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Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Jo-Anne O. Shepard, m.d., Associate Editor Sally H. Ebeling, Assistant Editor

Stacey M. Ellender, Assistant Editor Christine C. Peters, Assistant Editor

Case 3-2004: A 57-Year-Old Man with Invasive Transitional-Cell Carcinoma of the Bladder
Donald S. Kaufman, M.D., William U. Shipley, M.D., W. Scott McDougal, M.D., and Robert H. Young, M.D.

presentation of case
From the Division of HematologyOncology (D.S.K.) and the Departments of Radiation Oncology (W.U.S.), Urology (W.S.M.), and Pathology (R.H.Y.), Massachusetts General Hospital; and the Departments of Medicine (D.S.K.), Radiation Oncology (W.U.S.), Urology (W.S.M.), and Pathology (R.H.Y.), Harvard Medical School. N Engl J Med 2004;350:394-402.
Copyright 2004 Massachusetts Medical Society.

A 57-year-old man came to this hospital for bladder-sparing treatment of invasive transitional-cell carcinoma of the bladder. He had had a slight burning sensation on urination for six months, and then he observed gross hematuria. Cystoscopy at another institution revealed a midline, posteriorwall mass, 3.0 by 3.0 by 1.4 cm, that involved the left ureteral orifice and that extended to the left lateral bladder wall. The mass was resected by the transurethral route, and pathological examination revealed transitional-cell carcinoma, grade 3 of 3, with invasion of the muscularis propria (Fig. 1). There was invasion of the prostatic urethra, but no invasion of the prostatic stroma was detected. An abdominopelvic computed tomographic (CT) scan showed thickening of the left wall of the urinary bladder but no evidence of hydronephrosis and no lymph-node metastasis. A bone scan disclosed no evidence of metastatic disease. A chest radiograph was normal. Total cystectomy with removal of the urethra and prostate was recommended. The patient came to this hospital for a second opinion and to seek other options for treatment. On physical examination, there was no palpable lymphadenopathy and no thyroid enlargement. The lungs, heart, and abdomen were normal. Rectal examination revealed a normal-sized prostate gland with no mass above it; the stool was normal in color and was negative for occult blood. There was no peripheral edema.

pathological discussion
Dr. Robert H. Young: Microscopical examination of the specimen obtained during transurethral resection of the tumor at the other hospital showed that the tumor was morphologically typical of transitional-cell carcinoma. There was a surface component of papillary carcinoma (Fig. 1A), beneath which nests and sheets of malignant cells infiltrated the lamina propria and muscle bundles of the muscularis propria (Fig. 1B). The tumor extended into the periurethral glands and, to a limited extent, invaded the connective tissue of the suburethral lamina propria. The tumor showed focal squamous and glandular differentiation (Fig. 1C). The spectrum of morphologic features seen in the specimen illustrates the remarkable histologic diversity of bladder cancer.

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lamina propria and then the thick muscle bundles of the muscularis propria. The pathology report should indicate whether the tumor invades the lamina propria, whether the specimen includes muscularis propria, and whether the muscularis propria is invaded by tumor, as it was in this case. There are pitfalls in assessing the depth of invasion.1 A layer of muscle fibers known as the muscularis mucosae may be present in the lamina propria. These are interrupted, thin, wispy fragments of muscle, which contrast with the thick muscle bundles of the muscularis propria. The pathology report should specifically note whether the muscle involved is muscularis propria, as opposed to muscularis mucosae.

management discussion
Dr. W. Scott McDougal: I would like to emphasize that carcinoma of the bladder that invades only the lamina propria is treated quite differently from carcinoma that invades the muscularis propria. We often see patients who have received a diagnosis of invasive disease at another hospital, but when the slides are reviewed at our institution, the pathologist finds that the tumor invades only the lamina propria. We are very cognizant of the need to communicate carefully with the pathologist about the extent of the invasion of disease.
surgical management of invasive bladder cancer

The standard of care for transitional-cell carcinoma of the bladder with invasion of the muscularis propria is cystoprostatectomy with or without urethrectomy and bilateral pelvic lymph-node dissection. We have developed a method of performing this procedure en bloc, allowing removal of the entire bladder, Figure 1. Specimen Obtained by Transurethral Resection prostate gland, and urethra as a single specimen.2 of the Bladder (Hematoxylin and Eosin). The resection is then followed by some form of At a low magnification (Panel A, 30), thickening of the bladder reconstruction or urinary diversion. urothelium with the typical papillary fronds of transitionalUrinary diversions may either preserve conticell carcinoma can be seen. At a higher magnification (Panel B, 250), small groups of malignant cells (arrows) can nence or result in incontinence. The latter, also be seen invading the large muscle bundles (arrowhead) known as conduits, involve the use of a segment of of the muscularis propria. Prominent glandular differenileum or colon or, on rare occasions, a segment of tiation (Panel C, 70) is a common feature of transitionaljejunum. The distal end is brought to the skin, and cell carcinoma. the ureters are implanted into the proximal end. The patient wears a urine-collection appliance. The advantages of a conduit are its simplicity and the low Pathological evaluation has an important role in number of immediate and long-term postoperative planning the treatment of bladder cancer.1 Bladder complications (about 13 percent in most series). The two types of urinary diversions that preserve cancers first invade the connective tissue of the

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continence are abdominal and orthotopic. Abdominal diversions require a continence valve, whereas an orthotopic neobladder depends on the urethral sphincter for continence. In both, the reservoir is made of bowel, which is fashioned into a globular structure. In the abdominal type of diversion, the stoma is brought through the abdominal wall to the skin. The patient catheterizes the pouch every four hours. Orthotopic urinary diversions entail the use of bowel brought to the urethra, thus allowing the patient to void by Valsalvas maneuver. Patients with either type of diversion must be able to catheterize themselves, since catheterization is mandatory with the abdominal reconstruction and occasionally necessary with the orthotopic reconstruction. It is my preference to use the large bowel in these reconstructions because it has a slightly more muscular wall and does not tend to become hypotonic. The patient in the current case did not wish to have his bladder removed. At this hospital, a bladder-sparing protocol has been instituted. Dr. Shipley and Dr. Kaufman, would you explain the rationale and development of this treatment?
bladder-sparing therapy for invasive bladder cancer

Dr. William U. Shipley: Radical cystectomy results in effective local control of bladder carcinoma. In the past, radiation treatment, in comparison with cystectomy, had inferior results; in no more than 40 percent of the cases was there local eradication of the tumor. Patients whose cancer did not completely respond to radiation therapy and who did not undergo an immediate salvage cystectomy were rarely cured. Those in whom transurethral resection of the tumor was visibly complete before radiation therapy and those in whom there was no hydronephrosis as a result of obstruction of the ureter by the tumor had a significantly higher cure rate.3 However, both methods of local treatment are associated with a high probability (approaching 50 percent) of subsequent distant metastasis, which generally is seen within two years after the initial treatment in cases in which it does occur.4 In the 1970s, we and others thus realized that transitional-cell carcinoma of the bladder that invades the muscle is often a systemic disease and that local therapy alone, such as cystectomy or irradiation, often did not cure these patients.5 Dr. Donald S. Kaufman: In the late 1970s, it was determined that cisplatin had activity against transi-

tional-cell carcinoma. In experimental systems initially, and later in clinical studies, it was shown to have both an important cytotoxic effect and a potent radiosensitizing effect. Clinical investigations, which were carried out under the auspices of the National Bladder Cancer Group, were directed toward the treatment of patients with muscle-invasive bladder cancer who were considered not to be candidates for cystectomy. This research required a multidisciplinary team comprising urologic surgeons, medical oncologists, and radiation oncologists. These early studies showed that irradiation of the bladder and pelvis could be combined with intravenous administration of cisplatin without damage to the bladder or adverse effects on bladder function.6 Dr. Shipley: These observations led us as well as investigators at other institutions in the 1980s to evaluate combination therapy for patients with muscle-invasive cancer, with the goal of making cystectomy unnecessary. The steps of the bladder-sparing protocol are outlined in Figure 2. The primary goal of all such protocols has been to offer the maximal chance of cure while preserving the function of the bladder. The first step is a transurethral resection of the primary tumor that is as complete as safely possible, followed by concurrent chemotherapy and radiation therapy. An important component of the protocol is an evaluation of the early response of the primary tumor to treatment. If the response is less than complete, cystectomy is recommended. If a complete response is documented by the pathologist, consolidation treatment consisting of additional concurrent chemotherapy and radiotherapy, to a total dose of 64 to 65 Gy, is given. Patients who undergo consolidation treatment and have a complete response receive adjuvant chemotherapy and are subsequently monitored indefinitely with regular cystoscopic examinations. Those whose tumors recur are advised to undergo salvage cystectomy. Six phase 2 or phase 3 trials have been completed since 1986. Since 1989, many of these protocols have been carried out under the auspices of the Radiation Therapy Oncology Group, a national cooperative multicenter group.7 Since 1993, the duration of induction treatment before evaluation of the urologic response has been shortened to three weeks with the use of radiation administered twice daily and concurrent chemotherapy given several times weekly. This approach shortens the time to cystectomy for patients whose disease does not completely respond to the induction treatment.

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Transurethral resection

Induction Therapy
Radiation Chemotherapy (cisplatin, paclitaxel)

Cystoscopy (after 1 mo)

No tumor

Residual tumor

Consolidation Therapy
Radiation Chemotherapy (cisplatin, paclitaxel)

Cystoscopy (after 2 mo)

No tumor

Residual tumor

Adjuvant Therapy
Chemotherapy (cisplatin, gemcitabine)

Cystectomy

Figure 2. Bladder-Sparing Therapy Protocol. In the bladder-sparing protocol, induction treatment consists of a cisplatin-based regimen given in conjunction with twice-daily radiation treatments five days per week over a three-week period. If cystoscopic examination shows no residual tumor, consolidation therapy consisting of twice-daily radiation treatments five days per week over a two-week period is given with concurrent chemotherapy. Repeated cystoscopy and biopsy are performed two months later. If no residual tumor is detected, the patient proceeds to adjuvant chemotherapy consisting of three monthly cycles of cisplatin-based combination chemotherapy. Patients with residual tumor in the bladder after either induction or consolidation therapy undergo radical cystectomy, followed by the same adjuvant therapy.

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100

75

Stage T2

50

Stage T3 or T4a

26

0
0 1 2 3 4 5 6 7 8 9 10

Years after Enrollment No. at Risk

Stage T2 Stage T3 or T4a 90 100 40 40 11 17

Figure 3. Estimates of Disease-Specific Survival among Patients Undergoing the Bladder-Sparing Protocol for Invasive Bladder Cancer, According to Clinical Tumor Stage. The five-year actuarial survival rate among patients with early (stage T2) disease is 74 percent, and that among patients with locally advanced disease is 53 percent. Adapted from Shipley et al.,8 with permission from the publisher.

The 10-year overall and disease-specific survival rates among patients who have undergone surgery and combination therapy (Fig. 3)8-10 are similar to those in contemporary series of patients with similar clinical and pathological stages of disease who have undergone radical cystectomy.11,12 Dr. Kaufman: Bladder-sparing treatment may be considered an alternative to cystectomy in selected patients with muscle-invasive bladder cancer. The initial evaluation includes a complete hematologic assessment, blood chemical analysis (including measurement of the serum creatinine level and calculation of the creatinine clearance), an abdominopelvic CT scan, a thoracic CT scan, and a bone scan. Criteria for ruling out bladder-sparing treatment include poor renal function, moderate (or greater) unilateral or bilateral hydronephrosis, an irritable bladder, a bladder of low capacity, prior pelvic radiation therapy, involvement of the prostatic stroma,13 or diffuse carcinoma in situ on examination of a mucosal biopsy specimen.12,14 Dr. Heney, will you describe the technique of transurethral tumor resection and the operative findings in this case? Dr. Niall M. Heney (Urology): The approach to transurethral resection of a bladder tumor when the

bladder-sparing protocol is used is different from the approach in the case of a possible cystectomy. In the latter situation, the objective is simply to obtain tissue at a deep enough level to detect muscle invasion. In the former, the goal is to resect as widely and deeply as possible so that there is substantial debulking, if not total resection, of all the visible tumor. In addition, we take biopsy specimens from an area adjacent to the tumor, from other sites in the bladder, from the prostatic urethra, and from the base of the resected area. The resection to remove an invasive tumor may be very deep; if necessary, it may even extend into the perivesical fat. This patient had undergone transurethral resection of the bladder. We performed a second cystoscopic examination to ensure that all the visible tumor had been removed. On examination, it became evident that an extensive resection had been carried out on the left side of the prostatic urethra, with healing mucosa lateral to the left ureteral orifice and extending down to the bladder neck and the left side of the prostatic urethra. Both ureteral orifices were patent. A small, exophytic papillary tumor high on the posterior wall proved on biopsy to be a noninvasive papillary transitional-cell carcinoma. Biopsy specimens were obtained from the mucosa lateral to both ureteral orifices, the prostatic urethra, and the anterior bladder wall. The remainder of the bladder appeared normal. Retrograde pyelographic examination revealed a normal right ureter and collecting system and some dilatation of the left lower ureter but no obstruction. Careful bimanual examination did not reveal any induration on the left side of the base of the bladder. Examination of the biopsy specimen from the left ureteral orifice showed high-grade transitional-cell carcinoma; examination of the other specimens revealed no tumor.
outcomes of bladder-sparing therapy

Survival (%)

Dr. Kaufman: In our experience with 190 patients, 120 (63 percent) had an initial complete response and completed the protocol. Sixty-six patients (35 percent) ultimately required cystectomy: 41 for a less-than-complete response and the other 25 for recurrent invasive tumors. The 5-year and 10-year actuarial survival rates are shown in Table 1. No patient in our series required cystectomy because of urinary symptoms.8 Results from other institutions using bladder-sparing combination treatments are similar (Table 2).15-19 In the case under discussion, after the transure-

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thral resection, laboratory tests were performed to determine the patients eligibility for the bladdersparing protocol. The complete blood count was normal, as were the levels of urea nitrogen and creatinine and the creatinine clearance, and he was considered to be eligible for the bladder-sparing protocol. He tolerated three weeks of induction therapy consisting of twice-daily radiation treatments and chemotherapy with cisplatin, without complications. Repeated cystoscopy and transurethral resection of the bladder at the end of induction therapy showed no evidence of cancer. There was severe urothelial atypia, which was believed to have been caused by the radiation and chemotherapy. Cytologic examinations of the urine were negative for tumor cells. One week later, consolidation chemotherapy consisting of cisplatin and concurrent radiation treatments over a two-week period were begun; the patient tolerated this regimen without difficulty. Another cystoscopic evaluation and biopsy of the bladder revealed no evidence of tumor. Therefore, a course of adjuvant chemotherapy, consisting of cisplatin, methotrexate, and vinblastine given in three monthly cycles, was administered; he tolerated it well. One of the chief disadvantages of a bladder-sparing approach is the risk of local recurrence or the development of new bladder cancer. Lifelong bladder surveillance is essential for patients who retain their bladder after invasive cancer, because only prompt salvage therapy can prevent a focus of new or recurrent bladder cancer from disseminating. At three-month intervals after the completion of his adjuvant therapy, this patient underwent cystoscopic examinations, which revealed changes suggestive of radiation cystitis. Occasional bouts of hematuria occurred. Seventeen months after the completion of chemotherapy, cystoscopic examination showed cells that appeared to be transitional-cell carcinoma. Another cystoscopic examination two months later disclosed papillary transitional-cell carcinoma, grade 3 of 3, with extensive glandular differentiation that invaded the lamina propria; no muscularis propria was identified. A repeated cystoscopy with transurethral resection was performed one month later. Dr. Young: During the years after his initial diagnosis, this patient underwent a number of surveillance procedures and biopsies. Pathological evaluation of biopsy specimens in cases such as this one is not always straightforward, because radiation in-

Table 1. Results of Bladder-Sparing Treatment of Muscle-Invasive Bladder Carcinoma.* Patients Characteristics No. of Patients Overall Survival 5 yr % Overall Clinical stage T2 T3 or T4a Hydronephrosis No Yes 163 27 55 48 37 29 90 100 62 47 41 31 0.15 64 53 61 49 190 547.5 368.3 0.02 74 53 66 52 0.09 10 yr P Disease-Specific P Value Survival Value 5 yr % 637.5 598.0 0.01 10 yr

* Data are from Shipley et al.8 Plusminus values are means 95 percent confidence limits. P values are for the comparisons between stages T2 and T3 or T4a and between the absence and presence of hydronephrosis. Stage T2 denotes superficial invasion of the muscularis propria, T3 deep invasion of the muscularis propria, and T4a involvement of adjacent organs.

Table 2. Results of Bladder-Sparing Therapy and Cystectomy for the Treatment of Muscle-Invasive Bladder Cancer.* Therapy and Year of Series Overall Five-Year No. of Five-Year Survival with Patients Survival an Intact Bladder % Bladder-sparing therapy 1993 1994 1996 1997 1998 1998 2002 2002 Cystectomy 2001 2001 181 633 36 48 NA NA Dalbagni et al.11 Stein et al.10 42 79 91 120 162 123 190 415 52 52 62 63 55 49 54 50 42 41 44 NA 44 38 45 42 Tester et al.15 Dunst et al.16 Tester et al.17 Houssett et al.18 Sauer et al.19 Shipley et al.7 Shipley et al.8 Rodel et al.9

Reference

* NA denotes not available.

duces abnormalities such as fibroblasts with atypical, hyperchromatic nuclei (so-called radiation fibroblasts) in the lamina propria and atypia of the urothelium. Both of these abnormalities were seen in this case, as was true dysplastic urothelium, a

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Figure 4. Specimen Obtained on Transurethral Resection of the Bladder 20 Months after the Completion of Therapy (Hematoxylin and Eosin, 500). There is recurrent transitional-cell carcinoma on the surface (upper portion of the figure), with nests of tumor cells present in the lamina propria (arrows).

finding consistent with the patients history of bladder cancer. Eventually, this patient had unequivocal evidence of recurrence of the cancer with superficial invasion of the lamina propria, which was confirmed on examination of the transurethral-resection specimen 20 months after the completion of therapy (Fig. 4); muscularis propria was present and was not invaded. Dr. McDougal: Dr. Heney, would you discuss the management of recurrent cancer after bladder-sparing therapy? Dr. Heney: Like many of our patients, this man had sought us out initially because he absolutely did not want a cystectomy. He was a very burly, energetic, physically active man who ran his own business. He knew from the very beginning that if the cancer recurred, we would recommend removal of the bladder, according to our standard procedure, but he nevertheless continued to refuse cystectomy. After we were certain that he understood the risks, we offered him intravesical treatment with bacille CalmetteGurin. Over the years, we have treated 32 patients who

had superficially recurrent cancer after undergoing treatment according to the bladder-sparing protocol.20 Three of them subsequently had a cystectomy, and the remaining 28 received intravesical chemotherapy; 18 of them had a complete and durable response. The patient under discussion underwent resection of all visible tumor, followed by six weeks of intravesical immunotherapy with bacille Calmette Gurin and then three weekly treatments of bacille CalmetteGurin every six months. No abnormalities were found on his most recent cystoscopic examination or on examination of his most recent biopsy specimens. Dr. McDougal: Dr. Anthony Zietman and Dr. Dianne Sacco have been interested in assessing the quality of life of patients whose bladders have been preserved using this protocol. Could you summarize your studies and tell us how this patient is doing in this regard? Dr. Anthony L. Zietman (Radiation Oncology): Organ conservation is a common theme in contemporary oncology, with the most notable examples being conservation in breast, anal, and laryngeal cancers. There is merit to such an approach only if the preserved organ functions at a level acceptable to the patient. When a patient has been treated with radiation to the bladder, as in this case, one would like to know whether the patient has urinary symptoms and the status of his or her bowel and sexual functioning. Long-term follow-up is important, since radiation-induced effects on the bladder may take several years to be fully manifested. We have examined bladder function in 48 longterm survivors of combination therapy at this institution by conducting a quality-of-life questionnaire study and, in 32 of these patients, a formal urodynamic study as well. The results of the questionnaire showed that 39 of the patients (81 percent) had only mild urinary symptoms or no urinary symptoms at all and that 37 (77 percent) had no bowel symptoms; about half the treated male patients retained their erectile function.21 This study thus reinforced previous reports22,23 that the conserved bladder retains its normal function in most cases. Dr. Dianne E. Sacco (Urology): In the urodynamic studies, we mainly focused on the compliance and capacity of the bladder and on the stability of the detrusor muscle. There was reduced bladder compliance in 7 of the 32 patients (22 percent), but it was symptomatic in only 1 of them, and the median bladder capacity was within the normal range. The male

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patients had remarkably normal bladder function, even with some detrusor instability, which can also occur in patients with prostatic hyperplasia. Involuntary contractions and incontinence were seen in only two patients, both women, who also had a marked decrease in bladder compliance and urinary symptoms. Dr. Zietman: This patient did not undergo urodynamic testing but did respond to the questionnaire. Five years after his initial diagnosis, he reports fairly frequent urinary urgency as his only urinary symptom; he has no bowel symptoms and has normal erectile function, reporting the highest rating on the questionnaire for satisfaction with his sex life. In addition, no evidence of recurrent carcinoma has been found since his intravesical immunotherapy. Dr. Kaufman: In summary, radical cystectomy remains the standard of care for muscle-invasive bladder cancer, but bladder preservation is a reasonable goal in the treatment of this disease. Bladder-sparing treatment requires a coordinated approach by an experienced multidisciplinary team. In highly selected patients, such as the one discussed here, who
references
1. Young RH. Pathology of carcinomas of the urinary bladder. In: Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS, eds. Comprehensive textbook of genitourinary oncology. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:310-21. 2. McDougal WS. Urethrectomy. In: McDougal WS, ed. Rob & Smiths operative surgery, urology. 4th ed. London: Butterworths, 1986:526-9. 3. Shipley WU, Rose MA, Perrone TL, Mannix CM, Heney NM, Prout GR Jr. Fulldose irradiation for patients with invasive bladder carcinoma: clinical and histological factors prognostic of improved survival. J Urol 1985;134:679-83. 4. Kaufman DS, Shipley WU, Griffin PP, Heney NM, Althausen AF, Efird JT. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med 1993;329:1377-82. 5. Prout GR Jr, Griffin PP, Shipley WU. Bladder carcinoma as a systemic disease. Cancer 1979;43:2532-9. 6. Shipley WU, Prout GR Jr, Einstein AB, et al. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA 1987;258:931-5. 7. Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by

desire preservation of the bladder and in whom control of the disease is confirmed by cystoscopic examination during treatment, bladder-sparing treatment offers results comparable to those in patients with similar grades and stages of disease who undergo radical cystectomy. As this case illustrates, the risk of recurrence in the bladder is not trivial (17 percent, among our patients), and lifelong surveillance is necessary for patients with intact bladders. We are continuing to modify our protocols in randomized clinical trials in order to identify more effective treatment regimens with less toxicity.

anatomical diagnosis
Transitional-cell carcinoma of the urinary bladder, grade 3 of 3, with invasion of the muscularis propria and involvement of the prostatic urethra (stage T2N0M0 [muscle invasion without nodal or distant metastasis]). Recurrent transitional-cell carcinoma of the urinary bladder, grade 3 of 3, after treatment according to a bladder-sparing protocol, with invasion of the lamina propria.

combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16: 3576-83. 8. Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology 2002;60:62-7. 9. Rodel C, Gabenbauer GG, Kuhn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002;20: 3061-71. 10. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19:666-75. 11. Dalbagni G, Genega E, Hashibe M, et al. Cystectomy for bladder cancer: a contemporary series. J Urol 2001;165:1111-6. 12. Shipley WU, Kaufman DS, Heney NM, Althausen AF, Zeitman AL. An update of combined modality therapy for patients with muscle invading bladder cancer using selective bladder preservation or cystectomy. J Urol 1999;162:445-51. 13. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, eds. AJCC cancer staging handbook. 6th ed. New York: Springer-Verlag, 2002. 14. Kaufman DS, Winter KA, Shipley WU.

The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist 2000;5:471-6. 15. Tester W, Porter A, Asbell S, et al. Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys 1993;25:783-90. 16. Dunst J, Sauer R, Schrott KM, Kuhn R, Wittekind C, Altendorf-Hofmann A. Organsparing treatment of advanced bladder cancer: a 10-year experience. Int J Radiat Oncol Biol Phys 1994;30:261-6. 17. Tester W, Caplan R, Heaney J, et al. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol 1996;14:119-26. 18. Houssett M, Dufour B, Maulard-Durdux C, Chretien Y, Mejean A. Concomitant fluorouracil (5-FU)-cisplatin (CDDP) and bifractionated split course radiation therapy (BSCRT) for invasive bladder cancer. Prog Proc Am Soc Clin Oncol 1997;16:319a. abstract. 19. Sauer R, Birkenhake S, Kuhn R, Wittekind C, Schrott KM, Martus P. Efficacy of

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radiochemotherapy with platin derivatives compared to radiotherapy alone in organsparing treatment of bladder cancer. Int J Radiat Oncol Biol Phys 1998;40:121-7. 20. Zietman AL, Grocela J, Zehr E, et al. Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, Tis recurrence within the retained bladder. Urology 2001;58:380-5.

21. Zietman AL, Sacco D, Skowronski U, et

al. Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors. J Urol 2003;170:1772-6. 22. Caffo O, Fellin G, Graffer U, Luciani L. Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma: a sur-

vey by a self-administered questionnaire. Cancer 1996;78:1089-97. [Erratum, Cancer 1996;76:2037.] 23. Henningsohn L, Wijkstrom H, Dickman PW, Bergmark K, Steineck G. Distressful symptoms after radical radiotherapy for urinary bladder cancer. Radiother Oncol 2002; 62:215-25.
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