Current Management of Invasive and Metastatic Transitional Cell Carcinoma of the Bladder

0022-5347/93/1495-0957$03.00/0 THE JOURNAL OF UROLOGY Copyright © 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Vol. 149,957-972, May 1993

Printed in U.S.A.

Review Article CURRENT MANAGEMENT OF INVASIVE AND METASTATIC TRANSITIONAL CELL CARCINOMA OF THE BLADDER J. BRANTLEY THRASHER

AND

E. DAVID CRAWFORD*

From the Department of Surgery (Division of Urology), Duke University Medical Center, Durham, North Carolina and Division of Urology, University of Colorado Health Sciences Center, Denver, Colorado KEY WORDS:

bladder neoplasms; neoplasm metastasis; carcinoma, transitional cell

Transitional cell carcinoma of the bladder is the second most common malignancy of the genitourinary tract and the fifth most common cause of cancer deaths among American men more than 75 years old. The age-adjusted incidence of transitional cell carcinoma of the bladder has increased by 0.9% annually during the last 2 decades, with estimates of approximately 50,000 new cases of the disease diagnosed annually in the United States.1 Of these new patients approximately 10,000 will die of the disease. From the early 1970s to the early 1980s the 5-year survival percentage has improved from 61% and 36% to 76% and 53% in white and black patients, respectively.1 The modest improvement in survival in the face of an increasing incidence may be attributed to early diagnosis and referral, better patient selection, improved surgical technique and perioperative care, unidentified host variables and the biological nature of the neoplasm. Approximately 75 to 85% of the patients present with transitional cell carcinoma confined to the superficial mucosa of the bladder. The risk of recurrence in these patients is 75% but only 10 to 15% will have advanced invasive carcinoma of the bladder. The majority of these superficial lesions present little mortal threat, and are usually treated with initial transurethral resection and in selected cases topical chemotherapy or immunotherapy.2 Invasive disease comprises a spectrum of tumor diatheses that range from infiltration of the lamina propria to extension through the muscularis propria into the perivesical soft tissues. Recent literature has expressed some concern in classifying cancers of the bladder that invade the lamina propria (stage Tl) as purely superficiallesions. 3•4 High grade stage Tl tumors may progress to muscle invasion in 30 to 50% of the cases, exemplifying the more aggressive nature of many of these tumors.4 This level of invasion, therefore, may require a more aggressive approach than a stage Ta lesion, requiring early adjunctive cytotoxic intravesical therapy or possibly early radical cystectomy. Muscle invasion (stage T2) of any degree is the usual indication for recommending more radical therapy, such as definitive radiotherapy, cystectomy with pelvic lymphadenectomy, neoadjuvant or adjuvant chemotherapy, or combinations of these procedures. Select cases of more superficial tumors, such as those with high grade, diffuse carcinoma in situ and involvement of the prostatic urethra, in conjunction with a poor response to repeated transurethral resections and intravesical chemotherapy may also require

these forms of therapy. However, in most cases muscle invasion is the trigger point for more radical therapies. The fact that the neoplasm has breached the basement membrane and into the muscularis propria reflects a different biological potential with a propensity for metastases despite the depth of penetration. The management of invasive and metastatic bladder carcinoma is one of the most controversial and dynamic problems facing urologists today. A review of the contemporary management of this tumor diathesis is presented. DIAGNOSIS AND PREOPERATIVE EVALUATION

Patients with bladder carcinoma usually present with hematuria or irritative voiding symptoms. After first excluding urinary infection, voided urine is obtained for cytology studies and an excretory urogram (IVP) is performed to exclude upper tract lesions. This test is followed by cystoscopy. The advantage of performing the IVP before cystoscopy is that if the upper urinary tracts were not visualized adequately, retrograde ureteropyelograms can be performed at cystoscopy. The cystoscopic demonstration of bladder cancer or a report of positive cytology with radiographically normal upper tracts prompts the scheduling of transurethral resection of the bladder tumor and/or multiple biopsies with the patient under anesthesia. Preoperative evaluation includes an electrocardiogram, chest x-ray, and serum creatinine and liver function tests. Patients with an elevated alkaline phosphatase level undergo a 99~echnetium bone scan. If the tumOJ; appears to be invasive or involves a large portion of the bladder, preoperative computerized tomography (CT) of the abdomen and pelvis with contrast enhancement is obtained. CT will determine bladder wall thickening and aid in the staging of the bladder cancer by determining involvement of adjacent structures (that is pelvic side wall and occasionally involvement of the pelvic lymph nodes). Additionally, it will provide a baseline for later comparison. Recent studies have advocated magnetic resonance imaging (MRI) as a more sensitive mode of staging for bladder cancer.5•6 Other investigators have found no significant advantage of MRI over CT for staging purposes. 7 The 2 modalities have· similar staging characteristics and 1 or the other can be used as a radiographic staging modality. Once the patient is anesthetized, either vaginoabdominal in the female patient or rectoabdominal in the male patient, bimanual examination· is performed to determine the mobility of the bladder and extent of the tumor. When a bladder tumor is discovered a biopsy is performed and as much of the tumor that can be safely resected is removed. Adequate staging requires that the resection be deep enough to include the muscularis propria. All suspicious The views of the authors do not purport to reflect the position of lesions should be biopsied in a similar fashion, making note of the Army or the Department of Defense. * Requests for reprints: Division of Urology, University of Colorado the number, site and configuration of all lesions. We recomHealth Sciences Center, Campus Box C-319, 4200 East Ninth Ave., mend using a bladder diagram to document the location of the tumors. After thorough cystoscopic evaluation, transurethral Denver, Colorado 80262. 957

958

THRASHER AND CRAWFORD

resection and/or biopsies, laboratory studies, radiological evaluation and examination with the patient under anesthesia the disease can be clinically staged. Many urologists in the United States are currently moving toward the use of the tumor, nodes and metastasis staging system developed by the International Union Against Cancer: stage Tis-carcinoma in situ, stage TA-papillary noninvasive carcinoma (confined to mucosa), stage Tl-papillary tumor-lamina propria invasion, stage T2superficial muscle invasion, stage T3A-deep muscle invasion, stage T3B-invasion of perivesical fat, stage T4-invasion of contiguous viscera, and Nl-solitary pelvic nodal metastasis less than 2 cm., N2-1 or more pelvic nodes 2 or more cm. and 5 or less cm., N3-fixed pelvic mass or more than 5 cm. pelvic node and Ml-distant metastasis or nodes positive above the aortic bifurcation.8 SURGICAL THERAPY IN LOCALLY ADVANCED BLADDER CANCER

Surgical therapy for muscle invasive bladder cancer (stages T2 to T3), specifically radical cystectomy, constitutes the standard by which all other modes of therapy are judged. Optimal therapy, however, is yet to be determined. A review of contemporary surgical series is difficult due to problems with staging accuracy, attempting to compare the results of noncurrent surgical series to other modes of therapy and comparing studies with various levels of completeness of endoscopic resection. Transurethral biopsy results constitute the pathological portion of the initial staging in a patient with invasive bladder cancer. Several large series have currently shown that clinical stage often does not correlate with pathological stage. As much as 50 to 60% of the cases will be either understaged or overstaged with initial clinical staging.9 In a review of 4 large series in the literature 35% of the cases were clinically understaged and 23% were clinically overstaged.9 It is apparent that transurethral resection cannot accurately assess the depth of tumor invasion in all cases. In addition, some resectionists simply perform biopsy, while others may attempt to resect the lesion completely. In any case, complete pathological staging would require a full thickness specimen of bladder wall that would have to be obtained with an open procedure. Transurethral resection. Transurethral resection is the most conservative surgical approach to invasive bladder cancer and has been shown to exert a therapeutic effect in patients who undergo complete local tumor resection. 1O- 16 The impact of transurethral resection on muscle-infiltrating bladder cancer is addressed in table 1. In 1951 Flocks reported 5-year survival rates of 56% and 43% for stages Bl (superficial muscle invasion) and B2 (deep muscle invasion) tumors, respectively.lO Barnes et al reported a slightly lower overall 5-year survival rate of 31 % for stages Bl and B2 tumors combined treated with transurethral resection.14 More recently, Herr reported the Memorial Sloan-Kettering Cancer Center (MSKCC) experience with the conservative management of 217 consecutive patients with muscle-infiltrating bladder cancer.15 Within 2 to 3 weeks of referral the disease was restaged by bimanual examination with the patient under anesthesia, urine cytology and repeat resection of the lesion. An attempt was made to TABLE 1. Reported 5-year survival rates following transurethral

resection for muscle-infiltrating bladder cancer Clinical Stage

Reference Flocks'O Milner" Barnes et al" O'Flynn et al" Barnes et al14 Herr" Henry et al'·

B1

B2

B1 andB2

28/50 (56) 37/65 (57)

40/92 (43) 10/23 (43)

60/101 (59)

4/21 (20)

26/37 (70) - / - (63)

4/7 (57) - / - (38)

68/142 (47) 47/88 (53) 46/114 (40) 64/123 (52) 23/75 (31) 30/44 (68) 23/43 (55)

Values are reported as number of patients/total (%).

resect completely all abnormal regions in the tumor bed using transurethral resection. Of the 217 patients 172 (79%) were judged to have invasive tumors not amenable to local excision and, therefore, they underwent total or partial cystectomy. A total of 45 patients (21%, 37 with stage T2, 7 with stage T3A and 1 with stage T4 disease) underwent conservative management because restaging revealed no residual tumor (stage To) in 20, carcinoma in situ in 17, stage Tl tumor in 4 and local stage T2 cancer in 4. Of the 45 patients 30 (67%) are reported free of disease with followup of slightly more than 5 years. Repeated transurethral resection with or without intravesical therapy for recurrent superficial tumor was required in 21 patients and no further treatment was needed in 9. Of the 15 failures 11 required cystectomy for subsequent development of muscle-infiltrating tumor (8) or superficial bladder tumors refractory to conservative measures (3). Of the 11 patients 7 are free of disease and 4 died of bladder cancer. The overall disease-free survival was reportedly 82% and for those with a functioning bladder it was 67%. Henry et al recently reported on 114 patients with initial diagnosis of stage T2 or T3A disease placed retrospectively within 1 of 4 treatment groups: group I-transurethral resection alone (43), group 2-6,500 to 7,500 rad radiation therapy alone (16), group 3-radical cystectomy alone (15) and group 4-4,000 to 6,000 rad preoperative irradiation in 4 to 6 weeks followed by radical cystectomy (40).16 The reported 5-year cancer-specific survival rates for stages T2 and T3A tumors, respectively, were 63% and 38% in group 1, 53% and 11% in group 2, 33% and 25% in group 3, and 48% and 54% in group 4. The stage, grade, number and size of the largest tumors were not significantly different. They concluded that transurethral resection of muscle-invasive bladder tumor yielded similar longterm survival results when compared to more radical therapy, such as cystectomy with or without radiotherapy. These conclusions are overly optimistic. A review of the previously noted literature revealed that overall results for transurethral resection alone for muscle-infiltrating bladder cancer are inferior to results obtained with radical cystectomy and are generally characterized by a high local failure or recurrence rate. Clearly, however, some patients benefit from complete local tumor resection as shown by Herr when 20 of his 217 patients (9%) achieved a complete response based on cystoscopic reevaluation and repeat resection of the tumor bed or endoscopically abnormal regions. Therefore, restaging and vigorous repeat resection with the identification of no persistent muscle-infiltrating tumor may select a subset of patients who can be managed with close surveillance in an attempt at bladder preservation. The value of an initial complete endoscopic resection before further therapy, however, is controversial. Those tumors amenable to complete resection alone may have a better prognosis regardless of further therapy. Nevertheless, radical cystectomy continues to be the standard of therapy and withholding this treatment in a good surgical candidate in an attempt at bladder preservation may result in the death of the patient. It is probably best to recommend transurethral resection therapy alone to patients in whom more radical therapy is precluded due to medical condition or individual patient request. The patient should understand the risks and possibly consider adjuvant radiation therapy or chemotherapy to help (at least theoretically) prevent the high rate of local recurrence and metastatic spread. Partial (segmental) cystectomy. Another therapeutic option for invasive transitional cell carcinoma of the bladder is partial or segmental cystectomy, which presents the advantage of bladder preservation but has specific indications. Novick and Stewart reported a 57% 5-year survival rate for muscle-infiltrating bladder cancer (stages T2 and T3) after partial cystectomyP Indications for partial cystectomy included tumors at the dome of the bladder, involving a ureteral orifice, confined

959

MANAGEMENT OF INVASJ:VE AND METASTATIC BLADDER CANCER

within a diverticulum or not amenable to transurethral resection because of size or location. In this series 2 to 5% of the patients with bladder carcinoma were candidates for this form of treatment. Kaneti reported a 40% (8 of 20 patients) 5-year survival rate for stages B1 and B2 lesions treated with partial cystectomy alone. ls Again, specific indications were used to consider patients for treatment. The patients had to have a solitary lesion in a region amenable to partial cystectomy, no evidence of atypia or carcinoma in situ elsewhere in the bladder or prostatic urethra by biopsy and attainable clear surgical margins. However, even with strict adherence to these selection criteria Kaneti reported a relatively low 5-year survival rate (40%) for patients with stages B1 and B21esions. Overall, approximately 10 to 15% of the patients with muscleinfiltrating carcinoma of the bladder are suitable candidates for this treatment. 19 The indications are those noted previouslyI7,I8 with the addition of no history of bladder carcinoma. Extremely high recurrence rates (up to 70%) have been reported in some studies with many of these patients subsequently requiring radical cystectomy.20,21 The selection criteria for this mode of therapy should be adhered to strictly with compulsive followup surveillance. Radical cystectomy. Radical cystectomy remains the standard therapy in the United States for patients with muscle-infiltrating bladder cancer.22 The initial observations of Jewett and Strong in 1946 concerning the significance of bladder wall penetration by transitional cell carcinoma23 laid the groundwork for the treatment of muscle-infiltrating bladder cancer by radical cystectomy. Difficulties are immediately evident in attempting to compare radical cystectomy results to those in which radiation therapy or chemotherapy is used either alone, or in a neoadjuvant or adjuvant setting. These difficulties arise due to differences in patient selection, differences in years covered by the studies, studies comparing clinically staged to pathologically staged results and attempts to compare retrospective data to prospectively accrued data. Nevertheless, better patient selection, early diagnosis and referral, and improvements in clinical staging, and surgical and anesthetic techniques have significantly improved recent survival rates reported with radical cystectomy.24-26 Overall survival data for contemporary surgical series indicate a 5-year survival rate of 62 to 88% for stage P2 disease, 57 to 74% for stage P3A and 29 to 57% for stage P3B (table 2).9,24-26 Therefore, concurrent surgical controls are mandatory as a comparison when assessing the efficacy of experimental or combined modality therapy. Some believe this recent improvement in survival to be a reflection of stage migration 27 based on improved preoperative staging, rather than a change in the natural history of the disease or improvement in therapy. The concept of stage migration refers to a phenomenon brought about by newer radiological imaging modalities. When comparing a cohort of patients treated before the age of routine CT and MRI used for staging to a cohort of patients treated in the more recent past, patients in the more recent group may have metastases that are silent or early. The patients from the earlier group would be found to have advanced stage disease after TABLE 2.

becoming symptomatic 01' manifesting physical findings referable to advanced stage disease. Therefore, the tumor, nodes and metastasis stages for the more recent patients would not be assigned according to the same data as in the pre-imaging era. The new data would allow patients with the silent or early metastases to migrate from lower into higher tumor, nodes and metastasis stages. The migration would improve survival in the lower stages because fewer patients with metastases would be assigned to the lower stages and improve survival in the higher stages, since the metastases in the newly added patients were silent rather than overt. The total survival rate may not be affected but the survival rates in each of the constituent stages could improve. Although this phenomenon may have a small part in the improved survival seen in contemporary cystectomy series, the overall outcome for those with invasive transitional cell carcinoma of the bladder has been minimally affected. Recent studies report an operative mortality rate of less than 5% and a risk of pelvic recurrence after radical cystectomy alone of 5 to 10% (table 2).9,24-26 Approximately 50% of these patients continue to die of distant (metastatic) disease, a figure similar to that reported in the 1950s even in the face of decreased pelvic recurrences and operative mortality. Therefore, local control is not the problem that must be addressed. Rather, effective systemic therapy must be developed to control the presumed microscopic metastases already present at operation before improved survival can be accomplished. Although it is the standard of care for invasive bladder cancer, radical cystectomy is not without social and psychological implications. Impotence has been a major disadvantage of radical cystectomy since its inception, especially in a disease with a male predominance. However, in 1982 Walsh and Donker demonstrated that impotence following radical prostatectomy arose from injury of the nervous innervation to the corpora cavernosa. 28 Subsequently, the technique for radical prostatectomy and cystoprostatectomy was modified accordingly to avoid injury to these nerves and preserve potency. The rate of impotence has currently decreased from previous historical figures of 90% to a recent reported value of 35%.29,30 This decrease in impotence after radical cystectomy, as well as a recent introduction (and rejuvenation) of an assortment of bladder substitutions and continent urinary diversion procedures have made radical cystectomy a much more palatable procedure. For patients with the desire, dexterity and intelligence to perform clean intermittent catheterization of the neobladder, this can greatly enhance social adjustment and lessen the psychological impact of loss of the bladder. Complications associated with continent diversion, such as electrolyte imbalance, infection, pouch stones and enuresis from bowel contractions, are being refined, making cystectomy with continent diversion available to more patients. SURGERY FOR NODE POSITIVE DISEASE

The prognosis for patients with bladder cancer metastatic to regional lymph nodes is dismal, and the role of surgery and pelvic lymphadenectomy for these patients is controversial. A

Survival and operative mortality with cystectomy alone as treatment of invasive transitional cell cancer of the bladder

Reference

No. Pts.

Whitmore (crude survival) Montie et al" (cause· specific survival) Mathur et al26 (crude survival) Skinner and Lieskovsky 26 (Kaplan-Meier actuarial survival) Reprinted with permission" * Does not include preoperative/postoperative radiation.

% 5-Yr. Survival by P Stage*

P2

P3A

P3B

% Operative Mortality

Study VIS.

137

1949-1958

60

26

11

14.0

99

1960-1979

62

74

57

9.0

58

1967-1974

88

57

40

3.4

197

1971-1984

83

69

29

1.0

960

THRASHER AND eRA WFORD

limited experience with surgery as a curative therapy in this setting has been obtained in the last decade. In 1981 Smith and Whitmore reported the MSKCC experience with 134 patients with regional lymph node metastases who underwent cystectomy between 1966 and 1977. 31 The reported 5-year survival rate for these patients was only 7% with 82% of them dying of metastatic bladder cancer. They noted a trend toward improved survival in patients with less extensive nodal involvement after stratification of the patients but the difference was slight. In 1982 Skinner reported on 36 patients with node positive disease who underwent bilateral pelvic lymph node dissection and radical cystectomy.32 He reported a 5-year survival rate of 36% and noted that in only 2 of 22 patients (9%) with metastatic disease was the pelvis the first site of recurrence. He concluded that pelvic node dissection did not increase the morbidity associated with radical cystectomy, effectively controlled pelvic disease and cured some patients with metastatic disease. More recently, Roehrborn et al reported their experience with 42 patients who underwent pelvic lymphadenectomy and radical cystectomy between 1971 and 1986, and who had histologically proved regional lymph node metastases.33 They divided the patients into 2 groups: 20 with 1 and 22 with more than 1 histologically positive nodes. The overall3-year survival rate for patients with positive lymph nodes was 27%. The 3year survival rate was 30% for stage pNl disease and 18.5% for stage pN2 disease. They found this survival advantage to be sustained for the first 3 years but not significantly different at 5 years. They concluded that a carefully executed pelvic lymph node dissection along with cystectomy had prognostic and therapeutic value. Current available data suggest that a significant percentage of patients with microscopic (Nl) node positive disease may benefit from bilateral pelvic lymph node dissection performed at the same time as radical cystectomy. However, the survival advantage conferred to these patients may not be sustained during long-term followup. Additionally, nodal involvement implies systemic disease and unless the patient has low volume microscopic disease in the lymph nodes cystectomy should probably be averted. The development of more efficacious chemotherapy regimens may make radical cystectomy in the face of metastatic disease standard but this remains to be proved. RADIATION THERAPY IN LOCALLY ADVANCED BLADDER CANCER

In the 1960s and 1970s external beam radiation therapy was used almost exclusively at some centers for invasive bladder cancer in an attempt to provide local control and preserve a functioning bladder. However, many studies have currently presented convincing data that external beam radiation alone is not adequate to achieve sustained local control of invasive bladder cancer. In several large series the disease-specific 5year survival rate for patients treated with primary radiotherapy varies from as low as 10% in deeply invasive disease to as high as 60% in superficially invasive disease (table 3).34-41 Overall, sustained local control is achieved in approximately 25 to 50% of the patients. However, comparisons among studies and certainly comparisons with series reporting results of radical cystectomy are difficult for several reasons. Many of the patients treated with radiation therapy alone in the United States are medically unfit for a radical operation, while some institutions in Europe use external beam radiation as the sole mode of therapy. Also, the technique of delivering external beam radiation is variable among studies using a 2, 3 or 4-field technique to deliver a total dose to the bladder of 5,000 to 7,000 rad. In addition, some centers have varied the mode of delivery to include interstitial implants, fast neutrons and radiation sensitizers, whose benefits over external beam radiation are unproved to date. Finally, these data suffer from the same problems noted in the discussion of surgery for invasive bladder cancer, such as differences in patient selection, clinical staging

discrepancies and, in most series, the absence of surgical staging with pelvic lymphadenectomy. Based on available data, it is evident that external beam radiation therapy alone is not adequate to achieve local control in the majority of patients with invasive bladder cancer. However, patients who are medically unfit for surgery may benefit from this treatment modality. Local control rates and 5-year disease-specific survival rates from published series approach 25 to 50%. Combination therapy with chemotherapy and radiation therapy may prove beneficial to this group of patients. However, many who are not suitable for more radical surgical treatments may be deemed unsuitable for combination therapy. In this high risk group of patients radiation therapy provides a chance for local control and possibly potential cure. Preoperative radiation therapy. Radiation therapy has been used in conjunction with radical cystectomy for the treatment of muscle-invasive bladder cancer for more than 3 decades. High pelvic recurrence rates (34 %) following radical cystectomy led to the introduction of preoperative radiation therapy by Whitmore in 1959. The earliest studies showing benefit from preoperative radiation therapy were conducted by Whitmore et al at MSKCC where patients judged to have clinical stage T3 disease were treated with 4,500 radpreoperatively.42 They noted a 37% 5-year survival rate, which was superior to the 17% rate in historical controls. They also noted a decrease in pelvic recurrence from 40 to 12% using the combined modality. Since these early studies, preoperative treatment regimens have varied widely from high dose, short course (1,600 to 2,000 rad in 1 week) to conventional doses of 4,500 to 7,000 rad in 4 weeks followed by surgery after a designated period. The continued use of preoperative radiation therapy has been advocated based on 3 principles: 1) preoperative radiation therapy may kill tumor cells, thus, decreasing the potential metastatic spread of tumor cells released into systemic circulation during surgical manipulation, 2) microscopic extensions or even macroscopic extensions of viable cancer remaining outside of the surgical resection may be controlled with preoperative radiation therapy and 3) preoperative irradiation may make a technically difficult tumor eaRier to resect by downstaging. The first premise has not been supported by clinical data. As stated previously, 50% of the patients continue to die of distant metastatic disease and this rate has remained relatively unchanged since the late 1950s despite decreasing pelvic recurrences. Additionally, Thrasher et al recently reported data refuting the premise that patients whose disease was rendered stage pTo by preoperative transurethral resection or radiation therapy have a survival advantage over those with tumor remaining in the cystectomy specimen. 43 It had been conjectured that patients with tumors remaining in the bladder may be at risk for dissemination of tumor cells at cystectomy.44 The survival advantage occasioned by a stage pTo finding in 66 of 433 patients who underwent radical cystectomy for transitional cell carcinoma of the bladder was evaluated. 43 Of the 433 patients studied 54 had clinical stage Tis or T A disease, 166 had clinical stage Tl and 213 had clinical stage T2. Within , each of the 3 clinical groups (clinical stages Tis/Ta, Tl and T2) Kaplan-Meier survival projections were generated comparing patients with stage pTo to those with a pathological stage identical to the original clinical stage. Among the 54 clinical stage Tis/Ta cancer patients, the 11 stage pTo and 24 stage pTis/pTa cancer patients had identical survival projections of 90% at 5 years; among the 166 clinical stage Tl cancer patients 32 with stage pTo and 78 with stage pTl had identical survival projections of 75% at 5 years, and ofthe clinical stage T2 cancer patients 23 with stage pTo and 71 with stage pT2 had identical survival rates of 68% at 5 years. T2, 23 stage pTo and 71 stage pT2 cancer patients. Therefore, survival projections failed to identify any survival advantage conferred by a stage pTo cystectomy specimen. These investigators concluded that the concept of metastatic disease caused by dissemination of tumor

961

MANAGEMENT OF INVASIVE AND METASTATIC BLADDER CANCER TABLE

3. Survival rates (5-year) and iocal control with definitive external beam radiation therapy % Clinical Stage'

No. Pts.

Reference Miller and Johnson" Timmer et al 35 Shipley et al 36

428 76 37

44

Greven et al 37 Quilty and Duncan3s

116 333

39t

Gospodarowicz et al 39

121

24 42t

39t

% Maintained Local

T3

T4

Complete Response

19 32t

9 ot

27 41

lOt 26t (T3A/T3B) 52/29.7t

ot

49 27 24

(T2/T3) 39t 59t 59t (T2/T3) 42

53

CQrcoran et al40 Reprinted with permission.

T2

T1

(T4A/T4B) 50/16t

35 41

4l

* Per cent 5-year survival by stage.

t Actuarial calculation.

cells during radical cystectomy was not supported by the available data. Two prospective randomized studies were performed to address the subject of a survival advantage conferred by preoperative radiation therapy. The Veterans Administration Cooperative Urological Research Group failed to show a survival advantage for preoperative radiation therapy over cystectomy alone. 45 The other study, conducted by the National Surgical Adjuvant Bladder Project Group from 1964 to 1970, randomized patients with clinical stage T2 or greater (N -) disease to surgery only or to treatment with standard fractionation radiation (4,500 rad) followed by radical cystectomy 4 to 6 weeks later. 46.47 This study suffered from a high patient dropout rate (greater than 50%), lack of uniformity in treatment delivery, and inconsistencies in reporting pathology and long-term patient followup. If all patients were considered, however, the 5-year survival rates were not significantly different between the 2 groups: 23% and 20%, respectively, with preoperative radiation therapy compared to cystectomy alone. More recently, several studies have reported data failing to support the survival advantage of preoperative radiation therapy.24-26.48 These studies report survival data of contemporary cystectomy series (table 2)24-26 and many address the second issue of the incidence of pelvic recurrence without the use of radiation therapy (table 4).24-26.49-51 It is obvious from these data that the underlying assumption that preoperative irradiation decreases microscopic or macroscopic extension of the tumor and, thus, decreases the incidence of pelvic recurrences is flawed. Contemporary series combining preoperative radiation with cystectomy report almost identical pelvic recurrence rates of 5 to 10%.52.53 Along these same lines, van der WerfMessing has argued for the use of external beam radiation therapy to decrease the potential implantability of tumor cells, based on her studies of patients treated with radium implants. 54 However, the validity of this argument is flawed because the bladder is not intentionally opened during radical cystectomy as it is during radium implantation. If gross tumor spillage occurs during radical cystectomy irradiation to the pelvis may, in fact, benefit the patient by decreasing implantability of tumor cells. Good surgical technique and attention to detail should make this unnecessary. Fossa et al reported a series of 122 patients treated from 1975 to 1982 with 3 different regimens. 48 Group 1 (42 patients) TABLE 4. Pelvic recurrence rates in contemporary radical cystoprostatectomy series without the use of radiation therapy

Reference

Yrs. of Study

Montie et al24 Skinner and Lieskovsky26 Pagano et al49 Prout et al'o Wishnow and Dmochowski61

1960-1979 1978-1982 1979-1982 1967-1975 1983-1985

Reprinted with permission."

% Pelvic Recurrence

Rate 9.1 7.2 11.3 7.0 5.6

received long-term radiotherapy with 46 Gy. for 4 to 5 weeks (2 Gy. daily) and then surgery, group 2 (34 patients) received short course radiation therapy with 4 Gy. 5 times during 1 week and then surgery, and group 3 (46 patients) underwent surgery alone. They reported no survival difference among the different groups and noted that the recent literature raises considerable doubt about the effectiveness of preoperative radiation therapy in muscle-invasive bladder cancer. Skinner and Lieskovsky recently reported a series of 197 consecutive patients treated between 1971 and 1982.26 In this series 100 of the patients received 1,600 rad of radiation therapy for 4 days preoperatively followed immediately by surgery, while 97 underwent radical cystectomy alone. They found no significant survival advantage for preoperative radiation therapy and their pelvic recurrence rates were similar, with a rate of 9% among those receiving preoperative radiation therapy and 7% among those undergoing surgery alone. The 5-year disease-free survival rate among the patients treated with cystectomy alone was 75% for those with pathological stages P2 and P3A disease, 44 % for those with stages P3A and P3B disease, and 36% for those with stage P4N+ disease. Finally, evidence to support the benefits of preoperative irradiation based on downstaging the tumor before cystectomy may be lacking. The pathological stage of the cystectomy specimen is being compared to the initial clinical stage. As previously noted, however, the clinical stage often does not correlate with the pathological stage in 50 to 60% of the cases. 9 Therefore, patients believed to have undergone downstaging may, in fact, have been overstaged initially. Additionally, in patients who receive the long course preoperative radiation there is a substantial delay in performing cystectomy. In patients whose tumors are less radioresponsive this delay may allow dissemination of a tumor that may have been cured by early cystectomy. Other adverse effects also are associated with this treatment, including an increased incidence of wound infections and bowel complications. 44 A critical analysis of the available data suggests that preoperative radiation therapy is not an effective addition to radical surgery alone for the treatment of muscle-invasive cancer. 55 There is a subset of patients who originally respond to this treatment and subsequently prove to be long-term survivors. However, these patients may represent a subgroup with less aggressive tumors who would have done well with or without pre-cystectomy radiation therapy. Due to the expense, delay in definitive treatment and potential morbidity associated with preoperative radiation therapy, there has been a recent tendency among urologists to omit this therapy as an adjunct in the treatment of muscle-invasive bladder cancer. Intraoperative radiation therapy. The rationale behind the use of intraoperative radiotherapy in the treatment of bladder cancer is the ability to deliver high doses of radiation to the bladder while sparing the neighboring tissues. 56 This method of treatment delivery has been used in breast and gynecological malignancies but the use of this modality in muscle-invasive

962

THRASHER AND eRA WFORD

bladder cancer has been limited. There has been a greater experience with this mode of therapy in superficial bladder cancer to attempt prevention of local and heterotopic recurrences. Matsumoto et al reported their experience with the use of intraoperative radiotherapy for carcinoma of the bladder.57 Of the 116 patients treated 66 had stage TA/Tl, 28 had clinical stage T2, 15 had clinical stage T3 and 7 had clinical stage T4 cancer. Staging was performed by bimanual examination with the patient under anesthesia, cystoscopy, IVP and pelvic angiography. No transurethr al resection was done before the cystotomy. The patients underwent cystotomy with biopsies of the tumor for histopathological examination. Matsumoto et al reported that stage T2 tumors were understaged by the aforementioned clinical staging methods 28% of the time (8 of 28 patients) and overstaged 14% of the time (4 of 28). Because a biopsy was done instead of transurethral resection this number may have been larger than reported. The patients were treated with 2,500 to 3,000 rad of 4 to 6 MeV. electrons delivered by 1 shot in 5 to 10 minutes. The bladder was closed and an additional dose of 3,000 to 4,000 rad was given to the whole bladder 3 to 4 weeks later. The 5-year actuarial survival rates were reported as 61.6% for stage T2 and 7.3% for stages T3 and T4. No serious late complications were reported. Because of the significant percentage of incorrectly staged cancer patients and the small number of patients with muscleinvasive disease, few statements can be made regarding the efficacy of treatment based on this study. It is apparent, however, that the survival rates in this series are much worse than those reported in contemporary cystectomy series. 24- 26,49-51 It is also apparent that the increased morbidity associated with an open cystotomy and the poor survival, especially of patients with higher stage disease, make the use of this modality for muscle-infiltrating bladder cancer suboptimal. CHEMOTHERAPY FOR MUSCLE-INVASIVE AND METASTATI C BLADDER CANCER

Although the basic biol ogical behaviors of muscle-invasive and metastatic bladder cancers are poorly understood, the recent addition of effective chemotherapy regimens has provided new hope to the treatment of these diseases. Bladder cancer is a chemosensitive tumor and the rationale for using chemotherapy in muscle-invasive bladder cancer is 2-fold. 1) As previously stated, greater than 50% of the patients who are treated locally for invasive bladder cancer will have relapse at distant sites and usually die of the disease within 2 years postoperatively,58 presumably because of microscopic metastases that were present at diagnosis. Chemotherapy could potentially eradicate these tumor deposits. 2) Chemotherapy, when used in conjunction with other modalities, might increase the local control rate and possibly facilitate bladder salvage by providing an alternative to cystectomy. Single agent chemotherapy. Recent advances in the chemotherapy of advanced urothelial malignancies have resulted in complete or partial responses in 50 to 70% of the patients.9 Combination regimens result in 10 to 15% of the patients enjoying long-term disease-free survival. 59-62 However, metastatic transitional cell carcinoma is almost uniformly lethal and new agents or combinations, as well as effective salvage therapies are needed. The differences in drug efficacy noted among studies may be a function of the setting in which the drug was studied (single institution versus multi-institutional studies), the period in which the study was performed, doses of the drug administered, or the patient population receiving the particular drug or drugs. Before the development of effective imaging techniques (that is CT), response rates of various lesions to chemotherapeutic agents were more inaccurately measured. Also, reports from single institutions often indicate a greater drug efficacy than results from multi-institutional studies, usually due to patient

selection.63 The patient population is also crucial because some patients have fewer intercurrent medical problems, such as renal insufficiency and cardiac dysfunction, that immediately bias results. Factors, such as absence of prior chemotherapy, a good performance status and normal renal function, are associated with a greater chance of response to chemotherapy.63 Cisplatin and methotrexate are the 2 most active single agents (table 5)64-72 and are the 2 agents that form the backbone for most currently used combinations for advanced transitional cell carcinoma. Cisplatin has been the most widely studied in a range of doses from 50 to 100 mg./m.2 but a dose-response relationship has not been established. Soloway et al observed a 33% partial response rate using cisplatin alone with an additional 45% of the patients obtaining stabilization of disease. 64 The likelihood of surviving 1 year in this study was 61% for the group with disease in the abdomen or pelvis compared with 29% for those with metastatic disease. Yagoda initiated clinical trials with this agent and, in summarizing the literature, reported an overall response rate (complete plus partial response) of 30%in phases 2 and 3 studies .65,73 Because of the nephrotoxicity of cisplatin, analogues of the agent have been studied. One of the more widely studied agents, carboplatin, was developed with the intent of providing similar efficacy to cisplatin with less renal toxicity. Myelosuppression is the primary dose-limiting toxicity and could potentially be combated with hematopoietic growth factor.74 Several studies have been conducted using this agent. 75-78 Response rates have varied from 14 to 21%, with partial responses almost exclusively. Trump et aI, reporting for the Eastern Cooperative Oncology Group, noted a 31% incidence of myelosuppression and a 9% incidence of severe nausea and vomiting in 40 patients receiving carboplatin at a dose of 400 mg./m. 2 every 28 days.78 Among evaluable patients with measurable disease there were 3 of 22 responses (14%) and all were partial response. Cumulative data suggest a slightly lower response proportion with this agent compared to cisplatin. Presently, the cisplatin analogues in doses studied have not proved as effective as their parent compound and await further study before their widespread use in combination therapy. Methotrexate is the second most active single agent presently known, and has been used in a variety of doses and schedules for the treatment of transitional cell carcinoma of the bladder. Oliver et al reviewed methotrexate as a single agent in 60 patients with recurrent or metastatic transitional cell carcinoma of the bladder.71 They assigned patients to receive either 50 mg. every 2 weeks or 100 mg. every 2 weeks based on the age and renal function of the patient (lower dose if creatinine was more than 1.6 mg./dl. or age was more than 70 years). Overall, 43% of the patients with measurable metastases and 28% with recurrent primary tumors responded for an average of 6 months. These investigators noted a trend toward better response with lower volume of disease. Most of the patients in TABLE 5.

Single agent chemotherapy for advanced bladder cancer % Response

Reference Yagoda66 Soloway et al"' Soloway et al66 Hillcoat et al67 Natale et al72 Oliver et al71 Gagliano et a16' Yagoda et al68 Blumenreich et al70

Drug

No. Pts.

Cisplatin Cisplatin Cisplatin Cisplatin Methotrexate Methotrexate Doxorubicin hydrochloride Doxorubicin hydrochloride Vinblastine

38 27 50 55 42 21 41

Reprinted with permission."

35 28

. Complete Plus Complete Partial Partial

10

9 5

3

33 10 22 26 38 19

40 33 20 31 26 43 19

11

14

18

18

MANAGEMENT OF INVASIVE AND METASTATIC BLADDER CANCER

this series had disease confined to the pelvis. Natale et al evaluated methotrexate using 2 different dosing schedules: 40 mg./m. 2 intravenous weekly and a 250 mg./m. 2 2-hour infusion with citrovorum factor rescue. 72 The majority received the lowdose weekly regimen but the authors observed no significant differences in response rates between the 2 doses. Overall, a partial response was seen in 11 of 42 patients (26%) with a median response duration of 6 months. Those with a better performance status had a higher partial response rate (50% versus 19%). In a review of the literature, Yagoda noted a 29% overall objective response rate among 236 patients treated with methotrexate for advanced transitional cell carcinoma of the bladder. 65 Caution should be used when administering this agent in patients with ureteral obstruction, long ileal conduits or continent urinary diversions due to delayed excretion and increased reabsorption. 79 Doxorubicin hydrochloride was one of the earliest drugs analyzed for activity in bladder cancer. Yagoda et al reported experience treating 35 patients (half previously treated) and found a 14% objective response rate. 68 Only 3% ofthe patients experienced a complete response in this study. Gagliano et al reported a 20% response rate to doxorubicin, compared with 36% for those receiving the combination of doxorubicin plus cisplatin.69 This difference was significant. However, no significant difference in survival was found. A literature review by Loening revealed that of 246 patients studied 6 achieved a complete and 41 achieved a partial response, for a total response rate of 19%.80 Vinblastine sulfate has also been studied with phase 2 trials. Blumenreich et al observed an 18% response rate to this agent, with an average duration of response of only 4 months. 70 Toxicity was minimal, making the agent acceptable for combination therapy. Unfortunately, responses to single-agent therapy are partial and of short duration, with complete responses noted to be almost anecdotal. 41 It is clear that the goal of contemporary chemotherapy in the treatment of advanced bladder cancer should be a complete response, since patients who do not achieve this goal die of the disease. Many of the previously reported single-agent studies have led to contemporary combination regimens, in which recently moderate success has been achieved in the way of better response rates and some cases of long-term disease-free survival. Combination chemotherapy. The most common combinations tested have relied upon the 2 most active single agents available, cisplatin and methotrexate, as the backbone. Combinations tested include cisplatin and methotrexate;62 cisplatin, doxorubicin and cyclophosphamide (CISCA);61 cisplatin, methotrexate and vinblastine,59 and methotrexate, vinblastine, doxorubicin and cisplatin (M_VAC).6o,81-B5 Evaluation of the results of these different regimens remains difficult due to variable patient selection, variable means of identifying and recording response, and variable means of reporting survival data. Few studies have been performed documenting combination therapy as superior to single-agent therapy. Although 6 randomized trials have been conducted comparing a single agent to a combination,66,67,86-89 no combination had been shown to be superior to a single agent before 1990. Recently, 2 randomized trials compared the most active combination regimen, M-VAC, to cisplatin86 and CISCA. 90 The M-VAC combination proved to be superior in both cases and response proportions of up to 70% have been observed, with a small but definite portion of patients with metastatic disease achieving prolonged diseasefree survival. 82 This 4-drug regimen, developed at MSKCC in 1983,81 has proved in phase 2 trials to be the most active combination to date (table 6).41,59,60,62,69,71,85,89-94 In the preliminary report by the Memorial group the M-VAC regimen (table 7)82 was used to treat 25 patients with metastatic or unresectable urothelial tract transitional cell carcinoma.81 Significant tumor regression

963

was noted in 71 % of the patients. Complete clinical remission was observed in 12 of 24 patients (50%, 95% confidence limits 30 to 70%). After surgical exploration 6 patients had confirmation of a pathological complete response and 4 were reclassified as having a partial response. An updated report on 133 patients with advanced urothelial tract cancer given the same M-VAC doses noted significant tumor regression in 72 ± 8% of 121 evaluable patients. 6o Complete response was achieved in 36% of the patients, of whom 11 % required the addition of surgical resection of residual disease with 55 % of these patients surviving 3 years. The median survival for complete responders will exceed 38 months, compared with 11 months for partial responders and 8 months for nonresponders (fig. 1).60 Of 21 patients with metastatic disease involving only lymph nodes (N3-4MO) and of 100 with visceral metastases (N+M+) 52% and 33%, respectively, achieved a complete response. Median response duration was 35 months for N + patients compared with 11 months for M+, with 4 and 10 cases, respectively, in remission at the time of the report. As mentioned in the initial report, approximately 16% of the responders had central nervous system lesions, half of whom had no systemic relapse at the time of progression. Also stage Tis and nontransitional cell histology or mixed histology tumors responded poorly. These investigators note that of the responding metastatic sites hepatic lesions responded the poorest. Toxicity was significant with 4 drug-related deaths (3%), a 25% incidence of nadir sepsis, 58% for myelosuppression and 49% for mucositis. Four cycles of therapy appear to be the minimum required to achieve a durable complete response. Other combinations have not produced superior results to those reported from the M-VAC series (table 6).82 Several centers have reported their experience with the cyclophosphamide, doxorubicin and cisplatin or CISCA regimen championed by the M.D. Anderson Hospital and Tumor Institute in Houston. 91 Troner and Hemstreet reported an overall response rate of 38%,92 while the experience at MSKCC was slightly better, with a 46% response rate (7% complete and 39% partial responses) for 28 patients treated. 93 The largest combined experience with the CISCA regimen has originated from the M.D. Anderson Hospital and Tumor Institute. Logothetis et al treated 97 patients with measurable metastatic disease (64% with local nodal disease) using CISCA (650 mg./m. 2 cyclophosphamide on day 1, 50 mg./m. 2 doxorubicin on day 2 and 70 to 100 mg./m. 2 cisplatin following the doxorubicin on day 2).91 Of the 74 patients with pure transitional cell carcinoma 52 (70%) responded, with 29 (39%) complete and 23 (31%) partial responses. Mean survival was 80.9 weeks for the total population, 85.6 weeks for 62 patients with nodal disease and 72.6 weeks for those with visceral metastases. Of 29 patients with pure transitional cell carcinoma 14 (77.8%) remained in complete remission for greater than 100 weeks. Logothetis et al also compared M -VAC to CISCA in a prospective randomized trial in an attempt to assess overall survival and response to the different chemotherapy regimens. 90 After 110 patients were entered into the study the M -VAC was found to be significantly superior to CISCA and the trial was concluded. In comparing response proportions between the 2 groups 48 patients were treated with CISCA and 54 with M -VAC. Complete responses for the CISCA and M-VAC groups were 25% and 35%, respectively (p = 0.263). The partial responses were 21% and 30%, respectively (p = 0.307). The total objective response rate for the CISCA group was 46% (95% confidence limits of 32 to 62%) and 65% for the M-VAC group (95% confidence limits of 52 to 77%, p <0.05). Complete remission status was determined solely by clinical criteria and not by pathological confirmation. The survival duration of M-VAC-treated patients was significantly longer than that of CISCA-treated patients (mean 62.6 weeks, median 48.3, range 5.0+ to 162.3+ versus mean 40.4 weeks, median 36.1, range 7+ to 147.1+). They found that the histological subtype of transi-

964

THRASHER AND eRA WFORD TABLE

6. Combination chemotherapy for advanced bladder cancer % Response

Reference

Drug

Gagliano et al69 Oliver et al 71 Stoter et al62 Carmichael et al" Troner and Hemstreet92

No. Pts.

Cisplatin, doxorubicin hydrochloride Cisplatin, methotrexate Cisplatin, methotrexate Cisplatin, methotrexate Cyclophosphamide, doxorubicin hy· drochloride, cisplatin Cyclophosphamide, doxorubicin hydrochloride, cisplatin Cyclophosphamide, doxorubicin hydrochloride, cisplatin Cyclophosphamide, doxorubicin hydrochloride, cisplatin Methotrexate, cisplatin, vinblastine !,dethotrexate, vinblastine, doxorubicin hydrochloride, cisplatin Methotrexate, vinblastine, doxorubicin hydrochloride, cisplatin Methotrexate, vinblastine, doxorubicin hydrochloride, cisplatin

Schwartz et al93 AI-Sarraf et al89 Logothetis et al91 Harker et al69 Sternberg et 0100 Logothetis et aloo 19awa et al"

37

Complete

Partial

3

40

23 21

23 47

11

43 19 25 28

Complete Plus Partial 43 64 46 68 38

39

46

36

14

28

42

48

25

21

46

50 121

28 37

28 31

56 68

54

35

30

65

58

17

40

57

Reprinted with permission."

TABLE

1.0

7. M-VAC regimen Day (mg./m?)

Drug 1 Methotrexate Vinblastine Doxorubicin Cisplatin

2

30 3 30 (15)' 70

15

22

30 3

30 3

D

0

O.S

N~al metastasis.only>p = .000184 Visceral metastasIS

The regimen is recycled on day 29. Reprinted with permission.·2 , Doxorubicin is decreased to 15 mg./m? in patients who had more than 2,000 rad of prior pelvic irradiation. 1.0

Q)

o

AlleR A PR o MR Progression

0.8

(44 pIS. 21 censored) (43 pIS. 2 censored) ( 7 pIS. o censored) (27 pIS. o censored)

o

01

c: .:; .~

::J

>

0.6

~

-~ c:

G)

0-

0.4

0.6


c:

0

1: 0 a.

e

0.4

0.2

Q..

0.2

0.0 0

12

24

36

48

60

72

Months from start of MVAC

o

~

~

~

00

1001~1~ 1~

1M

Weeks

FIG. 1. Survival distribution in months by Kaplan-Meier method for 121 patients with transitional cell carcinoma adequately treated at MSKCC and categorized as having complete response (CR), partial response (PR), minimal response (MR) and progression. Reprinted with permission. 60

FIG. 2. Kaplan-Meier survival plots for 110 patients with metastatic urothelial cancer comparing survival with disease confined to lymph nodes to that of further dissemination. Reprinted with permission. 90

tional cell carcinoma did not influence survival, whereas the degree of tumor dissemination (nodal versus visceral) and the selection of chemotherapy regimen indicated a significant survival advantage for patients treated with M -VAC (figs. 2 and 3).90 No significant difference in toxicity was noted between the 2 groups except for renal toxicity (increase in baseline serum creatinine greater than 0.4 mg./dl.), which was 41% in the CISCA group and 17% in the M-VAC group. Another active regimen that has not been compared directly to M-VAC is cisplatin, methotrexate and vinblastine. Harker

et aI, reporting for the National California Oncology Group, treated 58 patients with metastatic transitional cell carcinoma with the 3-drug regimen (30 mg./m. 2 methotrexate on days 1 and 8,4 mg./m. 2 vinblastine on days 1 and 8, and 100 mg./m. 2 cisplatin on day 2).59 This regimen was administered in 21-day cycles. Complete responses were noted in 14 of 50 evaluable patients (28%) and partial responses were noted in 14 (28%), for an overall response rate of 56% (95% confidence limits 42 to 70%). The median duration of the complete responses was 9

:MANAGEMENT OF INVASIVE AND METASTATIC BLADDER CANCER

HI

0.8

o MVAC tI

I\N\-:I

CiSCA >P '" .1N\I,)15

0.2

o

20

40

80 100 120 140 160 Weeks

FIG. 3. Comparison of survival plots for 110 patients with metastatic urothelial cancer randomized to receive M -VAC (MVAC) versus CISCA chemotherapy. Reprinted with permission. 90

months. The median survival for patients with a complete response was 11 months versus 7 months for those with a partial response, with an overall median survival of 8 months. Four additional patients benefited from the aggressive addition of either surgery or radiation therapy after chemotherapy. The toxicity of this regimen was similar to that of M-VAC with universal nausea and vomiting, moderate nephrotoxicity (26%) and myelosuppression. Of the patients 14 (24%) required hospitalization because of leukopenia and fever, and there were 13 cases (22%) of moderate to severe mucositis and 2 treatmentrelated deaths. When the reported median survivals for complete response patients in this study59 were compared with those previously reported in the M -VAC seriesGO a survival advantage is obvious (11 months and 38+ months, respectively). However, direct comparisons cannot be made due to differences in study design and patient selection. A statement that can be made with confidence is that the toxicity of most of the combination regimens is significantY The recent trials using hematopoietic growth factors provide hope for decreasing the side effects of these toxic combinations and possibly improving outcome with higher dose intensity. The first study by the Memorial group tested M -VAC with granulocyte colony-stimulating factor and without the growth factor.74 When compared to cycles without granulocyte colonystimulating factor, those with this factor had more frequent ability to administer planned chemotherapy on days 14 and 21 (100% versus 29%, p = 0.0015), significantly fewer days with an absolute neutrophil count of less than 1,000 cells per mm. 3 (3 versus 32, p = 0.0039) and less mucositis (11% versus 44%, p = 0.041). Another study performed at M.D. Anderson Hospital used granulocyte macrophage colony-stimulating factor plus escalated doses of M -VAC as salvage for patients who had progressed on M -VAC with or without CISCA. 95 Complete and

965

overall response rates of 23% and 40%, respectively, were observed. In summary, we have learned a great deal about the use of chemotherapy for advanced bladder cancer in the last decade. It appears that combination chemotherapy is more effective than single-agent therapy. M -VAC chemotherapy is the most active drug combination tested to date, with a small subgroup of patients achieving a sustained complete response. The role of adjuvant surgery remains unproved but it does appear to benefit a subgroup of patients who initially respond but have residual resectable disease. Further studies are needed, and presently adjuvant surgery should be performed on a select basis and not routinelyY The toxicity of the M-VAC combination is formidable and the value of dose intensity is unanswered. In many series the planned dosage schedule of M -VAC is not reached, possibly compromising response rates. Hematopoietic growth factors may allow studies to evaluate responses to different dose intensities and subsequently answer many of these questions. Additionally, it appears that patients with low volume disease and those with nodal disease only exhibit a greater response to chemotherapy than those with advanced metastatic disease. Of 21 patients with nodal disease 11 (52%) achieved a complete response with M -VAC in the Memorial series, compared to only 33 of 100 (33%) with visceral metastases. GO It also was noted that the central nervous system appears to be a sanctuary for transitional cell carcinoma, with 16 to 18% ofthe responders having brain lesions. 6o ,82 This is due to low concentrations of the chemotherapeutic agents entering cerebrospinal fluid. The plasma-to-cerebrospinal fluid ratio for cisplatin is 21:1 or greater with concentrations of methotrexate noted to be 3% of those found in the plasma. 96 These central nervous system lesions represent a therapeutic dilemma, possibly solved by increased dose intensity with hematopoietic growth factors, intrathecal administration of certain agents or surgery for isolated central nervous system lesions in selected responding patients. 82 The answer will require further research with these agents but considering the small number of patients achieving a sustained complete response new agents and combinations must be identified in carefully designed prospective trials. Neoadjuvant chemotherapy. The rationale behind the use of chemotherapy in the neoadjuvant setting is the treatment of microscopic metastases, the presumed cause of systemic failure. This approach takes advantage of the lower tumor burden and possible early metastatic stage (stages N+Mo versus NxM+) and the prognostic implications of these factors. It is controversial whether chemotherapy is best applied in the preoperative or postoperative setting, since they both have distinct advantages. Presently, each case should be individualized with the presence of intercurrent cardiac or renal disease factoring into the decision. Also, the therapeutic goal of bladder preservation or treatment of microscopic metastases should be defined before treatment. The advantages and disadvantages of adjuvant and neoadjuvant chemotherapy are outlined in table 8. The advantages of neoadjuvant therapy are multiple. It allows an in vivo assessment of chemosensitivity by observing the response of a marker lesion in the bladder. The response of microscopic metastases is presumed to be similar to that of the primary lesion. Patients who respond can continue therapy to the point of maximal response, and a complete clinical response could allow for bladder preservation. Also, neoadjuvant therapy may produce some downstaging and an initial response from the primary lesion may be a good prognostic indicator. Preoperative chemotherapy eliminates the potential for accelerated growth in the postoperative period. Higher dose intensity is possible because no prior therapy has been given. Disadvantages of the neoadjuvant approach include the fact that not all patients need systemic therapy-approximately 50% can be cured with local therapy alone. Another weakness

966

THRASHER AND eRA WFORD TABLE

8. Comparison of adjuvant and neoadjuvant therapy Neoadjuvant

Rationale: Early treatment of microscopic metastases: Inverse relationship of tumor burden and curability Small tumors may be more chemosensitive due to higher growth fraction Decreased chance of spontaneous resistance Factors favoring neoadjuvant therapy: In vivo evaluation of chemosensitivity: Response assessment in vivo Prognostic information of response versus nonresponse Organ preservation possible Downstaging of primary tumor can: Decrease extent and need for additional therapy Convert unresectable to resectable t umor Allow drug delivery not compromised by previous surgery or radiation therapy Prognostic importance of response in primary tumor on prognosis Potential for accelerated growth postop. Better pt. tolerance Factors favoring adjuvant therapy: Case selection Staging error of T versus P Need for therapy based on pathological as opposed to clinical criteria Exposure of more pts. cured by local therapies to cytotoxic agents Timing of definitive local therapy: Jeopardize curative therapy by prolonged treatment with ineffective agents Refusal of potentially curative therapy If bladder preserved, continued risk of new tumor formation in bladder Difficulties with neoadjuvant and adjuvant therapy: Chemotherapy: Limited efficacy of best available agents Therapy selected empirically Increased metastatic potential of surviving cells Tumor biology: Absence of reliable markers of invasion Absence of reliable markers of metastases If bladder preserved, continued risk of new tumor formation in bladder

Adjuvant

Yes

Yes

Yes

Yes

Yes

Yes

Yes Yes

No No

Yes

No

Yes

No

Yes Yes

No No

Yes

No

Yes Yes

No Yes/No

No No

Yes Yes

No

Yes

No

Yes

No No

Yes Yes

No No No

No No No

No No No

No No Yes

Reprinted with permission from Scher, H. I.: Sem. Oncol., 17: 555, 1990.

is the reliance upon clinical staging to assess response, which as mentioned previously is inaccurate. This weakness may also result in more patients receiving chemotherapy than may require it. Also, waiting for a response or a false interpretation of response can delay definitive treatment. Even if bladder preservation is successful, patients must be followed with close surveillance for extended periods due to the risk of new tumor formation.97 Adjuvant therapy, conversely, is administered based on pathological criteria, such as nodal metastases or extravesical tumor extension. This allows less room for staging error and may decrease the number of patients exposed to cytotoxic drugs. Also, the organ at risk is removed early, thus reducing the potential for further growth and metastases while waiting on response and eliminating the risk of new tumor formation in the bladder. The major disadvantage is the inability to assess response of the tumor to chemotherapy, thus potentially exposing the patient again to ineffective cytotoxic drugs. Also, the prognostic information gained from initial response of the lesion is lost with this form of therapy. Both approaches suffer from the inaccuracies of the initial clinical urological assessment and the absence of available biological markers of invasiveness or metastatic potential. Presently, available data cannot predict those who will or will not respond to chemotherapy or those who really need it. Also, treatment is currently selected without predetermined sensitiv-

ities. The toxicity and limited efficacy of contemporary chemotherapy regimens combined with the aforementioned problems make recommending these agents in the neoadjuvant or adjuvant setting, outside of protocols, inadvisable. The results of randomized trials are presently not available to answer adequately the question of efficacy of neoadjuvant chemotherapy. Scher reviewed 43 published trials comprising more than 1,000 patients who received neoadjuvant therapy in an investigational setting. 98 Almost all of these trials were nonrandomized, with differences in case selection, chemotherapy schedules and response criteria, as well as small numbers of patients (most studies included less than 50 patients). Scher also reported heterogeneity in the extent of disease and variable proportions of patients actually completing treatment programs. 98 Table 9 summarizes data from several trials reporting results of neoadjuvant chemotherapy followed by definitive surgery. Recognizing the limitations of these series, these data give some idea of the efficacy of neoadjuvant chemotherapy. However, randomized trials with adequate followup are required to assess the true impact of neoadjuvant chemotherapy. Six randomized trials of neoadjuvant versus no neoadjuvant chemotherapy have been recently closed to accrual (4) or are ongoing (2) and have enrolled a large number of patients (table 10).99 Only 2 of these trials are evaluating cisplatin/methotrexate-based combinations, considered to be the backbone of the most effective chemotherapy combinations. These 2 studies are from the Medical Research Council-European Organization for Research and Treatment of Cancer (MRC-EORTC) and the Southwest Oncology Group/United States Intergroup. Hopefully, these studies will resolve the issue of the value of neoadjuvant chemotherapy in the treatment of this diathesis. However, a review of several of the nonrandomized trials can provide important information. Miller et al reported on 9 patients with locally advanced transitional cell carcinoma of the bladder treated with neoadjuvant M-VAC followed by radical cystectomy and modified pelvic lymphadenectomy.lOo Ofthe patients 5 (55 %) had clinical stage T4NOMO tumors, while the remainder had stage T3NOMO tumors. All patients underwent pathological restaging, revealing a complete response rate of 22% and a partial response rate of 44%, for a total objective response rate of66%. The majority of patients experienced downstaging of the disease. Seven patients received 2 preoperative courses of chemotherapy, with 1 receiving 1 cycle and 1 receiving 3 cycles. Median survival has not been reached but 7 of 9 patients were alive an average of 21 months postoperatively. McCullough et al reported 17 cases (stages T2 to T4) treated with CISCA. lOl Of these patients 82% completed all 3 preoperative treatments but only 41% continued to complete the additional 2 postoperative treatments. Of the 17 patients 9 (53%) exhibited an objective tumor response (all were partial responses). All 9 of the responders remained clinically free of disease at a median of 19 months. The 8 nonresponders have done poorly, with 63% dead of disease. Using M-VAC in patients with stages T2 to T4 tumors followed by surgical restaging, Scher et al noted that 42 of 84 (50%) who received neoadjuvant therapy were free of tumor when restaged by cystoscopy, transurethral resection and cytology.l02 However, only 14 of 60 patients (23%) undergoing subsequent partial or radical cystectomy were proved to be pathologically disease-free. Response proportions were noted to vary inversely with the depth of invasion. Of the patients with stages T2 and T4 tumors 43% and 8%, respectively, were pathologically free of disease. Tumors that were not of pure transitional cell histology or those classified as carcinoma in situ were less chemosensitive. Scher et al noted similar findings in their initial report on 50 patients treated with M-VAC.103 In that series all 6 stage T2 (100%) versus 17 of 25 stage T3 (68%) versus 6 of 12 stage T4 (50%) cases achieved stage To/Tis. Also, despite extensive reevaluation by transure-

967

MANAGEMENT OF INVASIVE AND METASTATIC BLADDER CANCER TABLE 9.

Complete pathological response in the bladder using combination chemotherapy Complete Response at Cystectomy No.(%)

95 % Confidence Interval (%)

83

7 (43) 26 (35) 22 (31) 18 (22)

19-68 24-45 20-42 13-31

138

42 (30)

23-38

Agents

No. Trials

Evaluable

Cisplatin/5-fluorouracil Cisplatin/methotrexate Cisplatin, methotrexate and vinblastine Cyclophosphamide, doxorubicin and cisplatin M-VAC

1 2 3 4

16 75

7

71

Reprinted with permission from Scher, H. 1.: Sem. Oncol., 17: 555, 1990.

TABLE

10. Randomized trials of neoadjuvant versus no neoadjuvant chemotherapy in invasive bladder cancer

Trial Radiotherapy plus cisplatin versus radiotherapy

Doxorubicin plus cisplatin plus cystectomy versus cystectomy Cisplatin plus cystectomy versus cystectomy M -VAC plus cystectomy versus cystectomy Cisplatin, methotrexate and vinblastine plus local treatment versus local treatment

No. Pts. Entered or Planned'

Status

255

Closed to accrual

102

Closed to accrual

300

Closed to accrual

121 298

Closed to accrual Ongoing

1,000

Ongoing

Location or Organizations (principal investigator) Australia/British West Midlands (D. Raghaven/D. M. Wallace) Canada (M. K. Gospodarowicz/ Coppin) Scandinavia (S. D. Fossa) Spain (L. Martinez-Pineiro) United States Intergroup (E. D. Crawford) MRC-EORTC (Hall)

Reprinted with permission.-• The number of patients entered is given for the trials closed to accrual and the number planned is given for the ongoing trials.

thral resection of the bladder and other noninvasive staging procedures, a clinical staging error of 38% was observed. This finding brings forth questions as to the accuracy of repeat transurethral resection in determining complete response after chemotherapy and the role of surgery for partial or nonresponders. Herr et al reviewed a series of 6 contemporary trials and compared the preoperative clinical stage after chemotherapy with the pathological stage found after a definitive post-chemotherapy operation.104 Of the 90 patients believed to have stage To or Tis disease by transurethral resection 29 (32%) had residual muscle-infiltrating cancer at operation. The role of surgery for patients with partial or no response to chemotherapy is controversial but it is obvious that chemotherapy in conjunction with the original transurethral resection is not adequate. Herr et al reported the fate of patients who achieved stage To or Tis status after chemotherapy and transurethral resection, and were followed without a definitive operation. lo4 After review of 4 recent studies, they noted that approximately 25 to 30% of the patients had metastatic disease 18 to 24 months after chemotherapy. Therefore, presently chemotherapy should not be viewed as a substitute for a definitive operation. They also noted in their review that cystectomy salvaged only 28% of the chemotherapy failures. Nonresponding patients with stages T3B and T4 tumors were rarely cured by an operation but some patients with stage T2 or T3A tumors may be salvaged. They stated that, realizing potential errors in assessing response and realizing that surgery is the standard method of treatment for operable invasive bladder cancer, it is currently reasonable to remove surgically muscle-invasive bladder cancer that persists after neoadjuvant chemotherapy. Although preliminary data regarding intra-arterial administration of neoadjuvant chemotherapy have shown some activity against transitional cell carcinoma of the bladder/o5-lo9 it remains to be proved that this mode of therapy increases the efficacy of chemotherapeutic agents. The comparative efficacy of intra-arterial chemotherapy has never been tested. Therefore, this method presently cannot be considered routine and further studies are needed to define the role of this route of administration. In summary, neoadjuvant chemotherapy remains an investigative approach to invasive (stages T2 to T4) transitional cell carcinoma of the bladder. It should not be considered a substi-

tute for a definitive operation. Definitive surgery includes radical cystectomy, with selected patients being candidates for partial cystectomy. Additionally, a minimum of 2 cycles of chemotherapy and possibly 3 is advocated, and nonresponders or patients with progression should undergo immediate cystectomy. Also, patients with stages T2 and T3A tumors are most likely to respond completely to chemotherapy and bladder preservation may be a reasonable goal in these patients but not patients with stages T3B and T4 disease. Such patients, however, would need compulsive followup surveillance, since the bladder remains at significant risk for development of new or persistent invasive tumors. Adjuvant chemotherapy. Chemotherapy in an adjuvant setting has the distinct advantage of administration based upon pathological criteria and it is administered after the organ at risk has been removed. Those who advocate this mode of therapy stress the theoretical importance of removing the bulk of tumor in the bladder, which is the oldest and perhaps most chemoresistant tumor, before treating the potential microscopic metastases. Additionally, radical cystectomy with bilateral pelvic lymph node dissection is the most effective and curative modality for localized bladder cancer, and chemotherapy can be administered to those at high risk for distant relapse. Several trials using adjuvant chemotherapy have been reportedl lO-1l4 but most are limited by the small numbers of patients treated and nonrandomization. Logothetis et al reported a single institution phase 2 trial that retrospectively compared the survival distribution of 3 groups of patients: 1) those who were at high risk for relapse and received adjuvant chemotherapy, 2) those who were at high risk for relapse and did not receive adjuvant chemotherapy, and 3) those who had none of the high risk features and were identified as low risk controls.113 Patients were considered at high risk for recurrence postoperatively if they had extravesical involvement of tumor (stage T3B), evidence of vascular or lymphatic invasion, direct invasion into pelvic viscera (stage T4) or the presence of resected nodal metastases. These patients were considered candidates for CISCA chemotherapy (70 to 100 mg./m. 2 cisplatin, 50 mg./m2 doxorubicin and 500 mg./m. 2 cyclophosphamide) and those in the high risk category who did not receive chemotherapy had either medical contraindications to treatment, or were not offered or refused chemotherapy. The majority of

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patients (75 %) received 5 courses of chemotherapy at monthly intervals. The outcome of the 71 high risk patients who received CISCA was compared t o the 62 high risk patients who did not receive CISCA and the 206 low risk controls. They found a significant survival advantage for the adjuvant-treated patients when compared with the high risk group that did not receive adjuvant therapy (70 % versus 37%, 2-year disease-free survival, p = 0.00012) . The 2-year disease-free survival of those who received adjuvant therapy more closely approximated that of the low risk group (70% versus 76 %, p = 0.33). Benefit was restricted to patients with extravesical, node positive or locally extensive disease. No benefit was noted for the patients with vascular or lymphatic invasion. These physicians concluded that adjuvant CISCA chemotherapy prolongs the disease-free survival of some patients after cystectomy. These data are promising but suffer from absence of prospective randomization and the use of CISCA chemotherapy (instead of a more active combination, such as M-VAC). The only randomized controlled trial published to date randomized 91 patients either to adjuvant CISCA chemotherapy or observation after radical cystectomy and meticulous pelvic lymph node dissection. 114 A total of 229 patients met the pathological criteria for protocol, with 69 patients excluded due to age (38), prior malignancy (19) and medical factors (12) . Therefore, 160 patients were considered eligible for study. Of the 160 patients 101 agreed to participate with 10 more excluded due to nontransitional cell histology, resulting in 91 of the eligible 160 patients (57%) entered into the study. These 91 patients had pathological stage P3, P4 or N+MO disease and all had transitional cell carcinoma of the bladder. Chemotherapy was begun 6 weeks after cystectomy with planned 4 courses at 28-day intervals of 100 mg.jm. 2 cisplatin, 60 mg.jm.2 doxorubicin and 600 mg.jm. 2 cyclophosphamide. The results show a significant delay in interval to progression, with 70% of the chemotherapy-treated versus 46% ofthe observation group free of disease at 3 years (p = 0.001). Median survival time was 4.3 years, compared to 2.4 years in the chemotherapy versus the observation group, respectively (p = 0.0062). The number of involved lymph nodes was noted to be the single most important prognostic feature, although no benefit was noted with 2 or more involved lymph nodes. Protocol violations, unfortunately, temper the conclusions of the study and the power of the observations. In the chemotherapy study arm 11 of 44 patients (25%) randomized to receive the chemotherapy did not receive it and only 21 of 44 (48%) completed the planned 4 cycles. Also, the small number of patients in each arm and in each subgroup comparison decreased the power of observation. Additionally, the use of CISCA instead of the best presently available combinations may further decrease the impact of this study. However, this trial and the phase 2 trial reported by Logothetis et al113 can be interpreted as a trend toward improved survival with adjuvant chemotherapy. Additional studies, prospectively randomized, with the best available combinations of chemotherapeutic agents and, more importantly, adequate numbers of patients and followup will be needed to answer the question of the benefit of adjuvant chemotherapy in locally advanced bladder cancer. COMBINED RADIATION THERAPY AND CHEMOTHERAPY

The rationale behind the combined use of chemotherapy and radiotherapy developed from studies suggesting that cisplatin acts as a radiation sensitizerY5-123 This prompted investigators to combine cisplatin with full-dose radiotherapy in patients who were poor surgical candidates or who refused cystectomy.119. 120,122 These early studies reported complete response rates of 70 to 75%120,122 and durable local control rates of approximately 50%.120 These preliminary results, combined with encouraging results from combination chemotherapy trials, prompted investigators to study combination chemotherapy along with radia-

tion therapy in an attempt at bladder preservation. However, the question was raised as to which treatment should come first-the chemotherapy or the radiation therapy. The advantage of radiotherapy before chemotherapy is that the radiotherapy is more effective on the bulky tumor at the primary site (that is the bladder). On the other hand, it delays treatment of potential microscopic metastases for 6 weeks. If chemotherapy is administered first it is not as effective on bulky tumors and resistant tumor cells may metastasize during chemotherapy. Both schedules may delay definitive treatment in nonresponders. This finding led to the development of integrated approaches that split courses of radiotherapy and interdigitate chemotherapy theoretically to allow treatment of the microscopic metastases and the bulky primary tumorY The group at Massachusetts General Hospital Cancer Center has one of the largest experiences with this integrated approach, and has published and recently updated their data using this approach.124-127 Prout et al reported the data on a phase 1/2 trial that included patients with clinical stages T2 to T4 bladder tumors.125 The purpose of the trial was to select only patients who achieved a complete response to initial chemotherapy and intermediate dose radiotherapy to be spared cystectomy. A total of 53 patients was entered into the study (15 with stage T2, 29 with stage T3 and 9 with stage T4 disease). The planned therapy was maximal transurethral resection followed by 2 cycles of cisplatin, methotrexate and vinblastine (30 mg.jm. 2 methotrexate on days 0, 14 and 21,70 mg./m. 2 cisplatin on day 1, and 3 mg.jm. 2 vinblastine on days 1, 14 and 21) chemotherapy plus 2 additional courses of cisplatin (70 mg.jm. 2 ) ; 1 before 4,000 rad radiotherapy and 1 on day 21. If tumor was found on cystoscopic reevaluation by biopsy and/or cytology, immediate cystectomy was advised. If tumor was not found a radiation boost to a total of 6,480 rad plus 1 additional course of cisplatin (same dose) was given. Of the 53 patients entered into the study 42 (79%) actually completed the protocol. Of the 42 patients 34 completed the full chemotherapy and radiotherapy protocol, while 8 underwent immediate radical cystectomy due to positive biopsy and/or cytology results. The median followup was 26 months (range 15 to 42 months) , with 72 % of all entered patients alive and 53% with a disease-free bladder. The overall actuarial survival of all entered patients was 64 % at 3 years. Among the 34 patients receiving full chemotherapy and radiation therapy to 6,480 rad the proportion of patients achieving durable local control was 82 % in those with a complete response after cisplatin, methotrexate and vinblastine therapy versus 25% in those who achieved less than a complete response after this therapy (p = 0.005). Of the 42 patients treated 39% experienced significant stomatitis, myelosuppression and/or renal dysfunction. There were no treatment-related deaths. This study highlights several controversies associated with the use of neoadjuvant chemotherapy or radiochemotherapy in attempts at bladder salvage. The question of the possible deleterious effects of awaiting response to these various therapies and delaying cystectomy has already been mentioned. Also, any study evaluating the response of a tumor to neoadjuvant therapy must rely on clinical staging, which may be inaccurate as often as 50% of the time.9 The value of an initial complete endoscopic resection remains controversial-it may simply identify tumors with a better prognosis independent of therapy. Also, once a tumor is completely resected, chemotherapy is then applied in an adjuvant instead of a neoadjuvant setting and an in vivo response can no longer be assessed. Patients can only be followed from that point until recurrence of the tumor. Nevertheless, these data encourage further prospective randomized studies to test the credibility of bladder-sparing techniques. Before the completion of these trials, however, combination chemotherapy and radiotherapy should remain experimental.

MANAGEMENT OF INVASIVE AND METASTATIC BLADDER CANCER THE NEODYMIUM:YAG LASER IN LOCALLY ADVANCED BLADDER CANCER

Recent advances in laser technology have led to their experimental use in muscle-invasive bladder cancer. The neodymium:YAG laser has been one of the most widely studied, usually in patients deemed poor surgical candidates because of advanced age or poor health. 128-l33 An aggressive transurethral resection is usually performed before laser therapy and a power output of 35 to 80 watts has been used for a duration of 1 to 5 seconds. 128-l33 Most often, however, the power output is approximately 45 watts, used with a duration of 3 or 4 seconds in a given area. 128 General or spinal anesthesia is usually required but hospitalization is rarely required. 128 Table 11 shows the results of laser treatment for invasive bladder cancer reported from 4 institutions. Local recurrence has been reported in these studies as the measure of efficacy. Clearly, minimal muscle invasion has resulted in much lower recurrence rates after treatment. Smith reported effective ablation of local tumor in 80% of the patients treated with stage T2 disease. 133 Deeper muscle invasion and extravesical invasion have resulted in high rates of recurrence after treatment. Additionally, Smith noted that the laser appears to be less effective than electrocautery resection for debulking and controlling symptoms of advanced local bladder cancer.133 Two other disadvantages of the use of the neodymium: YAG laser in the treatment of invasive bladder cancer are 1) an inability to control precisely the depth of penetration and 2) the ability of the laser to produce a transmural bladder injury without perforation. Because the laser results in a coagulative necrosis and the bladder wall maintains its structural integrity, the injury is not immediately apparent. A loop of bowel overlying the bladder can be injured, with the patient presenting with a bowel perforation approximately 2 weeks later. Presently, based upon limitations of the neodymium:YAG laser and the results achieved to date with its use in muscleinvasive bladder cancer, laser treatment should be reserved for patients who are poor candidates for radical surgery or who refuse cystectomy and request alternative treatment. It does appear to be useful in the management of superficial bladder cancer and may become more useful for the treatment of stage T2 tumors as newer clinical staging modalities increase staging accuracy. In summary, the management of invasive and metastatic bladder cancer remains one of the most controversial problems facing urologists to date. Based on our current understanding of the biology of muscle-invasive bladder cancer and the data available regarding its treatment, radical cystectomy with bilateral pelvic lymphadenectomy remains the standard of care. A select group of patients may be amenable to partial cystectomy. The true efficacy of neoadjuvant and adjuvant chemotherapy (including combination chemoradiotherapy) awaits the results of prospective randomized trials with adequate maturation of the data. If these studies indicate a significant advantage to the use of neoadjuvant therapy, then further studies should be directed toward chemotherapy with bladder preservation in mind. Additionally, further studies into biological predictors of prognosis and treatment response must be conducted to guide decisions in planning appropriate management

TABLE 11. Laser treatment of invasive bladder cancer: local recurrence rates by stage No./Total Recurrences by Stage (%) Reference T2 T3A T3B T4 Beisland and Sander"· 4/15 (27) McPhee et al'31 0/12 (0) 4/7 (57) 6/7 (86) 6/6 (100) Shanberg et al"o 1/3 (33) 8/10 (80) Smith'28 3/20 (15) 6/16 (37) 8/12 (67) 10/11 (91) Reprinted with permission."

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