DOI: https://doi.org/10.21203/rs.3.rs-120045/v1
Purpose：We focus on adverse events in colorectal cancer patients with advanced age, high Eastern Cooperative Oncology Group scores and comorbidities.
Methods：408 Chinese colorectal cancer patients undergoing adjuvant chemotherapy at Peking Union Medical College Hospital were included. The cumulative incidences of different adverse events and mediation analyses were analyzed with respect to age, Eastern Cooperative Oncology Group status and comorbidities.
Results：Young patients and patients with Eastern Cooperative Oncology Group score 1 had a significantly higher incidence of digestive adverse events related to adjuvant therapy. There were no significant mediation effects of adverse events on survival.
Conclusion：Advanced age did not directly lead to poor survival outcomes and adverse events. Although higher Eastern Cooperative Oncology Group scores and comorbidity led to impaired survival and higher incidence of adverse events, the latter had no mediation effects on survival outcomes.
Colorectal cancer (CRC) has long been the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide 1. In China, both the incidence and mortality of CRC have increased in recent decades, with estimated rates of 376.3 and 191.0 per 100,000 patients, respectively 2. Most CRC patients in China are diagnosed between 60 and 74 years of age 2. As the population is aging 3, older patients will be exposed to the risks of CRC. Combination of surgery and postoperative adjuvant chemotherapy is recommended as standard for resectable advanced-grade tumors 4–6. 5-Fluorouracil (5-FU)/oxaliplatin (FOLFOX) and capecitabine/oxaliplatin (CAPEOX) are used as first-line adjuvant chemotherapy and improve overall survival (OS) compared with surgery alone 6–8. 5-FU/leucovorin and 5-FU/irinotecan (FOLFIRI) are alternative choices in clinical practice.
When making clinical decisions, adverse events related to chemotherapy must be taken into consideration. However, few clinical trials have focused on the effects of adverse events, especially in patients with advanced age and high Eastern Cooperative Oncology Group (ECOG) scores, partly because those patients are generally excluded from clinical trials 9. According to a European cohort, only a small percentage of older patients with stage III CRC received adjuvant chemotherapy 10. In addition, advanced aged, more comorbidity, poor health status, and concern for adverse events are related to the choice of nonaggressive chemotherapy, which might lead to higher recurrence rates and mortality in older patients with CRC 11, 12. Because of the lack of literature, clinicians have had to rely on their experience, which might result in undertreatment of patients in poor physical condition. Moreover, few studies have systematically investigated the adverse events related to adjuvant chemotherapy in Chinese CRC patients.
Patients with various clinicopathological parameters, such as different age and performance status, might respond differently to postoperative adjuvant chemotherapy 13. Furthermore, adverse events related to chemotherapy could play an important role in this process, as their incidence may determine the outcomes of specific groups of patients.
The aim of our study was to calculate the cumulative incidences of adverse events in patients with different clinicopathological parameters and chemotherapy regimens. Furthermore, we conducted a mediation analysis to explore whether adverse events related to chemotherapy affected survival outcomes.
Population
This retrospective study included 408 CRC patients who received standard adjuvant chemotherapy according to the standard guidelines after tumor resection at the Department of Oncology, Peking Union Medical College Hospital (PUMCH) from 2015 to 2018. The records of each patient were reviewed independently by two researchers. We recorded basic characteristics including demographic data (sex and age); tumor characteristics (tumor location, differentiation level and TNM stage at diagnosis); ECOG score; comorbidity (hepatitis, diabetes mellitus and hypertension); and chemotherapy information (drugs and regimens). An age of 65 years, which is commonly accepted as the definition of old people in most nations including China, was selected as the cutoff age in the two groups.
All patients gave signed informed consent before the study. The study was approved by the Ethics Committee of PUMCH.
Follow-up
Overall survival (OS) was defined as the time from surgery until death or last follow-up. We compared the OS curves of different groups of patients. All patients were followed up until January 2019.
Survival Analysis
Median OS was 71 months in the young and 56 months in the old patients (p = 0.33). Median OS was 59 months in the ECOG score 0 group and 56 months in the ECOG score ≥1 group (p = 0.05) (Supplementary Fig. 1). We investigated whether comorbidity affected OS in all patients (Supplementary Fig. 2 and Supplementary Fig. 3). Hepatitis, diabetes and hypertension did not influence OS significantly. In subgroup analysis, old patients with hepatitis tended to have shorter OS (p = 0.16) compared with those without hepatitis, while young patients with hepatitis had significantly longer OS compared with those without hepatitis (p = 0.088). Diabetes was another predictor for old patients with shorter OS (p = 0.044).
Adverse Events
Adverse events were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, 2017, and included: myelosuppression (grade I–IV), digestive adverse events (nausea, vomiting and diarrhea), fever and numbness. For patients who received more than 1 chemotherapy programs in different time periods, we only included adverse events took place the first time in each program. The specific chemotherapy cycle in which an adverse event took place for first time was recorded. The incidence for each type of adverse events related to different drugs in all cycles and the first 4 cycles were calculated and compared among different groups.
Mediation Analysis
Nausea, vomiting and diarrhea had significant different incidences in different patient populations, and were chosen as potential mediators that might influence survival outcomes. No significant mediation effects were found (Fig. 1 and Fig. 2).
Population
Basic characteristics of the 408 CRC patients enrolled in this study are presented in Table 1. Patients were divided into groups according to age and ECOG score. There was no significant difference in clinicopathological characteristics between young (≤65 years, N = 119) and old (> 65 years, N = 289) patients, except that the latter had a significantly higher incidence of hepatitis. Patients with higher ECOG scores ≥1 (N = 60) had comparable clinicopathological characteristics to patients with lower ECOG score 0 (N = 95). The rates of different chemotherapy regimens utilized in clinical practice were also counted: for the old, irinotecan alone was more commonly used compared to the young (p = 0.002); for those with higher ECOG scores, capecitabine was more commonly used (p = 0.003). (Table 1)
|
Age groups |
ECOG groups |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
Characteristics |
Young(≤ 65) N = 289 |
Old (> 65) N = 119 |
p value |
ECOG = 0 N = 95 |
ECOG ≥ 1 N = 60 |
p value |
||||
|
Sex, male/female |
165/124 |
75/44 |
0.325 |
58/37 |
31/29 |
0.325 |
||||
|
Age, mean ± SE |
54.53 ± 9.71 |
70.15 ± 3.84 |
58.43 ± 9.83 |
61.31 ± 11.16 |
||||||
|
Location of tumor |
||||||||||
|
Colon |
140 |
65 |
0.338 |
56 |
27 |
0.126 |
||||
|
Right colon |
66 |
35 |
0.457 |
22 |
17 |
0.073 |
||||
|
Left colon |
74 |
29 |
34 |
10 |
||||||
|
Rectum |
149 |
54 |
39 |
33 |
||||||
|
Differentiation level |
0.438 |
0.799 |
||||||||
|
Low |
29 |
17 |
2 |
2 |
||||||
|
Medium |
162 |
64 |
54 |
29 |
||||||
|
High |
23 |
8 |
15 |
9 |
||||||
|
x |
77 |
31 |
24 |
20 |
||||||
|
T stage |
0.104 |
0.762 |
||||||||
|
1 |
8 |
1 |
1 |
0 |
||||||
|
2 |
18 |
9 |
3 |
4 |
||||||
|
3 |
157 |
45 |
50 |
29 |
||||||
|
4 |
70 |
36 |
27 |
16 |
||||||
|
x |
36 |
28 |
14 |
11 |
||||||
|
N stage |
0.064 |
0.189 |
||||||||
|
0 |
46 |
16 |
14 |
5 |
||||||
|
1 |
128 |
47 |
30 |
26 |
||||||
|
2 |
72 |
23 |
33 |
16 |
||||||
|
3 |
0 |
2 |
0 |
0 |
||||||
|
x |
43 |
31 |
18 |
13 |
||||||
|
M stage |
0.468 |
0.066 |
||||||||
|
0 |
143 |
54 |
43 |
19 |
||||||
|
1 |
77 |
40 |
32 |
30 |
||||||
|
x |
68 |
25 |
20 |
11 |
||||||
|
ECOG |
0.175 |
|||||||||
|
0 |
73 |
22 |
/ |
/ |
||||||
|
1 |
31 |
20 |
/ |
/ |
||||||
|
2 |
5 |
2 |
/ |
/ |
||||||
|
3 |
3 |
1 |
/ |
/ |
||||||
|
x |
179 |
75 |
/ |
/ |
||||||
|
Comorbidities |
||||||||||
|
Hypertension |
38 |
18 |
0.716 |
27 |
16 |
0.957 |
||||
|
Diabetes |
20 |
7 |
0.88 |
9 |
12 |
0.104 |
||||
|
Hepatitis |
17 |
18 |
0.004 |
17 |
7 |
0.414 |
||||
|
Chemotherapy regimens |
||||||||||
|
FOLFOX |
66 |
28 |
0.983 |
25 |
16 |
0.999 |
||||
|
CAPEOX |
158 |
67 |
0.848 |
34 |
13 |
0.092 |
||||
|
FOLFIRI |
37 |
22 |
0.184 |
13 |
5 |
0.450 |
||||
|
Capecitabine |
25 |
11 |
0.999 |
2 |
9 |
0.003 |
||||
|
Irinotecan |
7 |
12 |
0.002 |
5 |
5 |
0.511 |
||||
Adverse Events In Different Age Groups
There was significantly higher incidences of digestive adverse events in the young and old patients: the incidence of nausea were 40% versus 27% (p = 0.014) and the incidence of vomiting were 28% versus 13% (p = 0.002) (Table 2). There was no significant difference in other adverse events (diarrhea, hematological toxicity, numbness and fever) between young and old patients. The rates of adverse events related to different drugs are summarized in Table 3. In the oxaliplatin group, young patients had higher rates of digestive adverse events including nausea (36% versus 22%, p = 0.024) and vomiting (23% versus 10%, p = 0.011) for all cycles. In the 5-FU group, 27% of young patients experienced vomiting during treatment compared with 10% of old patients (p = 0.028). In the capecitabine and irinotecan group, no significant difference was observed between the young and old patients.
|
Old |
Young |
p value |
ECOG = 0 |
ECOG\(\ge\)1 |
p value |
|
|---|---|---|---|---|---|---|
|
N = 119 |
N = 289 |
N = 95 |
N = 60 |
|||
|
I |
4(3%) |
10(3%) |
0.254 |
4(4%) |
5(8%) |
0.361 |
|
II |
11(9%) |
15(5%) |
11(12%) |
3(5%) |
||
|
III |
5(4%) |
22(8%) |
6(6%) |
4(7%) |
||
|
IV |
2(2%) |
4(1%) |
3(3%) |
3(5%) |
||
|
Digestive toxicity |
||||||
|
Nausea |
32(27%) |
116(40%) |
0.014 |
28(30%) |
28(47%) |
0.049 |
|
Vomit |
15(13%) |
80(28%) |
0.002 |
21(22%) |
24(40%) |
0.026 |
|
Diarrhea |
19(16%) |
46(16%) |
1 |
13(14%) |
21(36%) |
0.003 |
|
General toxicity |
||||||
|
Numb |
20(17%) |
50(18%) |
1 |
16(17%) |
11(18%) |
1 |
|
Fever |
15(13%) |
39(13%) |
1 |
14(15%) |
16(27%) |
0.104 |
|
Oxaliplatin |
5-Fluorouracil |
Capecitabine |
Irinotecan |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Old |
Young |
p value |
Old |
Young |
p value |
Old |
Young |
p value |
Old |
Young |
p value |
|
|
N = 95 |
N = 224 |
N = 50 |
N = 103 |
N = 78 |
N = 183 |
N = 34 |
N = 44 |
|||||
|
Hematologic |
0.457 |
0.104 |
1 |
0.559 |
||||||||
|
toxicity |
||||||||||||
|
I |
2(2%) |
7(3%) |
1(2%) |
5(5%) |
2(3%) |
3(2%) |
1(3%) |
2(5%) |
||||
|
II |
8(8%) |
10(5%) |
5(10%) |
7(7%) |
5(6%) |
7(4%) |
2(6%) |
1(2%) |
||||
|
III |
5(5%) |
15(7%) |
0(0%) |
8(8%) |
5(6%) |
9(5%) |
1(3%) |
3(7%) |
||||
|
IV |
0(0%) |
2(1%) |
2(4%) |
2(2%) |
0(0%) |
1(1%) |
3(9%) |
1(2%) |
||||
|
Digestive toxicity |
||||||||||||
|
Nausea |
21(22%) |
80(36%) |
0.024 |
11(22%) |
35(34%) |
0.184 |
16(21%) |
61(33%) |
0.072 |
8(24%) |
12(27%) |
0.968 |
|
Vomit |
9(10%) |
52(23%) |
0.011 |
5(10%) |
28(27%) |
0.028 |
9(12%) |
40(22%) |
0.087 |
5(15%) |
11(25%) |
0.424 |
|
Diarrhea |
5(5%) |
20(9%) |
0.322 |
6(12%) |
22(21%) |
0.257 |
6(8%) |
12(7%) |
0.981 |
9(27%) |
15(34%) |
0.677 |
|
General toxicity |
||||||||||||
|
Numb |
13(14%) |
32(14%) |
1 |
8(16%) |
14(14%) |
0.933 |
9(12%) |
24(13%) |
0.985 |
2(6%) |
3(7%) |
1 |
|
Fever |
9(10%) |
26(12%) |
0.748 |
7(14%) |
15(15%) |
1 |
4(5%) |
17(9%) |
0.395 |
5(15%) |
4(9%) |
0.492 |
Adverse Events In Groups With Different Ecog Scores
The rates of digestive adverse events were significantly higher in patients with ECOG score ≥1 compared with ECOG score 0 (p = 0.049 for nausea, p = 0.026 for vomiting and p = 0.003 for diarrhea) (Table 2). The rates of adverse events related to different drugs are summarized in Table 4. No significant different incidences were observed between patients with ECOG scores 0 and ≥1.
|
Oxaliplatin |
5-Fluorouracil |
Capecitabine |
Irinotecan |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
ECOG = 0 |
ECOG ≥ 1 |
p value |
ECOG = 0 |
ECOG ≥ 1 |
p value |
ECOG = 0 |
ECOG ≥ 1 |
p value |
ECOG = 0 |
ECOG ≥ 1 |
p value |
|
|
N = 59 |
N = 29 |
N = 38 |
N = 21 |
N = 36 |
N = 22 |
N = 18 |
N = 10 |
|||||
|
Hematologic toxity |
||||||||||||
|
I |
3(5%) |
3(10%) |
1 |
3(8%) |
2(10%) |
0.697 |
1(3%) |
1(5%) |
1 |
2(11%) |
0(0%) |
0.232 |
|
II |
3(5%) |
2(7%) |
4(11%) |
0(0%) |
2(6%) |
2(9%) |
2(11%) |
0(0%) |
||||
|
III |
4(7%) |
2(7%) |
2(5%) |
0(0%) |
2(6%) |
2(9%) |
0(0%) |
1(10%) |
||||
|
IV |
1(2%) |
0(0%) |
1(3%) |
0(0%) |
0(0%) |
0(0%) |
0(0%) |
0(0%) |
||||
|
Digestive toxicity |
||||||||||||
|
Nausea |
19(32%) |
12(41%) |
0.562 |
17(45%) |
9(43%) |
1 |
7(19%) |
8(36%) |
0.258 |
4(22%) |
6(60%) |
0.097 |
|
Vomit |
14(24%) |
11(38%) |
0.284 |
12(32%) |
9(43%) |
0.576 |
7(19%) |
8(36%) |
0.258 |
5(28%) |
5(50%) |
0.412 |
|
Diarrhea |
6(10%) |
4(14%) |
0.724 |
7(18%) |
8(38%) |
0.167 |
3(8%) |
3(14%) |
0.664 |
4(22%) |
5(50%) |
0.211 |
|
General toxicity |
||||||||||||
|
Numb |
7(12%) |
5(17%) |
0.768 |
3(8%) |
3(14%) |
0.656 |
5(14%) |
3(14%) |
1 |
0(0%) |
0(0%) |
1 |
|
Fever |
7(12%) |
5(17%) |
0.768 |
8(21%) |
3(14%) |
0.754 |
1(3%) |
4(18%) |
0.063 |
3(17%) |
2(20%) |
1 |
Adverse Events In Different Comorbidity Groups
Hepatitis and diabetes were negative predictors for OS in old patients; therefore, we divided patients according to comorbidity in old and young patients. The incidence of adverse events did not differ significantly in old patients with or without hepatitis (Supplementary Table 1). Although not significant, there was a trend towards more adverse events in old patients with diabetes compared with those without diabetes (Supplementary Table 2). Consistent with survival analysis in which hepatitis was a predictor for longer OS, when adverse events were compared in young patients with or without hepatitis, there was a trend towards less digestive toxicity in patients with hepatitis (Supplementary Table 3).
To our knowledge, this is the first Chinese population-based study to explore the adverse events related to adjuvant chemotherapy in CRC patients. We found that the incidence of adverse events differed according to age, ECOG score and comorbidity, and adverse events had no mediation effects on survival outcomes.
Distant metastasis 15, lymph node metastasis 16, 17, and performance scores 15, 18, 19 have been reported as prognostic factors for CRC patients. We found some other factors that may influence survival outcomes in certain groups of patients. For example, impaired survival outcomes were observed in old patients with diabetes compared with those without diabetes. As previously reported, the increased mortality in diabetes patients was mainly related to cardiovascular diseases 20 and cancer-specific complications 21. However, we found no significantly high incidence of treatment-related adverse events in patients with diabetes. We suppose that diabetes may lead to impaired survival by causing more cardiovascular events or infections rather than treatment-related toxicity.
We observed a trend that young patients with hepatitis tended to have longer survival outcomes than those without hepatitis. As previously reported, chronic HBV infection may be associated with reduced hepatic metastasis of CRC 22, 23 and prolonged survival of CRC patients 22. After HBV infection, hepatic microenvironment may change, including gene products about immune function 24. Cytotoxic T lymphocytes and Kupffer cells are activated during HBV replication and may play important roles in preventing hepatic metastasis 25. In addition, patients with hepatitis may have sufficient supportive cares in their family, which leads to better treatment results. The positive effect of hepatitis on survival of young patients was not observed in old patients, partly because of the less-functional immune system in the latter. Moreover, there was no significant difference in adverse events between the groups, which means that hepatitis may not reduce the incidence of treatment-related toxicity in young CRC patients.
In the literature, it is controversial whether CRC patients with advanced age and/or higher ECOG scores have more adverse events after receiving adjuvant chemotherapy 13. For example, a pooled analysis of 3351 patients showed that 5-FU- or capecitabine-based adjuvant chemotherapy benefitted older patients to the same extent as younger patients, without a significant increase in adverse events 26. Hamza et al. reported no significant difference in adverse events among old compared with young patients, which meant that tolerance to FOLFOX regimen was comparable among old and young patients 27. Lund et al. reported that age had no impact on disease-free survival and CRC mortality 28. In a recent study, advanced age and poor performance status were negative predictors of severe adverse events and long hospitalization 29. In the present study, the incidence of adverse events was comparable between the old and young patients, except for digestive adverse events, which were more common among young patients using oxaliplatin and 5-FU. Digestive adverse events, especially nausea, are related to subjective sensations; therefore, old patients might ignore the discomfort caused by weak gastrointestinal function. However, a trend towards higher frequency of digestive toxicity in older patients was reported by Hamza et al. 27. The inconsistent results might have originated from racial differences among the patients and the small sample size of both studies. In addition, we found more digestive adverse events in patients with ECOG score ≥1, which was consistent with previous studies that showed that patients with poor performance scores were less responsive to chemotherapy 18, 29. However, mediation analysis showed that the incidence of digestive adverse events did not lead to poor survival. We suggest that, as long as patients receive proper treatment on time, the occurrence of digestive adverse events does not lead directly to death. However, it is possible that those adverse events may impair quality of life or lead to longer hospitalization and higher expense for cancer patients.
It is reported that older patients might suffer from undertreatment when receiving chemotherapy, mainly because of the reluctance of doctors, risk of severe adverse events, and comorbidity 30–32. However, based on our study, advanced age and higher ECOG scores do not directly lead to poor survival outcomes and adverse events. In addition, mediation analysis showed that adverse effects do not influence survival outcomes. Therefore, we suggest that concern about treatment-related adverse events in patients with advanced age, higher ECOG scores and comorbidity should not be considered as an independent indicator for less-aggressive treatment.
There were some limitations to this research. First, this was a single-center retrospective study, which could have led to selection bias. Besides, the medical records of several patients were not complete, such as only 155 patients in our study had ECOG scores. However, we had compared the basic characteristics and survival outcomes between those with and without ECOG scores and found no selectin bias in most indexes (Supplementary table 4) .Prospective studies are required to explore the potential adverse events and efficiency of adjuvant chemotherapy in Chinese CRC patients. Moreover, physicians will always choose to adjust the dose of chemotherapy regimens once adverse events occurred in clinical practice. Although we only recorded the incidence of adverse events which took place the first time, the change of dose may influence the survival outcomes. Finally, long-term survivals could not be analyzed because of the short follow-up. We are keeping contact with the patients included in our study and we intend to report the updated survival outcomes in the future.
In conclusion, this is believed to be the first Chinese population study to focus on adverse events related to adjuvant chemotherapy in CRC patients. We found that advanced age did not directly lead to poor survival outcomes and adverse events. Although higher ECOG scores and comorbidity led to impaired survival and higher incidence of adverse events, the latter had no mediation effects on survival outcomes. Therefore, we propose a more aggressive treatment strategy for patients with advanced age, poor ECOG score and comorbidity, without undue concern about the possible adverse events after chemotherapy. We believe that monitoring adverse events related to chemotherapy instead of potential undertreatment may help prolong survival and improve quality of life for more patients.
Ethics approval and consent to participate
This retrospective study was approved by the Ethics Committee of Peking Union Medical College Hospital, and the informed consent were signed by patients when they admitted into hospital. The procedure in this study was performed in accordance to the Code of Conduct of the China Medical Scientific Societies.
Consent for publication
Not applicable.
Availability of data and materials
The datasets generated during the current study are not publicly available since they will contain patient data and the informed consent agreement does not include sharing data publicly. An anonymized form of the data could be made available from the corresponding author upon reasonable request.
Competing interests
None
Funding
This study was supported by grants from CAMS Initiative for Innovative Medicine (No. 2017-I2M-4-002; No. 2016-I2M-1-001) and National Natural Science Foundation of China (No. 81472785; No. 61435001)
Authors' contributions
W.Y. contributed to the study conception and design, G.C. and T.Y. collected the clinical data, G.C., T.Y. and Z.N. wrote the main manuscript and prepared figures and tables. All authors reviewed the manuscript.
Acknowledgments
We thank Huanhuan Liu and Cathel Kerr for editing the English text of the manuscript. We also thank all involved patients and their relatives, physicians and pathologists for their collaboration.
[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424.
[2] Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016 Mar-Apr;66(2):115-32.
[3] Yi Z, Vaupel JW, Xiao Z, Zhang C, Liu Y. The Healthy Longevity Survey and the Active Life Expectancy of the Oldest Old in China. Popul Engl Selection. 2001;13(1):95-116.
[4] Laurie J, G Moertel C, R Fleming T, S Wieand H, E Leigh J, Rubin J, et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1989 11/01;7:1447-56.
[5] Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. The New England journal of medicine. 1990 Feb 8;322(6):352-8.
[6] Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. The New England journal of medicine. 2004 Jun 3;350(23):2343-51.
[7] Gill S, Loprinzi CL, Sargent DJ, Thome SD, Alberts SR, Haller DG, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004 May 15;22(10):1797-806.
[8] Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet (London, England). 2007 Dec 15;370(9604):2020-9.
[9] Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA. Examining the evidence: a systematic review of the inclusion and analysis of older adults in randomized controlled trials. Journal of general internal medicine. 2011 Jul;26(7):783-90.
[10] Aparicio T, Navazesh A, Boutron I, Bouarioua N, Chosidow D, Mion M, et al. Half of elderly patients routinely treated for colorectal cancer receive a sub-standard treatment. Crit Rev Oncol Hematol. 2009 Sep;71(3):249-57.
[11] Droz JP, Aapro M, Balducci L. Overcoming challenges associated with chemotherapy treatment in the senior adult population. Critical Reviews in Oncology/hematology. 2008;68(1):S1-S8.
[12] Krzyzanowska MK, Regan MM, Powell M, Earle CC, Weeks JC. Impact of patient age and comorbidity on surgeon versus oncologist preferences for adjuvant chemotherapy for stage III colon cancer. J Am Coll Surg. 2009;208(2):202-9.
[13] McCleary NJ, Meyerhardt JA, Green E, Yothers G, de Gramont A, Van Cutsem E, et al. Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: findings from the ACCENT database. J Clin Oncol. 2013 Jul 10;31(20):2600-6.
[14] Tingley D, Yamamoto T, Hirose K, Keele L, Imai K. mediation: R Package for Causal Mediation Analysis. 2014. 2014 2014-09-02;59(5):38.
[15] Kemeny N, Braun DW. Prognostic factors in advanced colorectal carcinoma: Importance of lactic dehydrogenase level, performance status, and white blood cell count. The American Journal of Medicine. 1983 1983/05/01/;74(5):786-94.
[16] Greene FL, Stewart AK, Norton HJ. A new TNM staging strategy for node-positive (stage III) colon cancer: an analysis of 50,042 patients. Ann Surg. 2002 Oct;236(4):416-21; discussion 21.
[17] Resch A, Langner C. Lymph node staging in colorectal cancer: old controversies and recent advances. World J Gastroenterol. 2013 Dec 14;19(46):8515-26.
[18] Crosara Teixeira M, Marques DF, Ferrari AC, Alves MF, Alex AK, Sabbaga J, et al. The effects of palliative chemotherapy in metastatic colorectal cancer patients with an ECOG performance status of 3 and 4. Clinical colorectal cancer. 2015 Mar;14(1):52-7.
[19] Lavin P, Mittelman A, Douglass Jr H, Engstrom P, Klaassen D. Survival and response to chemotherapy for advanced colorectal adenocarcinoma. An eastern cooperative oncology group report. Cancer. 1980 1980/10/01;46(7):1536-43.
[20] Luo J, Lin HC, He K, Hendryx M. Diabetes and prognosis in older persons with colorectal cancer. Br J Cancer. 2014;110(7):1847-54.
[21] Huang YC, Lin JK, Chen WS, Lin TC, Yang SH, Jiang JK, et al. Diabetes mellitus negatively impacts survival of patients with colon cancer, particularly in stage II disease. J Cancer Res Clin Oncol. 2011 Feb;137(2):211-20.
[22] Song E, Chen J, Ou Q, Su F. Rare occurrence of metastatic colorectal cancers in livers with replicative hepatitis B infection. American journal of surgery. 2001 Jun;181(6):529-33.
[23] Qiu H-B, Zhang L-Y, Zeng Z-L, Wang Z-Q, Luo H-Y, Keshari RP, et al. HBV infection decreases risk of liver metastasis in patients with colorectal cancer: A cohort study. World J Gastroenterol. 2011;17(6):804-8.
[24] Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006 Aug;10(2):99-111.
[25] Tordjmann T, Soulie A, Guettier C, Schmidt M, Berthou C, Beaugrand M, et al. Perforin and granzyme B lytic protein expression during chronic viral and autoimmune hepatitis. Liver. 1998 Dec;18(6):391-7.
[26] Sargent DJ, Goldberg RM, Jacobson SD, Macdonald JS, Labianca R, Haller DG, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. The New England journal of medicine. 2001 Oct 11;345(15):1091-7.
[27] Hamza S, Bouvier AM, Rollot F, Lepage C, Faivre J, Bedenne L. Toxicity of oxaliplatin plus fluorouracil/leucovorin adjuvant chemotherapy in elderly patients with stage III colon cancer: a population-based study. Ann Surg Oncol. 2014 Aug;21(8):2636-41.
[28] Lund CM, Nielsen D, Dehlendorff C, Christiansen AB, Ronholt F, Johansen JS, et al. Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colorectal cancer: the ACCORE study. ESMO Open. 2016;1(5):e000087.
[29] Abdel-Rahman O, Ahmed O. Predictors of toxicity-related hospitalization in four randomized studies of 5-fluorouracil-based chemotherapy in metastatic colorectal cancer. Int J Colorectal Dis. 2019 Apr;34(4):675-80.
[30] Bouvier AM, Launoy G, Lepage C, Faivre J. Trends in the management and survival of digestive tract cancers among patients aged over 80 years. Alimentary Pharmacology & Therapeutics. 2005;22(3):233.
[31] Ayanian JZ, Zaslavsky AM, Fuchs CS, Edward G, Creech CM, Cress RD, et al. Use of adjuvant chemotherapy and radiation therapy for colorectal cancer in a population-based cohort. Journal of Clinical Oncology. 2003;21(7):1293-300.
[32] Sundararajan V, Grann VR, Jacobson JS, Ahsan H, Neugut AI. Variations in the use of adjuvant chemotherapy for node-positive colon cancer in the elderly: a population-based study. Cancer Journal. 2001;7(3):213