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  • Research article
  • Open Access
  • Open Peer Review

Impact of timing of adjuvant chemotherapy on survival in stage III colon cancer: a population-based study

Contributed equally
BMC Cancer201818:234

https://doi.org/10.1186/s12885-018-4138-7

  • Received: 6 December 2017
  • Accepted: 16 February 2018
  • Published:
Open Peer Review reports

Abstract

Background

There is no consensus regarding the optimal time to initiate adjuvant chemotherapy after surgery for stage III colon cancer, and the relevant postoperative complications that cause delays in adjuvant chemotherapy are unknown.

Methods

Eligible patients aged ≥66 years who were diagnosed with stage III colon cancer from 1992 to 2008 were identified using the linked Surveillance, Epidemiology, and End Results-Medicare database. Kaplan-Meier analysis and a Cox proportional hazards model were utilized to evaluate the impact of the timing of adjuvant chemotherapy on overall survival (OS).

Results

A total of 18,491 patients were included. Delayed adjuvant chemotherapy was associated with worse OS (9–12 weeks: hazard ratio [HR] = 1.222, 95% confidence interval [CI] = 1.063–1.405; 13–16 weeks: HR = 1.252, 95% CI = 1.041–1.505; ≥ 17 weeks: HR = 1.969, 95% CI = 1.663–2.331). The efficacies of adjuvant chemotherapy within 5–8 weeks and ≤4 weeks were similar (HR = 1.045, 95% CI = 0.921–1.185). Compared with the non-chemotherapy group, chemotherapy initiated at ≥21 weeks did not significantly improve OS (HR = 0.882, 95% CI = 0.763–1.018). Patients with postoperative complications, particularly cardiac arrest, ostomy infection, shock, and septicemia, had a significantly higher risk of a 4- to 11-week delay in adjuvant chemotherapy (p < 0.05).

Conclusions

Adjuvant chemotherapy initiated within 8 weeks was acceptable for patients with stage III colon cancer. Delayed adjuvant chemotherapy after 8 weeks was significantly associated with worse OS. However, adjuvant chemotherapy might still be useful even with a delay of approximately 5 months. Moreover, postoperative complications were significantly associated with delayed adjuvant chemotherapy.

Keywords

  • Colon cancer
  • Stage III
  • Timing of adjuvant chemotherapy
  • Postoperative complications
  • SEER-Medicare program

Background

Colon cancer is an important cause of cancer-related incidence and mortality and remains a major public health problem worldwide [1]. The current clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) recommend adjuvant chemotherapy following surgical resection as a standard treatment for patients with stage III colon cancer because of the benefit of chemotherapy in reducing the risk of recurrence and death by eradicating micrometastases [2].

Several studies have reported that the surgical resection of a primary tumor might induce angiogenesis and proliferation of dormant micrometastases by releasing growth-stimulating factors and triggering immunosuppression that leads to tumor growth [37]. Moreover, Harless et al. reported that the effectiveness of adjuvant chemotherapy was inversely proportional to the time from adjuvant chemotherapy initiation to surgical resection [8]. Therefore, it is a reasonable hypothesis that there may be a time-dependent cut-off point after surgery after which the benefit of adjuvant chemotherapy is not significant because of the failure to eradicate micrometastases. However, the NCCN and ESMO guidelines do not specify an optimal time to initiate adjuvant chemotherapy after surgical resection. Most clinical trials of adjuvant chemotherapy in colon cancer require adjuvant chemotherapy initiation within 6 to 8 weeks after surgical resection [912]. Routine preclinical and clinical data suggest that adjuvant chemotherapy in colon cancer should be initiated earlier rather than later, but, in real practice, the initiation of adjuvant chemotherapy in colon cancer is often delayed [13, 14].

There is no direct and high-quality evidence regarding the importance of the timing of adjuvant chemotherapy in colon cancer. Although two meta-analyses demonstrated that delays in the initiation of adjuvant chemotherapy were detrimental to survival in colorectal cancer [15, 16], these meta-analyses included both rectal and colon cancer, and it was thus not clear whether the conclusions could be applied to the treatment of colon cancer because of the biological differences between colon cancer and rectal cancer. To date, few retrospective studies evaluated the impact of the timing of adjuvant chemotherapy on survival in colon cancer, and the results were inconsistent [1723]. Moreover, the relevant postoperative complications that cause delays in adjuvant chemotherapy are unknown.

Therefore, this population-based study was conducted to assess the impact of the timing of adjuvant chemotherapy on survival in stage III colon cancer and to assess whether postoperative complications were associated with the timing of adjuvant chemotherapy.

Methods

Data source

This study was conducted utilizing the Surveillance, Epidemiology, and End Results (SEER) program and Medicare-linked databases. The SEER program is a comprehensive source of population-based data on patient demographics, tumor characteristics, cancer-related treatments, and causes of death that covers approximately 28% of the population of the United States [24]. The Medicare database contains individual health insurance claims for approximately 97% of the population aged ≥65 years in the United States and complements the SEER with diagnoses, cancer-related treatments, and outcomes. In the Medicare database, Part A provides health-insurance data about hospitals, skilled-nursing facilities, hospices, and home health care, and Part B provides data about physician and outpatient services [25, 26]. The SEER-Medicare database was described in our previous study [27].

The access to the SEER-Medicare database was approved by National Cancer Institute and Information Management Services, Inc. (D6-MEDIC-821), and this study was approved by the Institutional Review Board of the First Hospital of China Medical University.

Study population

This study included eligible patients aged ≥66 years from SEER-Medicare database who were diagnosed with primary colon adenocarcinoma from 1992 to 2008 (SEER cancer site codes 18.0, and 18.2 to 18.9). The participating patients fulfilled the American Joint Committee on Cancer (AJCC) staging criteria for stage III colon cancer and underwent primary tumor resection with curative intent within 180 days of diagnosis. The adjuvant chemotherapy regimens were 5-fluorourcil (5-FU)/capecitabine alone or 5-FU/capecitabine plus oxaliplatin (FOLFOX/CapeOX). The non-chemotherapy group included patients with no record of chemotherapy within one year of surgery. The FOLFOX/CapeOX group included patients with any record of 5-FU/capecitabine plus oxaliplatin within 4 weeks of their first chemotherapy dose.

The exclusion criteria were the following: (1) patients who previous non-colon cancer or a diagnosis of non-colon cancer within 1 year of the colon cancer diagnosis, (2) those with incomplete pathological stage entries or diagnostic data, (3) those who received adjuvant chemotherapy only after tumor relapse or metastasis, (4) those who received preoperative neoadjuvant treatments or other adjuvant chemotherapy regimens, (5) those who died within 30 days of diagnosis, and (6) those lacked full coverage from Medicare Parts A and B from 12 months before diagnosis to 9 months after diagnosis or were enrolled in a health maintenance organization.

The National Drug Codes for the drugs and the Health Care Financing Administration Common Procedure Coding System have been previously reported [27].

Study variables

We obtained the patient demographics from the SEER patient entitlement and diagnosis summary file, including gender, age at diagnosis, race, marital status, residence location, household income, education level, and year of diagnosis. The disease characteristics, including primary tumor site (right-side or left-side colon), histologic grade (well differentiated, moderately differentiated, or poorly differentiated/undifferentiated), histologic type (adenocarcinoma, mucinous carcinoma, or signet-ring cell carcinoma), tumor stage, presence of preoperative obstruction or perforation, and number of examined lymph nodes (≥12 or < 12) were also studied. The tumor stage was assessed based on the seventh edition of the AJCC TNM staging system [28, 29]. The time to the initiation of adjuvant chemotherapy was defined as the interval between the curative surgery and the administration of the first chemotherapy.

For the evaluation of the comorbidities, we used the Hierarchical Condition Category (HCC) risk score to summarize the health care problems and predict the future health care cost of the population compared with the average Medicare beneficiary (HCC = 1.0), and the HCC risk score was derived from the Medicare inpatient and outpatient claims for various comorbidities within 12 months before the colon cancer diagnosis [30]. The postoperative complications were identified by assessing the discharge diagnoses within 1 month of surgery.

Statistical analysis

For the descriptive analysis, the categorical variables were compared using χ2 tests and the continuous variables were compared using the Mann-Whitney U tests. In the univariate analysis of survival, Kaplan–Meier survival curves for overall survival (OS) were generated according to the chemotherapy regimen and timing of adjuvant chemotherapy, and these curves were compared using log-rank tests. A spline-based hazard ratio (HR) curve with the corresponding confidence limits was used to evaluate the effect of the continuous covariate of interest (i.e., the timing of adjuvant chemotherapy) on the outcome (OS) [31, 32]. Multivariate Cox proportional hazards models were used to determine the relationships of multiple survival-related variables with survival.

All statistical analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC, USA), STATA version 12.0 (Stata Corporation, College Station, TX, USA), SPSS version 18.0 (SPSS, Inc., Somers, NY, USA), and R version 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria). For all analyses, a two-sided p-value of less than 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 18,491 patients with stage III colon cancer who underwent surgical resection between 1992 and 2008 were identified using the SEER-Medicare database. Among these, 8058 patients received 5-FU or capecitabine alone, 1664 patients received FOLFOX, and 8769 patients did not receive adjuvant chemotherapy. With respect to the timing of adjuvant chemotherapy, 746 patients received adjuvant chemotherapy within 4 weeks after surgery, 6165 patients received adjuvant chemotherapy within 5–8 weeks after surgery, 1883 patients received adjuvant chemotherapy within 9–12 weeks after surgery, 466 patients received adjuvant chemotherapy within 13–16 weeks after surgery, and 462 patients received adjuvant chemotherapy ≥17 weeks after surgery. The patient profiles and disease characteristics are presented in Table 1.
Table 1

Clinicopathologic features of patients subjected to different chemotherapy regimens

 

No-chemo

5FU/Capecitabine

FOLFOX/CapeOX

Gender

 Male

3124

3591

799

 Female

5645

4467

865

Age at diagnosis, years

 66–70

554

1826

584

 71–75

1002

2422

514

 76–80

1784

2180

419

  > 80

5429

1630

147

Race

 White

7369

6909

1407

 Black

841

592

132

 Asian

244

260

52

 Other

315

297

73

Marital status

 Single+Separated

823

551

125

 Married

3105

4620

1044

 Divorced+Widowed

4535

2654

443

 Other

306

233

52

Residence location

 Big Metro

4802

4219

878

 Metro or Urban

2963

2853

588

 Less Urban or Rural

1002

986

198

Median household income

 1st quartile

2203

1803

371

 2nd quartile

2102

1976

375

 3rd quartile

2062

1949

393

 4th quartile

2035

2029

443

 Unknown

367

301

82

Level of education

 1st quartile

2064

2003

401

 2nd quartile

2029

2015

373

 3rd quartile

2136

1920

400

 4th quartile

2173

1819

408

 Unknown

367

301

82

Year of diagnosis

 1992–1996

1837

1902

0

 1997–2000

1678

1887

0

 2001–2004

2739

3169

240

 2005–2008

2515

1100

1424

Primary tumor site

 right-sided colon

5867

5111

1068

 left-sided colon

2730

2809

572

 unknown

172

138

24

Histologic grade

 Well

432

422

99

 Moderate

5360

5169

1046

 Poor+Undifferentiated

2756

2251

486

 Unknown

221

216

33

Histologic type

 Adenocarcinoma

7402

6811

1425

 Mucinous carcinoma

1216

1140

212

 Signet-ring cell carcinoma

151

107

27

pT category

 pT1

173

302

69

 pT2

571

721

150

 pT3

6185

5805

1223

 pT4a

1040

861

150

 pT4b

800

369

72

pN category

 pN1a

3315

2898

500

 pN1b

2889

2750

554

 pN2a

1550

1518

357

 pN2b

1015

892

253

pTNM stage

 pTNM IIIa

673

920

190

 pTNM IIIb

6239

5814

1132

 pTNM IIIc

1857

1324

342

Preoperative intestinal obstruction

 No

6406

6648

1367

 Yes

2363

1410

297

Preoperative intestinal perforation

 No

8576

7998

1648

 Yes

193

60

16

HCC risk score

 1st quartile

2557

1811

289

 2nd quartile

1685

2427

539

 3rd quartile

1972

2195

492

 4th quartile

2555

1625

344

Number of examined lymph node

  ≥ 12

4674

4274

1213

  < 12

4095

3784

451

Postoperative radiotherapy

 No

8692

7765

1639

 Yes

77

293

25

Timing to AC

  ≤ 4 weeks

0

660

86

 5–8 weeks

0

5118

1047

 9–12 weeks

0

1502

381

 13–16 weeks

0

369

97

  ≥ 17 weeks

0

409

53

 No-chemo

8769

0

0

Abbreviation: AC Adjuvant chemotherapy, HCC Hierarchical Condition Categories; No-chemo, without adjuvant chemotherapy, 5-FU 5-fluorouracil, FOLFOX/CapeOX 5-FU/capecitabine plus oxaliplatin

Overall comparison of the timing of chemotherapy

We used a spline-based HR curve to explore the impact of the timing of adjuvant chemotherapy on overall survival in patients with stage III colon cancer. The results indicated that a minimum risk of mortality was achieved at 4 weeks after surgery, and the survival benefits decreased with a delay in the timing of adjuvant chemotherapy of more than 4 weeks (Fig. 1). Therefore, we used the value of ≤4 weeks as a reference for the survival analysis, and the results of univariate analyses indicated that delayed chemotherapy was significantly associated with worse OS (9–12 weeks: HR = 1.169, 95% confidence interval [CI] = 1.019–1.341, p = 0.026; 13–16 weeks: HR = 1.237, 95% CI = 1.031–1.483, p = 0.022; ≥ 17 weeks: HR = 2.207, 95% CI = 1.870–2.604, p < 0.001). However, chemotherapy that was initiated within 5–8 weeks after surgery did not significantly increase the risk of mortality (HR = 0.982, 95% CI = 0.867–1.113, p = 0.780). A Kaplan–Meier survival curve that was stratified by the timing of chemotherapy is presented in Fig. 2. Multivariate Cox proportional hazards models produced results similar to those of the univariate analyses (5–8 weeks: HR = 1.045, 95% CI = 0.921–1.185, p = 0.498; 9–12 weeks: HR = 1.222, 95% CI = 1.063–1.405, p = 0.005; 13–16 weeks: HR = 1.252, 95% CI = 1.041–1.505, p = 0.017; ≥ 17 weeks: HR = 1.969, 95% CI = 1.663–2.331, p < 0.001, Table 2). Moreover, the survival benefit of adjuvant chemotherapy was statistically insignificant when adjuvant chemotherapy was initiated ≥21 weeks after resection compared with the non-chemotherapy group (HR = 0.882, 95% CI = 0.763–1.018, p = 0.087, Fig. 3), and chemotherapy initiated ≥25 weeks after surgery did not elicit an OS benefit compared with the non-chemotherapy group (HR = 1.019, 95% CI = 0.863–1.204, p = 0.821, Fig. 3).
Fig. 1
Fig. 1

Splines-based hazard ratio curve for identification of the effect of timing of chemotherapy on overall survival. The solid line presents the relationship (log hazard ratio) between timing of chemotherapy and overall survival, and the dotted line presents the corresponding 95% confidence limits

Fig. 2
Fig. 2

Kaplan–Meier curve of the timing of chemotherapy and overall survival. The p value is derived from log-rank test for the overall comparison of overall survival between different timing of chemotherapy and non-chemotherapy group

Table 2

Univariate and multivariate Cox proportional hazards analysis of factors influencing the 5-year overall survival for patients who underwent chemotherapy

Variables

Univariate analysis

Multivariate analysis*

HR

95% CI

P

HR

95% CI

P

Gender

  

0.136

   

 Male

1

     

 Female

0.952

0.893–1.015

    

Age at diagnosis, years

  

< 0.001

  

< 0.001

 66–70

1

  

1

  

 71–75

1.157

1.054–1.269

 

1.133

1.030–1.245

 

 76–80

1.359

1.238–1.492

 

1.330

1.209–1.463

 

  > 80

1.929

1.752–2.123

 

1.834

1.657–2.029

 

Race

  

< 0.001

  

0.001

 White

1

  

1

  

 Black

1.039

0.922–1.171

 

0.980

0.864–1.112

 

 Asian

0.625

0.503–0.777

 

0.636

0.511–0.793

 

 Other

0.989

0.836–1.169

 

0.961

0.811–1.139

 

Marital status

  

< 0.001

  

0.011

 Single+Separated

1

  

1

  

 Married

0.818

0.723–.926

 

0.856

0.755–0.970

 

 Divorced+Widowed

0.994

0.874–1.129

 

0.948

0.833–1.079

 

 Other

0.838

0.670–1.047

 

0.905

0.723–1.133

 

Residence location

  

0.222

   

 Big Metro

1

     

 Metro or Urban

0.942

0.878–1.010

    

 Less Urban or Rural

0.996

0.901–1.102

    

Median household income

  

0.023

  

0.872

 1st quartile

1

  

1

  

 2nd quartile

0.993

0.906–1.088

 

1.042

0.943–1.152

 

 3rd quartile

0.926

0.843–1.016

 

1.000

0.895–1.119

 

 4th quartile

0.872

0.795–0.957

 

1.013

0.893–1.15

 

 Unknown

0.945

0.795–1.123

 

1.056

0.860–1.298

 

Level of education

  

< 0.001

  

0.001

 1st quartile

1

  

1

  

 2nd quartile

1.164

1.061–1.278

 

1.154

1.045–1.274

 

 3rd quartile

1.159

1.055–1.272

 

1.142

1.022–1.276

 

 4th quartile

1.262

1.149–1.385

 

1.286

1.130–1.463

 

 Unknown

1.142

0.960–1.358

 

N/Aa

N/Aa

 

Year of diagnosis

  

< 0.001

  

< 0.001

 1992–1996

1

  

1

  

 1997–2000

0.863

0.784–0.950

 

0.833

0.756–0.918

 

 2001–2004

0.814

0.748–0.885

 

0.754

0.692–0.822

 

 2005–2008

0.667

0.605–0.737

 

0.609

0.549–0.675

 

Primary tumor site

  

< 0.001

  

0.006

 right-sided colon

1

  

1

  

 left-sided colon

0.822

0.767–0.880

 

0.891

0.829–0.957

 

 unknown

1.241

0.988–1.559

 

1.034

0.821–1.302

 

Histologic grade

  

< 0.001

  

< 0.001

 Well

1

  

1

  

 Moderate

1.156

0.987–1.353

 

1.073

0.915–1.257

 

 Poor+Undifferentiated

1.748

1.487–2.055

 

1.384

1.174–1.630

 

 Unknown

1.274

0.991–1.638

 

1.120

0.869–1.445

 

Histologic type

  

< 0.001

  

0.101

 Adenocarcinoma

1

  

1

  

 Mucinous carcinoma

1.123

1.026–1.229

 

1.024

0.934–1.123

 

 Signet-ring cell carcinoma

1.893

1.503–2.384

 

1.289

1.019–1.632

 

pT category

  

< 0.001

  

< 0.001

 pT1

1

  

1

  

 pT2

1.071

0.824–1.391

 

1.019

0.783–1.325

 

 pT3

2.025

1.616–2.536

 

1.594

1.269–2.002

 

 pT4a

2.98

2.348–3.782

 

2.205

1.732–2.806

 

 pT4b

5.459

4.253–7.008

 

3.404

2.636–4.395

 

pN category

  

< 0.001

  

< 0.001

 pN1a

1

  

1

  

 pN1b

1.374

1.263–1.495

 

1.305

1.199–1.420

 

 pN2a

1.844

1.682–2.021

 

1.675

1.526–1.838

 

 pN2b

3.215

2.920–3.541

 

2.874

2.595–3.183

 

Preoperative intestinal obstruction

  

< 0.001

  

< 0.001

 No

1

  

1

  

 Yes

1.425

1.319–1.540

 

1.246

1.152–1.349

 

Preoperative intestinal perforation

  

< 0.001

  

0.001

 No

1

  

1

  

 Yes

2.284

1.723–3.028

 

1.628

1.223–2.168

 

HCC risk score

  

< 0.001

  

< 0.001

 1st quartile

1

  

1

  

 2nd quartile

0.950

0.865–1.043

 

1.161

1.053–1.280

 

 3rd quartile

1.109

1.010–1.217

 

1.347

1.223–1.483

 

 4th quartile

1.447

1.315–1.593

 

1.644

1.489–1.815

 

Number of examined lymph node

  

0.003

  

< 0.001

  ≥ 12

1

  

1

  

  < 12

1.102

1.034–1.175

 

1.295

1.209–1.387

 

Postoperative radiotherapy

  

< 0.001

  

< 0.001

 No

1

  

1

  

 Yes

1.620

1.391–1.887

 

1.323

1.133–1.545

 

Timing to AC

  

< 0.001

  

< 0.001

  ≤ 4 weeks

1

  

1

  

 5–8 weeks

0.982

0.867–1.113

 

1.045

0.921–1.185

 

 9–12 weeks

1.169

1.019–1.341

 

1.222

1.063–1.405

 

 13–16 weeks

1.237

1.031–1.483

 

1.252

1.041–1.505

 

  ≥ 17 weeks

2.207

1.870–2.604

 

1.969

1.663–2.331

 

Abbreviation: HR Hazard ratio, CI Confidence interval, HCC Hierarchical Condition Categories, AC Adjuvant chemotherapy

*Only variables with a p < 0.05 in the univariate analysis were included in the multivariate analysis

aunavailable because of colinearity with the variable of Median household income

Fig. 3
Fig. 3

Hazard ratio plot for the relationship between timing of chemotherapy and overall survival compared with the non-chemotherapy group

Comparison of the timing of FOLFOX/CapeOX chemotherapy

Our results indicated that the survival benefit from FOLFOX/CapeOX chemotherapy was more evident than that from 5-FU alone in patients with stage III colon cancer (HR = 0.615, 95% CI = 0.555–0.683, p < 0.001, Fig. 4), although both chemotherapy regimens significantly improved the OS (p < 0.001) compared with the non-chemotherapy group. Therefore, the relationship between the timing of FOLFOX/CapeOX chemotherapy and OS was further evaluated. The results of the multivariate analysis indicated that FOLFOX/CapeOX chemotherapy that was initiated within 5–8 weeks did not increase the risk of mortality compared with FOLFOX/CapeOX chemotherapy that was initiated ≤4 weeks after surgery (HR = 1.009, 95% CI = 0.619–1.644, p = 0.971, Table 3). However, FOLFOX/CapeOX chemotherapy initiated within 9–12, 13–16, and ≥17 weeks tended to produce worse OS (9–12 weeks: HR = 1.640, 95% CI = 0.990–2.717, p = 0.055; 13–16 weeks: HR = 1.422, 95% CI = 0.788–2.566, p = 0.243; ≥ 17 weeks: HR = 2.482, 95% CI = 1.354–4.549, p = 0.003, Table 3). Indeed, the spline-based HR curve for FOLFOX/CapeOX chemotherapy indicated that the survival benefit of FOLFOX/CapeOX chemotherapy was not statistically significant when it was initiated at ≥19 weeks compared with the non-chemotherapy group (HR = 0.672, 95% CI = 0.441–1.024, p = 0.064, Fig. 5).
Fig. 4
Fig. 4

Kaplan–Meier curve of chemotherapy regimen and overall survival. The p value is derived from log-rank test for the overall comparison of overall survival between different chemotherapy regimens and non-chemotherapy group

Table 3

Univariate and multivariate Cox proportional hazards analysis of factors influencing 5-year overall survival for patients who underwent FOLFOX/CapeOX chemotherapy

Variables

Univariate analysis

Multivariate analysis*

HR

95% CI

P

HR

95% CI

P

Gender

  

0.092

   

 Male

1

     

 Female

0.845

0.695–1.028

    

Age at diagnosis, years

  

0.003

  

0.007

 66–70

1

  

1

  

 71–75

1.122

0.872–1.443

 

1.149

0.888–1.486

 

 76–80

1.286

0.994–1.665

 

1.293

0.991–1.688

 

  > 80

1.812

1.305–2.517

 

1.816

1.285–2.566

 

Race

  

0.206

   

 White

1

     

 Black

1.028

0.719–1.469

    

 Asian

1.156

0.677–1.972

    

 Other

0.502

0.259–0.973

    

Marital status

  

0.167

   

 Single+Separated

1

     

 Married

1.036

0.696–1.543

    

 Divorced+Widowed

1.318

0.869–1.999

    

 Other

1.066

0.540–2.104

    

Residence location

  

0.329

   

 Big Metro

1

     

 Metro or Urban

1.071

0.865–1.327

    

 Less Urban or Rural

1.252

0.929–1.686

    

Median household income

  

0.007

  

0.497

 1st quartile

1

  

1

  

 2nd quartile

0.962

0.733–1.261

 

1.021

0.755–1.380

 

 3rd quartile

0.745

0.561–0.989

 

0.814

0.575–1.152

 

 4th quartile

0.620

0.465–0.826

 

0.792

0.529–1.186

 

 Unknown

0.800

0.496–1.291

 

0.947

0.514–1.743

 

Level of education

  

0.006

  

0.263

 1st quartile

1

  

1

  

 2nd quartile

1.524

1.117–2.079

 

1.371

0.979–1.920

 

 3rd quartile

1.552

1.147–2.100

 

1.379

0.960–1.982

 

 4th quartile

1.744

1.298–2.343

 

1.289

0.854–1.947

 

 Unknown

1.417

0.863–2.327

 

N/Aa

N/Aa

 

Year of diagnosis

  

0.398

   

 2001–2004

1

     

 2005–2008

0. 897

0.697–1.154

    

Primary tumor site

  

0.150

   

 right-sided colon

1

     

 left-sided colon

0.878

0.711–1.084

    

 unknown

1.602

0.824–3.114

    

Histologic grade

  

< 0.001

  

0.022

 Well

1

  

1

  

 Moderate

1.170

0.724–1.892

 

1.015

0.623–1.653

 

 Poor+Undifferentiated

1.973

1.211–3.215

 

1.407

0.856–2.315

 

 Unknown

1.376

0.598–3.165

 

0.987

0.422–2.309

 

Histologic type

  

0.008

  

0.148

 Adenocarcinoma

1

  

1

  

 Mucinous carcinoma

1.491

1.146–1.940

 

1.306

0.997–1.712

 

 Signet-ring cell carcinoma

1.467

0.728–2.959

 

1.147

0.556–2.366

 

pT category

  

< 0.001

  

< 0.001

 pT1

1

  

1

  

 pT2

1.374

0.499–3.780

 

1.472

0.531–4.080

 

 pT3

3.645

1.506–8.823

 

2.730

1.118–6.667

 

 pT4a

6.221

2.494–15.521

 

5.077

2.014–12.801

 

 pT4b

7.165

2.766–18.559

 

4.350

1.656–11.424

 

pN category

  

< 0.001

  

< 0.001

 pN1a

1

  

1

  

 pN1b

1.581

1.172–2.132

 

1.475

1.090–1.996

 

 pN2a

2.301

1.691–3.132

 

1.970

1.440–2.696

 

 pN2b

4.310

3.195–5.814

 

3.408

2.497–4.650

 

Preoperative intestinal obstruction

  

< 0.001

  

0.055

 No

1

  

1

  

 Yes

1.680

1.340–2.106

 

1.258

0.995–1.590

 

Preoperative intestinal perforation

  

0. 165

   

 No

1

     

 Yes

1.770

0.790–3.966

    

HCC risk score

  

< 0.001

  

< 0.001

 1st quartile

1

  

1

  

 2nd quartile

0.936

0.683–1.283

 

1.129

0.816–1.561

 

 3rd quartile

1.033

0.754–1.415

 

1.273

0.918–1.765

 

 4th quartile

1.994

1.469–2.705

 

2.197

1.592–3.033

 

Number of examined lymph node

  

0.382

   

  ≥ 12

1

     

  < 12

0.906

0.727–1.130

    

Postoperative radiotherapy

  

0.055

   

 No

1

     

 Yes

1.850

0.988–3.467

    

Timing to AC

  

< 0.001

  

< 0.001

  ≤ 4 weeks

1

  

1

  

 5–8 weeks

1.028

0.635–1.663

 

1.009

0.619–1.644

0.971

 9–12 weeks

1.665

1.012–2.739

 

1.640

0.990–2.717

0.055

 13–16 weeks

1.671

0.935–2.988

 

1.422

0.788–2.566

0.243

  ≥ 17 weeks

3.144

1.731–5.710

 

2.482

1.354–4.549

0.003

Abbreviation FOLFOX/CapeOX 5-FU/capecitabine plus oxaliplatin, HR Hazard ratio, CI Confidence interval, HCC Hierarchical Condition Categories, AC Adjuvant chemotherapy

*Only variables with a p < 0.05 in the univariate analysis were included in the multivariate analysis

aunavailable because of colinearity with the variable of Median household income

Fig. 5
Fig. 5

Hazard ratio plot for the relationship between timing of FOLFOX/CapeOX chemotherapy and overall survival compared with the non-chemotherapy group

Postoperative complications and the timing of chemotherapy

We examined the correlation of postoperative complications with the delayed initiation of adjuvant chemotherapy. The results indicated that patients with postoperative complications had a significantly higher risk of delayed adjuvant chemotherapy (p < 0.05; Fig. 6). Among the postoperative complications, cardiac arrest (19.50 vs. 8.22 weeks; Δ = 11.28 weeks), ostomy infection (14.60 vs. 8.22 weeks; Δ = 6.38 weeks), shock (13.69 vs. 8.18 weeks; Δ = 5.51 weeks), and septicemia (12.02 vs. 8.13 weeks; Δ = 3.89 weeks) had strong influences on chemotherapy delay with a delay of approximately 4–11 weeks. Additionally, disruption of the operation wound (Δ = 3.11 weeks), peritonitis (Δ = 3.07 weeks), fistula of the gastrointestinal tract (Δ = 2.97 weeks), acute renal failure (Δ = 3.34 weeks), postoperative infection (Δ = 2.85 weeks), intestinal perforation (Δ = 2.02 weeks), acute myocardial infarction (Δ = 1.88 weeks), and stroke (Δ = 1.96 weeks) could result in delays in the initiation of adjuvant chemotherapy of approximately 2–3 weeks. In turn, hemorrhage, pneumonia, urinary infection, pulmonary embolism, respiratory disease, gastrointestinal disorder, anemia, vein disease, gastrointestinal disease, nausea and vomiting, and obstruction had relatively weak impacts on the chemotherapy delay (a delay of approximately 0.5–1.5 weeks), although the differences were significant.
Fig. 6
Fig. 6

Association between postoperative complications and timing of adjuvant chemotherapy (AC) after surgical resection. Orange color bars present the timing of AC among patients with postoperative complications. Blue color bars present the timing of AC among patients without postoperative complications. “**” present a significant difference with p value < 0.01

Discussion

There is no evidence about the optimal time to initiate adjuvant chemotherapy after surgical resection, or whether there is an ideal timing for adjuvant therapy after which treatment benefit decreases. This population-based study based on the SEER-Medicare databases was conducted to evaluate the relationship between the timing of adjuvant chemotherapy and survival in stage III colon cancer. The results indicated that adjuvant chemotherapy that was initiated within 5–8 weeks after surgery did not increase the risk of mortality compared with chemotherapy initiated at ≤4 weeks after surgery, and the initiation of adjuvant chemotherapy within 8 weeks after surgery was thus feasible. However, adjuvant chemotherapy after 8 weeks of surgery was significantly associated with worse OS. The survival benefit of adjuvant chemotherapy became statistically insignificant when chemotherapy was initiated after 21 weeks compared with the non-chemotherapy group, thus, adjuvant chemotherapy might be still useful even with a delay of approximately 5 months (Fig. 3). Our results indicated that the survival benefits of the FOLFOX/CapeOX chemotherapy regimen within 5–8 weeks and ≤4 weeks were similar, and chemotherapy initiated ≥19 weeks did not have a significant OS benefit compared with the non-chemotherapy group.

The favorable effect of adjuvant chemotherapy on survival primarily involves the eradication of residual disease and micrometastases. However, the relationship between the timing of adjuvant chemotherapy and survival is unclear. Several studies reported that primary tumor removal could accelerate angiogenesis and growth of residual disease and micrometastases by releasing growth-stimulating factors and promoting immunosuppression [37]; thus, a delay in adjuvant chemotherapy might favor tumor angiogenesis and growth, and a long delay could lead to tumor recurrence or metastasis and a consequent failure to achieve the curative potential of adjuvant chemotherapy. Furthermore, Goldie et al. suggested that the drug sensitivity of a tumor was related to the spontaneous mutation rate toward phenotypic drug resistance, which was a function of time [33]. Moreover, the mathematical model by Harless et al. demonstrated that the effectiveness of chemotherapy was inversely proportional to the tumor burden that had to be eradicated, which, in turn, was a function of the time of the initiation of chemotherapy after surgery [8]. Therefore, the survival benefit of adjuvant chemotherapy was time-dependent. Studies have also reported that delayed chemotherapy might reflect poor patient and disease characteristics and increase comorbidity, which would be associated with poor prognoses [13, 34].

Our spline-based HR model revealed that the efficacies of adjuvant chemotherapy within 5–8 weeks and ≤4 weeks were similar, although the minimum risk of mortality was achieved at 4 weeks after surgery. Bos et al. demonstrated that adjuvant chemotherapy within 5–6 weeks or 7–8 weeks after surgery did not decrease OS compared to the initiation of chemotherapy within 4 weeks, and the start of chemotherapy 8 weeks after surgery was associated with a decreased OS [35]. In clinical practice, it is important to note that the toxicity of chemotherapy may be maximized due to poor immune and performance statuses after surgery, and thus, initiating chemotherapy early may cause severe chemotherapy-related adverse events and even death [36]. Therefore, an additional survival benefit of excess-early adjuvant chemotherapy may be difficult to detect because of the severe adverse events caused by chemotherapy. The initiation of adjuvant chemotherapy within 8 weeks after surgery was feasible. However, adjuvant chemotherapy that was initiated ≥21 weeks after surgery did not have a significant survival OS benefit compared with the non-chemotherapy group, and conversely, this delay may cause additional chemotherapy-related adverse events. Further studies are needed to explore the optimal timing for adjuvant chemotherapy, for example, identifying the time at which the survival benefit from chemotherapy maximally outweighs the risks of chemotherapy-related adverse events and death.

Several studies reported that patient and disease characteristics, including older age, low income, and high comorbidity, were associated with delayed adjuvant chemotherapy [13, 34]. Cheung et al. reported that the determinants of delayed adjuvant chemotherapy might be primarily influenced by their relationships with the postoperative complications that ultimately resulted in chemotherapy delay, and these complications seemed to be a more important driver for chemotherapy delay [37]. Therefore, the relationship between postoperative complications and delayed adjuvant chemotherapy was evaluated, and the results indicated that patients with postoperative complications had a significantly higher risk of delayed adjuvant chemotherapy (p < 0.05). Specifically, cardiac arrest, ostomy infection, shock, and septicemia had strong influences on delayed chemotherapy and caused delays of 4–11 weeks. Moreover, disruption of the operation wound, peritonitis, fistula of the gastrointestinal tract, acute renal failure, postoperative infection, intestinal perforation, acute myocardial infarction, and stroke could cause delays of 2–3 weeks. These results were expected because patients with severe postoperative complications were likely to require more time for recovery. Therefore, multidisciplinary treatment strategies are needed to reduce postoperative complications and promote timely adjuvant chemotherapy.

This study has limitations. First, this was a retrospective SEER-Medicare study, and thus the potential for confounding based on patient selection could not be completely eliminated. Second, the data on the patient/disease characteristics and treatments were obtained from a fee-for-service insurance database. Some clinical variables were not available, and the presence of other important confounding factors could not be discarded. Third, the use of adjuvant chemotherapy may decrease in older patients mainly because older patients are more likely to have high comorbidity and poor performance statuses, and oncologists may be less willing to use adjuvant chemotherapy [38, 39]. In our study, the results demonstrated that the use of adjuvant chemotherapy was common in older patients with stage III colon cancer (9722/18,491, 52.6%), and adjuvant chemotherapy significantly improved the prognoses compared with the non-chemotherapy group. Additionally, several studies have also demonstrated that older patients with stage III colon cancer gain a significant survival benefit from adjuvant chemotherapy [4043]. Therefore, further large-scale, high-quality studies are needed to evaluate the interactions of age and the timing of adjuvant chemotherapy with survival in stage III colon cancer. Fourth, disease-free survival was also an appropriate measure for assessing the survival benefit of adjuvant chemotherapy; however, disease-free survival could not be evaluated because the data on disease-free survival was not available in the SEER-Medicare database. Further studies are required to investigate the impact of the timing of adjuvant chemotherapy on disease-free survival. Moreover, it was not feasible to conduct a randomized controlled trial to specifically address the impact of the timing of adjuvant chemotherapy on survival in colon cancer. Thus, larger-scale and well-designed retrospective studies are needed to explore the optimal timing of adjuvant chemotherapy after surgical resection.

Conclusions

The survival benefits of adjuvant chemotherapy within 5–8 weeks and ≤4 weeks were similar, and thus, initiation of adjuvant chemotherapy within 8 weeks in patients with stage III colon cancer was feasible. Adjuvant chemotherapy 8 weeks after surgical resection was significantly associated with worse OS. However, adjuvant chemotherapy might still be useful even with a delay of approximately 5 months, although the survival benefit was reduced. Additionally, postoperative complications were significantly associated with the delayed initiation of adjuvant chemotherapy in patients with stage III colon cancer.

Abbreviations

5-FU: 

5-fluorourcil

AJCC: 

American Joint Committee on Cancer

CIs: 

Confidence intervals

ESMO: 

The European Society for Medical Oncology

HCC: 

Hierarchical Condition Category.

HR: 

Hazard ratio.

NCCN: 

The National Comprehensive Cancer Network.

OS: 

Overall survival.

SEER: 

Surveillance, Epidemiology, and End Results

Declarations

Acknowledgements

This work was funded by Clinical Capability Construction Project for Liaoning Provincial Hospitals (LNCCC-A01-2014), Program of Education Department of Liaoning Province (L2014307), and the National Key R&D Program of China (MOST-2016YFC1303200, MOST-2016YFC1303202). The authors thank the department of Surgical Oncology of First Hospital of China Medical University for technical assistance. The corresponding author had full access to all the data and analyses.

Funding

This work was funded by Clinical Capability Construction Project for Liaoning Provincial Hospitals (LNCCC-A01–2014), Program of Education Department of Liaoning Province (L2014307), and the National Key R&D Program of China (MOST-2016YFC1303200, MOST-2016YFC1303202). The sponsors had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials

The data that support the findings of this study are available from SEER-Medicare database but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of SEER-Medicare database.

Authors’ contributions

PG: Design of the work, data acquisition, data analysis, data interpretation, writing-original draft, and writing-review and editing. XZH: Design of the work, data acquisition, data interpretation, writing-original draft, and writing-review and editing. YXS: Data acquisition, data analysis, data interpretation, writing-original draft, and writing-review and editing. JXS: Data acquisition, data analysis, data interpretation, writing-original draft, and writing-review and editing. XWC: Data acquisition, data interpretation, writing-original draft, and writing-review and editing. YS: Data acquisition, data interpretation, writing-original draft, and writing-review and editing. YMJ: Data acquisition, data interpretation, writing-original draft, and writing-review and editing. ZNW: Responsible for conception and design of the work, data acquisition, data analysis, data interpretation, writing-original draft, and writing-review and editing. All authors read and approve the final manuscript.

Ethics approval and consent to participate

Because the SEER-Medicare data are de-identified and are based on registry data, no prior informed consent was required. The access to the SEER-Medicare database was approved by the National Cancer Institute and Information Management Services, Inc. (D6-MEDIC-821), while this study was approved by the Institutional Review Board of the First Hospital of China Medical University.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interest.

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Authors’ Affiliations

(1)
Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, People’s Republic of China
(2)
Department of Chemotherapy and Radiotherapy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 Xueyuan West Road, Lucheng District, Wenzhou City, 325027, People’s Republic of China

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.View ArticlePubMedGoogle Scholar
  2. Gill S, Loprinzi CL, Sargent DJ, Thome SD, Alberts SR, Haller DG, Benedetti J, Francini G, Shepherd LE, Francois Seitz J, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004;22(10):1797–806.View ArticleGoogle Scholar
  3. Hensler T, Hecker H, Heeg K, Heidecke CD, Bartels H, Barthlen W, Wagner H, Siewert JR, Holzmann B. Distinct mechanisms of immunosuppression as a consequence of major surgery. Infect Immun. 1997;65(6):2283–91.PubMedPubMed CentralGoogle Scholar
  4. Baum M, Demicheli R, Hrushesky W, Retsky M. Does surgery unfavourably perturb the "natural history" of early breast cancer by accelerating the appearance of distant metastases? European journal of cancer (Oxford, England : 1990). 2005;41(4):508–15.View ArticleGoogle Scholar
  5. Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E. Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res. 1989;49(8):1996–2001.PubMedGoogle Scholar
  6. Gunduz N, Fisher B, Saffer EA. Effect of surgical removal on the growth and kinetics of residual tumor. Cancer Res. 1979;39(10):3861–5.PubMedGoogle Scholar
  7. Stalder M, Birsan T, Hausen B, Borie DC, Morris RE. Immunosuppressive effects of surgery assessed by flow cytometry in nonhuman primates after nephrectomy. Transplant international : official journal of the European Society for Organ Transplantation. 2005;18(10):1158–65.View ArticleGoogle Scholar
  8. Harless W, Qiu Y. Cancer: a medical emergency. Med Hypotheses. 2006;67(5):1054–9.View ArticlePubMedGoogle Scholar
  9. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343–51.View ArticlePubMedGoogle Scholar
  10. Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(19):3109–16.View ArticleGoogle Scholar
  11. Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, Topham C, Tabernero J, Andre T, Sobrero AF, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(19):3117–25.View ArticleGoogle Scholar
  12. Wolmark N, Bryant J, Smith R, Grem J, Allegra C, Hyams D, Atkins J, Dimitrov N, Oishi R, Prager D, et al. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and bowel project protocol C-05. J Natl Cancer Inst. 1998;90(23):1810–6.View ArticlePubMedGoogle Scholar
  13. Xu F, Rimm AA, Fu P, Krishnamurthi SS, Cooper GS. The impact of delayed chemotherapy on its completion and survival outcomes in stage II colon cancer patients. PLoS One. 2014;9(9):e107993.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Chan A, Woods R, Kennecke H, Gill S. Factors associated with delayed time to adjuvant chemotherapy in stage iii colon cancer. Current oncology (Toronto, Ont). 2014;21(4):181–6.View ArticleGoogle Scholar
  15. Des Guetz G, Nicolas P, Perret GY, Morere JF, Uzzan B. Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis. European journal of cancer (Oxford, England : 1990). 2010;46(6):1049–55.View ArticleGoogle Scholar
  16. Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA. 2011;305(22):2335–42.View ArticlePubMedGoogle Scholar
  17. Bayraktar UD, Chen E, Bayraktar S, Sands LR, Marchetti F, Montero AJ, Rocha-Lima CM. Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma? Cancer. 2011;117(11):2364–70.View ArticlePubMedGoogle Scholar
  18. Haynes A, Chiang Y, Feig B, Xing Y, Chang G, You Y, Cormier J. Association between delays in adjuvant chemotherapy for stage III colon cancer and increased mortality. J Clin Oncol (Meeting Abstracts). 2012;30(4_suppl):541.View ArticleGoogle Scholar
  19. Czaykowski PM, Gill S, Kennecke HF, Gordon VL, Turner D. Adjuvant chemotherapy for stage III colon cancer: does timing matter? Dis colon rectum. 2011;54(9):1082–9.View ArticlePubMedGoogle Scholar
  20. Yu S, Shabihkhani M, Yang D, Thara E, Senagore A, Lenz HJ, Sadeghi S, Barzi A. Timeliness of adjuvant chemotherapy for stage III adenocarcinoma of the colon: a measure of quality of care. Clin Colorectal Cancer. 2013;12(4):275–9.View ArticlePubMedGoogle Scholar
  21. Peixoto RD, Kumar A, Speers C, Renouf D, Kennecke HF, Lim HJ, Cheung WY, Melosky B, Gill S. Effect of delay in adjuvant oxaliplatin-based chemotherapy for stage III colon cancer. Clin Colorectal Cancer. 2015;14(1):25–30.View ArticlePubMedGoogle Scholar
  22. Zeig-Owens R, Gershman ST, Knowlton R, Jacobson JS. Survival and time interval from surgery to start of chemotherapy among colon cancer patients. J Registry Manag. 2009;36(2):30–41. quiz 61-32PubMedGoogle Scholar
  23. Berglund A, Cedermark B, Glimelius B. Is it deleterious to delay the start of adjuvant chemotherapy in colon cancer stage III? Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2008;19(2):400–2.View ArticleGoogle Scholar
  24. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. [https://seer.cancer.gov/index.html].
  25. Potosky AL, Riley GF, Lubitz JD, Mentnech RM, Kessler LG. Potential for cancer related health services research using a linked Medicare-tumor registry database. Med Care. 1993;31(8):732–48.View ArticlePubMedGoogle Scholar
  26. SEER-Medicare Linked Database. [https://healthcaredelivery.cancer.gov/seermedicare/].
  27. Gao P, Song YX, Sun JX, Chen XW, Xu YY, Zhao JH, Huang XZ, Xu HM, Wang ZN. Which is the best postoperative chemotherapy regimen in patients with rectal cancer after neoadjuvant therapy? BMC Cancer. 2014;14:888.View ArticlePubMedPubMed CentralGoogle Scholar
  28. Edge SBBD, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.Google Scholar
  29. Sobin LHGM, Wittekind C. UICC: TNM classification of malignant tumours. 7th ed. Oxford: Wiley-Blackwell; 2009.Google Scholar
  30. Ash AS, Ellis RP, Pope GC, Ayanian JZ, Bates DW, Burstin H, Iezzoni LI, MacKay E, Yu W. Using diagnoses to describe populations and predict costs. Health care financing review. 2000;21(3):7–28.PubMedPubMed CentralGoogle Scholar
  31. Meira-Machado L, Cadarso-Suarez C, Gude F, Araujo A. smoothHR: an R package for pointwise nonparametric estimation of hazard ratio curves of continuous predictors. Computational and mathematical methods in medicine. 2013;2013:745742.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Zhang Z. Semi-parametric regression model for survival data: graphical visualization with R. Annals of translational medicine. 2016;4(23):461.View ArticlePubMedPubMed CentralGoogle Scholar
  33. Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer treatment reports. 1979;63(11–12):1727–33.PubMedGoogle Scholar
  34. Hershman D, Hall MJ, Wang X, Jacobson JS, McBride R, Grann VR, Neugut AI. Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer. Cancer. 2006;107(11):2581–8.View ArticlePubMedGoogle Scholar
  35. Bos AC, van Erning FN, van Gestel YR, Creemers GJ, Punt CJ, van Oijen MG, Lemmens VE. Timing of adjuvant chemotherapy and its relation to survival among patients with stage III colon cancer. European journal of cancer (Oxford, England : 1990). 2015;51(17):2553–61.View ArticleGoogle Scholar
  36. Goldman LI, Lowe S, al-Saleem T: Effect of fluorouracil on intestinal anastomoses in the rat. Arch Surg.(Chicago, Ill : 1960) 1969, 98(3):303–304.Google Scholar
  37. Cheung WY, Neville BA, Earle CC. Etiology of delays in the initiation of adjuvant chemotherapy and their impact on outcomes for stage II and III rectal cancer. Dis colon rectum. 2009;52(6):1054–1063; discussion 1064.View ArticlePubMedGoogle Scholar
  38. van Erning FN, Creemers GJ, De Hingh IH, Loosveld OJ, Goey SH, Lemmens VE. Reduced risk of distant recurrence after adjuvant chemotherapy in patients with stage III colon cancer aged 75 years or older. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2013;24(11):2839–44.View ArticleGoogle Scholar
  39. van den Broek CBM, Puylaert C, Breugom AJ, Bastiaannet E, de Craen AJM, van de Velde CJH, Liefers GJ, Portielje JEA. Administration of adjuvant chemotherapy in older patients with stage III colon cancer: an observational study. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2017;19(10):O358–64.View ArticleGoogle Scholar
  40. Sanoff HK, Carpenter WR, Sturmer T, Goldberg RM, Martin CF, Fine JP, McCleary NJ, Meyerhardt JA, Niland J, Kahn KL, et al. Effect of adjuvant chemotherapy on survival of patients with stage III colon cancer diagnosed after age 75 years. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(21):2624–34.View ArticleGoogle Scholar
  41. van Steenbergen LN, Lemmens VE, Rutten HJ, Wymenga AN, Nortier JW, Janssen-Heijnen ML. Increased adjuvant treatment and improved survival in elderly stage III colon cancer patients in The Netherlands. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2012;23(11):2805–11.View ArticleGoogle Scholar
  42. Kim KY, Cha IH, Ahn JB, Kim NK, Rha SY, Chung HC, Roh JK, Shin SJ. Estimating the adjuvant chemotherapy effect in elderly stage II and III colon cancer patients in an observational study. J Surg Oncol. 2013;107(6):613–8.View ArticlePubMedGoogle Scholar
  43. van Erning FN, Janssen-Heijnen ML, Creemers GJ, Pruijt JF, Maas HA, Lemmens VE. Recurrence-free and overall survival among elderly stage III colon cancer patients treated with CAPOX or capecitabine monotherapy. International journal of cancer Journal international du cancer. 2017;140(1):224–33.View ArticlePubMedGoogle Scholar

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