Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial | Esophageal Cancer | JAMA Oncology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.170.64.36. Please contact the publisher to request reinstatement.
1.
Ferlay  J, Soerjomataram  I, Dikshit  R,  et al.  Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.   Int J Cancer. 2015;136(5):E359-E386. doi:10.1002/ijc.29210PubMedGoogle ScholarCrossref
2.
Cunningham  D, Starling  N, Rao  S,  et al; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom.  Capecitabine and oxaliplatin for advanced esophagogastric cancer.   N Engl J Med. 2008;358(1):36-46. doi:10.1056/NEJMoa073149PubMedGoogle ScholarCrossref
3.
Al-Batran  SE, Hartmann  JT, Hofheinz  R,  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):1882-1887. doi:10.1093/annonc/mdn403PubMedGoogle ScholarCrossref
4.
Van Cutsem  E, Moiseyenko  VM, Tjulandin  S,  et al; V325 Study Group.  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):4991-4997. doi:10.1200/JCO.2006.06.8429PubMedGoogle ScholarCrossref
5.
Guimbaud  R, Louvet  C, Ries  P,  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 (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study.   J ClinOncol. 2014;32:3520-3526. doi:10.1200/JCO.2013.54.1011PubMedGoogle ScholarCrossref
6.
Seymour  MT, Thompson  LC, Wasan  HS,  et al; FOCUS2 Investigators; National Cancer Research Institute Colorectal Cancer Clinical Studies Group.  Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial.   Lancet. 2011;377(9779):1749-1759. doi:10.1016/S0140-6736(11)60399-1PubMedGoogle ScholarCrossref
7.
Hall  PS, Lord  SR, Collinson  M,  et al.  A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO).   Br J Cancer. 2017;116(4):472-478. doi:10.1038/bjc.2016.442PubMedGoogle ScholarCrossref
8.
Handforth  C, Hall  P, Marshall  H, Seymour  M.  Overall treatment utility: a novel outcome measure to convey the balance of benefits and harms from cancer treatment.   J Geriatr Oncol. 2013 4:S49. doi:10.1016/j.jgo.2013.09.064Google Scholar
9.
Bang  YJ, Van Cutsem  E, Feyereislova  A,  et al; ToGA Trial Investigators.  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):687-697. doi:10.1016/S0140-6736(10)61121-XPubMedGoogle ScholarCrossref
10.
Leal  AD, Allmer  C, Maurer  MJ,  et al.  Variability of performance status assessment between patients with hematologic malignancies and their physicians.   Leuk Lymphoma. 2018;59(3):695-701. doi:10.1080/10428194.2017.1347930PubMedGoogle ScholarCrossref
11.
Therasse  P, Arbuck  SG, Eisenhauer  EA,  et al.  New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.   J Natl Cancer Inst. 2000;92(3):205-216. doi:10.1093/jnci/92.3.205PubMedGoogle ScholarCrossref
12.
Pallis  AG, Ring  A, Fortpied  C,  et al; European Organisation for Research and Treatment of Cancer Elderly Task Force.  EORTC workshop on clinical trial methodology in older individuals with a diagnosis of solid tumors.   Ann Oncol. 2011;22(8):1922-1926. doi:10.1093/annonc/mdq687PubMedGoogle ScholarCrossref
13.
Soubeyran  P, Bellera  CA, Gregoire  F,  et al  Validation of a screening test for elderly patients in oncology.   J Clin Oncol. 2008;26 (15 Suppl). doi:10.1200/jco.2008.26.15_suppl.20568Google Scholar
14.
Lawton  MP.  Scales to measure competence in everyday activities.   Psychopharmacol Bull. 1988;24(4):609-614.PubMedGoogle Scholar
15.
Podsiadlo  D, Richardson  S.  The timed “Up & Go”: a test of basic functional mobility for frail elderly persons.   J Am Geriatr Soc. 1991;39(2):142-148. doi:10.1111/j.1532-5415.1991.tb01616.xPubMedGoogle ScholarCrossref
16.
Aaronson  NK, Ahmedzai  S, Bergman  B,  et al.  The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.   J Natl Cancer Inst. 1993;85(5):365-376. doi:10.1093/jnci/85.5.365PubMedGoogle ScholarCrossref
17.
Lagergren  P, Fayers  P, Conroy  T,  et al; European Organisation for Research Treatment of Cancer Gastrointestinal and Quality of Life Groups.  Clinical and psychometric validation of a questionnaire module, the EORTC QLQ-OG25, to assess health-related quality of life in patients with cancer of the oesophagus, the oesophago-gastric junction and the stomach.   Eur J Cancer. 2007;43(14):2066-2073. doi:10.1016/j.ejca.2007.07.005PubMedGoogle ScholarCrossref
18.
Kind  P. The EuroQoL instrument: an index of health-related quality of life. In Spiker  B, ed.  Quality of life in pharmacoeconomicsin clinical trials. 2nd ed. Philadelphia: Lippincott-Raven; 1996.
19.
Handforth  C, Clegg  A, Young  C,  et al.  The prevalence and outcomes of frailty in older cancer patients: a systematic review.   Ann Oncol. 2015;26(6):1091-1101 doi:10.1093/annonc/mdu540PubMedGoogle ScholarCrossref
20.
Wildiers  H, Mauer  M, Pallis  A,  et al.  End points and trial design in geriatric oncology research: a joint European organisation for research and treatment of cancer—Alliance for Clinical Trials in Oncology—International Society Of Geriatric Oncology position article.   J Clin Oncol. 2013;31(29):3711-3718. doi:10.1200/JCO.2013.49.6125PubMedGoogle ScholarCrossref
21.
US Food and Drug Administration. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics.  Federal Register. May 16, 2007. https://www.federalregister.gov/documents/2007/05/16/E7-9345/guidance-for-industry-on-clinical-trial-endpoints-for-the-approval-of-cancer-drugs-and-biologics
22.
Knobel  H, Loge  JH, Brenne  E, Fayers  P, Hjermstad  MJ, Kaasa  S.  The validity of EORTC QLQ-C30 fatigue scale in advanced cancer patients and cancer survivors.   Palliat Med. 2003;17(8):664-672.PubMedGoogle Scholar
23.
Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations.   Journal of the American statistical association. 1958 Jun 1;53(282):457-81. doi:10.1080/01621459.1958.10501452Google ScholarCrossref
24.
Cox  DR,.  Regression Models and Life-Tables.   Journal of the Royal Statistical Society. 1972;34 (2): 187–220.Google Scholar
25.
McCullagh  P.,  Regression Models for Ordinal Data.   Journal of the Royal Statistical Society. 1980;42 (2): 109–142. Google Scholar
26.
White  IR, Royston  P, Wood  AM.  Multiple imputation using chained equations: Issues and guidance for practice.   Stat Med. 2011;30(4):377-399. doi:10.1002/sim.4067PubMedGoogle ScholarCrossref
27.
Folprecht  G, Seymour  MT, Saltz  L,  et al.  Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: combined analysis of 2,691 patients in randomized controlled trials.   J Clin Oncol. 2008;26(9):1443-1451. doi:10.1200/JCO.2007.14.0509PubMedGoogle ScholarCrossref
28.
Corre  R, Greillier  L, Le Caër  H,  et al.  Use of a comprehensive geriatric assessment for the management of elderly patients with advanced non–small-cell lung cancer: the phase III randomized ESOGIA-GFPC-GECP 08-02 study.   J Clin Oncol. 2016;34(13):1476-1483. doi:10.1200/JCO.2015.63.5839PubMedGoogle ScholarCrossref
29.
Lichtman  S.M.  Clinical trial design in older adults with cancer—the need for new paradigms.   J. Geriatr. Oncol. 2012;3:368–375. doi:10.1016/j.jgo.2012.03.002Google ScholarCrossref
30.
Hurria  A, Togawa  K, Mohile  SG,  et al.  Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study.   J Clin Oncol. 2011;29(25):3457-3465. doi:10.1200/JCO.2011.34.7625PubMedGoogle ScholarCrossref
31.
Wagner  AD, Grothe  W, Haerting  J, Kleber  G, Grothey  A, Fleig  WE.  Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data.   J Clin Oncol. 2006;24(18):2903-2909. doi:10.1200/JCO.2005.05.0245PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Views 7,564
    Citations 0
    Original Investigation
    May 13, 2021

    Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial

    Author Affiliations
    • 1University of Leeds, Leeds, United Kingdom
    • 2University of Edinburgh, Edinburgh, United Kingdom
    • 3Leeds Teaching Hospitals National Health Service Trust, United Kingdom
    • 4Maidstone and Tunbridge Wells National Health Service Trust, Maidstone, United Kingdom
    • 5University of Dundee, Dundee, United Kingdom
    • 6Bristol Oncology Centre, Bristol, United Kingdom
    • 7Weston Park Cancer Centre, Sheffield, United Kingdom
    • 8Hull University Hospitals National Health Service Trust, Hull, United Kingdom
    • 9Royal United Hospitals Bath, Bath, United Kingdom
    • 10North Cumbria University Hospitals National Health Service Trust, Carlisle, United Kingdom
    • 11Royal Surrey County Hospital National Health Service Foundation Trust, Guildford, United Kingdom
    • 12The Royal Wolverhampton National Health Service Trust, Wolverhampton, United Kingdom
    • 13The Dudley Group National Health Service Foundation Trust, Dudley, United Kingdom
    • 14United Lincolnshire Hospitals National Health Service Trust, Lincoln, United Kingdom
    • 15Mid Yorkshire Hospitals National Health Service Trust, Wakefield, United Kingdom
    • 16The Shrewsbury and Telford Hospital National Health Service Trust, Shrewsbury, United Kingdom
    • 17Betsi Cadwaladr University Local Health Board, Bangor, United Kingdom
    • 18The Christie National Health Service Foundation Trust, Manchester, United Kingdom
    • 19Worcestershire Acute Hospitals National Health Service Trust, Worcester, United Kingdom
    • 20Guys and St Thomas’s National Health Service Foundation Trust, London, United Kingdom
    • 21York Teaching Hospital National Health Service Foundation Trust, Scarborough, United Kingdom
    • 22Calderdale and Huddersfield National Health Service Foundation Trust, Huddersfield, United Kingdom
    • 23University of Oxford, Oxford, United Kingdom
    • 24Maastricht University Medical Center, Maastricht, the Netherlands
    JAMA Oncol. 2021;7(6):869-877. doi:10.1001/jamaoncol.2021.0848
    Key Points

    Question  Do older and/or frail patients with advanced gastroesophageal cancer benefit from less intensive palliative chemotherapy, and can a formal geriatric assessment assist treatment decision-making?

    Findings  This phase 3 randomized clinical trial including 559 patients with advanced gastroesophageal cancer found that reducing the intensity of chemotherapy provided an improved patient experience with no significant detriment in cancer control. Baseline frailty, quality of life, and neutrophil/lymphocyte ratio (an inflammation marker) were predictive of outcome and may contribute to treatment decisions.

    Meaning  Decision-making for older and/or frail patients with advanced cancer can be enhanced using geriatric assessment; such patients generally benefit from reducing the intensity of chemotherapy.

    Abstract

    Importance  Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap.

    Objective  The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making.

    Design, Setting, and Participants  This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty.

    Interventions  There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m2 on day 1, capecitabine 625 mg/m2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care.

    Main Outcomes and Measures  First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival.

    Results  A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes.

    Conclusions and Relevance  This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment.

    Trial Registration  isrctn.org Identifier: ISRCTN44687907

    ×