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How I treat bladder cancer in elderly patients
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How I treat bladder cancer in elderly patients Matthew D. Galsky⁎ Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
AR TIC LE I N FO
ABS TR ACT
Article history:
Bladder cancer is a disease of the elderly. There is a disconnect between the efficacy of
Received 16 August 2014
treatments for patients with advanced disease, and their effectiveness, at least in part
Received in revised form
related to the advanced age at diagnosis. Standard treatments for patients with locally
26 October 2014
advanced or metastatic bladder cancer include radical cystectomy and/or cisplatin-based
Accepted 20 November 2014
combination chemotherapy. However, there is significant potential for morbidity, and even
Available online 4 December 2014
mortality, with these treatments necessitating tools to risk stratify elderly patients to optimize the safety and benefit of treatments and alternative strategies in situations where
Keywords:
the potential risks are likely to outweigh the potential benefits. This review considers the
Bladder cancer
current standard treatments for advanced bladder cancer, approaches to risk stratify elderly
Urothelial cancer
patients, and highlights our relatively poor knowledge base regarding the optimal care of
Elderly
elderly patients with this disease. © 2014 Elsevier Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Treatment of Muscle-Invasive Bladder Cancer in the Elderly 3. Treatment of Metastatic Bladder Cancer in the Elderly . . . 4. Future Directions . . . . . . . . . . . . . . . . . . . . . . . Disclosures and Conflict of Interest Statements . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Bladder cancer is a disease of the elderly (Fig. 1). The median age of diagnosis of bladder cancer in the United States is 73 years old and the median age of death is 79 years old. Due to the advanced age at the time of diagnosis, at least in part,
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there is a major disconnect between the efficacy of treatment of patients with advanced bladder cancer, as established through clinical trials, and the effectiveness of such treatment when applied to the general population of patients with the disease. The “gold standard” treatments for advanced bladder cancer are associated with significant potential for morbidity
⁎ Mount Sinai School of Medicine, Tisch Cancer Institute, 1 Gustave L Levy Place, New York, NY 10029, USA. Tel.: + 1 212 824 8583; fax: + 1 212 659 5599. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.jgo.2014.11.006 1879-4068/© 2014 Elsevier Ltd. All rights reserved.
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Fig. 1 – Age distribution of new bladder cancer diagnoses in the United States (data derived from the Surveillance, Epidemiology, and End Results Program*). *http://seer.cancer.gov/statfacts/html/urinb.html.
and even mortality. A radical cystectomy with pelvic lymph node dissection, with diversion or reconstruction of the urinary tract, involves major abdominal surgery and typically a prolonged recovery period. When systemic chemotherapy is utilized, cisplatin-based combination chemotherapy is supported by Level I evidence. Unfortunately, the bulk of evidence establishing these treatments as “gold standards” has been generated in younger patients. For example, Hutchins and colleagues reported that at a time when > 75% of patients with bladder cancer in the United States were ≥ 65 years old, only 55% of patients with bladder cancer participating in Southwest Oncology Group (SWOG) trials were ≥65 years old [1]. Further complicating an evidenced-based approach to the management of elderly patients with bladder cancer is a lack of uniform reporting guidelines regarding the age of participants in clinical trial publications. While some trials report the percentage of enrolled patients above a certain age (e.g., percent ≥65 years old), most trials only report median age, and range, preventing a full appreciation for the number of elderly patients included. Of course, care decisions in patients with bladder cancer, and other malignancies, are not optimally based on chronological age but rather functional age. Measures of functional status or frailty are generally much more important determinants of treatment tolerability, and benefit, than age alone. Nonetheless, there is physiologic decline in virtually every organ system associated with aging, functional reserve may differ in younger and older patients with the same baseline functional status, and chronological age still contributes to medical decision-making. The chronological age that defines “elderly” is arbitrary and most analyses have used a cut-off of ≥65 or ≥ 70 to define an elderly population. With this background, the care of the elderly patient with advanced bladder cancer is probably best discussed within the context of a case. An 80 year-old woman undergoes a cystoscopy and transurethral resection of bladder tumor, after presenting with gross hematuria, and is diagnosed with muscle-invasive urothelial cancer. She undergoes a computed tomography scan of the chest, abdomen, and pelvis that reveals no radiographic evidence of metastatic disease. She has hypertension and type II diabetes mellitus and a creatinine of 1.5. Her Eastern Cooperative Oncology Group (ECOG) performance status is 2.
What else do we need to know about this patient to guide management? There are several other aspects to her history and physical that may be important to clinical decision making, most of which are important to elicit in the work-up of any patient, but some that may be particularly germane to the elderly patient. Has cognition been adequately assessed? What is the patient's level of mobility, living situation, and social support system? How is her nutritional status? Does she prepare her own meals? How many other medications is she taking and who administers these medications? Has organ function been adequately assessed? When feasible, these domains are likely best assessed in the setting of a Comprehensive Geriatric Assessment (CGA) [2] or a formal geriatrics consultation, though key information can often be ascertained through a more detailed history. As we dig a bit deeper, we learn that our patient suffers from mild dementia. She lives in an assisted living facility. She has a very supportive family that accompanies her to appointments and assists with transportation. She needs assistance with her instrumental activities of daily living.
2. Treatment of Muscle-Invasive Bladder Cancer in the Elderly Treatment options for clinically localized muscle-invasive bladder cancer (i.e., cT2-4a) include radical cystectomy with or without perioperative chemotherapy, radiation therapy with or without concomitant chemotherapy, or transuretheral resection of bladder tumor/supportive care alone. In the United States, radical cystectomy is the preferred treatment for patients with muscle-invasive bladder cancer and is potentially curative. Long-term outcomes are correlated highly with pathologic stage of disease with approximately 80%, 70%, and 30%, of patients remaining disease-free with organ-confined disease, extravesical disease, and lymph node-positive disease, respectively [3]. Unfortunately, clinical staging in bladder cancer poorly predicts pathologic stage such that such refined risk stratification information is not available prior to surgery, when treatment decisions need to be made [4]. Not surprisingly, as radical cystectomy is a major surgical procedure, population-based data suggest that this operation is performed much less commonly in elderly patients. In an analysis of the National Cancer Database (NCDB), Fedeli et al. demonstrated that approximately 40–50% and 13–30% of septuagenarians and octogenarians with muscle-invasive bladder cancer, respectively, underwent radical cystectomy [5]. Gore et al. examined a cohort of 3262 Medicare beneficiaries aged 66 or older with muscle-invasive bladder cancer using Surveillance, Epidemiology, and End Results-Medicare data. These investigators determined that only 21% of patients underwent cystectomy; notably, overall survival was better for patients that underwent cystectomy [6]. Similar findings have been confirmed in a more contemporary analysis of NCDB data also highlighting that similar survival outcomes were achieved with either cystectomy or concurrent chemoradiation, both of which were better than other therapies or no treatment [7].
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Not only is information regarding the likelihood of a curative outcome with radical cystectomy potentially important for clinical decision-making, information regarding the likelihood of morbidity and mortality is also critical. Nielsen at al. examined the 90-day postoperative mortality in a retrospective cohort of 35,055 patients undergoing cystectomy from the NCDB and reported that 90-day mortality increased with age and was approximately 10% for patients ≥80 years old [8]. A nomogram has been developed to calculate the probability of 90-day mortality after radical cystectomy incorporating a patient's age, tumor stage, grade, and histology [9]. This nomogram has been externally validated and extended but still offers only moderate discrimination likely due to the lack of other variables that may be important in this context including comorbidities and functional status [10]. A universal surgical risk calculator has been developed using standardized clinical data from the American College of Surgeons National Surgical Quality Improvement Program which utilizes 21 preoperative factors to calculate the likelihood of post-operative mortality, morbidity, and specific complications with excellent performance [11]. This tool, which is publically available (http://riskcalculator.facs.org/) and is increasingly utilized, may help refine shared decisions regarding surgical management of muscle-invasive bladder cancer. The standard assessments, and criteria, to define patients that are “medically inoperable” or “ineligible for cystectomy” remain ambiguous. Furthermore, just because surgery can be done doesn't necessarily mean it should be done. Rather, several factors must be considered when considering a radical cystectomy in an elderly patient with bladder cancer including the likelihood of benefit with surgery, the likelihood of perioperative morbidity and mortality, the patients expected longevity independent of the bladder cancer diagnosis, and the likelihood of severe bladder-cancer associated morbidity during that time period. All of these factors must be considered within the context of an individual patient's goals, objectives, and preferences. Tools to optimize risk prediction in each of these areas are lacking. The CGA assesses multiple domains of health, including function, comorbidities, socioeconomics, cognition, emotion, medications, nutrition, and problems specific to the geriatric population such as dementia and fall risk [2]. The CGA has been widely utilized and validated and shown to be more effective than performance status in reflecting the general health of elderly patients [9]. Additionally, the CGA was shown to better identify elderly patient's suitability for treatment compared with “physicians' judgment” [10]. The use of the CGA in surgical oncology has recently been the subject of a systematic review by Feng et al. [12] While components of the CGA have been evaluated as predictors of post-operative morbidity and mortality in the context of several cancer surgeries, the heterogeneity of these studies has contributed to somewhat conflicting results. The CGA is a lengthy exam and is only recently being investigated as a pre-surgical risk assessment tool prior to radical cystectomy. When radical cystectomy is employed for the treatment of muscle-invasive bladder cancer, two randomized trials and a meta-analysis support the integration of cisplatin-based neoadjuvant chemotherapy [13–15]. The SWOG trial randomized patients with muscle-invasive bladder cancer to three
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cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by cystectomy versus cystectomy alone. The median age of patients enrolled on this study was 63 years old. However, when the results were stratified by age, a numerical improvement in survival was also demonstrated in patients ≥ 65 year old (median survival: neoadjuvant chemotherapy arm = 61 months versus surgery alone arm = 30 months). Nonetheless, population-based data suggest that neoadjuvant chemotherapy is vastly underutilized. In an analysis of the National Cancer Database, only 1% of patients undergoing cystectomy for muscle-invasive bladder cancer received neoadjuvant chemotherapy [16]. More recent analyses have demonstrated a modest increase in this percentage [17]. While there are multiple reasons for the underutilization of neoadjuvant chemotherapy for the treatment of muscleinvasive bladder cancer, obstruction-, comorbidity-, and agerelated renal dysfunction is likely a major contributor. Dash et al. demonstrated, in a large cohort of patients with muscleinvasive bladder cancer, that approximately 16%, 36%, and 68% of patients age 60–69, 70–79, and 80+, respectively, had a calculated creatinine clearance of ≤60 ml/min, a commonly utilized cut-off for cisplatin administration [18]. Radiation therapy is another treatment option for muscleinvasive bladder cancer. Two randomized trials have demonstrated an improvement in outcomes (locoregional disease control was the primary endpoint in both trials) with the addition of concurrent chemotherapy to radiation [19,20]. There have been no completed randomized trials comparing cystectomy with chemoradiation for this disease. A barrier to the development of a standard chemoradiation regimen as a potentially preferred treatment option for elderly patients with bladder cancer has been that there are two very different patient populations that may benefit from chemoradiation: (1) fit patients, with optimal disease characteristics (e.g., solitary T2 lesion that can be completely resected transuretherally), that are operative candidates but are pursuing chemoradiation as a bladder-sparing strategy and (2) medically inoperable patients for whom chemoradiation is being considered because surgery is felt to be associated with excessive risk. Clinical trials exploring chemoradiation in bladder cancer have largely focused on the former population. A notable exception is a trial conducted in the United Kingdom that enrolled patients with muscle-invasive bladder cancer and randomized patients to radiation alone or radiation plus concurrent 5-fluorouracil plus mitomycin-C [19]. This trial allowed patients with an ECOG performance status of 0–2 and a glomerular filtration rate of > 25 ml/min/1.73 m2 and the median age of enrollment was 72 years old. The trial met the primary endpoint of improving locoregional disease control. While not powered to detect an improvement in overall survival, the 5-year overall survival for the chemoradiation arm was 48%, similar to outcomes reported in large cystectomy series. Non-cisplatin containing chemoradiation regimens have been developed by several groups including concurrent gemcitabine plus radiation [21]. This regimen is currently being compared with radiation plus concurrent 5-fluorouracil and cisplatin in a Radiation Therapy Oncology Group randomized phase II study (RTOG 0712) but has already become commonly utilized for the treatment of elderly patients with muscle-invasive bladder cancer, even in
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Table 1 – Potential management algorithm for elderly patients with muscle-invasive bladder cancer. Patient characteristics a Medically operable cisplatin-eligible Medically operable cisplatin-ineligible Medically inoperable cisplatin-eligible Medically inoperable cisplatin-ineligible
Treatment options • • • • • • •
Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy Radiation therapy with concurrent cisplatin if opts for bladder sparing Radical cystectomy Radiation therapy with concurrent chemotherapy? Radiation therapy with concurrent cisplatin Radiation therapy with concurrent chemotherapy (5-fluorouracil + mitomycin; gemcitabine, etc.) Radiation therapy alone
a Components of the Comprehensive Geriatric Assessment (function, mobility, nutrition, comorbidity, cognition, mood, social support) may further refine risk/benefit assessment.
the absence of randomized trials, due to a favorable tolerability profile [22]. Little data is available regarding the use of chemoradiation with curative intent specifically for elderly patients with bladder cancer. A recent review of this topic by Turgeon et al. identified only one prospective study though additional retrospective studies and subset analyses of larger prospective studies were evaluated [23]. This series included studies exploring a variety of different chemotherapeutic regimens, radiation doses and schedules, and eligibility criteria limiting definitive conclusions. Overall, the data suggested that concurrent chemoradiation can be delivered safely in elderly patients with a subset of patients experiencing durable disease control. The optimal chemotherapy regimen, and radiation regimen, for integration into a trimodality bladder preserving approach for elderly patients with bladder cancer remain to be defined. Acknowledging the limited Level I evidence to guide the care of elderly patients with muscle-invasive bladder cancer, and the lack of a standard definition of medical inoperability, a potential management algorithm is outlined in Table 1. Our patient undergoes a preoperative evaluation and she is felt to be at high risk for morbidity and mortality with cystectomy. She declines surgery and is treated with radiation therapy with twice weekly gemcitabine. She achieves a complete response to treatment. Approximately one year after completing treatment, she develops lung metastases.
3. Treatment of Metastatic Bladder Cancer in the Elderly The MVAC regimen, developed in the 1980s, represented a step forward in the management of metastatic bladder cancer with objective response rates achieved in up to 50% of patients, complete responses in 10–20% of patients, and durable responses in approximately 5–10% of patients [24]. Several other cisplatin-based chemotherapy regimens have subsequently been compared with MVAC in randomized trials though no regimen has yet demonstrated superiority. The doublet of gemcitabine plus cisplatin demonstrated similar outcomes compared with MVAC in a randomized phase III trial (median survival: gemcitabine plus cisplatin = 14 months versus MVAC = 15.2 months) [25]. However, gemcitabine plus cisplatin was associated with less severe side effects and
has been adopted as a commonly utilized first-line treatment standard. Age alone should generally not be used to exclude patients with metastatic bladder cancer from cisplatin-based chemotherapy. In an analysis of the impact of age on outcomes of patients with metastatic bladder cancer receiving cisplatinbased chemotherapy in a series of phase II and III clinical trials, there was no significant difference in response rate, survival, or select toxicities, in patients ≥70 years old compared with younger patients [26]. This does represent a highly selected group of elderly patients, meeting clinical trial eligibility criteria, and as such applies only to the fittest elderly patients. Though there have been no randomized phase III trials comparing cisplatin-based and carboplatin-based chemotherapy for metastatic bladder cancer, a meta-analysis of randomized phase II trials demonstrates a significantly higher likelihood of achieving an objective response, and a complete response, with cisplatin-based chemotherapy [27]. Cisplatin-based chemotherapy is the preferred first-line treatment standard and is supported by practice guidelines. As discussed above, however, a large proportion of patients with bladder cancer are ineligible for cisplatin. In an attempt to codify a definition of cisplatinineligibility, particularly to establish uniformity in clinical trial eligibility and facilitate the development of novel regimens for this population, an expert panel was convened in 2011 [28,29]. This panel established a definition of cisplatin-ineligibility, through consensus, as shown in Table 2. Given the large proportion of cisplatin-ineligible patients with metastatic bladder cancer, particularly elderly patients, several phase II trials and a single phase III trial have explored chemotherapy regimens specifically for this patient population. The EORTC conducted a randomized phase II/III trial of gemcitabine plus carboplatin (GCa) versus methotrexate, vinblastine, plus carboplatin (M-CAVI) in cisplatin-ineligible Table 2 – Consensus definition for cisplatin-ineligibility in patients with metastatic bladder cancer. At least one of the following • • • • •
ECOG PS of 2 (KPS of 60–70) Creatinine clearance <60 ml/min CTCAE v4 grade ≥2 audiometric hearing loss CTCAE v4 grade ≥2 peripheral neuropathy NYHA Class III heart failure
ECOG PS, Eastern Cooperative Oncology Group Performance Status; KPS, Karnofsky Performance Status; CTCAE, Common Terminology Criteria for Adverse Events; NYHA, New York Heart Association.
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patients with metastatic bladder cancer [30]. The median age of patients enrolled was 71 years old. Both regimens resulted in a similar median overall survival (GCa = 9.3 months, M-CAVI = 8.1 months). However, M-CAVI was associated with a higher rate of toxicity. Importantly, 27% of patients that had both impaired renal function and a performance status of 2 at baseline experienced severe acute toxicities. These findings suggest that a subset of patients are not appropriate candidates for combination cytotoxic chemotherapy regimens and may not be optimal candidates for chemotherapy at all. Hurria and colleagues have developed a model for predicting the risk of grade 3–5 chemotherapy-related toxicity in an effort to improve risk stratification and facilitate shared decision-making regarding treatment in elderly patients [31]. Baseline variables in this model associated with a higher risk of toxicity include a diagnosis of a genitourinary cancer, use of poly-chemotherapy, impaired renal function, and age ≥ 72 years old, in addition to other characteristics common among patients with bladder cancer. There is no standard treatment for patients with metastatic bladder cancer with disease progression despite first-line chemotherapy. This is an area of active investigation. A potential management algorithm for elderly patients with metastatic bladder cancer is shown in Table 3. Our patient receives 6 cycles of single-agent gemcitabine. She achieves a partial response to treatment. She tolerates treatment relatively well though her cognitive function slowly worsens and further treatment is held.
4. Future Directions While there will always likely be some treatment divide between younger and older patients with cancer given the special considerations in the latter population, it is important to acknowledge that the value proposition of current treatments is in direct relation to their associated balance of potential benefits and harms. As more efficacious and less toxic treatments emerge, artificial classifications such as
Table 3 – Potential management algorithm for elderly patients with metastatic bladder cancer. Patient characteristics a PS 0–1 and creatinine clearance ≥60 • • • PS 2 or creatinine clearance <60 • • PS 2 and creatinine clearance <60 • • • PS >2 •
Treatment options Gemcitabine plus cisplatin Dose-dense MVAC b Clinical trial Gemcitabine plus carboplatin Clinical trial Single agent chemotherapy Clinical trial Best supportive care Best supportive care
PS, Performance Status. Chemotherapy toxicity risk prediction tool [31] may further refine risk/benefit assessment. b In select patients with PS 0 and potential candidates for consolidative surgery (e.g., cN+ disease). a
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“cisplatin-ineligible” will likely disappear in favor of classifications more relevant to tumor biology. Knowledge regarding the molecular pathogenesis of bladder cancer has dramatically expanded in recent years. Comprehensive integrated genomic profiling efforts, such as those conducted by The Cancer Genome Atlas and others, have both refined classification of bladder cancers to better reflect the heterogeneity of the disease but have also identified “actionable” therapeutic targets [32–34]. At the same time, there has been an increasing realization that patients with bladder cancer, even in the setting of advanced disease, may be treated with therapies that modulate the host immune response. Though these observations are important for patients with bladder cancer of all age groups, the elderly may benefit in particular given the favorable risk:benefit ratio of some of these newer interventions compared with traditional cytotoxic chemotherapy. Preliminary data with two fibroblast-growth factor receptor 3 (FGFR3) orally bioavailable small molecule kinase inhibitors reveal single agent objective responses in patients with metastatic bladder cancer harboring FGFR3 alterations [35,36]. Anecdotally, in the preliminary presentation reporting the activity of the FGFR3 inhibitor BGJ398 in patients with bladder cancer, the most durable response at the time of the report had occurred in an 86 year-old patient. Along the same lines, immune checkpoint blockade with antibodies to PD-1 or PD-L1 has demonstrated durable responses in patients with metastatic bladder cancer in early reports [37]. Expression of PD-L1 in tumor specimens (or tumor infiltrating cells) has been associated with a higher likelihood of response. In addition, grade 3 and 4 adverse events with these agents have been uncommon. Taken together, a new generation of interventions for which the likelihood of benefit can be predicted based on mechanism-relevant biomarkers, and that are much better tolerated than conventional cytotoxic chemotherapy, has the potential to change the value proposition of systemic therapy for elderly patients with invasive or advanced bladder cancer. However, whether the safety and efficacy of such treatments, particularly immune checkpoint blockade given the impact of aging on the immune system, are similar in older and younger patients requires further investigation. In the meantime, developing better means to individualize risk assessment of the benefits and harms of existing therapies, integrating these tools into standard practice, and communicating this information in a manner which optimizes shared medical decisions, is critical to practice true “personalized” medicine in the elderly.
Disclosures and Conflict of Interest Statements MDG has served as a consultant for Astellas, Dendreon, Jannsen, Glaxo Smith-Kline, and BioMotiv and is a co-founder of Dual Therapeutics.
Funding MDG is supported by a Prostate Cancer Foundation Young Investigator Award.
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32. Iyer G, Al-Ahmadie H, Schultz N, et al. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol 2013;31(25):3133–3140, http://dx.doi.org/10.1200/JCO.2012.46.5740. 33. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014, http://dx.doi.org/ 10.1038/nature12965. 34. Lindgren D, Sjodahl G, Lauss M, et al. Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma. PLoS One 2012;7(6):e38863, http:// dx.doi.org/10.1371/journal.pone [[pii]0038863 PONE-D-12-06243].
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35. Sequist LV, Cassier P, Varga A, Sequist LV, Cassier P, Varga A, et al. Phase I Study of BGJ398, a Selective Pan-FGFR Inhibitor in Genetically Preselected Advanced Solid Tumors. American Association for Cancer Research 2014 Annual Meeting; 2014. p. CT326. 36. Bahleda R, Dienstmann R, Adamo B, et al. Phase 1 study of JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced solid tumors. ASCO Meet Abstr 2014;32(15_suppl):2501. 37. Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC). ASCO Meet Abstr 2014;32(15_suppl):5011.
Available online at www.sciencedirect.com
ScienceDirect
Meet the Experts
How I treat bladder cancer in elderly patients Matthew D. Galsky⁎ Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
AR TIC LE I N FO
ABS TR ACT
Article history:
Bladder cancer is a disease of the elderly. There is a disconnect between the efficacy of
Received 16 August 2014
treatments for patients with advanced disease, and their effectiveness, at least in part
Received in revised form
related to the advanced age at diagnosis. Standard treatments for patients with locally
26 October 2014
advanced or metastatic bladder cancer include radical cystectomy and/or cisplatin-based
Accepted 20 November 2014
combination chemotherapy. However, there is significant potential for morbidity, and even
Available online 4 December 2014
mortality, with these treatments necessitating tools to risk stratify elderly patients to optimize the safety and benefit of treatments and alternative strategies in situations where
Keywords:
the potential risks are likely to outweigh the potential benefits. This review considers the
Bladder cancer
current standard treatments for advanced bladder cancer, approaches to risk stratify elderly
Urothelial cancer
patients, and highlights our relatively poor knowledge base regarding the optimal care of
Elderly
elderly patients with this disease. © 2014 Elsevier Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Treatment of Muscle-Invasive Bladder Cancer in the Elderly 3. Treatment of Metastatic Bladder Cancer in the Elderly . . . 4. Future Directions . . . . . . . . . . . . . . . . . . . . . . . Disclosures and Conflict of Interest Statements . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Bladder cancer is a disease of the elderly (Fig. 1). The median age of diagnosis of bladder cancer in the United States is 73 years old and the median age of death is 79 years old. Due to the advanced age at the time of diagnosis, at least in part,
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there is a major disconnect between the efficacy of treatment of patients with advanced bladder cancer, as established through clinical trials, and the effectiveness of such treatment when applied to the general population of patients with the disease. The “gold standard” treatments for advanced bladder cancer are associated with significant potential for morbidity
⁎ Mount Sinai School of Medicine, Tisch Cancer Institute, 1 Gustave L Levy Place, New York, NY 10029, USA. Tel.: + 1 212 824 8583; fax: + 1 212 659 5599. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.jgo.2014.11.006 1879-4068/© 2014 Elsevier Ltd. All rights reserved.
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Fig. 1 – Age distribution of new bladder cancer diagnoses in the United States (data derived from the Surveillance, Epidemiology, and End Results Program*). *http://seer.cancer.gov/statfacts/html/urinb.html.
and even mortality. A radical cystectomy with pelvic lymph node dissection, with diversion or reconstruction of the urinary tract, involves major abdominal surgery and typically a prolonged recovery period. When systemic chemotherapy is utilized, cisplatin-based combination chemotherapy is supported by Level I evidence. Unfortunately, the bulk of evidence establishing these treatments as “gold standards” has been generated in younger patients. For example, Hutchins and colleagues reported that at a time when > 75% of patients with bladder cancer in the United States were ≥ 65 years old, only 55% of patients with bladder cancer participating in Southwest Oncology Group (SWOG) trials were ≥65 years old [1]. Further complicating an evidenced-based approach to the management of elderly patients with bladder cancer is a lack of uniform reporting guidelines regarding the age of participants in clinical trial publications. While some trials report the percentage of enrolled patients above a certain age (e.g., percent ≥65 years old), most trials only report median age, and range, preventing a full appreciation for the number of elderly patients included. Of course, care decisions in patients with bladder cancer, and other malignancies, are not optimally based on chronological age but rather functional age. Measures of functional status or frailty are generally much more important determinants of treatment tolerability, and benefit, than age alone. Nonetheless, there is physiologic decline in virtually every organ system associated with aging, functional reserve may differ in younger and older patients with the same baseline functional status, and chronological age still contributes to medical decision-making. The chronological age that defines “elderly” is arbitrary and most analyses have used a cut-off of ≥65 or ≥ 70 to define an elderly population. With this background, the care of the elderly patient with advanced bladder cancer is probably best discussed within the context of a case. An 80 year-old woman undergoes a cystoscopy and transurethral resection of bladder tumor, after presenting with gross hematuria, and is diagnosed with muscle-invasive urothelial cancer. She undergoes a computed tomography scan of the chest, abdomen, and pelvis that reveals no radiographic evidence of metastatic disease. She has hypertension and type II diabetes mellitus and a creatinine of 1.5. Her Eastern Cooperative Oncology Group (ECOG) performance status is 2.
What else do we need to know about this patient to guide management? There are several other aspects to her history and physical that may be important to clinical decision making, most of which are important to elicit in the work-up of any patient, but some that may be particularly germane to the elderly patient. Has cognition been adequately assessed? What is the patient's level of mobility, living situation, and social support system? How is her nutritional status? Does she prepare her own meals? How many other medications is she taking and who administers these medications? Has organ function been adequately assessed? When feasible, these domains are likely best assessed in the setting of a Comprehensive Geriatric Assessment (CGA) [2] or a formal geriatrics consultation, though key information can often be ascertained through a more detailed history. As we dig a bit deeper, we learn that our patient suffers from mild dementia. She lives in an assisted living facility. She has a very supportive family that accompanies her to appointments and assists with transportation. She needs assistance with her instrumental activities of daily living.
2. Treatment of Muscle-Invasive Bladder Cancer in the Elderly Treatment options for clinically localized muscle-invasive bladder cancer (i.e., cT2-4a) include radical cystectomy with or without perioperative chemotherapy, radiation therapy with or without concomitant chemotherapy, or transuretheral resection of bladder tumor/supportive care alone. In the United States, radical cystectomy is the preferred treatment for patients with muscle-invasive bladder cancer and is potentially curative. Long-term outcomes are correlated highly with pathologic stage of disease with approximately 80%, 70%, and 30%, of patients remaining disease-free with organ-confined disease, extravesical disease, and lymph node-positive disease, respectively [3]. Unfortunately, clinical staging in bladder cancer poorly predicts pathologic stage such that such refined risk stratification information is not available prior to surgery, when treatment decisions need to be made [4]. Not surprisingly, as radical cystectomy is a major surgical procedure, population-based data suggest that this operation is performed much less commonly in elderly patients. In an analysis of the National Cancer Database (NCDB), Fedeli et al. demonstrated that approximately 40–50% and 13–30% of septuagenarians and octogenarians with muscle-invasive bladder cancer, respectively, underwent radical cystectomy [5]. Gore et al. examined a cohort of 3262 Medicare beneficiaries aged 66 or older with muscle-invasive bladder cancer using Surveillance, Epidemiology, and End Results-Medicare data. These investigators determined that only 21% of patients underwent cystectomy; notably, overall survival was better for patients that underwent cystectomy [6]. Similar findings have been confirmed in a more contemporary analysis of NCDB data also highlighting that similar survival outcomes were achieved with either cystectomy or concurrent chemoradiation, both of which were better than other therapies or no treatment [7].
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Not only is information regarding the likelihood of a curative outcome with radical cystectomy potentially important for clinical decision-making, information regarding the likelihood of morbidity and mortality is also critical. Nielsen at al. examined the 90-day postoperative mortality in a retrospective cohort of 35,055 patients undergoing cystectomy from the NCDB and reported that 90-day mortality increased with age and was approximately 10% for patients ≥80 years old [8]. A nomogram has been developed to calculate the probability of 90-day mortality after radical cystectomy incorporating a patient's age, tumor stage, grade, and histology [9]. This nomogram has been externally validated and extended but still offers only moderate discrimination likely due to the lack of other variables that may be important in this context including comorbidities and functional status [10]. A universal surgical risk calculator has been developed using standardized clinical data from the American College of Surgeons National Surgical Quality Improvement Program which utilizes 21 preoperative factors to calculate the likelihood of post-operative mortality, morbidity, and specific complications with excellent performance [11]. This tool, which is publically available (http://riskcalculator.facs.org/) and is increasingly utilized, may help refine shared decisions regarding surgical management of muscle-invasive bladder cancer. The standard assessments, and criteria, to define patients that are “medically inoperable” or “ineligible for cystectomy” remain ambiguous. Furthermore, just because surgery can be done doesn't necessarily mean it should be done. Rather, several factors must be considered when considering a radical cystectomy in an elderly patient with bladder cancer including the likelihood of benefit with surgery, the likelihood of perioperative morbidity and mortality, the patients expected longevity independent of the bladder cancer diagnosis, and the likelihood of severe bladder-cancer associated morbidity during that time period. All of these factors must be considered within the context of an individual patient's goals, objectives, and preferences. Tools to optimize risk prediction in each of these areas are lacking. The CGA assesses multiple domains of health, including function, comorbidities, socioeconomics, cognition, emotion, medications, nutrition, and problems specific to the geriatric population such as dementia and fall risk [2]. The CGA has been widely utilized and validated and shown to be more effective than performance status in reflecting the general health of elderly patients [9]. Additionally, the CGA was shown to better identify elderly patient's suitability for treatment compared with “physicians' judgment” [10]. The use of the CGA in surgical oncology has recently been the subject of a systematic review by Feng et al. [12] While components of the CGA have been evaluated as predictors of post-operative morbidity and mortality in the context of several cancer surgeries, the heterogeneity of these studies has contributed to somewhat conflicting results. The CGA is a lengthy exam and is only recently being investigated as a pre-surgical risk assessment tool prior to radical cystectomy. When radical cystectomy is employed for the treatment of muscle-invasive bladder cancer, two randomized trials and a meta-analysis support the integration of cisplatin-based neoadjuvant chemotherapy [13–15]. The SWOG trial randomized patients with muscle-invasive bladder cancer to three
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cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by cystectomy versus cystectomy alone. The median age of patients enrolled on this study was 63 years old. However, when the results were stratified by age, a numerical improvement in survival was also demonstrated in patients ≥ 65 year old (median survival: neoadjuvant chemotherapy arm = 61 months versus surgery alone arm = 30 months). Nonetheless, population-based data suggest that neoadjuvant chemotherapy is vastly underutilized. In an analysis of the National Cancer Database, only 1% of patients undergoing cystectomy for muscle-invasive bladder cancer received neoadjuvant chemotherapy [16]. More recent analyses have demonstrated a modest increase in this percentage [17]. While there are multiple reasons for the underutilization of neoadjuvant chemotherapy for the treatment of muscleinvasive bladder cancer, obstruction-, comorbidity-, and agerelated renal dysfunction is likely a major contributor. Dash et al. demonstrated, in a large cohort of patients with muscleinvasive bladder cancer, that approximately 16%, 36%, and 68% of patients age 60–69, 70–79, and 80+, respectively, had a calculated creatinine clearance of ≤60 ml/min, a commonly utilized cut-off for cisplatin administration [18]. Radiation therapy is another treatment option for muscleinvasive bladder cancer. Two randomized trials have demonstrated an improvement in outcomes (locoregional disease control was the primary endpoint in both trials) with the addition of concurrent chemotherapy to radiation [19,20]. There have been no completed randomized trials comparing cystectomy with chemoradiation for this disease. A barrier to the development of a standard chemoradiation regimen as a potentially preferred treatment option for elderly patients with bladder cancer has been that there are two very different patient populations that may benefit from chemoradiation: (1) fit patients, with optimal disease characteristics (e.g., solitary T2 lesion that can be completely resected transuretherally), that are operative candidates but are pursuing chemoradiation as a bladder-sparing strategy and (2) medically inoperable patients for whom chemoradiation is being considered because surgery is felt to be associated with excessive risk. Clinical trials exploring chemoradiation in bladder cancer have largely focused on the former population. A notable exception is a trial conducted in the United Kingdom that enrolled patients with muscle-invasive bladder cancer and randomized patients to radiation alone or radiation plus concurrent 5-fluorouracil plus mitomycin-C [19]. This trial allowed patients with an ECOG performance status of 0–2 and a glomerular filtration rate of > 25 ml/min/1.73 m2 and the median age of enrollment was 72 years old. The trial met the primary endpoint of improving locoregional disease control. While not powered to detect an improvement in overall survival, the 5-year overall survival for the chemoradiation arm was 48%, similar to outcomes reported in large cystectomy series. Non-cisplatin containing chemoradiation regimens have been developed by several groups including concurrent gemcitabine plus radiation [21]. This regimen is currently being compared with radiation plus concurrent 5-fluorouracil and cisplatin in a Radiation Therapy Oncology Group randomized phase II study (RTOG 0712) but has already become commonly utilized for the treatment of elderly patients with muscle-invasive bladder cancer, even in
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Table 1 – Potential management algorithm for elderly patients with muscle-invasive bladder cancer. Patient characteristics a Medically operable cisplatin-eligible Medically operable cisplatin-ineligible Medically inoperable cisplatin-eligible Medically inoperable cisplatin-ineligible
Treatment options • • • • • • •
Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy Radiation therapy with concurrent cisplatin if opts for bladder sparing Radical cystectomy Radiation therapy with concurrent chemotherapy? Radiation therapy with concurrent cisplatin Radiation therapy with concurrent chemotherapy (5-fluorouracil + mitomycin; gemcitabine, etc.) Radiation therapy alone
a Components of the Comprehensive Geriatric Assessment (function, mobility, nutrition, comorbidity, cognition, mood, social support) may further refine risk/benefit assessment.
the absence of randomized trials, due to a favorable tolerability profile [22]. Little data is available regarding the use of chemoradiation with curative intent specifically for elderly patients with bladder cancer. A recent review of this topic by Turgeon et al. identified only one prospective study though additional retrospective studies and subset analyses of larger prospective studies were evaluated [23]. This series included studies exploring a variety of different chemotherapeutic regimens, radiation doses and schedules, and eligibility criteria limiting definitive conclusions. Overall, the data suggested that concurrent chemoradiation can be delivered safely in elderly patients with a subset of patients experiencing durable disease control. The optimal chemotherapy regimen, and radiation regimen, for integration into a trimodality bladder preserving approach for elderly patients with bladder cancer remain to be defined. Acknowledging the limited Level I evidence to guide the care of elderly patients with muscle-invasive bladder cancer, and the lack of a standard definition of medical inoperability, a potential management algorithm is outlined in Table 1. Our patient undergoes a preoperative evaluation and she is felt to be at high risk for morbidity and mortality with cystectomy. She declines surgery and is treated with radiation therapy with twice weekly gemcitabine. She achieves a complete response to treatment. Approximately one year after completing treatment, she develops lung metastases.
3. Treatment of Metastatic Bladder Cancer in the Elderly The MVAC regimen, developed in the 1980s, represented a step forward in the management of metastatic bladder cancer with objective response rates achieved in up to 50% of patients, complete responses in 10–20% of patients, and durable responses in approximately 5–10% of patients [24]. Several other cisplatin-based chemotherapy regimens have subsequently been compared with MVAC in randomized trials though no regimen has yet demonstrated superiority. The doublet of gemcitabine plus cisplatin demonstrated similar outcomes compared with MVAC in a randomized phase III trial (median survival: gemcitabine plus cisplatin = 14 months versus MVAC = 15.2 months) [25]. However, gemcitabine plus cisplatin was associated with less severe side effects and
has been adopted as a commonly utilized first-line treatment standard. Age alone should generally not be used to exclude patients with metastatic bladder cancer from cisplatin-based chemotherapy. In an analysis of the impact of age on outcomes of patients with metastatic bladder cancer receiving cisplatinbased chemotherapy in a series of phase II and III clinical trials, there was no significant difference in response rate, survival, or select toxicities, in patients ≥70 years old compared with younger patients [26]. This does represent a highly selected group of elderly patients, meeting clinical trial eligibility criteria, and as such applies only to the fittest elderly patients. Though there have been no randomized phase III trials comparing cisplatin-based and carboplatin-based chemotherapy for metastatic bladder cancer, a meta-analysis of randomized phase II trials demonstrates a significantly higher likelihood of achieving an objective response, and a complete response, with cisplatin-based chemotherapy [27]. Cisplatin-based chemotherapy is the preferred first-line treatment standard and is supported by practice guidelines. As discussed above, however, a large proportion of patients with bladder cancer are ineligible for cisplatin. In an attempt to codify a definition of cisplatinineligibility, particularly to establish uniformity in clinical trial eligibility and facilitate the development of novel regimens for this population, an expert panel was convened in 2011 [28,29]. This panel established a definition of cisplatin-ineligibility, through consensus, as shown in Table 2. Given the large proportion of cisplatin-ineligible patients with metastatic bladder cancer, particularly elderly patients, several phase II trials and a single phase III trial have explored chemotherapy regimens specifically for this patient population. The EORTC conducted a randomized phase II/III trial of gemcitabine plus carboplatin (GCa) versus methotrexate, vinblastine, plus carboplatin (M-CAVI) in cisplatin-ineligible Table 2 – Consensus definition for cisplatin-ineligibility in patients with metastatic bladder cancer. At least one of the following • • • • •
ECOG PS of 2 (KPS of 60–70) Creatinine clearance <60 ml/min CTCAE v4 grade ≥2 audiometric hearing loss CTCAE v4 grade ≥2 peripheral neuropathy NYHA Class III heart failure
ECOG PS, Eastern Cooperative Oncology Group Performance Status; KPS, Karnofsky Performance Status; CTCAE, Common Terminology Criteria for Adverse Events; NYHA, New York Heart Association.
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patients with metastatic bladder cancer [30]. The median age of patients enrolled was 71 years old. Both regimens resulted in a similar median overall survival (GCa = 9.3 months, M-CAVI = 8.1 months). However, M-CAVI was associated with a higher rate of toxicity. Importantly, 27% of patients that had both impaired renal function and a performance status of 2 at baseline experienced severe acute toxicities. These findings suggest that a subset of patients are not appropriate candidates for combination cytotoxic chemotherapy regimens and may not be optimal candidates for chemotherapy at all. Hurria and colleagues have developed a model for predicting the risk of grade 3–5 chemotherapy-related toxicity in an effort to improve risk stratification and facilitate shared decision-making regarding treatment in elderly patients [31]. Baseline variables in this model associated with a higher risk of toxicity include a diagnosis of a genitourinary cancer, use of poly-chemotherapy, impaired renal function, and age ≥ 72 years old, in addition to other characteristics common among patients with bladder cancer. There is no standard treatment for patients with metastatic bladder cancer with disease progression despite first-line chemotherapy. This is an area of active investigation. A potential management algorithm for elderly patients with metastatic bladder cancer is shown in Table 3. Our patient receives 6 cycles of single-agent gemcitabine. She achieves a partial response to treatment. She tolerates treatment relatively well though her cognitive function slowly worsens and further treatment is held.
4. Future Directions While there will always likely be some treatment divide between younger and older patients with cancer given the special considerations in the latter population, it is important to acknowledge that the value proposition of current treatments is in direct relation to their associated balance of potential benefits and harms. As more efficacious and less toxic treatments emerge, artificial classifications such as
Table 3 – Potential management algorithm for elderly patients with metastatic bladder cancer. Patient characteristics a PS 0–1 and creatinine clearance ≥60 • • • PS 2 or creatinine clearance <60 • • PS 2 and creatinine clearance <60 • • • PS >2 •
Treatment options Gemcitabine plus cisplatin Dose-dense MVAC b Clinical trial Gemcitabine plus carboplatin Clinical trial Single agent chemotherapy Clinical trial Best supportive care Best supportive care
PS, Performance Status. Chemotherapy toxicity risk prediction tool [31] may further refine risk/benefit assessment. b In select patients with PS 0 and potential candidates for consolidative surgery (e.g., cN+ disease). a
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“cisplatin-ineligible” will likely disappear in favor of classifications more relevant to tumor biology. Knowledge regarding the molecular pathogenesis of bladder cancer has dramatically expanded in recent years. Comprehensive integrated genomic profiling efforts, such as those conducted by The Cancer Genome Atlas and others, have both refined classification of bladder cancers to better reflect the heterogeneity of the disease but have also identified “actionable” therapeutic targets [32–34]. At the same time, there has been an increasing realization that patients with bladder cancer, even in the setting of advanced disease, may be treated with therapies that modulate the host immune response. Though these observations are important for patients with bladder cancer of all age groups, the elderly may benefit in particular given the favorable risk:benefit ratio of some of these newer interventions compared with traditional cytotoxic chemotherapy. Preliminary data with two fibroblast-growth factor receptor 3 (FGFR3) orally bioavailable small molecule kinase inhibitors reveal single agent objective responses in patients with metastatic bladder cancer harboring FGFR3 alterations [35,36]. Anecdotally, in the preliminary presentation reporting the activity of the FGFR3 inhibitor BGJ398 in patients with bladder cancer, the most durable response at the time of the report had occurred in an 86 year-old patient. Along the same lines, immune checkpoint blockade with antibodies to PD-1 or PD-L1 has demonstrated durable responses in patients with metastatic bladder cancer in early reports [37]. Expression of PD-L1 in tumor specimens (or tumor infiltrating cells) has been associated with a higher likelihood of response. In addition, grade 3 and 4 adverse events with these agents have been uncommon. Taken together, a new generation of interventions for which the likelihood of benefit can be predicted based on mechanism-relevant biomarkers, and that are much better tolerated than conventional cytotoxic chemotherapy, has the potential to change the value proposition of systemic therapy for elderly patients with invasive or advanced bladder cancer. However, whether the safety and efficacy of such treatments, particularly immune checkpoint blockade given the impact of aging on the immune system, are similar in older and younger patients requires further investigation. In the meantime, developing better means to individualize risk assessment of the benefits and harms of existing therapies, integrating these tools into standard practice, and communicating this information in a manner which optimizes shared medical decisions, is critical to practice true “personalized” medicine in the elderly.
Disclosures and Conflict of Interest Statements MDG has served as a consultant for Astellas, Dendreon, Jannsen, Glaxo Smith-Kline, and BioMotiv and is a co-founder of Dual Therapeutics.
Funding MDG is supported by a Prostate Cancer Foundation Young Investigator Award.
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