Richard Adams1, Kaitlyn Goey2, Benoist Chibaudel3, Miriam Koopman4, Cornelis Punt5, Dirk Arnold6, Axel Hinke7, Susanna Hegewisch-Becker8, Aimery de Gramont9, Roberto Labianca10, Eduardo Diaz Rubio11, Kjell Magne Tveit12, Harpreet Wasan13, Richard Kaplan14, Louise Brown15, Tim Maughan16, David Fisher17. 1. Cardiff University and Velindre Cancer Centre, United Kingdom. Electronic address: Richard.adams@wales.nhs.uk. 2. University Medical Center, Utrecht, the Netherlands. Electronic address: k.k.h.goey@umcutrecht.nl. 3. Institut Hospitalier Franco-Britannique, Paris, France. Electronic address: benoist.chibaudel@ihfb.org. 4. University Medical Center, Utrecht, the Netherlands. Electronic address: M.Koopman-6@umcutrecht.nl. 5. Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht University, the Netherlands. Electronic address: C.J.A.Punt@umcutrecht.nl. 6. Asklepios Tumorzentrum Hamburg, Germany and Instituto CUF de Oncologia, Lisbon, Portugal. Electronic address: dirk.arnold@arcor.de. 7. CCRC, Düsseldorf, Germany. Electronic address: axel.hinke@hotmail.de. 8. Onkologische Schwerpunktpraxis, Hamburg, Germany. Electronic address: hegewisch@t-online.de. 9. Hôpital Saint-Antoine, Paris, France. Electronic address: aimery.de-gramont@sat.aphp.fr. 10. Ospedali Riuniti, Bergamo, Italy. Electronic address: rlabian@tin.it. 11. Hospital Clínico San Carlos, Madrid, Spain. Electronic address: ediazrg@seom.org. 12. Oslo University Hospital, Norway. Electronic address: kjell.magne.tveit@ous-hf.no. 13. Imperial College Healthcare NHS Trust, United Kingdom. Electronic address: h.wasan@imperial.ac.uk. 14. MRC Clinical Trials Unit at UCL, United Kingdom. Electronic address: r.kaplan@ucl.ac.uk. 15. MRC Clinical Trials Unit at UCL, United Kingdom. Electronic address: l.brown@ucl.ac.uk. 16. University of Oxford, United Kingdom. Electronic address: tim.maughan@oncology.ox.ac.uk. 17. MRC Clinical Trials Unit at UCL, United Kingdom. Electronic address: d.fisher@ucl.ac.uk.
Abstract
BACKGROUND: Intermittent systemic anti-cancer therapy in patients with advanced colorectal cancer (aCRC) may improve quality of life without compromising overall survival (OS). We aimed to use individual patient data meta-analysis (IPDMA) from multiple randomised controlled trials evaluating intermittent strategies to inform clinical practice. We also aimed to validate whether thrombocytosis as a predictive biomarker identified patients with significantly reduced OS receiving a complete treatment break. PATIENTS AND METHODS: An IPDMA of intermittent strategy impact on survival was undertaken, including all relevant trials in which data were available. Intermittent strategies were classified into two groups: a planned stopping of all therapy ("treatment break strategy"; 6 trials; 2,907 patients) or to the same treatment omitting oxaliplatin ("maintenance strategy"; 3 trials; 1,271 patients). The primary analysis sample was of patients successfully completing induction therapy. Additionally, a pre-planned analysis of the predictive value of thrombocytosis on survival under a continuous versus an intermittent strategy was undertaken. RESULTS: All trials had comparable inclusion criteria. The overall IPDMA of intermittent therapy versus continuous therapy demonstrated no detriment in OS (HR = 1.03 [95% CI 0.93-1.14]), whether from complete break (HR 1.04 [95% CI 0.87-1.26]) or maintenance strategies (HR 0.99 [95% CI 0.87-1.13]). Thrombocytosis was confirmed as a marker of poor prognosis in aCRC, but did not predict for OS detriment from treatment break strategies (interaction HR = 0.97 [95% CI 0.66-1.40] compared to continuous therapy). CONCLUSION: The highest levels of evidence from this IPDMA indicate no detriment in survival for patients receiving an intermittent therapy strategy, either for maintenance or complete break strategies. Although, thrombocytosis is confirmed as a marker of poor prognosis, it is not predictive of poor outcome for patients treated with intermittent therapy. An intermittent chemotherapy strategy can therefore be applied irrespective of baseline platelet count and does not result in inferior OS compared to continuous chemotherapy.
BACKGROUND: Intermittent systemic anti-cancer therapy in patients with advanced colorectal cancer (aCRC) may improve quality of life without compromising overall survival (OS). We aimed to use individual patient data meta-analysis (IPDMA) from multiple randomised controlled trials evaluating intermittent strategies to inform clinical practice. We also aimed to validate whether thrombocytosis as a predictive biomarker identified patients with significantly reduced OS receiving a complete treatment break. PATIENTS AND METHODS: An IPDMA of intermittent strategy impact on survival was undertaken, including all relevant trials in which data were available. Intermittent strategies were classified into two groups: a planned stopping of all therapy ("treatment break strategy"; 6 trials; 2,907 patients) or to the same treatment omitting oxaliplatin ("maintenance strategy"; 3 trials; 1,271 patients). The primary analysis sample was of patients successfully completing induction therapy. Additionally, a pre-planned analysis of the predictive value of thrombocytosis on survival under a continuous versus an intermittent strategy was undertaken. RESULTS: All trials had comparable inclusion criteria. The overall IPDMA of intermittent therapy versus continuous therapy demonstrated no detriment in OS (HR = 1.03 [95% CI 0.93-1.14]), whether from complete break (HR 1.04 [95% CI 0.87-1.26]) or maintenance strategies (HR 0.99 [95% CI 0.87-1.13]). Thrombocytosis was confirmed as a marker of poor prognosis in aCRC, but did not predict for OS detriment from treatment break strategies (interaction HR = 0.97 [95% CI 0.66-1.40] compared to continuous therapy). CONCLUSION: The highest levels of evidence from this IPDMA indicate no detriment in survival for patients receiving an intermittent therapy strategy, either for maintenance or complete break strategies. Although, thrombocytosis is confirmed as a marker of poor prognosis, it is not predictive of poor outcome for patients treated with intermittent therapy. An intermittent chemotherapy strategy can therefore be applied irrespective of baseline platelet count and does not result in inferior OS compared to continuous chemotherapy.
Authors: Dominik Paul Modest; Meinolf Karthaus; Stefan Fruehauf; Ullrich Graeven; Lothar Müller; Alexander Otto König; Ludwig Fischer von Weikersthal; Karel Caca; Albrecht Kretzschmar; Eray Goekkurt; Siegfried Haas; Annika Kurreck; Arndt Stahler; Swantje Held; Armin Jarosch; David Horst; Anke Reinacher-Schick; Stefan Kasper; Volker Heinemann; Sebastian Stintzing; Tanja Trarbach Journal: J Clin Oncol Date: 2021-09-17 Impact factor: 44.544
Authors: Jenny F Seligmann; David J Fisher; Louise C Brown; Richard A Adams; Janet Graham; Philip Quirke; Susan D Richman; Rachel Butler; Enric Domingo; Andrew Blake; Emma Yates; Michael Braun; Fiona Collinson; Rob Jones; Ewan Brown; Emma de Winton; Timothy C Humphrey; Mahesh Parmar; Richard Kaplan; Richard H Wilson; Matthew Seymour; Timothy S Maughan Journal: J Clin Oncol Date: 2021-09-18 Impact factor: 50.717
Authors: Richard A Adams; David J Fisher; Janet Graham; Jenny F Seligmann; Matthew Seymour; Richard Kaplan; Emma Yates; Mahesh Parmar; Susan D Richman; Philip Quirke; Rachel Butler; Ewan Brown; Fiona Collinson; Stephen Falk; Harpreet Wasan; Kai-Keen Shiu; Gary Middleton; Leslie Samuel; Richard H Wilson; Louise C Brown; Timothy S Maughan Journal: J Clin Oncol Date: 2021-09-13 Impact factor: 50.717