Treatment for Muscle Invasive Carcinoma of the Bladder

0022-534) /83/l3'Sb- i l 69S02.JO/O ThE JOORNAL OF UROLOGY

Copyright(¢) 1986 by The YViHian1s & ·1)\/ilki:is Co.

te of the A TREATMENT FOR MUSCLE INVASIVE CARCINOMA BLADDER IRA W. KLIMBERG

AND

THE

ZEV W AJSMAN

From the Division of Urology, Department of Surgery, University of Fiorida, College of Medicine, Gainesville, Florida

The incidence of urothelial cancer has increased dramatically in the United States, with the rate for male patients increasing more than 50 per cent during the last 50 years. 1 During the coming year it is estimated that more than 40,000 new cases will be diagnosed and that nearly 11,000 patients will die of bladder cancer. In light of the continued trends toward aging of our population and increased exposure to environmental carcinogens, the magnitude of the problem will continue to grow. Bladder cancer can appear in one or a combination of several forms: a superficial papillary form that recurs frequently, an infiltrating solid form that often disseminates and carcinoma in situ. The•pathogenesis and evolution of these various manifestations of urothelial disease remain unclear. Significant strides have been made in recent years in the reduction of recurrence and progression of superficial cancer of the bladder. Diligent followup, urothelial mapping, urine cytology and flow cytometry studies, and the identification of cell markers that indicate invasive potential have enhanced our understanding of superficial disease. Intravesical chemotherapy and immunotherapy with bacillus Calmette-Guerin have given us an effective treatment for patients with carcinoma in situ and diffuse urothelial disease.2- 4 Patients with invasive bladder cancer continue to be a difficult group to manage effectively. Standard techniques of therapy use morbid exenterative procedures that result in significant derangements in the patient's ability to manage urinary wastes effectively and to maintain sexual function. Despite our aggressive therapy roughly half of these patients will die of bladder cancer, most within 2 years." The specter of high failure rates coupled with morbid treatment methods has caused urologists, and radiotherapists to explore modifications in and alternatives to the traditional treatments for invasive bladder cancer. The goals of these treatment initiatives include 1) improvement in survival I"ates the use of therapy, 2) improvement in the techniques of urinary diversion in patients who require cystectomy and 3) application of mixed modality treatment methods that allow for bladder preservation. The ultimate goal of treatment for bladde,· cancer remains the attainment of high rates of survival coupled with the preservation of normal bladder function. TRADITIONAL THERAPY

The heterogeneity of bladder cancer is striking. Superficial disease, comprising nearly 80 per cent of bladder tumors, progresses to invade muscle in only 10 to 15 per cent of the patients. In contrast, more than 60 per cent of the patients with invasive bladder cancer do not have a history of superficial disease. The prognosis clearly is different in these 2 groups. The necessity for early aggressive therapy is demonstrated by 2-year survival rates less than 5 per cent in patients with untreated invasive bladder cancer. 6 Management of patients with invasive cancer of the bladder

has remained an area of controversy in uro-oncology. The relative merits of surgery and radiation, separately or in combination, continue to be debated. 7- 10 Early experience with surgical therapy alone for muscle invasive bladder cancer has resulted in 5-year survival rates of 15 to 30 per cent. 11 - 13 Surgical failures generally were attributed to incomplete resection and dissemination of the tumor (either locally or to distant sites) as a result of surgical manipulation or as a result of pre-existing, unrecognized metastasis. 14 The advent of effective high energy, external beam :radiation permitted attempts at curative therapy of bladder cancer. Despite the application of intensive high dose "definitive" radiation with 6,000 to 7,000 rad, 5-year survival rates remained in the 15 to 35 per cent range. 14- 18 As a result of the continued poor experience encountered in treatment in 1959 Whitmore reported the use of integrated preoperative radiotherapy in conjunction with radical cystectomy.19 Since the initial experience at the Memorial SloanKettering Cancer Center with 4,000 rad during 4 weeks, various regimens of preoperative radiotherapy have been used, ranging from 2,000 rad in 4 days to 5,000 rad in 5 weeks. In general, the integrated treatment regimens using preoperative radiotherapy in conjunction with radical·cystectomy have recorded 5-year survival rates of 30 to 50 per cent. 19-23 Evidence for the efficacy of integrated preoperative radiotherapy is based upon the improved survival demonstrated in these patients compared to a group of historical controls treated by an operation or radiotherapy alone. In there is evidence that preoperative radiation can reduce significantly the risk of pelvic recurrences in patients with high stage disease. 24 In recent years the argument seemingly has come full circle, with several authors proposing that radical cv:stect<)rrtY provides similar cure rates as the combined re~;m1en,s use radiation. 9 • 10 These authorn have maintained that groups are improvement in operative technique and nenc,nerati and reflect the natural history of a specific rather than as a result of tbe biological of used. The addition of radiation therapy may have served to identify patients who were destined to do well rather than improve the efficacy of the treatment. Despite the controversy surrounding the issue of preoperative radiation certain observations seem clear. Significant downstaging of tumor, that is pathologicai stage less than clinical stage, is seen in at least 50 per cent of the patients following 4,000 to 5,000 rad preoperative radiation. Roughly a third of the patients will have no tumor in the cystectomy specimens (stage pT0). 24 -29 Patients whose disease is downstaged will have significantly higher 5-year survival rates than patients whose cancer is resistant to radiotherapy. Whether these results reflect the therapeutic efficacy of integrated preoperative radiation in conjunction with radical cystectomy or merely the identification of patients with a better prognosis is not clear.

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Clearly, some of these tumors are radiosensitive and some are radioresistant. Perhaps more relevant considerations that must be addressed are the need for additional treatment in radiosensitive tumors that are downstaged to pTO after radiotherapy and the efficacy of a subsequent operation on tumors that are radioresistant. Careful analysis of survival data in recent clinical series demonstrates that the question of preoperative radiation ultimately will impact only slightly on our ability to control this disease. In the best experiences with combination therapy nearly half of the patients continue to die of bladder cancer. The presence of distant metastases continues to be the cause of failure in the majority of these patients. It is doubtful that significantly improved survival can be anticipated until effective systemic therapy for bladder cancer is identified. 28 SYSTEMIC THERAPY

To date several chemotherapeutic agents have been shown to possess activity against disseminated bladder cancer. Among the most active of these drugs are cisplatin, methotrexate, cyclophosphamide, doxorubicin and 5-fluorouracil. 30 In single agent trials these agents have accounted for objective response rates in the neighborhood of 20 to 40 per cent. Unfortunately, the patients who obtain complete responses are in the minority, generally Oto 10 per cent of the total group, and these responses often are transient and of short duration. 30- 35 Various regimens of combination chemotherapy have been studied in the treatment of disseminated bladder cancer. The goal of these various combinations is to combine single agents with known antitumor activity into a regimen that will have increased efficacy while minimizing the toxicities associated with higher doses of the component agents. Although some combination chemotherapy regimens have increased the response rate to 45 to 50 per cent, nearly all of the responses have been partial and ephemeral. 30• 31 • 35- 38 A major advance in the systemic treatment of advanced bladder cancer occurred with the recognition of the potent antitumor activity of the combination of cisplatin and methotrexate. Recent experience with these agents used in combination has resulted in significantly improved complete and total response rates. Harker and associates recently reported results with a cisplatin, methotrexate and vinblastine regimen in 50 patients. 39• 40 In this group there were 14 complete responses (28 per cent) and an over-all response rate of 56 per cent. Oliver and associates similarly reported a 64 per cent response rate in patients treated with methotrexate and cisplatin.41 The most impressive report of successful chemotherapy in patients with bladder cancer has been ~hat of Sternberg and associates on the ongoing results of the methotrexate, vinblastine, doxorubicin and cisplatin regimen (M-VAC). 42 • 43 Complete clinical remission was observed in 18 of 45 patients (40 per cent), with an over-all response rate of 67 per cent. Surgical restaging of disease in -patients obtaining a clinical complete remission was an integral part of the study. Sternberg and associates reported that 8 clinical complete responses were confirmed pathologically and 4 patients had downstaging to partial response because of microscopically persistent disease. In the initial series of the 12 clinical complete responders 3 died and 9 are alive after a median duration of 16+ months. The M-VAC regimen has substantial toxicity, and 3 drugrelated deaths and marked morbidity have occurred. Despite this toxicity the initial results of this and other similar methotrexate and cisplatin-based regimens give us significant hope that effective systemic therapy for bladder cancer is at hand. The discovery of effective combination chemotherapy for bladder cancer has rekindled interest in the concept of adjuvant chemotherapy. As we have noted previously, the primary cause of failure in the treatment of invasive bladder cancer is the emergence of widespread metastases. Distant failures have

continued to occur in half of all patients seemingly independent of the treatment with an operation and/or radiation. The inclusion of some form of systemic therapy in an adjuvant role appears to hold the best outlook for improved cure rates in these patients. Nearly all trials of adjuvant chemotherapy and cystectomy have been disappointing until recently. Most of these trials have used single agents, usually cisplatin or cyclophosphamide, and have not demonstrated any efficacy. Similar studies with combination therapy also have failed to demonstrate significant benefit. 30• 44 Logothetis and associates recently reported the effectiveness of adjuvant chemotherapy following cystectomy for invasive bladder cancer. 45 Adjuvant cisplatin, cyclophosphamide and doxorubicin chemotherapy was used in patients at high risk following cystectomy. The addition of adjuvant therapy resulted in a statistically significant increase in the survival rate free of disease of high risk patients compared to concurrently treated controls, and a survival rate identical to that of simultaneously treated low risk patients. 45 The concept of combination therapy with adjuvant chemotherapy and definitive radiation therapy in lieu of cystectomy has been explored, and has yielded some provocative results. These will be reviewed in more detail under the discussion of treatment modalities that allow bladder preservation. SURGICAL ADVANCES

The treatment modality applied most often in the United States for invasive carcinoma of the bladder involves radical cystoprostatectomy, either with or without preoperative radiation, and some form of urinary diversion, usually via an ileal conduit. Despite the fact that it has little or no bearing on the curability of a patient, the details of the urinary diversion will impact greater than nearly any other factor on the day-to-day life of the patient and the quality of the life-style. Although great strides have been made in recent years in our techniques of operative and perioperative care, cystectomy and urinary diversion continue to be associated with significant morbidity. Although operative mortality has decreased from 14 to 2 per cent during the last 30 years, 24• 46- 48 radical cystectomy continues to be associated with significant postoperative morbidity. Recent experience reveals early postoperative complications in 22 to 50 per cent of the patients and late complications in 15 to 30 per cent. 46- 49 In addition to the easily recognized and quantifiable operative morbidity, patients who undergo urinary diversion must come to grips with the disfigurement of the body image, impotence and the chronic care that is necessary after cutaneous urinary diversion. Impotence after radical cystoprostatectomy may be avoidable. The etiology of impotence following a radical pelvic operation has been defined clearly by Walsh and Donker. 50 Impotence results from injury to the branches of the pelvic plexus that innervate the corpora cavernosa and modifications in the surgical technique frequently can prevent this complication. Although this technique of nerve sparing was described originally for radical retropubic prostatectomy, in which case potency has been maintained in 86 per cent of the patients, it equally is applicable to radical cystoprostatectomy.51• 52 Initial results have indicated a preservation of potency in 67 per cent of the patients following the modified cystoprostatectomy. Optimal management of urinary collection devices and the skin at the ostomy site is the foundation for successful medical and social rehabilitation of the ostomy patient. The importance of this aspect of postoperative care cannot be over-emphasized. Many problems at the stoma site, including excoriation, incrustation, chronic irritation and hyperkeratosis, result in the development of stomal stenosis. The recognition that these stomal problems are preventable has led to the increased role of enterostomal therapists.

TREATMENT FOR MUSCLE INVASIVE BLADDER CANCER

Enterostomal therapists should be included in an integrated fashion during the perioperative period. Preoperative teaching in the techniques of skin care, and appliance selection and use are critical in enabling the patient to adjust to life with a stoma and to assume self-care of the ostomy. Careful preoperative evaluation allows the enterostomal therapist in conjunction with the surgeon to optimize placement of the stoma. Postoperatively, the enterostomal therapist and the local ostomy association can provide superb long-term counseling and educational expertise in helping the patient deal with the realities of living with urinary diversion. The construction of an adequate stoma remains paramount in the avoidance of complications at the ostomy site. Proper stoma site selection that avoids skin folds, previous scars and the belt line allows for adequate adhesion of the faceplate and collection device. The everting or rosebud stoma usually functions best. Flush or retracted stomas lead to difficulty with appliance fit and peristomal complications. 53 Despite the improvements in stomal care, stomal stenosis remains the most common cause for reoperation following the construction of an ileal conduit. 54 Stomal stenosis occurs in 4 to 32 per cent of end stomas. Use of the Turnbull loop stoma has increased as surgeons recognize that this technique obviates the problem of stomal stenosis. This has been demonstrated in more than 150 patients reported on in 2 recent series. 54 • 55 The technique of urinary diversion via a continent ileal reservoir (Kock pouch) has been hailed as one of the most important advances in urological surgery by its proponents. The Kock pouch offers several advantages over the ileal conduit. 56· 57 The patient is able to remain continent without the use of an external collecting device, thereby avoiding problems with the stoma or parastomal skin. The ability to place the stoma low in the abdomen, where it can be concealed easily by underwear or a bathing suit, results in less defacement of the body image. Kock and associates reported their initial experience with the continent ileal reservoir in 1982. 56 Since that time Skinner and associates have reported with enthusiasm their own results in 51 patients. 57 The procedure has been well described and basically relies on 2 intussuscepted ileal segments secured with staples and Marlex mesh to function as 1-way nipple valves. One segment into which the ureters are reimplanted has a reflux-preventing nipple valve. The other nipple valve maintains the continence of the pouch. The patient drains the reservoir via intermittent clean catheterization. In the hands of Skinner and associates the Kock pouch has been remarkably free of complications. Approximately 10 per cent of the patients have required revision of the valves. There has been excellent preservation of renal function in all patients except 1 who had compromised renal function preoperatively. Metabolic derangements have been rare. Reflux occurred in 1 patient, 2 had stones on exposed staples and there have been 3 episodes of clinical pyelonephritis. 57 The ability of other surgeons to perform the Kock pouch technique with similarly low morbidity awaits confirmation. The short-term· benefits of a continent urinary diversion, including a better self-image and freedom from an external appliance, are clear. The long-term benefits of a nonrefluxing form of low pressure urinary diversion remain uncertain. If the initial experience with this form of urinary diversion is maintained the ultimate significance of the Kock pouch may lie in its ability to maintain stable renal function, and prevent nephrolithiasis, chronic pyelonephritis and reflux nephropathy. The initial experience with the Kock pouch and the enthusiasm of patients for more socially acceptable and psychically more palatable types of urinary diversion have rekindled interest in internal forms of urinary diversion. The absence of a stoma coupled with volitional control of voiding makes internal forms of urinary diversion appealing. The classic form of internal diversion is ureterosigmoidos-

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tomy, which was the most popular type of urinary diversion before 1950 when Bricker described the ileal conduit. 53 •58 •59 Problems with ureterosigmoidostomy usually were related to difficulties with the ureterocolonic anastomosis. Subsequently, Leadbetter and Clarke,60 • 61 and Goodwin and associates 62 described effective methods of ureterocolonic anastomosis that minimize the incidence of reflux and obstruction. Widespread use of ureterosigmoidostomy has been limited because of concerns about late complications. Pyelonephritis, ureteral obstruction, nephrolithiasis, electrolyte disturbances and systemic acidosis all have been reported frequently. 53 The induction of primary neoplasms, usually of colonic origin, at the site of the ureterosigmoid anastomosis also has diminished enthusiasm for this type of diversion. 63 • 64 Others have reported good long-term results with ureterosigmoidostomy via modern techniques of ureteral implantation. 65 • 66 Bladder cancer patients are an average of 65 years old, and few of these patients will survive long enough to be at risk for anastomotic carcinomas, which have an average latency of 20 years. Carefully selected patients can do well with ureterosigmoidostomy and it remains a viable form of urinary diversion. The absence of a stoma, freedom from catheterization and use of the rectum for urinary evacuation minimize the damage to the self-image of the patient. Lower urinary tract reconstruction with bowel segments, with or without implantation of the artificial urinary sphincter, recently has been described. 67 Little data are available concerning the use of this type of internal urinary diversion in patients who have undergone cystectomy for malignancy. To date these forms of reconstruction do not appear to provide substantial benefits beyond those obtainable with ureterosigmoidostomy. An intriguing and controversial form of internal urinary diversion was described by Camey, which consisted of construction of a functional, continent reservoir following cystectomy. 68 A 40 cm. ileal loop is isolated and the ureters are implanted in a nonrefluxing fashion into both ends of the loop. The ends of the loop are closed and the midpoint of the antimesenteric border is anastomosed to the urethral stump. Continence is achieved via the external sphincter mechanism. Voiding occurs via the Valsalva maneuver. Little experience with this procedure in the United States is available for analysis. Lilien and Camey have reported excellent results in 84 patients with up to 16 years of followup, and daytime continence was achieved in more than 90 per cent and sterile urine in more than 70 per cent. 68 Controversy has arisen concerning the use of the retained urethral segment and the risk of urethral recurrence. Some oncologists have questioned the use of the Camey procedure in cancer patients and they note the 4 urethral recurrences in the original series of Camey. In an attempt to minimize the risk of recurrent disease, urethrectomy and ileal conduit urinary diversion were performed by Camey when there was evidence of tumor involving the bladder neck, evidence of atypia at the urethral margin or multifocal carcinoma in situ. Since these criteria were adopted there has been no evidence of urethral recurrence. In summary, recent developments in surgical techniques and perioperative care have improved dramatically the plight of patients undergoing urinary diversion. Although these techniques will not impact significantly on the frequency and duration of survival, they represent major advances in improving the quality of survival. BLADDER PRESERVATION

In the United States curative treatment regimens established for invasive bladder cancer are predicated upon the effectiveness of radical excision of the tumor. In practice this traditionally has meant cystoprostatectomy and pelvic lymphadenectomy with or without integrated preoperative radiation therapy.

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Radical excision affords effective local control with pelvic recurrences in the 5 to 15 per cent range. 24 However, despite this aggressive posture 50 to 70 per cent of the patients will die within 5 years and most will have relapse with systemic disease within 18 months. Improved survival will require the incorporation of effective systemic therapy. The inability of radical excision to prevent death of invasive bladder cancer is clear. The recognition of the limits of radical surgery has stimulated research in alternate forms of treatment that may provide survival comparable to cystectomy without the associated morbidity. Several centers have explored the use of alternative forms of treatment that allow for bladder preservation. The hallmark of these regimens is combination, mixed modality treatment. Conservative excisional biopsy of the tumor, usually transurethrally, is coupled with radiation therapy and/or systemic chemotherapy. Many patients experience complete remissions, with tumor downstaged to pTO, adequate local control and long-term survival equivalent to radical surgical excision while preserving bladder function. Definitive external beam radiation therapy coupled with delayed or so-called salvage cystectomy for patients with persistent or recurrent tumor allows for some patients to preserve the bladder. Experience accumulated at several centers indicates that 15 to 35 per cent of patients with invasive bladder cancer will survive 5 years when treated with definitive radiation therapy. 14 · 18 These patients may be spared cystectomy. Patients with local recurrence after radiation therapy or who have persistent disease remain at high risk for disseminated disease. These patients require cystectomy. Although clearly representing a highly selected group of radiation therapy failures, several authors have described survival after salvage cystectomy to be similar to that seen in patients treated with regimens combining radiotherapy and immediate cystectomy. Bloom and associates reported a 60 per cent 5-year survival rate and 11 per cent operative mortality rate for cystectomy following 6,000 rad of radical radiotherapy.17 Smith and Whitmore reported a 37 per cent 5-year survival rate and 5 per cent operative mortality rate for patients after salvage cystectomy. 69 Freiha and Faysal reported a 45 per cent 5-year survival rate and a 5 per cent operative mortality rate in the Stanford series. 7° Crawford and Skinner reported 38 per cent survival and 8 per cent operative mortality rates. 71 Survival is related closely to the stage of tumor at the time of salvage cystectomy. 72 In patients with stage pTl or less disease the 5-year survival rate was 65 per cent. In patients with stage pT2 or more the 5-year survival rate was 22 per cent. 69 -72 Approximately 5 per cent of the patients requiring cystectomy have done so because they were bladder cripples following high dose radiotherapy. Definitive combination radiotherapy using external beam with either intraoperative or interstitial irradiation permits bladder retention in eligible patients. The rationale for the use of this approach is that direct tumor irradiation can deliver a higher radiobiological dose to the tumor without exceeding the limited radiation tolerance of the bladder and neighboring tissues. The selectivity in dose delivery should produce an improved therapeutic ratio, which results in a high tumor control rate and minimal morbidity. 73 lntraoperative radiation therapy for bladder cancer has been studied most extensively in Japan. In the United States considerable experience has been accumulated in the treatment of various locally advanced cancers with intraoperative radiation therapy, although meaningful data do not exist regarding the treatment of invasive bladder cancer. Matsumoto and associates recently reported their experience with combined external beam and intraoperative radiation therapy for carcinoma of the bladder. 74 Suprapubic cystostomy was done and the patients were treated with 2,500 to 3,000 rad intraoperatively to the tumor. The bladder was closed and a

Foley catheter was placed for approximately 7 days. Three to 4 weeks postoperatively the patients were treated with 3,000 to 4,000 rad of additional external beam radiation. The 5-year survival rate for patients with stage cT2 disease was 61 per cent. Survival for those with higher stage disease was poor. Definitive treatment of bladder cancer by interstitial radiotherapy has been studied extensively by van der Werf-Messing and associates in Rotterdam. 75- 79 More than 1,000 patients have been treated with this technique and nearly 400 had stage cT2 or cT3 disease. Before 1962 therapy consisted only of interstitial radiation. However, retrospective analysis revealed the presence of scar implants in roughly 10 per cent of the patients. The addition of preoperative external beam radiation (350 rad X 3 fractions) has controlled scar implants completely in the last 345 patients. 75 After transurethral resection preoperative radiation is given as described previously. The bladder then is opened via a suprapubic approach and the threaded radium needles are implanted into the tumor. A suprapubic drain is placed through which the radium needles can be removed and the bladder is closed. Radiographically guided dosimetry is used so that the needles may be withdrawn when a dose that is the biological equivalent of 6,500 rad in 168 days is delivered. The needles usually are removed 2 to 4 days postoperatively. van der Werf-Messing treated 391 patients (average age 65 years) with muscle invasive bladder cancer. Well or moderately well differentiated tumors were noted in 223 patients (57 per cent) and poorly differentiated tumors occurred in 167 (43 per cent). None of the tumors was more than 5 cm. in diameter. Patients with stage cT2 disease treated with this technique had an over-all 5-year survival rate of 56 per cent. Survival at 5 years in the stage cT3 group was 39 per cent. A second bladder cancer beyond the originally treated area was diagnosed in about 6 per cent of the patients. Although not strictly comparable to other series of patients with stages cT2 and cT3 carcinoma of the bladder, the results obtained by interstitial radiation rival the best survival figures achieved by cystectomy with or without preoperative radiation. 75 -79 Morbidity and mortality in the interstitially irradiated patients reportedly are low. Postoperative mortality is 1 per cent, and the combined early and late complication rate is 29 per cent. 75 Although these figures are not significantly better than those achieved with radical cystectomy, it must be remembered that these patients have had the immeasurable benefit of retaining bladder function. Perhaps even more remarkable is the Rotterdam experience with interstitial irradiation for stage cTl disease: Despite the inclusion of 28 per cent poorly differentiated tumors, 82 per cent of the patients were entirely free of relapse at 5 years. This group had a 10-year actuarial survival rate of 85 per cent. 77 The combination of bladder preservation and impressive 5year survival rates with interstitial irradiation in muscle invasive bladder cancer has led us to institute a similar treatment regimen at our university. During the last 3 years patients who were not candidates for radical excision because of other medical problems or who refused radical cystectomy were offered treatment with interstitial irradiation. Ten patients have been treated to date. Although it is too early to draw any conclusions about the efficacy of such treatment, it is interesting to note that in all patients the disease was downstaged to cTO after irradiation. During followup there have been no local recurrences in the bladder. All patients remain free of disease except 1 in whom microscopic lymph node involvement was noted at implantation. Bladder preservation also may be affected through the use of mixed modality treatment regimens that include systemic therapy. Chemotherapy has been combined with local resection and/or radiotherapy. 80- 82 Hall and associates reported a 58 per cent complete response rate and a 59 per cent 2-year survival rate with transurethral

1173 82 Of the comresection and dose methotrex&te plete responders 46 per cent remained free at 2 years. These results were obtained in patients m whom half had histological proof of deep muscle (stage or perivesical (stage cT3b) invasion. Survival rates 2 years after cystectomy are not substantially better in this high risk group of patients. Theoretical considerations suggest that combination therapy with radiation and chemotherapeutic agents believed to be radiosensitizers should be effective. Experimental data on F ANFT-induced bladder tumors have demonstrated increased tumor necrosis when doxorubicin, cyclophosphamide or cisplatin was given with tumor irradiation. 83 - 85 Herr showed the synergistic effect of platinum and irradiation in humans by demonstrating increased downstaging of tumors before cystectomy.86 Preliminary reports supporting the effectiveness of platinum and radiation have been noted. Jakse and associates reported that 6 of 8 patients so treated had a complete response, 87 and Soloway and associates reported 3 transient complete responses.80 The National Bladder Cancer Collaborative Group A recently presented a preliminary report on the tolerance and local response to a regimen of platinum and irradiation. 88 A total of 27 patients with stages cT2, cT3 and cT4 bladder carcinoma who were not candidates for cystectomy were treated by transurethral resection, cisplatin and definitive (6,500 rad) external beam radiation. Only 8 of the 27 patients completed the planned 8 courses of platinum (the median number of courses completed was 4). The toxicity attributable to radiation was minimal. However, chemotherapy caused nausea and vomiting in most patients, mild renal insufficiency in 4 and moderately depressed white blood counts in about half of the patients who received 4 or more courses of cisplatin. Followup cystoscopy revealed a complete response (no evidence of tumor) in 19 of 23 patients (83 per cent). Of the 17 patients who had known residual tumor in the bladder after transurethral resection 13 (76 per cent) achieved a complete response. All but 2 of the complete responses have been maintained locally. Distant metastases developed in 4 patients. 88 Although not strictly comparable, historical data suggest that downstaging to cTO (complete response) is seen in 40 to 50 per cent of the patients after definitive external beam radiation. 15- 17 A synergistic effect of platinum and radiation therapy appears real, since the complete response rate in patients with residual disease was 76 per cent in the experience of the National Bladder Cancer Collaborative Group A. Complete response following definitive external beam radiation therapy in patients with bladder cancer has been noted to be a favorable prognostic indicator of long-term survival. 17 Long-term survival free of disease after treatment with and radiation awaits historical confirmation. Several advances in the treatment of disease eventually may be applicable to the treatment of invasive bladder for the control cancer. The effectiveness of intravesical of superficial disease may allow liberalization in the use of partial cystectomy. If multifocal and recurrent disease can be controlled adequately with intravesical therapy then wide local excision of invasive tumors may be curative and may allow for bladder preservation. Additional exciting areas awaiting further research include the use of bacillus Calmette-Guerin immunotherapy and the application of laser treatment to invasive disease. 89 • 90 Although only preliminary data exist concerning these new treatment modalities, they are potentially effective treatments that must be explored and added to our growing armamentarium of weapons in the battle against bladder cancer.

CONCLUSIONS

Muscle invasive bladder cancer remains a difficult disease to treat. Despite the significant strides that have been made,

half of all cancero

The identification of the active methotrexate-platinum based combination regimens heralds a new era in our ability to treat high stage disease. The role of adjuvant chemotherapy will become clearer in the future. Progress has been made on multiple fronts in our ability to preserve bladder function. The ability of the new mixed modality treatment regimens to produce survival statistics equal to that of radical exenteration is an important landmark on the route toward an ideai treatment for bladder cancero The synergistic effect of radiation and platinum is clear. The ability of interstitial radiation to control urothelial disease offers yet another treatment modality that warrants further study. We have come to recognize the profound effect that urinary diversion has on patients. Advances in the techniques of diversion and the importance of an integrated team approach to the cystectomy patient allow for the successful medical and social rehabilitation of these patients. The availability of several treatment options increases the burden of responsibility on the urologist and patient. It is incumbent on the physician to educate the patient concerning the various therapeutic alternatives, and the relative risks and benefits attendant to each. The patient, of necessity, will have a more active role in determining the course of treatment he desires to pursue. There no longer can be a single standard approach to all patients with invasive bladder cancer. Increasingly, decisions will focus on the life-style and sacrifice that each form of treatment entails. The particular desires, abilities and fears of each individual patient must be weighed carefully, and a judicious treatment plan must be formulated that is comfortable to the patient, his family and the treating physician. Over-all, recent advances in the treatment of invasive bladder cancer are substantial. Identification of effective combination chemotherapy, efficacious bladder-sparing modes of treatment and the development of easily manageable forms of urinary diversion are having profound effects on the current management of patients with invasive carcinoma of the bladder and offer great hope for the future. REFERENCES 1. Morrison, A. S.: Advances in the etiology of urothelial cancer. Urol.

Clin. N. Amer., H: 557, 1984. 2. Utz, D. C., Hanash, K. A. and Farrow, G. A.: The plight of the patient with carcinoma in situ of the bladde1. J. Urol., 103: 160, 1970. 3. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. 116: 180, 1976. 4. Lamm, L., Thor, D. E., Harris, S. C., Reyna, J. A., Stogdill, V. D. and Radwin, H. M.: Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J. Ural., 124: 38, 1980. 5. Whitmore, W. F., Jr., Batata, M. A., Ghoneim, M. A., Grabstald, H. and Una!, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Uro!., 118: 184, 1977. 6. Nichols, J. A. and Marshall, V. F.: The treatment of bladder carcinoma by local excision and fulguration. Cancer, 9: 559, 1956. 7. Prout, G. R., Jr., Griffin, P. and Shipley, W. U.: Bladder carcinoma as a systemic disease. Cancer, 43: 2532, 1979. 8. Catalona, W. J.: Bladder carcinoma. Guest editorial. J. Urol., 123: 35, 1980. 9. Droller, M. J.: The controversial role of radiation therapy as adjunctive treatment of bladder cancer. J. Urol., 129: 897, 1983. 10. Radwin, H. M.: Radiotherapy and bladder cancer: a critical review. J. Urol., 124: 43, 1980. 11. Marshall, V. F. and Whitmore, W. F., Jr.: The surgical treatment of cancers of the urinary bladder. Cancer, 9: 609, 1956. 12. Brice, M., II, Marshall, V. F., Green, J. L. and Whitmore, W. F., Jr.: Simple total cystectomy for carcinoma of the urinary bladder:

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~,.1,1ith

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