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PERSONALIZED MEDICINE IN THE MANAGEMENT OF INVASIVE BLADDER CANCER: Edited by Maximilian Burger and Andrea B. Apolo

Management of muscle-invasive bladder cancer in the elderly

Rose, Tracy L.; Milowsky, Matthew I.

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doi: 10.1097/MOU.0000000000000190
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Abstract

INTRODUCTION

Bladder cancer is primarily a disease of the elderly. The majority of cases are diagnosed after age 65 with a median age at diagnosis of 73 [1]. It is the fourth leading cause of cancer-related death among men age 80 and older, and historically over 80% of deaths from bladder cancer occur in people over age 65 [2,3]. 20–30% of patients with bladder cancer have muscle invasion at diagnosis and many with noninvasive disease will eventually progress to muscle invasion [4].

The number of incident cases of muscle-invasive bladder cancer (MIBC) will rise in the future because of the projected 35 million person increase in the elderly population by 2030 [3]. MIBC is an aggressive disease and treatment is associated with significant morbidity and mortality in all age groups. The normal physiologic decline and medical complexity associated with aging makes treatment decisions challenging. Although radical cystectomy is the standard of care for treatment of MIBC, fewer than half of elderly patients undergo the procedure. The complex nature of MIBC in the elderly necessitates a critical look at the management of this disease.

Box 1
Box 1:
no caption available

EPIDEMIOLOGY

Bladder cancer has a complex pathogenesis and its predilection for development in the elderly is likely caused by a combination of tumor biology, alterations in host defense, and cumulative exposures. Elderly patients with MIBC are more likely to have advanced stage disease at diagnosis with a higher likelihood of nonorgan-confined disease, disease recurrence, and disease-specific morbidity and mortality, suggesting a potential inherent aggressiveness to bladder cancer in the elderly that is not yet explained by known genetic drivers of bladder cancer development [5–8].

Both aging and the development of bladder cancer share many of the same mechanisms involving genes of DNA replication and repair, including an association with TP53 mutations, oxidative stress, telomere shortening, and DNA methylation [9]. Age has been associated with epigenetic silencing via promoter methylation of tumor suppressor genes, correlating with higher stage, grade, and lower survival, suggesting a possible mechanism for increased tumor aggression [10].

In a mouse model, the mutational frequency of bladder cancer increases substantially with age although the spectrum of mutations does not change [11]. The Cancer Genome Atlas report on the molecular characterization of urothelial cancer also did not report specific mutational associations with age, but this will be an area ripe for research in the future [12▪▪].

ASSESSMENT OF THE GERIATRIC PATIENT AND SURGICAL CANDIDACY

Ideally, each elderly patient with MIBC would have a comprehensive geriatric assessment prior to treatment decisions (Table 1). An average assessment takes around 27 min although completion may not be feasible in some oncology clinics [25,26]. At the minimum, each elderly patient should have a limited assessment of functional status, nutrition, and comorbidities, as those factors are most heavily correlated with mortality and chemotoxicity [27,28]. Frailty (including weight loss, exhaustion, weakness, slow walking, and low activity) has also become increasingly accepted as a marker of fitness in the geriatric patient and is associated with increased risk of hospitalization and death [29].

Table 1
Table 1:
Components of a comprehensive geriatric assessment

Accurate preoperative assessment of the geriatric patient prior to consideration of radical cystectomy is crucial. American Society of Anesthesiologists classification, ECOG performance status, and Charlson comorbidity index have all been correlated with risk of mortality [30▪,31,32]. Classification of ‘not independent’ in activities of daily living is also predictive of postoperative complications [33]. A recent study by Psutka et al.[34▪] showed that the presence of skeletal muscle wasting (sarcopenia) is associated with higher mortality after radical cystectomy, which may provide an objective measure of surgical fitness in patients with difficult subjective measures for evaluation. The National Surgical Quality Improvement Program also maintains a surgical risk calculator to help estimate perioperative morbidity and mortality [35].

USE OF NEOADJUVANT CHEMOTHERAPY

Two large randomized clinical trials and a meta-analysis have established neoadjuvant cisplatin-based combination chemotherapy as the standard of care prior to radical cystectomy in patients with MIBC [36–38]. Data from clinical trials can be challenging to generalize to the elderly population because trials typically include young, healthy patients [39]. The SWOG trial that randomized patients to methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) or no chemotherapy prior to surgery enrolled patients with a median age of only 63 years with not a single patient over age 80 in the group receiving neoadjuvant chemotherapy (NAC) [36]. Results were similar in the BA06 EORTC trial that randomized patients to chemotherapy with cisplatin, methotrexate, and vinblastine or no chemotherapy prior to surgery or radiotherapy (XRT) [38].

If patients are eligible for cisplatin, the combination of gemcitabine and cisplatin is widely used based on similar efficacy and improved tolerability when compared with MVAC in the metastatic setting [40] and a similar pathologic response rate in the neoadjuvant setting [41]. For patients with borderline renal function (glomerular filtration rate 50–60 ml/min) but otherwise adequate organ function and performance status, split-dose cisplatin can be considered [42]. Elderly patients do have higher rates of grades 3–4 neutropenia and renal toxicity and need to be monitored closely for complications [43].

Galsky et al.[44] sought a consensus definition of cisplatin eligibility and has proposed that ineligible patients have at least one of the following: ECOG performance status of 2, creatinine clearance less than 60 ml/min, grade 2 or greater hearing loss, grade 2 or greater neuropathy, and/or New York Heart Association Class III heart failure. Although age is not included in this definition, more than 40% of patients aged 70 and older are not eligible for cisplatin due to inadequate renal function and this proportion increases with age [45]. For ineligible patients, carboplatin should not be substituted as it has proved inferior to cisplatin in the metastatic setting and no randomized data exist to suggest a benefit in the neoadjuvant setting [46].

Several recent analyses show that NAC remains underutilized in the elderly population [47▪,48]. Underutilization may be related to increased comorbidities, frailty, and decreased performance status, but a substantial number of elderly patients are likely not offered NAC solely based on age. More efforts should be focused on encouraging NAC use in the fit, elderly patient.

USE OF ADJUVANT CHEMOTHERAPY

Most trials evaluating adjuvant chemotherapy in patients with MIBC are small and underpowered, making extrapolation to the elderly difficult [49–51]. A large meta-analysis showed a significant benefit of adjuvant cisplatin-based chemotherapy compared with cystectomy alone and subgroup analysis showed no effect of age on this relationship [52▪▪,53]. However, every study included had a median age of less than 65. Further attempts at randomized clinical trials have suffered from poor accrual, although initial results presented from EORTC 30994 suggest a benefit of immediate chemotherapy after radical cystectomy with a significant improvement in progression-free survival (PFS) and a nonsignificant improvement in overall survival (OS) [54▪]. At this time, adjuvant therapy should be restricted to cisplatin-eligible elderly patients with high-risk disease (positive lymph nodes on pathology or extravesical tumor extension) and acceptable performance status [55].

CONSIDERATIONS OF RADICAL CYSTECTOMY

Radical cystectomy has long been considered standard management for MIBC. However, it is an aggressive and morbid procedure. The decision to undergo radical cystectomy should be made after careful discussion of risks and benefits. Historically, older patients have been less likely to undergo radical cystectomy for treatment of MIBC, with estimates of less than 30% of patients aged 80 or greater with significant variation between institutions [56–58].

Benefit of radical cystectomy

Several studies have demonstrated that even octogenarians with MIBC appreciate a survival benefit after radical cystectomy. Using Surveillance, Epidemiology, and End Results (SEER) data, Hollenbeck et al.[59] found that octogenarians treated with cystectomy had a hazard ratio (HR) for death from any cause of 0.4 compared with other treatment modalities. Gore et al.[60] found similar results. Another SEER analysis showed that there is an OS benefit for octogenarians undergoing radical cystectomy with lymphadenectomy, but that benefit becomes negligible without lymphadenectomy [61]. Other studies have also demonstrated comparable 5-year cancer-specific survival to younger patients after radical cystectomy [62]. Radical cystectomy may also help reduce local symptoms such as pain and hematuria [63].

Complications and mortality of radical cystectomy

There remains some controversy regarding use of radical cystectomy in the elderly [64,65]. Overall, 30-day mortality appears to be slightly higher among elderly patients than their younger counterparts, although reported mortality rates vary widely [56,66,67]. Recent studies have shown a 30 and a 90-day mortality range of 2.3–7.3% and 6.8–11% at 90 days in patients over age 65 [68▪,69–70]. Data are conflicting on the exact increase in risk in the elderly compared with younger patients [71–73].

If a patient chooses to undergo radical cystectomy, it should be performed at a hospital with a high annual cystectomy volume because mortality rates are consistently lower at such hospitals [74]. More than 30% of patients age 65 and over have at least one complication after radical cystectomy [75]. Increasing age is associated with renal complications, and octogenarians are more likely to have neurologic and cardiac complications than younger patients [66,71]. Other common complications in the elderly include pyelonephritis, delirium, pneumonia, and ileus [76].

Despite the frequency of complications, available studies have shown a consistent, acceptable rate of morbidity and mortality after radical cystectomy in the elderly population and radical cystectomy should not be excluded based on age alone [76–83]. 90-day mortality rates should be used in addition to 30-day rates to assess risk given the substantial rate of late mortality [84▪].

Choice of procedure for radical cystectomy

Several options exist for the surgical approach to radical cystectomy including urinary diversion with ileal conduit, cutaneous ureterostomy, or continent urinary diversion with orthotopic neobladder. Elderly patients undergo continent urinary diversion with neobladder less often than younger patients [7,66,69,72]. They have slower resumption of continence after surgery and higher rates of stress incontinence, but the majority of elderly patients do achieve continence with a neobladder [85,86]. The overall complication rate, survival, and quality of life do not appear to differ between procedures [67,87]. Patients should have a pelvic lymph node dissection during radical cystectomy regardless of age. Ability to care for a urinary diversion or perform intermittent catheterization should also be considered prior to surgery.

ALTERNATIVES TO RADICAL CYSTECTOMY

The minority of elderly patients actually undergoes radical cystectomy and TMT has emerged as an alternative combining a complete transurethral resection of bladder tumor as safely possible, XRT, and concurrent chemotherapy. TMT can be used in selected candidates for cystectomy with certain tumor characteristics who prefer bladder preservation or in those who are not candidates for cystectomy. TMT remains underutilized, with less than 10% of all patients with MIBC receiving radiation of any kind [88].

In a recent review of TMT in elderly patients published by Turgeon and Souhami [89▪], the median complete response (CR) rate based on eight studies was 72% with comparable median 5-year cancer-specific survival rates to radical cystectomy (52%). Notably, about two-thirds of the patients included were not cystectomy candidates and many of the tumor characteristics did not meet optimal criteria for TMT [90]. Therefore, elderly patients that are not cystectomy candidates or do not have optimal tumor characteristics may still be considered for curative-intent TMT. Long-term outcomes of several pooled Radiation Therapy Oncology Group (RTOG) studies showed favorable 5-year OS with TMT (57%) and patients age 75 or greater had no difference in outcomes compared with younger patients [91▪▪]. Chamie et al.[61] showed octogenarians treated with chemoradiation had lower median OS compared with radical cystectomy, but the difference was small (15 vs. 18 months) and there was no difference between the two groups if a limited or no pelvic lymph node dissection was completed. Other single institution series have also shown little difference in survival of patients with XRT vs. radical cystectomy with curative intent [92].

The most effective chemotherapy against urothelial cancer is cisplatin and it should be used as a radiosensitizing agent when possible. If cisplatin is unable to be used, options include gemcitabine, and 5-fluorouracil with mitomycin, paclitaxel, and carboplatin (Table 2). Twice weekly gemcitabine has shown excellent CR and OS rates when used as part of TMT based on the University of Michigan experience [97]. Chemoradiotherapy with 5-fluorouracil and mitomycin has shown an improvement in locoregional disease-free survival at 2 years compared with XRT alone (67 vs. 54%, HR 0.68, P = 0.03) [96]. There was also a 13% improvement in OS in the chemoradiotherapy group (48 vs. 35% at 5 years), although this difference did not reach significance (P = 0.16). Both studies included elderly patients, had acceptable toxicity, and had similar outcomes in terms of locoregional control. Results have not yet been reported from the recently closed RTOG 0712, which compares 5-fluorouracil/cisplatin to gemcitabine in conjunction with XRT [99].

Table 2
Table 2:
Selected concurrent chemotherapy regimens for trimodality therapy

For patients that are unable (or do not desire) to undergo surgery and XRT, chemotherapy alone may be considered and administered in a manner similar to treatment in the metastatic setting. Cisplatin-based combination chemotherapy is the most likely to result in disease response with improved tolerability of gemcitabine and cisplatin compared with MVAC [40]. The combination of gemcitabine and carboplatin also has a modest response rate of 24% and pretreatment geriatric assessment scores predict response [100].

FUTURE DIRECTIONS

Future research will lead to an improved understanding of tumor biology and the biology of aging. Recent data in breast cancer have suggested that cytotoxic chemotherapy not only results in tumor response but also increases p16 expression, a cellular senescence marker that accumulates with aging [101▪]. Distinct intrinsic subtypes of bladder cancer have recently been identified and the more aggressive basal subtype did have a nonsignificantly higher mean age than the luminal subtype [102▪,103▪]. The Cancer Genome Atlas published an analysis of molecular alterations in bladder cancer and identified potential actionable alterations in approximately 70% of tumors [12▪▪]. Clinical trial design with targeted therapy in the neoadjuvant setting for MIBC has the potential to lead to substantial breakthroughs in the treatment of MIBC and is an optimal model for studying tumor biology [104]. Targeted therapy may come with less toxicity than conventional cisplatin-based chemotherapy, allowing a larger percentage of elderly patients to be treated.

Clinical trials of immune checkpoint inhibitors have shown promising results in the metastatic setting and may be better tolerated than conventional chemotherapy [105▪,106▪]. Other molecular biomarkers are also being studied to correlate with therapy-specific disease response, such as the correlation of MRE11 expression and survival after XRT [107].

CONCLUSION

MIBC treatment decisions should not be made on chronologic age alone. A suggested algorithm for management decisions is included in Fig. 1. A comprehensive assessment of organ function, comorbidities, frailty, and functional status should be included in the evaluation of older patients. Definitive therapy via radical cystectomy or TMT should be considered in every patient with organ-confined disease because without such treatment, the majority of patients with MIBC will die of their disease within 2 years [108]. Neoadjuvant cisplatin-based combination chemotherapy should be given to fit, cisplatin-eligible, elderly patients undergoing radical cystectomy. Chemotherapy should also be given concurrently with XRT when possible if a bladder preservation approach is pursued. Despite current optimal therapy, however, morbidity and mortality from both MIBC and its treatment are not insignificant. Novel treatment strategies for elderly patients including clinical trials investigating targeted and immunotherapies specific to older patients will need to be pursued to move the field forward.

FIGURE 1
FIGURE 1:
Suggested algorithm for management of elderly patients with muscle-invasive bladder cancer.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

T.L.R. has no conflicts of interest to declare. M.I.M. has received research funding from Pfizer, BIND Therapeutics, Dendreon, Exelixis, Johnson & Johnson, Astellas Pharma, Mirati Therapeutics, Merck, and Cerulean Pharma, Inc. Otherwise, M.I.M. has no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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79. Gupta NP, Goel R, Hemal AK, et al. Radical cystectomy in septuagenarian patients with bladder cancer. Int Urol Nephrol 2004; 36:353–358.
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83. Zakaria AS, Santos F, Dragomir A, et al. Postoperative mortality and complications after radical cystectomy for bladder cancer in Quebec: a population-based analysis during the years 2000–2009. Canad Urol Assoc J 2014; 8:259–267.
84▪. Nielsen ME, Mallin K, Weaver MA, et al. Association of hospital volume with conditional 90-day mortality after cystectomy: an analysis of the National Cancer Database. BJU Int 2014; 114:46–55.

This study demonstrated that hospitals with a low volume of cystectomy cases were associated with greater 30 and 90-day mortality rates.

85. Elmajian DA, Stein JP, Esrig D, et al. The Kock ileal neobladder: Updated experience in 295 male patients. J Urol 1996; 156:920–925.
86. Kessler TM, Burkhard FC, Perimenis P, et al. Attempted nerve sparing surgery and age have a significant effect on urinary continence and erectile function after radical cystoprostatectomy and ileal orthotopic bladder substitution. J Urol 2004; 172 (4 Pt 1):1323–1327.
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88. Gray PJ, Fedewa SA, Shipley WU, et al. Use of potentially curative therapies for muscle-invasive bladder cancer in the United States: results from the National Cancer Database. Eur Urol 2013; 63:823–829.
89▪. Turgeon GA, Souhami L. Trimodality therapy for bladder preservation in the elderly population with invasive bladder cancer. Front Oncol 2014; 4:1–9.

This is a review article on TMT for MIBC in the elderly.

90. Rodel C, Weiss C, Sauer R. Trimodality treatment and selective organ preservation for bladder cancer. J Clin Oncol 2006; 24:5536–5544.
91▪▪. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of radiation therapy oncology group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 2014; 32:3801–3809.

This is a pooled analysis of RTOG trials evaluating bladder preservation with combined modality therapy that showed a 69% CR rate and 5-year OS rate of 57%. This study supports the safety and efficacy of TMT for MIBC.

92. 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 Rad Oncol Biol Phys 2008; 70:456–463.
93. Weiss C, Engehausen DG, Krause FS, et al. Radiochemotherapy with cisplatin and 5-fluorouracil after transurethral surgery in patients with bladder cancer. Int J Rad Oncol Biol Phys 2007; 68:1072–1080.
94. Rodel C, Grabenbauer GG, Kuhn R, et al. Organ preservation in patients with invasive bladder cancer: initial results of an intensified protocol of transurethral surgery and radiation therapy plus concurrent cisplatin and 5-fluorouracil. Int J Rad Oncol Biol Phys 2002; 52:1303–1309.
95. Gogna NK, Matthews JH, Turner SL, et al. Efficacy and tolerability of concurrent weekly low dose cisplatin during radiation treatment of localised muscle invasive bladder transitional cell carcinoma: a report of two sequential phase II studies from the Trans-Tasman Radiation Oncology Group. Radiother Oncol 2006; 81:9–17.
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99. Coen JJ RTOG 0712: a phase II randomized study for patients with muscle-invasive bladder cancer evaluating transurethral surgery and concomitant chemoradiation by either BID irradiation plus 5-fluorouracil and cisplatin or QD irradiation plus gemcitabine followed by selective bladder preservation and gemcitabine/cisplatin adjuvant chemotherapy; 2014. http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0712. [Accessed 2 March 2015].
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101▪. Sanoff HK, Deal AM, Krishnamurthy J, et al. Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer. J Natl Cancer Inst 2014; 106:dju057.

This is a prospective analysis of 33 breast cancer patients demonstrating that adjuvant chemotherapy increased serum senescence markers such as p16INK4a suggesting that chemotherapy is gerontogenic.

102▪. Choi W, Porten S, Kim S, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014; 25:152–165.

This study described several distinct molecular subtypes of bladder cancer and correlated subtype of bladder cancer with chemotherapy response, demonstrating that the p53-like subtype is associated with a poor response to chemotherapy.

103▪. Damrauer JS, Hoadley KA, Chism DD, et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 2014; 111:3110–3115.

This study described two distinct molecular subtypes of bladder cancer termed “basal” and “luminal” after the subtypes of breast cancer that have similarly been described.

104. Chism DD, Woods ME, Milowsky MI. Neoadjuvant paradigm for accelerated drug development: an ideal model in bladder cancer. Oncologist 2013; 18:933–940.
105▪. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014; 515:558-562.

This is a phase 1 expansion study of programmed death-ligand 1 (PD-L1) antibody MPDL3280A showing activity in metastatic bladder cancer. Objective response rate was 26% and many responses were durable (median not reached).

106▪. Plimack ER, Gupta S, Bellmunt J, et al. Lba23 – a phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (pts) with advanced urothelial tract cancer. Annals of Oncology 2014; 25:1–41.

Initial results from this phase 1b study of pembrolizumab showed promising results in advanced urothelial cancer of a PD-1 antibody.

107. Choudhury A, Nelson LD, Teo MT, et al. Mre11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. Cancer Res 2010; 70:7017–7026.
108. Prout GR, Marshall VF. The prognosis with untreated bladder tumors. Cancer 1956; 9:551–558.
Keywords:

bladder cancer; elderly; geriatric; muscle-invasive bladder cancer; urothelial cancer

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