Between January 2012 and December 2016, 987 patients were newly diagnosed with CRC. Of them, 702 patients with localized colorectal cancer and 25 patients who received radical R0 surgery were excluded. Finally, 260 patients with mCRC were evaluated. We stratified the patients into two groups according to age at the time of diagnosis: the super-elderly group (n = 43, ≥80 years) and the younger group (n = 217, <80 years).
Characteristics of the participants
The clinical and pathological characteristics of the patients (n = 260) are presented in Table 1.
Table 1 Baseline Characteristics of patients diagnosed with mCRC, separated according to those aged <80 and ≥80 years old
|
Younger group (n = 217)
|
Super-elderly group (n = 43)
|
Variables
|
n or median (range)
|
n or median (range)
|
P value
|
Age (years)
|
68 (27–79)
|
83 (80–93)
|
<0.0001
|
Male sex (%)
|
135 (62%)
|
21 (49%)
|
0.11
|
PS score of 0–1
|
197 (91%)
|
28 (65%)
|
<0.0001
|
Tumor located on the right side
|
83 (38%)
|
11 (26%)
|
0.12
|
Albumin level (g/dL)
|
3.8
|
3.7
|
0.21
|
BMI
|
22.9
|
21.4
|
0.03
|
PNI
|
46.2
|
42.6
|
0.04
|
Creatinine level (mg/dL)
|
0.77
|
0.84
|
0.1
|
CEA level (ng/mL)
|
20.1
|
11.4
|
0.04
|
RAS mutation type
|
78 (46%)
|
7 (54%)
|
0.58
|
Poorly differentiated cancer and signet-ring cell carcinoma
|
14 (6%)
|
9 (21%)
|
<0.0001
|
The proportion of patients with good PS was lower in the super-elderly group than in the younger group (65% vs. 91%; P < 0.0001). The BMI (21.4 vs. 22.9; P = 0.03) and PNI (42.6 vs. 46.2; P = 0.04) of the super-elderly group were lower than those of the younger group. The creatinine and albumin levels were not significantly different between the two groups. The proportion of patients with poorly differentiated cancer and signet-ring cell carcinoma was higher in the super-elderly group than in the younger group (21% vs. 6%; P < 0.0001).
Treatment
No significant differences were found between the two groups in terms of the resection rate of primary and metastatic tumors. The number of patients who received chemotherapy in the super-elderly group was significantly lower than that in the younger group (28% vs. 84%; P < 0.0001).
These data are summarized in Table 2.
Table 2 Treatments administered to patients with mCRC, separated according to those <80 and ≥80 years old
|
Younger group (n = 217)
|
Super-elderly group (n = 43)
|
Variable
|
n (range)
|
n (range)
|
P value
|
Resction of primary tumor
|
152 (70%)
|
32 (74%)
|
0.7
|
Chemotherapy
|
182 (84%)
|
12 (28%)
|
<0.0001
|
No treatment
|
34 (16%)
|
31 (72%)
|
<0.0001
|
Chemotherapy
Only 12/43 patients (28%) in the super-elderly group received chemotherapy, and the prescribed chemotherapeutic agents were capecitabine, 5-FU/LV, oxaliplatin, bevacizumab, and panitumumab. Of them, 10 (83%) received combination chemotherapy, and the most common (n = 9, 75%) combination was a fluoropyrimidine plus oxaliplatin, with or without a molecular-targeted agent. Of the 12 patients who had first-line palliative chemotherapy, only 5 (42%) received chemotherapy for >6 months, although most patients in the younger group (n = 152, 84%) received chemotherapy for >6 months. In addition, only 5 (42%) patients and only 1 (8%) patient in the super-elderly group received second-line and third-line chemotherapy, respectively. Meanwhile, most (128) patients in the younger group (70%) and 78 (43%) patients received second-line and third-line chemotherapy, respectively. Table 3 presents the summary of the chemotherapy regimens.
Table 3 Chemotherapy regimens received by patients in the first-, second-, and third-line treatments separated according to those aged <80 and ≥80 years
|
First-line treatment
|
|
Second-line treatment
|
|
Third-line treatment
|
|
No. of patients (%)
|
|
No. of patients (%)
|
|
No. of patients (%)
|
Regimen
|
<80 years
|
≥80 years
|
|
<80 years
|
≥80 years
|
|
<80 years
|
≥80 years
|
Single-agent chemotherapy
|
3 (2)
|
2 (17)
|
|
12 (9)
|
2 (40)
|
|
59 (76)
|
0
|
Capecitabine
|
2
|
1
|
|
1
|
-
|
|
-
|
-
|
5FU
|
-
|
-
|
|
1
|
-
|
|
-
|
-
|
TS1
|
-
|
-
|
|
3
|
-
|
|
-
|
-
|
Panitumumab
|
-
|
1
|
|
1
|
-
|
|
2
|
-
|
TAS102
|
1
|
-
|
|
3
|
-
|
|
29
|
-
|
Regorafenib
|
-
|
-
|
|
3
|
2
|
|
28
|
-
|
Combination chemotherapy
|
179 (98)
|
10 (83)
|
|
116 (91)
|
3 (60)
|
|
19 (24)
|
1 (100)
|
CapOX
|
21
|
2
|
|
1
|
-
|
|
-
|
-
|
CapOX+BV
|
56
|
5
|
|
1
|
-
|
|
-
|
-
|
Capecitabine+BV
|
1
|
1
|
|
-
|
1
|
|
-
|
-
|
FOLFOX
|
13
|
1
|
|
4
|
-
|
|
2
|
-
|
FOLFOX+BV
|
15
|
-
|
|
8
|
-
|
|
4
|
-
|
FOLFOX+EGFR mAb
|
40
|
1
|
|
6
|
-
|
|
-
|
-
|
FOLFIRI
|
2
|
-
|
|
17
|
1
|
|
2
|
-
|
FOLFIRI+BV
|
15
|
-
|
|
47
|
-
|
|
3
|
-
|
FOLFIRI+RAM
|
-
|
-
|
|
5
|
-
|
|
6
|
-
|
FOLFIRI+EGFR mAb
|
12
|
-
|
|
23
|
-
|
|
2
|
-
|
FOLFOXIRI
|
3
|
-
|
|
2
|
-
|
|
-
|
-
|
FOLFOXIRI+BV
|
1
|
-
|
|
-
|
-
|
|
-
|
-
|
Other
|
-
|
-
|
|
2
|
1
|
|
-
|
1
|
Patients who received chemotherapy had significantly better PS than those who did not receive it in the super-elderly group (100% vs. 34%; P = 0.006). Albumin levels and PNI of patients who received chemotherapy were higher than those who did not receive it in the super-elderly group (4.1 vs. 3.4 g/dl; P = 0.005 and 48.9 vs. 42.1; P = 0.009).
Adverse events
Grade 3 or 4 adverse events in first-line chemotherapy were reported in 31.9% and 66.7% of patients in the younger and super-elderly groups, respectively (P = 0.02). The most frequent adverse events ≥grade 3 in the younger group were neutropenia, with grade 3 or 4 neutropenia reported in 14.3% of patients; meanwhile, the most frequent adverse events ≥grade 3 in the super-elderly group were fatigue, with grade 3 or 4 fatigue reported in 33.3% of patients. Meanwhile, super-elderly patients receiving mono-chemotherapy (n = 2) did not report any grade 3 or 4 adverse events.
These data are summarized in Table4.
Table 4 Adverse events, separated according to those <80 and ≥80 years old
|
Younger group (n = 182)
|
Super-elderly group (n = 12)
|
Variable
|
n (range)
|
n (range)
|
P value
|
Any toxicity Grade≥3
|
58 (31.9%)
|
8 (66.7%)
|
0.02
|
fatigue Grade≥3
|
3 (1.6%)
|
4 (33.3%)
|
0.003
|
Anorexia Grade≥3
|
6 (3.2%)
|
2 (16.7%)
|
0.08
|
Diarrhoea Grade≥3
|
1 (0.5%)
|
0 (0%)
|
1
|
Neurosensory Grade≥3
|
17 (9.3%)
|
0 (0%)
|
0.61
|
hand-foot syndrome Grade≥3
|
2 (1.1%)
|
0 (0%)
|
1
|
Neutropenia Grade≥3
|
26 (14.3%)
|
1 (8.3%)
|
1
|
Prognostic factors of OS
The results of the univariate and multivariate analyses of OS in the super-elderly and younger groups are shown in Table 5a and 5b, respectively. The univariate analysis in the super-elderly group (Table 5a) revealed that a PS score of 2–4, PNI ≤35, CEA level ≥5 ng/mL, and resection of primary tumors were significantly associated with OS. Based on the multivariate analysis, a CEA level ≥5 ng/mL (hazard ratio: 2.27; 95% CI: 1.09–4.74; P = 0.03) and PNI ≤35 (hazard ratio: 8.57; 95% CI: 2.63–27.9; P = 0.0003) were independently associated with poor OS.
The multivariate analysis in the younger group (Table 5b) identified resection of primary tumors (hazard ratio: 0.46; 95% CI: 0.32–0.66; P < 0.0001) and chemotherapy (hazard ratio: 0.22; 95% CI: 0.13–0.38; P < 0.0001) as significant independent good prognostic factors.
In contrast, OS was significantly reduced when the albumin level was ≤3.5 g/dL (hazard ratio: 1.62; 95% CI: 1.14–2.30; P = 0.007).
These data are summarized in Table5a and 5b
Table 5a Analysis of prognostic factors in the super-elderly group
|
Univariate analysis
|
|
Multivariate analysis
|
|
Variables
|
Hazard ratio (95% CI)
|
P value
|
Hazard ratio (95% CI)
|
P value
|
Sex (male/female)
|
0.85 (0.43–1.66)
|
0.63
|
|
|
PS score of 2–4
|
2.07 (0.99–4.29)
|
0.052
|
0.98 (0.35–2.75)
|
0.98
|
Tumor located on the right side
|
1.23 (0.59–2.57)
|
0.58
|
|
|
Albumin level ≤ 3.5 g/dL
|
1.56 (0.80–3.07)
|
0.19
|
|
|
BMI ≤18.5
|
1.74 (0.66–4.54)
|
0.26
|
|
|
PNI ≤35
|
6.15 (2.00–18.9)
|
0.001
|
8.57(2.63–27.9)
|
0.0003
|
Creatinine level ≥ 1.5 mg/dL
|
1.78 (0.61–5.20)
|
0.29
|
|
|
CEA level ≥5 ng/mL
|
1.85 (0.91–3.77)
|
0.089
|
2.27 (1.09–4.74)
|
0.03
|
RAS mutation type
|
1.20 (0.36–4.02)
|
0.76
|
|
|
Poorly differentiated cancer and signet-ring cell carcinoma
|
0.64 (0.28–1.51)
|
0.3
|
|
|
Resection of primary tumor
|
0.41 (0.18–0.92)
|
0.026
|
0.45 (0.20–1.04)
|
0.06
|
Chemotherapy
|
0.68 (0.32–1.47)
|
0.33
|
|
|
Table 5b Analysis of prognostic factors in the younger group
|
Univariate analysis
|
|
Multivariate analysis
|
|
Variables
|
Hazard ratio (95% CI)
|
P value
|
Hazard ratio (95% CI)
|
P value
|
Sex (male/female)
|
1.09 (0.77–1.54)
|
0.63
|
|
|
PS score of 2–4
|
3.40 (1.82–6.38)
|
<0.0001
|
1.15 (0.57–2.34)
|
0.69
|
Tumor located on the right side
|
1.03 (0.73–1.46)
|
0.87
|
|
|
Albumin level ≤3.5 g/dL
|
1.61 (1.14–2.27)
|
0.007
|
1.62 (1.14–2.30)
|
0.007
|
BMI ≤18.5
|
1.15 (0.66–2.00)
|
0.62
|
|
|
PNI ≤35
|
1.37 (0.83–2.25)
|
0.22
|
|
|
Creatinine level ≥1.5 mg/dL
|
0.63 (0.26–1.55)
|
0.32
|
|
|
CEA level ≥5 ng/mL
|
1.29 (0.85–1.96)
|
0.23
|
|
|
RAS mutation type
|
1.08 (0.74–1.58)
|
0.69
|
|
|
Poorly differentiated cancer and signet-ring cell carcinoma
|
0.74 (0.37–1.45)
|
0.38
|
|
|
Resection of primary tumor
|
0.46 (0.33–0.66)
|
<0.0001
|
0.46 (0.32–0.66)
|
<0.0001
|
Chemotherapy
|
0.23 (0.14–0.39)
|
<0.0002
|
0.22 (0.13–0.38)
|
<0.0001
|
Survival
During the follow-up period, 35 (81%) patients in the super-elderly group and 140 (65%) in the younger group died. There were significant differences in terms of the median OS between the two groups (14.0 vs. 25.8 months; P < 0.0001). The 1- and 3-year OS in the in the younger group were 79% and 36% respectively, and those in the super-elderly group were 54% and 14%, respectively. These data are summarized in Figure 1.
The median OS of patients in super-elderly patients was significantly different between patients with PNI ≤35 and PNI >35 (3.4 months vs 15.4 months, P = 0.001). These data are summarized in Figure 2.
The median OS of patients in the super-elderly group who received chemotherapy was 18.5 months, and that of patients in the younger group was 28.8 months, and the difference in median OS between the two groups was close to significance (P = 0.057). These data are summarized in Figure 3.
There were no significant differences in the median OS between those who received chemotherapy and those did not receive it in the super-elderly group; however, OS of patients who received chemotherapy tended to be longer (18.5 vs. 8.4 months; P = 0.33), and a similar trend was noted for patients with PNI > 35 (18.5 vs. 12.9 months; P = 0.64). These data are summarized in Figure 4a and 4b.