Older adults with colon cancer are not different from younger ones,but treated differently: Retrospective analysis from single centre

Abstract

Aim

Decision- making of the treatment of colon cancer for the older patients becomes more complicated in consequence of comorbidities and geriatric syndromes, most importantly frailty. In the present study, we aimed to investigate whether there is a difference between tumour characteristics, treatment choices, and outcomes between the younger and older adults.

Method

The patients who were diagnosed with colorectal carcinoma in our centre between 2010 and 2015 included. Clinicopathological features of tumour, treatment choices and survivals of the patients were recorded. Patients were separated into two groups according to their chronological age.

Results

The present study included 465 patients, there were 173 patients aged 65 years and older. Clinicopathological features were similar in both groups. Adjuvant chemotherapy was given in similar rates. Whereas combination chemotherapies were preferred in younger patients as first-line therapy, single agents were given to the older group(p-value < 0.001). No significant differences were observed between combination therapy and monotherapy as progression-free and overall survival in older adults(p value > 0.05). It was observed that 53.2% of the older patients was not treated with any biological treatment (p-value < 0.001).

Discussion

Geriatric people are underrepresented in clinical trials,because of the presence of the limitations in the older patients. The results of our study revealed older patients with colon cancer patients underwent surgery less than the younger ones, they recieved monotherapy more frequently as first-line chemotherapy, and less frequently targeted therapy. Their mortality was higher. It was shown that decision-making of colon cancer therapy is influenced by age according to our results.

Keywords

Cancer treatment colon cancer age difference decision-making

Introduction

Colon cancer is estimated as the third most common cancer worldwide and the third most common cause of death among all cancers in both sexes in 2019.¹ The incidence of colon cancer is increasing with age. Most of the cases diagnosed with colon cancer and cancer deaths occur in individuals older than 65 years.² It is estimated that in 2,02,054% of the new colorectal cancer cases will be occurred in patients aged 65 years and older. In addition to that It is estimated that 68% of deaths due to colorectal cancer will occur in people aged 65 and over in 2020.³

Decision- making of the treatment of colon cancer for the older patients becomes more complicated in consequence of comorbidities and geriatric syndromes, most importantly frailty. Furthermore, older adults are under-represented in clinical trials, age is an exclusion criterion in many studies. Most of the patients who are excluded from the clinical trials are aged 65 years and older.⁴ Older patients diagnosed with cancer is determined to receive inappropriate care, they are under-treated due to their chronological age, or over-treated for their degree of frailty.⁵

The main treatment options for colon cancer are surgery for stage 1-2 disease and adjuvant chemotherapy for those who had a high risk of recurrence. Adjuvant chemotherapy prolongs disease-free survival and overall survival, and reduces recurrence rates.

5-Fluorouracil(FU) plus oxaliplatin regimen is superior to 5-FU alone.⁶ In patients older than 70 years, the benefit of adding oxaliplatin to 5-FU has not been shown.⁷

Palliative chemotherapy and the targeted therapy are chosen for metastatic disease and increase progression-free survival and overall survival. 5-FU/LV or oral capecitabine is the drug of choice for palliative chemotherapy with a combination of oxaliplatin or irinotecan. Palliative targeted agents that are used for metastatic colon cancer are bevacizumab, aflibercept, cetuximab, panitumumab, and regorafenib regarding k-ras status and tumour sidedness.

In the present study, we aimed to investigate whether there is a difference between tumor characteristics, treatment choices, and outcomes between the younger and geriatric population who admitted to our clinic with metastatic colon cancer.

Material and method

Our study was conducted by Declaration of Helsinki. This study was reviewed by the approval of Ege University Medical School Clinical Research Committee with the decision number 17-5/8 on the date 21.06.2017.

Study population

The patients included in this study were those who were diagnosed with colorectal carcinoma in our centre between 2010 and 2015 and were determined with distant organ metastasis at the time of diagnosis or during follow-up. Patients were excluded from the study if they had hereditary colon cancer syndrome, were determined with a synchronous tumour, had an additional primary malignancy or localized tumour. Previously being received adjuvant chemotherapy was not an exclusion criterion. Data of age, gender, k-ras mutation status, primary tumour localization, surgical history, pathology of the tumour, tumoural and nodal stage, lymphovascular and perineural invasion and adjuvant and palliative chemotherapies were recorded.

Progression-free survival was recorded as the time from the determination of the first metastasis to the date of the first detected radiological progression. Overall survival was defined as the time from diagnosis to death or the last follow-up examination until the day study was finished.

Patients were separated into two groups according to their chronological age. Geriatric population is defined as adults older than 65 years old and it is known that both incidence and mortality of colorectal cancer increase after this age. Patients who were younger than 65 years old defined as a younger patient group, the patients who aged 65 years or older defined as an older patient group.

Statistical analyses

The data of younger and older patient groups were analysed statistically. Categorical variables were stated as number (n) and percentage (%), and continuous variables as median, mean ± Standard deviation (SD) values. Tests of normality were performed. To evaluate relationships between two categorical variables, Chi-square and Fisher Exact tests were used. Survival analysis was performed by using the Kaplan-Meier method and statistical comparisons of potential predictive factors were made using Log-Rank analysis for univariate analysis. A value of p < 0.05 (two-sided) was accepted as statistically significant. The data obtained in the study were analysed statistically using IBM SPSS Statistics vn. 24.0 software (IBM Co., Armonk, NY, USA).

Results

The present study included 465 patients who were admitted to our clinic. Clinicopathological features of the patients were summarized in Table 1. The rate of patients who were younger than 65 years old was 62.8% (292 patients). One hundred seventy-three patients, (37.2% of the patients) were belonged to the older patients with cancer group.

Table 1.

Clinicopathological features of the tumour according to age groups.

	Younger (n, %)n = 292	Older (n, %)n = 173	p-value
Gender
Female	125 (42.8)	58 (33.5)	0.048
Male	167 (57.2)	115 (66.5)
K-ras
Wild	113 (71.1)	46 (28.9)	0.190
Mutated	81 (63.8)	46 (36.2)
Primary tumour localization
Right	40 (13.7)	26 (15)	0.683
Left	252 (86.3)	147 (85)
Surgery
Present	131 (44.9)	61 (35.3)	0.042
Absent	161 (55.1)	112 (64.7)
Pathology
Adenocarcinoma	252 (87.8)	153 (89.0)
Mucinous carcinoma	24 (8.4)	11 (6.4)	0.307
Signet ring cell	4 (1.4)	0 (0)
Neuroendocrine diff	2 (0.7)	2 (1,2)
Tumour stage
T1-T2	6 (3)	5 (4.7)	0.374
T3	91 (45)	56 (52.8)
T4	84 (41.6)	34 (31.6)
TX	21 (10.4)	11 (10.4)
Nodal stage
N0	60 (32.3)	33 (33.3)	0.996
N1	90 (48.4)	48 (48.5)
N2	36 (19.4)	18 (18.2)
NX	36 (19.4)	18 (18.2)
Lymphovascular invasion
Present	73 (48.7)	40 (54.1)	0.712
Absent	32 (21.3)	13 (17.6)
Perineural invasion
Present	53 (40.2)	38 (51.4)	0.242
Absent	32 (24.2)	17 (23)
Adjuvant therapy
Yes	65 (22.3)	28 (16,2)	0.113
No	227 (77.7)	146 (83.8)
Adjuvant chemotherapy
Oxaliplatin based^a	40 (75.5)	13 (50.0)	0.024
Monotherapy^c	13 (24.5)	13 (50.0)	0.024
First-line chemotherapy
Oxaliplatin based^a	183 (62.7)	116 (67.1)	<0.001
Irinotecan based^b	90 (30.8)	30 (17.3)
Monotherapy^c	7 (2.4)	18 (10.4)
Other	12 (4.1)	9 (5.2)
First-line targeted therapy
Anti-VEGF	184 (63.0)	73 (42.2)
Anti-EGFR	22 (7.5)	8 (4.6)	<0.001
None	86 (29.5)	92 (53.2)
Progression
Present	234 (80.1)	130 (75.1)	0.207
Absent	58 (19.9)	43 (24.9)
Second-line chemotherapy
Oxaliplatin based^a	70 (24.0)	37 (21.4)	0.162
Irinotecan based^b	139 (47.6)	69 (39.9)
Monotherapy^c	17 (5.8)	11 (6.4)
Regorafenib	3 (1.0)	1 (0.6)
None	63 (21.6)	55 (31.8)
Second-line targeted therapy
Anti-VEGF	109 (62.6)	42 (60)	0.701
Anti-EGFR	65 (109)	28 (65)	0.701
Third-line chemotherapy
Oxaliplatin based^a	50 (34.2)	18 (29.5)	0.255
Irinotecan based^b	48 (32.9)	26 (42.6)
Monotherapy^c	15 (10.3)	10 (16.4)
Regorafenib	27 (18.5)	7 (11.5)
Raltitrexed-Mitomycin C	2 (1.4)	–
Triplet(Folfirinox)	4 (2.7)	–
Third-line targeted therapy
Anti-VEGF	56 (61.5)	35 (70.3)	0.351
Anti-EGFR	26 (38.5)	11 (29.7)	0.351
Outcome
Exitus	201 (69.3)	140 (80.9)	0.006
Follow-up	89 (30.7)	33 (19.1)	0.006

VEGF: vascular endothelial growth factor; EGFR: epithelial growth factor receptor.

^aOxaliplatin plus 5-FU or capecitabine.

^bIrinotecan plus 5-FU or capecitabine.

^cCapecitabine/5-FU or Raltitrexed.Statistically significant values are underlined.

Table 3.

Survival analysis according to age groups.

Median overall survival						Median progression-free survival
	Est	StdErr	95% Confidence interval			Est	StdErr	95% Confidence interval
	Est	StdErr	Lower bound	Upperbound	p-value	Est	StdErr	Lower bound	Upperbound	p-value
Younger patients	35.975	1.994	32.067	39.883	<0.001	15.551	.814	13.955	17.146	0.352
Older patients	27.584	2.551	22.584	32.583		13.940	1.104	11.776	16.104
Total	33.314	1.680	30.021	36.607		15.090	.542	14.029	16.152

Statistically significant values are underlined.

The female rate of the older patients with cancer was 33.5%, however, 42.8% of the young population was female (p value < 0.05). Primary tumour localization, pathology of the tumour, tumoural and nodal stages, and k-ras mutation status were similar in both groups. There were no differences between groups according to lymphovascular and perineural invasion.

The surgery rate was 44.9% in the younger patient group, though only 35.3% of the older patients group undergone surgery. This difference is statistically significant (p-value < 0.05).

Adjuvant chemotherapy was given in similar rates in both groups. Considering the agents used in adjuvant chemotherapy, 50% of the older patients were given a single agent, this rate was 24.5% in the younger group, this difference was statistically significant (p-value < 0.05).

Whereas combination chemotherapies were preferred in younger patients as first-line therapy, single agents were given to the older patient group (p-value < 0.001).

Outcomes of the first-line treatment in the older patient group were compared, results are summarized in Table 2. No significant differences were observed between combination therapy and monotherapy as progression-free survival and overall survival (p value > 0.05).

Table 2.

Survival analysis according to regimens as first-line treatment in older patients with cancer.

Median overall survival						Median progression-free survival
	Est	StdErr	95% Confidence interval			Est	StdErr	95% Confidence interval
	Est	StdErr	Lower bound	Upperbound	p-value	Est	StdErr	Lower bound	Upperbound	p-value
5-FU plus Ox^a	25.561	3.086	19.511	31.610	0.187	12.263	.510	11.263	13.263	0.095
5-FU plus Iri^b	31.836	1.972	27.970	35.701		19.956	2.498	15.059	24.853
Monotherapy^c	24.575	1.656	21.329	27.820		11.079	5.929	.000	22.700

^a5-FU/Capecitabine plus oxaliplatin.

^b5-FU/Capecitabine plus irinotecan.

^cMonotherapy includes infusional 5-FU or capecitabine.

Looking at the targeted therapies preferred as a first-line; it was observed that 53.2% of the older patients was not treated with any biological treatment (p-value < 0.001).

Progression rates were similar in groups. No differences were shown between groups according to second and third-line chemotherapy regimens.

Exitus rates were 80.9% in older patients during follow up since 69.3% were deceased in younger patients (p-value 0.006)

Progression-free and overall survivals were analysed and detailed numbers were shown in Table 3. Median progression-free survival was 15.5 months in the young group (95% CI:13.9–17.1) and 13.9 months (95% CI 11.7–16.1) in the older patient group, the difference was not significant.

The median overall survival was 27.5 months in the older patients with cancer whereas it was 35.9 months in the younger population (p-value< 0.001). The survival scopes of OS and PFS were shown in Figure 1.

Discussion

Older people with cancer are underrepresented in clinical trials, because of the presence of the limitations in the older patients.⁴ The decision-making mostly relies on subgroup analysis in randomized-controlled studies. The results of this study revealed that older patients with colon cancer underwent surgery less than the younger ones, they received monotherapy more frequently as first-line chemotherapy, and less frequently as targeted therapy. Their mortality was higher. It was shown that decision-making of colon cancer therapy is influenced by age according to our results.

There are no significant differences in tumor pathology and biology according to age. However, in the present study because of the lack of information about the functional status of the patients (neither ECOG PS/Karnofsky score nor clinical frailty scores), we could not show the compliance differences to the treatments between groups.

Surgery is curative for early-stage colon cancer. In the present study, patients who are older than 65 years old, had undergone less surgery than the younger group (p-value < 0.05). In the literature, there are many studies show that the older patients with cancer have undergone surgery to a lesser extent. In a systematic review published in Lancet by Colorectal Cancer Collaborative Group,⁸ curative surgery was found less offered older patients because of the tolerability. It may be caused by comorbidities and frailty according to another study.⁹

Adjuvant chemotherapy in the older patients is the issue of debate. Rates of receiving adjuvant chemotherapy in the older patients with cancer have been lower in our study, though not significant. In a study reported by Potosky et al in 2002, lower rates of adjuvant chemotherapy in the older patients were found¹⁰ with stage 3 colon cancer. In another study revealed that there is an improvement in disease outcomes with adjuvant chemotherapy in older patients.¹¹ The reason for the lack of adjuvant chemotherapy in the older patients can be considered as the fear of adverse effects and toxicities. In the presented study by Schrag et al, increased hospitalization was found by the treatment of 5-FU. Another study defined increased leukopenia after 5-FU, conversely not increase in adverse events in older patients.¹²

Addition of oxaliplatin to adjuvant chemotherapy in low-risk stage 3 disease over 75 years old¹³ and in high- risk disease over 82 years old was not determined any contribution. Adjuvant chemotherapy of high-risk stage 2 and 3 disease should be planned according to comorbidities, organ functions and geriatric assessments in geriatric population between 65-75 years old.¹⁴ The risk of neutropenia and neuropathy because of oxaliplatin is higher in geriatric population compared to their younger counterparts.¹⁵ When a patient was evaluated in the light of these knowledge, oral capecitabine or 5-FU/LV is recommended for the patient who did not fit for oxaliplatin regimen. In X-ACT study, oral capecitabine had similar results with infusional FU.¹⁶

5-Fluorouracil or oral capecitabine is the recommended drug of choice for adjuvant chemotherapy for geriatric population.¹⁷ In patients older than 70 years, the benefit of addition oxaliplatin to 5-FU has not been shown in a subgroup analysis of MOSAIC trial.⁷ In ACCENT trial, no improvement was noted in disease outcomes with the addition of oxaliplatin to 5-FU¹⁸. In the current study, monotherapy was chosen for the geriatric patients. Despite the fact that higher rates of toxicity were observed with the addition of oxaliplatin in these studies, authors cannot state about toxicity due to the absence of recorded toxicity rates.

Figure 1.

(a) Overall survival scopes according to age groups. (b) Progression-free survival scopes according to age groups.

According to the recent National Comprehensive Cancer Network guideline, 5-FU plus oxaliplatin or irinotecan is recommended as a first-line treatment for advanced disease. Bevacizumab or its FDA- approved biosimilar is appropriate for first-line targeted treatment.^17–19 In the present study, mostly given regimens were oxaliplatin or irinotecan-based therapies in younger and older patients. Single-agent therapies (infusional 5-FU or capecitabine) were preferred in the older patients, and the difference among groups is statistically significant (p < 0.001). the use of combination therapy versus monotherapy is controversial in the treatment of advanced disease in the older adults with colon cancer. Some studies have noted no superiority of combination therapy to monotherapy with flouropyrimidines.^20–22 As compatible with the literature in our study, the survival benefit was not found in the comparison of combination therapy with single-agent therapy in the older patient group (p > 0.05). On the other hand, monotherapy has better outcomes compared to best supportive care in metastatic disease.²³ Combination therapy can be preferred in non-frail patients, and the monotherapy should be the choice of therapy in frail patients according to best supportive care.

The addition of the bevacizumab to the standard chemotherapy improves progression-free survival and overall survival. It is shown in many studies that older patients had similar outcomes as their young counterparts in clinical trials.^24,25 Even though the benefits of the vascular epidermal growth factors antibodies in the geriatric patients, the present study revealed that older group has given bevacizumab lesser extent (p < 0.05). This may be related to fear of increased adverse events in the older patients, mostly arterial tromboembolism.²⁶

In our study, similar progression rates and similar progression-free survival were found among younger and older patients (p > 0.05). An analysis searching the efficacy of fluoropyrimidine-based chemotherapies in an advanced setting defined no difference in overall survival, overall response rate, and progression-free survival compared to younger patients.²⁷ According to The International Cancer Benchmarking Partnership (ICBP)—a collaboration that compares outcome data between Australia, Canada, Denmark, England, Northern Ireland, Norway, Sweden, and Wales—has shown that poorer survival for older adults.⁵ Another study from Europe, EUROCARE 5 study has indicated decreased survival in older adults with colon cancer.²⁸ Even though there is no difference in progression-free survival, it was seen that older patients had worse overall survival and higher rates of death in our work (p < 0.05).

In a study released in 2017 by Antonio et al, comprehensive geriatric assessment predicts survival. Three groups were generated according to their comprehensive geriatric assessment scores, as unfit, medium- fit and fit, and their overall survival were compared. This study showed that comprehensive geriatric assessment has prognostic value.²⁹ The absence of the comprehensive geriatric assessment in the present study is another limitation of this study. It is hard to estimate the difference in overall survival may be related to geriatric assessment.

By the nature of retrospective study, as aforementioned, there are some limitations. Because of the retrospective design, comprehensive geriatric assessment was not performed. No data is available on the comorbidities of the patients, researchers did not register any data about the functional status of the patients, ECOG or Karnofsky scores, and frailty scores. The interpretation of the decision- making process may be also related to the functional status of the patients, comorbidities, not only age. Further studies are needed to elucidate this point. However, the aim of this study was to investigate the difference between older patients with colon cancer and younger patients with colon cancer, so this is not a major limitation.

Another limitation of the study is about the causes of death. All- causes of death were recorded during the study, though because of all the patients had metastatic disease deaths of the patients could be acceptable as cancer-related death.

Even though it is a retrospective study, results of the current study are compatible with the data of the prospective studies in the literature. Treatment of older patients with cancer is a challenge for oncologist and multiple factors are needed to be considered with caution. This study is important to orient the therapy oncologically. Comprehensive geriatric assessment is important to dissociate non-frail patients from frail ones in the older patients and to give them appropriate treatment. Age should not be the only factor for the decision-making of cancer therapy.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Gülcan Bulut

Merve Güner Oytun

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