Jan 16, 2015 - Oncology, Florida Cancer Affiliates, Ocala, USA; 4Leeds Institute of Cancer and Pathology and St James's
original articles
Annals of Oncology
Annals of Oncology 26: 715–724, 2015 doi:10.1093/annonc/mdv003 Published online 16 January 2015
Impact of age and medical comorbidity on adjuvant treatment outcomes for stage III colon cancer: a pooled analysis of individual patient data from four randomized, controlled trials D. G. Haller1*, M. J. O’Connell2, T. H. Cartwright3, C. J. Twelves4, E. F. McKenna5, W. Sun6, M. W. Saif7, S. Lee5, G. Yothers8 & H.-J. Schmoll9 1 Abramson Cancer Center at the University of Pennsylvania, Philadelphia; 2National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh; 3Department of Oncology, Florida Cancer Affiliates, Ocala, USA; 4Leeds Institute of Cancer and Pathology and St James’s University Hospital, Leeds, UK; 5US Medical Affairs, Genentech, Inc., South San Francisco; 6University of Pittsburgh Cancer Institute, Pittsburgh; 7Tufts University School of Medicine, Boston; 8Biostatistical Center and University of Pittsburgh Graduate School of Public Health Department of Biostatistics, Pittsburgh, USA; 9University Clinic, Martin Luther University, Halle, Germany
Received 9 July 2014; revised 17 December 2014; accepted 18 December 2014
Background: Adjuvant oxaliplatin plus capecitabine or leucovorin/5-fluorouracil (LV/5-FU) (XELOX/FOLFOX) is the standard of care for stage III colon cancer (CC); however, there is disagreement regarding oxaliplatin benefit in patients aged >70. In most analyses, the impact of medical comorbidity (MC) has not been assessed. Efficacy and safety of adjuvant XELOX/FOLFOX versus LV/5-FU were compared with respect to age and MC using pooled data from four randomized, controlled trials, selected for access to patient-level MC data and including commonly endorsed and utilized regimens. Patients and methods: Individual data from patients with stage III CC in NSABP C-08, XELOXA, X-ACT, and AVANT were pooled, excluding bevacizumab-treated patients. Patients were grouped by treatment, MC (low versus high), or age (1 groups. OS was also significantly improved in all groups. Grade 3/4 serious AE rates were comparable across cohorts and MC scores and higher in patients aged ≥70. Oxaliplatin-relevant grade 3/4 AEs, including neuropathy, were comparable across ages and MC scores. Conclusions: Results further support consideration of XELOX or FOLFOX as standard treatment options for the adjuvant management of stage III CC in all age groups and in patients with comorbidities, consistent with those who were eligible for these clinical trials. Key words: age groups, capecitabine, adjuvant chemotherapy, colon cancer, comorbidity, oxaliplatin
introduction MOSAIC [1, 2], XELOXA [3, 4], and NSABP C-07 [5] showed significant improvements in disease-free survival (DFS) when oxaliplatin was added to a fluoropyrimidine for the adjuvant therapy of colon cancer (CC), regardless of whether the
*Correspondence to: Prof. Daniel G. Haller, Abramson Cancer Center at the University of Pennsylvania, 16 Penn Tower, 3400 Spruce Street, Philadelphia, PA 19104, USA. Tel: +1-610-212-7531; E-mail: daniel.haller@uphs.upenn.edu
fluoropyrimidine was infusional leucovorin/5-fluorouracil (LV/ 5-FU) (FOLFOX), bolus LV/5-FU (FLOX), or oral capecitabine (Xeloda®, F. Hoffmann-La Roche Ltd, Basel, Switzerland) (XELOX). MOSAIC (at a minimum of 6 years’ overall follow-up in patients with stage III CC) [2] and XELOXA [4] also showed an overall survival (OS) benefit for oxaliplatin-treated patients. Adjuvant oxaliplatin-based therapy is standard of care for stage III CC [6, 7], although reports conflict on the degree of oxaliplatin benefits in elderly patients. The ACCENT project’s initial analysis of MOSAIC and NSABP C-07 showed that the
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original articles oxaliplatin treatment effect was preserved in patients aged 1)], and age (1, 335 and 309; NCI ≤1, 1564 and 1567; NCI >1, 357 and 330; age 12 nodes examined. Median duration of follow-up was 36 months in NSABP C-08, 50 months in AVANT, 83 months in XELOXA, and 74 months in X-ACT.
efficacy A DFS benefit was shown for oxaliplatin, independent of age or MC (Figure 1). Significantly fewer patients experienced an event with XELOX/FOLFOX. A significant oxaliplatin treatment benefit was seen in both age cohorts, but was modestly attenuated in patients aged ≥70. MC did not appear to impact the oxaliplatin benefit. The HR of XELOX/FOLFOX versus LV/5-FU was consistent in patients with ≤12 and >12 lymph nodes examined [HR, 0.73 (95% CI 0.61–0.87; P = 0.0005) and HR, 0.78 (95% CI 0.66–0.92; P = 0.0036), respectively].
Volume 26 | No. 4 | April 2015
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original articles
Annals of Oncology
OS results were in line with DFS results (Figure 2). The HRs of XELOX/FOLFOX versus LV/5-FU in patients with ≤12 and >12 lymph nodes examined were 0.76 (95% CI 0.61–0.94; P = 0.0122) and 0.72 (95% CI 0.59–0.88; P = 0.0017), respectively. Multivariable analyses confirmed the unadjusted analyses (Table 2); however, age did not appear to impact the DFS benefit when MC was adjusted for in the same model, while age appeared to impact OS regardless of adjustment. As the HRs for DFS and OS were consistent regardless of the number of lymph nodes examined, this variable was not included in the multivariable model. No significant oxaliplatin-by-age interaction was found (supplementary Table S2). A numerical trend for an interaction with oxaliplatin was exhibited for NCI. In comparison with patients not receiving oxaliplatin, patients aged 1 and receiving oxaliplatin. Analyses were repeated in the entire stage III cohorts, adjusting for bevacizumab use, and showed similar results: DFS HR Table 1. Patient demographics and disease characteristics (intention-to-treat population) Characteristic
LV/5-FU (n = 1921)
Age (years) [17] Median 62.0 Range 22–82 Sex, n (%) [17] Female 890 (46) Male 1031 (54) Race, n (%) [17] Asian/Pacific Islander 134 (7) Black 30 (2) Caucasian/white 1734 (90) Hispanic 14 (1) Other 9 (
