Adjuvant chemotherapy for stage III colon cancer: relative dose intensity and survival among veterans

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 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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Duration of Adjuvant Chemotherapy for Colon Cancer and Survival Among the Elderly

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.5005 ◽

2006 ◽

Vol 24 (15) ◽

pp. 2368-2375 ◽

Cited By ~ 106

Author(s):

Alfred I. Neugut ◽

Matthew Matasar ◽

Xiaoyan Wang ◽

Russell McBride ◽

Judith S. Jacobson ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Proportional Hazards ◽

Dose Intensity ◽

The Elderly ◽

Cox Proportional Hazards ◽

Stage Iii ◽

Duration Of Treatment ◽

Stage Iii Colon Cancer ◽

Medicare Database

Purpose In randomized trials, patients with stage III colon cancer who received 6 months of fluorouracil (FU)-based adjuvant chemotherapy had better survival than patients who did not. However, little is known about the predictors of, or the survival associated with, duration of chemotherapy in the community. Patients and Methods The linked Surveillance, Epidemiology, and End Results-Medicare database was used to identify individuals ≥ 65 years of age diagnosed with stage III colon cancer between 1995 and 1999. We used logistic and Cox proportional hazards regression models to analyze factors associated with early discontinuation of FU-based chemotherapy among these elderly colon cancer patients. Results Among 1,722 patients who received 1 to 7 months of FU-based chemotherapy, older age, being unmarried, and having comorbid conditions were associated with receiving less than 5 months of treatment. Among the 1,579 patients who survived ≥ 8 months, the 1,091 (69.1%) who received 5 to 7 months of treatment had lower overall (hazard ratio [HR], 0.59; 95%, CI 0.49 to 0.71) and colon cancer-specific (HR, 0.53; 95% CI, 0.43 to 0.66) mortality than the 488 (30.9%) who received 1 to 4 months of treatment. Conclusion More than 30% of elderly patients who initiated FU-based chemotherapy for stage III colon cancer and survived for at least 8 months discontinued treatment early. Mortality rates among such patients were nearly twice as high as among patients who completed 5 to 7 months of treatment. If the association we observed between duration of treatment and survival is confirmed, additional investigation is warranted to determine whether dose-intensity, cumulative dose, or other factors related to receipt of full adjuvant treatment are responsible.

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Impact of relative dose intensity and G-CSF use in the adjuvant treatment of resected colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.752 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 752-752

Author(s):

Daniel Adam Breadner ◽

Frances Whiston ◽

Larry Stitt ◽

Stephen Welch

Keyword(s):

Colon Cancer ◽

Prognostic Significance ◽

Disease Free Survival ◽

Dose Intensity ◽

Secondary Prophylaxis ◽

Relative Dose Intensity ◽

Stage Iii ◽

Cancer Center ◽

Stage Iii Colon Cancer ◽

The Difference

752 Background: The benefits of adjuvant chemotherapy in stage III colon cancer (CC) are well established. However, the consequences of dose delays and modifications are not well established. Relative dose intensity (RDI) and dose scheduling have been shown to have prognostic significance in a number of cancers. We examine the effect of RDI, dose intensity (DI) and dose delays on disease free survival (DFS) and overall survival (OS) in stage III CC. Furthermore, we investigate the role of G-CSF in CC and its role in preserving RDI, and its effect on outcomes. Methods: A retrospective review was conducted for patients with stage III CC seen at a Canadian academic cancer center between 2006 and 2011. Patients who received at least three cycles of FOLFOX or at least two cycles capecitabine were included in the analysis. The RDI and DI were calculated and examined for correlation with DFS and OS. The influence of G-CSF on RDI and DI was also investigated. Results: FOLFOX was used more commonly than capecitabine, 64% vs. 36%. Within the FOLFOX regimen median RDI for oxaliplatin was 76.3%, and 83.5% for 5-FU. Median capecitabine RDI was 73.8%. Median DI were similar at 75.4%, 86.5%, and 69.1%, respectively. 60% of patients receiving FOLFOX got over 80% of their intended dose, while only 29% of patients receiving capecitabine achieved this DI. 3-year DFS was higher when RDI or DI was > 80%, compared to ≤ 80%, for each chemotherapeutic, however the differences did not reach significance. 3-year OS trended towards being higher in patients with an RDI and DI > than 80%, however there were limited events in these groups. Over half of patients on FOLFOX experienced a dose delay, 56.9%, most of whom then received G-CSF, 64.9%. Patients who received G-CSF had a higher DI than those who did not, 74.9% and 87.4% versus 66.5% and 76.8%, for the oxaliplatin and 5-FU components, respectively. 3-year DFS and OS was higher in patients who received G-CSF versus those who did not, 78.3% and 97.5% vs. 69.8% and 91.5%, respectively. Conclusions: In patients with stage III colon cancer an RDI or DI is associated with improved 3-year DFS and OS, although the difference did not reach significance in our review. G-CSF as secondary prophylaxis improves RDI, DI, DFS and OS.

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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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