Abstract
Background:
Octogenarians constitute a growing percentage of patients diagnosed with colon malignancies. This study aims to determine if the clinical and pathologic presentation of octogenarians with colon cancer differs from that of patients diagnosed at a younger age.
Methods:
Data were collected retrospectively for all patients diagnosed with colon cancer who underwent resection at a single institution between January 1, 2004 and December 31, 2017; patients with rectal cancer were excluded. Patients were categorized by age at diagnosis: either 50 to 79 years of age or ≥80 years of age; those <50 years of age were excluded because of the greater risk of a hereditary etiology. The primary outcome was the correlation between patient age and pathologic features of the tumor, including tumor size, lymph node metastases, perineural invasion, and extramural venous invasion.
Results:
Of 1,301 patients, 329 (25%) were ≥80. Female patients predominated the octogenarian cohort (61% vs 39%; P < .001). Octogenarians presented with larger tumors when compared to patients age 50 to 79 (5.2 cm vs 4.5 cm; P < .001). More patients ≥80 had tumors which were >8 cm (17.3% vs 8.9%; P < .001). Tumors in younger patients were more often detected on screening colonoscopy (23.1% vs 7.3%; P < .001). Regardless of tumor size, octogenarians were less likely to have positive lymph nodes than younger patients (P = .02). In addition, octogenarians were less likely to exhibit extramural venous invasion compared to younger patients across all tumor sizes (P < .001). Younger patients had greater median overall survival (6.4 years vs 4.4 years; P < .001), yet 3-year disease-free survival was comparable between age groups (P = .12).
Conclusion:
Octogenarians with colon cancer present with larger tumors but appear to have less aggressive disease, as reflected in a lower pathologic stage, less extramural venous invasion, and less lymph node metastases, than younger patients with similar size tumors. Three-year disease-free survival is comparable between octogenarians and patients aged 50 to 79.
Introduction
Colon cancer is the most prevalent gastrointestinal malignancy and the second leading cause of cancer deaths in the United States.1 Octogenarians constitute a growing number of new diagnoses each year. Currently, 11.7% of new colorectal cancer cases are in patients greater than 84 years of age, and patients of this age account for 20.9% of all colon cancer deaths.1 This number will continue to grow, because there are over 11 million octogenarians in the United States, and this age group constitutes the fastest growing portion of the US population.2 Historically, there have been minimal advancements in treatment options for octogenarians due to their exclusion from clinical trials and due to provider or patient preference for less aggressive treatment strategies, both medical and operative.3,4 But the average lifespan of an octogenarian has increased, with 80-year-old American men and women expected to live, on average, an additional 8.4 years and 9.8 years, respectively.5 Therefore, care for this population warrants additional consideration than previously given.
Prior studies of colon cancer in octogenarians are small in the number of patients evaluated and lack pathologic and outcomes details. While a majority of previous reports delineate the obvious differences in patient comorbidities and American Society of Anesthesiologists (ASA) classification between octogenarians with colorectal cancer compared to younger patients, few studies have examined potential differences in disease presentation or tumor pathology between these groups.6,7 Additionally, there are mixed reports regarding survival. Although some studies report that octogenarians have worse morbidity and mortality than younger patients, many often analyze only overall survival (OS), which would be expected to be less than patients at much younger ages with colon cancer, without reporting rates of disease recurrence or disease-free survival (DFS). Findings on OS are often confounded by the natural effect of age and the reality that octogenarians often die from causes unrelated to their cancer in the years after colectomy. This inconsistent data has led to much variation in treatment approaches for octogenarians.8
We hypothesize that incident colonic tumors in octogenarians constitute a different phenotype than those patients who present at a younger age. The principal aim of this work was to identify the clinical and pathologic characteristics of tumors in octogenarians in comparison to younger patients. Our secondary aim was to analyze postoperative outcomes, the effect of adjuvant chemotherapy, and DFS in this population. Results of this work may help to guide future treatment strategies for an aging population.
Methods
All consecutive patients with colon cancer who underwent operative resection at the Massachusetts General Hospital (MGH) between January 1, 2004, and December 31, 2017 were reviewed retrospectively. Patients with rectal cancer were excluded because they are more likely to have a hereditary influence on the development of colon cancer. Data were maintained in a prospectively collected, institutional database approved by the Institutional Review Board of the MGH. An initial query of patients excluded those with a final pathology other than adenocarcinoma. Patients were also excluded if they had incomplete operative or pathologic records or were <50 years of age.
The patients were divided into 2 cohorts categorized by a patient’s age at the time of operation. Patients were separated into those who had an operation between the age of 50 and 79 and those aged 80 or greater. Tumor size was evaluated in the following tertiles: <4 cm, 4–8 cm, and >8 cm. Electronic medical records were reviewed for operative notes, imaging studies, pathology reports, and laboratory values to analyze patient demographics as well as perioperative variables. Pathologic stage was based on postoperative pathology reports and was described according to the American Joint Commission on Cancer (AJCC) seventh edition.9
The primary outcome addressed in this study was the correlation between patient age and pathologic features of the tumor, including tumor size, lymph node (LN) metastases, perineural invasion, and extramural venous invasion. Secondary outcomes included administration of chemotherapy and rates of readmission, reoperation, recurrence, and mortality. Mortality was analyzed at 30 days after operation, DFS at 3 years, and OS.
Statistical analyses were performed using Stata data analysis software version 15.0 (StataCorp LLC, College Station, TX). Categorical outcome variables were analyzed using the Fischer exact and χ2 tests. Continuous variables were compared by use of the Student t test. Median values are presented with interquartile range and mean values with standard deviation. Statistical significance was accepted at P ≤ .05. All tests were 2-sided. An adjusted Cox regression analysis was used to analyze 3-year DFS; a 3-year time point was chosen, because this time point reflects an accepted time point for disease recurrence and allows for the shorter expected survival in the octogenarian group. Both DFS and OS were modeled by use of a Kaplan Meier graph. Results of the Cox analysis were reported as hazard ratios (HR) with corresponding 95% confidence intervals (CI) and P values.
Results
Patient demographics
From January 1, 2004, through December 31, 2017, 1,787 patients with colon cancer underwent colectomy at the MGH. Final pathology other than adenocarcinoma was detected in 231 patients, excluding them from analysis. An additional 45 patients were excluded for having incomplete operative and/or pathologic records, and 210 were under the age of 50 (Fig 1).
Fig 1.
Study schema.
A total of 1,301 patients had resection of a colon adenocarcinoma, with 972 between the ages of 50 and 79 (74.7%) and 329 of age 80 or greater (25.3%). The median age of patients in the younger cohort was 66 years and 85 years in the older cohort. There were proportionately more women in the cohort ≥80 (61.4%) compared with only 48.5% in the younger cohort (P < .001; Table I). Older patients had a lesser mean body mass index of 24.7 compared with a mean of 28.2 in younger patients (P < .001). Younger patients were more likely to have a history of current or prior smoking when compared to octogenarians (54.9% vs 46.8%; P = .01). Patients ≥80 were more likely to be ASA class 3 or 4 (63.7%), while patients 50 to 79 were more often ASA class 2 (59.5%; P < .001).
Table I.
Patient demographics
| Total (N = 1,301) | Age 50–29 (n = 972) | Age ≥80 (n = 329) | P value |
|---|---|---|---|
| Male patients, n (%) | 501 (51.5) | 127 (38.6) | < .001 |
| BMI, mean (SD) | 28.2 (6.4) | 24.7 (4.8) | < .001 |
| Smoking Hx, n (%) | 533 (54.9) | 154 (46.8) | .01 |
| ASA, n (%) | |||
| ASA 1 | 28 (2.9) | 0 | < .001 |
| ASA 2 | 577 (59.5) | 118 (36.0) | |
| ASA 3 | 337 (34.7) | 192 (58.5) | |
| ASA 4 | 28 (2.9) | 17 (5.2) | |
| First degree relative with CRC, n (%) | 136 (13.9) | 30 (9.1) | .02 |
| Personal Hx of polyps, n (%) | 140 (14.4) | 51 (15.5) | .63 |
| Tumor found on screening, n (%) | 224 (23.1) | 24 (7.3) | < .001 |
| Presenting symptoms, n (%) | |||
| Anemia | 198 (20.4) | 134 (40.7) | < .001 |
| Fatigue | 108 (11.1) | 62 (18.8) | < .001 |
| Gastrointestinal bleed | 27 (2.8) | 27 (8.2) | < .001 |
| Pain | 267 (27.5) | 80 (24.3) | .26 |
| Obstruction | 66 (6.8) | 29 (8.8) | .22 |
| Perforation | 26 (2.7) | 7 (2.1) | .59 |
| Weight loss | 100 (10.3) | 32 (9.7) | .77 |
| Neoadjuvant chemotherapy, n (%) | 66 (6.8) | 3 (0.9) | < .001 |
| Embryologic origin, n (%) | |||
| Right-sided | 541 (55.7) | 241 (73.3) | < .001 |
| Left-sided | 431 (44.3) | 88 (26.8) | |
| Tumor size, n (%) | |||
| <4 cm | 427 (43.9) | 119 (36.2) | < .001 |
| 4–8 cm | 459 (47.2) | 153 (46.5) | |
| >8 cm | 86 (8.9) | 57 (17.3) |
Bolded values are statistically significant.
BMI, body mass index; CRC, colorectal cancer; Hx, history; SD, standard deviation.
Younger patients were more likely to have a first degree relative with a current or prior diagnosis of colorectal cancer (13.9% vs 9.1%; P = .02). There was no difference between groups in personal history of prior polyps found on colonoscopy. Patients 50 to 79 were more likely to have their tumor found on a screening colonoscopy compared to patients ≥80 (23.1% vs 7.3%; P < .001). The remaining patients not diagnosed by screening were evaluated and diagnosed after the development of symptoms. Older patients were more likely to have presenting symptoms of anemia (40.7% vs 20.4%; P < .001), fatigue (18.8% vs 11.1%; P < .001), or a gastrointestinal bleed (8.2% vs 2.8%; P < .001). Younger patients were more likely to have received neoadjuvant chemotherapy before their operation (6.8% vs 0.9%; P < .001). A greater proportion of octogenarians had right-sided tumors (73.3%) compared to patients age 50 to 79 (55.7%; P < .001).
Pathologic variables
Octogenarians when compared to patients 50 to 70 presented with larger tumors (mean 5.2 cm vs 4.5 cm; P < .001);17.3% of tumors in patients ≥80 were larger than 8 cm compared to 8.9% in patients <80 (P < .001; Table I). Patients 50 to 79 more often had AJCC Stage IV disease on final pathology both in total (17.9% vs 6.1%; P < .001) and across all size tertiles (Fig 2). Regardless of tumor size, octogenarians were less likely to have positive LNs than younger patients (36.8% vs 44.3%; P = .02). This observation held true when comparing tumors across each size tertile between the 2 age cohorts (P < .01; Table II). There was no difference in the average number of LNs examined per age group, with both age groups having an average of 22 LNs examined (P = .10). Less perineural invasion was present in octogenarians compared to younger patients overall (18.6% vs 25.5%, P = .04), yet there was no difference when analyzing separate size tertiles (P = .08). Tumors in octogenarians were less likely to be extramural venous invasion-positive when compared to young patients across each size tertile (P < .001).
Fig 2.
Patient AJCC stage by age and tumor size.
Table II.
Postoperative outcomes
| Total (N = 1,301) | Age 50–79 (n = 972) | Age ≥80 (n = 329) | P Value | ||||
|---|---|---|---|---|---|---|---|
| <4 cm (n = 427) | 4–8 cm (n = 459) | >8 cm (n = 86) | <4 cm (n = 119) | 4–8 cm (n = 153) | >8 cm (n = 57) | ||
| LN evaluated, mean (SD) | 20 (9.4) | 24 (11.9) | 27 (11.8) | 20 (10.7) | 23 (10.8) | 25 (10.6) | .10 |
| LN positive, n (%) | 175 (41.0) | 220 (47.9) | 36 (41.9) | 31 (26.1) | 67 (43.8) | 23 (40.4) | < .01 |
| PNI positive, n (%) | 96 (22.6) | 128 (27.9) | 23 (26.7) | 16 (13.6) | 31 (20.3) | 14 (24.6) | .08 |
| EMVI positive, n (%) | 111 (26.0) | 182 (39.7) | 31 (36.1) | 27 (22.7) | 55 (36.0) | 20 (35.1) | < .001 |
| Adjuvant chemotherapy, n (%) | 185 (43.3) | 225 (29.2) | 52 (60.5) | 13 (10.9) | 14 (9.2) | 4 (7.0) | < .001 |
| Duration of stay, d, median (IQR) | 4 (3–6) | 4 (3–6) | 6 (4–8) | 5 (4–7) | 5 (4–7) | 6 (4–7) | < .001 |
| 30-d readmission, n (%) | 31 (7.3) | 33 (7.2) | 4 (4.7) | 15 (12.6) | 9 (5.9) | 3 (5.3) | .25 |
| 30-d reoperation, n (%) | 11 (2.7) | 13 (2.8) | 2 (2.3) | 5 (4.2) | 1 (0.7) | 0 | .38 |
| 30-d mortality, n (%) | 8 (1.9) | 9 (2.0) | 3 (3.5) | 5 (4.2) | 6 (3.9) | 2 (3.5) | .49 |
| Cancer recurrence, n (%) | 110 (25.7) | 169 (36.8) | 35 (40.7) | 22 (18.5) | 34 (22.2) | 13 (22.8) | < .001 |
Bolded values are statistically significant.
IQR, interquartile range; EMVI, extramural venous invasion; PNI, perineural invasion; SD, standard deviation.
Postoperative outcomes
Octogenarians with tumor sizes <4 cm and 4 to 8 cm were more likely to have a greater postoperative hospital duration of stay when compared to younger patients with comparable size tumors (5 days vs 4 days, P < .001; Table II), yet there was no difference between age groups in tumors size >8 cm (6 days). Additionally, there was no difference in 30-day readmission, 30-day reoperation, or 30-day mortality rates between the groups. Patients 50 to 79 were more likely to receive adjuvant chemotherapy compared to octogenarians (47.6% vs 9.4%; P < .001). Of the patients who received adjuvant chemotherapy, this difference by age held true when analyzing patients of all stages and when excluding patients determined to have pathologic AJCC Stage IV disease. Interestingly, in younger patients, the administration of adjuvant chemotherapy increased as tumor size increased, in contrast to octogenarians, in which adjuvant chemotherapy usage decreased with increasing tumor size. Older patients had less overall disease recurrence (20.9% vs 32.3%; P < .001). The greatest recurrence rates were in patients 50 to 79 with tumors >8 cm at a rate of 40.7% compared to 22.8% in tumors of similar size in octogenarians (P < .001). There was no difference in the time to disease recurrence with the average time being 225 days for patients age 50 to 79 and 285 days for octogenarians (P = .05).
Survival analysis
No significant difference was found in 3-year DFS between age groups, with 63.8% of patients ≥80 and 59.0% of patients 50 to 79 reaching that milestone (P = .12, Fig 3, A). Yet, octogenarians had a significantly decreased OS at a median of 4.4 years compared with 6.4 years in patients 50 to 79 (P < .001; Fig 3, B). On multivariable adjusted Cox regression, age was not found to be associated with 3-year DFS (HR 1.04, CI 0.70–1.54; P = .83; Table III). Patients were increasingly less likely to have 3-year DFS with each increase in tumor stage. Decreased likelihood of 3-year DFS was also associated with pathologic markers of more aggressive disease, including positive perineural invasion (HR 1.63, CI 1.22–2.65; P = .001) and positive extramural venous invasion (HR 1.98, CI 1.48–2.65; P < .001). Tumor size, ASA class, receipt of adjuvant chemotherapy, and LN positivity were not associated with 3-year DFS.
Fig 3.
Kaplan Meier of (A) DFS and (B) OS by age.
Table III.
Multivariable Cox regression of disease-free survival
| Variable | Hazard ratio | 95% CI | P value |
|---|---|---|---|
| Age ≥80 | 1.04 | 0.70–1.54 | .83 |
| Male sex | 1.10 | 0.84–1.43 | .50 |
| Positive smoking history | 1.07 | 0.83–1.39 | .61 |
| ASA | |||
| ASA 1 | Reference | ||
| ASA 2 | 0.99 | 0.49–2.06 | .99 |
| ASA 3 | 1.15 | 0.55–2.41 | .71 |
| ASA 4 | 1.47 | 0.55–3.98 | .44 |
| Embryologic origin | |||
| Right-sided | Reference | ||
| Left-sided | 1.30 | 0.99–1.71 | .07 |
| Tumor size | |||
| <4 cm | Reference | ||
| 4–8 cm | 0.99 | 0.75–1.32 | .96 |
| >8 cm | 1.20 | 0.78–1.84 | .40 |
| Pathologic AJCC stage | |||
| Stage I | Reference | ||
| Stage II | 2.67 | 1.41–5.07 | .003 |
| Stage III | 4.40 | 1.65–11.8 | .003 |
| Stage IV | 40.4 | 12.2–133.9 | < .001 |
| Adjuvant chemotherapy | 1.19 | 0.82–1.72 | .37 |
| Positive LN | 1.07 | 0.50–2.26 | .87 |
| Positive PNI | 1.63 | 1.22–2.65 | .001 |
| Positive EMVI | 1.98 | 1.48–2.65 | < .001 |
Bolded values are statistically significant.
EMVI, extramural venous invasion; PNI, perineural invasion.
Discussion
Octogenarians with incident colon adenocarcinoma present with larger tumors but less extracolonic spread compared with younger patients. This study determined that regardless of tumor size octogenarians had less LN spread, less extramural venous invasion, and had a lower pathologic stage compared with younger patients. These findings indicate that older patients diagnosed with colon adenocarcinoma are presenting with a different, less-aggressive phenotype than patients diagnosed at a younger age. In addition, 3-year DFS was comparable between age groups showing that octogenarians do well postoperatively and should not be restricted from an operation based on age alone.
Despite arising from the same primary organ, colon adenocarcinoma has distinct features dependent on the age of presentation. In this study, 17.3% of tumors in octogenarians were >8 cm compared with only 8.9% in patients 50 to 79. The overall tumor size is likely increased in older patients owing to only 7.3% being found on screening colonoscopy. This screening rate is within reason because the median age of the octogenarian cohort was 85, which is 10 years after traditional screening ends per National Comprehensive Cancer Network (NCCN) guidelines.10 Nevertheless, despite the increased size of tumors in octogenarians, these tumors displayed less-aggressive features when compared to similar sized tumors in younger patients. Patel et al found similar results when analyzing the Surveillance, Epidemiology, and End Results (SEER) database and determined that octogenarians presented at a lesser stage and with less LN positivity.11 These findings corroborate our results; however, our study went further by determining that additional pathologic markers of malignant spread, including perineural invasion and extramural venous invasion, were also both less prevalent in octogenarians. This novel finding is crucial, for in addition to pathologic stage, perineural invasion and extramural venous invasion were important determinants of attaining 3-year DFS on multivariable analysis. The culmination of these pathologic differences suggests a distinct phenotype of adenocarcinoma that presents in octogenarians.
More important than presentation is how these patients fare after colectomy. Historically, there has been a relative hesitancy to operate on octogenarians due to the well-described increase in comorbidities and diminished physiologic reserve that can occur with age; however, no definitive treatment guidelines exist given mixed findings within the literature.11–13 Perez Dominguez et al analyzed a cohort of patients ≥75 years of age with operatively resected colon cancer and found that they had greater rates of overall postoperative complications and 30-day mortality.12 Our findings disagree with those results and indicate that in our cohort, short-term, postoperative outcomes were comparable between younger and older patient age groups. Our study found no difference in rates of 30-day readmission, reoperation, or mortality between older and younger patient groups. Interestingly, in contrast to Perez Dominguez et al, our patients were older and had a greater ASA. Although these results differ, it has been shown that operative mortality is improving for older patients. A study of the Netherlands Cancer Registry showed that from 2009 to 2013, among patients ≥75 years of age with colon cancer, 30-day mortality decreased from 8.3% to 6.2%, and 1-year mortality decreased from 18.5% to 15.0%.14 Our overall 30-day mortality in octogenarians was 3.9%, demonstrating that postoperative survival is improving in this patient population. These findings indicate that it is appropriate and safe to operate on select octogenarians with colon cancer.
A majority of prior studies report worse OS for older patients with colon cancer after resection.7,11,15 Like prior studies, our OS was worse in octogenarians, with a median OS of 4.4 years compared with 6.4 years in the younger patients. Yet, of the 84% of our patients (1,089 of 1,301) who had a known cause of death, only 18% of all deaths in octogenarians were related to colon cancer, which indicates that the majority of deaths were due to other causes, likely related to disease processes that are more prevalent at advanced age. In comparison, 25% of total deaths in patients 50 to 79 were due to colon cancer. Therefore, we maintain that 3-year DFS is a more accurate indicator of long-term postoperative outcomes for older patients than OS. Our results found no difference in 3-year DFS between the 2 age groups with 63.8% of patients ≥80 and 59.0% of patients 50 to 79 reaching this time point. Multivariable analysis reaffirmed that age is not associated with attaining 3-year DFS. Rather, disease stage, perineural invasion, and extramural venous invasion are strongly associated with DFS. Similarly, Nitsche et al analyzed 2-year, tumor-specific survival in patients with colon cancer, where survival rates for patients ≥75 were 83%, which was comparable to 87% for the younger patients.13 These consistent results illustrate that age should not be a sole limiting factor in the decision to undergo colectomy, because long-term, disease-related survival is independent of age alone.
We acknowledge that age likely did have a role in the treatment selection for each of these patients. Statistically significant differences were found in the receipt of both neoadjuvant and adjuvant chemotherapy when comparing octogenarians to the younger cohort. Decisions regarding chemotherapy are often a joint discussion between medical oncologists and surgeons that are formed by a subjective assessment of a patient’s ability to “tolerate” the toxicities associated with systemic treatment. The greater ASA classification of our octogenarian cohort as a surrogate marker of comorbidity may have been taken into account when treatment plans were made. Additionally, the increase in adjuvant chemotherapy used in the patients aged 50 to 79 may have been due to their increase in stage III & IV disease compared with the octogenarians. Nevertheless, despite these differences in systemic treatment, 3-year DFS was still comparable between groups, and adjuvant chemotherapy was not shown to be associated with DFS on multivariable analysis, further supporting the notion that octogenarians may have a less aggressive phenotype of disease.
As with all retrospective studies, there are limitations. Our institution is a high-volume referral center, and a number of our patients are referred from other practices both in and out of state. This referral practice results in an incomplete screening history of some patients because colonoscopies and decisions regarding colonoscopy screening were determined elsewhere. A subset of our patients arrives solely for an operation and then are lost to our follow-up once they return to their home institutions for continued postoperative care. Also, this study addresses only colon cancer and not rectal cancer. Additionally, this study captures only those patients who underwent colectomy and does not capture patients who may have been evaluated but either chose not to undergo operative treatment at our institution or were deemed unfit by their treating physician to undergo an operation. There may be a selection bias present in that octogenarians with severe comorbidities may not have been offered surgical resection as a treatment option.
In conclusion, of all patients undergoing colectomy for colon cancer at our institution, octogenarians present with larger colon cancer tumors but have less aggressive disease, reflected in a lesser pathologic stage, less extramural venous invasion, and less LN metastases, than younger patients with comparable size tumors. This milder phenotype, along with DFS rates comparable to younger patients, should increase awareness that resection is an appropriate treatment strategy for some octogenarian patients with colon cancer.
Acknowledgments
NMS was supported by the National Institutes of Health T32 Research Training in Aging grant 5T32AG023480-13. The National Institutes of Health had no involvement in study design; collection, analysis or interpretation of data; writing of the report; or decision to submit the article for publication.
Funding/Support
The authors have indicated that they received no funding related to the content of this article.
Footnotes
Presented at the 2020 Annual Meeting of the Academic Surgical Congress (ASC) on February 4, 2020, in Orlando, FL.
Conflict of interest/Disclosure
The authors have indicated no conflicts of interest regarding the content of this article.
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