- Email: [email protected]
Radical cystectomy vs. chemoradiation in T2-4aN0M0 bladder cancer: A case-control study
Urologic Oncology: Seminars and Original Investigations 33 (2015) 19.e1–19.e5
Original article
Radical cystectomy vs. chemoradiation in T2-4aN0M0 bladder cancer: A case-control study Ofer N. Gofrit, M.D., Ph.D.a,*, Rony Nof, M.D.a, Amichai Meirovitz, M.D.b, Dov Pode, M.D.a, Stephen Frank, M.D.b, Ran Katz, M.D.a, Amos Shapiro, M.D.a, Ezekiel H. Landau, M.D.a, Guy Hidas, M.D.a, Vladimir Yutkin, M.D.a, Mordechai Duvdevani, M.D.a, Mark Wygoda, M.D.b a b
Department of Urology, Hadassah Hebrew University Hospital, Jerusalem, Israel Department of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
Received 18 July 2014; received in revised form 8 September 2014; accepted 21 September 2014
Abstract Background: Muscle-invasive bladder cancer is most commonly treated by radical cystectomy. Patients who are too sick to go through this surgery or who are unwilling to accept the mutilation associated with it are referred to chemoradiation. We compared the results of these 2 modalities using age-matched populations. Participants and methods: Between 1998 and 2008, 33 patients were treated with chemoradiation for biopsy-proven T2-4aN0M0 urothelial bladder cancer. For every patient treated with chemoradiation, an age-matched patient who underwent radical cystectomy on the same year was selected for comparison. Mean radiotherapy dose was 62 Gy (standard deviation ¼ 8.4) and median follow-up of both groups was approximately 36 months. Results: The groups were similar in age, proportion of men, and length of follow-up. However, the Charlson comorbidity index was significantly lower for operated patients (3.45 vs. 4.36, P ¼ 0.01). Furthermore, 2 patients (6%) in the chemoradiation group had salvage cystectomy (one for disease recurrence and another for bladder shrinkage). The 2- and 5-year overall survival rates after surgery were 74.4% and 54.8%, respectively, and after chemoradiation were 70.2% and 56.6% (P ¼ 0.8), respectively. The 2- and 5-year disease-free survival rates after surgery were 67.8% and 63.2%, respectively, and after chemoradiation were 63% and 54.3% (P ¼ 0.89), respectively. Side effects were mild in both groups, with grade 3þ toxicity seen in only 2 operated and 4 irradiated patients. Conclusions: Despite having a significantly higher comorbidity index, patients treated with chemoradiation had similar overall and disease-free survival rates with low toxicity. Treatment with chemoradiation should be considered in patients with T2-4aN0M0 bladder cancer. r 2014 Elsevier Inc. All rights reserved.
Keywords: Muscle-invasive bladder cancer; Radical cystectomy; Chemoradiation
1. Introduction Muscle-invasive bladder cancer is most commonly treated by radical cystectomy [1]. This treatment usually provides excellent locoregional control of the disease. Adjuvant or neoadjuvant treatment can be used for targeting The first two authors contributed equally to this work. Rony Nof's participation in this study was performed in fulfilment of the research requirements toward the M.D. degree at the Hebrew University Hadassah School of Medicine. * Corresponding author. E-mail address: [email protected] (O.N. Gofrit). http://dx.doi.org/10.1016/j.urolonc.2014.09.014 1078-1439/r 2014 Elsevier Inc. All rights reserved.
occult metastases [2]. The commonly cited results of radical cystectomy are quite good with overall 5-year survival rate up to 84% without chemotherapy [3]. However, these results came from a center of excellence and probably reflect meticulous patient selection and superb operative technique. In a more mixed population, like in the one that was reported in the SWOG neoadjuvant trial performed across 126 institutions, the overall 5-year survival rate was only 58% in the group receiving neoadjuvant chemotherapy [2]. Patients who are too sick to safely undergo surgery or who are unwilling to accept the morbidity of surgery including the loss of sexual function, potential deterioration
19.e2
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 19.e1–19.e5
of the upper tract, and the mutilation associated with urinary diversion often select chemoradiation. Various regimens of chemotherapy and radiotherapy were reported. In a combined study including 348 patients from 7 protocols and “off protocol” patients, treated from 1986 to 2006, the 5-year disease-specific and overall survival rates were 64% and 52%, respectively, and cystectomy was required in only 22% of them [4]. The long-term toxicity of this treatment is usually moderate, with only 7% late (4180 d) grade 3 pelvic toxicity, no late grade 4 toxicity, and no treatmentrelated deaths in 285 patients participating in 4 Radiation Therapy Oncology Group (RTOG) trials [5]. In another study, the overall 5-year survival rate was 58.5%, and 76% of the patients were cystectomy free [6]. To directly compare the results of radical cystectomy and chemoradiation, a randomized trial is necessary. Such a trial has never been done and probably cannot be done. Retrospective comparisons are also lacking in the literature, probably because of the dissimilar populations referred to the different modalities, as the patients referred to surgery are typically younger and healthier. In a report by Kotwal et al., 97 patients treated by radiotherapy were compared with 72 treated by radical cystectomy. Although patients treated by radiotherapy were 7 years older, the overall 5-year survival rates were similar, although the results of both groups were rather disappointing (34.6% and 41.3% for radiotherapy and surgery, respectively) [7]. In another study comparing radiotherapy (302 patients) with surgery (96 patients), Chahal et al. [8] showed similar 5-year overall survival (37.4% and 36.5%) despite a 5-year age difference between the groups. In this study, in an attempt to compare chemoradiation to surgery overcoming at least the age factor, we matched patients with T2-4aN0M0 bladder cancer treated by chemoradiation to patients treated by radical cystectomy according to age and year of treatment.
Participants and methods Patients and treatment Information was obtained from the hospital registry containing information on 760 patients treated for bladder cancer between 1998 and 2008. The study was approved by the Institutional Review Board Committee (Institutional Helsinki committee, IRB number 207-31.10.08). The diagnosis of bladder cancer was made using transurethral resection of bladder tumor histological specimens. Pathologic staging was performed according to the 1997 TNM system. The diagnosis of muscle-invasive bladder cancer initiated metastatic workup, which included computed tomography scans of the chest, abdomen, and pelvis and assessment of operative risk. Comorbidity was graded according to the Charlson comorbidity index [9]. Patients with no evidence of metastases and a reasonable
risk for general anesthesia were offered radical cystectomy. Chemoradiation was considered in patients who were too sick to go through this surgery or who were interested in preservation of their bladder.
Surgery Radical cystectomy included standard (common iliac, external iliac, and obturator) pelvic lymph node dissection. Postoperative complications were graded according to the Clavien and Dindo classification [10]. Postoperative followup included evaluation of kidney function and CT scans of the chest, abdomen, and pelvis at 3 and 6 months, then at 6-month intervals for 3 years, and then according to clinician discretion.
Chemoradiation Chemoradiation was given with a curative intent after maximal transurethral resection of the tumor. Radiotherapy was given with 3-dimensional planning (6 patients) and intensity-modulated radiation therapy (27 patients), aiming at delivering approximately 45 to 46 Gy to the bladder and pelvic nodes (internal and external iliac nodes and obturator nodes) followed by a bladder boost to a total dose of approximately 66 Gy (fractionated at 1.8–2 Gy). Imageguided radiotherapy was not used. Chemotherapy consisted of weekly administration of cisplatin at a dose of 40 mg/m2. For patients older than 75 years, the dose was reduced to 25 mg/m2. If renal function was impaired cisplatin was replaced by weekly administration of carboplatin area under the curve 2, as calculated by the Calvert Formula. Patients with a bulky tumor or with an obstructed kidney were not considered candidates for chemoradiation. The follow-up procedure paralleled that of postoperative follow-up with the addition of periodic cystoscopic evaluation and liberal use of biopsies of suspicious lesions. Complications of therapy were graded according to the Common Terminology Criteria for Adverse Events v 4.0 for chemotherapy and the RTOG toxicity grading systems for radiation [11,12]. For each patient treated with chemoradiation, a patient of a similar age (⫾2 y) operated in the same year was matched. Matching for treatment year was done to provide similar periods of posttreatment follow-up.
Statistical analysis The overall and disease-free survival rates were calculated from date of diagnosis using the using the KaplanMeier method. Continuous variables were compared using a 2-tailed t-test for paired samples and categorical variables using the Fischer exact test and the chi-square test. P o 0.05 was considered statistically significant.
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 19.e1–19.e5 Table 1 Baseline characteristics of patients who underwent chemoradiation or surgery for muscle-invasive bladder cancer
Number Mean age, y (S.D.) Mean Charlson comorbidity index (S.D.) Male gender (%) Median follow-up, mo
Chemoradiation Radical cystectomy
P value
33 73.6 (11) 4.36 (1.9)
33 72.8 (11) 3.45 (1.2)
– 0.736 0.0099
26 (78.8) 35
25 (75.6) 36
1 –
S.D. ¼ standard deviation.
Results A total of 33 patients were treated with chemoradiation for T2-4aN0M0 urothelial bladder cancer and were age-matched with patients who underwent radical cystectomy at the same year. The characteristics of the patients are shown in Table 1. The groups were similar in age, proportion of men, and length of follow-up. However, the Charlson comorbidity index was significantly lower for operated patients (3.45 vs. 4.36, P ¼ 0.01). The mean radiotherapy dose was 62 Gy (standard deviation ¼ 8.36, range: 45–72). Overall, 20 patients received cisplatin, and carboplatin was given to 12 patients with decreased renal function. In 6 patients, gemcitabine was given (with carboplatin in 3 patients, with cisplatin in 2 patients, and as an only agent in 1 patient). Final surgical pathology findings in the group that underwent radical cystectomy were as follows: T0 in 2 patients, Ta/Tis in 1 patient, T2 in 12 patients, T3 in 14 patients, and T4a in 1 patient. The nodal status was as follows: N0 in 25 patients, and N1 and N2 each in 4 patients. Of the 25 men in this group, 7 (28%) also had prostate cancer. Surgical margins were negative in all cases. Reconstruction of the urinary system was accomplished by a neobladder in 4 patients (12.1%) and by an ileal conduit in 29 patients (87.9%). Table 2 presents the side effects of the treatments. Most patients had at least 1 postoperative complication, the most common (70%) was blood transfusion (Clavien grade 2). More severe complications were rare, and there was no postoperative mortality. Chemoradiation was well tolerated Table 2 Side effects of chemoradiation (CTCAE and RTOG toxicity grading systems) and surgery (Clavien-Dindo) for muscle-invasive bladder cancer Grade
Chemoradiation genitourinary
Chemoradiation gastrointestinal
Radical cystectomy
0 1 2 3 4 5
20 4 8 1 0 0
28 2 3 1 0 0
3 5 23 1 1 0
(60.6%) (12.1%) (24.2%) (3%)
(84.8%) (6%) (9%) (3%)
(9.1%) (15%) (69.7%) (3%) (3%)
CTCAE ¼ Common Terminology Criteria for Adverse Events.
19.e3
by most patients. Most side effects were genitorurinary and gastrointestinal. There were only 4 cases of grade 3þ toxicity. Two patients in the chemoradiation group had salvage cystectomy (1 for stage T1 disease recurrence and 1 for bladder shrinkage). Reconstruction of the urinary system was accomplished using an ileal conduit in 1 patient and neobladder in another. The overall and disease-free survival curves of operated and irradiated patients have been presented in Fig. The 2- and 5-year overall survival rates after surgery were 74.4% and 54.8%, respectively, and after chemoradiation were 70.2% and 56.6% (P ¼ 0.8), respectively. The 2- and 5-year disease-free survival rates after surgery were 67.8% and 63.2%, respectively, and after chemoradiation were 63% and 54.3% (P ¼ 0.89), respectively.
Discussion Explaining the consequences of muscle-invasive bladder cancer to a newly diagnosed patient is one of the most difficult tasks in urologic oncology. In patients without metastatic disease and a reasonable operative risk, most clinicians offer radical cystectomy [1] with or without neoadjuvant chemotherapy. The rest of the discussion addresses the method of urinary diversion. Chemoradiation is traditionally reserved for patients who are too sick to undergo radical surgery. When a patient eligible for surgery asks about nonoperative treatments, a clinician has to admit that although there are encouraging reports on chemoradiation, there are no good comparative studies. Comparing surgery with chemoradiation is difficult as operated patients are usually younger and healthier. In this study, we matched patients with T2-4aN0M0 bladder cancer treated by either chemoradiation or radical cystectomy according to age and year of treatment. We found that the overall and disease-free survival rates of both groups were remarkably similar (Fig.). Importantly, these similar survival rates were obtained despite the significantly higher Charlson comorbidity index of the chemoradiation group. The survival rates obtained in both arms of the study were similar to the rates reported in the literature (Table 3). The literature does include superior, although exceptional, results reported by Zapatero et al. [16] with chemoradiation and by Stein et al. [3] with radical cystectomy, both potentially explained by selection and referral biases. Only a few studies attempted to compare surgery with chemoradiation [7,8,19]. All comparisons were noncontrolled, retrospective, and operated patients were younger (5–7 y) and healthier than the irradiated patients. Nevertheless, all 3 studies showed similar overall and cancerspecific survival rates. However, it must be remembered, that patients with a bulky tumor or obstructed kidney were not candidates for chemoradiation, neither in this study nor in many other studies [23]. This can potentially increase
19.e4
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 19.e1–19.e5
Fig. The Kaplan-Meier survival curves comparing the disease-specific survival (A) and overall survival (B) in patients with T2-4aN0M0 bladder cancer treated by either radical cystectomy (green) or chemoradiation (red).
tumor burden in the operated group and act as a factor decreasing the longevity of those treated with surgery. When comparing the side effects of treatment (Table 2), it can be noticed that surgery, although associated with a high frequency of blood transfusions (70%), classified as Clavien grade 2, is usually not accompanied with more severe complications. Chemoradiation is also well tolerated by most patients, with grade 3þ toxicity occurring in only Table 3 Overall and disease-specific 5-year survival rates of patients with T24aN0M0 bladder cancer treated with either surgery or chemoradiation References (number of patients)
5-Year overall survival (%)
5-Year disease-free survival (%)
Radical cystectomy Kotwal et al. [7] (89) Stein et al. [3] (1,054) Madersbacher et al. [13] (507) Hautman et al. [14] (788) Chahal et al. [8] (96) Grossman et al. [2]a (153) Current study (33)
41.3 84 62 57.7 36.5 58 54.8
53.4 68 59 68
Chemoradiation Efstathiou (348) [4] James et al. [15] (182)b Danesi et al [6] (77) Zapatero et al. [16] (80) Sabaa et al. [17] (104) Kotwal et al. [7] (97)c Rödel et al. [18] (326)d Chahal et al. [8] (302)c Maarouf et al. [20] (33) Arias et al. [21] (55) Oh et al. [22] (24) Current study (33)
52 48 58.8 73 59.4 34.6 45 37.4 64.3 (1 y) 45 76 56.6
a
Neoadjuvant arm. Chemoradiation arm. c Radiotherapy only. d Including “high-risk” T1. b
63.2 64 53.5 82 68.8 56.8
39 (1 y) 82 54.3
12% of the patients, and only 1 patient (given 72 Gy) requiring cystectomy for a contracted bladder. This rate is similar to the rate reported by Efstathiou et al. [4] in a combined study of 4 RTOG protocols. However, there is a fundamental difference between postoperative complications graded by the Clavien system and postchemoradiation grading systems. The Clavien system is based on the magnitude of effort needed to treat the complication. Although this system accurately grades the severity of the early surgical complications, it ignores the expected mutilating sequel of it, namely the loss of the bladder. This can be assessed more adequately by quality-of-life questionnaires. When patients who underwent radical cystectomy were compared with patients treated by chemoradiation, Caffo et al. [24] found that the quality of life after cystectomy was lowered by the presence of stoma, decreased sexual activity, and worsened physical condition. In another study, it was found that patients who had an orthotopic reconstruction had better quality of life than patients who had an ileal conduit did [25]. However, many candidates for cystectomy, especially elderly ones, are not fit for orthotopic diversion and diverted diversion is performed with an ileal conduit after radical cystectomy. In another study, Zietman et al. [26] assessed 32 patients treated by chemoradiation by questionnaires and by urodynamics. Their global healthrelated quality of life was high, 59% of the men were satisfied with their sex life, and 75% of the patients had a normally functioning bladder. An additional concern with chemoradiation is the possible need for salvage cystectomy. This surgery was needed in 22% of the patients in the study by Efstathiou et al. [4] and in 2 patients in the current study. Salvage cystectomy is expected to be associated with a higher rate of cardiovascular/hematological complications, reflecting the effect of chemotherapy, and with a higher rate of tissuehealing complications, reflecting radiotherapy. However, in
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 19.e1–19.e5
a series of 91 salvage cystectomies, the complication rate was only slightly higher than the reported rate for primary cystectomies, whereas the frequency of major complications and postoperative mortality was not higher [27]. The current study is limited by its retrospective nature, the small number of patients, and the matching that was based only on age and year of diagnosis. Designing a prospective study to answer this question seems highly unlikely at this moment. Conclusion In this study, age-matched patients with T2-4aN0M0 bladder cancer treated by either radical cystectomy or chemoradiation were compared. To the best of our knowledge, this methodology has never been reported before. Similar overall and disease-specific survival rates were found, despite significantly higher comorbidity index of the irradiated patients. Treatment with chemoradiation should be considered in patients with T2-4aN0M0 bladder cancer. However, it must be remembered that chemoradiation is not suitable for patients with a bulky tumor that was not (or cannot) be resected (maximal transurethral resection) and for patients with an obstructed kidney, and there is a question regarding its usefulness in patients with bladder carcinoma in situ. References [1] Gakis G, Efstathiou J, Lerner SP, et al. CUD-EAU International Consultation on Bladder Cancer 2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013;63:45–57. [2] Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–66. [3] 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. [4] Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol 2012;61: 705–11. [5] Efstathiou JA, Bae K, Shipley WU, et al. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol 2009;27:4055–61. [6] Danesi DT, Arcangeli G, Cruciani E, et al. Conservative treatment of invasive bladder carcinoma by transurethral resection, protracted intravenous infusion chemotherapy, and hyperfractionated radiotherapy: long term results. Cancer 2004;101:2540–8. [7] Kotwal S, Choudhury A, Johnston C, et al. Similar treatment outcomes for radical cystectomy and radical radiotherapy in invasive bladder cancer treated at a United Kingdom specialist treatment center. Int J Radiat Oncol Biol Phys 2008;70:456–4563. [8] Chahal R, Sundaram SK, Iddenden R, et al. A study of the morbidity, mortality and long-term survival following radical cystectomy and radical radiotherapy in the treatment of invasive bladder cancer in Yorkshire. Eur Urol 2003;43:246–57.
19.e5
[9] Charlson ME, Pompe P, Ales K, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. [10] Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13. [11] Common Terminology Criteria for Adverse Events v4.0 (CTCAE). 〈Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_201006-14_QuickReference_57.pdf〉. [12] Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–6. [13] Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer today: a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21:690–6. [14] Hautmann RE, Gschwend JE, de Petriconi RC, et al. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. J Urol 2006;176:486–92. [15] James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–88. [16] Zapatero A, Martin De Vidales C, et al. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radiochemotherapy. Urology 2012;80:1056–62. [17] Sabaa MA, El-Gamal OM, Abo-Elenen M, et al. Combined modality treatment with bladder preservation for muscle invasive bladder cancer. Urol Oncol 2010;28:14–20. [18] Rödel C, Grabenbauer GG, Kühn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002;20:3061–71. [19] Haresh KP, Julka PK, Sharma DN, et al. A prospective study evaluating surgery and chemo radiation in muscle invasive bladder cancer. J Cancer Res Ther 2007;3:81–5. [20] Maarouf AM, Khalil S, Salem EA, et al. Bladder preservation multimodality therapy as an alternative to radical cystectomy for treatment of muscle invasive bladder cancer. BJU Int 2011;107: 1605–10. [21] Arias F, Domínguez MA, Martínez E, et al. Chemoradiotherapy for muscle invadingbladder carcinoma. Final report of a single institutional organ-sparing program. Int J Radiat Oncol Biol Phys 2000;47: 373–8. [22] Oh KS, Soto DE, Smith DC, et al. Combined-modality therapy with gemcitabine andradiation therapy as a bladder preservation strategy: long-term results of a phase I trial. Int J Radiat Oncol Biol Phys 2009;74:511–7. [23] Gospodarowicz M. Radiotherapy and organ preservation in bladder cancer: are we ignoring the evidence? J Clin Oncol 2002;20:3048–50. [24] Caffo O, Fellin G, Graffer U, et al. Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma. A survey by a self-administered questionnaire. Cancer 1996;78:1089–97. [25] Henningsohn L, Steven K, Kallestrup EB, et al. Distressful symptoms and well-being after radical cystectomy and orthotopic bladder substitution compared with a matched control population. J Urol 2002;168:168–74. [26] 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 longterm survivors. J Urol 2003;170:1772–6. [27] Eswara JR, Efstathiou JA, Heney NM, et al. Complications and longterm results of salvage cystectomy after failed bladder sparing therapy for muscle invasive bladder cancer. J Urol 2012;187:463–8.
Original article
Radical cystectomy vs. chemoradiation in T2-4aN0M0 bladder cancer: A case-control study Ofer N. Gofrit, M.D., Ph.D.a,*, Rony Nof, M.D.a, Amichai Meirovitz, M.D.b, Dov Pode, M.D.a, Stephen Frank, M.D.b, Ran Katz, M.D.a, Amos Shapiro, M.D.a, Ezekiel H. Landau, M.D.a, Guy Hidas, M.D.a, Vladimir Yutkin, M.D.a, Mordechai Duvdevani, M.D.a, Mark Wygoda, M.D.b a b
Department of Urology, Hadassah Hebrew University Hospital, Jerusalem, Israel Department of Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel
Received 18 July 2014; received in revised form 8 September 2014; accepted 21 September 2014
Abstract Background: Muscle-invasive bladder cancer is most commonly treated by radical cystectomy. Patients who are too sick to go through this surgery or who are unwilling to accept the mutilation associated with it are referred to chemoradiation. We compared the results of these 2 modalities using age-matched populations. Participants and methods: Between 1998 and 2008, 33 patients were treated with chemoradiation for biopsy-proven T2-4aN0M0 urothelial bladder cancer. For every patient treated with chemoradiation, an age-matched patient who underwent radical cystectomy on the same year was selected for comparison. Mean radiotherapy dose was 62 Gy (standard deviation ¼ 8.4) and median follow-up of both groups was approximately 36 months. Results: The groups were similar in age, proportion of men, and length of follow-up. However, the Charlson comorbidity index was significantly lower for operated patients (3.45 vs. 4.36, P ¼ 0.01). Furthermore, 2 patients (6%) in the chemoradiation group had salvage cystectomy (one for disease recurrence and another for bladder shrinkage). The 2- and 5-year overall survival rates after surgery were 74.4% and 54.8%, respectively, and after chemoradiation were 70.2% and 56.6% (P ¼ 0.8), respectively. The 2- and 5-year disease-free survival rates after surgery were 67.8% and 63.2%, respectively, and after chemoradiation were 63% and 54.3% (P ¼ 0.89), respectively. Side effects were mild in both groups, with grade 3þ toxicity seen in only 2 operated and 4 irradiated patients. Conclusions: Despite having a significantly higher comorbidity index, patients treated with chemoradiation had similar overall and disease-free survival rates with low toxicity. Treatment with chemoradiation should be considered in patients with T2-4aN0M0 bladder cancer. r 2014 Elsevier Inc. All rights reserved.
Keywords: Muscle-invasive bladder cancer; Radical cystectomy; Chemoradiation
1. Introduction Muscle-invasive bladder cancer is most commonly treated by radical cystectomy [1]. This treatment usually provides excellent locoregional control of the disease. Adjuvant or neoadjuvant treatment can be used for targeting The first two authors contributed equally to this work. Rony Nof's participation in this study was performed in fulfilment of the research requirements toward the M.D. degree at the Hebrew University Hadassah School of Medicine. * Corresponding author. E-mail address: [email protected] (O.N. Gofrit). http://dx.doi.org/10.1016/j.urolonc.2014.09.014 1078-1439/r 2014 Elsevier Inc. All rights reserved.
occult metastases [2]. The commonly cited results of radical cystectomy are quite good with overall 5-year survival rate up to 84% without chemotherapy [3]. However, these results came from a center of excellence and probably reflect meticulous patient selection and superb operative technique. In a more mixed population, like in the one that was reported in the SWOG neoadjuvant trial performed across 126 institutions, the overall 5-year survival rate was only 58% in the group receiving neoadjuvant chemotherapy [2]. Patients who are too sick to safely undergo surgery or who are unwilling to accept the morbidity of surgery including the loss of sexual function, potential deterioration
19.e2
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 19.e1–19.e5
of the upper tract, and the mutilation associated with urinary diversion often select chemoradiation. Various regimens of chemotherapy and radiotherapy were reported. In a combined study including 348 patients from 7 protocols and “off protocol” patients, treated from 1986 to 2006, the 5-year disease-specific and overall survival rates were 64% and 52%, respectively, and cystectomy was required in only 22% of them [4]. The long-term toxicity of this treatment is usually moderate, with only 7% late (4180 d) grade 3 pelvic toxicity, no late grade 4 toxicity, and no treatmentrelated deaths in 285 patients participating in 4 Radiation Therapy Oncology Group (RTOG) trials [5]. In another study, the overall 5-year survival rate was 58.5%, and 76% of the patients were cystectomy free [6]. To directly compare the results of radical cystectomy and chemoradiation, a randomized trial is necessary. Such a trial has never been done and probably cannot be done. Retrospective comparisons are also lacking in the literature, probably because of the dissimilar populations referred to the different modalities, as the patients referred to surgery are typically younger and healthier. In a report by Kotwal et al., 97 patients treated by radiotherapy were compared with 72 treated by radical cystectomy. Although patients treated by radiotherapy were 7 years older, the overall 5-year survival rates were similar, although the results of both groups were rather disappointing (34.6% and 41.3% for radiotherapy and surgery, respectively) [7]. In another study comparing radiotherapy (302 patients) with surgery (96 patients), Chahal et al. [8] showed similar 5-year overall survival (37.4% and 36.5%) despite a 5-year age difference between the groups. In this study, in an attempt to compare chemoradiation to surgery overcoming at least the age factor, we matched patients with T2-4aN0M0 bladder cancer treated by chemoradiation to patients treated by radical cystectomy according to age and year of treatment.
Participants and methods Patients and treatment Information was obtained from the hospital registry containing information on 760 patients treated for bladder cancer between 1998 and 2008. The study was approved by the Institutional Review Board Committee (Institutional Helsinki committee, IRB number 207-31.10.08). The diagnosis of bladder cancer was made using transurethral resection of bladder tumor histological specimens. Pathologic staging was performed according to the 1997 TNM system. The diagnosis of muscle-invasive bladder cancer initiated metastatic workup, which included computed tomography scans of the chest, abdomen, and pelvis and assessment of operative risk. Comorbidity was graded according to the Charlson comorbidity index [9]. Patients with no evidence of metastases and a reasonable
risk for general anesthesia were offered radical cystectomy. Chemoradiation was considered in patients who were too sick to go through this surgery or who were interested in preservation of their bladder.
Surgery Radical cystectomy included standard (common iliac, external iliac, and obturator) pelvic lymph node dissection. Postoperative complications were graded according to the Clavien and Dindo classification [10]. Postoperative followup included evaluation of kidney function and CT scans of the chest, abdomen, and pelvis at 3 and 6 months, then at 6-month intervals for 3 years, and then according to clinician discretion.
Chemoradiation Chemoradiation was given with a curative intent after maximal transurethral resection of the tumor. Radiotherapy was given with 3-dimensional planning (6 patients) and intensity-modulated radiation therapy (27 patients), aiming at delivering approximately 45 to 46 Gy to the bladder and pelvic nodes (internal and external iliac nodes and obturator nodes) followed by a bladder boost to a total dose of approximately 66 Gy (fractionated at 1.8–2 Gy). Imageguided radiotherapy was not used. Chemotherapy consisted of weekly administration of cisplatin at a dose of 40 mg/m2. For patients older than 75 years, the dose was reduced to 25 mg/m2. If renal function was impaired cisplatin was replaced by weekly administration of carboplatin area under the curve 2, as calculated by the Calvert Formula. Patients with a bulky tumor or with an obstructed kidney were not considered candidates for chemoradiation. The follow-up procedure paralleled that of postoperative follow-up with the addition of periodic cystoscopic evaluation and liberal use of biopsies of suspicious lesions. Complications of therapy were graded according to the Common Terminology Criteria for Adverse Events v 4.0 for chemotherapy and the RTOG toxicity grading systems for radiation [11,12]. For each patient treated with chemoradiation, a patient of a similar age (⫾2 y) operated in the same year was matched. Matching for treatment year was done to provide similar periods of posttreatment follow-up.
Statistical analysis The overall and disease-free survival rates were calculated from date of diagnosis using the using the KaplanMeier method. Continuous variables were compared using a 2-tailed t-test for paired samples and categorical variables using the Fischer exact test and the chi-square test. P o 0.05 was considered statistically significant.
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 19.e1–19.e5 Table 1 Baseline characteristics of patients who underwent chemoradiation or surgery for muscle-invasive bladder cancer
Number Mean age, y (S.D.) Mean Charlson comorbidity index (S.D.) Male gender (%) Median follow-up, mo
Chemoradiation Radical cystectomy
P value
33 73.6 (11) 4.36 (1.9)
33 72.8 (11) 3.45 (1.2)
– 0.736 0.0099
26 (78.8) 35
25 (75.6) 36
1 –
S.D. ¼ standard deviation.
Results A total of 33 patients were treated with chemoradiation for T2-4aN0M0 urothelial bladder cancer and were age-matched with patients who underwent radical cystectomy at the same year. The characteristics of the patients are shown in Table 1. The groups were similar in age, proportion of men, and length of follow-up. However, the Charlson comorbidity index was significantly lower for operated patients (3.45 vs. 4.36, P ¼ 0.01). The mean radiotherapy dose was 62 Gy (standard deviation ¼ 8.36, range: 45–72). Overall, 20 patients received cisplatin, and carboplatin was given to 12 patients with decreased renal function. In 6 patients, gemcitabine was given (with carboplatin in 3 patients, with cisplatin in 2 patients, and as an only agent in 1 patient). Final surgical pathology findings in the group that underwent radical cystectomy were as follows: T0 in 2 patients, Ta/Tis in 1 patient, T2 in 12 patients, T3 in 14 patients, and T4a in 1 patient. The nodal status was as follows: N0 in 25 patients, and N1 and N2 each in 4 patients. Of the 25 men in this group, 7 (28%) also had prostate cancer. Surgical margins were negative in all cases. Reconstruction of the urinary system was accomplished by a neobladder in 4 patients (12.1%) and by an ileal conduit in 29 patients (87.9%). Table 2 presents the side effects of the treatments. Most patients had at least 1 postoperative complication, the most common (70%) was blood transfusion (Clavien grade 2). More severe complications were rare, and there was no postoperative mortality. Chemoradiation was well tolerated Table 2 Side effects of chemoradiation (CTCAE and RTOG toxicity grading systems) and surgery (Clavien-Dindo) for muscle-invasive bladder cancer Grade
Chemoradiation genitourinary
Chemoradiation gastrointestinal
Radical cystectomy
0 1 2 3 4 5
20 4 8 1 0 0
28 2 3 1 0 0
3 5 23 1 1 0
(60.6%) (12.1%) (24.2%) (3%)
(84.8%) (6%) (9%) (3%)
(9.1%) (15%) (69.7%) (3%) (3%)
CTCAE ¼ Common Terminology Criteria for Adverse Events.
19.e3
by most patients. Most side effects were genitorurinary and gastrointestinal. There were only 4 cases of grade 3þ toxicity. Two patients in the chemoradiation group had salvage cystectomy (1 for stage T1 disease recurrence and 1 for bladder shrinkage). Reconstruction of the urinary system was accomplished using an ileal conduit in 1 patient and neobladder in another. The overall and disease-free survival curves of operated and irradiated patients have been presented in Fig. The 2- and 5-year overall survival rates after surgery were 74.4% and 54.8%, respectively, and after chemoradiation were 70.2% and 56.6% (P ¼ 0.8), respectively. The 2- and 5-year disease-free survival rates after surgery were 67.8% and 63.2%, respectively, and after chemoradiation were 63% and 54.3% (P ¼ 0.89), respectively.
Discussion Explaining the consequences of muscle-invasive bladder cancer to a newly diagnosed patient is one of the most difficult tasks in urologic oncology. In patients without metastatic disease and a reasonable operative risk, most clinicians offer radical cystectomy [1] with or without neoadjuvant chemotherapy. The rest of the discussion addresses the method of urinary diversion. Chemoradiation is traditionally reserved for patients who are too sick to undergo radical surgery. When a patient eligible for surgery asks about nonoperative treatments, a clinician has to admit that although there are encouraging reports on chemoradiation, there are no good comparative studies. Comparing surgery with chemoradiation is difficult as operated patients are usually younger and healthier. In this study, we matched patients with T2-4aN0M0 bladder cancer treated by either chemoradiation or radical cystectomy according to age and year of treatment. We found that the overall and disease-free survival rates of both groups were remarkably similar (Fig.). Importantly, these similar survival rates were obtained despite the significantly higher Charlson comorbidity index of the chemoradiation group. The survival rates obtained in both arms of the study were similar to the rates reported in the literature (Table 3). The literature does include superior, although exceptional, results reported by Zapatero et al. [16] with chemoradiation and by Stein et al. [3] with radical cystectomy, both potentially explained by selection and referral biases. Only a few studies attempted to compare surgery with chemoradiation [7,8,19]. All comparisons were noncontrolled, retrospective, and operated patients were younger (5–7 y) and healthier than the irradiated patients. Nevertheless, all 3 studies showed similar overall and cancerspecific survival rates. However, it must be remembered, that patients with a bulky tumor or obstructed kidney were not candidates for chemoradiation, neither in this study nor in many other studies [23]. This can potentially increase
19.e4
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 19.e1–19.e5
Fig. The Kaplan-Meier survival curves comparing the disease-specific survival (A) and overall survival (B) in patients with T2-4aN0M0 bladder cancer treated by either radical cystectomy (green) or chemoradiation (red).
tumor burden in the operated group and act as a factor decreasing the longevity of those treated with surgery. When comparing the side effects of treatment (Table 2), it can be noticed that surgery, although associated with a high frequency of blood transfusions (70%), classified as Clavien grade 2, is usually not accompanied with more severe complications. Chemoradiation is also well tolerated by most patients, with grade 3þ toxicity occurring in only Table 3 Overall and disease-specific 5-year survival rates of patients with T24aN0M0 bladder cancer treated with either surgery or chemoradiation References (number of patients)
5-Year overall survival (%)
5-Year disease-free survival (%)
Radical cystectomy Kotwal et al. [7] (89) Stein et al. [3] (1,054) Madersbacher et al. [13] (507) Hautman et al. [14] (788) Chahal et al. [8] (96) Grossman et al. [2]a (153) Current study (33)
41.3 84 62 57.7 36.5 58 54.8
53.4 68 59 68
Chemoradiation Efstathiou (348) [4] James et al. [15] (182)b Danesi et al [6] (77) Zapatero et al. [16] (80) Sabaa et al. [17] (104) Kotwal et al. [7] (97)c Rödel et al. [18] (326)d Chahal et al. [8] (302)c Maarouf et al. [20] (33) Arias et al. [21] (55) Oh et al. [22] (24) Current study (33)
52 48 58.8 73 59.4 34.6 45 37.4 64.3 (1 y) 45 76 56.6
a
Neoadjuvant arm. Chemoradiation arm. c Radiotherapy only. d Including “high-risk” T1. b
63.2 64 53.5 82 68.8 56.8
39 (1 y) 82 54.3
12% of the patients, and only 1 patient (given 72 Gy) requiring cystectomy for a contracted bladder. This rate is similar to the rate reported by Efstathiou et al. [4] in a combined study of 4 RTOG protocols. However, there is a fundamental difference between postoperative complications graded by the Clavien system and postchemoradiation grading systems. The Clavien system is based on the magnitude of effort needed to treat the complication. Although this system accurately grades the severity of the early surgical complications, it ignores the expected mutilating sequel of it, namely the loss of the bladder. This can be assessed more adequately by quality-of-life questionnaires. When patients who underwent radical cystectomy were compared with patients treated by chemoradiation, Caffo et al. [24] found that the quality of life after cystectomy was lowered by the presence of stoma, decreased sexual activity, and worsened physical condition. In another study, it was found that patients who had an orthotopic reconstruction had better quality of life than patients who had an ileal conduit did [25]. However, many candidates for cystectomy, especially elderly ones, are not fit for orthotopic diversion and diverted diversion is performed with an ileal conduit after radical cystectomy. In another study, Zietman et al. [26] assessed 32 patients treated by chemoradiation by questionnaires and by urodynamics. Their global healthrelated quality of life was high, 59% of the men were satisfied with their sex life, and 75% of the patients had a normally functioning bladder. An additional concern with chemoradiation is the possible need for salvage cystectomy. This surgery was needed in 22% of the patients in the study by Efstathiou et al. [4] and in 2 patients in the current study. Salvage cystectomy is expected to be associated with a higher rate of cardiovascular/hematological complications, reflecting the effect of chemotherapy, and with a higher rate of tissuehealing complications, reflecting radiotherapy. However, in
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 19.e1–19.e5
a series of 91 salvage cystectomies, the complication rate was only slightly higher than the reported rate for primary cystectomies, whereas the frequency of major complications and postoperative mortality was not higher [27]. The current study is limited by its retrospective nature, the small number of patients, and the matching that was based only on age and year of diagnosis. Designing a prospective study to answer this question seems highly unlikely at this moment. Conclusion In this study, age-matched patients with T2-4aN0M0 bladder cancer treated by either radical cystectomy or chemoradiation were compared. To the best of our knowledge, this methodology has never been reported before. Similar overall and disease-specific survival rates were found, despite significantly higher comorbidity index of the irradiated patients. Treatment with chemoradiation should be considered in patients with T2-4aN0M0 bladder cancer. However, it must be remembered that chemoradiation is not suitable for patients with a bulky tumor that was not (or cannot) be resected (maximal transurethral resection) and for patients with an obstructed kidney, and there is a question regarding its usefulness in patients with bladder carcinoma in situ. References [1] Gakis G, Efstathiou J, Lerner SP, et al. CUD-EAU International Consultation on Bladder Cancer 2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013;63:45–57. [2] Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–66. [3] 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. [4] Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol 2012;61: 705–11. [5] Efstathiou JA, Bae K, Shipley WU, et al. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol 2009;27:4055–61. [6] Danesi DT, Arcangeli G, Cruciani E, et al. Conservative treatment of invasive bladder carcinoma by transurethral resection, protracted intravenous infusion chemotherapy, and hyperfractionated radiotherapy: long term results. Cancer 2004;101:2540–8. [7] Kotwal S, Choudhury A, Johnston C, et al. Similar treatment outcomes for radical cystectomy and radical radiotherapy in invasive bladder cancer treated at a United Kingdom specialist treatment center. Int J Radiat Oncol Biol Phys 2008;70:456–4563. [8] Chahal R, Sundaram SK, Iddenden R, et al. A study of the morbidity, mortality and long-term survival following radical cystectomy and radical radiotherapy in the treatment of invasive bladder cancer in Yorkshire. Eur Urol 2003;43:246–57.
19.e5
[9] Charlson ME, Pompe P, Ales K, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. [10] Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13. [11] Common Terminology Criteria for Adverse Events v4.0 (CTCAE). 〈Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_201006-14_QuickReference_57.pdf〉. [12] Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–6. [13] Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer today: a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21:690–6. [14] Hautmann RE, Gschwend JE, de Petriconi RC, et al. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. J Urol 2006;176:486–92. [15] James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–88. [16] Zapatero A, Martin De Vidales C, et al. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radiochemotherapy. Urology 2012;80:1056–62. [17] Sabaa MA, El-Gamal OM, Abo-Elenen M, et al. Combined modality treatment with bladder preservation for muscle invasive bladder cancer. Urol Oncol 2010;28:14–20. [18] Rödel C, Grabenbauer GG, Kühn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002;20:3061–71. [19] Haresh KP, Julka PK, Sharma DN, et al. A prospective study evaluating surgery and chemo radiation in muscle invasive bladder cancer. J Cancer Res Ther 2007;3:81–5. [20] Maarouf AM, Khalil S, Salem EA, et al. Bladder preservation multimodality therapy as an alternative to radical cystectomy for treatment of muscle invasive bladder cancer. BJU Int 2011;107: 1605–10. [21] Arias F, Domínguez MA, Martínez E, et al. Chemoradiotherapy for muscle invadingbladder carcinoma. Final report of a single institutional organ-sparing program. Int J Radiat Oncol Biol Phys 2000;47: 373–8. [22] Oh KS, Soto DE, Smith DC, et al. Combined-modality therapy with gemcitabine andradiation therapy as a bladder preservation strategy: long-term results of a phase I trial. Int J Radiat Oncol Biol Phys 2009;74:511–7. [23] Gospodarowicz M. Radiotherapy and organ preservation in bladder cancer: are we ignoring the evidence? J Clin Oncol 2002;20:3048–50. [24] Caffo O, Fellin G, Graffer U, et al. Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma. A survey by a self-administered questionnaire. Cancer 1996;78:1089–97. [25] Henningsohn L, Steven K, Kallestrup EB, et al. Distressful symptoms and well-being after radical cystectomy and orthotopic bladder substitution compared with a matched control population. J Urol 2002;168:168–74. [26] 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 longterm survivors. J Urol 2003;170:1772–6. [27] Eswara JR, Efstathiou JA, Heney NM, et al. Complications and longterm results of salvage cystectomy after failed bladder sparing therapy for muscle invasive bladder cancer. J Urol 2012;187:463–8.