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Treatment of Urothelial Cancer in Elderly Patients: Focus on Immune Checkpoint Inhibitors

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Abstract

Urothelial carcinoma, or bladder cancer, is a malignancy that most commonly affects older patients. The median age at diagnosis is 73 years, and care of these patients requires consideration not just of the disease-related factors such as stage and histology, but also of patient-related factors. Many of these patients have concurrent medical morbidities and additional changes related to the aging process. Older patients with cancer are a unique population requiring additional considerations and assessment in treatment decision-making. It is important to look beyond chronologic age. The traditional treatment for advanced disease has relied on platinum-based chemotherapy. These multi-agent regimens require consideration of baseline organ function as well as competing conditions that may heighten toxicity. The advent of a new class of cancer therapeutics, the immune checkpoint inhibitors, has changed the care of patients with advanced disease considerably. These immunotherapeutics have been approved for treating patients with disease progression on chemotherapy, or those who are ineligible (or unfit) to receive cisplatin-based therapy. This expansion of the population of patients eligible for treatment has great applicability to the unique considerations in an older patient population. In general, these new immunotherapies are well tolerated and effective in this group of patients.

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References

  1. Gray PJ, Fedewa SA, Shipley WU, Efstathiou JA, Lin CC, Zietman AL, et al. Use of potentially curative therapies for muscle-invasive bladder cancer in the United States: results from the National Cancer Data Base. Eur Urol. 2013;63(5):823–9.

    Article  PubMed  Google Scholar 

  2. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (editors). SEER Cancer Statistics Review, 1975–2014, Bethesda, MD: National Cancer Institute. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed 25 Apr 2018 (based on November 2016 SEER data submission, posted to the SEER web site, April 2017).

  3. Burger M, Grossman HB, Droller M, Schmidbauer J, Hermann G, Dragoescu O, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol. 2013;64(5):846–54.

    Article  PubMed  Google Scholar 

  4. Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011;306(7):737–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Lara P, Brunson A, White Rd, Dall’Era MA, Evans CP, Yap SA, et al. Survival of patients (pts) with metastatic bladder cancer (MBC) in the past quarter century: sobering results from the California Cancer Registry (CCR). J Clin Oncol. 2016;34(15_suppl):e16033-e.

  6. Goossens-Laan CA, Leliveld AM, Verhoeven RH, Kil PJ, de Bock GH, Hulshof MC, et al. Effects of age and comorbidity on treatment and survival of patients with muscle-invasive bladder cancer. Int J Cancer. 2014;135(4):905–12.

    Article  PubMed  CAS  Google Scholar 

  7. Singh H, Beaver JA, Kim G, Pazdur R. Enrollment of older adults on oncology trials: an FDA perspective. J Geriatr Oncol. 2017;8(3):149–50.

    Article  PubMed  Google Scholar 

  8. VanderWalde N, Jagsi R, Dotan E, Baumgartner J, Browner IS, Burhenn P, et al. NCCN guidelines insights: older adult oncology, version 2.2016. J Natl Compr Canc Netw. 2016;14(11):1357–70.

    Article  PubMed  Google Scholar 

  9. Wildiers H, Heeren P, Puts M, Topinkova E, Janssen-Heijnen ML, Extermann M, et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol. 2014;32(24):2595–603.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ommundsen N, Wyller TB, Nesbakken A, Jordhoy MS, Bakka A, Skovlund E, et al. Frailty is an independent predictor of survival in older patients with colorectal cancer. Oncologist. 2014;19(12):1268–75.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Soubeyran P, Fonck M, Blanc-Bisson C, Blanc JF, Ceccaldi J, Mertens C, et al. Predictors of early death risk in older patients treated with first-line chemotherapy for cancer. J Clin Oncol. 2012;30(15):1829–34.

    Article  PubMed  Google Scholar 

  12. Decoster L, Van Puyvelde K, Mohile S, Wedding U, Basso U, Colloca G, et al. Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations. Ann Oncol. 2015;26(2):288–300.

    Article  PubMed  CAS  Google Scholar 

  13. Kenis C, Decoster L, Van Puyvelde K, De Greve J, Conings G, Milisen K, et al. Performance of two geriatric screening tools in older patients with cancer. J Clin Oncol. 2014;32(1):19–26.

    Article  PubMed  Google Scholar 

  14. Soubeyran P, Bellera C, Goyard J, Heitz D, Cure H, Rousselot H, et al. Screening for vulnerability in older cancer patients: the ONCODAGE Prospective Multicenter Cohort Study. PLoS One. 2014;9(12):e115060.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Martinez-Tapia C, Canoui-Poitrine F, Bastuji-Garin S, Soubeyran P, Mathoulin-Pelissier S, Tournigand C, et al. Optimizing the G8 screening tool for older patients with cancer: diagnostic performance and validation of a six-item version. Oncologist. 2016;21(2):188–95.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Repetto L, Fratino L, Audisio RA, Venturino A, Gianni W, Vercelli M, et al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol. 2002;20(2):494–502.

    Article  PubMed  Google Scholar 

  17. Gillis C, Li C, Lee L, Awasthi R, Augustin B, Gamsa A, et al. Prehabilitation versus rehabilitation: a randomized control trial in patients undergoing colorectal resection for cancer. Anesthesiology. 2014;121(5):937–47.

    Article  PubMed  Google Scholar 

  18. Li C, Carli F, Lee L, Charlebois P, Stein B, Liberman AS, et al. Impact of a trimodal prehabilitation program on functional recovery after colorectal cancer surgery: a pilot study. Surg Endosc. 2013;27(4):1072–82.

    Article  PubMed  Google Scholar 

  19. Kalsi T, Babic-Illman G, Ross PJ, Maisey NR, Hughes S, Fields P, et al. The impact of comprehensive geriatric assessment interventions on tolerance to chemotherapy in older people. Br J Cancer. 2015;112(9):1435–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Prout GR Jr, Wesley MN, Yancik R, Ries LA, Havlik RJ, Edwards BK. Age and comorbidity impact surgical therapy in older bladder carcinoma patients: a population-based study. Cancer. 2005;104(8):1638–47.

    Article  PubMed  Google Scholar 

  21. Noon AP, Albertsen PC, Thomas F, Rosario DJ, Catto JW. Competing mortality in patients diagnosed with bladder cancer: evidence of undertreatment in the elderly and female patients. Br J Cancer. 2013;108(7):1534–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Clark PE, Stein JP, Groshen SG, Cai J, Miranda G, Lieskovsky G, et al. Radical cystectomy in the elderly: comparison of clinical outcomes between younger and older patients. Cancer. 2005;104(1):36–43.

    Article  PubMed  Google Scholar 

  23. Froehner M, Brausi MA, Herr HW, Muto G, Studer UE. Complications following radical cystectomy for bladder cancer in the elderly. Eur Urol. 2009;56(3):443–54.

    Article  PubMed  Google Scholar 

  24. Berger I, Martini T, Wehrberger C, Comploj E, Ponholzer A, Wolfgang M, et al. Perioperative complications and 90-day mortality of radical cystectomy in the elderly (75+): a retrospective, multicentre study. Urol Int. 2014;93(3):296–302.

    Article  PubMed  Google Scholar 

  25. Clayman RH, Shipley WU, Galland-Girodet S, Niemierko A, Gray PJ, Paly J, et al. Outcomes of selective bladder preservation in the elderly treated with conservative surgery and chemoradiation. Int J Radiat Oncol. 2013;87(2):S83-S.

  26. Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, 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(34):3801–9.

    Article  PubMed  PubMed Central  Google Scholar 

  27. McPherson VA, Rodrigues G, Bauman G, Winquist E, Chin J, Izawa J, et al. Chemoradiotherapy in octogenarians as primary treatment for muscle-invasive bladder cancer. Can Urol Assoc J Journal de l’Association des urologues du Canada. 2017;11(1–2):24–30.

  28. Chau C, Wheater M, Geldart T, Crabb SJ. Clinical outcomes following neoadjuvant cisplatin-based chemotherapy for bladder cancer in elderly compared with younger patients. Eur J Cancer Care (Engl). 2015;24(2):155–62.

    Article  CAS  Google Scholar 

  29. Galsky MD, Moshier E, Krege S, Lin CC, Hahn N, Ecke T, et al. Posttreatment prognostic nomogram for patients with metastatic urothelial cancer completing first-line cisplatin-based chemotherapy. Urol Oncol. 2014;32(1):48 e1–8.

  30. Guancial EA, Roussel B, Bergsma DP, Bylund KC, Sahasrabudhe D, Messing E, et al. Bladder cancer in the elderly patient: challenges and solutions. Clin Interv Aging. 2015;10:939–49.

    PubMed  PubMed Central  CAS  Google Scholar 

  31. Efstathiou JA, Spiegel DY, Shipley WU, Heney NM, Kaufman DS, Niemierko A, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol. 2012;61(4):705–11.

    Article  PubMed  Google Scholar 

  32. James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477–88.

    Article  PubMed  CAS  Google Scholar 

  33. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–66.

    Article  PubMed  CAS  Google Scholar 

  34. Cowan NG, Chen Y, Downs TM, Bochner BH, Apolo AB, Porter MP, et al. Neoadjuvant chemotherapy use in bladder cancer: a survey of current practice and opinions. Adv Urol. 2014;2014:746298.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997;15(7):2564–9.

    Article  PubMed  CAS  Google Scholar 

  36. Logothetis CJ, Dexeus FH, Sella A, Amato RJ, Kilbourn RG, Finn L, et al. Escalated therapy for refractory urothelial tumors: methotrexate-vinblastine-doxorubicin-cisplatin plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor. J Natl Cancer Inst. 1990;82(8):667–72.

    Article  PubMed  CAS  Google Scholar 

  37. Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10(7):1066–73.

    Article  PubMed  Google Scholar 

  38. Sternberg CN, de Mulder PH, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19(10):2638–46.

    Article  PubMed  CAS  Google Scholar 

  39. Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42(1):50–4.

    Article  PubMed  CAS  Google Scholar 

  40. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–77.

    Article  PubMed  Google Scholar 

  41. Dash A, Pettus JA, Herr HW, Bochner BH, Dalbagni G, Donat SM, et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008;113(9):2471–7.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Zargar-Shoshtari K, Zargar H, Lotan Y, Shah JB, van Rhijn BW, Daneshmand S, et al. A multi-institutional analysis of outcomes of patients with clinically node positive urothelial bladder cancer treated with induction chemotherapy and radical cystectomy. J Urol. 2016;195(1):53–9.

    Article  PubMed  Google Scholar 

  43. De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191–9.

    Article  PubMed  CAS  Google Scholar 

  44. Sonpavde G, Watson D, Tourtellott M, Cowey CL, Hellerstedt B, Hutson TE, et al. Administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community. Clin Genitourin Cancer. 2012;10(1):1–5.

    Article  PubMed  Google Scholar 

  45. Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol. 2012;30(10):1107–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, et al. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012;30(5):507–12.

    Article  PubMed  CAS  Google Scholar 

  47. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006;24(21):3451–7.

    Article  PubMed  CAS  Google Scholar 

  48. Ward PR, Wong MD, Moore R, Naeim A. Fall-related injuries in elderly cancer patients treated with neurotoxic chemotherapy: a retrospective cohort study. J Geriatr Oncol. 2014;5(1):57–64.

    Article  PubMed  Google Scholar 

  49. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 2016;375(18):1767–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 2002;99(19):12293–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet (London, England). 2016;387(10031):1909–20.

  52. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet (London, England). 2017;389(10064):67–76.

  53. Powles T, Duran I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet (London, England). 2018;391(10122):748–57.

  54. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–22.

    Article  PubMed  CAS  Google Scholar 

  55. Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483–92.

    Article  PubMed  CAS  Google Scholar 

  58. Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol. 2011;12(3):211–4.

    Article  PubMed  Google Scholar 

  59. Keytruda [package insert]. Merck & Co. I, Whitehouse Station, NJ; 2017. [cited 11/1/17]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s017s018lbl.pdf.

  60. Palou J, Wood D, Bochner BH, van der Poel H, Al-Ahmadie HA, Yossepowitch O, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: urothelial carcinoma of the prostate. Eur Urol. 2013;63(1):81–7.

    Article  PubMed  Google Scholar 

  61. Elias R, Karantanos T, Sira E, Hartshorn KL. Immunotherapy comes of age: Immune aging & checkpoint inhibitors. J Geriatr Oncol. 2017;8(3):229–35.

    Article  PubMed  Google Scholar 

  62. Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30–7.

    Article  PubMed  CAS  Google Scholar 

  63. Marrone KA, Forde PM. Cancer immunotherapy in older patients. Cancer J (Sudbury, Mass). 2017;23(4):219–22.

  64. Metter EJ, Talbot LA, Schrager M, Conwit R. Skeletal muscle strength as a predictor of all-cause mortality in healthy men. J Gerontol A Biol Sci Med Sci. 2002;57(10):B359–65.

    Article  PubMed  Google Scholar 

  65. Kalsi T, Babic-Illman G, Fields P, Hughes S, Maisey N, Ross P, et al. The impact of low-grade toxicity in older people with cancer undergoing chemotherapy. Br J Cancer. 2014;111(12):2224–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Correspondence to Elizabeth R. Kessler.

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Gray Jodon, Stacy Fischer, and Elizabeth Kessler declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Jodon, G., Fischer, S.M. & Kessler, E.R. Treatment of Urothelial Cancer in Elderly Patients: Focus on Immune Checkpoint Inhibitors. Drugs Aging 35, 409–421 (2018). https://doi.org/10.1007/s40266-018-0540-8

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