Patient characteristics
There were 168 patients with high risk (T4 and/or N2) and 239 with low risk (T1-3/N1) stage III colon cancer included in this study (Table 1). In the high-risk group, patients aged 60 years or older accounted for more than half of the cases. Most patients were male, two-thirds were non-Hispanic Whites, and over a half were privately insured (56%). Sixty percent of patients resided in urban areas, 71% lived in low poverty areas, 78% were in high education areas, 51% were in high married census tracts, and more than 70% were from the states of Florida, Louisiana and North Carolina. More than half of patients had tumor size greater than 4 cm (57%). Most patients had 12 or greater lymph nodes examined (92%), well or moderately differentiated tumors (65%), no comorbid conditions (67%), cancer located in proximal colon (62%), and colon cancer as the only cancer (82%). The mean number of positive lymph nodes was 6. About 80% of the patients were alive at the end of follow up, with the mean follow up time of 35 months. Among deceased patients with a known cause of death, 16% died from non-colon cancer causes.
Table 1
Demographic and clinical characteristics of patients with stage III colon cancer by different risk groups
Characteristics | High risk (T4 and/or N2) | Low risk (T1-3/N1) |
N (%) | N (%) |
All | | 168 | 239 |
Age at diagnosis | | |
| < 50 | 31 (18.5) | 48 (20.1) |
| 50–59 | 37 (22.0) | 60 (25.1) |
| 60–69 | 56 (33.3) | 75 (31.4) |
| ≥ 70 | 44 (26.2) | 56 (23.4) |
Sex | | | |
| Male | 92 (54.8) | 126 (52.7) |
| Female | 76 (45.2) | 113 (47.3) |
Race/Ethnicity | | |
| Non-Hispanic white | 113 (67.3) | 161 (67.4) |
| Non-Hispanic black | 31 (18.5) | 44 (18.4) |
| Hispanics | 21 (12.5) | 29 (12.1) |
| Other | 3 (1.8) | 5 (2.1) |
Insurance coverage | | |
| Private | 94 (56.0) | 130 (54.4) |
| Medicare/ Other public | 48 (28.6) | 71 (29.7) |
| Medicaid | 15 (8.9) | 21 (8.8) |
| Not insured | 9 (5.4) | 16 (6.7) |
| Unknown | 2 (1.2) | 1 (0.4) |
Census tract residence | | |
| 100% Urban | 101 (60.1) | 126 (52.7) |
| 100% Rural | 10 (6.0) | 16 (6.7) |
| Mixed | 55 (32.7) | 95 (39.8) |
| Unknown | 2 (1.2) | 2 (0.8) |
Census tract poverty | | |
| < 20% | 120 (71.4) | 184 (77.0) |
| ≥ 20% | 45 (26.8) | 53 (22.2) |
| Unknown | 3 (1.8) | 2 (0.8) |
Census tract education | | |
| < 25% (high) | 131 (78.0) | 186 (77.8) |
| ≥ 25% (low) | 35 (20.8) | 51 (21.3) |
| Unknown | 2 (1.2) | 2 (0.8) |
Census tract marital status | | |
| ≤ 50% married | 81 (48.2) | 104 (43.5) |
| > 50% married | 85 (50.6) | 133 (55.7) |
| Unknown | 2 (1.2) | 2 (0.8) |
State of residence | | |
| AK | 2 (1.2) | 1 (0.4) |
| CO | 21 (12.5) | 42 (17.6) |
| FL | 48 (28.6) | 54 (22.6) |
| ID | 7 (4.2) | 15 (6.3) |
| LA | 45 (26.8) | 64 (26.8) |
| NC | 38 (22.6) | 58 (24.3) |
| NH | 6 (3.6) | 4 (1.7) |
| RI | 1 (0.6) | 1 (0.4) |
Tumor size (cm) | | |
| ≤ 4 | 69 (41.1) | 130 (54.4) |
| > 4 | 96 (57.1) | 97 (40.6) |
| Unknown | 3 (1.8) | 12 (5.0) |
Lymph nodes examined | | |
| < 12 | 13 (7.7) | 34 (14.2) |
| ≥ 12 | 155 (92.3) | 205 (85.8) |
Tumor grade | | |
| Well/moderately differentiated | 109 (64.9) | 194 (81.2) |
| Poor/Undifferentiated | 58 (34.5) | 39 (16.3) |
| Unknown | 1 (0.6) | 6 (2.5) |
Charlson Comorbidity Index | | |
| 0 | 113 (67.3) | 176 (73.6) |
| ≥ 1 | 55 (32.7) | 63 (26.4) |
Anatomic subsite | | |
| Proximal colon (C18.0, C18.2-C18.5) | 104 (61.9) | 141 (59.0) |
| Distal colon (C18.6-C18.7) | 63 (37.5) | 92 (38.5) |
| Other (C18.8-C18.9) | 1 (0.6) | 6 (2.5) |
Colon cancer classification | | |
| Only with colon cancer | 138 (82.1) | 197 (82.4) |
| Multiple cancers, first primary colon | 12 (7.1) | 16 (6.7) |
| Multiple cancers, non-first colon | 18 (10.7) | 26 (10.9) |
Number of positive lymph nodes | 6.4 ± 4.5 | 2.0 ± 1.7 |
Vital status | | |
| Alive | 135 (80.4) | 210 (87.9) |
| from colon cancer | 21 (12.5) | 15 (6.3) |
| Death from other causes | 4 (2.4) | 8 (3.3) |
| Death reasons unknown | 8 (4.8) | 6 (2.5) |
Follow up time among alive patients (mean ± standard deviation) | 34.6 ± 21.9 | 35.0 ± 22.8 |
The low-risk stage III colon cancer cases had similar distributions of sociodemographic characteristics as those high-risk stage III colon cancer. However, their clinical characteristics were less advanced and aggressive compared to high-risk stage III colon cancer cases; the majority of low-risk patients had tumor size less than or equal to 4 cm (54%), a higher percentage of well or moderately differentiated tumor grade (81%), no comorbid conditions (74%), slightly lower percentage of 12 or greater lymph nodes examined (86%) and cancer located in proximal colon (59%). The mean number of positive lymph nodes was 2. There were 88% of the patients alive at the end of follow up, with the mean follow up time of 35 months. Among deceased patients with a known cause of death, 35% died from competing risks.
Regression analysis for all-cause and cause-specific mortality in high-risk stage III colon cancer patients
Kaplan-Meier crude survival curves and cumulative incidence function (CIF) plots showed that among the high-risk stage III colon cancer cases, those receiving lower RDI had statistically significantly (borderline significant in CIF plots for cutoff point of 65%) lower overall survival probability and a higher risk of colon-cancer death than those receiving higher RDI, when the cut off points were 55%, 60%, 65% (Fig. 1. and Fig. 2). The survival probability and risk of death were not statistically significantly different for other RDI comparisons: RDI < 70% vs. RDI ≥ 70%, RDI < 75% vs. RDI ≥ 75%, and RDI < 80% vs. RDI ≥ 80%. The univariable analysis showed consistent results with hazard ratios (Supplemental Material 3).
In multivariable analysis, age, sex, race/ethnicity, insurance coverage (private insurance vs. non-private insurance), number of positive lymph nodes, tumor grade, Charlson comorbidity index, anatomic subsite and colon cancer classification (colon as the only cancer vs. multiple primary cancers), were included as confounders or significant factors for cancer survival (Table 2). Compared to the higher RDI groups, the lower RDI groups had a higher risk of overall mortality: RDI < 65% vs. RDI ≥ 65% (HR = 2.72 (1.22, 6.04); HR = 2.87 (1.30, 6.36) for RDI < 60% vs. RDI ≥ 60%; and HR = 3.90 (1.68, 9.08) for RDI < 55% vs. RDI ≥ 55%). A similar trend was found in cause-specific mortality. In the sensitivity analysis which included cases with colon cancer as the only or the first primary tumor, results followed a similar pattern (data not shown). The survival probability and risk of death showed no statistically significant difference for RDI comparisons: RDI < 70% vs. RDI ≥ 70%, RDI < 75% vs. RDI ≥ 75%, and RDI < 80% vs. RDI ≥ 80%.
Table 2
Impact of RDI Levels of FOLFOX Chemotherapy on All-cause Mortality and Cause-Specific Mortality in High-Risk Stage III Colon Cancer— Multivariable Analysis
| All-cause mortality (N = 161) | Cause-specific mortality (N = 153) |
RDI | Low RDI% (RDI < selected cutoffs | Adjusted HR* (95% CI) | P | Adjusted HR* (95% CI) | P |
| | | | | |
RDI < 55% vs. RDI ≥ 55% | 20.5 | 3.90 (1.68, 9.08) | 0.002 | 3.89 (1.44, 10.47) | 0.007 |
| | | | | |
RDI < 60% vs. RDI ≥ 60% | 26.7 | 2.87 (1.30, 6.36) | 0.009 | 2.83 (1.13, 7.06) | 0.03 |
| | | | | |
RDI < 65% vs. RDI ≥ 65% | 31.1 | 2.72 (1.22, 6.04) | 0.01 | 2.61 (1.06, 6.45) | 0.04 |
| | | | | |
RDI < 70% vs. RDI ≥ 70% | 39.8 | 1.87 (0.84, 4.19) | 0.13 | 1.72 (0.61, 4.85) | 0.3 |
| | | | | |
RDI < 75% vs. RDI ≥ 75% | 47.8 | 1.99 (0.91, 4.34) | 0.08 | 1.90 (0.73, 4.92) | 0.19 |
| | | | | |
RDI < 80% vs. RDI ≥ 80% | 59.6 | 1.52 (0.63, 3.63) | 0.35 | 1.47 (0.49, 4.36) | 0.49 |
*Models adjusted for age, sex, race/ethnicity, insurance coverage, number of positive lymph nodes, tumor grade, Charlson comorbidity index, anatomic subsite and colon cancer classification (colon as the only cancer vs. multiple primary cancers). |
To avoid loss from risk of death, this study showed a minimum RDI of 70% may be administered.
Regression analysis for all-cause and cause-specific mortality in low-risk stage III colon cancer patients
Kaplan-Meier crude survival curves and cumulative incidence function plots were not significantly different at any of the RDI cut-off points from 45–70% (Figs. 3 and 4). The univariable analysis showed consistent results with hazard ratios (Supplemental Material 4).
In multivariable analysis, we adjusted for age, sex, race, insurance coverage (private insurance vs. non-private insurance), number of positive lymph nodes, tumor grade, Charlson comorbidity index, anatomic subsite, and colon cancer classification (colon as the only cancer vs. multiple primary cancers), which were confounders or significant factors for cancer survival (Table 3). Similar to results in Figs. 3 and 4, no cut-off points were found for significant hazard ratios in either all-cause or cause-specific mortality. Because of the small sample size, we did not explore the mortality influence of RDI < 40%. Results were similar in the sensitivity analysis which included cases with colon cancer as the only or the first primary tumor (data not shown).
Table 3
Impact of RDI Levels of FOLFOX Chemotherapy on All-cause Mortality and Cause-Specific Mortality in Low-Risk Stage III Colon Cancer— Multivariable Analysis
| All-cause mortality (N = 225) | Cause-specific mortality (N = 220) |
RDI | Low RDI% (RDI < selected cutoffs | Adjusted HR* (95% CI) | P | Adjusted HR* (95% CI) | P |
| | | | | |
RDI < 45% vs. RDI ≥ 45% | 16.0 | 0.79 (0.23, 2.67) | 0.71 | 0.49 (0.05, 4.84) | 0.54 |
| | | | | |
RDI < 50% vs. RDI ≥ 50% | 19.6 | 1.37 (0.53, 3.54) | 0.52 | 0.81 (0.18, 3.66) | 0.79 |
| | | | | |
RDI < 55% vs. RDI ≥ 55% | 21.8 | 1.34 (0.52, 3.47) | 0.54 | 0.80 (0.18, 3.61) | 0.78 |
| | | | | |
RDI < 60% vs. RDI ≥ 60% | 26.7 | 1.21 (0.47, 3.08) | 0.7 | 0.49 (0.11, 2.11) | 0.34 |
| | | | | |
RDI < 65% vs. RDI ≥ 65% | 31.1 | 1.16 (0.46, 2.90) | 0.76 | 0.93 (0.26, 3.37) | 0.91 |
| | | | | |
RDI < 70% vs. RDI ≥ 70% | 40.0 | 0.99 (0.42, 2.34) | 0.98 | 1.07 (0.34, 3.38) | 0.91 |
*Models adjusted for age, sex, race/ethnicity, insurance coverage, number of positive lymph nodes, tumor grade, Charlson comorbidity index, anatomic subsite and colon cancer classification (colon as the only cancer vs. multiple primary cancers). |