Chemotherapy for colorectal cancer in the elderly

Table 1 Major studies regarding adjuvant chemotherapy in elderly patients with colon cancer

Ref.	Type of study	No. of total patients	No. of older patients/age (yr)	Endpoint	Outcome [HR (95%CI)]
Iwashyna et al[23]	Population-based cohort study (SEER-Medicare)	3357	3357 (100%)/≥ 70	5-FU vs observation:	OS: 0.73 (0.65-0.82)
				OS
Sargent et al[24]	Pooled analysis of 7 randomized phase III trials	3351	506 (15%)/≥ 70	5-FU/LV vs observation:	(1) TTR: 0.68 (0.60-0.76; P < 0.01)
				(1) TTR	(2) OS: 0.76 (0.68-0.85; P < 0.01)
				(2) OS
Sanoff et al[26]	Retrospective, database analysis (SEER-Medicare, NSYSCR, CanCONS, NCCN)	5489	5489 (100%)/≥ 75	OS in stage III:	(1) 0.60 (0.53-0.68)
				(1) CTx vs no CTx	(2) SEER-Medicare: 0.84 (0.69-1.04)
				(2) Oxaliplatin-based vs non-oxaliplatin regimens	NYSCR: 0.82 (0.51-1.33)
McCleary et al[27]	ACCENT group analysis in stage II/III	14528	2575 (22%)/≥ 70	5-FU/LV or oral 5-FU vs combination regimens: DFS, OS, TTR in (1) older and (2) younger patients	(1) DFS: 1.05 (0.94-1.19; P = 0.09)
					OS: 1.08 (0.95-1.23; P = 0.05)
					TTR: 1.06 (0.93-1.22; P = 0.36)
					(2) DFS: 0.89 (0.80-0.99; P < 0.01)
					TTR: 0.88 (0.79-0.98; P = 0.02)
					OS: 1.08 (0.95-1.23; P = 0.04)1
Yothers et al[28]	Exploratory subset analysis of updated results of NSABP C-07 trial	2409	396 (16%)/≥ 70	5-FU/LV vs oxaliplatin plus 5-FU/LV:
				(1) DFS	(1) DFS: 1.03 (0.77-1.36; P = 0.87)
				(2) OS	(2) OS: 1.18 (0.86-1.62; P = 0.30)
Tournigand et al[29]	Subgroup analysis of MOSAIC trial for stage II disease and elderly patients	2246	315 (14%)/70-75	5-FU/LV vs FOLFOX4:
				(1) DFS	(1) DFS: 0.93 (0.64-1.35; P = 0.73)
				(2) OS	(2) OS: 1.10 (0.73-1.65; P = 0.66)

¹The benefit of adding oxaliplatin was restricted to patients younger than 70 years for OS. CTx: Chemotherapy; DFS: Disease-free survival; 5-FU/LV: 5-Fluorouracil/leucovorin; OS: Overall survival; TTR: Time to recurrence.

Table 2 Major studies regarding palliative therapy in elderly patients with advanced/metastatic colorectal cancer

Ref.	Type of study	No. of total patients	No. of older patients/age (yr)	Endpoint	Outcome
Folprecht et al[43]	Retrospective analysis of data from 22 European trials	3825	629 (16%)/≥ 70	5-FU-based CTx in older vs younger patients
				(1) ORR	(1) ORR: 23.9% vs 21.1%; P = 0.14
				(2) PFS	(2) PFS: 5.5 mo vs 5.3 mo; P = 0.01
				(3) OS	(3) OS: 10.8 mo vs 11.3 mo; P = 0.31
Folprecht et al[49]	Pooled analysis of data from four randomized phase III trials	2691	559 (22%)/≥ 70	Irinotecan/5-FU vs 5FU as first-line CTx in younger and older patients:	Improved with irinotecan-based CTx:
					(1) ORR:
				(1) ORR	younger, 46.6% vs 29.0%; P < 0.01
				(2) PFS	elderly, 50.5% vs 30.3%; P < 0.01
				(3) OS	(2) PFS:
					younger, HR = 0.77 (95%CI: 0.70-0.85; P < 0.01)
					elderly, HR = 0.75 (95%CI: 0.61-0.90; P < 0.01)
					(3) OS:
					younger, HR = 0.83 (95%CI: 0.75-0.92; P < 0.01)
					elderly, HR = 0.87 (95%CI: 0.72-1.05; P = 0.15)
Jackson et al[50] (BICC-C trial)	Randomized phase III in a 3-by-2 design	430	117 (21%)/> 70	Irinotecan + fluoropyrimidine at period 1 and irinotecan + 5-FU/LV + bevacizumab at period 2 in the older vs younger	Period 1:
					(1) PFS: 7.5 mo vs 6.6 mo, HR = 0.98 (95%CI: 0.74-1.29)
					(2) OS: 21.2 mo vs 19.0 mo
				(1) PFS	Period 2:
				(2) OS	(1) PFS: 10.6 mo vs 7.6 mo; P = 0.14
					(2) OS: 19.4 mo vs 25.1 mo
Seymour et al[51] (MRC FOCUS2)	Open-label, multi-center, randomized phase III	438	199 (43%)/≥ 75	a. IV infusion 5-FU/LV	(1) PFS (addition of oxaliplatin vs no addition): 5.8 mo vs 4.5 mo, HR = 0.84 (95%CI: 0.69-1.01; P = 0.07)
				b. Oxaliplatin + 5-FU	(2) Capecitabine did not improve QoL
				c. Oxaliplatin + capecitabine
				d. Capecitabine
				(1) PFS (a vs b and c vs d)
				(2) QoL with capecitabine instead of 5-FU
Figer et al[52] (OPTIMOX1 study)	Exploratory cohort	620	37 (6%)/76-80	FOLFOX4 until PD or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (1) PFS and (2) OS in the older vs younger	(1) PFS: 9.0 mo vs 9.0 mo; P = 0.63
					(2) OS: 20.7 mo vs 20.2 mo; P = 0.57
					(3) AEs ≥ grade 3: neutropenia, 41% vs 24%; P = 0.03, neurotoxicity, 22% vs 11%; P = 0.06
Cassidy et al[53]	Retrospective pooled analysis (AVF2107g, AVF219g, NO16966, E3200 trials)	3007	1142 (38%)/≥ 65	5-FU/LV-based CTx ± bevacizumab	(1) ≥ 65 yr: 9.3 mo (+ bevacizumab) vs 6.9 mo, HR = 0.58 (95%CI: 0.49-0.68; P < 0.01)
				(1) PFS	≥ 70 yr: 9.2 mo (+ bevacizumab) vs 6.4 mo, HR = 0.54 (95%CI: 0.44-0.66; P < 0.01)
				(2) OS	(2) ≥ 65 yr: 17.9 mo (+ bevacizumab) vs 15 mo, HR = 0.85 (95%CI: 0.74-0.97; P = 0.02)
					≥ 70 yr: 17.4 mo (+ bevacizumab) vs 14.1 mo, HR = 0.7 (95%CI: 0.66-0.93; P < 0.01)
Cunningham et al[55] (AVEX trial)	Open-label, multi-center, randomized phase III	280	280 (100%)/≥ 70	(1) PFS	(1) PFS: 9.1 mo (+ bevacizumab) vs 5.1 mo, HR = 0.53 (95%CI: 0.41-0.61; P < 0.01)
				a. Capecitabine (n = 140)	(2) AEs ≥ grade 3: 40% (+ bevacizumab) vs 22%
				b. Capecitabine + bevacizumab (n = 140)
				(2) Assessment of treatment-related AEs
Sastre et al[59] (Spanish TTD Group Study)	Phase II	66	66 (100%)/≥ 70	Cetuximab + capecitabine as first-line therapy	(1) ORR: 31.8% (48.3% in w-KRAS vs 20.7% in m-KRAS; P = 0.027)
				(1) ORR	(2) PFS: 7.1 mo, OS: 16.1 mo
				(2) PFS, OS	(3) AEs ≥ grade 3: paronychia (29.6%), rash (29.6%)
				(3) Safety

AEs: Adverse events; CTx: Chemotherapy; 5-FU: 5-Fluorouracil; IV: Intravenous; m-KRAS: Mutant-type KRAS; ORR: Overall response rate; OS: Overall survival; PD: Progression of disease; PFS: Progression-free survival; QoL: Quality of life; w-KRAS: Wild-type KRAS.