Oncologic outcomes and associated factors of colon cancer patients aged 70 years and older
Article information
Abstract
Purpose
The aim of this study was to examine the prognosis and associated risk factors, including adjuvant chemotherapy (CTx), in elderly patients with colon cancer
Methods
This retrospective study included patients who underwent radical resection for colon cancer between January 2010 and December 2014 at Asan Medical Center. The effects of stage, risk factors, and chemotherapy on overall survival (OS) and recurrence-free survival (RFS) were compared in patients aged ≥70 and <70 years.
Results
Of 3,313 patients, 933 (28.1%) was aged ≥70 years. Of the 1,921 patients indicated for adjuvant CTx, 1,294 of 1,395 patients (92.8%) aged <70 years and 369 of 526 patients (70.2%) aged ≥70 years received adjuvant CTx. Old age (≥70 years) was independently associated with RFS in overall cohort. Among patients aged ≥70 years indicated for adjuvant CTx, the 5-year OS (81.6% vs. 50.4%, P<0.001) and RFS (82.9% vs. 67.4%, P=0.025) rates were significantly higher in those who did than did not receive adjuvant CTx. Additionally, adjuvant CTx was confirmed as independent risk factor of both OS and RFS in patients aged ≥70 years indicated for adjuvant CTx.
Conclusion
Old age was associated with poor RFS and adjuvant CTx had benefits in OS as well as RFS in elderly patients eligible for adjuvant CTx.
INTRODUCTION
Colorectal cancer is the third most common cancer worldwide after breast and lung cancers and the second most common cause of cancer-related deaths after lung cancer [1]. Increases in the elderly population have been accompanied by increases in the proportion of elderly persons with colorectal cancer, with about 60% of colon cancer patients diagnosed at age ≥65 years. In addition, the mortalities of aged 60 years and older has been reported to be increased and comprised 83.5% of the total colorectal cancer mortalitied in 2020 [2]. Therefore, the screening, treatment and prognosis of elderly patients with colorectal cancer are social concerns [3–6].
Studies regarding the prognosis and treatment of elderly colorectal cancer patients have yielded conflicting results. For example, several studies have reported that patient prognosis was poor, even with active treatment [7, 8], whereas other studies found that treatment improved prognosis [9, 10]. Various factors have been found to affect prognosis including underlying diseases, general performance status, and comorbidities, making it challenging to establish treatment guidelines for elderly patients. Age-related physiological changes, such as organ decline, comorbidities, and functional deterioration, create a distinct set of obstacles. Cancer itself adds another level of difficulty to the aging process, as older adults with cancer are more likely to experience impairments in their capacity to take care of themselves, have poorer self-rated health, and have additional age-related syndromes, such as cognitive impairments and falls. Several studies have therefore analyzed methods of enhancing physical and mental performance and of accurately assessing performance in elderly cancer patients [11, 12].
Improving the prognosis of elderly patients may result in overall improvements in the prognosis of all patients with colorectal cancer as the proportion of elderly patients increases. The present study therefore retrospectively investigated the prognosis in elderly patients with colon cancer and assessed the effects of factors, including adjuvant chemotherapy, on patient prognosis. These findings may assist in establishing guidelines for treatment of elderly patients
METHODS
Ethics statement
The study protocol was approved by the Institutional Review Board of Asan Medical Center (No. ****). The requirmenet for informed consent was waived due to the retrospective nature of the study. The study was conducted in accordance with the ethical principles of the 1964 Declaration of Helsinki.
Patients
The records of consecutive patients who underwent curative surgery for colon cancer between January 2010 and December 2014 at Asan Medical Center (Seoul, Korea), were reviewed retrospectively. Clinicopathologic features, pathologic staging, adjuvant chemotherapy (CTx), recurrence, and survival were recorded. Patients were included if they were diagnosed with histologically confirmed colon cancer and underwent curative resection. Patients with rectal cancer, concurrent or prior malignancies, and distant metastases, as well as those who did not undergo surgical treatment, were excluded. Patients aged ≥70 years were defined as elderly, whereas those aged <70 years were defined as nonelderly.
Radical resection including primary tumor and mesocolon was performed. The extent of surgery was not affected by age. Adjuvant CTx was recommended for patients with pathologic stage III colon cancer and for patients with pathologic stage II colon cancer with high-risk features such as preoperative obstruction, including both endoscopic obstruction and clinically total obstruction; inadequate lymph node examination (<12 lymph nodes retrieved); lymphovascular invasion (LVi); perineural invasion (PNi); histologically poor differentiation; high tumor budding; or resection margin involvement. The final decision to administer adjuvant CTx was determined after discussions among medical oncologist, surgeon, and patient, with considerations including pathologic report, the general health condition, family support, and socioeconomic status of each patient.
Surveillance
Patients were followed up every 3 to 12 months for up to 5 years after surgery. Follow-up evaluations included physical examination, blood tests, including measurements of carcinoembryonic antigen (CEA) levels, and abdominopelvic, and/or chest computed tomography (CT). These CT scans were performed every 6 to 12 months. Patients were evaluated by colonoscopy within 1 year after surgery and then once every 2 or 3 years. Patients with preoperative obstruction underwent colonoscopy within 6 months after surgery.
Statistical analysis
Recurrence-free survival (RFS) was defined as the time from the date of surgery to the date of tumor recurrence or last date of follow-up. Overall survival (OS) was defined as the time from the date of surgery to the date of death from any cause (not cancer-specific death) or last date of follow-up. Categorical variables were compared using chi-square test and continuous variables were compared using t-test. OS and RFS were determined using the Kaplan-Meier method and compared by log-rank test. Multivariable Cox proportional hazards analyses were used to evaluate risk factors associated with RFS, including age, sex, LVi, PNi, pathologic staging, and adjuvant CTx. Rrisk factors associated with OS was also analyzed in patients aged ≥70 years. All statistical analyses were performed using IBM SPSS ver. 21.0 (IBM Corp), with P-values of <0.05 considered statistically significant.
RESULTS
Patient characteristics
During the study period, 3,313 patients, including 1,888 men (56.9%) and 1,425 women (43.1%), underwent R0 surgical resection for colon cancer. The mean age was 61.4±11.4 years. LVi was present in 893 patients (26.9%) and PNi in 579 (17.4%). Pathologically, most patients (77.3%) had moderately differentiated tumors, with the more common primary tumor site being the left colon (56.5%). The mean number of harvested lymph nodes was 27.7±13.9, with <12 lymph nodes harvested from about 2% of all patients. Of 3,313 patients, 933 (28.2%) were aged ≥70 years and 2,380 (71.8%) were aged <70 years.
The demographic and clinicopathologic characteristics of the 2 age groups are presented in Table 1. Pathologic stage was differently distributed among 2 groups (P<0.001). The percentage of patients with stages I and III colon cancer was significantly higher in the nonelderly than in the elderly group. The LVi was significantly common (P=0.003), but the PNi was less (P=0.003) in the elderly group. Less patients in the elderly than in the nonelderly group received adjuvant CTx (P<0.001). Of 3,313 patients, 1,921 (58.0%) were indicated for adjuvant CTx, and among those who indicated for adjuvant CTx, 1,663 patients (86.6%) received adjuvant CTx. Patients who received adjuvant CTx among patients indicated advjuant CTx was significantly lower (P<0.001) in elderly patients (70.2%) than nonelderly patients (92.8%). Of 124 elderly patients who were indiciated for adjuvant CTx but did not receive adjuvant CTx, the proportion of patients according to the reason for not implementing adjuvant CTx is as follows: recommendation of medical ongologist (n=47), patient and family reluctant to CTx (n=49), and follow-up loss or unknown (n=28).
Demographic and clinicopathologic characteristics of the study population (n=3,313)
Oncologic outcomes and associated factors in the overall cohort
The 5-year RFS rate was significantly higher in the nonelderly (89.8%) than in the elderly (86.4%) group (P<0.001). When analyzing the survival rate according to the staging, there was no significant difference between 2 troups in stage I (97.5% vs. 96.3%, P=0.391) and stage III (80.6% vs. 75.9%, P=0.100). The 5-year RFS rate, however, was significantly higher in the nonelderly than in the elderly patients with stage II colon cancer with high-risk features (91.7% vs. 85.4%, P=0.004) (Fig. 1). Multivariable analysis found that age, LVi, PNi, and stage were significantly associated with RFS, whereas CTx and sex were not (Table 2).
The recurrence-free survival (RFS) in nonelderly (<70 years) and elderly (≥70 years) patients according to pathologic stage. Elderly patients with stage II disease showed lower RFS. (A) Stage I colon cancer. (B) Stage II colon cancer with high-risk features. (C) Stage III colon cancer.
Univariable and multivariable analyses of risk factors for recurrence-free survival
Oncologic outcomes and associated factors in the elderly group
The elderly group who received adjuvant CTx showed higher 5-year OS rates (81.6% vs. 74.6%, P=0.014) than patients who were not treated with adjuvant CTx (Fig. 2). According to the subgroup analysis of elderly group by stage, patients receiving adjuvant CTx showed significantly higher 5-year OS rates in both high-risk stage II (83.4% vs. 67.2%, P=0.02) and stage III (80.3% vs. 27.5%, P<0.001) colon cancer than those who received adjuvant CTx (Fig. 2).
The overall survival (OS) according to adjuvant chemotherapy (CTx) treatment in the elderly group. Patients received adjuvant CTx showed improved OS. (A) All elderly patients. (B) Elderly patients indicated for adjuvant chemotherapy. (C) Elderly patients with stage II colon cancer with high-risk features. (D) Elderly patients with stage III colon cancer.
The 5-year RFS rate in the elderly group was significantly lower in those who received adjuvant CTx than patients did not receive adjuvant CTx (83.0% vs. 89.0%, P=0.027). But, among patients indicated for adjuvant CTx, the 5-year RFS rate was higher in patients treated with adjuvant CTx than those who did not (82.9% vs. 67.4%, P=0.024) (Fig. 3B). The 5-year RFS rate was significantly higher in elderly patients with stage III colon cancer who did than did not receive adjuvant CTx (79.9% vs. 41.4% P=0.001) (Fig. 3D), although these rates did not differ in elderly patients with high-risk stage II colon cancer (80.0% vs. 87.6%, P=0.517) (Fig. 3C).
The recurrence-free survival (RFS) according to adjuvant chemotherapy (CTx) treatment in the elderly group. In the overall group, adjuvant CTx group showed lower RFS; however, the adjuvant CTx group showed higher RFS in patients who were indicated for adjuvant CTx. (A) All elderly patients. (B) Elderly patients indicated for adjuvant chemotherapy. (C) Elderly patients with stage II colon cancer with high-risk features. (D) Elderly patients with stage III colon cancer.
In elderly patients, tumor stage and adjuvant CTx were significantly associated with both OS and RFS. Additionally, LVi and PNi were associated with RFS but not with OS (Table 3). In elderly patients who were indicated for adjuvant CTx, adjuvant CTx was significantly associated with OS and RFS. Tumor stage was associated with RFS but not with OS (Supplementary Table 1).
Univariable and multivariable analysis of risk factors for overall survival and recurrence-free survival in colon cancer patients aged ≥70 years
DISCUSSION
The present study found that elderly colon cancer patients showed significantly lower RFS as well as OS than nonelderly patients. Insufficient adjuvant CTx treatment in patients who indicated for adjuvant CTx might be responsible for poor oncologic outcome because adjuvant CTx was associated with OS and RFS in elderly patients indicated for adjuvant CTx. Because overall death rates are naturally higher in the elderly than in the nonelderly, this may affect the comparisons of OS rates in the entire study population. Therefore, only RFS between the elderly and the nonelderly was compared and analyzed its risk factors in the entire cohort.
Old age is a contextual concept that cannot be uniformly defined. Discrepancies between chronological age and biological age and interindividual differences in the aging process complicate the determination of standard definitions. The World Health Organization (WHO) has set a cutoff of 60 years, reporting that 1/6 of the population worldwide will be aged ≥60 years by 2030. Research studies have utilized various definitions of old age [13–15]. A survey by the Cabinet Office of the Japanese Government found that many people regard an age of >70 or 75 years as elderly [16], with these cutoffs adjustable for populations of other developed eastern countries. The present study therefore defined persons aged ≥70 as elderly.
The effects of old age on prognosis of colorectal cancer has been reported inconsistently [17–20]. Some reported that oncologic outcomes, especially late period survival, were similar in younger and older patients with resectable colorectal cancer [18], whereas other studies reported that prognosis was poorer in elderly than in younger patients with colorectal cancer [19, 20]. One of the reason suggested is that delyaed diagnosis of colon cancer of more advanced stage was comprised in the eldelry patients. The multimodal adjuvant therapy was less given in the elderly [21] and may cause medical comorbidities, which are more frequent in the elderly than in younger patients [22, 23]. Multivariable analyses in the present study found that age was a significant risk factor for RFS and that prognosis in elderly patients varied depending on whether adjuvant CTx was administered considering the pathologic stage.
Elderly patients, even those without additional comorbidities or a poor general performance status, tend to avoid aggressive treatment. In the present study, 39.5% of elderly patients who did not receive adjuvant CTx among the indicated adjuvant CTx group had no specific medical reason to avoid adjuvant CTx. On the other hand, 37.9% of patients were recommended not to undergo adjuvant treatment by a medical oncologist. Some studies reported that more than 50% of patients with indications for adjuvant CTx did not receive treatment [24–26]. Although it is higher than previous reports, only 70.2% of elderly patients with indications for adjuvant CTx received treatment, with the proportion being lower in the high-risk stage II group (62.3%) than in the stage III group (76.2%). The efficacy of adjuvant CTx in patients with high-risk stage II colon cancer remains unclear. Several trials [27–29] have reported that adjuvant CT was not associated with improved OS or disease-free survival rates in patients aged ≥70 years with stage II colon cancer, whereas another trial [30] found that adjuvant CTx in these patients was associated with improved prognosis. Additionally, the number of risk features has been associated with survival in patients with high-risk stage II colon cancer, with adjuvant CTx reported to benefit some patients with 3 or more high-risk features [31]. The survival benefit of adjuvant CTx in stasge III disease is more evident and generally accepted, and more elderly patients with stage III disease would receive adjuvant CTx than elderly with high-risk stage II disease.
The present study found that age was a key determinant of OS and RFS, and that adjuvant CTx was associated with improved oncologic outcomes in elderly patients. These findings assume that active treatment would improved ioncologic outcomes including RFS and OS in elderly paitents.
The toxicities of adjuvant CTx may be of particular concern in elderly patients. CTx has various adverse effects, including nausea, vomiting, fatigue, rash, and peripheral neuropathy. Moreover, the toxicities of CTx can be lethal, especially in elderly patients with poor general performance status or other severe comorbidities [32, 33]. Most elderly patients with cancer, however, can tolerate CTx, although some may require dose reductions [34, 35]. The present study showed that, among patients aged ≥70 years with indications for adjuvant CTx, those who received adjuvant CTx had a higher RFS rate than those who did not. If toxicities of CTx affect all elderly patients lethally, it compromise OS. The present study found that patients who received CTx aged ≥70 years, had a higher OS rate than those who did not, suggesting that the efficacy of CTx has a greater effect than its toxicities on oncologic outcomes in elderly patients. Indeed, based on the anesthesiology record sheets, there was no significant difference in the American Society of Anesthesiologists (ASA) physical status (PS) grade between patients who received CTx and those who did not receive it within the high-risk stage II group (P=0.126), stage III group (P=0.126), and group indicated for CTx (P=0.073) among the elderly patients. These findings suggest that old age itself becomes a hindering factor for adjuvant CTx, not necessarily due to medical problem, bur rather due to negative assumptions about adverse effects of adjuvant CTx in the elderly colon cancer patients.
The present study had some limitations, including its retrospective and nonrandomized design, which may have introduced selection biases. Although ASA PS grade was reported, detailed health condition could not be sufficiently assessed and why adjuvant CTx was not given might not be clearly evaluated. Moreover, toxicity of CTx could not be evaluated in the elderly patients and could not assess the actual risk of adjuvant CTx in the elderly group. Although this study included a large number of patients, all included patients were treated at a single center. Nevertheless, this large, single-center cohort study reflects real-world practice in patients with colon cancer. The finding that elderly patients with high-risk stage II colon cancer are less likely to receive adjuvant CTx than those with stage III colon cancer may also reflect real-world practice.
In conclusion, aging was shown to be substantially associated with RFS in patients with colon cancer. Adjuvant CTx improved OS and RFS rates even in elderly colon cancer patients indicated for adjuvant CTx. More active CTx would therefore be recommended for elderly patients who are eligible for it, regardless of age. Prospective studies are required to ascertain whether active treatment can improve prognosis for elderly patients with colon cancer in practice and to establish reliable treatment guidelines for adjuvant CTx in this patient population.
Notes
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Author contributions
Conceptualization: BLL, IJP; Data curation: IJP; Formal analysis: BLL, IJP; Funding acquisition: BLL; Investigation: IJP; Methodology: JSR, YIK, SBL, CSY; Project administration: BLL, IJP; Visualization: YIK, SBL, CSY; Writing–original draft: BLL, IJP; Writing–review & editing: all authors. All authors read and approved the final manuscript.
SUPPLEMENTARY MATERIALS
Supplementary Table 1.
Univariable and multivariable analysis of risk factors for overall survival and recurrence-free survival in colon cancer patients aged ≥70 years who were indicated for adjuvant CTx
Supplementary materials for this study are presented online (available at https://doi.org/10.3393/ac.2023.00367.0052).