Abstract
Purpose
This study aimed to analyze the benefit of neoadjuvant chemoradiation therapy (nCRT) versus adjuvant chemotherapy alone after surgery without nCRT on oncologic and perioperative outcomes of patients with extremely low rectal cancer requiring abdominoperineal resection (APR) when initially diagnosed.
Methods
Between March 2001 and December 2018, 88 patients who underwent APR for low rectal adenocarcinoma (anal verge <4 cm) with clinical stage II and III (clinical T3/4, N −/+) were retrieved from a retrospective database. Sixty-eight patients received adjuvant chemotherapy alone after APR without nCRT, and 20 patients received nCRT before APR.
Results
Median follow-up was 59.7 months. The 5-year disease-free survival rate was significantly higher in the nCRT group compared to in chemotherapy alone group (85.5% vs. 58.2%, P=0.022). The 5-year overall survival rate was also significantly higher in nCRT group compared to in chemotherapy alone group (79.6% vs. 60.0%, P=0.042). The total recurrence rate was 45.6% in chemotherapy alone group and 15.0% in the nCRT group (P=0.010). There was no significant difference in circumferential resection margin positive rate, postoperative morbidity, and mortality between the two groups.
Conclusion
Based on present data, the oncologic outcomes are better in nCRT compared to adjuvant chemotherapy alone after surgery without nCRT in patient with extremely low rectal cancer requiring APR initially diagnosed, even if curative resection is possible at first.
Keywords: Rectal neoplasms, Proctectomy, Neoadjuvant therapy
INTRODUCTION
In rectal cancer, radical resection of the rectum with mesorectal excision along the mesorectal fascia has been performed to remove mesentery, lymphatics, and tumor deposits, which improves local recurrence rate, postoperative bleeding, and injury of the autonomic nerves [1]. However, it is hard to achieve the negative circumferential margin in locally advanced rectal cancer, in which the tumor extends beyond the fascia propria of rectum. Tumor involvement of the circumferential resection margin (<1 mm) is an independent prognostic factor associated with local recurrence and overall survival in rectal cancer [2]. To achieve the circumferential resection margin, chemoradiation therapy (CRT) has been developed since the late 1980s. In the latest consensus, neoadjuvant CRT (nCRT) is accepted for standard treatment in clinical stage II/III rectal cancer [3].
The nCRT reduces the local recurrence rate in advanced rectal cancer compared to postoperative CRT (6%–13%) [4,5]. Also, nCRT is known as increasing the rate of the anal sphincter saving surgery (39% vs. 19%) [6]. However, nCRT leads to acute toxicities such as diarrhea and skin problems due to radiation. There are long-term toxicities as radiation enteritis, anastomotic stricture, and urinary or sexual dysfunction [7].
Low rectal cancer is defined as tumors located less than 5 cm from the anal verge. The type of surgery for low rectal cancer is chosen by the location and clinical stage of the tumor according to the distance from the anal verge and relation to the anal sphincter. Ultra-low anterior resection, intersphincteric resection, or abdominoperineal resection (APR) are the surgical options for low rectal cancer. The tumor extended to the external anal sphincter or involved below or at the anal verge should be treated with APR [8,9]. And also, extremely low rectal cancer should achieve the oncologic satisfaction of the distal and circumferential resection margin by performing APR with cylindrical en-bloc resection of the tumor with removal of the levator ani muscle and external anal sphincter [10].
The study was designed from the question that the patient of extremely low rectal cancer requiring APR when initially diagnosed is really necessary for the nCRT, because this group of the patients can achieve curative resection margins with APR and there is no need to save the anal sphincter, which is the advantage of nCRT. Also, acute and long-term complications of radiation could impact the lifetime of the patients. This study aimed to analysis the oncological outcomes and postoperative morbidity of the patients with clinical stage II and III extremely low rectal cancer (<4 cm from the anal verge) requiring APR when initially diagnosed by dividing into two groups (nCRT group: patients who received nCRT; adjuvant chemotherapy alone group: patient who received adjuvant chemotherapy alone without nCRT after surgery).
METHODS
Participants
Between March 2001 and December 2018, 88 patients underwent curative surgical resection (APR) for an extremely low rectal adenocarcinomas (<4 cm from anal verge) with clinical stages II and III (clinical T3/4, N −/+: including T3 or T4, or clinical node positive) were identified from a retrospective database. The patients with stages I and IV in the present study were excluded. Of these, 68 patients received adjuvant chemotherapy alone after surgery and 20 patients received nCRT. All data of the clinical and pathological features were reviewed retrospectively. All patients underwent colonoscopy and biopsy, staging scans (computed tomography scan: chest, abdomen and pelvis; magnetic resonance imaging scan: pelvis) and occasionally positron emission tomography scans. Morbidity was determined as a complication that occurred within 30 days after surgery. The nCRT was performed long course CRT (5-fluorouracil [5-FU] based chemotherapy, 50.4 Gy) with intravenous infusion or oral 5-FU as they were clinically T3 or T4 and/or node positive. Surgery was performed 6 to 8 weeks after completion of nCRT. All patients received full bowel preparation and a single shot of prophylactic antibiotics. All patients underwent complete total mesorectal excision. Adjuvant chemotherapy in the nCRT group was performed with a 5-FU and leucovorin calcium-based regimen (six cycles of monthly bolus intravenous 5-FU [400–425 mg/m2/day] and leucovorin [20 mg/m2/day], days 1–5). Adjuvant chemotherapy alone group performed FOLFOX regimens (leucovorin calcium, fluorouracil, and oxaliplatin). Patients receive close follow-up and are recorded on a database till death or December 2023. Disease-free survival was defined from the date of surgery to the date of the detection of recurrence or last follow-up or death. Patients in the two groups undergoing adjuvant chemotherapy alone and nCRT were compared with respect to demographics and oncologic outcomes. Informed consent was waived from the Institutional Review Board of Soonchunhyang University Bucheon Hospital due to the retrospective design.
Statistical analysis
All statistical analyses were performed using SAS version 9.1.3 (SAS Institute Inc.) and SPSS software, version 24.0 (SPSS; IBM Corp.). Categorical variables were analyzed using the chi-square or Fisher exact test, and continuous variables were analyzed using the Student t-test/Mann-Whitney U rank tests. Cumulative-incidence methods were used to estimate the rate of cancer recurrence. Overall survival and disease-free survival were analyzed using the Kaplan-Meier method, and a comparison was performed using the log-rank test. P-values of less than 0.05 were considered statistically significant. The differences in overall and disease-free survival were assessed using the log-rank test.
RESULTS
Patient characteristics
All patients were clinical stage II and III (clinical T3/4, N −/+). Patient characteristics were analyzed through a comparison of the adjuvant chemotherapy alone group (n=68) and nCRT group (n=20) (Table 1). Mean age, sex ratio, height, weight, body mass index (BMI), and American Society of Anesthesiologists scores, as well as initial carcinoembryonic antigen level, show significant differences between the two groups. Operation time, time to sips of water, time to liquid diet, time to soft diet, also did not significant different between the two groups. The blood loss was significantly higher in adjuvant chemo group compared to nCRT group (P=0.029). Total morbidity rate was 22.1% (n=15) in adjuvant chemotherapy alone group and 10.0% (n=2) in CRT group (P=0.095).
Table 1.
Patient characteristics (n=88)
| Characteristic | Adjuvant chemotherapy alone (n=68) | nCRT (n=20) | P-value |
|---|---|---|---|
| Age (yr) | 62.0±13.0 (31–90) | 58.0±7.7 (48–75) | 0.009 |
|
| |||
| Sex | 0.981 | ||
| Male | 44 (64.7) | 13 (65.0) | |
| Female | 24 (35.3) | 7 (35.0) | |
|
| |||
| Weight (kg) | 58.1±9.0 (43.3–94.3) | 64.9±11.6 (39.6–84.0) | 0.147 |
|
| |||
| Height (cm) | 159.8±8.9 (139.6–185.5) | 163.0±9.5 (147.3–179.0) | 0.530 |
|
| |||
| BMI (kg/m2) | 22.8±3.0 (16.9–31.8) | 24.3±3.5 (16.7–30.4) | 0.461 |
|
| |||
| ASA score | 0.099 | ||
| 1 | 46 (67.6) | 10 (50.0) | |
| 2 | 18 (26.5) | 10 (50.0) | |
| 3 | 4 (5.9) | 0 | |
|
| |||
| Initial CEA (ng/mL) | 10.6±20.7 (0.0–138.1) | 12.1±20.6 (0.5–80.9) | 0.567 |
|
| |||
| Operation time (min) | 273.9±72.5 (170–590) | 282.5±53.5 (210–420) | 0.204 |
|
| |||
| Blood loss (mL) | 629.7±381.7 (100–2,000) | 367.5±193.5 (100–1,000) | 0.029 |
|
| |||
| Time to sips of water (day) | 4.3±1.9 | 2.5±1.5 | 0.360 |
|
| |||
| Time to liquid diet (day) | 5.8±1.6 | 4.5±1.1 | 0.267 |
|
| |||
| Time to soft diet (day) | 7.1±1.6 | 5.5±1.1 | 0.350 |
|
| |||
| Total morbidity | 15 (22.1) | 2 (10.0) | 0.095 |
| Urinary dysfunction | 4 (5.9) | 0 | |
| Ileus | 3 (4.4) | 1 (5.0) | |
| Wound infection | 5 (7.4) | 1 (5.0) | |
| Perineal abscess | 1 (1.5) | 0 | |
| Bleeding | 1 (1.5) | 0 | |
| Sepsis | 1 (1.5) | 0 | |
|
| |||
| Total mortality | 0 | 0 | NS |
Values are presented as mean±standard deviation (range) or number (%).
nCRT, neoadjuvant chemoradiation therapy; BMI, body mass index; ASA, American Society of Anesthesiologists; CEA, carcinoembryonic antigen; NS, not significant.
Pathologic results
The TNM stage, pT stage, pN stage, and pM stage were classified according to the American Joint Committee on Cancer (AJCC, 7th edition) [11]. In the distribution of TNM stage, complete response rate after nCRT was 20.0% (n=4) in nCRT group. The histological grades of differentiation, lymphovascular invasion rate, perineural invasion rate and harvested number of lymph nodes were not significantly different between the two groups. Proximal resection margin, distal resection margin and circumferential resection margin were not significantly different between the two groups (Table 2).
Table 2.
Pathologic results of rectal cancer patient with requiring abdominoperineal resection
| Variable | Adjuvant chemotherapy alone (n=68) | nCRT (n=20) | P-value |
|---|---|---|---|
| AJCC stage | 0.002 | ||
|
| |||
| 0 | 0 | 4 (20.0) | |
| 1 | 0 | 6 (30.0) | |
| 2a | 28 (41.2) | 4 (20.0) | |
| 2b | 1 (1.5) | 1 (5.0) | |
| 3a | 2 (2.9) | 0 | |
| 3b | 30 (44.1) | 4 (20.0) | |
| 3c | 7 (10.3) | 1 (5.0) | |
|
| |||
| T stage | 0.000 | ||
| 0 | 0 | 4 (20.0) | |
| 1 | 0 | 4 (20.0) | |
| 2 | 2 (2.9) | 2 (10.0) | |
| 3 | 60 (88.3) | 9 (45.0) | |
| 4 | 6 (8.8) | 1 (5.0) | |
|
| |||
| N stage | 0.187 | ||
| 0 | 29 (42.6) | 15 (75.0) | |
| 1a | 14 (20.6) | 3 (15.0) | |
| 1b | 10 (14.7) | 1 (5.0) | |
| 1c | 1 (1.5) | 0 | |
| 2a | 7 (10.3) | 0 | |
| 2b | 7 (10.3) | 1 (5.0) | |
|
| |||
| Grade of differentiation | 0.619 | ||
| Well | 13 ( 19.1) | 2 (10.0) | |
| Moderate | 44 (64.7) | 16 (80.0) | |
| Poorly | 7 (10.3) | 1 (5.0) | |
| Others | 4 (5.9) | 1 (5.0) | |
|
| |||
| Harvested no. of lymph nodes | 15.6±10.1 | 14.7±10.1 | 0.956 |
|
| |||
| Lymphovascular invasion | 0.047 | ||
| Negative | 41 (60.3) | 17 (85.0) | |
| Positive | 27 (39.7) | 3 (15.0) | |
|
| |||
| Perineural invasion | 0.105 | ||
| Negative | 49 (72.1) | 17 (85.0) | |
| Positive | 19 (27.9) | 3 (15.0) | |
|
| |||
| PRM (cm) | 20.7±9.7 | 18.3±7.3 | 0.191 |
|
| |||
| DRM (cm) | 3.9±2.1 | 3.7±2.2 | 0.841 |
|
| |||
| Circumferential resection margin | 0.212 | ||
| Negative | 63 (92.6) | 20 (100.0) | |
| Positive | 5 (7.4) | 0 | |
|
| |||
| Mass size (cm) | 4.8±2.2 | 3.4±2.0 | 0.228 |
Values are presented as number (%) or mean±standard deviation.
nCRT, neoadjuvant chemoradiation therapy; AJCC, American Joint Committee on Cancer; PRM, proximal resection margin; DRM, distal resection margin.
Oncologic outcomes and recurrent patterns of APR for low rectal cancer
The mean follow-up period was 59.7 months. The 5-year overall survival rate was 58.2% in adjuvant chemotherapy alone group and 85.5% in nCRT group (P=0.022). The 5-year disease-free survival rate was 60.0% in adjuvant chemotherapy alone group and 79.6% in nCRT group (P=0.042) (Fig. 1). Total recurrence rate was 45.6% (n=31) in adjuvant chemotherapy alone group and 15.0% (n=3) in nCRT group (P=0.010). The local recurrence rate was 10.3% (n=7) in adjuvant chemotherapy alone group and 5.0% (n=1) in nCRT group (P=0.469). The systemic recurrence rate was 35.3% (n=24) in adjuvant chemotherapy alone group and 10.0% (n=2) in nCRT alone group (P=0.029) (Table 3).
Fig. 1.
Five-year oncologic outcomes of patient with rectal cancer requiring abdominoperineal resection: (A) disease-free survival rate and (B) overall survival rate. nCRT, neoadjuvant chemoradiation therapy.
Table 3.
Recurrence patterns of abdominoperineal resection for rectal cancer
| Variable | Adjuvant chemotherapy alone (n=68) | nCRT (n=20) | P-value |
|---|---|---|---|
| Systemic recurrence | 24 (35.3) | 2 (10.0) | 0.029 |
| Lung | 9 (13.2) | 0 | |
| Liver | 9 (13.2) | 1 (5.0) | |
| Paraaortic node | 3 (4.4) | 0 | |
| Bone | 3 (4.4) | 0 | |
| Inguinal node | 0 | 1 (5.0) | |
|
| |||
| Local recurrence | 7 (10.3) | 1 (5.0) | 0.469 |
| Pelvic side wall | 2 (2.9) | 1 (5.0) | |
| Perineum | 1 (1.5) | 0 | |
| Rectal fossa | 4 (5.9) | 0 | |
|
| |||
| Total number of recurrence | 31 (45.6) | 3 (15.0) | 0.010 |
Values are presented as number (%).
nCRT, neoadjuvant chemoradiation therapy.
Univaiate and multicariate analysis of prognostic factors for DFS
In univariate analysis, advanced BMI (<25 kg/m2), N(+) stage, lymphovascular invasion, and circumferential resection margin invasion were analyzed as prognostic factors for disease-free survival. And nCRT was also analyzed as a prognostic factor in univariate analysis (hazard ratio, 0.22; 95% confidence interval, 0.05–0.93; P=0.039). In multivariate analysis, N(+) stage was a prognostic factor for disease-free survival (Table 4).
Table 4.
Univariate and multivariate analysis of prognostic factor for 5-year disease-free survival of rectal cancer patient with requiring abdominoperineal resection
| Factor | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
|
|
|
|||
| HR (95% CI) | P-value | HR (95% CI) | P-value | |
| Age (<70 yr vs. ≥70 yr) | 1.41 (0.66–3.01) | 0.377 | ||
|
| ||||
| Sex (male vs. female) | 0.73 (0.34–1.57) | 0.421 | ||
|
| ||||
| BMI (<25 kg/m2 vs. ≥25 kg/m2) | 0.23 (0.07–0.77) | 0.017 | 4.32 (0.99–18.85) | 0.052 |
|
| ||||
| T stage (T1–2 vs. T3–4) | 5.03 (0.69–36.94) | 0.112 | ||
|
| ||||
| N stage (N0 vs. N1–2) | 4.23 (1.81–9.91) | 0.001 | 0.36 (0.15–0.91) | 0.030 |
|
| ||||
| Grade of differentiation (well-mod vs. poorly-other) | 1.51 (0.94–2.43) | 0.091 | ||
|
| ||||
| CRM (negative vs. positive) | 5.31 (1.77–15.09) | 0.003 | 0.35 (0.12–1.09) | 0.072 |
|
| ||||
| LVI (negative vs. positive) | 2.23 (1.07–4.63) | 0.032 | 0.96 (0.44–2.10) | 0.927 |
|
| ||||
| Perineural invasion (negative vs. positive) | 1.45 (0.54–3.87) | 0.463 | ||
|
| ||||
| Adjuvant chemotherapy (alone vs. nCRT) | 0.22 (0.05–0.93) | 0.039 | 2.27 (0.51–9.97) | 0.283 |
HR, hazard ratio; CI, confidence interval; BMI, body mass index; CRM, circumferential resection margin; LVI, lymphovascular invasion; nCRT, neoadjuvant chemoradiation therapy.
DISCUSSION
The CRT affects favorable to oncologic outcome in advanced rectal cancer referred as previous studies [12–14]. The Dutch Colorectal Cancer Group studied the preoperative radiotherapy versus surgery alone which showed the lower local recurrence rate in preoperative radiotherapy group compared to surgery alone group (2.4% vs. 8.4%, P<0.001) [15,16]. “Long-course” chemoradiotherapy was introduced in the German Rectal Cancer trial (CAO/ARO/AIO9). In this trial, it was reported that preoperative chemoradiation group had a low local recurrence rate of 6% and a high sphincter sparing operation of 39% [6,17].
Various complications of radiation therapy have been reported, including radiation-induced tissue damage, perineal wound complication, fecal incontinence, sexual dysfunction, radiation enteritis and anastomosis site adverse effects [18–21]. However, in the present study, the postoperative complication rate is not statistically different between nCRT group (10%, n=2) and adjuvant chemo group (22.1%, n=15). The nCRT group had just ileus (n=1) and wound infection (n=1). Since rectal cancer surgery must be performed in a narrow pelvic cavity, the risk of blood loss is somewhat high. It is generally believed that radiation therapy can increase the risk of bleeding during surgery [18–21], but in present study, the blood loss was higher in the adjuvant chemo group compared to nCRT group.
One of the important goals of nCRT in the treatment of rectal cancer is to improve oncologic outcomes through downstaging [12–14]. However, it was questionable whether nCRT would be effective in patients who need APR when initially diagnosed because this group of the patients can achieve curative resection margins with APR and is no need for saving the anal sphincter. Recently, one of the studies reported that not all patients with clinical stage II/III rectal cancer require the nCRT as the guideline of rectal cancer. This study reported that a subset group of clinical T3 rectal adenocarcinoma with good prognosis (distance to the mesorectal fascia greater than 1mm, T3 with less than 5 mm of extramural depth of invasion) could be treated by surgery alone rather than receiving the nCRT [22]. In other words, radiation therapy can be overtreatment in the treatment of rectal cancer. In another study, there was no difference in 5-year oncological outcomes between patients with clinical T3N0 rectal adenocarcinoma that need an APR who received nCRT and those who are not receiving nCRT [23].
However, the present study revealed significant the better oncologic outcome of nCRT group compared to adjuvant chemotherapy alone group (79.6% vs. 60.0%, P=0.042). The recurrence rate also was significantly different between the two groups (45.6% in adjuvant chemotherapy alone group vs. 15.0% in nCRT group, P=0.010). This is similar to the results of an existing large-scale study that showed that the received radiation had better oncologic outcomes than the group that did not receive radiation [24–27]. The adjuvant chemotherapy alone group has a high T stage and nCRT group has a relatively low T stage, it is thought that this is a radiation effect. Even if the clinical T stage is the same, receiving radiation before surgery will lower the T stage after surgery. Although T stage was not analyzed as an effect factor on disease-free survival in present study, it is thought to be a factor that has the potential to effect oncological outcomes. This also applied to N stage. The N stage is relatively high in the adjuvant chemotherapy alone group in the present study and is analyzed to effect factor on disease-free survival.
The present study is designed retrospectively, the patient’s selection bias could be affected to the results and small sized sample, single institution study is a limitation of present study. Nevertheless, the present study can be meaningful, considering that it was limited to patients requiring APR, and there are very few studies. Based on present data, the oncologic outcomes are better in nCRT compared to adjuvant chemotherapy alone after surgery in patients with extremely low rectal cancer requiring APR initially diagnosed, even if curative surgery is possible. It seems that more and large-scale study is needed on this.
Footnotes
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the Soonchunhyang University Research Fund.
Author Contributions
Conceptualization: GWP, NHP, DRL. Validation: JCK, EJS. Formal analysis, GWP, DRL. Investigation, GWP, JCK. Writing- original draft: GWP, NHP, DRL. Writing - review and editing: DRL, JCK, EJS. Visualization: DRL; Supervision: DRL, EJS. Project administration, DRL, EJS. All authors contributed to the manuscript and approved the final version for publication.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Soonchunhyang University Bucheon Hospital (protocol code: 2025-04-002; date of approval: May 2, 2025). Informed consent was waived from the Institutional Review Board of Soonchunhyang University Bucheon Hospital due to the retrospective design.
Data Availability Statement
Data analyzed in this study are available from the corresponding author upon reasonable request.
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