Katrin M Sjoquist1,2, Lindsay A Renfro3, R John Simes1, Niall C Tebbutt4, Stephen Clarke5, Matthew T Seymour6, Richard Adams7, Timothy S Maughan8, Leonard Saltz9, Richard M Goldberg10, Hans-Joachim Schmoll11, Eric Van Cutsem12, Jean-Yves Douillard13, Paulo M Hoff14, Joel Randolph Hecht15, Christophe Tournigand16,17, Cornelis J A Punt18, Miriam Koopman19, Herbert Hurwitz20, Volker Heinemann21, Alfredo Falcone22, Rainer Porschen23, Charles Fuchs24, Eduardo Diaz-Rubio25, Enrique Aranda26, Carsten Bokemeyer27, Ioannis Souglakos28, Fairooz F Kabbinavar15, Benoist Chibaudel29, Jeffrey P Meyers3, Daniel J Sargent3, Aimery de Gramont29, John R Zalcberg30. 1. NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia. 2. Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia. 3. Mayo Clinic, Rochester, MN. 4. Austin Health, Heidelberg, Victoria, Australia. 5. Royal North Shore Hospital, St Leonards, Australia. 6. Cancer Research UK Clinical Centre, Leeds, UK. 7. Cardiff University and Velindre Cancer Centre, Cardiff, UK. 8. St James's Hospital and University of Leeds, Leeds, UK. 9. Memorial Sloan Kettering Cancer Center, New York, NY. 10. West Virginia University Cancer Institute, Morgantown, WV. 11. Martin-Luther-University, Halle, Germany. 12. University Hospital Leuven, Leuven, Belgium. 13. European Society for Medical Oncology (ESMO) Chief Medical Officer (CMO), Institut de Cancérologie de l'Ouest (ICO) René Gauducheau, Saint-Herblain, France. 14. Instituto do Cancer do Estado de Sao Paulo, Universidade de Sao Paolo, Sao Paolo, Brazil. 15. David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA. 16. University of Paris Est Creteil, Paris, France. 17. Assistance Hopitaux Publique de Paris Henri-Mondor Hospital, Creteil, France. 18. Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 19. University Medical Center Utrecht, Utrecht University, the Netherlands. 20. Duke University Medical Center, Durham, NC. 21. University of Munich, Department of Medical Oncology and Comprehensive Cancer Center, Munich, Germany. 22. Department of Oncology, University of Pisa, Pisa, Italy. 23. Klinikum Bremen-Ost Klinik fur Innere Medizin, Bremen, Germany. 24. Dana-Farber Cancer Institute, Boston, MA. 25. Department of Oncology, Hospital Clínico San Carlos, CIBERONC Instituto de Salud Carlos III, Madrid, Spain. 26. Department of Medical Oncology IMIBIC, Reina Sofía Hospital, University of Córdoba, CIBERONC Instituto de Salud Carlos III, Córdoba, Spain. 27. University Hospital, Hamburg-Eppendorf, Germany. 28. University of Crete, Heraklion, Greece. 29. Franco-British Institute, Levallois-Perret, France. 30. School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia.
Abstract
Background: Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database. Methods: Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257). Results: In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted [>50% vs < 50% probability] and actual [yes/no] overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals. Conclusions: The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient-physician communication and balance risk in colorectal cancer trials.
RCT Entities:
Background: Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database. Methods: Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257). Results: In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted [>50% vs < 50% probability] and actual [yes/no] overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals. Conclusions: The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient-physician communication and balance risk in colorectal cancer trials.
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