Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer, and the second leading cause of cancer death for males and females combined in the United States (US).¹ For patients with stage III colon cancer, the National Comprehensive Cancer Network (NCCN) has recommended adjuvant chemotherapy with fluoropyrimidines and oxaliplatin by risk profiles.^{2, 3} FOLFOX (Oxaliplatin, fluorouracil aka 5-FU, and leucovorin) is one of the standard adjuvant therapies commonly administered.^{2, 4, 5}

Despite the efficacy of FOLFOX, this regimen usually results in significant toxicities.^6–9 Six randomized phase III clinical trials have been conducted in 12 countries to evaluate the noninferiority of adjuvant therapy with either FOLFOX or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months.¹⁰ The meta-analysis of these trials showed that for stage III colon cancer patients, 3-month FOLFOX therapy resulted in a lower disease-free survival rate, particularly for the high-risk subgroup (patients with T4, N2, or both) (definitions of T and N are in Appendix 1), whereas among patients with low-risk cancers (T1, T2, or T3 and N1), the noninferiority with the 3-month chemotherapy use was not proven.¹⁰

Previous observational studies have also found that patients who failed to complete the standard cycles of 5-FU chemotherapy had worse colon cancer-specific survival,^{11, 12} or overall survival.¹¹ These studies, however, didn’t consider dose intensity or cumulative dose. Dose intensity is defined as the amount of drug delivered per unit time per square meter of body surface area, and relative dose intensity (RDI) is the ratio of delivered dose intensity (DDI) to the standard dose intensity (SDI).^{13, 14} Aspinall et al investigated the effect of RDI of multiple chemotherapy regimens (FOLFOX included) on survival among 367 stage III colon cancer patients and found that those who received >70% of SDI had higher 5-year overall survival.¹⁵ A study based on data from Korea found that for patients with stage II/III CRC receiving adjuvant FOLFOX,¹⁶ >60% of the standard dose of oxaliplatin was necessary to achieve similar 5-year disease-free survival or overall survival to the standard dose group. Both studies used data from healthcare facilities with limited generalizability, and neither of these studies considered the effect of RDI by the tumor risk, as defined in clinical trial studies.

Hence, we used data collected by population-based cancer registries covering all patients in selected US states to identify the optimal RDI of FOLFOX for high-risk and low-risk stage III colon cancer, respectively, regarding the effect of FOLFOX RDI on overall and cause-specific mortality in these 2 patient populations.

To our knowledge, this is the first population-based study to examine the association of FOLFOX RDI with the risk of overall and cause-specific deaths in 2 subgroups of patients diagnosed with stage III colon cancer. We found that the association of RDI on overall and cause-specific mortalities varied significantly by the risk profile. The risk-stratified analysis showed that in high-risk stage III colon cancer patients, lower RDI was related to higher risk of all-cause mortality when the cutoff points were 55%, 60%, or 65%. The risk of deaths was not statistically significantly different for the RDI comparisons of RDI <70% versus RDI ≥70%, RDI< 75% versus RDI ≥75%, and RDI< 80% versus RDI ≥80%. Therefore, to preserve the survival benefits, the lowest RDI from this study is 70%. For low-risk (T1-T3 and N1) stage III colon cancer, we did not find a significant difference in overall and cause-specific mortalities at any predefined RDI cutoff points from 45% to 70%.

Our findings confirmed that higher chemotherapy RDI was needed in high-risk stage III colon cancers, compared with low-risk cancers, and are consistent with the conclusions from 6 randomized, phase 3 clinical trials.^{5, 10, 32, 33} Results from a pooled analysis of these 6 trials showed that in stage III colon cancer patients treated with FOLFOX, 6-month therapy had a higher rate of disease-free survival than 3-month therapy, particularly in the high-risk group.¹⁰ Data from the IDEA France suggested that for FOLFOX6 regimen, patients with high-risk stage III colon cancer need 6-month chemotherapy for a maximal relapse risk reduction, for low-risk cancer patients, the absolute difference in the 3-year disease-free survival rate between 6 and 3 months of chemotherapy was clinically less relevant (2%).³³ Older clinical trials have also shown that the efficacy of oxaliplatin is more significant in stage III N2 tumors, compared to stage III N1 tumors^{34, 35} (10-year overall survival advantage of 12.9% (P = .013) in those with N2 tumors, and 6% (P = .248) in those with N1 tumors, when adding oxaliplatin to 5-FU plus leucovorin³⁵). André et al suggested defining a low-risk subset of patients with stage III colon cancer to spare the toxicity of oxaliplatin.³⁵

Oxaliplatin can induce SPN, which can be long-lasting or even permanent.^{8, 9, 36} Reduced chemotherapy RDI to a minimal effective dose may spare neurotoxicity and maintain quality of life in cancer survivors. Our results found that the optimal cut-off point of RDI was 70% in the high-risk stage III colon cancer patients, which implied for patients who need dose reductions due to toxicities, a 70% of the preplanned dose does not seem to impact survival outcomes; we didn’t find significant differences in risk of death at predefined RDI cutoff points of 45%, 50%, 55%, 60%, 65%, and 70% for low-risk stage III colon cancer. A few other observational studies have investigated the effect of RDI on colon cancer survival. Aspinall et al found that patients from Veterans medical centers with stage III colon cancer who received >70% RDI adjuvant chemotherapy had improved 5-year overall survival, compared to the ones receiving RDI≤ 70%; and the survival benefits were only seen in the first year after the completion of chemotherapy.¹⁵ However, unlike the chemotherapy regime in our study, the regimens in their study included 5-FU/LV (30.8%), FOLFOX (34.3%), oxaliplatin plus capecitabine (5.4%), capecitabine monotherapy (12.5%), and mixed/others chemo (16.9%). Given that the toxicity of oxaliplatin is more severe than 5-FU, the optimal RDI of FOLFOX may be lower than 70% in combined high-risk and low-risk stage III colon cancer as the defined population in Aspinall’s study.¹⁵ Another study performed in Korea University Anam Hospital, with patients receiving FOLFOX as the only chemotherapy regimen, suggested that more than 60% of the standard dose of oxaliplatin was necessary to achieve similar 5-year disease-free survival or overall survival to those of the standard dose group, for patients with stage II/III CRC patients.¹⁶ Both of the studies from Veterans medical centers and Korea University Anam Hospital had a restricted population, and they didn’t take into consideration risk features in stage III colon cancers. Those are some reasons that may contribute to the discrepancies about optimal RDI cut off points.

There are several strengths in this study. The study cohort is from the CER study, which includes 10 population-based cancer registries covering about 27% of the US population.¹⁷ Our analytical data from 8 of the 10 cancer registries with complete chemotherapy data represents patients from different geographic regions and reflects clinical practice in the community. The collection of detailed chemotherapy data, including chemotherapy regimens, dosage, and duration by NPCR cancer registries met CDC’s objective to support CER, such as this RDI study. While the reported survival outcomes in the paper are short-term, this cohort of CER colon patients will continue to be followed by the registries and be able to present longterm survival and recurrence in the future.

Although our study was comprehensive in its evaluation of acceptable RDI to maintain efficacy in a relatively homogenous population, there are potential limitations. First, the small number of patients could restrict the power to achieve the statistical significance in mortality differences for certain RDI cut-off points, especially for low-risk cancer patients. Lack of multiple comparisons in the analysis increased Type I error. The results need to be interpreted with caution and with considerations of the retrospective study design. Second, there were substantial differences in the survival time or follow up time for different states, which resulted in a low percentage of events in the survival analysis and short-term survival outcome. Third, the data may under-estimate the comorbid conditions, since patients with unknown comorbidity were categorized as no comorbidity according to the Facility Oncology Registry Data Standard (FORDS) coding manual.^{20, 37} In addition, data about comorbidity severity, postoperative complications, and reasons for stopping chemotherapy were not available. Furthermore, our study had incomplete data on microsatellite instability (MSI) status and did not collect BRAF mutations, and those molecular factors may affect the adjuvant therapy benefits and survival outcomes in stage II or III colon cancer patients.^38–40 Given our study limitations, a single observational study is not sufficient to determine optimal RDI for high-risk or low-risk stage III colon cancer patients, but we provided some real-world evidence of individualized chemotherapy for patients with stage III colon cancer. Further studies with a larger number of patients and more completed data are needed to validate our findings.

In conclusion, among patients with stage III colon cancer who were receiving adjuvant therapy of FOLFOX, the acceptable RDI was 70% for high-risk stage III colon cancer patients, and we did not find a significant difference in the risk of death at any predefined RDI cutoff points from 45% to 70% for low-risk group. These results can be considered with the findings from clinical trials performed by the IDEA collaboration. Our findings add new evidence on the quality of cancer therapy, including how to administer FOLFOX to reduce chemotherapy toxicity and the use of health care resources if efficacy were maintained.