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Originally published as JCO Early Release 10.1200/JCO.2009.22.0863 on May 26 2009 © 2009 American Society of Clinical Oncology.
Validation of the Royal Marsden Hospital Prognostic Index in Advanced Esophagogastric Cancer Using Individual Patient Data From the REAL 2 StudyDepartment of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
Department of Clinical Research and Development, Royal Marsden Hospital, Surrey, United Kingdom
Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom To the Editor:
In the June 15, 2004, issue of Journal of Clinical Oncology, we reported a multivariate prognostic factor analysis in locally advanced and metastatic esophagogastric (EG) cancer, pooling survival data from 1,080 patients enrolled onto three multicenter, randomized, controlled trials (RCTs).1 Four independent poor prognostic factors were identified: performance status (PS) The REAL 2 study2 was a multicenter RCT with a 2 x 2 factorial design to assess capecitabine in place of protracted venous infusion fluorouracil and oxaliplatin in place of cisplatin in the regimen of epirubicin, cisplatin, and protracted venous infusion fluorouracil for patients with advanced EG cancer. The design and results of this trial—onto which 1,002 patients were enrolled—have been reported. To validate our previously reported prognostic index,1 the prognostic significances of the four independent poor prognostic factors were assessed in the REAL 2 data set. Overall survival was used as the primary end point. Overall survival was calculated from the date of random assignment until death as a result of any cause or censored at last follow-up using the Kaplan-Meier method. Survival end points were updated in October 2008, by which time 911 (91%) of 1,002 patients had died. Multivariate analysis was performed using the Cox proportional hazards regression model. Comparison of survival curves was performed using a log-rank test. A two-tailed P value < 0.01 was considered significant. All trials included in this analysis were approved by the multicenter research and ethics committees, and all patients provided written consent.
Table 1 shows the multivariate prognostic model determined on the basis of complete data for 905 patients in the REAL 2 study.2 Ninety-seven patients were not included because of ineligibility (n = 11) or missing serum alkaline phosphatase data (n = 86). Serum alkaline phosphatase
Restricting our analysis to patients in the good risk group, patients achieving radiologic responses had a highly significantly survival compared with nonresponders (P < .001; Fig 1C) both in the REAL 2 and our original cohorts. The 1- and 2-year survival rates for responders were 70.9% (95% CI, 61.8% to 78.3%) and 27.9% (95% CI, 20.0% to 36.2%), respectively, in the REAL 2 cohorts and 66.7% (95% CI, 57.5% to 75.9%) and 35.5% (95% CI, 25.9% to 45.0%), respectively, in our original pooled analysis. In contrast, for nonresponders, the 1- and 2-year survival rates were only 37.8% (95% CI, 29.7% to 45.9%) and 13.5% (95% CI, 8.3% to 20.1%), respectively, in the REAL 2 cohorts and 35.5% (95% CI, 25.0% to 42.2%) and 11.8% (95% CI, 6.6% to 18.5%), respectively, in our original pooled analysis. Interestingly, even in the good risk group, more than half of the patients were nonresponders to chemotherapy, with poor survival. In contrast, responders enjoyed 2-year survival rates of 28% to 36%, quite notable in patients with advanced inoperable EG cancer; 2-year survival rates are normally expected to be between 10% and 20%.3–5 It is therefore likely that some additional molecular determinants are at play in determining responsiveness to chemotherapy and subsequent survival. Since our original report in 2004,1 authors of two other studies have used their data sets to derive prognostic indexes in advanced gastric adenocarcinoma.6,7 Broadly similar prognostic factors were identified, including PS, serum alkaline phosphatase, peritoneal metastasis, and ascites (as surrogate for peritoneal metastasis). However, neither of these Asian studies included data from patients participating in RCTs. Compared with those in the Asian population, far fewer patients in our study population (mainly Caucasians) would have undergone prior resection. Our current analysis provides a validation of our previously reported Royal Marsden Hospital prognostic index. These factors are readily available in everyday clinical practice. This index could provide a basis for baseline stratification in future RCTs and also allow a more uniform comparison of study populations among trials in a fashion similar to those prognostic indexes used in aggressive non-Hodgkin's lymphoma,8 follicular lymphoma,9 and renal cell carcinoma.10 In conclusion, our Royal Marsden Hospital prognostic index1 in advanced EG cancer has undergone external validation with an independent multicenter RCT data set from the REAL 2 study.2 It is an extremely simple and reproducible prognostic index, determined on the basis of easily available clinical data, for patients with advanced EG cancer. This index may be a useful tool for improving the prognostic assessment of patients. It can also be of help in selecting the most appropriate treatment for individual patients, in comparing clinical trials, and in stratifying patients in prospective trials. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Ian Chau, Roche (C); David Cunningham, Roche (U) Stock Ownership: None Honoraria: Ian Chau, Roche, sanofi-aventis Research Funding: David Cunningham, Roche, sanofi-aventis Expert Testimony: None Other Remuneration: None ACKNOWLEDGEMENT We acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre. REFERENCES
1. Chau I, Norman AR, Cunningham D, et al: Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer—pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 22:2395–2403, 2004. 2. Cunningham D, Starling N, Rao S, et al: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36–46, 2008. 3. Van Cutsem E, Moiseyenko VM, Tjulandin S, 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 24:4991–4997, 2006. 4. Dank M, Zaluski J, Barone 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 19:1450–1457, 2008. 5. Al-Batran SE, Hartmann JT, Probst S, 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 26:1435–1442, 2008. 6. Lee J, Lim T, Uhm JE, et al: Prognostic model to predict survival following first-line chemotherapy in patients with metastatic gastric adenocarcinoma. Ann Oncol 18:886–891, 2007. 7. Kim JG, Ryoo BY, Park YH, et al: Prognostic factors for survival of patients with advanced gastric cancer treated with cisplatin-based chemotherapy. Cancer Chemother Pharmacol 61:301–307, 2008.[CrossRef][Medline] 8. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987–994, 1993. 9. Solal-Céligny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258–1265, 2004. 10. Motzer RJ, Bacik J, Schwartz LH, et al: Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22:454–463, 2004.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2, liver metastasis, peritoneal metastasis, and serum alkaline phosphatase 
