Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review

EURURO-7301; No. of Pages 11 EUROPEAN UROLOGY XXX (2017) XXX–XXX

available at www.sciencedirect.com journal homepage: www.europeanurology.com

Platinum Priority – Review – Bladder Cancer Editorial by XXX on pp. x–y of this issue

Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review Vale´rie Fonteyne a,y,*, Piet Ost a,y, Joaquim Bellmunt b, Jean Pierre Droz c, Pierre Mongiat-Artus d, Brant Inman e, Elena Paillaud f, Fred Saad g, Guillaume Ploussard h a

Department of Radiotherapy, Ghent University Hospital, Ghent, Belgium;

c

b

Department of Cancer Environment Research Unit, Le´on-Be´rard Cancer Center, Claude-Bernard-Lyon University, Lyon, France;

Bladder Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA; d

Department of Urology,

Saint-Louis Hospital, Paris, France; e Department of Urology, Duke University Medical Center, Durham, NC, USA; f Geriatric Department, CHU Henri Mondor, APHP, Cre´teil, France;

g

Prostate Cancer Research, Montreal Cancer Institute/CRCHUM, Centre de Hospitalier de Universite´ de Montre´al, Montre´al, QC,

h

Canada; Urology Department, Saint Jean Languedoc Hospital, Toulouse, France

Article info

Abstract

Article history: Accepted March 13, 2017

Context: The incidence of muscle invasive bladder cancer (MIBC) increases with age. With increased life expectancy the number of elderly MIBC patients is expected to increase. Existing guidelines on management of MIBC do not preclude curative treatments for elderly patients. However, it is necessary to assess the risks and benefits of a treatment to avoid overtreatment that results in decreased health-related quality of life without prolonging survival. Objective: To report on overall survival (OS), cancer specific survival (CSS), and morbidity after curative treatment in elderly patients, defined as age >70 yr, with nonmetastatic MIBC and to compare this with the outcome of younger MIBC patients. Evidence acquisition: A systematic review was performed using Medline, PubMed, and Embase databases. Articles were included if they addressed one of the three research questions:

Associate Editor: Giacomo Novara Keywords: Elderly MIBC Outcome Complications

1) Does a geriatric assessment improve outcome in elderly patients with MIBC? 2) Do elderly patients have inferior survival, both CSS and OS, after curative therapy compared to younger patients with MIBC? 3) Do elderly patients have an increased complication rate, defined as perioperative mortality (POM) and both early and late complication rate, after curative therapy compared to younger patients with MIBC? Only articles including >100 patients and with a clear age–stratification were included. Evidence synthesis: Forty-two articles were retrieved for review. No article directly addressed the use of geriatric assessment. OS and CSS worsen significantly with age both after radical cystectomy and radiotherapy regimens. While POM significantly increases with age, morbidity seems comparable between younger and older patients. Conclusions: Although a proportion of elderly patients with MIBC will benefit from curative treatment, we observed worse OS, CSS, and POM with age. The impact of age on

y

These authors contributed equally to the manuscript. * Corresponding author. Department of Radiotherapy, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium. Tel. +3293325972; Fax: +3293323040. E-mail address: [email protected] (V. Fonteyne).

http://dx.doi.org/10.1016/j.eururo.2017.03.019 0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 2

EUROPEAN UROLOGY XXX (2017) XXX–XXX

late morbidity is less clear. Prospective studies evaluating geriatric assessments are critically needed to optimize MIBC management in the elderly. Patient summary: We performed a systematic review to evaluate the outcome and complication rate in elderly patients with muscle invasive bladder cancer. We observed that overall survival and cancer specific survival significantly decrease and perioperative mortality significantly increases with age. The impact of age on late morbidity is less clear. There is a need for geriatric assessments to select those patients that will benefit from curative treatment. # 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

1.

Introduction

Bladder cancer is the ninth most frequently diagnosed cancer worldwide. Although the mortality rate of bladder cancer tends to decrease, bladder cancer still ranks 13th in terms of causes of death [1]. The incidence of bladder cancer increases steadily with age and due to an increase in overall life expectancy, population ages exponentially. Consequently, the number of elderly patients with bladder cancer is expected to further increase in the future. Radical cystectomy (RC) with extended pelvic lymph node dissection is considered to be the standard of care for nonmetastatic muscle invasive bladder cancer (MIBC) [2]. External beam radiotherapy combined with concomitant chemotherapy is an alternative to RC for carefully selected patients [2]. Existing guidelines for the management of MIBC do not preclude curative treatments for elderly patients and it is suggested that the decision to treat cancer patients should not be based solely on age, though life expectancy should be considered [3]. A thorough geriatric assessment (GA) can help avoid both undertreatment and overtreatment of elderly patients, both of which could result in decreased health-related quality of life [3]. The aim of this systematic review is to report on overall survival (OS) and cancer specific survival (CSS) as well as morbidity after curative treatment in elderly patients, defined as age >70 yr, with nonmetastatic MIBC, and to compare this with the outcome observed in a younger population with MIBC. 2.

Evidence acquisition

2.1.

Study design

A systematic review was conducted to identify studies of relevance for the predefined research questions: 1) Does a GA improve outcome in elderly patients with MIBC? 2) Do elderly patients have inferior survival, both cancer specific survival (CSS) and overall survival (OS), after curative therapy compared with younger patients with MIBC? 3) Do elderly patients have an increased complication rate, defined as perioperative mortality (POM) and both early and late complication rate, after curative therapy compared to younger patients with MIBC?

2.2.

Search strategy

Search strings were used to interrogate the following databases: Medline, PubMed, and Embase. Potential articles were identified using the National Library of Medicine’s Medical Subject Headings: ‘‘(urinary bladder neoplasms[mh] OR ) AND (Frail Elderly[mh] OR Aged[mh] OR elder$.ti,ab OR Geriatric$.ti,ab[tw] OR older person.ti,ab[tw] OR older adult.ti,ab[tw] OR octogenerians.ti,ab. [tw]) AND (Cystectomy[mh] OR surgery[mh] OR radiotherapy[mh] OR drug therapy[mh] OR resection.ti,ab OR radiotherapy.ti,ab OR radiation. ti,ab OR chemothera$ .ti,ab OR antineoplastic$.ti,ab) AND (treatment outcome[mh] OR survival rate[mh] OR effectiveness.ti,ab OR efficacy.ti,ab OR survival benefit ti,ab). The search was finalized on December 21, 2016. Relevant articles found in the reference section of the retrieved articles were also retained for evaluation. 2.3.

Eligibility criteria

Longitudinal and population-based studies as well as consecutive and nonconsecutive surgical series, reporting on CSS, OS, POM, or complication rate after radical treatment for MIBC, were included. Articles needed to be published in English. Only full papers were included. Articles reporting on at least 100 patients were maintained. Articles could still be rejected, despite inclusion of >100 patients, if the total number of patients in the younger or elderly group separately was <50 patients. Only articles comparing outcomes between different age groups were considered for inclusion. Age stratification was thus mandatory for being eligible. 2.4.

Selection of relevant articles

The selection of relevant articles was conducted in two steps. As a first step, one reviewer (V.F.) excluded clearly irrelevant studies or studies not meeting the eligibility criteria based on title and abstract. Two reviewers (V.F. and P.O.) performed the final selection based on review of the full text manuscripts. 2.5.

Data extraction

Point estimates, p values, and confidence intervals for effectiveness (CSS and OS) and safety outcomes (POM and complication rate) were extracted. It was decided a priori to

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 3

EUROPEAN UROLOGY XXX (2017) XXX–XXX

accept age subgroups as presented in articles but to attempt to examine the effectiveness of treatment among elderly (ie,  70 yr) compared with nonelderly patients with MIBC. The outcomes of patients aged <70 yr were used as a standard against which outcomes in the elderly subgroups were measured unless otherwise specified. 2.6.

Statistical analysis

Identification

Methodological quality of the retrieved articles was assessed using an 18-item validated quality appraisal tool for case series [4]. A quality appraisal judgment for different items was performed using a binary scoring system. A study with a total score of 14 was considered of acceptable quality [4]. Data were not combined for meta-analysis due to the heterogeneity of the included studies regarding population and setting. Instead each effectiveness outcome was examined within each study to determine whether the results showed statistically differences between elderly versus non-elderly MIBC patients. The relative effectiveness for a parameter under study between elderly and nonelderly was reported for each study individually.

Evidence synthesis

The systematic search strategy resulted in 6019 articles. Fig. 1 shows the article selection process. Data were retrieved from 42 articles [5–46]. None of the retrieved articles addressed the first research question regarding the use of a GA and its impact on outcome, while 21 articles reported on OS, 18 on CSS, and 23 on POM or complication rates. Evaluation of the impact of age on outcome was the primary aim in 24 articles. The quality assessment of the retrieved articles is presented in Supplementary Table 1. Only eight articles had a score of 14. For articles that were selected for evaluation of OS or CSS, additional information on tumour characteristics, as well as assessment of performance status and renal function, if provided, can be found in Supplementary Table 2. 3.1.

OS

OS point estimates for different age groups are presented in Table 1. The majority of the studies (9/14) indicate that the OS of patients with MIBC treated with RC decreases with advanced age [5–18].

Records identified through database searching: Medline: n=3246, Embase: n = 2769, Cochrane: n = 4) (n = 6019)

Records after duplicates removed (n = 5006)

Screening

3.

Additional records identified through other sources (n = 48)

Records screened by abstract (n = 5054 )

Records excluded for not meeting the predefined inclusion criteria (n = 4825)

Eligibility

Full-text articles excluded: N = 187

Full-text articles assessed for eligibility (n = 229)

-

Included

-

Studies included in systematic review (n = 42)

-

no age stratification: n = 36 not addressing the research questions (other then predefined outcome parameter): n = 72 patient number <50 per stratification group young versus old patient: n = 20 no full text: n = 34 review article: n =13 insufficient data: n = 6 update of included article: n =2 non-MIBC: n = 2 non-English/French: n = 2

Fig. 1 – Flow diagram of the article selection process for the systematic review. MIBC = muscle invasive bladder cancer.

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 4

EUROPEAN UROLOGY XXX (2017) XXX–XXX

Table 1 – Reported estimates of overall survival rates per age group and per study. The studies in grey represent the studies where a significant difference was observed between younger and older patients

Trials with radical cystectomy N

Author

Reported measure unit

Hafron et al [5] 2005 Horovitz et al [6] 2012 Figueroa et al [7] 1997

Rink et al [8] 2011

Liberman et al [9]

2011a

288 605 1168

390

12 722

Median survival (mo) 3 yr

60–64

Pollack et al [10]

Guillotreau et al [11] 2012 Fontana et al [12] 2015 Böstrum et al [13] 2009 Nisjiyama et al [14] 2004 Leveridge et al [15] 2015 Fairey et al [16] 2012 Patel et al [17] 2015 Hara et al [18] 2016

338

65–69

70.4 (N = 132) 70% (N = 165)

70–74

75–79

80–84

≥85

38.9 (N = 156) 67% (N = 192)

66% (N = 201)

<0.001 58% (N = 47)

3 yr

68% (N = 762)

60% (N = 404)

5 yr

63%

53%

2 yr

70% (N = 265)

68% (N = 125)

5 yr

57%

41%

1 yr

85% (N = 6803)

2 yr

71%

60%

46%

5 yr

54%

42%

23%

42%

25%

10%

10 yr 1994b

p value

Overall survival <60

76% (N = 4480)

0.4 0.001

0.16

64% (N = 1439)

5 yr

47% (N = 204)

41% (N = 134)

10 yr

36%

25%

<0.001

0.03

146

5 yr

87% (N = 72)

75% (N = 74)

0.03

180

5 yr

50% (N = 103)

50% (N = 77)

NS

248

10 yr

39% (N = 64)

0.159

52% (N = 62)

50% (N = 98)

1113

5 yr

71% (N = 691)

65% (N = 60% (N = 268) 110)

3320

5 yr

40% (N = 1362)

34% (N = 28% (N = 674) 627)

23% (N = 657)

<0.001

2263

5 yr

62% (N = 557)

60% (N = 679)

55% (N = 846)

36% (N = 181)

<0.0001

804

5 yr

60% (N = 150)

45% (N = 245)

41% (N = 339)

30% (N = 70)

<0.001

254

5 yr

63% (N = 162)

56% (N = 62)

0.001

62% (N = 92)

0.983

a

Studies based on Surveillance, Epidemiology, and End Results registries. Trial on preoperative radiotherapy. NS = not significant.

b

Twelve trials evaluate the impact of age on OS after RC in multivariate analysis (Table 2) [5,14–17,19–25]. All but two [16,19] confirm that increasing age is significantly associated with worse survival for patients aged >70 yr compared with patients <70 yr old with reported hazard ratios between 1.34 (95% confidence interval [CI]: 1.03–1.74) and 1.46 (95% CI: 1.08–1.97). Obviously, the risk of dying further increases for patients aged >80 yr when compared with patients <70 yr (reported hazard ratio between 1.63 [95% CI: 1.06–2.53] and 3.22 [95% CI: 2.6–3.98]). For patients treated with external beam radiotherapy, two trials reported similar hazard ratios with favourable outcome for younger people [24,25].

worse outcome for patients aged >70 yr compared with patients aged <60 yr (Table 4) [15–17,19,21,23,28,31]. However, age >80 yr remains a significant predictor for CSS with hazard ratios ranging from 1.56 to 2.54. Only two articles reported on CSS after combined chemoradiotherapy [32,33]. A pooled analysis of patients treated with selective bladder-preserving combined modality therapy, enrolled in different Radiation Therapy Oncology Group protocols, did not show worsening of outcome with age with 5-yr CSS of 70% and 71% for patients aged 75 yr and older, respectively [32].

3.2.

The incidence of morbidity after RC for MIBC in old versus young patients is presented in Fig. 2 and Supplementary Table 3 [7,8,11,12,15,16,18,27,30,34–39,41]. Overall perioperative mortality and early mortality is increased in older patients (absolute incidence of POM: 1–6% for patients aged <70 yr vs 0–15% for patients aged >70 yr). Multivariate analysis confirms that POM is significantly increased with

CSS

CSS estimates for different age groups are presented in Table 3. As for OS, CSS worsens with age when patients are treated with RC as is demonstrated in eight out of 12 articles [6,8,9,11,15–17,26–30]. Studies evaluating the impact of age on CSS in multivariate analysis are not able to demonstrate

3.3.

Morbidity

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 5

EUROPEAN UROLOGY XXX (2017) XXX–XXX

Table 2 – Multivariate analysis evaluating impact of age on overall survival rates per age group and per study. The studies in grey represent the studies where a significant difference was observed between younger and older patients Overall  survival Trials  with  radical  cystectomy Author

N <50

Hafron et al [5] 2005

50–54

60–64

55–59

65–69

75–79

80–84

≥85

2.09  (95% CI: 1.54-2.83, p < 0.001)  (N = 156)

ref  (N = 132)

288

70–74

 1.34  (95% CI:  1.03-1.74,  p = 0.027)  (N = 268)

ref  (N = 691)

Nisjiyama et al [14] 2004

1113

Leveridge et al [15] 2015

1701

Dalbagni et al [19] 2001

297

ref  (N = 73)

1.210  (95%CI: 0.687-2.133,  p = 0.5093)  (N = 106)

Fairey et al [16] 2012

2263

ref  (N = 557)

1.11 (95% CI: 0.87-1.4)  (N = 679)

 ref  (N = 582)

NR

1.44  (95% CI:  1.01-2.06,  p = 0.044)  (N = 110)

1.63  (95%CI: 1.06-2.53,  p = 0.027)  (N = 62)

1.16  (95% CI:  1.02-1.33)  (N = 541)

1.23  (95% CI: 1.08-1.41,  p = 0.007)  (N = 578)

 1.376 (95% CI: 0.815-2.324,  p = 0.2323)  (N = 118) 1.15  (0.92-1.44) (N = 846)

2.03 (1.51-2.75)  (N = 181)

Patel et al [17] 2015

804

ref  (N = 150)

1.64  (95% CI: 1.20-2.26)  (N = 245)

Zakaria et al [20] 2016

2671

ref  (N = 625)

1.66 (95% CI: 1.44-1.90,  p < 0.0001)  (N = 795)

Chromecki et al [21] 2012

4429

ref  (N = 321)

0.955  (95% CI: 0.795-1.202,  p = 0.697)  (N = 815)

1.400 (95% CI: 1.134-1.728,  p = 0.002)  (N = 1595)

1.864 (95% CI: 1.509-2.304,  p < 0.001)  (N = 1423)

3.077 (95% CI: 2.381-3.977,  p < 0.001) (N = 275)

Gore et al [22] 2005a

3976

ref  (N = 186)

 1.11 (95% CI: 0.9-1.28,  p = 0.315)  (N = 633)

1.47 (95% CI: 1.22-1.78,  p < 0.001)  (N = 1418)

 1.98 (95% CI: 1.63-2.39,  p < 0.001)  (N = 1458)

3.22 (95% CI: 2.6-3.98, p < 0.001)  (N = 281)

a Morgan et al [41] 2011

3170

1.7  (95% CI: 1.26-2.29)  (N = 339) 2.78  (95% CI: 1.87-4.13)  (N = 70) 1.79 (95% CI:  1.54-2.07,  p < 0.0001)     (N = 540)

2.30  (95% CI: 1.94-2.73,  p < 0.0001)  (N = 711)

1.41 (95% CI: 1.23-1.62,  p < 0.001)  (N = 1406)

ref (N=582)

1.8 (95% CI:  1.34-2.4,  p < 0.001)  (N =151)

Trials  with  radiotherapy Author

N <50

Goossens-Laanb et al [24] 2014

2445

Hayter et al [25] 1999

1372

50-54

55-59

ref  (N = 444) 0.71 (95% CI: 0.47-1.09) (N=51)

 0.82  (95% CI: 0.64-1.06)  (N = 150) 

60-64

65-69

70-74

 1.3  (95% CI: 1.1-1.5)  (N = 1062)

ref  (N = 549)

75-79

80-84

>/=85

2.0  (95% CI: 1.7-2.4)  (N = 939)

1.31 (95% CI: 1.11-1.53)  (N = 549)

1.49  (95% CI: 1.22-1.81)  (N = 218)

a

Studies based on Surveillance, Epidemiology, and End Results registries. Trial on radical cystectomy and external beam radiotherapy. CI = confidence interval; OR = odds ratio; Ref = reference.

b

age (Table 5) [9,16,36,38,40,42–46]. For patients aged >80 yr a 4.61–6.25-fold increased risk of POM is reported. From the age of 70 yr the 30-d and 90-d mortality rate is significantly increased with reported odds ratios up to 1.6 and 5.8, respectively. For patients aged >80 yr the odds ratios for 90-d mortality rises further to 2.4–7.9. In contrast, the incidence of late complications appear to be equal or even more prevalent in younger compared with older patients [7,12,27,35]. 4.

Discussion

From nationwide registries, it becomes clear that the treatment approach of young and elderly patients with nonmetastatic MIBC differs [47,48]. Evaluation of a population-based cancer registry in the UK for example indicates that the percentage of patients that receive a curative treatment drops from 52% to 12% for patients aged <60 yr versus >80 yr [49]. Fear of severe therapy-induced morbidity

and an estimated short life expectancy, as a result of poor health status, are suggested to be the main reasons why a less aggressive therapeutic approach is applied in elderly people. Whether it is justified to undertreat elderly patients is doubtful in view of available literature. This systematic review gives an overview of the reported outcome in elderly patients treated with curative therapies for nonmetastatic MIBC. These results are compared with the outcome observed in a younger population with MIBC. An age cut-off of 65 yr is often applied to discriminate young from old patients. However, the stratification of old versus young patients differs in the articles that were selected for this systematic review. Most of the included studies, reporting on outcome after RC, define elderly patients as patients aged >70 yr. In view of an aging population and taking into account that the median age at diagnosis of MIBC is 70 yr, age stratification with a cut-off of 70 yr for defining elderly patients is defendable. In contrast, included papers evaluating the outcome after radiotherapy

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 6

EUROPEAN UROLOGY XXX (2017) XXX–XXX

Table 3 – Reported estimates of cancer specific survival rates per age group and per study. The studies in grey represent the studies where a significant difference was observed between younger and older patients Cancer  specific  survival Author

N

Reported  measure  unit

Trasher et al [26] 1994

531

NR

Yamanaka et al [27] 2007

629

2-year

Horovitz et al [6] 2012

605

3-year

Rink et al [8] 2011

390

Trials with Radical cystectomy <60

12722

70–74

68%  (N = 272)

80–84

75–79

70%  (N = 192)

70%  (N = 165)

46%  (N = 72)

0.001

60%  (N = 47)

0.4

76%  (N=125)

0.22

57%

68%

5-year

89%  (N = 6803)

84%  (N =  4480)

75%  (N =  1439)

2-year

78%

72%

60%

5-year

65%

60%

50%

60%

10-year 3-year

<0.001

43%

55%

72%  (N = 331)

79%  (N = 240)

p - value <0.001

65%  (N = 201)

78%  (N = 265)

2-year

≥85

50% (N = 259) 70% (N = 557)

1-year Liberman et al [9] 2011a

65–69

60-64

65%  (N = 51)

70%  (N = 266)

Nielsen et al [28] 2007

888

Guillotreau et al [11] 2012

146

5-year

54%

51%

Madersbacher et al [29] 2010

845

5-year

NR

61%  (N = 517) 60%  (N = 269)

Leveridge et al [15] 2015

3320

5-year

37%  (N = 674) 34%  (N = 627)

32%  (N = 657)

<0.001

Fairey et al [16] 2012

2263

5-year

66%  (N = 557)

69%  (N = 679)

69%  (N = 846)

52%  (N = 181)

0.0014

70%  (N = 150)

65%  (N = 245)

58%  (N = 339)

42%  (N = 70)

<0.001

26%  (N = 117)

NS

7-year

70%

10-year

64%

63%

55%

59%

53%

42%  (N = 1362)

0.0331

58% 49%

0.7 46%  (N = 59)

0.01

Patel et al [17] 2015

804

5-year

Donat et al [30] 2010

1142

5-year

Author

N

Reported  measure  unit

Mak et al [32] 2014

467

5-year

70%  (N = 387)

71%  (N = 80)

0.84

Fossa et al [33] 1993

308

5-year

26% (N = 217)

19%  (N = 91)

0.01

25%  (N =  1025) Trials with Radiotherapy <60

60-64

65-69

70-74

75-79

80-84

>/=85

p - value

a Studies based on Surveillance, Epidemiology, and End Results registries. NR = not reported; NS = not significant.

regimens, most often defined elderly patients as patients aged 75 yr instead of 70 yr, reflecting the inclusion of an even older population in these trials. Our systematic review suggests that OS decreases in elderly patients and worsens for patients aged >80 yr, as expected. A shorter life expectancy due to an impaired health status accounts for this finding. The level of frailty, determined by dependency, comorbidities and nutrition status, as well as impaired renal function, which is on its own associated with reduced survival [50], defines the health status of elderly MIBC patients. Unfortunately, only a few articles included in this systematic review gave detailed information on either comorbidities or renal function (Supplementary Table 2). For elderly patients and in particular, patients aged >80 yr, life expectancy has to be weighted against the potential harms and benefits from a curative treatment for each patient individually. Existing life tables can be used to help us to define the expected years of life at separate ages [51]. Equally important is estimating the risk of dying of MIBC. After a curative treatment, the prognosis of patients with MIBC is reserved. But, when left untreated, the median

OS of patients with T3 MIBC is <1 yr [52]. Even when stratifying for Charlson comorbidity index group, curative treatments, either RC or chemoradiation therapy, provide a clear survival benefit compared with nonstandard treatments [53]. The balance of dying from MIBC versus other causes of death most often thus advocates treatment, even in the elderly patients. A systematic use of some form of geriatric assessments may allow physicians to select appropriate candidates for curative treatments. Ideally, all older cancer patients should be evaluated by a GA followed by interventions and follow-up [3]. This GA has proven to be independently associated with changes in cancer treatment [54]. Nowadays, there is no standard GA model. Thus, the prevalence of being frail and/or at risk may vary largely within a well-defined cohort depending on the questionnaires and definitions used. Moreover, this approach is resource consuming and not necessary in all patients. Therefore, the use of a screening tool has been proposed to identify patients in need of GA and multidisciplinary approach. If abnormal, screening should be followed by GA and guided multidisciplinary interventions. At this time, no specific screening tool can be recommended or

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 7

EUROPEAN UROLOGY XXX (2017) XXX–XXX

Table 4 – Multivariate analysis evaluating impact of age on cancer specific survival rates per age group and per study. The studies in grey represent the studies where a significant difference was observed between younger and older patients Cancer  specific  survival Trials with radical cystectomy Author

N <50

Chromecki et al [21] 2012

4429

Dalbagni et al [19] 2001

297

Dotan et al [31] 2007

1586

Fairey et al [16] 2012

2263

Patel et al [17] 2015 Nielsen et al [28] 2007 Morgan et al [23] 2012 Leveridge et al [15] 2015

804 888 3170 1701

ref  (N = 321)

50–54

55–59

0.795  (95% CI: 0.6101.044,  p = 0.1) (N = 815)

60–64

70–74

65–69

1.128  (95% CI: 0.880-

1.252,  p = 1.252)  (N = 1595)

1.446,  p ≤ 0.341) 

1.137  (95% CI: 0.605-

ref (N = 73)

75–79

0.979  (95% CI: 0.766-

2.137,  p = 0.6890) (N = 106)

ref  (N = 613)

80–84

≥85

1.763  (95% CI: 1.2382.424, p < 0.001)  (N = 275)

1.117  (95%CI: 0.619-2.017,  p = 0.7135)  (N = 118)

 1.26  (95% CI: 0.91-2.017,  p = 0.14)  (N = 973)  0.96  (95% CI: 0.74-1.26) 

ref  (N = 557)

(N = 679)  1.24 (95% CI: 0.86-1.80) 

ref  (N = 150)

(N = 245)  1.226  (0.884-1.700, 

ref  (N = 240)

p = 0.222)  (N =331)

 0.87 (95% CI: 0.68-1.13)   1.36 (95% CI: 0.96-1.90) 

(N = 181)  2.54 (95% CI: 1.62-3.96) 

(N = 339)  1.296 (95% CI: 0.9211.823, p =  0.136)  (N = 266)

(N = 70)  1.742 (1.015-2.990,  p = 0.044)  (N = 51)

 1.24 (95% CI: 1.05-1.46, 

ref  (N = 1613) NR

 1.56  (95% CI: 1.09-2.24) 

(N = 846)

p = 0.009)  (N = 1406) ref  (N = 582)

 1.02 (95%  CI:0.93-1.26) 

 1.32  (95%  CI: 0.91-

 1.02  (95% CI: 0.87-1.19,  p = 0.522)  (N = 578)

CI = confidence interval; OR = odds ratio; NR = not reported; Ref = reference.

discouraged, but the G8 seems the most robust [55]. Prospective studies evaluating the impact of using GAs on the decision-making process are needed. Not only OS but also CSS after RC is worse for older patients, implying that age alone is not responsible for worse outcome. Besides differences in health status, a poorer outcome in elderly patients might be explained by the observation that these patients often receive a suboptimal curative treatment. This, despite compelling evidence that, even in patients aged 80 yr, an aggressive approach improves survival [56]. There is Level 1 evidence that neoadjuvant chemotherapy improves survival significantly [57]. Poor performance status and impaired kidney function in elderly are contraindications for platinum-based chemotherapy and can discourage physicians to use perioperative chemotherapy [15,16,58,59] or lead to dosage reduction [60]. Data do, however, indicate that neoadjuvant chemotherapy can be administrated safely and with comparable clinical outcome to patients aged <70 yr in appropriately selected elderly patients [61]. Information of administration of perioperative chemotherapy in the selected articles was limited. Although it is recommended to perform a RC with a pelvic lymph node dissection, the place of an extended lymph node dissection remains debatable, particularly in elderly patients [62]. Nevertheless, several articles have suggested a correlation between extent of pelvic lymph node dissection and outcome [63,64], in both patients aged <80 yr and octogenarians [58]. In practice, an extended pelvic lymph node dissection is often omitted in elderly patients in order to limit operative time and reduce the risk of postsurgical complications [15,58].

Also, the type of urinary diversion differs between age groups. Therefore, will older patients more likely receive incontinent urinary diversions such as an ileal conduit (6,16,27,34–36,42,45). Whether the type of diversion on its own has a major impact on clinical outcome is doubtful [35,65]. However, this could suggest that elderly patients are diagnosed at more advanced stages [8,16,21] as patients with advanced clinical stage are more likely to receive incontinent urinary diversions [44]. Only eight articles included in this systematic review reported the tumor stage per age group. Four articles reported more advanced tumor stage at presentation in elderly patients with inferior CSS and/or OS for elderly patients in three of them [8,16,27]. Four articles [6,11,18,37] did not found differences in stage distribution between younger and older patients. Similar OS between both groups was reported in two of them [6,18]. In contrast to OS, CSS was not worse for elderly patients in the publication of Guillotreau et al [11]. With similar tumor stage at presentation the complication rate appears comparable between younger and older patients [37]. A major concern when treating older patients with radical cystectomy is POM. Good patient evaluation is crucial to improve patient survival. Not surprisingly, older patients have a poorer American Society of Anaesthesiologists physical status classification [66]. Despite improvements in perioperative care resulting in a significant reduction of POM, POM remains more prevalent in septuagenarians with a 2- to 6-fold increased risk compared with patients <70 yr old. Perioperative mortality has decreased significantly with time in high-volume and moderate-volume centres pointing out the importance of referring patients, certainly those who are most vulnerable of dying from the procedure, to those centres [17].

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 8

EUROPEAN UROLOGY XXX (2017) XXX–XXX

Table 5 – Multivariate analysis evaluating impact of age on morbidity rates per age group and study. The studies in grey represent the studies where a significant difference was observed between younger and older patients Trials with radical cystectomy

Trials with radiotherapy

Except for POM, the reported incidence of morbidity after RC is acceptable in elderly patients. However, these results should be interpreted with caution. It is important to point out the shortage of data on both long-term results of cystectomy and maintenance of autonomy after surgery in the elderly patients. Two studies reported lower incidence of late morbidity in older patients [7,35]. Patients included in both trials underwent a rigorous preoperative physical examination and screening to ensure adequate performance status prior to surgery. Our findings are different from the conclusions drawn by Froehner et al [67]. They reported an increased risk in perioperative morbidity in elderly patients, particularly when an extended postoperative period (90 d instead of 30 d) is applied. Also, the continence rates after orthotopic urinary diversion is impaired in an older population [67]. Our paper differs from the paper of Froehner et al [67] in several aspects, which might explain these conflicting observations. First, only papers including >100 patients were selected for this review in contrast to the paper of Froehner et al [67], where also smaller reports were taken

into consideration. Secondly, no clear age cut-off was defined by Froehner et al [67]. This systemic review is not free of shortcomings. The major limitations of our systematic review are the limitations of the literature itself. The retrospective nature of the implemented data, the low number of articles with an acceptable quality (Supplementary Table 1), as well as the heterogeneity of the studies makes drawing conclusions difficult. Differences in tumor stage at presentation and use of perioperative chemotherapy can have an impact on outcome as previously mentioned. Unfortunately, tumor stage and administration of neo-adjuvant chemotherapy were not reported in detail in the majority of the included papers. Taking into account that elderly patients are often denied curative treatment and recognizing the lack of information on performance status and presence of comorbidities we cannot exclude that we compare the best older patients with the average younger patients. Some evidence exists to suggest that the accuracy of death certificates could decrease with the age of the patient [68]. However, it should be remembered that the accuracy of cause of death is

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 9

EUROPEAN UROLOGY XXX (2017) XXX–XXX

Safety outcome

Old worse than young

Peri-operative mortality

2 (27, 36)a

Old = young

Young worse than old

2 (7,35)

30-d mortality 2 (7, 16)

3 (15, 34, 38)

90-d mortality

5 (15, 16, 30, 38, 41)

Early complications Late complications

3 (35, 36, 39) 1 (36)

2 (12, 27)

Minor complications

2 (8, 30)

Major complications

2 (8, 30)

Overall complication rate

a

4 (7, 12, 27, 37) 2 (7, 35)

a

3 (11, 18, 34)

Fig. 2 – Incidence of morbidity in old (>70 yr) versus young patients (<70 yr). The numbers represent the number of articles. a Two trials compared octogenarians with younger patients (<80 yr).

generally higher for cancer diagnoses than other common causes of death [69]. Consequently, the reduction in accuracy due to age would be expected to represent only a small decrement in cancer cause of death accuracy. Equally important is to recognize that for patients deemed unsuitable for curative treatment the option of less aggressive therapies should be regarded. External beam radiotherapy alone can be considered as a therapeutic option when the patient is unfit for cystectomy or multimodality bladder-preserving approach [70]. Short radiotherapy regimens have been proposed for elderly patients as an alternative for longer radiotherapy schedules and result in acceptable toxicity with median relapse free survival rates of 15–16 mo [71]. A palliative cystectomy should be considered for symptom relief if no other options are available [2]. 5.

Conclusions

Although a proportion of elderly patients with MIBC will benefit from curative treatment, we observed that OS, CSS, and POM significantly worsen with age. Further prospective studies evaluating GAs are critically needed to optimise MIBC management in the elderly.

Statistical analysis: Fonteyne, Ost. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Ploussard. Other: None. Financial disclosures: Vale´rie Fonteyne certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. eururo.2017.03.019. References [1] Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol 2016;71:96–108. [2] Alfred Witjes J, Lebret T, Compe´rat EM, et al. Updated 2016 EAU

Author contributions: Vale´rie Fonteyne had full access to all the data in

guidelines on muscle-invasive and metastatic bladder cancer. Eur

the study and takes responsibility for the integrity of the data and the

Urol 2017;71:462–75.

accuracy of the data analysis.

[3] Extermann M, Aapro M, Bernabei R, et al. Use of comprehensive

Study concept and design: Fonteyne, Ost, Ploussard.

geriatric assessment in older cancer patients: recommendations

Acquisition of data: Fonteyne, Ost.

from the task force on CGA of the International Society of Geriatric

Analysis and interpretation of data: Fonteyne, Ost. Drafting of the manuscript: Fonteyne.

Oncology (SIOG). Crit Rev Oncol Hematol 2005;55:241–52. [4] Moga C, Schopflocher D, Hartstall C. Development of a quality

Critical revision of the manuscript for important intellectual content: Ost,

appraisal tool for case series studies using a modified Delphi

Bellmunt, Droz, Mongiat-Artus, Inman, Paillaud, Saad, Ploussard.

technqiue. Institute of Health Economics. http://www.ihe.ca.

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 10

EUROPEAN UROLOGY XXX (2017) XXX–XXX

[5] Hafron J, Mitra N, Dalbagni G, Bochner B, Herr H, Donat SM. Does body mass index affect survival of patients undergoing radical or partial cystectomy for bladder cancer? J Urol 2005;173:1513–7. [6] Horovitz D, Turker P, Bostrom PJ, et al. Does patient age affect survival after radical cystectomy? BJU Int 2012;110:486–93. [7] Figueroa AJ, Stein JP, Dickinson M, et al. Radical cystectomy for elderly patients with bladder carcinoma: an updated experience with 404 patients. Cancer 1998;83:141–7. [8] Rink M, Dahlem R, Kluth L, et al. Older patients suffer from adverse histopathological features after radical cystectomy. Int J Urol 2011;18:576–84. [9] Liberman D, Lughezzani G, Sun M, et al. Perioperative mortality is

radiotherapy for invaisve bladder cancer. Int J Radiat Oncol Biol Phys 1999;45:1239–45. [26] Thrasher JB, Frazier HA, Robertson JE, Dodge RK, Paulson DF. Clinical variables which serve as predictors of cancer-specific survival among patients treated with radical cystectomy for transitional cell carcinoma of the bladder and prostate. Cancer 1994;73: 1708–15. [27] Yamanaka K, Miyake H, Hara I, Inoue TA, Fujisawa M. Significance of radical cystectomy for bladder cancer in patients over 80 years old. Int Urol Nephrol 2007;39:209–14. [28] Nielsen ME, Shariat SF, Karakiewicz PI, et al. Advanced age is associated with poorer bladder cancer-specific survival in patients

significantly greater in septuagenarian and octogenarian patients

treated with radical cystectomy. Eur Urol 2007;51:699–708.

treated with radical cystectomy for urothelial carcinoma of the

[29] Madersbacher S, Bauer W, Willinger M, Wehrberger C, Berger I,

bladder. Urology 2011;77:660–6. [10] Pollack A, Zagars GK, Dinney CP, Swanson DA, Von Eschenbach AC. Preoperative radiotherapy for muscle-invasive bladder carcinoma: Long term follow-up and prognostic factors for 338 patients. Cancer 1994;74:2819–27. [11] Guillotreau J, Miocinovic R, Gam X, et al. Outcomes of laparoscopic and robotic radical cystectomy in the elderly patients. Urology 2012;79:585–90. [12] Fontana PP, Gregorio SA, Rivas JG, et al. Perioperative and survival outcomes of laparoscopic radical cystectomy for bladder cancer in patients over 70 years. Cent European J Urol 2015;68:24–9.

Bro¨ssner C. Radical cystectomy for bladder cancer in the 70+ population: a nation-wide registry analysis of 845 patients. Urol Int 2010;85:287–90. [30] Donat SM, Siegrist T, Cronin A, Savage C, Milowsky MI, Herr HW. Radical cystectomy in octogenarians–does morbidity outweigh the potential survival benefits? J Urol 2010;183:2171–7. [31] Dotan K, Kavanagh O, Yossepowitch, et al. Positive surgical margins in soft tissue following radical cystectomy for bladder cancer and cancer specific survival. J Urol 2007;178:2308–13. [32] Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-pre-

[13] Bostrom PJ, Mirtti T, Kossi J, Laato M, Nurmi M. Twenty-year

serving combined-modality therapy: a pooled analysis of Radiation

experience of radical cystectomy for bladder cancer in a medi-

Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906,

um-volume centre. Scand J Urol Nephrol 2009;43:357–64.

and 0233. J Clin Oncol 2014;32:3801–9.

[14] Nishiyama H, Habuchi T, Watanabe J, et al. Clinical outcome of a

[33] Fossa SD, Waehre H, Aass N, Jacobsen AB, Olsen DR, Ous S. Bladder

large-scale multi-institutional retrospective study for locally ad-

cancer definitive radiation therapy of muscle-invasive bladder

vanced bladder cancer: a survey including 1131 patients treated

cancer. A retrospective analysis of 317 patients. Cancer 1993;72:

during 1990-2000 in Japan. Eur Urol 2004;45:176–81.

3036–43.

[15] Leveridge MJ, Siemens DR, Mackillop WJ, et al. Radical cystectomy

[34] Knap MM, Lundbeck F, Overgaard J. Early and late treatment-

and adjuvant chemotherapy for bladder cancer in the elderly: a

related morbidity following radical cystectomy. Scan J Urol Nephrol

population-based study. Urology 2015;85:791–8.

2004;38:153–60.

[16] Fairey AS, Kassouf W, Aprikian AG, et al. Age >80 years is indepen-

[35] Clark PE, Stein JP, Groshen SG, et al. Radical cystectomy in the

dently associated with survival outcomes after radical cystectomy:

elderly: comparison of clincal outcomes between younger and

results from the Canadian Bladder Cancer Network Database. Urol Oncol 2012;30:825–32. [17] Patel MI, Bang A, Gillatt D, Smith DP. Contemporary radical cystectomy outcomes in patients with invasive bladder cancer: a population-based study. BJU Int 2015;116:18–25. [18] Hara T, Matsuyama H, Kamiryo Y, et al. Use of preoperative performance status and hemoglobin concentration to predict overall survival for patients aged 75 years after radical cystectomy for treatment of bladder cancer. Int J Clin Oncol 2016;21:139–47. [19] Dalbagni G, Genega E, Hashibe M, et al. Cystectomy for bladder cancer: a contemporary series. J Urol 2001;165:1111–6. [20] Zakaria A, Santos F, Kassoul W, Tanguay S, Aprikian A. Survival after radical cystectomy for bladder cancer in relation to prior nonmuscle invasive disease in Quebec. Urol Int 2016;97:49–53.

older patients. Cancer 2005;104:36–43. [36] Roghmann F, Sukumar S, Ravi P, et al. Radical cystectomy in the elderly: national trends and disparities in perioperative outcomes and quality of care. Urol Int 2014;92:27–34. [37] Tilki D, Reich O, Karakiewicz PI, et al. Validation of the AJCC TNM substaging of pT2 bladder cancer: deep muscle invasion is associated with significantly worse outcome. Eur Urol 2010;58:112–7. [38] Schiffmann J, Larcher A, Sun M, et al. Contemporary 90-day mortality rates after radical cystectomy in the elderly. Eur J Surg Oncol 2014;40:1738–45. [39] Novotny V, Fro¨hner M, Zastrow S, Oehlschlaeger S, Weißflog C, Wirth MP. C94 Radical cystectomy in patients over 75 years of age with one or more severe comorbidities. Eur Urol Suppl 2012;11:104. [40] Fairey A, Chetner M, Metcalfe J, et al. Associations among age,

[21] Chromecki TF, Mauermann J, Cha EK, et al. Multicenter validation of

comorbidity and clinical outcomes after radical cystectomy: results

the prognostic value of patient age in patients treated with curative

from the Alberta urology Institute Radical cystectomy database.

cystectomy. World J Urol 2012;30:753–9. [22] Gore JL, Kwan L, Saigal CS, Litwin MS. Marriage and mortality in bladder carcinoma. Cancer 2005;104:1188–94. [23] Morgan TM, Barocas DA, Penson DF, et al. Lymph node yield at radical cystectomy predicts mortality in node-negative and not node-positive patients. J Urol 2012;80:632–40. [24] Goossens-Laan CA, Leliveld AM, Verhoeven RH, et al. Effects of age and comorbidity on treatment and survival of patients with muscle-invasive bladder cancer. Int J Cancer 2014;135:905–12. [25] Hayter CR, Paszat LF, Groome PA, Schulze K, Mackillop WJ. A population-based study of the use and outcome of radical

J Urol 2008;180:128–34. [41] Morgan TM, Keegan KA, Barocas DA, et al. Predicting the probability of 90-day survival of elderly patients with bladder cancer treated with radical cystectomy. J Urol 2011;186:829–34. [42] Abdollah F, Sun M, Schmitges J, et al. Development and validation of a reference table for prediction of postoperative mortality rate in patients treated with radical cystectomy: a population-based study. Ann Surg Oncol 2012;19:309–17. [43] Isbarn H, Karakiewicz PI, Shariat SF, et al. Residual pathological stage at radical cystectomy significantly impacts outcomes for initial T2N0 bladder cancer. J Urol 2009;182:459–65.

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019

EURURO-7301; No. of Pages 11 EUROPEAN UROLOGY XXX (2017) XXX–XXX

[44] Schmid M, Rink M, Traumann M, et al. Evidence from the ‘PROspective MulticEnTer RadIcal Cystectomy Series 2011 (PRO-

11

practice guidelines for bladder cancer treatment. J Urol 2011;185: 2078–84.

METRICS 2011)’ study: how are preoperative patient characteristics

[59] Reardon ZD, Patel SG, Zaid HB, et al. Trends in the use of perioperative

associated with urinary diversion type after radical cystectomy for

chemotherapy for localized and locally advanced muscle-invasive

bladder cancer? Ann Surg Oncol 2015;22:1032–42. [45] Fedeli U, Galassi C, Ficarra V, et al. Population-based analyses of

bladder cancer: a sign of changing tides. Eur Urol 2015;67:165–70. [60] Launay-Vacher V, Oudard S, Janus N, et al. Prevalence of Renal

radical cystectomy and urinary diversion for bladder cancer in

Insufficiency in cancer patients and implications for anticancer

northern Italy. Br J Urol 2010;108:266–71.

drug management: the renal insufficiency and anticancer medica-

[46] Efstathiou JA, Bae K, Shipley WU, et al. Late pelvic toxicity after

tions (IRMA) study. Cancer 2007;110:1376–84.

bladder-sparing therapy in patients with invasive bladder cancer:

[61] Chau CSY, Wheater MJ, Geldart TR, Crabb SJ. Comparison of cisplat-

RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol 2009;27:4055–61.

in-based neoadjuvant chemotherapy for bladder cancer in elderly

[47] Gray PJ, Fedewa SA, Shipley WU, et al. Use of potentially curative

versus younger patients. J Clin Oncol 2014;32:15.

therapies for muscle-invasive bladder cancer in the United States:

[62] Larcher A, Sun M, Schiffmann J, et al. Differential effect on survival

results from the National Cancer Data Base. Euro Urol 2013;63:

of pelvic lymph node dissection at radical cystectomy for muscle

823–9.

invasive bladder cancer. Eur J Surg Oncol 2015;41:353–60.

[48] Konety BR, Joslyn SA. Factors influencing aggressive therapy for

[63] Koppie TM, Vickers AJ, Vora K, Dalbagni G, Bochner BH. Standardi-

bladder cancer: an analysis of data from the SEER program. J Urol

zation of pelvic lymphadenectomy performed at radical cystec-

2003;170:1765–71. [49] Noon AP, Albertsen PC, Thomas F, Rosario DJ, Catto JW. Competing

tomy: can we establish a minimum number of lymph nodes that should be removed? Cancer 2006;107:2368–74.

mortlaity in patients diagnosed with bladder cancer: evidence of

[64] May M, Herrmann E, Bolenz C, et al. Association between the

udnertreatment in the elderly and female patients. Br J Cancer

number of dissected lymph nodes during pelvic lymphadenectomy

2013;108:1534–40. [50] Cao J, Zhao X, Zhong Z, Zhang L, Zhu X, Xu R. Prognostic value of preoperative renal insufficiency in urothelial carcinoma: a systematic review and meta-analysis. Sci Rep 2016;6:35214. [51] Walter LC, Schonberg MA. Screening mammography in older women: a review. JAMA 2014;311:1336–47. [52] Marshall VF, Whitmore WF. The surgical treatment of cancers of the urinary bladder. Cancer 1956;9:609–19.

and cancer-specific survival in patients with lymph node-negative urothelial carcinoma of the bladder undergoing radical cystectomy. Ann Surg Oncol 2011;18:2018–25. [65] Sogni F, Brausi M, Frea B, et al. Morbidity and quality of life in elderly patients receiving ileal conduit of orthotopic neobladder after radical cystectomy for invaisve bladder cancer. Urology 2008;71:919–23. [66] Prout GR, Wesley MN, Yancik R, Ries LA, Havlik RJ, Edwards BK. Age

[53] Bream M, Maurice M, Altschuler J, Zhu H, Abouassaly R. Increased

and comorbidity impact surgical therapy in older bladder carci-

use of cystectomy in patients 75 or older: a contemporary analysis

noma patients: a population-based study. Cancer 2005;104:

of survival and perioperative outcomes from the National Cancer database. Urology 2017;100:72–8. [54] Caillet P, Canoui-Poitrine F, Vouriot J, et al. Comprehensive geriatric assessment in the decision-making process in elderly patients with cancer: ELCAPA study. J Clin Oncol 2011;29:3636–42. [55] Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for

1638–47. [67] Froehner M, Brausi MA, Herr HW, Muto G, Studer UE. Complications following radical cystectomy for bladder cancer in the elderly. Eur Urol 2009;56:443–54. [68] Schaffar R, Rapiti E, Rachet B, Woods L. Accuracy of cause of death data routinely recorded in a population-based cancer registry:

multidimensional health problems warranting a geriatric assess-

impact on cuase-specific survival and validation using the Geneva

ment in older cancer patients: an update on SIOG recommenda-

Cancer Registry. BMC Cancer 2013;13:609.

tions. Ann Oncol 2015;26:288–300. [56] Hollenbeck BK, Miller DC, Taub D, et al. Aggressive treatment for bladder cancer is associated with improved overall survival among patients 80 years old or older. Urology 2004;64:292–7. [57] Advanced Bladder Cancer Overview Collaboration. Neoadjuvant chemotherapy for invasive bladder cancer. Cochrane database Syst Rev 2005:CD005246.

[69] Mieno MN, Tanaka N, Ara T, et al. Accuracy of death certificates ans assessment of factors for misclassification of underlying cause of death. J Epidemiol 2016;26:191–8. [70] Bellmunt J, Orsola A, Maldonado X, Kataja V, Group EGW. Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(Suppl 5):134–6. [71] Kouloulias V, Mosa E, Tolia M, et al. Evaluation of efficacy and

[58] Abdollah F, Sun M, Shariat SF, et al. The importance of pelvic

toxicity in two different hypofractionated 3D-conformal external

lymph node dissection in the elderly population: implications

beam radiotherapy schedules in localised muscle invasive bladder

for interpreting the 2010 national comprehensive cancer network

cancer. J BUON 2013;18:942–8.

Please cite this article in press as: Fonteyne V, et al. Curative Treatment for Muscle Invasive Bladder Cancer in Elderly Patients: A Systematic Review. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.019