Abstract
Introduction: Older patients (≤75 years) with advanced colorectal cancer (CRC) may have worse survival than non-older patients. We hypothesized that, rather than age alone, concurrent factors may be more relevant for real-world survival. Methods: Patients diagnosed with CRC in a 5-year period (2014–2018) were analyzed to determine which factors influenced in overall survival (OS). Kaplan-Meier method was used to estimate OS. Univariate and multivariate analysis was conducted by Cox regression analysis. The study was approved by Ethics Committee. Results: Out of 477 patients diagnosed with CRC, 231 had advanced disease. Ninety-two patients (40%) were older than 75 years; median OS (mOS) was 17.1 m (95% CI: 14.3–23.3), p < 0.001. In non-older patients, mOS was 26.7 m (95% CI: 21.9–32.6), p < 0.001. We evaluated eighteen concurrent factors that included characteristics related to the patient (age, sex, comorbidities, polypharmacy, Eastern Cooperative Oncology Group (ECOG), and nutritional status), to the tumor (stage at diagnosis, tumor side, molecular profile, tumor burden, location, and number of metastasis), and to the treatment administered (systemic treatment for advanced disease, chemotherapy schedule and number of lines, severe adverse events and dose reductions, and surgery of liver metastasis). In the univariate analysis, age at diagnosis, ECOG, nutritional status, tumor side, molecular profile, tumor burden, systemic treatment for advanced disease, and surgery of liver metastases had significant impact on survival. However, multivariate analysis revealed that only four factors (tumor burden, nutritional status, systemic treatment for advanced disease, and surgery of liver metastases) were independently associated with OS but not older age at diagnosis. Conclusion: Older age is not an independent survival prognostic factor for advanced CRC. Tumor burden, nutritional status, systemic treatment for advanced disease, and surgery of liver metastasis were significant factors associated with OS. These findings suggest that older patients should not be excluded from cancer treatment based on age alone.
Plain Language Summary
Older patients with advanced CRC constitute a heterogeneous population, including patients with excellent health status and others with multiple comorbidities, functional dependence, or limited life expectancy. Furthermore, the definition of an “elderly” or “older” patient is not widely accepted and may vary between studies, although 75 years may be an appropriate cut-off point, as confirmed in our study. At present, there are few prospective and randomized studies focused on the progression and treatment of advanced colorectal cancer in elderly patients, so understanding the factors that influence its clinical course is a difficult challenge. In this retrospective real-world study, we analyze the influence of advanced age on the survival of patients with advanced colorectal cancer. The analysis of eighteen characteristics that were grouped in three subcategories: characteristic related to the patient (age, sex, comorbidities, polypharmacy, ECOG, and nutritional status [albumin levels at diagnosis]), to the tumor (stage at diagnosis, tumor side, molecular profile, tumor burden [CEA levels at diagnosis], location and number of metastasis), and to the treatment administrated (systemic treatment for advanced disease, chemotherapy schedule and number of lines, severe adverse events and dose reductions, and surgery of liver metastasis) showed that older age at diagnosis is not an independent prognostic factor of overall survival in patients with metastatic colorectal cancer. However, tumor burden, nutritional status, systemic treatment of advanced disease, or surgery of liver metastases are independent predictors of survival.
Introduction
Colorectal cancer (CRC) is the third most common malignancy worldwide [1, 2] with highest incidence rates in Australia/New Zealand and European regions and increasing rates in transitioning countries [2]. According to the Global Cancer Observatory (GLOBOCAN), nearly 2 million new CRC cases and approximately 900,000 deaths were estimated in 2020 [2]. The number of new cases diagnosed each year is expected to increase due to longer life expectancy and population aging. Consequently, medical oncologists will confront an increasing number of older patients with CRC in their daily clinical practice [3]. It is considered that approximately 90% of all cancers develop after the age of 50 years [1], and in the case of CRC, 80% of patients with colon cancer are over 60 years at diagnosis [4]. International Society of Geriatric Oncology (SIOG) has made a major effort to implement geriatric oncology in clinical practice worldwide and improve healthcare for older patients with cancer [5‒7]. Currently, another aspect that deserves special attention is the increasing rates of CRC in young patients [2, 8].
CRC encompasses a complex interaction between individual genetic susceptibility and other well-known risk factors such as physical inactivity and obesity, a diet high in red and processed meats, smoking and alcohol consumption, and inflammatory bowel disease [8]. All risk factors described above are associated with alterations in the constitution of the gut microbiota [8, 9], a new emerging risk factor in CRC. Intestinal dysbiosis is considered to play a key role in carcinogenesis by altering the anti-inflammatory effects of the gut microbiome [8].
Diagnosis of CRC is routinely carried out by endoscopic methods in localized disease or by imaging techniques and biopsy in the advanced setting. A comprehensive pathological analysis of the tumor specimen is essential to identify possible biomarkers and molecular targets; deficient mismatch repair and KRAS/NRAS/BRAF testing are mandatory and should be assessed in all patients with diagnosis of CRC [10]. Similarly, testing human epidermal growth factor receptor 2 (HER-2) amplification would influence a treatment plan after at least first- or second-line progression [10].
Surgical resection is the standard of care for patients with localized stages at diagnosis followed by adjuvant chemotherapy based on clinicopathological risk factors [10, 11]. For advanced disease, chemotherapy based on fluoropyrimidines with oxaliplatin or irinotecan and molecular targeted agents (inhibiting the vascular endothelial growth factor [anti-VEGF therapy], or the epidermal growth factor receptor [anti-EGFR therapy]) is the gold standard [10]. In patients with oligometastasis, perioperative chemotherapy and metastasectomy should be considered [10].
Nowadays, new diagnostic tools are being developed with a focus on molecular biology, genetic engineering, and artificial intelligence. Circulating tumor DNA analysis, which is a minimally invasive biomarker, may enable postsurgical risk stratification and adjuvant chemotherapy treatment decision-making identifying patients at higher risk of recurrence who are likely to benefit from adjuvant chemotherapy [11]. The analysis of the tumor immune microenvironment has a prognostic and predictive value in CRC [12]. A multistain deep learning model utilizing artificial intelligence to determine an AImmunoscore was established in more than 1,000 patients with CRC providing clinicians a valuable decision-making tool based on the tumor immune microenvironment [12]. Also very recently, it has been suggested that the profiles of single-nucleotide polymorphisms and micro-RNAs could serve as a convenient approach for the prognosis and diagnosis of digestive cancers, such as CRCs [13].
Older patients represent the majority of CRC patients; however, this population is often underrepresented or not enrolled in randomized clinical trials (RCTs); because of this reason, many of these patients will likely be undertreated in clinical practice and they are therefore a population of particular interest [3, 6]. Moreover, the definition of “older patient” is not clear and it could often include patients aged from 65 to 75 or 80 years [14]. Chronological age does not always correlate to biological age due to the great disparity in the aging process [3, 6], and consequently, there is no specific chronological age to establish the exact limit that allows us to classify or define a person as “elderly.” In 2013, the Japan Gerontological Society and the Japan Geriatrics Society launched a joint committee to reconsider the definition of older patient and proposed a classification of people aged over 65 years as follows: aged from 65 to 74 years were considered as “pre-old age,” aged over 75 years were considered as “old age,” and, in addition, people aged over 90 years could be classified as “oldest-old or super-old” [15]. Therefore, a critical reevaluation of the role of “age” in the survival of patients with advanced CRC is essential.
Older patients constitute a heterogeneous population in terms of comorbidity and functional status [16] and age alone should not be used as an exclusive factor to deny access to potentially beneficial treatment to any CRC patient. Indeed, this broad population includes patients considered unfit for treatment, fit for single-agent treatments or for doublets; moreover, the real impact of chemotherapy outside RCTs is unclear [14, 17] and only a minority of RCTs are focused on older patients with metastatic CRC (mCRC) [18]. The most relevant prospective and RCTs, which specifically studied older patients with mCRC, older than 70 years of age, were FOCUS2 [19], FFCD-2001 [20], AVEX [21], and PRODIGE-20 [22, 23]. FFCD-2001 and FOCUS2 trial failed to demonstrate a significant benefit from the addition of irinotecan or oxaliplatin to fluorouracil or capecitabine in first-line treatment and showed in older patient increased toxicity when combination chemotherapy or capecitabine was used [19, 20]. The AVEX trial demonstrated that the combination of bevacizumab and capecitabine is an effective and well-tolerated regimen for older patients with mCRC in terms of progression-free survival (PFS) [21], and the PRODIGE-20 trial suggested a potential improvement in PFS with the addition of bevacizumab to fluorouracil [22]. Consequently, these studies demonstrate the benefit of chemotherapy treatment in older patients with advanced CRC but also the need to adapt our interventions according to the specific characteristics of this population. The aim of this study was retrospectively evaluating the influence of older age as an independent prognostic factor on the clinical course, defined by overall survival (OS), of patients with mCRC.
Methods
Study Design and Patient Population
This is a retrospective, observational, and longitudinal real-life study. Historical cohort of patients with advanced metastatic CRC was analyzed by accessing the electronic medical records of each patient at La Princesa University Hospital in Madrid.
All patients with diagnosis of gastrointestinal cancer who had been seen between January 1, 2014, and December 31, 2018, and had histopathological confirmation of colorectal adenocarcinoma and clinical and/or radiological confirmation of metastatic CRC, were selected for the final analysis. Minimum follow-up was 3 years and the end of follow-up date for data analysis was December 31, 2021. Patients with a synchronous or metachronous diagnosis of metastatic tumors of non-colorectal origin were excluded.
Cut-Off Point according to Age for the Definition of the Older Patient in Our Study
In our study, we first tested the use of “75 years” as the cut-off point to define “older patient” [15]. To confirm this approach, we decided to perform an exploratory univariate analysis by estimating the hazard ratio (HR) using unadjusted models for different age cut-off points defined by 5-year periods (shown in online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000535187). According to this analysis, the age of 75 years provided to be the best cut-off point since the HR for 60–65–70 years is similar, around 1.6, and a linear behavior is observed from 70 years onward, reaching a value of 2 with a cut-off point of 85 years. Furthermore, using the cut-off point of 75 years, we observed that the distribution of patients for the analysis is quite balanced; 92 patients (40%) of the total number of patients diagnosed with mCRC are considered “older patients” and the other 132 patients (60%) are considered “non-older” [24].
To complete this analysis of the optimal cut-off point for age, we also used the analysis using time-dependent ROC curves. This analysis allows estimation of ROC curves for a continuous marker in a survival analysis context [25]. The criterion for estimating the best cut-off point was to select the point closest to 0.1 on the ROC curve. This analysis shows ROC curves for 12, 24, and 36 months, slightly higher at the latter time. The cut-off point for 36 months with the criteria defined above is 73, with an overall performance similar to the cut-off point of 75 (shown in online suppl. Table 2; Fig. 1).
Statistical Analysis
A descriptive analysis of the sociodemographic, clinicopathological, molecular, and therapeutic variables of the patients was performed. For quantitative variables, measures of central tendency and dispersion were used (arithmetic mean and standard deviation, median and interquartile range). For qualitative variables, absolute and relative frequencies in percent were used. The possible association between variables was studied using Pearson’s χ2 for qualitative variables (Fisher’s exact test, if both variables were dichotomous) and the Student’s t test for quantitative variables. All p tests were two tailed (two tails) and a value of <0.05 was considered statistically significant due to exploratory nature of the study. The IBM SPSS Statistics 25 program was used for the statistical analysis.
In total, we evaluated eighteen characteristics that were grouped in three subcategories: characteristic related to the patient (age, sex, comorbidities, polypharmacy, Eastern Cooperative Oncology Group (ECOG), and nutritional status), to the tumor (stage at diagnosis, tumor side, molecular profile, tumor burden – carcinoembryonic antigen [CEA] level, location and number of metastasis), and to the treatment administrated (systemic treatment for advanced disease, chemotherapy schedule and number of lines, severe adverse events and dose reductions, and surgery of liver metastasis).
The HR and the 95% confidence intervals (95% CI) were estimated for each variable using the Cox univariate model. A multivariate Cox proportional-hazard model was also developed using stepwise regression (forward selection).
OS was calculated by the Kaplan-Meier product-limit method from the date of the diagnosis until death. The log-rank test was used to assess differences between subgroups. In all cases, all tests were considered bilateral and p values of less than 0.05 were considered statistically significant.
CEA levels at diagnosis of mCRC were used as a surrogate blood marker of tumor burden. Although this tumor marker also increases in non-cancerous conditions, it is not considered a useful test for cancer screening; however, elevated CEA levels have been associated with clinical course and increased disease burden. Nutritional status was defined with albumin levels [26‒28]. Cut-offs used were 5 ng/mL for CEA and 3.5 g/mL for albumin.
Results
Patient Characteristics
Between January 2014 and December 2018, 1,298 patients with gastrointestinal cancer were assessed. Of them, 477 had a diagnosis of CRC and 255 had a diagnosis of mCRC (initial or relapse). A total of 231 patients were included in the analysis (24 patients did not have a complete electronic history or had a synchronous or metachronous diagnosis of an advanced malignancy other than mCRC and were excluded).
Baseline Patients Characteristics (Sociodemographic, Clinicopathological)
We identified 139 (60%) patients <75 years old and 92 (40%) with age ≥75. A total of 109 (53%) patients were male.
Comorbidities, defined as the presence of at least two chronic diseases (cardiovascular disease, chronic obstructive pulmonary disease, diabetes, chronic renal disease, rheumatologic pathology) with risk of clinical deterioration for the patient, were present in 44 (19%) patients. Cardiovascular disease (heart failure, ischemic heart disease, hypertension, dyslipidemia, diabetes) was present in 34.5% of patients. The proportion of patients with polypharmacy, defined as the prescription, in the same patient, of 5 or more drugs for a period of more than 5 years [29], was 40%. Malnutrition or poor nutritional status, defined as albumin levels <3.5 g/mL, and ECOG ≥2 at diagnosis of mCRC, was reported in 13% and 22% of patients, respectively.
Regarding older patients, the proportion of patients with comorbidities and polypharmacy was significantly higher than in non-older patients (29% vs. 12% and 57% vs. 30%, respectively, p < 0.001 for both). ECOG ≥2 at diagnosis of mCRC was significantly higher in older than in non-older patients (34% vs. 14%, p < 0.001). No significant differences were found between older and non-older patients in terms of nutritional status (malnutrition; 86% vs. 87%, p = 0.821).
Tumor Characteristics
Advanced disease (stage IV) at diagnosis was observed in 67% of patients. In 65%, the primary tumor was left sided. RAS and BRAF statuses (KRAS/NRAS) were studied in 205 patients, of whom 67% showed RAS (KRAS/NRAS) mutation and 2% showed BRAF mutation. High tumor burden, defined as CEA levels >5 ng/mL at diagnosis of mCRC, was present in 75% of patients.
Liver-only and lung-only metastases were reported in 69 and 20 patients, respectively. At diagnosis of mCRC, 53% of patients had only one site of metastasis and 32% two. A total of 30% of patients met criteria for oligometastatic disease according to European Society for Medical Oncology (ESMO) [30].
In the older patient population, the proportion of patients with synchronous disease (stage IV at diagnosis) and multiple sites of metastatic disease at diagnosis of mCRC (≥3 sites) were significantly lower than in non-older patients (55% vs. 74%, p = 0.003, and 7% vs. 30%, p = 0.034). No significant differences were found between older and non-older patients in terms of tumor side and tumor burden (CEA levels).
Treatment of Advanced Disease
Of the 231 patients with diagnosis of mCRC, 190 (82%) received cancer treatment (almost first-line of chemotherapy); of them, 129 (56%) underwent second-line therapy and only 15 (6%) patients reached ≥5 lines of chemotherapy. Forty-one (18%) patients did not receive any treatment. In 57 of 151 patients with liver metastasis (liver-only and multiple sites), metastasectomy was done.
Of the 190 patients who received first-line chemotherapy treatment, 135 (58%) patients received combination therapy, and the most common combination was fluoropyrimidine plus oxaliplatin, with or without molecular targeted agent. Grade 3-4 adverse events in first-line chemotherapy were reported in 31% of patients and in 57% of patients a reduction of the planned chemotherapy dose ≥20% was done.
Regarding older patients, the proportion of patients who received chemotherapy treatment at diagnosis of mCRC was significantly lower than in non-older patients (67% vs. 92%, p < 0.001). Meanwhile, older patients received significantly lower number of lines of treatment than non-older (≥ third line; 13% vs. 25%, p < 0.001).
Of the 62 older patients who had first-line chemotherapy, only 18 (20%) received combination therapy, although most patients in non-older group (84%) received this type of therapy (p < 0.001). Characteristics of studied population according to age-groups (older patients ≥75 years vs. non-older patients <75 years) are shown in Tables 1 and 2.
Clinical characteristics of patients with mCRC according to age-groups
. | All patients (N = 231) . | Older patients (N = 92) . | Non-older patients (N = 139) . | Hypothesis testing (p value)a . |
---|---|---|---|---|
Baseline patients characteristics | ||||
Age, n (%) | ||||
<75 years | 139 (60) | 139 (100) | - | |
75–79 years | 92 (40) | 28 (31) | ||
80–84 years | 37 (40) | |||
≥85 years | 27 (29) | |||
Sex, n (%) | ||||
Female | 122 (47) | 44 (48) | 65 (47) | NS |
Male | 109 (53) | 48 (52) | 74 (53) | |
Comorbiditiesb, n (%) | ||||
No | 187 (81) | 65 (71) | 122 (88) | 0.001 |
Yes | 44 (19) | 27 (29) | 17 (12) | |
Polypharmacy, n (%) | ||||
No | 138 (60) | 40 (44) | 98 (17) | 0.001 |
Yes | 93 (40) | 52 (57) | 41 (30) | |
ECOG, n (%) | ||||
0–1 | 180 (78) | 61 (66) | 119 (86) | 0.001 |
≥2 | 51 (22) | 31 (34) | 20 (14) | |
Nutritional statusc (albumin levels), n (%) | ||||
Malnutrition (≤3.5 g/mL) | 24 (13) | 10 (14) | 14 (13) | NS |
Optimal (<3.5 g/mL) | 158 (87) | 62 (86) | 96 (87) | |
Tumor characteristics | ||||
Stage at diagnosis, n (%) | ||||
Localized (stage I-II-III) | 77 (33) | 41 (45) | 36 (26) | 0.003 |
Advanced (stage IV) | 154 (67) | 51 (55) | 103 (74) | |
Tumor sided, n (%) | ||||
Right | 78 (35) | 31 (34) | 47 (35) | NS |
Left | 147 (65) | 59 (66) | 88 (65) | |
Molecular profilee, n (%) | ||||
Wildtype | 64 (31) | 17 (22) | 47 (37) | 0.025 |
RAS mutated (KRAS/NRAS) | 136 (67) | 59 (77) | 77 (60) | |
(126/10) (62/5) | ||||
BRAF mutated | 5 (2) | 1 (1) | 4 (3) | |
Tumor burdenf (CEA level), n (%) | ||||
Low – CEA ≤5 ng/mL | 55 (25) | 22 (26) | 33 (25) | NS |
High – CEA >5 ng/mL | 162 (75) | 64 (74) | 98 (75) | |
Location of metastasis, n (%) | ||||
Liver | 69 (29) | 23 (25) | 46 (33) | NS |
Lung | 20 (9) | 11 (12) | 9 (7) | |
Liver + lung | 22 (10) | 9 (10) | 13 (9) | |
Other | 120 (52) | 49 (53) | 71 (51) | |
Number of locations of metastasis, n (%) | ||||
1 site of metastasis | 122 (53) | 53 (58) | 69 (50) | 0.034 |
2 sites of metastasis | 74 (32) | 32 (35) | 42 (30) | |
≥3 sites of metastasis | 35 (15) | 7 (7) | 28 (20) |
. | All patients (N = 231) . | Older patients (N = 92) . | Non-older patients (N = 139) . | Hypothesis testing (p value)a . |
---|---|---|---|---|
Baseline patients characteristics | ||||
Age, n (%) | ||||
<75 years | 139 (60) | 139 (100) | - | |
75–79 years | 92 (40) | 28 (31) | ||
80–84 years | 37 (40) | |||
≥85 years | 27 (29) | |||
Sex, n (%) | ||||
Female | 122 (47) | 44 (48) | 65 (47) | NS |
Male | 109 (53) | 48 (52) | 74 (53) | |
Comorbiditiesb, n (%) | ||||
No | 187 (81) | 65 (71) | 122 (88) | 0.001 |
Yes | 44 (19) | 27 (29) | 17 (12) | |
Polypharmacy, n (%) | ||||
No | 138 (60) | 40 (44) | 98 (17) | 0.001 |
Yes | 93 (40) | 52 (57) | 41 (30) | |
ECOG, n (%) | ||||
0–1 | 180 (78) | 61 (66) | 119 (86) | 0.001 |
≥2 | 51 (22) | 31 (34) | 20 (14) | |
Nutritional statusc (albumin levels), n (%) | ||||
Malnutrition (≤3.5 g/mL) | 24 (13) | 10 (14) | 14 (13) | NS |
Optimal (<3.5 g/mL) | 158 (87) | 62 (86) | 96 (87) | |
Tumor characteristics | ||||
Stage at diagnosis, n (%) | ||||
Localized (stage I-II-III) | 77 (33) | 41 (45) | 36 (26) | 0.003 |
Advanced (stage IV) | 154 (67) | 51 (55) | 103 (74) | |
Tumor sided, n (%) | ||||
Right | 78 (35) | 31 (34) | 47 (35) | NS |
Left | 147 (65) | 59 (66) | 88 (65) | |
Molecular profilee, n (%) | ||||
Wildtype | 64 (31) | 17 (22) | 47 (37) | 0.025 |
RAS mutated (KRAS/NRAS) | 136 (67) | 59 (77) | 77 (60) | |
(126/10) (62/5) | ||||
BRAF mutated | 5 (2) | 1 (1) | 4 (3) | |
Tumor burdenf (CEA level), n (%) | ||||
Low – CEA ≤5 ng/mL | 55 (25) | 22 (26) | 33 (25) | NS |
High – CEA >5 ng/mL | 162 (75) | 64 (74) | 98 (75) | |
Location of metastasis, n (%) | ||||
Liver | 69 (29) | 23 (25) | 46 (33) | NS |
Lung | 20 (9) | 11 (12) | 9 (7) | |
Liver + lung | 22 (10) | 9 (10) | 13 (9) | |
Other | 120 (52) | 49 (53) | 71 (51) | |
Number of locations of metastasis, n (%) | ||||
1 site of metastasis | 122 (53) | 53 (58) | 69 (50) | 0.034 |
2 sites of metastasis | 74 (32) | 32 (35) | 42 (30) | |
≥3 sites of metastasis | 35 (15) | 7 (7) | 28 (20) |
mCRC, metastatic colorectal cancer; n, number; NS, not significant.
aHypothesis testing performed between the subgroups of older and non-older patients.
bComorbidities: we define the presence of comorbidities as the presence of at least two chronic diseases (cardiovascular disease, chronic obstructive pulmonary disease, diabetes, chronic renal disease, rheumatologic pathology) with risk of clinical deterioration for the patient.
cUnknown = 49 pts.
dUnknown = 6 pts.
eUnknown = 26 pts.
fUnknown = 14 pts.
Treatment characteristics of patients with mCRC according to age-groups
. | All patients (N = 231) . | Older patients (N = 92) . | Non-older patients (N = 139) . | Hypothesis testing (p value)a . |
---|---|---|---|---|
Treatment of mCRC | ||||
Systemic treatment for mCRC, n (%) | ||||
No | 41 (18) | 30 (33) | 11 (8) | <0.001 |
Yes | 190 (82) | 62 (67) | 128 (92) | |
Number of chemotherapy lines, n (%) | ||||
No treatment | 41 (18) | 30 (33) | 11 (8) | <0.001 |
1-2 | 129 (56) | 48 (52) | 81 (58) | |
3-4 | 46 (20) | 12 (13) | 34 (25) | |
≥5 | 15 (6) | 2 (2) | 13 (9) | |
Surgery of liver metastasis, n (%) | ||||
No liver metastasis | 80 (35) | 40 (43) | 40 (29) | <0.001 |
Liver met. without surgery | 94 (40) | 42 (46) | 52 (37) | |
Liver met. with surgery | 57 (25) | 10 (11) | 47 (34) | |
Chemotherapy schedule, n (%) | ||||
No treatment | 41 (18) | 30 (32) | 11 (8) | <0.001 |
Combination therapy | 135 (58) | 18 (20) | 117 (84) | |
Single-agent therapy | 55 (24) | 44 (48) | 11 (8) | |
Treated patients (1st line) | N = 190 | N = 62 | N = 128 | |
Severe adverse events (≥G3), n (%) | ||||
No | 131 (69) | 48 (77) | 83 (65) | NS |
Yes | 59 (31) | 14 (23) | 45 (35) | |
Dose reduction (≥20%), n (%) | ||||
No | 81 (43) | 20 (48) | 61 (48) | 0.044 |
Yes | 109 (57) | 42 (52) | 67 (52) |
. | All patients (N = 231) . | Older patients (N = 92) . | Non-older patients (N = 139) . | Hypothesis testing (p value)a . |
---|---|---|---|---|
Treatment of mCRC | ||||
Systemic treatment for mCRC, n (%) | ||||
No | 41 (18) | 30 (33) | 11 (8) | <0.001 |
Yes | 190 (82) | 62 (67) | 128 (92) | |
Number of chemotherapy lines, n (%) | ||||
No treatment | 41 (18) | 30 (33) | 11 (8) | <0.001 |
1-2 | 129 (56) | 48 (52) | 81 (58) | |
3-4 | 46 (20) | 12 (13) | 34 (25) | |
≥5 | 15 (6) | 2 (2) | 13 (9) | |
Surgery of liver metastasis, n (%) | ||||
No liver metastasis | 80 (35) | 40 (43) | 40 (29) | <0.001 |
Liver met. without surgery | 94 (40) | 42 (46) | 52 (37) | |
Liver met. with surgery | 57 (25) | 10 (11) | 47 (34) | |
Chemotherapy schedule, n (%) | ||||
No treatment | 41 (18) | 30 (32) | 11 (8) | <0.001 |
Combination therapy | 135 (58) | 18 (20) | 117 (84) | |
Single-agent therapy | 55 (24) | 44 (48) | 11 (8) | |
Treated patients (1st line) | N = 190 | N = 62 | N = 128 | |
Severe adverse events (≥G3), n (%) | ||||
No | 131 (69) | 48 (77) | 83 (65) | NS |
Yes | 59 (31) | 14 (23) | 45 (35) | |
Dose reduction (≥20%), n (%) | ||||
No | 81 (43) | 20 (48) | 61 (48) | 0.044 |
Yes | 109 (57) | 42 (52) | 67 (52) |
mCRC, metastatic colorectal cancer; n, number; NS, no significant.
aHypothesis testing performed between the subgroups of older and non-older patients.
OS according to Prognostic Factors in Patients with mCRC
Median OS (mOS) was 22.9 months (95% CI: 19.7–26.5). The 1-, 3-, and 5-year OS rates were 73.2%, 31.5%, and 15.8%, respectively.
mOS in older and non-older patients was 17.1 (95% CI: 14.3–23.3) and 26.7 months (95% CI: 21.9–32.6, p < 0.001), respectively (Fig. 1). The analysis of OS by age evidenced that 2-year OS in older patients (≥75 years) was 38% and 54% in non-older patients (<75 years). mOS of patients with high tumor burden (CEA levels ≥5 ng/mL) was 17.2 months (95% CI: 14.3–22.2) compared to 37.2 months (95% CI: 24.1–46.7) in patients with low tumor burden, p < 0.001 (shown in Fig. 2a). The analysis of nutritional status at diagnosis of mCRC revealed that in the poor nutritional status group (albumin levels <3.5 g/mL) mOS was 9.6 months (95% CI: 3.8–13.5) compared to 24.1 months (95% CI: 21–30.9) in the good nutritional status group, p < 0.001 (shown in Fig. 2b).
Comparison of 5-year OS between older patients (≥75 years) and non-older (<75 years) with mCRC (Kaplan-Meier survival method and log-rank test).
Comparison of 5-year OS between older patients (≥75 years) and non-older (<75 years) with mCRC (Kaplan-Meier survival method and log-rank test).
OS according to prognostic factors. a Tumor burden (CEA level; <5 vs. ≥ 5 ng/mL). b Nutritional status (albumin levels; <3.5 vs. ≥ 3.5 g/mL). c Administration of systemic treatment (no treatment [no] vs. systemic treatment [yes]). d Surgery of liver metastasis (liver metastasis without surgery [no] vs. liver metastasis with surgery [yes].
OS according to prognostic factors. a Tumor burden (CEA level; <5 vs. ≥ 5 ng/mL). b Nutritional status (albumin levels; <3.5 vs. ≥ 3.5 g/mL). c Administration of systemic treatment (no treatment [no] vs. systemic treatment [yes]). d Surgery of liver metastasis (liver metastasis without surgery [no] vs. liver metastasis with surgery [yes].
mOS of patients who received almost first-line chemotherapy (treated group) was 26.8 months (95% CI: 22.3–31.6) compared to 4.4 months (95% CI: 2.2–7) in patients who did not receive chemotherapy at diagnosis of mCRC, p < 0.001 (shown in Fig. 2c). Patients with liver metastases and metastasectomy had longer OS than those in whom surgery was not performed (44.1 months [95% CI: 36.7 – not reached] vs. 14.4 months [95% CI: 11.8–18.3], p < 0.001) (shown in Fig. 2d), with a 5-year survival rate of 38% versus 0%.
Univariate and Multivariate Analysis (Cox Regression)
In the univariate analysis, the concurrent factors that were related to OS were age (<75 vs. ≥75 years; HR = 1.79, p < 0.001), ECOG status (0-1 vs. 2-3; HR = 3.18, p < 0.001), tumor side (right vs. left; HR = 0.73, p = 0.037), molecular profile (RAS mutated vs. wildtype; HR = 0.65, p = 0.013), tumor burden (CEA levels ng/mL [<5 vs. >5]; HR = 2.05, p < 0.001), nutritional status (albumin levels g/mL [<3.5 vs. >3.5]; HR = 0.36, p < 0.001), systemic treatment for advanced disease (no therapy vs. combination therapy; HR = 0.21, p < 0.001 and no therapy vs. single-agent therapy; HR = 0.34, p < 0.001), and surgery of liver metastasis (no met. vs. met. without surgery; HR = 2.29, p < 0.001 and no met. vs. met. with surgery; HR = 0.42, p < 0.001). Comorbidity or type of debut (synchronous met. vs. metachronous met.) was not significantly related to OS.
Multivariate analysis revealed that only tumor burden (CEA levels), nutritional status (albumin levels), systemic treatment for advanced disease, and surgery of liver metastases (met.) were independently associated with OS but not age at diagnosis of mCRC. Univariate and multivariate analysis for OS of the main prognostic factors, with clinical and statistical relevance, is summarized in Table 3.
Univariate and multivariate analysis of prognostic factors in patients with mCRC (Cox regression)
Variables . | Univariate . | Multivariate . | ||
---|---|---|---|---|
HR (95% CI) . | p value . | HR (95% CI) . | p value . | |
Age | ||||
<75 years versus ≥75 years | 1.79 (1.34–2.40) | <0.001 | 1.12 (0.66–1.92) | 0.671 |
Comorbidities | ||||
No versus yes | 1.36 (0.95–1.93) | 0.088 | 0.72 (0.43–1.21) | 0.215 |
ECOG | ||||
0/1 versus ≥2 | 3.18 (2.28–4.42) | <0.001 | 1.13 (0.67–1.93) | 0.643 |
Nutritional status | ||||
Albumin levels <3.5 vs. ≥ 3.5 g/mL | 0.36 (0.23–0.57) | <0.001 | 0.38 (0.23–0.63) | <0.001 |
Stage at diagnosis | ||||
Localized versus advanced | 1.30 (0.96–1.77) | 0.092 | 1.27 (0.81–2.00) | 0.299 |
Tumor side | ||||
Right versus left | 0.73 (0.54–0.98) | 0.037 | 0.83 (0.58–1.18) | 0.299 |
Molecular profile | 0.65 (0.46–0.92) | 0.013 | 0.92 (0.58–1.44) | 0.703 |
RAS mutated versus WT versus unknown* | - | - | 0.75 (0.35–1.60) | 0.454 |
Tumor burden | ||||
CEA level; <5 versus ≥ 5 ng/mL | 2.05 (1.42–2.96) | <0.001 | 2.01 (1.29–3.13) | 0.002 |
Systemic treatment for mCRC | 0.21 (0.14–0.30) | <0.001 | 0.19 (0.08–0.44) | <0.001 |
No treatment versus combination therapy versus single-agent therapy | 0.34 (0.22–0.51) | <0.001 | 0.30 (0.15–0.60) | 0.001 |
Surgery of liver metastasis | 2.29 (1.64–3.18) | <0.001 | 1.90 (1.25–2.90) | 0.003 |
No liver met. versus liver met. without surgery versus liver met. with surgery | 0.42 (0.28–0.64) | <0.001 | 0.53 (0.31–0.92) | 0.025 |
Variables . | Univariate . | Multivariate . | ||
---|---|---|---|---|
HR (95% CI) . | p value . | HR (95% CI) . | p value . | |
Age | ||||
<75 years versus ≥75 years | 1.79 (1.34–2.40) | <0.001 | 1.12 (0.66–1.92) | 0.671 |
Comorbidities | ||||
No versus yes | 1.36 (0.95–1.93) | 0.088 | 0.72 (0.43–1.21) | 0.215 |
ECOG | ||||
0/1 versus ≥2 | 3.18 (2.28–4.42) | <0.001 | 1.13 (0.67–1.93) | 0.643 |
Nutritional status | ||||
Albumin levels <3.5 vs. ≥ 3.5 g/mL | 0.36 (0.23–0.57) | <0.001 | 0.38 (0.23–0.63) | <0.001 |
Stage at diagnosis | ||||
Localized versus advanced | 1.30 (0.96–1.77) | 0.092 | 1.27 (0.81–2.00) | 0.299 |
Tumor side | ||||
Right versus left | 0.73 (0.54–0.98) | 0.037 | 0.83 (0.58–1.18) | 0.299 |
Molecular profile | 0.65 (0.46–0.92) | 0.013 | 0.92 (0.58–1.44) | 0.703 |
RAS mutated versus WT versus unknown* | - | - | 0.75 (0.35–1.60) | 0.454 |
Tumor burden | ||||
CEA level; <5 versus ≥ 5 ng/mL | 2.05 (1.42–2.96) | <0.001 | 2.01 (1.29–3.13) | 0.002 |
Systemic treatment for mCRC | 0.21 (0.14–0.30) | <0.001 | 0.19 (0.08–0.44) | <0.001 |
No treatment versus combination therapy versus single-agent therapy | 0.34 (0.22–0.51) | <0.001 | 0.30 (0.15–0.60) | 0.001 |
Surgery of liver metastasis | 2.29 (1.64–3.18) | <0.001 | 1.90 (1.25–2.90) | 0.003 |
No liver met. versus liver met. without surgery versus liver met. with surgery | 0.42 (0.28–0.64) | <0.001 | 0.53 (0.31–0.92) | 0.025 |
Met., metastasis; Y, years.
*Univariate analysis; molecular profile (RAS mutated/WT).
Discussion
Our first analysis found that older patients with mCRC had an unfavorable clinical course, as reported in other studies [24, 31, 32]. This was, however, only observed in the univariate analysis. Multivariate analysis showed that only tumor burden, nutritional status, systemic treatment for advanced disease, and surgery of liver met. were concurrent factors with significant impact in OS but not age at diagnosis.
Clinically, older patients with mCRC comprise a heterogeneous population, which includes patients with excellent health condition and others with multiple comorbidities or polypharmacy, functional dependence, and limited life expectancy [33]. Moreover, the definition of “elderly” or “older” patient often varies among studies although 75 years of age may be a suitable cut-off point and this was confirmed in our series. Currently, there is limited evidence related to the evolution and treatment of advanced CRC in older patients [24]. Only a few prospective and randomized studies have focused exclusively on this group of patients; therefore, knowing the factors that influence its evolution can be a difficult challenge [18‒23, 34].
The poor clinical course of older patients is consistent with reports from previous clinical trials and other retrospective studies in patients with mCRC [24, 31, 32]. However, our analysis of concurrent factors related to the evolution of mCRC highlighted the presence of other clinicopathological and therapeutic factors significantly associated with the survival of mCRC, independently of chronological age. In our series, malnutrition (defined by albumin level <3.5 g/dL) or high tumor burden (defined by CEA level ≥5 ng/mL) are independent prognostic factors significantly related to worse prognosis of mCRC, whereas systemic treatment for advanced disease or radical surgery for liver metastases are independent prognostic factors significantly related to better survival. However, age at diagnosis, comorbidity, ECOG, type of debut, or primary tumor side were not considered as independent prognostic factors for survival in our cohort.
Recent studies have correlated high CEA levels with worse OS rates in patients with mCRC [35]. Fackche et al. [35] and Liu et al. demonstrated that elevated CEA level was a prognostic marker of aggressive disease biology in patients with mCRC and conferred up to a fivefold increase in mortality [35, 36]. In our cohort, we correlated elevated CEA level with a twofold increase in the risk of death (HR = 2.01 [1.29–3.13], p = 0.002). Malnutrition has also been strongly related to poor survival rates in different types of malignancies, including advanced CRC [32, 37, 38]; consistently, in our study we significantly correlated poor nutritional status (albumin level <3.5 g/mL) with shorter survival (9.6 months vs. 24.1 months, p < 0.001).
Other prognostic factors of our study were systemic treatment for advanced CRC and radical surgery of liver metastases. A pooled analysis of 22 clinical trials including over 3,000 patients with mCRC (14% aged >70 years) evaluating the efficacy of 5-fluorouracil (5-FU) found no difference between age-groups in terms of OS, overall response rate, and PFS [39]. Similar observations were made for combination therapy with irinotecan and oxaliplatin in older patients. In a combined analysis of four RCTs assessed the efficacy of irinotecan and 5-FU, patients >70 years only 22.3% of the trial population showed that the benefit of irinotecan on PFS and OS was maintained in older patients [24, 40]. These results are consistent with those of other authors who evaluated combination therapy with oxaliplatin in patients >70 years [24].
Only few randomized trials (FOCUS2, AVEX, and FFCD 2001-2002) [19‒23] were specifically focused on older patients with mCRC. FOCUS2 (43%, >75 years) and FFCD 2001-2002 were designed to assess the impact of oxaliplatin- and irinotecan-based therapy in older mCRC patients in the first-line treatment setting [19, 20]. In the first of these, the data suggested a potential benefit from oxaliplatin-containing chemotherapy to single-agent fluoropyrimidine therapy, although the primary end point (PFS) was not met [19, 24]. In the second of these studies, irinotecan-based therapy showed a significant benefit over those who received single-agent 5-FU/leucovorin alone in terms of overall response rate, 46.3% versus 27.4% (OR: 2.3, 95% CI: 1.4–3.8, p = 0.001), a non-significant benefit in terms of PFS, 7.3 versus 5.2 months (HR: 0.84, 95% CI: 0.66–1.07, p = 0.15), and no benefit in terms of OS [20]. Efficacy and safety of combination therapy with target agent (TA) (bevacizumab, cetuximab, or panitumumab) were also studied in older patients with mCRC [21, 22, 24, 41]. Most recent SIOG guidelines recommend combination therapy with TAs in “fit” older patients with special attention to the specific toxicity profile of each drug and to the patient’s functional status and comorbidity [24]. In 2018, Zhao et al. [3] specifically assess the role of TAs in the treatment of older patients with mCRC and confirmed that the TAs-containing therapy offers improved survival benefits comparing to TAs-free regimens in older patients.
Recently, Lonardi et al. [34] published data from a randomized phase II noncomparative trial including untreated patients aged 70 years and older with mCRC (RAS/BRAF wildtype). Patients were randomly assigned to mFOLFOX plus panitumumab or 5-FU/leucovorin plus panitumumab demonstrating that avoiding oxaliplatin is a reasonable option as initial therapy in selected older patients with RAS/BRAF wildtype mCRC with a better safety profile, therefore could be considered as an alternative in frail older patients without significant detriment to its efficacy [34].
According to the ESMO Clinical Practice Guideline for diagnosis, treatment, and follow-up of mCRC, surgical resection of liver metastasis (R0) is a potentially curative treatment, with reported 5-year survival rates of 20–45% [30]. In a retrospective analysis of routine treatment modalities focused on older patients with CRC in France in 2009, hepatic surgery was an independent prognostic factor of survival (HR = 0.63 [95% CI: 0.47–0.84], p = <0.001) [32], consistently with our results. Thus far, there have been no RCTs focused on radical surgery for liver metastases in older patients with mCRC. The only data available were obtained from subgroup analyses or case reports. Guo et al. [42] in a Chinese study on the impact of advanced age on simultaneous resection of mCRC and liver metastasis showed a 3-year OS in the older group of 32.7% and 52.4% in the young group; nevertheless, no significant differences between groups were observed with respect to OS rate (p = 0.288). In another study, Mowbray et al. reported that liver resection for colorectal liver metastasis in patients 75 years and older was feasible, safe, and conferred a similar 5-year survival rate to younger patients (1-, 3-, and 5-year OS was 90.2%, 70.5%, and 52.3%, respectively, median 70 months) with no difference between age cohorts (p = 0.772) [43]. Consequently, surgery of liver metastases can be considered an optimal approach in the treatment of mCRC in older patients; all cases should be discussed in a multidisciplinary team.
Therefore, in our study, the lower survival observed in the older patient population compared to non-older patients is justified by the presence of age-independent prognostic factors in this group of patients related with a poor survival. In our research, older patient population was significantly characterized by a lower proportion of patients who received oncological treatment and underwent surgery of liver metastases compared to the younger population (11% vs. 24% and 67% vs. 92%, p < 0.001, respectively). Moreover, older patients who underwent systemic treatment received significantly less proportion of combination therapy (20% vs. 84%, p < 0.001). In the present study, about half of the older patients received single-agent therapy (5-FU, capecitabine, or irinotecan) as the front-line chemotherapy compared to 8% among younger patients (p < 0.001). These results were similar to those found in the French study by Doat et al. [32].
Furthermore, in older patients, we also observed a significantly higher proportion of patients with worse functional status at diagnosis of mCRC (ECOG ≥2; 34% vs. 14%, p < 0.001), higher comorbidity and polypharmacy (29% vs. 12% and 57% vs. 30%, p < 0.001, respectively), and RAS/BRAF mutation (78% vs. 63%, p = 0.025). These factors have traditionally been associated with worse survival in mCRC and lower prescription of systemic treatments and higher treatment-related toxicity. In addition, in our series, older patients received significantly lower proportion of advanced lines of treatment (≥3rd line). All these features demonstrate the presence of biological and clinicopathological characteristics related to the older group that could justify their worse prognosis regardless of age. However, the lower prescription of systemic treatment in older patients is what seems to be the strongest factor related to worse survival in this group of patients.
The current study had some limitations. First, this was a retrospective and single-center study. Therefore, we could not avoid information bias, particularly regarding comorbidities, functional status, and adverse events, which are important factors in studies involving older patients. Second, a comprehensive geriatric assessment (CGA) was not available for all older patients to determine the risk or benefit of systemic treatment, although CGA is a useful tool in the approach to older patients with advanced CRC [7, 24], which may have a negative influence on the prescription of chemotherapy treatment in older patients.
Conclusions
Age older than 75 years is not an independent prognostic factor of advanced CRC. Multivariate analysis showed that tumor burden, nutritional status, systemic treatment for advanced disease, and surgery of liver metastases were the only significant factors associated with OS. In our opinion, older patients should not be excluded from cancer treatment based on chronological age alone. Decisions should be based on comorbidities, patient preferences, treatment tolerance, and life expectancy. All older patients with cancer should benefit from performing an appropriate CGA before considering the administration of systemic treatment.
Acknowledgments
Most of all, we would like to extend our sincerest thanks to the patients who participated in this study – you made it possible for this research to be carried out.
Statement of Ethics
This study was reviewed and approved by Institutional Review Board and Drug Research Ethical Committee (CEIm) of La Princesa University Hospital (registration number 4546) and Research Ethics Committee of the Universidad Autónoma of Madrid (registration number CEI-117-2360) in accordance with the ethical principles stated in the Declaration of Helsinki. Drug Research Ethical Committee of La Princesa University Hospital and Research Ethics Committee of the Universidad Autónoma of Madrid did not require an informed consent form because of the retrospective nature of the study and all the data were retrospectively collected from medical records.
Conflict of Interest Statement
The authors have no conflicts of interest to declare. During the preparation of this work, the author(s) did not use AI technologies.
Funding Sources
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Author Contributions
Study conception and design: Patricia Toquero, Rebeca Mondéjar, Nuria Romero-Laorden, Olga Donnay, Elena Méndez, Lucía Castillo, Berta Hernández Marín, and Ramon Colomer. Data collection: Patricia Toquero, Elena Méndez, and Lucía Castillo. Data Analysis and interpretation: Patricia Toquero, Rebeca Mondéjar, Nuria Romero-Laorden, Elena Méndez, Berta Hernández Marín, and Ramon Colomer. Manuscript preparation, editing, and review: Patricia Toquero, Rebeca Mondéjar, Nuria Romero-Laorden, and Ramon Colomer. All authors read and approved the final manuscript.
Data Availability Statement
The data sets generated during and/or analyzed during the current study are not publicly available due to ethical reasons. Further inquiries can be directed to the corresponding author.