Treatment of Patients with Advanced Gastroesophageal Adenocarcinoma: Does Age Matter?

  • Sylvie Lorenzen
  • Ralf-Dieter HofheinzEmail author
Review Article


Gastroesophageal cancer is the fourth most frequent malignant disease and, despite significant advances in chemotherapy, the prognosis of unresectable or recurrent gastroesophageal cancer is poor. The majority of patients, nearly two-thirds, are over the age of 65 years at diagnosis. Elderly patients are a heterogeneous population and aging occurs at different rates in different individuals. The chronological age of a patient does not necessarily reflect the physiological age. However, elderly patients are more likely to have a number of concomitant diseases and impaired organ function, which should be considered when making treatment decisions. Therefore, treatment in older adults requires particular caution, and physiologic age rather than chronologic age should be considered when deciding for or against systemic therapy. Older patients are generally underrepresented in clinical trials and many elderly patients do not receive effective combination therapies due to concerns with tolerability. Age itself is not a negative predictive factor and treatment should not be omitted just on the basis of chronological age. Older patients who fulfill the standard inclusion criteria of clinical trials seem to have a similar advantage from palliative chemotherapy for gastroesophageal adenocarcinoma as younger patients; however, large prospective trials in the elderly population are needed to guide clinicians in making evidence-based decisions.


Compliance with Ethical Standards


No external funding was used in the preparation of this manuscript.

Conflict of interest

Sylvie Lorenzen has received honoraria from Amgen, Bristol-Myers-Squibb, Merck, MSD, Lilly, Roche Pharma, and Servier, and has served as an advisor for Bristol-Myers-Squibb, Merck, MSD, Lilly, Roche Pharma, and Sanofi Aventis. Ralf-Dieter Hofheinz has received honoraria from Amgen, Boehringer Ingelheim, Bristol-Myers-Squibb, Merck, MSD, Lilly, Roche Pharma, Medac, Servier, and Sanofi, and has served as an advisor for Merck, Lilly, Roche Pharma, Sanofi Aventis, Amgen, and Bristol-Myers-Squibb. His institution has received research funding from Sanofi Aventis, Merck, and Amgen.


  1. 1.
    Al-Batran SE, Kroening H, Hannig CV, Hamm T, Moorahrend E, Petersen V, et al. Trastuzumab in combination with different first-line chemotherapies for treatment of HER2-positive metastatic gastric or gastro-oesophageal junction cancer: updated findings from the German non-interventional study HerMES. Eur J Cancer. 2015;51(Suppl 3):S444.CrossRefGoogle Scholar
  2. 2.
    Al-Batran SE, Atmaca A, Hegewisch-Becker S, Jaeger D, Hahnfeld S, Rummel MJ, et al. Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol. 2004;22(4):658–63.CrossRefGoogle Scholar
  3. 3.
    Al-Batran SE, Hartmann JT, Hofheinz R, Homann N, Rethwisch V, Probst S, et al. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2008;19(11):1882–7.CrossRefGoogle Scholar
  4. 4.
    Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26(9):1435–42.CrossRefGoogle Scholar
  5. 5.
    Al-Batran SE, Pauligk C, Homann N, Hartmann JT, Moehler M, Probst S, et al. The feasibility of triple-drug chemotherapy combination in older adult patients with oesophagogastric cancer: a randomised trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65 +). Eur J Cancer. 2013;49(4):835–42.CrossRefGoogle Scholar
  6. 6.
    Bang YJ, Ruiz EY, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, et al. Phase 3, randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment for patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018;29(10):2052–60.CrossRefGoogle Scholar
  7. 7.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.CrossRefGoogle Scholar
  8. 8.
    Chen H, Cantor A, Meyer J, Beth Corcoran M, Grendys E, Cavanaugh D, et al. Can older cancer patients tolerate chemotherapy? A prospective pilot study. Cancer. 2003;97(4):1107–14.CrossRefGoogle Scholar
  9. 9.
    Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358(1):36–46.CrossRefGoogle Scholar
  10. 10.
    Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008;19(8):1450–7.CrossRefGoogle Scholar
  11. 11.
    El-Serag HB. The epidemic of esophageal adenocarcinoma. Gastroenterol Clin N Am. 2002;31(2):421–40.CrossRefGoogle Scholar
  12. 12.
    Extermann M, Overcash J, Lyman GH, Parr J, Balducci L. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol. 1998;16(4):1582–7.CrossRefGoogle Scholar
  13. 13.
    Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49(6):1374–403.CrossRefGoogle Scholar
  14. 14.
    Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014;15(1):78–86.CrossRefGoogle Scholar
  15. 15.
    Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5):e180013.CrossRefGoogle Scholar
  16. 16.
    Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, REGARD Trial Investigators, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9.CrossRefGoogle Scholar
  17. 17.
    Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol. 1997;8(2):163–8.CrossRefGoogle Scholar
  18. 18.
    Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, Andre T, et al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Federation Francophone de Cancerologie Digestive, Federation Nationale des Centres de Lutte Contre le Cancer, and Groupe Cooperateur Multidisciplinaire en Oncologie) study. J Clin Oncol. 2014;32(31):3520–6.CrossRefGoogle Scholar
  19. 19.
    Hall PS, Lord S, Collinson M, Marshall H, Jones M, Olivier C. Three, two, or one drug chemotherapy for frail or elderly patients with advanced gastroesophageal cancer (321GO): a feasibility study. J Clin Oncol. 2012;30(4 Suppl):97.CrossRefGoogle Scholar
  20. 20.
    Hurria A, Wildes T, Blair SL, Browner IS, Cohen HJ, Deshazo M, et al. Senior adult oncology, version 22014: clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2014;12(1):82–126.CrossRefGoogle Scholar
  21. 21.
    Hwang IG, Ji JH, Kang JH, Lee HR, Lee HY, Chi KC, et al. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017;8(3):170–5.CrossRefGoogle Scholar
  22. 22.
    Jatoi A, Foster NR, Egner JR, Burch PA, Stella PJ, Rubin J, et al. Older versus younger patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction, and stomach: a pooled analysis of eight consecutive North Central Cancer Treatment Group (NCCTG) trials. Int J Oncol. 2010;36(3):601–6.CrossRefGoogle Scholar
  23. 23.
    Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012;30(13):1513–8.CrossRefGoogle Scholar
  24. 24.
    Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461–71.CrossRefGoogle Scholar
  25. 25.
    Kim ST, Park KH, Oh SC, Seo JH, Shin SW, Kim JS, et al. Is chemotherapy in elderly patients with metastatic or recurrent gastric cancer as tolerable and effective as in younger patients? Asia Pac J Clin Oncol. 2012;8(2):194–200.CrossRefGoogle Scholar
  26. 26.
    Kripp M, Al-Batran SE, Rosowski J, Pauligk C, Homann N, Hartmann JT, et al. Quality of life of older adult patients receiving docetaxel-based chemotherapy triplets for esophagogastric adenocarcinoma: a randomized study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Gastric Cancer. 2014;17(1):181–7.CrossRefGoogle Scholar
  27. 27.
    Surveillance, Epidemiology, and End Results (SEER) Program (2007–2011).
  28. 28.
    Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, KEYNOTE-061 Investigators, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018;392(10142):123–33.CrossRefGoogle Scholar
  29. 29.
    Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, ESMO Guidelines Committee. Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(Suppl 5):38–49.CrossRefGoogle Scholar
  30. 30.
    Stein BN, Petrelli NJ, Douglass HO, Driscoll DL, Arcangeli G, Meropol NJ. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer. 1995;75(1):11–7.CrossRefGoogle Scholar
  31. 31.
    Tabernero J, Shitara K, Dvorkin M. Overall survival results from a phase III trial of trifluridine/tipiracil versus placebo in patients with metastatic gastric cancer refractory to standard therapies (TAGS). Ann Oncol. 2018;29(Suppl 5):v122.Google Scholar
  32. 32.
    Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004;22(22):4626–31.CrossRefGoogle Scholar
  33. 33.
    The population. The state of the Health in the European Community in 2000. Brussels: European Union; 2000, P. 2-12.Google Scholar
  34. 34.
    Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer–a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011;47(15):2306–14.CrossRefGoogle Scholar
  35. 35.
    Trumper M, Ross PJ, Cunningham D, Norman AR, Hawkins R, Seymour M, et al. Efficacy and tolerability of chemotherapy in elderly patients with advanced oesophago-gastric cancer: a pooled analysis of three clinical trials. Eur J Cancer. 2006;42(7):827–34.CrossRefGoogle Scholar
  36. 36.
    Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24(31):4991–7.CrossRefGoogle Scholar
  37. 37.
    Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;8:CD004064.Google Scholar
  38. 38.
    Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224–35.CrossRefGoogle Scholar
  39. 39.
    Zeng C, Wen W, Morgans AK, Pao W, Shu XO, Zheng W. Disparities by race, age, and sex in the improvement of survival for major cancers: results from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program in the United States, 1990 to 2010. JAMA Oncol. 2015;1(1):88–96.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Medizinische Klinik III, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany
  2. 2.Interdisziplinäres Tumorzentrum MannheimUniversitätsmedizin Mannheim, Universität HeidelbergMannheimGermany

Personalised recommendations