoadjuvant chemotherapy has been carefully studied and appears to be of value in improving survival, although further studies will be necessary before this combined approach can be considered standard treatment. For adjuvant treatment, the data are much less convincing. The results of studies recently begun using newer drug combinations may help to establish the role of adjuvant chemotherapy in improving survival.

In advanced (metastatic) disease, platinum-based regimens such as cisplatin and gemcitabine remain the standard therapy for advanced disease. The addition of taxanes to the initial regimen or as second-line therapy may provide further activity, and hopefully lead to prolonged survival. Nevertheless, overall survival remains poor in metastatic disease, and newer therapies such as targeted agents against tumor-specific growth factor pathways are needed to effect real advances in our treatment of this disease.

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Cancers of the Renal Pelvis and Ureter

The majority of tumors of the upper urinary collecting system are TCCs. However, these are uncommon tumors, with fewer than 3,000 cases diagnosed annually in the United States. Because of the difficulty in gaining access to the tumors in the upper urinary tract and their relative rarity, the diagnostic and staging maneuvers are more problematic and less accurate than for the TCCs of the bladder. Histologically, 90% of upper tract tumors are TCC. Squamous cell carcinoma accounts for nearly all of the remaining 10%. There is a predilection for these tumors to arise in the renal pelvis; primary tumors of the ureter occur only half as frequently as do tumors of the renal pelvis.163 Men develop upper tract TCC two to three times more than women, with the peak age of development of these tumors in the seventh and eighth decades of life.164 As discussed in the first section of this chapter, the majority of these tumors arise as a result of, or at least are associated with, environmental exposures and stresses.6,7,8,15

Clinical Presentations, Diagnosis, and Staging

Gross hematuria is the presenting symptom in 75% to 95% of all patients presenting with tumors of the renal pelvis and ureter. Hematuria may be accompanied by colicky flank pain if the tumor or blood clots cause obstruction of the upper urinary tract. Patients often describe the passage of vermiform clots, which are unusual in bleeding from a lower tract source. Hydronephrosis may also be a presenting sign. Urinary cytology is an important part of the workup for an upper tract tumor. Voided urine cytology, though, has only a 10% to 40% sensitivity in the detection of low-grade TCC lesions. Cytology is far more useful for high-grade tumors, for which the sensitivity may be as high as 70%. For patients in whom a positive urinary cytology is found during evaluation, but neither diagnostic radiology nor cystoscopy identifies the source, selective barbotage (saline rinsing of the ureter and renal pelvis through retrograde catheterization of the ureter) for cytologic analysis is performed at the time of a cystoscopic procedure.165,166

Improvements in endoscopic technology with flexible fiber endoscopes allow the urologist to directly view and to obtain tissue in many of the TCCs of the ureter and renal pelvis. Pathologic confirmation of the cell type of upper tract tumors may be obtained prior to treatment.

After diagnosis of the presence of an upper tract TCC, careful radiographic evaluation is important in determining tumor extent and stage. Intravenous urography had been the mainstay of radiographic evaluation of upper tract tumors because it gives a detailed image of the entire renal collecting system and the ureter, but now in most major centers helical CT scan is the preferred imaging method167 (Fig. 40.4.5). MRI urography may also be useful in patients when sensitivity to iodinated contrast prevents the use of that agent.168 For patients with poor renal function or in those who cannot tolerate intravenous contrast agents, retrograde pyelography is the preferred method of imaging. When a patient is found or judged to have a TCC more aggressive than a grade I and stage I tumor, more staging of the patient is indicated. Comprehensive staging includes chest CT as well as tomographic evaluation of the abdomen and pelvis for a possible hepatic or retroperitoneal lymph node metastases. Because standard therapy is radical excision of the kidney and the ipsilateral ureter, evaluation of the total remaining renal function prior to a proposed nephrectomy is indicated. Isotope renal scanning can accurately estimate the function of the uninvolved kidney.

. Abdominal computed tomographic scan of a stage T3 transitional cell carcinoma of the right renal pelvis, with intravenous contrast showing a large filling defect in the right renal pelvis (arrows).
Figure 40.4.5. Abdominal computed tomographic scan of a stage T3 transitional cell carcinoma of the right renal pelvis, with intravenous contrast showing a large filling defect in the right renal pelvis (arrows).

The current American Joint Committee on Cancer TNM staging for tumors of the upper urinary tract is shown in Figure 40.4.6 and in Table 40.4.10. The staging is determined by the extent of invasion by the primary tumor and by microscopic evaluation of the regional lymph nodes in high-grade tumors.

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Schematic diagram of the American Joint Committee on Cancer TNM staging of cancers of the renal pelvis. C, renal capsule; LP, lamina propria; M, muscularis propria; F., peripelvic fat; L, lumen.
Figure 40.4.6. Schematic diagram of the American Joint Committee on Cancer TNM staging of cancers of the renal pelvis. C, renal capsule; LP, lamina propria; M, muscularis propria; F., peripelvic fat; L, lumen.

Table 40.4.10 American Joint Committee on Cancer 2002 TNM Staging of Renal Pelvis and Ureter Cancers: Definition of TNM

Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Ta Papillary noninvasive carcinoma
Tis Carcinoma in situ
T1 Tumor invades subepithelial connective tissue
T2 Tumor invades the muscularis
T3 (For renal pelvis only) Tumor invades beyond muscularis into peripelvic fat or the renal parenchyma
T3 (For ureter only) Tumor invades beyond muscularis into periureteric fat
T4 Tumor invades adjacent organs or through the kidney into the perinephric fat.
Regional lymph nodes (N)a
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node 2 cm or less in greatest dimension
N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension or multiple lymph nodes; none more than 5 cm in greatest dimension
N3 Metastasis in a lymph node, more than 5 cm in greatest dimension
Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
aLaterality does not affect the N classification.
(From ref. 53, with permission.)

Surgical Treatment

The standard surgical treatment for patients with transitional cell cancer of the upper urinary tract of all grades and stages is radical nephroureterectomy. This involves a complete removal of the kidney with its surrounding perirenal fat contained within Gerota's fascia and en bloc removal of the ureter down to, and including, the portion of ureter within the urinary bladder (the ureteral orifice and the intramural ureter).169 A retroperitoneal lymph node dissection along the ipsilateral great vessel (the vena cava for right-sided tumors; the aorta for left-sided tumors) is performed for more complete surgical staging, especially for higher grade and invasive cancers (Fig. 40.4.7). When TCC of the renal pelvis invades the renal vein or the vena cava, an extensive surgical procedure including thrombus extraction or partial vena cava dissection may be required. Nephroureterectomy traditionally is performed through open surgical techniques. Common approaches employ either a single extended midline abdominal incision or nephrectomy via a thoracoabdominal incision and a separate incision in the lower abdomen to accomplish the distal ureterectomy with a cuff of the contiguous urinary bladder.

 Diagram of the kidneys, ureters, bladder, and retroperitoneal lymph nodes to demonstrate that a nephroureterectomy for upper tract transitional cell carcinoma requires complete excision of the distal ureter, including the portion within the wall of the bladder. The bladder here is open to reveal the distal ureter, which tunnels within the wall of the bladder.
Figure 40.4.7. Diagram of the kidneys, ureters, bladder, and retroperitoneal lymph nodes to demonstrate that a nephroureterectomy for upper tract transitional cell carcinoma requires complete excision of the distal ureter, including the portion within the wall of the bladder. The bladder here is open to reveal the distal ureter, which tunnels within the wall of the bladder.

Open surgical approach has been the standard of treatment for the majority of patients with tumors of the renal pelvis and ureter. Recent advances in technology and surgical technique have allowed a reduction in the morbidity from this procedure by using a laparoscopic surgical technique. An en bloc excision can be accomplished safely and effectively.170,171 The operative time and blood loss with the laparoscopic technique may be substantially less than those of an open surgical technique. With proper technique in resecting the distal ureter, laparoscopic nephroureterectomy is equally oncologically safe to open surgery.172 The hospital stay is also substantially reduced from a median of 6 days hospitalization for the open surgery group compared to an average of 2 days for the laparoscopic surgical group. Invasive TCC is known to have the capacity to seed the abdomen if spilled, allowing tumor implantation, and this has led to concern among surgical oncologists about the laparoscopic approach. One group has reported three cases of laparoscopic port-site recurrence; however, in all three of these cases, the tumor was spilled from the operative specimen, allowing growth of the tumor tissue at the trocar sites.173

In patients in whom radical excision of the tumor would result in severe renal insufficiency requiring dialysis (such as patients with a solitary kidney or in a patient with a substantially diminished renal function), other surgical therapies may be considered. Endoscopic resection techniques have been developed and P.1379


shown to be effective, when done selectively and in experienced hands.174 With current ureteroscope technology, it is possible to ablate small tumors of the ureter, particularly low-grade tumors, by fulguration or resection. TCCs of the renal pelvis and the calyceal system are more difficult to resect endoscopically. The success is of focal resection is thwarted by the common finding of multicentric tumors and the common concurrent existence of CIS.175 Improvements in electrosurgical instruments and the development of neodymium:yttrium aluminum garnet (Nd:YAG) laser technology have added to the urologists armamentarium for focal treatment of upper tract TCC.

Percutaneous endoscopic surgery of renal pelvic and calyceal TCC has been developed as a treatment option in highly select patients who have poor renal function or who medically could not withstand an open surgical procedure.176 Endoscopic access is gained percutaneously from the flank into the renal pelvis. Using standard endoscopic tools, it is possible to resect tumors in the fashion similar to that which is used for bladder tumors. Because of the technical complexity of these procedures, the risk of tumor seeding, and the difficulty of resecting all the microscopic foci of tumor, these procedures should be offered only to patients who have absolute contraindication to nephrectomy. All limited resection endoscopic procedures require vigilant follow-up with endoscopic re-evaluation on a regular schedule. Recurrence is very common.

A kidney-sparing approach may be advisable in selected cases of low-stage and low-grade distal ureteral tumors. Because recurrences and urothelial atypia are usually distal in the ureter to the index lesion, it is reasonable to spare the kidney without undue risk of recurrent disease. Surgically it is possible to remove approximately half of the distal ureter and reimplant it in the bladder. For upper ureteral tumors, replacement of the ureter with a segment of the ileum may be considered. Patients for whom this approach is appropriate are limited, and careful selection is mandatory.

Results of Surgical Therapy

The success rate of surgical procedures is primarily influenced by the pathologic stage of the disease at the resection. Tumors lower in the urinary tract have a better prognosis when matched by stage with tumor higher in the ureter and pelvis.177 The World Health Organization 1999 classification of grade offers the most accurate prognostic information.178 In a report with long follow-up from the University of Texas Southwestern Medical Center of 252 patients treated surgically for upper tract TCC, disease-specific and overall survival was strongly influenced by the pathologic stage of the primary tumor.179 The 5-year actuarial disease-specific survival rates by primary tumor pathologic stage were 100% for noninvasive tumors (Ta and Tis), 92% for pathologic stage T1, 73% for pathologic stage T2, and 41% for pathologic stage T3. There were no long-term survivors for those with stage T4 tumors (Table 40.4.11). The type of open surgical procedure used (nephroureterectomy in 77% of the patients compared with a kidney-sparing approach used in 17%) was evaluated by univariate and multivariate analysis. Patients undergoing nephroureterectomy were found to have a significantly improved recurrence-free and disease-specific survival on multivariate analysis but not on univariate analysis. However, in other series patients with ureteral cancers who were selected for kidney-sparing resections did not have a poorer outcome.

Table 40.4.11 Five-Year Disease-Specific Survival by Primary Tumor Pathologic Stage after Surgical Resection of Transitional Cell Carcinoma of the Upper Urinary Tract

Tumor Stage No. Percent
pTa/pTis 38 100
pT1 99 92
pT2 34 73
pT3 53 41
pT4 19 0
(From ref. 179, with permission.)

Adjuvant Topical Therapy Following Local Excision Only

In cases in which endoscopic resection is performed, topical immunotherapy or topical chemotherapy may be important in preventing or delaying local tumor recurrence. BCG appears to be useful in treating carcinomas of the upper tract that are stage Tis.175 Adriamycin given prophylactically following conservative resection of upper tract TCCs using an antegrade infusion also has been judged to be of some benefit in reducing recurrence.180 The risk of systemic absorption of BCG or the chemotherapeutic agents is substantially higher than in treatment of the bladder.

Adjuvant Combined-Modality Therapy: Advanced Primary Tumors

The most appropriate treatment for invasive transitional cell cancers of the upper urinary tract is nephroureterectomy. Despite aggressive surgery, cure rates are low when the disease has spread beyond the muscularis, with 5-year survival rates varying between 0% and 34%.180,181,182,183,184,185 Whether these low survival rates can be improved by adjuvant therapy depends on the pattern of failure and the efficacy of the available treatment. Metastatic relapse appears to predominate over local relapse and systemic cisplatin-based chemotherapy has been used, extrapolating from the experience with locally advanced bladder cancer. The true rate of locoregional failure is, however, unknown because many of the published series are old and employed pre-CT methods of intra-abdominal evaluation. The available data suggest an overall locoregional failure of 2% to 27%, although these figures may be an underestimate.186,187,188 Cozad et al.189report local failure rates of 50% in stage T3 disease, rising to 60% if the tumors were high grade. Brookland and Richter190 have reported locoregional recurrence in 45% and 62%, respectively. Most series report a close association between local failure and distant metastasis, although whether the association is causal or simply synchronous cannot be determined from the small numbers in the series.

Radiation has been employed as an adjuvant therapy with mixed results reported in the literature (Table 40.4.12). Several small phase II studies have suggested a local control and perhaps survival advantage for adjuvant radiation.191,192,193,194,195 One study reported no benefit, although their treated population was P.1380


diluted with 30% early-stage patients. Another study showed no advantage to radiation but the radiation doses given were inadequate. In others chemotherapy was given in addition. It is therefore difficult to determine the true benefit of adjuvant radiation, if any.

Table 40.4.12 Larger Published Series Using Surgery with or without Adjuvant Radiation for Carcinoma of the Upper Urinary Tract

Method/Study (Reference) No. of Patients Median Dose (Gy) Locoregional Failure % (Absolute) Overall 5-Year Survival (%)
Surgery + Radiotherapy
Ozsahin et al. (193) 45 50 38 (17/45) 21
Maulard-Durdux et al. (194) 26a 45 19 (5/26) 49 (T2, 60%; T3, 19%)
Catton et al. (195) 86b 35 34 (29/86) 43 (T3N0, 45%; N+, 15%)
Brookland and Richter(190) 11 50 9 (1/11) 27
Cozad et al. (189) 9 50 11 (1/9) 44
Czito et al. (191) 31 47 23 (7/31) 39 (67% in combined-modality group)
Surgery Only
Ozsahin et al. (193) 81   65 (53/81) 33
Cozad et al. (189) 17c   53 (9/17) 24
Brookland and Richter (ref. 190) 11   45 (5/11) 17
aThirty percent stage T2.
bTwenty-seven percent stage T1 to T2.
cAll stages 鈮3.

At the MGH a more aggressive approach has been taken during the last 20 years in which patients with high-risk disease were treated first with adjuvant radiation alone and then more recently with concomitant radiation-sensitizing chemotherapy and, if tolerable, further combination chemotherapy.191 Although our series of 31 patients is nonrandomized and small, we observed that local failure was lower if chemotherapy was combined with radiation (22% vs. 45%) and the survival rate at 5 years higher (67% vs. 27%) (Table 40.4.1). Kwak et al.,192 in a series of 43 nonrandomized patients, also suggested that cisplatin-based adjuvant chemotherapy may reduce the rate of relapse and death from disease at 5 years. The small size of these two series and the biases inherent in this kind of retrospective review make conclusions difficult to draw.

Very little published data exist to guide physicians managing patients with a local relapse following nephroureterectomy. If the relapse is bulky and metastases present elsewhere, then palliation with chemotherapy would be the most appropriate course. When the relapse appears isolated and the patient relatively vigorous, consideration can be given to an aggressive approach that holds out the chance for cure. The first step would be to downsize and perhaps improve the respectability of the recurrence using external radiation to a modest preoperative dose of 30 to 45 Gy along with sensitizing chemotherapy. An attempt could then be made at resection or debulking and, if the facility were available, intraoperative radiation could then be given directly onto the tumor bed or onto an unresectable mass with the bowel and other critical organs displaced out of the field. Such an approach allows the delivery of high doses of radiation to the target without the risk of bowel injury that is present when managing such disease using external radiation treatment alone (Fig. 40.4.8). This is a paradigm that has been used with considerable success for retroperitoneal sarcomas and locally advanced rectal cancer. Such cases are unusual and require individualized treatment that follows basic oncologic principles developed for other sites in the body. Multiple modalities are usually required and a strong case can be made for these patients to be managed in a multidisciplinary genitourinary oncology clinic.

Advanced Transitional Cell Carcinoma of the Upper Tract

Most patients with upper tract TCC have superficial disease, with a generally favorable prognosis.196,197 However, patients with disease that invades beyond the muscularis propria have a significantly worse prognosis. The most consistent prognostic variables for the outcome of patients with upper tract TCC, including renal pelvic and ureteral carcinomas, are tumor stage and grade.198,199,200,201 Molecular markers are being studied, and poor outcome may be predicted by overexpression of p53 and higher Ki-67 labeling index.202,203,204

In a series of 252 patients with mostly localized disease, relapse occurred in 67 patients (27%) after a median of 12 months.205 Survival was highly stage-specific, with 5-year disease-specific survival of 92% for T1, 73% for T2, 41% for T3, and 0% for T4. In a series of 126 patients with nonmetastatic but more advanced renal pelvic or ureteral tumors, relapsed disease was noted in 81 patients (64%) after a median of 9 months.193 Overall, 5- and 10-year survival rates were 29% and 19%, respectively. The most common sites of distant metastases were liver, bone, or lung. Utilization of postoperative radiation therapy did not impact on local or distant relapse. Factors that influenced survival outcome in multivariate analysis were initial tumor stage, residual postsurgery tumor, and location of initial tumor, with renal pelvic cancer being more favorable than ureteral cancer. The role of adjuvant chemotherapy in reducing relapse has not been explored in randomized fashion in this uncommon disease.

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 Sequential coronal magnetic resonance imaging (MRI) of a patient with an unresectable ureteral tumor mass.
Figure 40.4.8. Sequential coronal magnetic resonance imaging (MRI) of a patient with an unresectable ureteral tumor mass. The mass shown on the MRI on the left (arrows) was at the bifurcation of the aorta; it was initially judged unresectable because of involvement of the vessels. Partial resection, however, became possible as part of a combined-modality treatment approach that included preoperative conformal external-beam radiation. Intraoperative electron-beam radiation was given to the entire tumor bed after resection. On the right is the repeat MRI one year after treatment without any visible tumor.

The biology of upper tract TCC is considered to be identical to that of bladder TCC. Consequently, the chemotherapy regimens recommended for advanced or metastatic upper tract TCC are the same as that for bladder cancer, as previously described. Standard treatment is cisplatin-based combination therapy, such as gemcitabine and cisplatin or methotrexate, vinblastine, doxorubicin and cisplatin. As with bladder cancer, upper tract TCC is highly responsive to chemotherapy, but has a short median duration of response.

Section Summary

Tumors of the upper urinary tract are uncommon tumors, and less accessible than cancers of the bladder to accurate diagnosis, surgical identification, and effective local treatment. The epidemiology of these tumors, while generally similar to that of bladder cancer, exhibits some characteristics peculiar to these tumors.

Hematuria, the most common presenting symptom, is similar to that of bladder cancer, but the location of these tumors, much less accessible than tumors of the bladder, pose special problems for urologists in their attempts to locate these tumors precisely. Because urinary cytology is less useful in upper tract tumors than in bladder cancer, recent improvements in endoscopic technology allowing for the direct viewing of the ureters and renal pelvis are especially important, as are evaluations of the place of molecular tumor markers in diagnosis. Advances in radiologic studies are important, with the major improvement that of helical CT imaging.

Surgical treatment of upper tract tumors is in evolution, with new laparoscopic approaches likely to achieve wider usage as urologic surgeons in this country and abroad master this technique.

Despite aggressive surgery, cure rates of upper tract tumors are low, and both radiation and chemotherapy, often used in combination, may prove to be important in lengthening survival. The place of radiation and chemotherapy, however, has yet to be established. There is a paucity of published data to support this approach, and carefully planned studies are needed.

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