DOI: 10.5301/RU.2013.11554
Urologia 2013 ; 80 ( 3): 202- 206
FOCUS ON
ORIGINAL ARTICLE
The role of radiotherapy in bladder cancer Paola Pinnarò , Carolina Giordano , Giuseppe Giovinazzo , Biancamaria Saracino Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy
Abstract: In this article we report on the current role of radiotherapy in the management of non-muscle invasive as well as in muscle invasive bladder cancer. Radiotherapy seems to have no role in non-muscle invasive bladder cancer. In muscle invasive bladder tumors, the role of radiotherapy is under investigation in view of new radiotherapy techniques and novel cytotoxic and biological agents. Key words: Radiotherapy, Bladder cancer Parole chiave: Radioterapia, tumore della vescica Accepted: September 13, 2013
INTRODUCTION The clinical spectrum of bladder cancers includes nonmuscle invasive tumors, muscle invasive tumors and metastatic disease. Each one of these categories presents a specific clinical behavior, prognosis and management. Here we briefly report on the current role of radiotherapy in the management of non-muscle invasive as well as in muscle invasive bladder cancer.
Role of radiation therapy in non-muscle invasive bladder cancer (previously referred to as “Superficial” cancer) These include papillary non-invasive carcinoma (Ta), carcinoma in situ (Tis) and tumors invading the subepithelial connective tissue (T1). There are no clinical evidences in literature that support the routine use of radiotherapy in these contests. Radiotherapy, in fact, is usually considered ineffective in the superficial disease because, although it is effective in eradicating the primary condition with a relatively high rate of complete responses in Tis and Ta staged tumors, it has little impact on preventing recurrence, with five years recurrence rate of about 90% (1). 202
However, there has been some experience with T1G3 tumors. Rödel et al. reported on 74 patients with T1G3 bladder cancer who were treated by radiotherapy (median dose 54 Gy, range 45-60 Gy) ± concomitant chemotherapy (cisplatin 25 mg/m2/day) after TURB. A complete remission at restaging TURB was achieved in 62 patients (83.7%), 35 of whom (47% with regard to the total cohort of the 74 treated patients) remained disease-free. Overall survival was 72% at 5 years and 50% at 10 years, with 77% of the surviving patients maintaining their own bladder at 5 years. Negative prognostic factors for cancer-specific survival were noncomplete (R1/2) to initial TURB. Combined radio-chemotherapy was more effective than radiotherapy alone (2). The role of radiotherapy in T1G3 NXM0 transitional cell carcinoma of the bladder has been also tested in a multicenter phase III randomized trial by S. J. Harland et al. (3). In this study radiotherapy (60 Gy to the bladder) was compared to TURBT alone (unifocal disease) or intravesical BCG (multifocal disease). None of the patients received concurrent radio-chemotherapy. No evidence of an advantage with radiotherapy was found in terms of progression-free interval (hazard ratio 1.07; 95% CI 0.65, 1.74; p = 0.785), progression-free survival (hazard ratio 1.35; 95% CI 0.92, 1.98; p = 0.133) or overall survival (hazard ratio 1.32; 95% CI 0.86, 2.04; p = 0.193). A
© 2013 Wichtig Editore - ISSN 0391-5603
Pinnarò et al
slightly higher acute and late toxicity was observed in the radiotherapy arm. However, considering the satisfactory results obtained with TURBT followed by intravescical therapy (Bacillus Calmette-Guérin or chemotherapy), radiotherapy alone or radio-chemotherapy should be considered in the local management of high-grade, non-muscle invasive bladder cancer only on individual basis.
Role of radiation therapy in muscle invasive bladder cancer Although surgery is considered the standard therapy, considerable interest in bladder preservation has led to the use of radiotherapy as an alternative, particularly in less fit patients. Numerous studies have attempted to compare outcomes between radiotherapy and radical cystectomy. Such comparisons are difficult given inherent and often substantial selection bias. Typically, patients selected for radiotherapy as their definitive treatment, have more advanced disease at diagnosis, are older and in worse general conditions than patients selected for radical cystectomy (4). Nevertheless, when used alone, radiotherapy is associated with a relative high rate of incomplete response or local recurrence (up to 50%) (5). A Norwegian retrospective series focused on patients’ survival after radical treatment of transitional cell carcinoma of the bladder. The 10-year overall survival rates for surgery and radiotherapy groups were 26% and 5%, respectively (6). Definitive radiotherapy as monotherapy is given in various dosage schedules. A typical treatment course usually involves the administration of daily fractions of 1.8-2.0 Gy each, to a total dose of 60-70 Gy. Higher doses have been shown to improve long-term local control. W Majewski et al. (7) reported an increase in 5-year local control rate from 40% to 60%, when increasing from a total dose of 60 Gy to 70 Gy. A Dutch review emphasized the importance of the treatment dose; in this review Pos et al. found evidence for an overall dose-response relationship with an increase in local control by a factor of 1.44-1.47 for an increment in dose of 10 Gy (8). The benefits of altered fractionation radiotherapy schedules have been also investigated. A prospective randomized trial was undertaken in 229 patients comparing Accelerated Fractionation to a dose of 60.8 Gy in 32 fractions over
26 days with Conventional Fractionation, treating to 64 Gy in 32 fractions over 45 days. Accelerated fractionation was delivered using two fractions per day with a 6 h gap between fractions and with the first daily fraction size being 1.8 Gy and the second daily fraction size being 2.0 Gy. There was a 1-week treatment gap after the first 12 fractions. Conventional Fractionation was one fraction per day, 5 days per week. Eligible patients had clinical stage T2 or T3, N0 or N1, M0 transitional cell carcinoma. There was no significant difference between the treatment arms comparing disease-free survival and overall survival. The 5-year overall survival was 37% for Accelerated Fractionation and 40% for Conventional Fractionation. Local failure rates were 32% and 29% for Accelerated and Conventional schedules, respectively. It was concluded that the Accelerated Fractionation schedule did not improve on the efficacy of Conventional Fractionation for patients with T2 and T3 bladder cancer, but was associated with increased acute bowel toxicity (9). Hypofractionated radiation schedules (with larger daily doses in the range of 3-6 Gy) have also been used to treat bladder cancer patients, usually in palliative setting. There has been only one small phase III randomized study reporting on curative radiotherapy, in which increased doses per fraction (30 Gy in 3 Gy daily fractions, 4 weeks’ break, then 30 Gy in 1.5 Gy daily fractions) were compared with 60 Gy in 1.5 Gy fractions. The arm that received hypofractionated radiotherapy presented a lower 5-year survival (39% versus 52%) (10). In recent years, brachytherapy has been explored in the treatment of muscle invasive bladder cancer. In patients with solitary tumors of < 5 cm, a 30 Gy course of external-beam RT followed by 40 Gy brachytherapy has been shown to give good results. The largest experience is from the Netherlands, showing 5- and 10-year OS rates of 62% and 50%, and 5- and 10-year DSS rates of 73% and 67%. The actuarial local control rate was 73% at both 5 and 10 years. The 5- and 10-year DSS rates for patients with a preserved bladder were 68% and 59%, respectively. However, this cohort included high-grade T1 disease in addition to T2 cancers, which makes it difficult to compare these results (11, 12). In summary, the available data indicate that differences in local control between different radiation schedules are more related to total dose than to the fractionation regimens. New treatment techniques, such as intensity-modulated radiotherapy and image-guided radiotherapy, as well as inter-
© 2013 Wichtig Editore - ISSN 0391-5603
203
Radiotherapy in bladder cancer
stitial radiotherapy in selected cases (unifocal, small bulk disease) or the use of particle therapy, in particular protons, may allow dose escalation with the expectation to further improve tumor response and long-term local control. In conclusion, in its present state, radiotherapy alone is only indicated for patients who cannot tolerate a cystectomy or chemotherapy because of medical comorbidities. In an attempt to improve the results of bladder-sparing approaches, various combinations of radiotherapy with chemotherapy have been used for the treatment of muscle invasive bladder cancer. A combined integrated approach using combining chemo-radiotherapy might in fact improve outcomes by exploiting the synergistic effect of chemotherapy and radiation to enhance local control and also by addressing microscopic disease outside the bladder. There is a large number of phase I or phase II trials looking at various chemotherapy agents including cisplatinum, taxanes, 5-fluorouracil (5FU), and gemcitabine in combination with conventional or altered radiotherapy schedules. The RTOG 85-12 trial was the first phase II study designed to test the tolerance and effectiveness of concurrent cisplatin-radiotherapy in the treatment of invasive bladder cancer (13). Objectives were to determine toxicity, complete response rate, bladder preservation rate, and survival. Patients with invasive bladder cancer, clinical stages T2-4, NO-2 or NX, MO were treated with pelvic radiotherapy (40 Gy in 4 weeks) and cisplatin (100 mg/m2 on days 1 and 22). Complete responders were given an additional 24 Gy bladder boost plus a third dose of cisplatin; patients with residual tumor after 40 Gy were assigned radical cystectomy. At the reevaluation cystoscopy the complete remission following two doses of cisplatin and 40 Gy was achieved in about two-third of the patients (31/47), who therefore received an additional 24 Gy plus another dose of cisplatin. Actuarial survival was 64% at 3 years. The encouraging results of this first study led to several others. In general they all report good tolerability and feasibility but little in the way of comparative data. There are, however, very few prospective randomized trials in which radiotherapy alone is compared with chemo-radiotherapy. Danesi et al. (14) reported longterm results of a conservative approach by using transurethral resection, protracted infusion chemotherapy and hyperfractionated radiotherapy. After a median follow-up of 82.2 months (range 30-138 months) Complete Response and Partial Response were 90.3% and 9.7%, respectively. The 5-year overall, bladder-intact, tumor-specific, 204
disease-free, and cystectomy-free survival rates for all 77 patients were 58.5%, 46.6%, 75.0%, 53.5%, and 76.1%, respectively. The first randomized study was carried out by the National Cancer Institute of Canada Clinical Trials Group (15). This prospective randomized trial was conducted to determine whether the addition of concurrent cisplatin to pre-operative or definitive radiation therapy in patients with muscle invasive bladder cancer improved local control or survival. Patients were randomly allocated to receive intravenous cisplatin 100 mg/m2 at 2-week intervals for three cycles concurrent with pelvic radiation, or to receive radiation without chemotherapy. Patients were stratified by clinical tumor stage. A lower percentage of pelvic recurrence was observed in the combined therapy arm (40% versus 59%, p = 0.036). Overall survival after three years was higher in the group that received cisplatin (47% versus 33%), however with no statistical significance (p = 0.34). Recently, the phase III BC2001 trial randomly assigned 360 patients with muscle invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. At the outset of the study, centers could opt to administer either 55 Gy in 20 fractions over a 4-week period or 64 Gy in 32 fractions over a 6.5-week period in all patients. The regimen consisted of fluorouracil (500 mg per square meter of body surface area per day) during fractions 1 to 5, and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either wholebladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced). The primary end-point was survival free of locoregional disease. Secondary end-points included overall survival and toxic effects. With a median follow-up of 69.9 months, the 2-year locoregional disease-free survival was significantly improved for the group treated with chemo-radiation when compared with the group receiving radiotherapy alone (67% versus 54%; p = 0.03). Chemo-radiotherapy was associated with a trend toward a reduction in salvage cystectomy for local recurrence, with a 2-year rate of 11.4% in the chemo-radiotherapy group versus 16.8% CI, in the radiotherapy group (P = 0.07). Grade 3 or 4 acute adverse events (primarily gastrointestinal toxicities) were slightly more common in the chemoradiotherapy group than in the radiotherapy group during
© 2013 Wichtig Editore - ISSN 0391-5603
Pinnarò et al
treatment (36.0% versus. 27.5%, p = 0.07), althoug this did not translate into higher rates of late toxicity (16). Results of the comparison between whole-bladder and “partial” bladder irradiation are still pending. The authors concluded that synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. In conclusion, a radical surgical approach currently remains the standard treatment for muscle invasive bladder cancer. However, concurrent chemo-radiotherapy should be considered as the standard of care for less fit patients and for patients opting for bladder preservation treatment. Furthermore, a multimodality treatment of muscle invasive bladder cancer including limited surgery (transurethral resection) and chemo-radiation could be an alternative treatment to radical cystectomy for highly selected patients. The ideal candidates for this strategy have good baseline bladder function, are able to obtain a visibly complete TUR, have a small solitary tumor with limited CIS and no evidence of hydronephrosis. However, prospective trials comparing the above regimen to radical cystectomy are still needed to better define their
role in the treatment of muscle invasive bladder cancer. As more experience is acquired with organ-sparing treatment in bladder cancer, it is clear that future directions of clinical and basic research will focus on two main topics: first, the optimization of the respective treatment components, including optimization of radiation technique and fractionation schedules as well as incorporation of novel cytotoxic and biological agents; second, the proper selection of patients who will most probably benefit from the respective treatment alternative (17). Bladder cancer provides an excellent model of multidisciplinary team working, in which urologist, medical oncologist, and radiation oncologist must work closely to get the best results for patients.
REFERENCES
Wallace DM. Long-term risk of salvage cystectomy after radiotherapy for muscle-invasive bladder cancer. Eur Urol. 2000 Sep;38(3):279-86. 6. Dæhlin L, Haukaas S, Maartmann-Moe, Medby PC. Survival after radical treatment for transitional cell carcinoma of the bladder. Eur J Surg Oncol. 1999;25:66-70. 7. Majewski W, Maciejewski B, Majewski S, Suwinski R, Miszczyk L, Tarnawski R. Clinical radiobiology of stage T2T3 bladder cancer. Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):60-70. 8. Pos FJ, Hart G, Schneider C, Sminia P. Radical radiotherapy for invasive bladder cancer: What dose and fractionation schedule to choose? Int J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):1168-73. 9. Horwich A, Dearnaley D, Huddart R, Graham J, Bessell E, Mason M, Bliss J. A randomised trial of accelerated radiotherapy for localized invasive bladder cancer. Radiother Oncol. 2005;75:34-43. 10. Kob D, Arndt J, Kriester A, Schwenk M, Kloetzer KH. Results of percutaneous radiotherapy of bladder cancer
1.
2.
3.
4.
5.
Wolf H, Olsen PR, Højgaard K. Urothelial dysplasia concomitant with bladder tumours: a determinant for future new occurrences in patients treated by full-course radiotherapy. Lancet. 1985 May 4;1(8436):1005-8. Rödel C, Dunst J, Grabenbauer GG, Kühn R, Papadopoulos T, Schrott KM, Sauer R. Radiotherapy is an effective treatment for high-risk T1-bladder cancer. Strahlenther Onkol. 2001 Feb;177(2):82-8. Harland SJ, Kynaston H, Grigor K, Wallace DM, Beacock C, Kockelbergh R, Clawson S, Barlow T, Parmar MK, Griffiths GO. A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder. J Urol. 2007 Sep;178 :807-13. Fossa SD, Aass N, Ous S, Waehre H, Ilner K, Hannisdal E. Survival after curative treatment of muscle-invasive bladder cancer. Acta Oncol. 1996;35 Suppl 8:59-65. Cooke PW, Dunn JA, Latief T, Bathers S, James ND,
Disclaimers The Authors declare no conflicts of interest.
Corresponding Author: Paola Pinnarò, MD Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy [email protected]
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11.
12.
13.
14.
206
using 1 and 2 series of irradiation. Strahlentherapie. 1985 Nov;161(11):673-7. Nieuwenhuijzen JA, Pos F, Moonen LM, Hart AA, Horenblas S. Survival after bladder-preservation with brachytherapy versus radical cystectomy; a single institution experience. Eur Urol. 2005;48:239-45. Pos F, Horenblas S, Dom P, Moonen L, Bartelink H. Organ preservation in invasive bladder cancer: brachytherapy, an alternative to cystectomy and combined modality treatment? Int J Radiat Oncol Phys. 2005;61:678-86. Tester W, Porter A, Asbell S, Coughlin C, Heaney J, Krall J, Martz K, Venner P, Hammond E. Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys. 1993 Apr 2;25(5):783-90. Danesi DT, Arcangeli G, Cruciani E, Altavista P, Mecozzi A, Saracino B, Orefici F. Coppin CM, Conservative treatment
of invasive bladder carcinoma by transurethral resection, protracted intravenous infusion chemotherapy, and hyperfractionated radiotherapy: long term results. Cancer. 2004 Dec 1;101(11):2540-8. 15. Gospodarowicz MK, James K, Tannock IF, Zee B, Carson J, Pater J, Sullivan LD. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1996 Nov;14(11):2901-7. 16. James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. 17. Weiss C and Rödel C. Chemoradiation superior in muscle invasive bladder cancer. Nat Rev Clin Oncol. 2012;9:374-375.
© 2013 Wichtig Editore - ISSN 0391-5603
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Urologia 2013 ; 80 ( 3): 202- 206
FOCUS ON
ORIGINAL ARTICLE
The role of radiotherapy in bladder cancer Paola Pinnarò , Carolina Giordano , Giuseppe Giovinazzo , Biancamaria Saracino Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy
Abstract: In this article we report on the current role of radiotherapy in the management of non-muscle invasive as well as in muscle invasive bladder cancer. Radiotherapy seems to have no role in non-muscle invasive bladder cancer. In muscle invasive bladder tumors, the role of radiotherapy is under investigation in view of new radiotherapy techniques and novel cytotoxic and biological agents. Key words: Radiotherapy, Bladder cancer Parole chiave: Radioterapia, tumore della vescica Accepted: September 13, 2013
INTRODUCTION The clinical spectrum of bladder cancers includes nonmuscle invasive tumors, muscle invasive tumors and metastatic disease. Each one of these categories presents a specific clinical behavior, prognosis and management. Here we briefly report on the current role of radiotherapy in the management of non-muscle invasive as well as in muscle invasive bladder cancer.
Role of radiation therapy in non-muscle invasive bladder cancer (previously referred to as “Superficial” cancer) These include papillary non-invasive carcinoma (Ta), carcinoma in situ (Tis) and tumors invading the subepithelial connective tissue (T1). There are no clinical evidences in literature that support the routine use of radiotherapy in these contests. Radiotherapy, in fact, is usually considered ineffective in the superficial disease because, although it is effective in eradicating the primary condition with a relatively high rate of complete responses in Tis and Ta staged tumors, it has little impact on preventing recurrence, with five years recurrence rate of about 90% (1). 202
However, there has been some experience with T1G3 tumors. Rödel et al. reported on 74 patients with T1G3 bladder cancer who were treated by radiotherapy (median dose 54 Gy, range 45-60 Gy) ± concomitant chemotherapy (cisplatin 25 mg/m2/day) after TURB. A complete remission at restaging TURB was achieved in 62 patients (83.7%), 35 of whom (47% with regard to the total cohort of the 74 treated patients) remained disease-free. Overall survival was 72% at 5 years and 50% at 10 years, with 77% of the surviving patients maintaining their own bladder at 5 years. Negative prognostic factors for cancer-specific survival were noncomplete (R1/2) to initial TURB. Combined radio-chemotherapy was more effective than radiotherapy alone (2). The role of radiotherapy in T1G3 NXM0 transitional cell carcinoma of the bladder has been also tested in a multicenter phase III randomized trial by S. J. Harland et al. (3). In this study radiotherapy (60 Gy to the bladder) was compared to TURBT alone (unifocal disease) or intravesical BCG (multifocal disease). None of the patients received concurrent radio-chemotherapy. No evidence of an advantage with radiotherapy was found in terms of progression-free interval (hazard ratio 1.07; 95% CI 0.65, 1.74; p = 0.785), progression-free survival (hazard ratio 1.35; 95% CI 0.92, 1.98; p = 0.133) or overall survival (hazard ratio 1.32; 95% CI 0.86, 2.04; p = 0.193). A
© 2013 Wichtig Editore - ISSN 0391-5603
Pinnarò et al
slightly higher acute and late toxicity was observed in the radiotherapy arm. However, considering the satisfactory results obtained with TURBT followed by intravescical therapy (Bacillus Calmette-Guérin or chemotherapy), radiotherapy alone or radio-chemotherapy should be considered in the local management of high-grade, non-muscle invasive bladder cancer only on individual basis.
Role of radiation therapy in muscle invasive bladder cancer Although surgery is considered the standard therapy, considerable interest in bladder preservation has led to the use of radiotherapy as an alternative, particularly in less fit patients. Numerous studies have attempted to compare outcomes between radiotherapy and radical cystectomy. Such comparisons are difficult given inherent and often substantial selection bias. Typically, patients selected for radiotherapy as their definitive treatment, have more advanced disease at diagnosis, are older and in worse general conditions than patients selected for radical cystectomy (4). Nevertheless, when used alone, radiotherapy is associated with a relative high rate of incomplete response or local recurrence (up to 50%) (5). A Norwegian retrospective series focused on patients’ survival after radical treatment of transitional cell carcinoma of the bladder. The 10-year overall survival rates for surgery and radiotherapy groups were 26% and 5%, respectively (6). Definitive radiotherapy as monotherapy is given in various dosage schedules. A typical treatment course usually involves the administration of daily fractions of 1.8-2.0 Gy each, to a total dose of 60-70 Gy. Higher doses have been shown to improve long-term local control. W Majewski et al. (7) reported an increase in 5-year local control rate from 40% to 60%, when increasing from a total dose of 60 Gy to 70 Gy. A Dutch review emphasized the importance of the treatment dose; in this review Pos et al. found evidence for an overall dose-response relationship with an increase in local control by a factor of 1.44-1.47 for an increment in dose of 10 Gy (8). The benefits of altered fractionation radiotherapy schedules have been also investigated. A prospective randomized trial was undertaken in 229 patients comparing Accelerated Fractionation to a dose of 60.8 Gy in 32 fractions over
26 days with Conventional Fractionation, treating to 64 Gy in 32 fractions over 45 days. Accelerated fractionation was delivered using two fractions per day with a 6 h gap between fractions and with the first daily fraction size being 1.8 Gy and the second daily fraction size being 2.0 Gy. There was a 1-week treatment gap after the first 12 fractions. Conventional Fractionation was one fraction per day, 5 days per week. Eligible patients had clinical stage T2 or T3, N0 or N1, M0 transitional cell carcinoma. There was no significant difference between the treatment arms comparing disease-free survival and overall survival. The 5-year overall survival was 37% for Accelerated Fractionation and 40% for Conventional Fractionation. Local failure rates were 32% and 29% for Accelerated and Conventional schedules, respectively. It was concluded that the Accelerated Fractionation schedule did not improve on the efficacy of Conventional Fractionation for patients with T2 and T3 bladder cancer, but was associated with increased acute bowel toxicity (9). Hypofractionated radiation schedules (with larger daily doses in the range of 3-6 Gy) have also been used to treat bladder cancer patients, usually in palliative setting. There has been only one small phase III randomized study reporting on curative radiotherapy, in which increased doses per fraction (30 Gy in 3 Gy daily fractions, 4 weeks’ break, then 30 Gy in 1.5 Gy daily fractions) were compared with 60 Gy in 1.5 Gy fractions. The arm that received hypofractionated radiotherapy presented a lower 5-year survival (39% versus 52%) (10). In recent years, brachytherapy has been explored in the treatment of muscle invasive bladder cancer. In patients with solitary tumors of < 5 cm, a 30 Gy course of external-beam RT followed by 40 Gy brachytherapy has been shown to give good results. The largest experience is from the Netherlands, showing 5- and 10-year OS rates of 62% and 50%, and 5- and 10-year DSS rates of 73% and 67%. The actuarial local control rate was 73% at both 5 and 10 years. The 5- and 10-year DSS rates for patients with a preserved bladder were 68% and 59%, respectively. However, this cohort included high-grade T1 disease in addition to T2 cancers, which makes it difficult to compare these results (11, 12). In summary, the available data indicate that differences in local control between different radiation schedules are more related to total dose than to the fractionation regimens. New treatment techniques, such as intensity-modulated radiotherapy and image-guided radiotherapy, as well as inter-
© 2013 Wichtig Editore - ISSN 0391-5603
203
Radiotherapy in bladder cancer
stitial radiotherapy in selected cases (unifocal, small bulk disease) or the use of particle therapy, in particular protons, may allow dose escalation with the expectation to further improve tumor response and long-term local control. In conclusion, in its present state, radiotherapy alone is only indicated for patients who cannot tolerate a cystectomy or chemotherapy because of medical comorbidities. In an attempt to improve the results of bladder-sparing approaches, various combinations of radiotherapy with chemotherapy have been used for the treatment of muscle invasive bladder cancer. A combined integrated approach using combining chemo-radiotherapy might in fact improve outcomes by exploiting the synergistic effect of chemotherapy and radiation to enhance local control and also by addressing microscopic disease outside the bladder. There is a large number of phase I or phase II trials looking at various chemotherapy agents including cisplatinum, taxanes, 5-fluorouracil (5FU), and gemcitabine in combination with conventional or altered radiotherapy schedules. The RTOG 85-12 trial was the first phase II study designed to test the tolerance and effectiveness of concurrent cisplatin-radiotherapy in the treatment of invasive bladder cancer (13). Objectives were to determine toxicity, complete response rate, bladder preservation rate, and survival. Patients with invasive bladder cancer, clinical stages T2-4, NO-2 or NX, MO were treated with pelvic radiotherapy (40 Gy in 4 weeks) and cisplatin (100 mg/m2 on days 1 and 22). Complete responders were given an additional 24 Gy bladder boost plus a third dose of cisplatin; patients with residual tumor after 40 Gy were assigned radical cystectomy. At the reevaluation cystoscopy the complete remission following two doses of cisplatin and 40 Gy was achieved in about two-third of the patients (31/47), who therefore received an additional 24 Gy plus another dose of cisplatin. Actuarial survival was 64% at 3 years. The encouraging results of this first study led to several others. In general they all report good tolerability and feasibility but little in the way of comparative data. There are, however, very few prospective randomized trials in which radiotherapy alone is compared with chemo-radiotherapy. Danesi et al. (14) reported longterm results of a conservative approach by using transurethral resection, protracted infusion chemotherapy and hyperfractionated radiotherapy. After a median follow-up of 82.2 months (range 30-138 months) Complete Response and Partial Response were 90.3% and 9.7%, respectively. The 5-year overall, bladder-intact, tumor-specific, 204
disease-free, and cystectomy-free survival rates for all 77 patients were 58.5%, 46.6%, 75.0%, 53.5%, and 76.1%, respectively. The first randomized study was carried out by the National Cancer Institute of Canada Clinical Trials Group (15). This prospective randomized trial was conducted to determine whether the addition of concurrent cisplatin to pre-operative or definitive radiation therapy in patients with muscle invasive bladder cancer improved local control or survival. Patients were randomly allocated to receive intravenous cisplatin 100 mg/m2 at 2-week intervals for three cycles concurrent with pelvic radiation, or to receive radiation without chemotherapy. Patients were stratified by clinical tumor stage. A lower percentage of pelvic recurrence was observed in the combined therapy arm (40% versus 59%, p = 0.036). Overall survival after three years was higher in the group that received cisplatin (47% versus 33%), however with no statistical significance (p = 0.34). Recently, the phase III BC2001 trial randomly assigned 360 patients with muscle invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. At the outset of the study, centers could opt to administer either 55 Gy in 20 fractions over a 4-week period or 64 Gy in 32 fractions over a 6.5-week period in all patients. The regimen consisted of fluorouracil (500 mg per square meter of body surface area per day) during fractions 1 to 5, and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either wholebladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced). The primary end-point was survival free of locoregional disease. Secondary end-points included overall survival and toxic effects. With a median follow-up of 69.9 months, the 2-year locoregional disease-free survival was significantly improved for the group treated with chemo-radiation when compared with the group receiving radiotherapy alone (67% versus 54%; p = 0.03). Chemo-radiotherapy was associated with a trend toward a reduction in salvage cystectomy for local recurrence, with a 2-year rate of 11.4% in the chemo-radiotherapy group versus 16.8% CI, in the radiotherapy group (P = 0.07). Grade 3 or 4 acute adverse events (primarily gastrointestinal toxicities) were slightly more common in the chemoradiotherapy group than in the radiotherapy group during
© 2013 Wichtig Editore - ISSN 0391-5603
Pinnarò et al
treatment (36.0% versus. 27.5%, p = 0.07), althoug this did not translate into higher rates of late toxicity (16). Results of the comparison between whole-bladder and “partial” bladder irradiation are still pending. The authors concluded that synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. In conclusion, a radical surgical approach currently remains the standard treatment for muscle invasive bladder cancer. However, concurrent chemo-radiotherapy should be considered as the standard of care for less fit patients and for patients opting for bladder preservation treatment. Furthermore, a multimodality treatment of muscle invasive bladder cancer including limited surgery (transurethral resection) and chemo-radiation could be an alternative treatment to radical cystectomy for highly selected patients. The ideal candidates for this strategy have good baseline bladder function, are able to obtain a visibly complete TUR, have a small solitary tumor with limited CIS and no evidence of hydronephrosis. However, prospective trials comparing the above regimen to radical cystectomy are still needed to better define their
role in the treatment of muscle invasive bladder cancer. As more experience is acquired with organ-sparing treatment in bladder cancer, it is clear that future directions of clinical and basic research will focus on two main topics: first, the optimization of the respective treatment components, including optimization of radiation technique and fractionation schedules as well as incorporation of novel cytotoxic and biological agents; second, the proper selection of patients who will most probably benefit from the respective treatment alternative (17). Bladder cancer provides an excellent model of multidisciplinary team working, in which urologist, medical oncologist, and radiation oncologist must work closely to get the best results for patients.
REFERENCES
Wallace DM. Long-term risk of salvage cystectomy after radiotherapy for muscle-invasive bladder cancer. Eur Urol. 2000 Sep;38(3):279-86. 6. Dæhlin L, Haukaas S, Maartmann-Moe, Medby PC. Survival after radical treatment for transitional cell carcinoma of the bladder. Eur J Surg Oncol. 1999;25:66-70. 7. Majewski W, Maciejewski B, Majewski S, Suwinski R, Miszczyk L, Tarnawski R. Clinical radiobiology of stage T2T3 bladder cancer. Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):60-70. 8. Pos FJ, Hart G, Schneider C, Sminia P. Radical radiotherapy for invasive bladder cancer: What dose and fractionation schedule to choose? Int J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):1168-73. 9. Horwich A, Dearnaley D, Huddart R, Graham J, Bessell E, Mason M, Bliss J. A randomised trial of accelerated radiotherapy for localized invasive bladder cancer. Radiother Oncol. 2005;75:34-43. 10. Kob D, Arndt J, Kriester A, Schwenk M, Kloetzer KH. Results of percutaneous radiotherapy of bladder cancer
1.
2.
3.
4.
5.
Wolf H, Olsen PR, Højgaard K. Urothelial dysplasia concomitant with bladder tumours: a determinant for future new occurrences in patients treated by full-course radiotherapy. Lancet. 1985 May 4;1(8436):1005-8. Rödel C, Dunst J, Grabenbauer GG, Kühn R, Papadopoulos T, Schrott KM, Sauer R. Radiotherapy is an effective treatment for high-risk T1-bladder cancer. Strahlenther Onkol. 2001 Feb;177(2):82-8. Harland SJ, Kynaston H, Grigor K, Wallace DM, Beacock C, Kockelbergh R, Clawson S, Barlow T, Parmar MK, Griffiths GO. A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder. J Urol. 2007 Sep;178 :807-13. Fossa SD, Aass N, Ous S, Waehre H, Ilner K, Hannisdal E. Survival after curative treatment of muscle-invasive bladder cancer. Acta Oncol. 1996;35 Suppl 8:59-65. Cooke PW, Dunn JA, Latief T, Bathers S, James ND,
Disclaimers The Authors declare no conflicts of interest.
Corresponding Author: Paola Pinnarò, MD Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome - Italy [email protected]
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Radiotherapy in bladder cancer
11.
12.
13.
14.
206
using 1 and 2 series of irradiation. Strahlentherapie. 1985 Nov;161(11):673-7. Nieuwenhuijzen JA, Pos F, Moonen LM, Hart AA, Horenblas S. Survival after bladder-preservation with brachytherapy versus radical cystectomy; a single institution experience. Eur Urol. 2005;48:239-45. Pos F, Horenblas S, Dom P, Moonen L, Bartelink H. Organ preservation in invasive bladder cancer: brachytherapy, an alternative to cystectomy and combined modality treatment? Int J Radiat Oncol Phys. 2005;61:678-86. Tester W, Porter A, Asbell S, Coughlin C, Heaney J, Krall J, Martz K, Venner P, Hammond E. Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys. 1993 Apr 2;25(5):783-90. Danesi DT, Arcangeli G, Cruciani E, Altavista P, Mecozzi A, Saracino B, Orefici F. Coppin CM, Conservative treatment
of invasive bladder carcinoma by transurethral resection, protracted intravenous infusion chemotherapy, and hyperfractionated radiotherapy: long term results. Cancer. 2004 Dec 1;101(11):2540-8. 15. Gospodarowicz MK, James K, Tannock IF, Zee B, Carson J, Pater J, Sullivan LD. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1996 Nov;14(11):2901-7. 16. James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. 17. Weiss C and Rödel C. Chemoradiation superior in muscle invasive bladder cancer. Nat Rev Clin Oncol. 2012;9:374-375.
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