Carcinoma of the bladder (CaB) is an important tumor of the genitourinary tract with a total of 263,000 new patients being diagnosed in the world in 1999. 1 This tumor is more common in males with the incidence of 9.9 per 100,000 while the incidence in females is 2.3 per 100,000. There is a tenfold geographic variation in the incidence of CaB with the highest incidence being reported in North America and North Africa and the lowest in China. The incidence and mortality of genitourinary cancer in the United States are shown in Table 1. 2
Relative 5-year survival rates also vary significantly by world region with an overall reported survival of 84% for the white population in the United States and an overall survival of 46% for that of Eastern Europe. 1–3 These differences in survival rates may be due to decreased access to medical care for patients with CaB in Eastern Europe, which results in more advanced stages at diagnosis, which in turn are much more difficult to control; and a lack of consistency in reporting the incidence of superficial CaB.
In the past 25 years, there has been a steady increase in 5-year survival rates for patients with CaB in the United States. The overall 5-year survival for white patients has increased from 74% in 1976 to 84% in 1994. 3 It is of interest to note that 74% of CaB patients in the United States were diagnosed in localized stage, with 18% presenting with regional, and 3% with distant disease. At the same time, treatment for this disease has become more effective with major advances in surgical and radiotherapy techniques, which sharply lowered treatment toxicity. 4 The systematic use of adjuvant chemotherapy to a large extent was also responsible for improved survival. 4 Of particular importance to be noted is a common application of bladder conservation treatment and the use of continent bladder replacement techniques following radical cystectomy. All of these newer techniques are responsible for major improvement in quality of life of contemporarily treated patients. Additionally, a better understanding of natural history of CaB and new developments in molecular genetics have also contributed to improved patient survival and improved quality of life. 4–7 The purpose of this paper is to review the use of radiotherapy in the management of patients with CaB.
Radiotherapy has been used as an important treatment modality for CaB for more than half a century. In the past 15 years this treatment has undergone evolution with a major emphasis on a greater accuracy of treatment delivery and a reduction of target volume. This evolution was facilitated by the introduction of improved imaging techniques and application of modern computer assisted treatment planning. A better target volume definition permitted the routine use of conformal radiotherapy. 8,9 The use of megavoltage portal imaging systems further helped to improve the accuracy of treatment delivery, which was confirmed in a prospective randomized trial reported by Royal Marsden Hospital of London, UK. 10 An important study evaluating various prognostic factors critical in the selection process prior to definitive radiotherapy was reported in 1985 from Massachusetts General Hospital of Boston (MGH). 11 Prognostic factors favorably affecting treatment outcome reported in that study included: (1) clinical stage; (2) absence of ureteral obstruction; (3) complete transurethral resection of the visible bladder lesion; (4) complete response (CR) to radiotherapy; and (5) radiation dose given. 11 It is of interest to note the importance of ureteral obstruction on survival in patients with T2 and T3 tumors. The 5-year survival of radiotherapy-treated patients without ureteral obstruction was 54% versus 22% for those with ureteral obstruction (p = 0.02). 11 The authors of the MGH study recommended the use of a 4-field “box technique” delivering 50.4 Gy at 1.8 Gy daily to the bladder and its regional lymphatics with a boost dose to the bladder of 14 to 18 Gy. The dose to the posterior rectal wall was limited to <60 Gy and to the anus and hip joints to <50 Gy.
Two commonly used techniques for CaB at the University of Southern California School of Medicine (USC) are demonstrated in Figures 1 through 4 with either a 3- or 4-field portal arrangement being used for the treatment of patients. Preparation for CaB radiotherapy begins with patient placement in an immobilization device consisting of a Vac-Lock cushion (Med-Tec, Inc., Orange City, LA, U.S.A.) combined with a thermoplastc sheet. The use of this immobilization procedure greatly reduces patient motion during the treatment and helps to maintain treatment reproducibility. Computed tomography (CT) scan of the pelvis is obtained in the treatment position. The resulting images are downloaded to the treatment planning computer, which has a 3-D reconstruction capability and a virtual simulation feature. The target volume is typically not including the regional lymphatics. Care is taken to shape the radiation portals in order to optimize protection of the normal structures such as the posterior rectal wall or small bowel. The shaping of radiation portals is facilitated by the use of virtual simulation with its beam’s eye view feature. Figure 5 shows an example of lateral digitally reconstructed radiograph with field shaping in place. Radiation dose is defined to the 95% isodose surface and is given with a 20-MV photon beam. Total dose to the bladder is limited to 60 Gy given at 2.0 Gy daily increments. The dose restrictions to the neighboring structures are similar to those recommended by the MGH group.
A study of 347 T3 transitional cell CaB patients was reported from Western General Hospital of Edinburgh, Scotland. 12 Patients were scheduled to receive 55 Gy in 20 fractions over a period of 18 days. Local tumor regression was assessed cystoscopically 6 months following completion of radiotherapy in 272 (82%) patients. Of these 272 patients, 112 (41%) showed complete tumor regression. The incidence of tumor regression was similar for those with ulcerative and solid tumors (about 52%), while it was 27% for papillary and 31% for mixed lesions, (p = 0.024). Tumor grade and size (<5 cm vs. >5 cm) were also important factors influencing tumor regression (p = 0.003). It is of interest to note that grade I tumors had a regression rate of 17%, grade II of 31%, and grade III of 56% (p < 0.0001). The 5-year incidence of local tumor control was 10% for grade I, 14% for grade II, and 35% for grade III patients. In multivariate analysis only patient age (p = 0.06) and hemoglobin level (p = 0.025) were important prognostic factors. Local tumor regression following radiotherapy was an important factor predicting survival. The 5- and 10-year survival of patients with complete tumor regression was 45% and 25%, respectively, as compared with 21% and 15%, respectively, for those with partial tumor regression.
In a study of 121 patients from Princess Margaret Hospital, Toronto, Ontario, Canada, the reported 5-year actuarial survival was 32% and the cause-specific survival was 45%. 13 A total of 33 (27%) patients were long-term survivals with preserved bladder function. Important prognostic factors for cause-specific survival and complete tumor regression included clinical stage, hemoglobin level, and tumor appearance (solid, papillary, or mixed). Patients received radiotherapy to the bladder consisting of 60 Gy given in 30 equal daily fractions. Similar outcomes with the use of definitive radiotherapy in patients with CaB were reported by other investigators. 14–20
It is of interest to analyze a study of 74 CaB patients treated with radiotherapy in Western Sweden. 21 The authors reported on 701 CaB patients treated in their medical center between 1987 and 1994. This group included 74 (11%) patients who were selected for definitive radiotherapy. The policy was to treat younger patients and those in a better general condition with radical cystectomy while patients unfit for surgical therapy were selected for irradiation. Based on this biased selection the authors concluded that “full dose external beam radiotherapy in patients with bladder carcinoma was associated with high (84%) local recurrence and serious complication rates.” On the other hand studies from Denmark and Norway recommended a routine use of irradiation in elderly patients with CaB. 22,23
Hypofractionation or hyperfractionation treatment schedules were evaluated in patients treated for CaB. Reduced number of fractions is particularly appealing in elderly and symptomatic patients with CaB. The reported studies showed good treatment efficacy in terms of its palliative effect as well as reasonably good long-term survival. 24–26
Two out of three of these reports suggested good treatment tolerance with one study reporting higher incidence of late toxicity as compared to the standard-fraction treatment regimens. 26 Two fraction a day radiotherapy was studied in England. 27 A total of 24 patients with muscle-invasive CaB received radiotherapy at 1.8 Gy to 2.0 Gy fractions given twice daily and separated by an interval of 6 hours. Total tumor dose ranged from 54 Gy to 64 Gy. The 2-year actuarial survival was 35% with a 56% incidence of local control. Radiation Therapy Oncology Group (RTOG) grade 2 acute bowel toxicity was reported in 52%, grade 3 in 26%, and grade 4 and 5 in 4% (1 patient), respectively. The mean duration of this bowel toxicity was 4.5 weeks. Grade 2 and 3 acute urinary problems were reported in 30% and 17%, respectively, and its mean duration was 7.2 weeks. Late toxicity (grade 1 and 2) was reported in 4 (17%) patients. In view of the above data two-fraction radiotherapy schedules with the doses given should be studied only in controlled clinical trials.
In a prospective randomized trial 168 patients with T2 to T4 CaB were treated with a one a day (2.0-Gy fraction) treatment schedule and compared with three times a day (1.0 Gy per fraction) schedule. 28 Total radiation dose was 64 Gy for the former group and 84 Gy for the latter. In both groups treatment was completed in 8 weeks, which included a planned 2-week rest period for the hyperfractionation schedule-treated patients. There was an apparent survival and local control benefit at the 5- and 10-year level favoring patients who received three-fraction-a-day radiotherapy. In Cox’s regression analysis there was survival relative hazard of 1.52 and local control hazard of 1.33. The benefits of the hyperfractionation treatment schedule were apparent for early and more advanced clinical stages. It is apparent that the altered fractionation schedule should be the subject of a multiinstitutional prospective randomized trial in order to assess its usefulness in selected patients with muscle-invasive CaB.
In patients with muscle-invasive CaB it is difficult to compare the outcomes of definitive radiotherapy and surgical treatments. This is primarily due to the obvious selection bias favoring patients who are to undergo radical cystectomy. Nevertheless, a review of 13 selected studies with a total of 3,824 patients treated with radiotherapy alone and using various treatment techniques, shows 5-year survival rates ranging from a low of 7% to a high of 32%. The 10-year survival based on five reported studies show survival rates of 7% to 19% (Table 2).
Preoperative pelvic irradiation in patients with CaB has been used infrequently in the United States in the past 15 years. The reason for the lack of interest in preoperative radiotherapy in the United States has been due to: (1) improved treatment results with radical cystectomy;(2) a low incidence of local tumor recurrence following radical cystectomy; (3) a routine use of adjuvant chemotherapy in patients with muscle invasive CaB; and (4) inconclusive and relatively poor treatment outcomes reported with the use of adjuvant radiotherapy. 29–32 In recent years there has been some revival of the interest in preoperative irradiation in appropriately selected CaB patients. Two important studies supported the use of preoperative radiotherapy in selected patients with muscle invasive CaB. 33,34
A study from M.D. Anderson Cancer Center, Houston, TX, is of particular relevance. 34 A non-randomized comparison was made between two patient groups. Group I consisted of 301 evaluable T2 to T4 CaB patients who received preoperative irradiation from 1960 to 1983. Radiotherapy was given 4 to 6 weeks prior to cystectomy at 2.0 Gy daily to a total mean dose of 49 Gy. Group II consisted of 220 evaluable patients treated with radical cystectomy alone between 1985 and 1990. Median follow-up for group I was 91 months and for group II, 54 months. The two treatment groups were of comparable clinical stages of disease. There was no significant difference in survival between the two treatment groups in patients with clinical stage T2 and T3a. The 5-year actuarial survival for 92 T3b group I patients was 91% as compared to 72% for those 43 T3b patients who were treated with radical cystectomy alone (p = 0.003). The 5-year incidence of distant metastasis was 33% versus 46%, respectively, for patients in group I and II (nonsignificant [NS]). Multivariate analysis factors which independently were predictive of local tumor control included: (1) pretreatment hemoglobin level; (2) serum blood urea nitrogen (BUN) concentration; and (3) treatment given (group I vs. group II). Since patients who were treated with radical cystectomy were managed more recently with the use of contemporary surgical techniques and frequently (80%) with modern polychemotherapy the study outcomes are of even a greater significance. The authors recommended the use of preoperative radiotherapy in patients with clinical stage T3b tumors.
A prospective randomized trial in patients with clinical stage T2 to T4a CaB was reported by the Danish Vesical Cancer Group (DAVECA 8201). 35 Group I consisted of 88 patients who received preoperative irradiation (40 Gy) followed by a planned radical cystectomy. Group II (95 patients) received definitive radiotherapy (60 Gy) with radical cystectomy reserved to manage local recurrences. Patients were equally distributed by important prognostic factors. The protocol was followed by 66 (75%) group I patients and 88 (93%) of group II patients of whom 27 (31%) were treated with salvage radical cystectomy. There was no significant difference in survival, incidence of tumor control, or complication rate between patients of the two treatment groups. The study investigators recommended that clinicians managing patients with transitional cell carcinoma of the bladder (TCC) inform their patients with locally advanced CaB of the bladder preservation opportunity reserving radical cystectomy for those with tumor recurrence.
Treatment complications in patients receiving preoperative and definitive radiotherapy were analyzed at University of Umea, Umea, Sweden. 36 Complication rates were unusually high with 71% of preoperatively and with 78% definitively treated patients experiencing treatment toxicity. Gastrointestinal complications were common with 39% seen in preoperative patients and 67% in primarily treated patients. This high complication rate is contrary to other published data and contrary to our experience at USC. 11–21 The reason for this high complication rate at the University of Umea is not immediately apparent.
An important study evaluated all of the published evidence on the use of planned preoperative irradiation in patients with muscle-invasive CaB. 37 A total of five published prospective randomized trials on the use of preoperative radiotherapy were subjected to a meta-analysis. The conclusion of this study was that the available data do not support a routine use of planned preoperative pelvic irradiation in patients with muscle-invasive CaB.
The use of brachytherapy as a part of management of patients with CaB is almost exclusively reported from Europe. 38–43 Only a few studies on a small number of patients were published in the United States. 44,45 Modern brachytherapy in patients with CaB was introduced by Brigit Van Der Werf-Messing of Rotterdam, the Netherlands. 38 A large number of patients were treated with brachytherapy in Rotterdam Radiotherapy Institute. Excellent treatment outcomes were reported with a low incidence of toxicity. Patients selected for brachytherapy were those with tumors with a maximum dimension of 5 cm or less. A randomized trial was conducted of 345 patients with T1 tumors. A total of 148 (43%) patients were treated with transurethral resection (TURB) alone while 197 (57%) patients received a radioactive implant following TURB. There was a significant (p = 0.0002) survival advantage at 10 years following therapy in patients who received a radioactive implant after TURB. Similarly, freedom from metastasis at 10 years was reported in 85% of the patients treated with brachytherapy as compared to 49% in those treated with TURB alone. Freedom from local relapse at 5 years was reported in 80% of the combined treatment group as opposed to 20% of the TURB alone group. Similar excellent treatment results were obtained in selected patients with T2 and T3 tumors. A subsequent study on 66 muscle-invasive CaB patients with the use of TURB, iridium-192 implants, and external beam radiotherapy was reported from the same medical center. 39 Freedom from local relapse at 5 years was reported in 88% of patients, and bladder preservation was obtained in 98% of those who were long-term survivors. Grade 3 RTOG toxicity was reported in only 1 (1.5%) patient. Treatment results with the use of brachytherapy in muscle-invasive CaB were reported in nearly 2,000 patients from the Netherlands, France, and Belgium. 38–43 All of these reports validated this therapeutic approach in properly selected patients with muscle-invasive CaB.
Management of patients with locally advanced bladder tumors presents a challenge to clinicians. These patients are frequently old, severely symptomatic, may have coexisting medical problems and may have received prior intensive chemotherapy. The symptoms and signs of progressive locoregional CaB may include the following: (1) pelvic pain; (2) obstruction of ureter(s); (3) problems due to the presence of a large tumor mass in the pelvis; (4) urinary obstructive and irritative symptoms and signs; (5) hematuria; and (6) lower extremity edema. While the presence of microscopic hematuria usually does not present a major management problem, patients with gross hematuria need to be treated to prevent anemia resulting from chronic blood loss. Radiotherapy has been frequently applied in these patients in order to improve their quality of life by reducing or eliminating their symptoms due to tumor growth. A standard course of palliative pelvic irradiation consists of 50 Gy given in 25 daily fractions with shorter courses (30 Gy in 10 fractions) frequently being selected to reduce the number of times the patient needs to report for daily therapy. A report on 39 advanced CaB patients treated with 30 Gy in 2 weeks from the Norwegian Radium Hospital in Oslo, Norway suggests a lack of efficacy of this treatment course. 46,47 In another report a single high-dose pelvic radiotherapy was found to be very effective in controlling gross hematuria. 48 It is apparent that no single course of radiotherapy is superior in obtaining a desired palliative effect. Oncologists managing patients with locally advanced and symptomatic CaB should select an appropriate treatment schedule to optimally address clinical problems of a given patient. It is obvious that patient quality of life following a course of palliative irradiation should improve with a low probability of treatment-related toxicity. Hypofractionation treatment schedules should be considered because they are effective and require fewer patient visits for therapy. 22–24 Radiotherapy is a frequently used and effective treatment for patients with metastatic CaB. Treatment response in those with bone pain is over 70% with a similar effectiveness seen in patients with tumor involvement of the spine. Spinal cord or cauda equina involvement should be diagnosed early and treated promptly to prevent the occurrence of significant neurologic dysfunction.
COMBINED MODALITY THERAPY
About 15 years ago a trend developed to treat patients with muscle-invasive TCC of the bladder with a combination of radical cystectomy and adjuvant chemotherapy. The reported treatment results were better than those obtained with definitive bladder irradiation. The USC results of radical cystectomy at 5 years after treatment ranged from a low of about 55% for pT3 tumors to a high of 100% for those with pT1 or carcinoma in situ lesions. 49 It is of interest to note that of the 20 patients treated with any T-stage and pelvic lymphadenopathy, 42% were 5-year survivals. At the same time there has been a sharp decrease in the incidence of surgical complications and an improvement in patient quality of life due to a wide application of orthotopic ileal reservoir anasthomosed to the urethra. This procedure was initially performed in male patients and subsequently also in selected female patients. 49 Based on such excellent results, radical cystectomy became a gold standard treatment for muscle-invasive CaB.
In spite of these impressive surgical results a search continued for a more effective therapy that would preserve bladder function, maintain a good quality of life, and produce survival rates comparable to those of radical cystectomy. The centers to pioneer modern bladder preservation therapy using multimodality therapeutic approach included University of Erlangen, Erlangen, Germany and Harvard University, Cambridge, Massachusetts. 50–53 Results of a phase I/II study on the treatment of 67 muscle-invasive CaB patients was reported from the University of Erlangen. 50 Patients were treated with TURB followed by 50.4 Gy given at 1.8 Gy daily fraction with simultaneous cisplatin chemotherapy. This chemotherapy was given at 25 mg/m2daily for 5 days during the first and last week of radiotherapy. Complete remission was obtained in 42 of 56 (75%) patients, including 14 of 16 (88%) with T2 tumors, 27 of 37 (75%) with T3, and 1 in 4 (25%) with T4 tumors. Local recurrence was reported in 10 of the 61 (16%) patients who underwent bladder preservation procedures. The overall 3-year survival was 66% including 73% for T1, 68% for T2 to T3, and 25% for T4 patients. A comparison between complete remission rates obtained following TURB in 62 matched patients treated without chemotherapy and 66 patients who were treated with a chemoradiotherapy combination showed a significant (p < 0.005) difference in remission rates favoring patients who received combined therapy (Table 3). There was, however, no difference between the two treatment groups in the overall 3-year survival with 66% incidence for each group. The combined modality therapy was well tolerated by the study patients and no severe complications were observed.
The same group of investigators published a report based on 333 CaB patients, which included 128 (38%) TURB plus radiotherapy (RT) patients and 205 (62%) of those also receiving simultaneous carboplatin chemotherapy. 51 A CR was obtained in 57% (56/98) of the former and in 80% (145/181) of the latter group (p = 0.003). The most important factors influencing initial CR included T-stage and completeness of TURB (p = 0.0003). The authors concluded that the addition of cisplatin or carboplatin chemotherapy to the TURB + RT treatment regimen resulted in survivals comparable to those obtained with radical cystectomy. Based on their experience they recommended radical cystectomy in patients who failed combined modality therapy. Similar conclusions were reached by Shipley et al. from Harvard University. 52,53 The overall 5-year survival rates of approximately 50% and up to 45% incidence of bladder-preserved survival were obtained with the use of a multimodality therapeutic approach. 53,54
In a study of 94 cases of muscle-invasive CaB published from the University of Florida College of Medicine, Gainesville, Florida, patients were treated with TURB followed by 2 to 3 courses of cisplatin-based chemotherapy. 55 Subsequently, 49 (52%) patients received radiotherapy consisting of 64.8 Gy, while 8 (8%) had partial cystectomy and 7 (7%) were only observed. Median follow-up was more than 5 years. Following the initial therapy 53 (56%) patients were alive with preserved bladder. Of these 57 patients, 30 (57%) eventually had a local recurrence. The final relapse-free survival for all patients was 49%—with 84% for patients with T2 tumors, 53% for patients with T3, and 11% for patients with T4 tumors. Preserved bladder was recorded in 50% of patients with T2 tumors, 37% with T3, and 0% with T4. The 5-year survival rate for patients who had a radical cystectomy as the primary treatment or as a salvage procedure was 65% versus 40% for those who were treated with bladder preservation techniques (p < 0.01). The authors concluded that radical cystectomy alone is a superior treatment in terms of disease-free survival when compared with more conservatively treated patients. There was also a low rate of disease-free preservation of intact bladders leading to a recommendation that bladder preservation therapy be reserved for a carefully selected group of muscle-invasive CaB patients.
The pessimistic outcomes of the University of Florida, Gainesville study were contradicted by multiple European reports including those from Paris and Avignon, France, 56,57 Pamplona, Spain, 58 Palermo, Italy, 59 and Lubljana, Slovenia. 60
In 1993, the Radiation Therapy Oncology Group (RTOG 85-12) published results of a phase II prospective clinical trial in 49 muscle-invasive CaB patients. 61 Patients were treated with TURB followed by radiotherapy consisting of 40 Gy in 4 weeks and cisplatin chemotherapy on day 1 and 21 of radiation course at a dose of 100 mg/m2 . Those with CR were scheduled to receive an additional 24 Gy radiotherapy while patients with residual tumor were scheduled for radical cystectomy. A CR following 40 Gy RT and chemotherapy was obtained in 31 of 47 (66%) patients, including 28 of 42 evaluable patients. Of these, 11 remained in CR and 8 relapsed locally in the bladder as the only site of failure. A total of 14 study patients failed the induction therapy with only 3 remaining disease-free at the last follow up. The 3-year actuarial survival was 64%. The study conclusions were: (1) tumor clearance in 66% of patients; (2) infrequent isolated local recurrences in the bladder; (3) moderate degree treatment tolerance; and (4) more work needs to be done to optimize the selection of patients most suitable for bladder preservation therapy.
A phase III prospective randomized trial was reported by RTOG (89-03) 62 in which a total of 123 T2 to T4aNxM0 patients were randomized to receive two cycles of methotrexate, cisplatin, and vinblastin (MCV) chemotherapy followed by 39.6 Gy radiotherapy concurrently with cisplatin chemotherapy at 100 mg/m2 for two cycles (N = 61) in a similar fashion to RTOG study 05-12 (group I). Group II (N = 62) patients received no prior MCV chemotherapy. Patients with a CR received an additional dose of 25.2 Gy or a total dose of 64.8 Gy and one more cycle of cisplatin chemotherapy. Patients who failed to show a CR were scheduled for radical cystectomy. Median follow-up was 5 years. The 5-year actuarial survival was 49% for group I and 48% for group II patients. Distant metastases at 5 years after treatment were noted in 33% of group I and in 39% of group II patients. A functioning bladder was reported in 36% of the former and 40% in the latter arm, respectively. Treatment toxicity was significant with 3 (2.4%) lethal complications due to neutropenia resulting in sepsis, 9 (7.3%) patients with grade IV toxicity, and 26 (21%) patients with grade III toxicity.
There is overwhelming published data to support the use of bladder preservation therapy consisting of an optimal TURB followed by simultaneous radiotherapy with cisplatin-based chemotherapy. More work needs to be done to: (1) identify risk factors that enable a better selection of patients for radical cystectomy versus those who are well-suited for the conservative therapy; (2) study long-term quality of life issues relevant to either treatment approach; and (3) continue the search for more effective and less toxic chemotherapy.
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