Impact of relative dose intensity of FOLFOX adjuvant chemotherapy on risk of death among stage III colon cancer patients

Abstract Background Clinical trials have indicated high-risk (T4 and/or N2) and low-risk (T1-T3 and N1) stage III colon cancer patients might need different doses of FOLFOX to reserve a similar survival probability. Observational studies have investigated the effect of relative dose intensity (RDI) of FOLFOX on cancer survival for patients with stage III colon cancer, but nonetheless, the studies focused on very specific populations, and none performed stratified analysis by risk profiles. This study aims to identify the optimal RDI of FOLFOX administered for high-risk and low-risk stage III colon cancer patients.Methods Data on 407 eligible patients, diagnosed with stage III colon cancer in 2011 who received FOLFOX, were collected by the eight population-based cancer registries for a CDC National Program of Cancer Registries (NPCR) project focused on Comparative Effectiveness Research. We employed Kaplan-Meier method, cumulative incidence function (CIF), Multivariable Cox model and Fine-Gray competing risks model to explore Optimal Relative Dose Intensity (RDI) defined as the lowest RDI administered without significant differences in either overall or cause-specific death.Results Among the 168 high-risk patients, the optimal RDI cut-off point was 70% where there was no statistically significant difference in overall mortality (HR=1.87; 95% CI: 0.84-4.19) and cause-specific mortality (HR=1.72; 95% CI: 0.61-4.85) when RDI<70% vs. RDI≥70%, adjusting for sociodemographic and clinical covariates. When the RDI cut-off was lower than the optimal one (<55% vs. ≥55%, <60% vs. ≥60%, or <65% vs. ≥65%), the overall and cause-specific mortalities were significantly statistically different between the two groups of each comparison. Among the 239 low-risk patients, none of the evaluated cut-offs were associated with statistically significant differences in overall and cause-specific mortalities between comparison groups. The lowest RDI we assessed was 45%, HR=0.79; 95% CI: 0.23-2.67 for the overall mortality and HR=0.49; 95% CI: 0.05-4.84 for the cause-specific mortality, when RDI<45% vs. RDI≥45%.Conclusions To best utilize health care resources while maintaining efficacy, RDI can be maintained at a minimum of 70% in high-risk stage III colon cancer patients. For low-risk patients, we found that RDI as low as 45% did not impact risk of death.

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Impact of relative dose intensity of FOLFOX adjuvant chemotherapy on risk of death among stage III colon cancer patients

10.21203/rs.2.20511/v2 ◽

2020 ◽

Author(s):

Meijiao Zhou ◽

Trevor D. Thompson ◽

Hui-Yi Lin ◽

Vivien W. Chen ◽

Jordan J. Karlitz ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Cancer Patients ◽

Dose Intensity ◽

Low Risk ◽

Stage Iii ◽

Risk Of Death ◽

Stage Iii Colon Cancer ◽

Risk Patients ◽

Overall Mortality

Abstract Background: Clinical trials have suggested high-risk (T4 and/or N2) and low-risk (T1-T3 and N1) stage III colon cancer patients might need different doses of FOLFOX to reserve a similar survival probability. Observational studies have investigated the effect of relative dose intensity (RDI) of FOLFOX on cancer survival for patients with stage III colon cancer, but nonetheless, the studies focused on very specific populations, and none performed stratified analysis by risk profiles. This study aims to identify the optimal RDI of FOLFOX administered for high-risk and low-risk stage III colon cancer patients. Methods: Data on 407 eligible patients, diagnosed with stage III colon cancer in 2011 who received FOLFOX, were collected by the eight population-based cancer registries for a CDC National Program of Cancer Registries (NPCR) project focused on Comparative Effectiveness Research. We employed Kaplan-Meier method, cumulative incidence function (CIF), Multivariable Cox model and Fine-Gray competing risks model to explore Optimal RDI defined as the lowest RDI administered without significant differences in either overall or cause-specific death. Results: Among the 168 high-risk patients, the optimal RDI cut-off point was 70% where there was no statistically significant difference in overall mortality (HR=1.59; 95% CI: 0.69-3.66) and cause-specific mortality (HR=1.24; 95% CI: 0.42-3.64) when RDI<70% vs. RDI≥70%, adjusting for sociodemographic and clinical covariates. When the RDI cut-off was lower than the optimal one (<55% vs. ≥55%, <60% vs. ≥60%, or <65% vs. ≥65%), the overall mortality was significantly statistically different between the two groups of each comparison. Among the 239 low-risk patients, none of the evaluated cut-offs were associated with statistically significant differences in overall and cause-specific mortalities between comparison groups. The lowest RDI we assessed was 45%, HR=0.80; 95% CI: 0.24-2.73 for the overall mortality and HR=0.53; 95% CI: 0.06-4.95 for the cause-specific mortality, when RDI<45% vs. RDI≥45%. Conclusions: To best utilize health care resources while maintaining efficacy, RDI can be maintained at a minimum of 70% for high-risk stage III colon cancer patients. For low-risk patients, we found that RDI as low as 45% did not significantly affect the risk of death.

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Impact of relative dose intensity of FOLFOX adjuvant chemotherapy on risk of death among stage III colon cancer patients

Clinical Colorectal Cancer ◽

10.1016/j.clcc.2021.09.008 ◽

2021 ◽

Author(s):

Meijiao Zhou ◽

Trevor D. Thompson ◽

Hui-Yi Lin ◽

Vivien W. Chen ◽

Jordan J. Karlitz ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Dose Intensity ◽

Relative Dose Intensity ◽

Stage Iii ◽

Risk Of Death ◽

Stage Iii Colon Cancer

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Impact of relative dose intensity of oxaliplatin in adjuvant therapy among stage III colon cancer patients on early recurrence: a retrospective cohort study

10.21203/rs.3.rs-35659/v3 ◽

2020 ◽

Author(s):

Jolanta Żok ◽

Michał Bieńkowski ◽

Barbara Radecka ◽

Jan Korniluk ◽

Krzysztof Adamowicz ◽

...

Keyword(s):

Colon Cancer ◽

Multivariate Analysis ◽

Adjuvant Therapy ◽

Risk Group ◽

Dose Intensity ◽

Early Recurrence ◽

Low Risk ◽

Relative Dose Intensity ◽

Stage Iii ◽

Stage Iii Colon Cancer

Abstract Background: Oxaliplatin-based therapy with FOLFOX-4 or CAPOX administered over 6 months remains the standard adjuvant treatment for stage III colon cancer (CC) patients. However, many patients experience dose reduction or early termination of chemotherapy due to oxaliplatin toxicity, which may increase the risk of early recurrence. The objective of this study was to analyze the relationship between the relative dose intensity of oxaliplatin (RDI-O) and early recurrence among stage III CC patients. Methods: The study included 365 patients treated at five oncology centers in Poland between 2000 and 2014.Survival analysis was performed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazard model; multivariate analysis was performed with the stepwise forward approach. For all analyses the αlevel of 0.05 was employed. Results: The median follow-up was 51.8 months (range 8.2-115.1). Early recurrence <36 months after surgery occurred in 130 patients (37.8%). In this group 51 (39.2%) and 87 (66.9%) of patients were low and high-risk, respectively. Receipt <60% of RDI-O was associated with early recurrence within 18 months after surgery (OR=2.05; 95%CI: 1.18-3.51; p=0.010),especially in low-risk group (HR=1.56 (95%CI: 0.96-2.53), p=0.07). In the multivariate analysis early recurrence was correlated with grade (OR=2.47; 95% CI: 1.25-4.8; p=0.008), pN (OR=2.63; 95% CI: 1.55-4.54; p<0.001), the number of lymph nodes harvested (OR=0.51; 95% CI: 0.29-0.86; p=0.013) and RDI-O (OR=1.91; 95%CI: 1.06-3.39; p=0.028). The early vs. late recurrence negatively correlated with OS regardless of the RDI-O (HR=22.9 (95%CI: 13.9-37.6; p<0.001). Conclusions: RDI-O <60% in adjuvant therapy among stage III CC (especially in low-risk group) increases the risk of early recurrence within 18 months of surgery. Patients with early recurrence showed worse overall survival regardless of the RDI-O.

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A new look at the IDEA classification: Defining novel predictive and prognostic markers in stage III colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.845 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 845-845

Author(s):

Ofer Margalit ◽

Ronac Mamtani ◽

Yu-Xiao Yang ◽

Kim Anna Reiss ◽

Talia Golan ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Cox Regression ◽

Secondary Analysis ◽

Risk Groups ◽

Low Risk ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Risk Patients ◽

Doublet Chemotherapy

845 Background: The IDEA pooled analysis compared 3 to 6 months of adjuvant chemotherapy for newly defined low- and high-risk stage III colon cancer patients, suggesting low-risk patients may be offered only 3 months of treatment. We aimed to evaluate the benefit of monotherapy vs doublet chemotherapy in low and high IDEA risk groups. Methods: Using the NCDB (2004-2014) we identified 56,728 and 47,557 individuals as low and high IDEA risk groups, respectively. We used multivariate COX regression to evaluate the magnitude of survival differences between IDEA risk groups, according to treatment intensity (doublet vs monotherapy). In a secondary analysis, we examined the predictive value of subgroups of age. Results: Low and high IDEA risk groups derived similar benefit from doublet chemotherapy compared to monotherapy, with hazard ratios of 0.83 (95%CI 0.79-0.86) and 0.80 (95%CI 0.78-0.83), respectively. The only subpopulations that did not benefit from doublet chemotherapy were low-risk patients above the age of 72 (HR = 0.95, 95%CI 0.90-1.01) and high-risk patients above the age of 85 (HR = 0.90, 95%CI 0.77-1.05). Conclusions: IDEA risk classification does not predict benefit from doublet chemotherapy in stage III colon cancer. However, omission of oxaliplatin can be considered in IDEA low-risk patients above the age of 72.

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Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with mFOLFOX6 (three versus six months) in the prospective IDEA France cohort study (PRODIGE-GERCOR).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.10 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 10-10

Author(s):

Franck Pages ◽

Thierry Andre ◽

Julien Taieb ◽

Dewi Vernerey ◽

Julie Henriques ◽

...

Keyword(s):

Colon Cancer ◽

Cohort Study ◽

High Risk ◽

Cancer Patients ◽

Predictive Value ◽

External Validation ◽

Disease Free Survival ◽

Low Risk ◽

Stage Iii ◽

Stage Iii Colon Cancer

10 Background: In stage III colon cancer patients treated with CAPOX, 3 months of therapy was as effective as 6 months. It was not the case for those receiving mFOLFOX6. We assessed the prognostic and predictive value of the Immunoscore (IS) in the mFOLFOX6 subgroup (90% of patients enrolled) of the IDEA France cohort study. Methods: 1200 patients randomly assigned to 3 months (n = 593) or 6 months (n = 607) of mFOLFOX6, with available tumor sample, were included. Densities of CD3+ and cytotoxic CD8+ T-cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS using the pre-defined cut-off. The IS performance to predict disease-free survival (DFS) was assessed in each arm and adjusted in multivariate Cox models. Results: In a two-category IS analysis, Low and (Int+High) IS were observed in 423 (43.5%) and 550 (56.5%) patients, respectively. Low IS identified patients with higher-risk of relapse or death (HR = 1.60; 95% CI 1.27-2.01, P < 0.0001). The 3-year DFS was 66.34% (95% CI 61.54-70.69) and 77.66% (95% CI 73.86-80.97) for Low and (Int+High) IS, respectively. In multivariate analysis, IS remained independently associated with DFS (P = 0.0007) when combined with T/N stage. A statistically significant interaction was observed for the IS predictive value for treatment duration (3 vs 6 months) in term of DFS in the whole population (P = 0.0566) and TN subgroups (Low-risk T1-3, N1 vs High-risk T4 and/or N2; P = 0.0015). The 3-year DFS of patients with (Int+High) IS in the 3-month arm was 71.5% (95% CI 65.7-76.6) versus 83.8% (95% CI, 78.8-87.8) in the 6-month arm (HR = 0.528; 95% CI 0.372-0.750; log-rank P = 0.0004); the benefit retained in low-risk and high-risk patients (all P≤0.010). 6-month mFOLFOX6 showed no significant benefit for patients with Low IS (HR = 0.836, log-rank P = 0.269). Conclusions: The IS prognostic value in patients treated with mFOLFOX6 was confirmed. Its predictive value for benefit of longer duration treatment, despite a strong statistical signal, needs to be confirmed in an external validation cohort. Clinical trial information: NCT03422601.

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Impact of relative dose intensity of oxaliplatin in adjuvant therapy among stage III colon cancer patients on early recurrence: a retrospective cohort study

10.21203/rs.3.rs-35659/v1 ◽

2020 ◽

Author(s):

Jolanta Żok ◽

Michał Bieńkowski ◽

Barbara Radecka ◽

Jan Korniluk ◽

Krzysztof Adamowicz ◽

...

Keyword(s):

Colon Cancer ◽

Multivariate Analysis ◽

Adjuvant Therapy ◽

Risk Group ◽

Dose Intensity ◽

Early Recurrence ◽

Low Risk ◽

Relative Dose Intensity ◽

Stage Iii ◽

Stage Iii Colon Cancer

Abstract Background The oxaliplatin-based therapy with FOLFOX-4 or CAPOX administrated over 6 months remains the standard adjuvant treatment for stage III colon cancer (CC) patients. However, many patients experience dose reduction or early termination of chemotherapy due to oxaliplatin toxicity, which may increase the risk of early recurrence. The objective of this study was to analyze the relationship between the relative dose intensity of oxaliplatin (RDI-O) and early recurrence among stage III CC patients. Methods The study included 365 patients treated at five oncology centers in Poland, between 2000–2014. Survival analysis was performed using the Kaplan-Meier method. Univariate analysis was performed using the Cox’ proportional hazard model; multivariate analysis was performed with the stepwise forward approach. For all analyses the α level of 0.05 was employed. Results The median follow-up was 51.8 months (range 8.2-115.1). The early recurrence < 36 months after surgery occurred in 130 patients (37.8%). In this group 51 (39.2%) and 87 (66.9%) at low and high-risk, respectively. Receipt < 60% RDI-O was associated with early recurrence within 18 months after surgery (OR = 2.05; 95%CI: 1.18–3.51; p = 0.010), especially in low-risk group (HR = 1.56 (95%CI: 0.96–2.53), p = 0.07). In the multivariate analysis early recurrence were correlated with grade (OR = 2.47; 95% CI: 1.25–4.8; p = 0.008), pN (OR = 2.63; 95% CI: 1.55–4.54; p < 0.001), the number of lymph nodes harvested (OR = 0.51; 95% CI: 0.29–0.86; p = 0.013) and RDI-O (OR = 1.91; 95%CI: 1.06–3.39; p = 0.028). The early vs. late recurrence negatively correlated with OS regardless of the RDI-O (HR = 22.9 (95%CI: 13.9–37.6; p < 0.001). Conclusions RDI-O < 60% in adjuvant therapy among stage III CC (especially in low-risk group) increase the risk of early recurrence within 18 months after surgery. Patients with early recurrence showed worse overall survival regardless of the RDI-O.

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Impact of relative dose intensity of oxaliplatin in adjuvant therapy among stage III colon cancer patients on early recurrence: a retrospective cohort study

BMC Cancer ◽

10.1186/s12885-021-08183-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jolanta Żok ◽

Michał Bieńkowski ◽

Barbara Radecka ◽

Jan Korniluk ◽

Krzysztof Adamowicz ◽

...

Keyword(s):

Colon Cancer ◽

Multivariate Analysis ◽

Adjuvant Therapy ◽

Risk Group ◽

Dose Intensity ◽

Early Recurrence ◽

Low Risk ◽

Relative Dose Intensity ◽

Stage Iii ◽

Stage Iii Colon Cancer

Abstract Background Oxaliplatin-based therapy with FOLFOX-4 or CAPOX administered over 6 months remains the standard adjuvant treatment for stage III colon cancer (CC) patients. However, many patients experience dose reduction or early termination of chemotherapy due to oxaliplatin toxicity, which may increase the risk of early recurrence. The objective of this study was to analyze the relationship between the relative dose intensity of oxaliplatin (RDI-O) and early recurrence among stage III CC patients. Methods The study included 365 patients treated at five oncology centers in Poland between 2000 and 2014. Survival analysis was performed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazard model; multivariate analysis was performed with the stepwise forward approach. For all analyses the α level of 0.05 was employed. Results The median follow-up was 51.8 months (range 8.2–115.1). Early recurrence < 36 months after surgery occurred in 130 patients (37.8%). In this group 51 (39.2%) and 87 (66.9%) of patients were low and high-risk, respectively. Receipt < 60% of RDI-O was associated with early recurrence within 18 months after surgery (OR = 2.05; 95%CI: 1.18–3.51; p = 0.010), especially in low-risk group (HR = 1.56 (95%CI: 0.96–2.53), p = 0.07). In the multivariate analysis early recurrence was correlated with grade (OR = 2.47; 95% CI: 1.25–4.8; p = 0.008), pN (OR = 2.63; 95% CI: 1.55–4.54; p < 0.001), the number of lymph nodes harvested (OR = 0.51; 95% CI: 0.29–0.86; p = 0.013) and RDI-O (OR = 1.91; 95%CI: 1.06–3.39; p = 0.028). The early vs. late recurrence negatively correlated with OS regardless of the RDI-O (HR = 22.9 (95%CI: 13.9–37.6; p < 0.001). Conclusions RDI-O < 60% in adjuvant therapy among stage III CC (especially in low-risk group) increases the risk of early recurrence within 18 months of surgery. Patients with early recurrence showed worse overall survival regardless of the RDI-O.

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Impact of relative dose intensity of oxaliplatin in adjuvant therapy among stage III colon cancer patients on early recurrence: a retrospective cohort study

10.21203/rs.3.rs-35659/v2 ◽

2020 ◽

Author(s):

Jolanta Żok ◽

Michał Bieńkowski ◽

Barbara Radecka ◽

Jan Korniluk ◽

Krzysztof Adamowicz ◽

...

Keyword(s):

Colon Cancer ◽

Multivariate Analysis ◽

Adjuvant Therapy ◽

Risk Group ◽

Dose Intensity ◽

Early Recurrence ◽

Low Risk ◽

Relative Dose Intensity ◽

Stage Iii ◽

Stage Iii Colon Cancer

Abstract Background: Oxaliplatin-based therapy with FOLFOX-4 or CAPOX administered over 6 months remains the standard adjuvant treatment for stage III colon cancer (CC) patients. However, many patients experience dose reduction or early termination of chemotherapy due to oxaliplatin toxicity, which may increase the risk of early recurrence. The objective of this study was to analyze the relationship between the relative dose intensity of oxaliplatin (RDI-O) and early recurrence among stage III CC patients.Methods: The study included 365 patients treated at five oncology centers in Poland between 2000 and 2014. Survival analysis was performed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazard model; multivariate analysis was performed with the stepwise forward approach. For all analyses the α level of 0.05 was employed. Results: The median follow-up was 51.8 months (range 8.2-115.1). Early recurrence <36 months after surgery occurred in 130 patients (37.8%). In this group 51 (39.2%) and 87 (66.9%) of patients were low and high-risk, respectively. Receipt <60% of RDI-O was associated with early recurrence within 18 months after surgery (OR=2.05; 95%CI: 1.18-3.51; p=0.010), especially in low-risk group (HR=1.56 (95%CI: 0.96-2.53), p=0.07). In the multivariate analysis early recurrence was correlated with grade (OR=2.47; 95% CI: 1.25-4.8; p=0.008), pN (OR=2.63; 95% CI: 1.55-4.54; p<0.001), the number of lymph nodes harvested (OR=0.51; 95% CI: 0.29-0.86; p=0.013) and RDI-O (OR=1.91; 95%CI: 1.06-3.39; p=0.028). The early vs. late recurrence negatively correlated with OS regardless of the RDI-O (HR=22.9 (95%CI: 13.9-37.6; p<0.001).Conclusions: RDI-O <60% in adjuvant therapy among stage III CC (especially in low-risk group) increases the risk of early recurrence within 18 months of surgery. Patients with early recurrence showed worse overall survival regardless of the RDI-O.

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Genomic classifiers (ColoPrint/MSI-Print) predict outcome and chemotherapy benefit in stage II and III colon cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.378 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 378-378 ◽

Cited By ~ 2

Author(s):

Scott Kopetz ◽

Zhi-Qin Jiang ◽

Michael J. Overman ◽

Christa Dreezen ◽

Sun Tian ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Additional Treatment ◽

Low Risk ◽

Stage Ii ◽

High Risk Patients ◽

Risk Patients

378 Background: Although the benefit of chemotherapy in stage II and III colon cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and has been validated in public datasets, independent European patient cohorts and technical studies (Salazar 2011 JCO, Maak 2012 Ann Surg). Methods: In this study, the commercial ColoPrint test was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center from 2003 to 2009. Frozen tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 64 months) were available. The 64-gene MSI-signature developed to identify patients with deficient mismatch repair system (Tian 2012 J Path) was evaluated for its accuracy to identify MSI patients and also for prognosis. Results: In this cohort, ColoPrint classified 56% of stage II and III patients as being at low risk. The 3-year Relapse-Free-Survival (RFS) was 90.6% for Low Risk and 78.4% for High Risk patients with a HR of 2.33 (p=0.025). In uni-and multivariate analysis ColoPrint and stage were the only significant factors to predict outcome. The MSI-signature classified 47 patients (24.6%) as MSI-H and most MSI-H patients were ColoPrint low risk (81%). Patients who were ColoPrint low risk and MSI-H by signature had the best outcome with a 3-year RFS of 95% while patients with ColoPrint high risk had a worse outcome independently of the MSI-status. Low risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (90.1% 3-year RFS for treated patients, 91.4% for untreated patients) while ColoPrint high risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70.1% 3-year RFS in untreated patients (p=0.026). Conclusions: The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help the identification of patients at higher risk who are more likely to benefit from additional treatment

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