Effect of Age and Comorbidities on Short- and Long-Term Results in Patients Undergoing Laparoscopic Curative Resection for Rectal Cancer

Abstract

Background and Aim:

Conflicting findings have been reported in older patients undergoing laparoscopic surgery for rectal cancer. The aim of this study was to evaluate the effects of age and comorbidities on short- and long-term results of patients undergoing laparoscopic curative resection for rectal cancer (LCRRC).

Materials and Methods:

We retrospectively evaluated all 173 consecutive patients undergoing LCRRC at our unit (June 2005–September 2015). They were divided into two age groups as follows: <75 (n = 122) and ≥75 (n = 51) years. Comorbidities were evaluated using American Society of Anesthesiologists (ASA) score, Charlson Comorbidity Index (CCI), and age-related Charlson Comorbidity Index (ACCI).

Results:

Tumor characteristics were similar in the two groups. Comorbidity status (ASA, CCI, ACCI) was worse in elderly patients. Type of surgery performed was similar in the two groups. Medical complications were significantly higher in elderly (10.7% versus 29.4%, P = .006), while surgical complications were similar. Postoperative stay was longer in older patients (13 days versus 9 days, P = .0007). Multivariable analysis identified older age, higher CCI, and longer operative time as independent predictors of morbidity. Five years overall survival and disease-free survival were 49% and 43% in older and 84% and 77% in younger group (P < .0001). Multivariable analysis identified age, CCI, tumor, node, metastasis stage, and postoperative morbidity as independent risk factors for overall and disease-free survival.

Conclusions:

LCRRC achieves excellent short- and long-term results, but age and comorbidities may significantly affect postoperative morbidity and survival.

Introduction

The increase of life expectancy and the widespread diffusion of laparoscopic techniques have gathered attention on the feasibility of laparoscopic colorectal surgery in elderly patients, for both cancer and benign disease.^1,2 Previous studies suggested the benefits for elderly patients undergoing major colorectal surgery in terms of reduced intraoperative blood loss, postoperative pain, and faster return of bowel function, as allowed by minimally invasive surgery.^1–5 However, these studies mainly focused on colon cancer, including only few patients with rectal cancer.

Rectal cancer is a disease of the elderly reaching a peak around the age of 75–80 years.⁶ In rectal resection, the minimally invasive approach has shown to be associated with favorable postoperative results (i.e., improved bowel functions and shorter hospital stay) and oncological and pathological results.^7–12 The aging of the population is associated with an increased prevalence of rectal cancer expected in the future; thus, the potential benefits of laparoscopic approach for elderly patients require further investigation. So far, only few reports specifically focused on minimally invasive resection for rectal cancer in the elderly. The aim of this study was to evaluate the effects of age and comorbidities on the short- and long-term results of laparoscopic curative resection for rectal cancer (LCRRC).

Materials and Methods

Patients

All consecutive patients with primary rectal disease referred to our unit between June 2005 and September 2015. Our surgical unit is part of a community hospital serving a population of about 150,000 in Northeastern Italy. Data were extracted from a prospectively collected dedicated database. We excluded from the study patients not operated with curative intent or by laparoscopy and those with rectal resection as part of pelvic exenteration due to other nonrectal malignancies.

Preoperative staging and treatment

Preoperative cancer staging included endoscopic ultrasound, abdominal CT scan, and/or pelvic MRI. All patients with locally advanced tumor (cT3-4 and/or N+) of the mid/low rectum on preoperative examinations underwent a long course of neoadjuvant chemoradiotherapy (CRT) and subsequent surgery usually 8 weeks after completing the treatment. One day before surgery, all patients received a mechanical bowel cleansing comprising 4 L of polyethylene glycol electrolyte solution.

Comorbidities

Patient comorbidities were assessed using the American Society of Anesthesiologists (ASA) score,¹³ the Charlson Comorbidity Index (CCI), and the age-related Charlson Comorbidity Index (ACCI).^14,15 The calculation of CCI and ACCI includes major comorbidities with different weights (1, 2, 3, or 6) according to their relevance, and ACCI includes also an age penalization by adding one point for each decade over 50 years to CCI score. Cardiovascular comorbidities included cardiac arrhythmia, coronary artery disease, and congestive heart failure; pulmonary disease included chronic obstructive pulmonary disease.

Surgery

We referred to the standard principles of oncological rectal resection, with ligation of the inferior mesenteric artery close to its origin from the aorta. The splenic flexure was fully mobilized. In case of high rectal tumor, the resection was extended at least 5 cm below the tumor, and a partial mesorectal excision was accomplished (rectal anterior resection). For tumors located in the middle or lower third we extended the dissection toward the pelvic floor. A complete mesorectal resection was performed in these patients (low anterior resection [LAR]). For tumors located very close to the anal margin, we decided for an inter-sphincteric resection to obtain at least 1-cm tumor-free margin, starting usually with a perineal approach first. Anastomosis was either stapled or hand-sewn (colo-rectal anastomosis; colo-anal anastomosis). In case of tumor involvement of the external sphincter, we performed an abdominoperineal resection. Patients undergoing a total mesorectal excision after neoadjuvant CRT for a locally-advanced mid-/low rectal tumor had a diverting ileostomy or colostomy.

Conversion to open surgery was decided in case of: (1) infiltration of surrounding structures for advanced disease; (2) technical issues; (3) intraoperative complications we were not able to manage laparoscopically; and (4) patients not tolerating pneumoperitoneum, especially elderly ones with severe comorbidities.

Antibiotics were given i.v. at induction of anesthesia; low-molecular weight heparin and anti-thrombotic stockings were used in the perioperative period (usually the same day of surgery) and continued for 20–25 days after the patient's discharge to prevent deep vein thrombosis. An epidural catheter was used for analgesia.

A liquid diet was usually started on day 3. Epidural and urinary catheters were removed within 3 to 4 days after surgery. Patients were discharged if they tolerated soft diet, bowel movement present, and no need for in-hospital stay. We did not apply any specific “fast-track” recovery program.

We classified as postoperative morbidity both minor and major, medical (cardiopulmonary, urinary, neurological complications, etc.) or surgical (anastomotic leak, abdominal/pelvic abscess, intra-abdominal bleeding, wound abscess, prolonged ileus, etc.) complications, occurring during hospital stay.

We routinely followed up patients: they were seen 1 month after hospital discharge and subsequently by the oncologists, on a regular basis, for follow-up.

Statistical analysis

Continuous data were expressed as median and interquartile range (IQR). Patients were divided into two age groups (<75 and ≥75 years) according to previous studies.^5,16,17 Categorical data were compared between the two age groups using Fisher exact test and continuous data using Mann–Whitney test. A logistic regression model was estimated to identify the effect of age and comorbidities (measured by CCI) on postoperative morbidity, adjusting for clinically relevant confounders (sex, neoadjuvant treatment, pathologic tumor node metastasis (pTMN) stage, and operative time). Overall survival and disease-free survival curves were calculated using Kaplan–Meier method according to proposed guidelines on cancer end points and compared with Log-rank test.¹⁸ Two Cox regression models were estimated to identify the effect of age and comorbidities (measured by CCI) on overall survival and disease-free survival, adjusting for clinically relevant confounders (neoadjuvant treatment, pTMN stage, and postoperative morbidity). A P value less than .05 was considered statistically significant. Statistical analysis was performed using SAS 9.1 software (SAS Institute, Inc., Cary, NC).

Ethics

The study was conducted according to the Helsinki Declaration, and patients gave their consent to have their data collected for scientific purposes. The study was approved by the local ethics committee (#4029/U15/16).

Results

Clinicopathological characteristics

One hundred seventy-three patients were included in the study and divided into two groups according to their age: <75 (n = 122) and ≥75 (n = 51) years. Demographics and clinical characteristics are summarized in Table 1. Cardiovascular and pulmonary comorbidities were more frequent in elderly patients, who also showed higher CCI and ACCI. Table 2 summarizes operative and pathological data. Type of surgery, type of anastomosis, and conversion rate were similar in the two groups. The number of associated procedures was also similar, but the number of temporary diverting ileo/colostomies was significantly higher in older patients (Table 2). There was no statistically significant difference in pTNM tumor stage (Table 2).

Table 1.

Demographics and Clinical Characteristics

	<75 years old	≥75 years old	P
No. of patients	122	51	—
Sex (M/F)	86:36	31:20	.22
Age,^a years	64 (55–70)	80 (77–83)	<.0001
BMI,^a kg/m²	25.6 (23.6–28.1)	25.8 (23.7–28.1)	.84
Cardiovascular comorbidities	20 (16.4)	23 (45.1)	.0002
Pulmonary comorbidities	9 (7.4)	11 (21.6)	.02
Diabetes	17 (13.9)	7 (13.7)	.99
ASA score
1–2	91 (74.6)	18 (35.3)	<.0001
3–4	31 (25.4)	33 (64.7)
CCI	2 (2–3)	3 (2–3)	.03
ACCI	4 (3–5)	6 (6–7)	<.0001
Previous major abdominal procedures, laparotomy	11 (9.0)	10 (19.6)	.07
Neoadjuvant treatment	41 (33.6)	21 (41.2)	.39

Data are expressed as n (%) or ^amedian (interquartile range).

ACCI, age-related Charlson Comorbidity index; ASA, American Society of Anesthesiologists; F, female; CCI, Charlson Comorbidity index; M, male.

Table 2.

Operative and Pathological Data

	<75 Years old	≥75 Years old	P
No. of patients	122	51	—
Operative time,^a minutes	210 (175–260)	220 (195–260)	.26
Type of surgery
RAR	53 (43.5)	12 (23.5)	.05
LAR	62 (50.8)	36 (70.6)
APR	6 (4.9)	3 (5.9)
Total colectomy^b	1 (0.8)	0
Type of anastomosis
CRA	104 (90.4)	40 (83.3)	.28
CAA	11 (9.6)	8 (16.7)
Conversions	2 (1.6)	2 (3.9)	.58
Associated surgical procedures	24 (19.7)	12 (23.5)	.68
Diverting ileo/colostomy (excluding APR procedures)	65/116 (56.0)	40/48 (83.3)	.001
Intraoperative complications	3 (2.5)	3 (5.9)	.36
pTMN stage
0 (post-CRT)/Tis	14 (11.5)	5 (9.8)	.61
I/II	74 (60.6)	28 (54.9)
III/IV	34 (27.9)	18 (35.3)
Lymph nodes removed^a	17 (13–23)	15 (13–21)	.30
Metastatic lymph nodes^a	0 (0–1)	0 (0–1)	.30
Length of stay, days^a	9 (8–12)	13 (9–21)	.0007
Adjuvant therapy	33 (27.1)	10 (19.6)	.34

Data are expressed as n (%) or ^amedian (interquartile range).

In a patient with previous right hemicolectomy for cancer.

APR, abdominoperineal resection; CAA, colo-anal anastomosis; CRA, colo-rectal anastomosis; CRT, chemoradiotherapy; LAR, low anterior resection; RAR, rectal anterior resection.

The median number of lymph nodes collected was 16 (IQR 13–22) with a similar number of nodes collected in younger and older patients. A complete mesorectal excision was achieved in 164 patients (94.8%).

Morbidity and mortality

The mortality rate was 0.6%, with 1 younger patient who died of massive bleeding from the right gastric artery. The overall morbidity rate was 22.1% and 41.2% in younger and older patients, respectively (P = .02). Details of the postoperative complications are shown in Table 3. Medical complications were significantly higher in older patients (29.4% versus 10.7%, P = .006), while surgical complications were similar (13.7% versus 13.1%, P = .99). Eight patients required reoperation, due to anastomotic leak (3 patients), segmental ischemic colon (2 patients), volvulus (1 patient), and problems related to the ostomy (2 patients). Removal of naso-gastric (NG) tube (median 1 day [IQR 1–1] in both younger and elderly groups, P = .20) and resumption of bowel function (median gas canalization was 4 days [IQR 2–5] in younger and 3 days [IQR 3–5] in elderly, P = .54; median bowel movement was 5 days [IQR 3–6] in younger and 5 days [IQR 3–7] in elderly, P = .39) were similar in the two groups.

Table 3.

Postoperative Morbidity

	<75 Years old	≥75 Years old	P
No. of patients	122	51	—
Overall morbidity	27 (22.1)	21 (41.2)	.02
Medical morbidity	13 (10.7)	15 (29.4)	.006
Type of medical complications
Cardiovascular^a	2	8	—
Pulmonary^b	1	1
Urinary^c	6	3
Neurological^d	3	4
Others	2	2
Surgical morbidity	16 (13.1)	7 (13.7)	.99
Type of surgical complications
Anastomotic leak^e	4	1	—
Abdominal collection	2	—
Hemorrhage	1	—
Colonic ischemia	1	1
Ileus	6	2
Internal hernia	—	—
Divided ureter	—	—
Others^f	2	3
Reoperations	4 (3.3)	4 (7.8)	.24

Data are expressed as n (%).

Including: atrial fibrillation, other arrhythmias, heart failure, myocardial infarction, deep vein thrombosis, pulmonary embolism, and so on.

Including: pneumonia.

Including: urinary infection, urinary retention, patient discharged home with urinary catheter, and so on.

Including: temporary right hemiparesis, right temporal ischemia, hearing loss, superior/inferior limb hyposthenia, and so on.

Purulent of fecal discharge from the drains and/or peritonitis prompting abdominal CT scan revealing abdominal abscess close to the anastomotic ring.

Including: ileal volvulus, substenosis of the ileostomy, and so on.

Median hospital stay was 9 days (IQR 8–12) for patients <75 years and 13 days (IQR 9–21) for those older (P = .0007).

Multivariable analysis identified age (odds ratio [OR] 2.38, confidence interval [95% CI] 1.11–5.09), CCI (OR 1.31, 95% CI 1.03–1.67) and operative time (OR 1.01, 95% CI 1.00–1.01) as independent predictors of postoperative morbidity (Table 4).

Table 4.

Multivariable Analysis of Morbidity

	P	OR (95% CI)
Age (years): ≥75 versus <75	.02	2.38 (1.11–5.09)
Sex: male versus female	.39	—
CCI (as continuous variable)	.03	1.31 (1.03–1.67)
Neoadjuvant treatment: yes versus no	.51	—
pTMN stage: III-IV versus 0-Tis-I-II	.78	—
Operative time, minutes	.0006	1.01 (1.00–1.01)

CCI, Charlson Comorbidity index; CI, confidence interval; OR, odds ratio; pTMN, pathologic tumor node metastasis.

Survival

Overall, median follow-up was 52 months (IQR 28–76). Five-years overall survival was 74% and was lower in older group than in younger group (49% versus 84%, P < .0001). Five-years disease-free survival was 67% and it was lower in older group (43% versus 77%, P < .0001) (Fig. 1a–b). Multivariable analysis identified age, CCI, tumor, node, metastasis (TNM) stage, and postoperative morbidity as independent risk factors for both overall survival and disease-free survival (Table 5).

FIG. 1.

OS (a) and DFS (b) according to age. DFS, disease-free survival; OS, overall survival.

Table 5.

Multivariable Analysis of Survival

	Overall survival		Disease-free survival
	P	HR (95% CI)	P	HR (95% CI)
Age (years): ≥75 versus <75	<.0001	4.90 (2.59–9.27)	.001	2.46 (1.42–4.26)
CCI (as continuous variable)	<.0001	1.67 (1.37–2.03)	<.0001	1.67 (1.40–1.97)
Neoadjuvant treatment: yes versus no	.84	—	.57	—
pTMN stage: III-IV versus 0-Tis-I-II	.04	2.08 (1.05–4.15)	.0009	2.80 (1.52–5.11)
Postoperative morbidity: yes versus no	.003	2.56 (1.37–4.78)	.0005	2.71 (1.54–4.74)

CCI, Charlson Comorbidity index; CI, confidence interval; HR, hazard ratio; pTMN, pathologic tumor node metastasis.

Discussion

The aim of this study was to assess the effects of age and comorbidities on short- and long-term outcome of LCRRC. Our findings showed that age and comorbidities impaired both short-term results, in terms of morbidity, and long-term results, in terms of survival.

There is a growing interest in the medical literature for the results of surgery in elderly patients. The reason is that aging of the population, as a matter of fact, is a process we have been observing now for a while and has had a widespread diffusion worldwide.¹⁹ Improvements in healthcare and advances in medicine have led to an increase in life expectancy in most countries. As a result, more people are expected to live longer with a greater number of patients being operated in their 70's and 80's. Furthermore, more patients are arriving at the last “season” of their life in good health, searching for curative treatments, not just palliative care. In the present study, the cutoff age of 75 years was based on previous studies reporting an increase in postoperative complications in patients of ≥75 years undergoing laparoscopic colorectal resections.²⁰ This threshold was adopted in three of the four studies available in the literature specifically focusing on elderly patients undergoing laparoscopic rectal cancer resection (Table 6).^5,16,17,21 In addition, Kurian et al. reported a significant increase in 30-day mortality of over 5% per decade, starting from the age of 75 years, in over 100,000 patients undergoing major gastrointestinal resection.²²

Table 6.

Available Studies Specifically Assessing Results of Laparoscopic Rectal Resection for Cancer in Elderly

Author	Year	No. of patients	Age group (years)	Morbidity %	P	Anastomotic leak %	P	Reoperation rate %	P	Length of stay (days)	P
Scheidbach al.⁵	2005	193	>75	44.3	.007	13.4	.715	10.3	.379	NR	NR
		508	<75	28.4		11.9		7.6		NR
Chautard et al.²¹	2008	22^a	≥70	33	NS	3.7	NS	15	NR	15 (11)^b	NS
		24	<70	44		5.9		9		15 (12)^b
Akiyoshi et al.¹⁶	2009	44	≥75	13.6	.8	2.3	NS	NR	NR	19 (7–123)^c	.083
		228	<75	11.8		3.1		NR		15 (5–55)^c
Manceau et al.¹⁷	2015	61	≥75	43	.48	13	.49	NR	NR	11 (5–63)^c	.20
		385	<75	38		16		NR		9 (3–138)^c
Present study	2016	51	≥75	41.2	.02	3.3	.99	3.3	.24	9 (8–12)^c	.0007
		122	<75	22.1		2		7.8		13 (9–21)^c

Reported data in this study are referred to 27 patients ≥70 years and 34 < 70 years undergoing rectal resection although only 22 and 24, respectively, ≥70 and <70 years, were cancer patients.

Mean (SD).

Median (interquartile range).

NR, not reported; NS, not significant.

The issue of the feasibility of laparoscopic colorectal surgery in elderly patients has already been addressed, with previous reports suggesting that older patients might benefit from the advantages of laparoscopic approach in terms of reduced cardiopulmonary stress, postoperative pain, and hospital stay.²³ Some authors also reported a reduced morbidity associated with their learning curve. However, some concerns remain about high morbidity and mortality rates in elderly patients following LCRRC. Reluctance of anesthesiologists for the latter, aside from surgeons' reluctance due to technical difficulties, relies in the idea that pneumoperitoneum may adversely affect hemodynamic in already fragile elderly patients with limited cardiopulmonary capacity, especially if laparoscopic surgery reveals to last significantly longer than open one. Actually, previous studies showed that minimally invasive approach can preserve pulmonary function.²⁴ In the present study, overall morbidity was nearly twofold in elderly patients compared with younger ones. The higher proportion of cardiovascular and pulmonary comorbidities translates in higher postoperative medical complications, which are mostly cardiovascular and neurological. Despite a higher prevalence of cardiovascular and pulmonary comorbidities in elderly, pulmonary postoperative complications were similar to younger counterpart. Therefore, we confirm that any doubt on pulmonary effects in elderly after laparoscopic surgery, even prolonged and complex as for rectal cancer, should be overcome.

In contrast, occurrence of surgical complications was similar in elderly and in younger patients. These findings were in agreement with previous studies suggesting that postoperative surgical complications should not be blamed on the patient and his preoperative conditions.^5,16,17,21 We think that a proper surgical technique performed by experienced surgeon can make rectal cancer resection “similar” in younger and elderly patients, with virtually identical surgical complications, irrespective of age and comorbidities.

A limited number of studies specifically addressed the issue of elderly patients undergoing laparoscopic curative resection of rectal cancer, with different thresholds for considering a patient “old.”^5,16,17,21 Results of these studies are conflicting: some reveal a significantly higher proportion of complications in the elderly compared to younger patients, while others showed similar morbidity rates in younger and older patients. All the four studies published so far confirmed that anastomotic leak was not a matter of age, with comparable rates in younger and older patients. Similarly to our data, 2 authors of these studies also observed a trend toward a longer stay in elderly.^16,17 Panis' group performed a multivariable analysis showing that not age but ASA score and preoperative CRT, other than prolonged surgery, predicted morbidity.²¹ Neoadjuvant therapy, in our center, was equally used in younger and older patients, with a higher percentage in older ones, because of the higher proportion of LAR in the latter. We did not find preoperative CRT to be a predictive factor of morbidity and we will keep offering the same type of approach (neoadjuvant CRT in locally advanced mid/low rectal cancer) regardless of the age of patients.

An important remark from multivariable analysis was that older age significantly affected postoperative morbidity, aside from comorbidities. We think that older age, per se, may increase postoperative morbidity due to the overall fragile physical status that is not gathered by clinical comorbidity indexes as ASA or CCI.

These findings were confirmed by multivariable analysis of survival that estimated both age and comorbidities as independent risk factors, taking into account the effect of tumor stage and postoperative morbidity. Our results were in agreement with previous large cohort studies,^25,26 despite a recent Dutch study which failed to identify a significant effect of CCI on survival due to small sample size and type II error, according to the authors.²⁷ Furthermore, in our series the treatment strategy (including neoadjuvant therapy and surgical approach) was similar between younger and older patients, thus avoiding possible selection bias.

This study has some limitations that need to be considered when reading the results. First, the retrospective nature of the study usually affects the completeness of data, but our data were prospectively collected in an electronic database, and follow-up information was updated before the analysis, thus avoiding loss of data. Second, all operations were performed in a single Italian center; thus, the generalizability of the results may be limited to similar healthcare context. However, the same surgical team—a surgeon well experienced in laparoscopic surgery and 2 surgeons completing their learning curve for minimally-invasive rectal resection—performed all interventions, thus ensuring homogeneity of the surgical approach. Third, the cutoff of 75 years old in age dichotomization was not based on clinical evidence but on previous studies,^5,16,17 thus allowing future comparisons with the literature, including meta-analysis. Fourth, this study spans an 11-year period, and, necessarily, a few changes may have occurred in chemotherapeutic regimens, as well as refinements in surgical technique.

The strengths of the study include the evaluation of comorbidity status using the CCI, which is a validated comorbidity index and allows for comparisons with other studies, and the analysis of both short- and long-term outcomes adjusting for clinically relevant factors.

The results of this study might be useful when assessing the operability of a patient or when discussing the surgical risk of an operation with the patient himself. Even in the setting of an optimal pre-, intra-, and postoperative management, a significant proportion of elderly patients suffer from postoperative medical complications, compared to younger ones. Although advanced age, per se, is not a contraindication, it represents a risk for patients undergoing laparoscopic resection for rectal cancer, both in the short- (morbidity) and long run (survival). In elderly patients, this surgical approach should be considered preferably in well experienced centers to reduce postoperative risk and improve survival.

Footnotes

Disclosure Statement

No competing financial interests exist.

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