Abstract
Background/Aim: The safety of neoadjuvant chemoradiotherapy (NACRT) combined with total mesorectal excision (TME) and selective lateral pelvic lymph node dissection (LLND) is unclear in elderly patients with locally advanced rectal cancer (LARC). Patients and Methods: Forty-two patients with LARC underwent TME and selective LLND following NACRT at Kobe University Hospital. The clinical outcomes were retrospectively compared between the elderly (aged ≥70 years, n=13) and non-elderly patients (aged <70, n=29). Results: Twelve of the thirteen elderly patients could complete NACRT. Although the overall rate of postoperative complications did not differ between the groups, abdominal wound infection and deep vein thrombosis developed more frequently in the elderly group. The length of the postoperative hospital stay was similar. Three-year overall survival and 3-year relapse-free survival rates were similar between the groups. Conclusion: Selective LLND after NACRT is safe for elderly patients with LARC.
Rectal cancer has the 8th highest incidence rate and is the 10th most deadly cancer in the world, with 310,000 deaths estimated for 2018 constituting 3.2% of all cancer deaths (1). In clinical practice, an increasing population of elderly patients with rectal cancer requires a multidisciplinary approach, including surgery (2). However, as people grow older, the risk of postoperative complications increases with an increasing number of comorbidities (3).
In Western countries, neoadjuvant chemoradiotherapy (NACRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Meanwhile, in Japan, lateral pelvic lymph node dissection (LLND) is performed in patients with locally advanced, lower rectal cancer to improve local control after surgery (4). However, it has been demonstrated that intraoperative blood loss, operative time, or dysuria from nerve damage increases after LLND because of its high invasiveness (5, 6).
NACRT combined with TME and selective LLND has been recently performed in several institutions as an effective treatment option for LARC (7, 8). This treatment strategy was associated with improved local control and favorable oncological outcomes; however, the efficacy and safety of this treatment in elderly patients have not been clarified.
In this retrospective study, we compared the clinical outcomes of selective LLND after NACRT for LARC between elderly (aged ≥70) and non-elderly patients (aged <70) and evaluated the efficacy and safety of this treatment strategy.
Patients and Methods
Patients. Between November 2005 and September 2019, a total of 42 patients with LARC underwent TME and selective LLND following NACRT due to clinically positive metastasis of lateral pelvic lymph nodes (LLNs) at Kobe University Hospital. The clinical outcomes were retrospectively compared between the elderly patients (aged ≥70, n=13) and the non-elderly patients (aged <70, n=29). Patients with histologically diagnosed adenocarcinoma, lower tumor margins below the peritoneal reflection, and cT3-4 or any cT/cN+ disease were included in the study. Patients who previously underwent pelvic surgery or received radiation to the pelvis were excluded. Tumors were classified according to the American Joint Committee on Cancer TNM system (9).
This study was conducted with the approval of the Institutional Review Board and Ethics Committee of Kobe University Graduate School of Medicine.
Treatment strategy. The patients were treated with NACRT comprising a total radiation dose of 45-50.4 Gy and oral 5-fluorouracil (5-FU)-based chemotherapy, as described previously (10). Radiotherapy was delivered in 25 fractions for 5 weeks. The lateral pelvic area was included in the radiation target volume. Surgery was performed 6-8 weeks following NACRT completion. LLND was indicated only in patients with clinically positive LLNs based on the pretreatment images, regardless of their clinical response to NACRT. LLNs with a short-axis diameter >8 mm based on computed tomography (CT) scan, magnetic resonance imaging, a positive diffusion-weighted image by MRI, or a high intensity spot based on positron emission tomography were considered clinically positive for metastasis. LLND was performed only on the side ipsilateral to the swollen LLNs. For patients with swollen LLNs on both sides, bilateral LLND was performed. For all patients in this study, TME with selective LLND was performed either with an open or laparoscopic approach. Adjuvant chemotherapy was considered for all patients regardless of the pathological stage. The regimen for adjuvant chemotherapy included one of the following: the Roswell Park regimen comprising intravenous 5-FU plus LV, oral UFT plus LV, oral capecitabine, or oral capecitabine plus oxaliplatin.
Follow-up. Follow-up was conducted every 3 months for the first 3 years and every 6 months thereafter. Tumor markers, including carcinoembryonic antigen and carbohydrate antigen 19-9, were examined during each follow-up. The first CT was performed 3 months after surgery and then routinely performed every 6 months. Total colonoscopy was performed every year. Local recurrence was defined as the recurrence that developed within the pelvic cavity, while distant recurrence was defined as that developed outside of the pelvic cavity.
Statistical analysis. Statistical analysis was performed using JMP software (SAS Institute Inc., Cary, NC, USA). Continuous variables were expressed as median (range). Comparisons of continuous variables were performed by Student’s t-test or Mann–Whitney’s U-test, according to the data distribution. The Chi-square test was used to analyze categorical variables. Survival analysis was performed using the Kaplan–Meier method, and univariate survival comparison was performed using the log-rank test. A p-value <0.05 was considered statistically significant.
Results
Patient and tumor characteristics are summarized in Table I. Hypertension and clinical Stage IV cancer were more frequent in the elderly group than in the non-elderly group. The number of patients with an American Society of Anesthesiologists (ASA) score of 1 was considerably less in the elderly than in the non-elderly group. Completion of NACRT was achieved in most patients of both groups. Only one patient in the elderly group could not complete NACRT due to febrile neutropenia and grade III diarrhea.
Patient demographics.
Operative outcomes are summarized in Table II. Open surgery was performed more frequently in the non-elderly group. The duration of the operation was longer in the elderly group than in the non-elderly group. However, intraoperative blood loss or the rate of transfusion did not differ significantly between the groups.
Surgical outcomes.
Postoperative outcomes are shown in Table III. The rate of overall postoperative complications (≥Clavien–Dindo Grade II) did not differ between the groups. The number of cases that developed abdominal wound infection and DVT was observed to be significantly higher in the elderly group than in the non-elderly group (6.9% vs. 30.8%, p=0.041 and 0% vs. 15.3%, p=0.03, respectively). The length of postoperative hospital stay, 30-day mortality, or 30-day reoperation rate did not differ between the groups.
Postoperative outcomes.
Pathological outcomes are shown in Table IV. No significant differences were found in any factor. A complete pathological response was achieved in two patients for the elderly group (15.4%) and four patients for the non-elderly group (13.8%).
Pathological outcomes.
The changes in the serum albumin, hemoglobin, and prognostic nutritional index (PNI) levels after NACRT are summarized in Table V. The PNI was calculated according to the following formula: PNI=albumin (g/l)+5× total lymphocyte counts per liter. The decrease in the serum albumin and hemoglobin levels was found to be significantly larger in the elderly patients than in the non-elderly patients.
The changes of serum albumin, hemoglobin, and PNI after NACRT.
The Kaplan–Meier curves for overall survival (OS) and relapse-free survival (RFS) in each group are shown in Figure 1. The median follow-up period was 94 months. There were no significant differences between the groups in either OS or RFS rates. The 3-year OS rates were 84.9% for the non-elderly and 100% for the elderly patients (p=0.11). The 3-year RFS rates were 71.5% in the non-elderly and 56.4% in the elderly patients (p=0.47).
Three-year overall survival curves (A) and 3-year recurrence-free survival curves (B) for non-elderly and elderly patients who underwent selective lateral lymph node dissection after neoadjuvant chemoradiotherapy.
Discussion
As the population of elderly people increases, the number of rectal cancer patients with an advanced age is also expected to increase. This population has more comorbidities, an increased complication rate, and a poorer prognosis as compared to the non-elderly patients (2, 3). Therefore, short-course radiotherapy, dose reduction, or omission of chemoradiotherapy is sometimes preferred for elderly or frail patients (11). However, there have been no previous reports that have clarified the safety and usefulness of NACRT followed by TME and selective LLND in elderly patients. The present study demonstrated that the clinical outcomes of NACRT followed by selective LLND for elderly patients (aged ≥70) were comparable to those in non-elderly patients.
In this study, laparoscopic surgery was performed more frequently in the elderly than in the non-elderly (84.6% vs. 48.3%, p=0.027). This is a retrospective study and more non-elderly patients were included in the early period of this study. However, our data demonstrated that laparoscopic LLND after NACRT could be performed safely even in elderly patients. Generally, LLND is notorious as a technically demanding procedure due to the complicated anatomy of the pelvic sidewall and the difficult accompanying procedures. However, several advantages of laparoscopic LLND over open LLND have been reported in recent studies in terms of postoperative complications and hospital stay (12-14). Although it is well known that elderly people are likely to have more serious postoperative complications (15), this is the first to show the safety of laparoscopic LLND after NACRT in elderly patients with LARC.
Although the overall rate of postoperative complications was similar between the two groups, DVT and abdominal wound infection were found to develop more frequently in elderly patients. Previous large-scale studies reported that a significant risk factor of DVT after colorectal cancer surgery include an age >70, emergent admission, anesthesia length >150 min, ASA score greater than 2, obesity, hypoalbuminemia, disseminated cancer, steroid use, and open surgical approach (16, 17). Although most of the elderly group underwent laparoscopic surgery and had an ASA score of 2 in the present study, DVT still developed more frequently. As recommended by Zaghiyan et al., preoperative screening for DVT and perioperative chemical thromboprophylaxis should be considered for elderly patients (17).
In addition, laparoscopic colorectal surgery has been reported to be associated with a lower incidence of surgical site infection (SSI) as compared to open surgery (18). However, the frequency of abdominal SSI was higher in the elderly group in this study. This finding may be due to the changes in the nutritional status during NACRT in the elderly. In the present study, a significant decrease in serum albumin and hemoglobin levels after NACRT was observed in the elderly patients. Yamano et al. reported that changes in the nutritional status during NACRT, such as a decrease in serum albumin levels, were significantly associated with postoperative complications (19). Several investigators also reported that malnutrition, such as hypoalbuminemia, contributes to postoperative mortality, morbidity, and length of total hospital stay in colorectal cancer patients (20, 21). Early interventions in order to maintain or improve the nutritional status during NACRT may help reduce the development of abdominal SSI.
Still, the present study has several limitations. First, a potential bias cannot be completely excluded because of the retrospective nature of the study. Furthermore, the study was done in a single institution, and the number of included patients was small. Second, the group of non-elderly patients underwent open surgery more frequently than the group of elderly patients because more non-elderly patients were included in the early study period. There is a possibility that this negatively affected the operative and postoperative outcomes of the non-elderly patients.
In conclusion, selective LLND following NACRT in elderly patients with lower LARC was found to be an appropriate treatment with an acceptable level of safety. Large-scale, prospective studies are necessary for a more definitive conclusion.
Footnotes
Authors’ Contributions
Conception and design: KA and TM. Surgery: TM, KY, HH, and TN. Acquisition of data: KA, MU, and HH. Analysis and interpretation of data: TM, SK, TO, and SS. Writing: KA and TM. Review and revision of the manuscript: YK.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received January 5, 2021.
- Revision received January 19, 2021.
- Accepted January 20, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
