Outcomes of neoadjuvant chemoradiotherapy in Japanese locally advanced rectal carcinoma patients
© Tokuhara et al. 2016
Received: 10 February 2016
Accepted: 24 April 2016
Published: 30 April 2016
We investigated the efficacy and prognosis of neoadjuvant chemoradiotherapy (NACRT) for Japanese locally advanced rectal carcinoma patients.
Fifty-seven patients diagnosed with cT3-4 or any cT/cN+ disease using enhanced computed tomography or magnetic resonance imaging from 2002 to 2014 were enrolled. The male/female ratio was 42/15, and the median age was 67 years. Ra/Rb/Rb-P/P was expressed by 6/35/14/2 patients. Histological tumor types were tub1/tub2/por/muc in 22/30/4/1 patients. For NACRT, radiotherapy doses were 40–50.4 Gy chemotherapy consisted of 5′-DFUR, capecitabine, or S1.
All 57 patients received curative surgical treatment. The anal preservation rate was 65.0 %. The ypStage of 0/I/II/IIIa/IIIb was 7/10/25/11/4 cases. The histological antitumor effect (HATE) was ≥grade (G) 2 and G3 in 31 (54.4 %) and 7 (12.3 %) cases, respectively. Postoperative complications occurred in 17 patients and exceeded GIII (Clavien–Dindo classification) in four patients. Recurrence was observed in 19 patients; the primary local recurrence rate was 5.3 %. The 3-year relapse-free survival (RFS) and overall survival (OS) rates were 64.8 and 95.5 %, respectively; the 5-year RFS and OS rates were 60.2 and 61.0 %, respectively. In multivariate analysis, ypN+ was a high-risk factor for distant organ recurrence. As predictive factors regarding the efficacy of NACRT, a neutrophil concentration <70 % and a neutrophil/lymphocyte ratio <3.0 in peripheral blood prior to treatment indicated that NACRT would be significantly more effective.
NACRT was effective in reducing local recurrence but did not suppress distant organ recurrence in Japanese locally advanced rectal carcinoma patients. A further investigation of an extension of the NACRT regimen is required.
The incidence of colorectal cancer has gradually increased. In Japan, this cancer was ranked as the second and fourth most common type among women and men, respectively, in 2014 . Locally advanced rectal cancer (LARC) has often developed postoperative local recurrence. To manage postoperative pelvic local control and downstage LARC, multimodal therapy such as neoadjuvant chemoradiotherapy (NACRT) is frequently used in Western countries [2–4]. Several randomized studies have shown that NACRT provided better local control and was more effective than postoperative radiotherapy [4, 5]. Based on these studies, NACRT for rectal cancer has been recommended for LARC in the NCCN version 2.2015 guidelines .
In Japan, the standard treatment for LARC is total mesorectal excision and lateral pelvic lymph node dissection; postoperative outcomes using surgery alone were better than those of Western countries, and consequently, NACRT has not been introduced aggressively. However, in some institutes, adjuvant therapy for LARC such as chemoradiotherapy (CRT) or chemotherapy has been introduced. Several phase II studies regarding the safety and efficacy of NACRT in Japanese patients have been reported [7–9].
In the present study, we investigated the usefulness, efficacy, and prognosis of NACRT in Japanese LARC patients, concerning the histological antitumor effect (HATE) and long-term outcomes such as relapse-free survival (RFS), overall survival (OS), and recurrence rate.
Between September 2002 and April 2014, a total of 57 patients with LARC underwent NACRT and total mesorectal excision (TME) at the Department of Surgery in Kansai Medical University Hospital. Inclusion criteria for this retrospective study were LARC patients with cT3-4 or any cT/cN+ disease assessed using colonoscopy, enhanced computed tomography, and magnetic resonance imaging.
NACRT was administered by a multidisciplinary team of radiotherapists and colorectal surgeons. The patients received long-course radiotherapy at two different doses. At the initial stage of the study, the radiation dose was 40 Gy (4 weeks), and at the latter stage, it was 50.4 Gy (5.5 weeks). Radiotherapy was performed using the classic four-field technique. In combination chemotherapy, three different protocols were used. All patients took oral fluorouracil, 5′-DFUR, capecitabine, or S1 only on the day of irradiation.
Surgery was undertaken at 4–6 weeks after NACRT. We performed abdominoperitoneal resection (APR), low anterior resection (LAR), internal sphincteric resection (ISR), and total pelvic floor exenteration (TPE) with TME; surgery was performed with or without lateral pelvic lymph node dissection. All patients provided informed consent. The type of surgery was determined at a preoperative doctor’s conference based on the oncological condition of each patient.
Staging and HATE was performed according to the Japanese Society for Cancer of the Colon and Rectum (Eighth Edition) guidelines . The histological tumor response to NACRT was determined using scale grade (G) 0, 1a, 1b, 2, and 3 as follows: HATE G0, no response to treatment; HATE G1a, tumor size reduction of 1/3; HATE G1b, tumor size reduction of 1/3–2/3; HATE G2, tumor size reduction of >2/3; and HATE G3, complete tumor ablation, equal to a pathological complete response (pCR).
To investigate the factors associated with postoperative distant organ recurrence, we analyzed age, sex, type of surgical procedure, histological depth of tumor, HATE grade, radiation dose, type of combination chemotherapy, and presence or absence of pathological lymph node metastasis. To evaluate the predictive factors regarding the efficacy of NACRT, we analyzed the number of leukocytes, the percentage of neutrophils and lymphocytes, the neutrophil-to-lymphocyte ratio (NLR), hemoglobin and albumin levels, platelet count, and carcinoembryonic antigen (CEA) in peripheral blood prior to treatment.
JMP ver.9 software was used for statistical analysis. Continuous variables are presented as the median and range. The univariate analysis data were assessed using the Yates chi-square test. The Cox regression model (logistic regression analysis) was used for multivariate analysis. RFS and OS were analyzed using the log-rank test and were plotted as Kaplan–Meier curves. In all analyses, p < 0.05 indicated statistical significance.
Demographics, preoperative variables, surgical procedure, and postoperative complications
67 (range 40–87)
Median distant from lower edge of tumor to anal verge (cm)
Operative procedure (laparoscopic surgery)
Total perineal excision
Low anterior resection
Inferior sphincter resection
No. of anus preserving cases (%)
No. of patient with complication (Clavien–Dindo classification score ≥3)
Perianal wound infection
Stoma related complication
Abscess in pelvic cavity
Sepsis (enterocolitis induced)
NACRT regimen, effect of NACRT, and recurrence cases after surgery
Histological antitumor effect of NACRT (grade)
8 (14.0 %)
18 (31.6 %)
24 (42.1 %)
7 (12.3 %)
19 (33.3 %)
Distant lymph nodes
Univariate and multivariate analysis of factors associated with postoperative distant organ recurrence
p value of univariate analysis
p value of multivariate analysis
95 % CI
APR + TPE
Histological depth of tumor
Histological antitumor effect
Total radiation dose
Pathological lymph nodes metastasis
Predictive factors in pretreatment peripheral blood regarding the effectiveness of NACRT (≥grade 2)
p value of univariate analysis
Rate of neutrophil
Rate of lymphocyte
Treatment with NACRT in patients with LARC has been beneficial in terms of local tumor control and sphincter preservation [11, 12]. However, the most important goal of rectal cancer therapy is improvement in survival. In the present study, the percentage of patients who achieved a HATE grade ≥G2 was 54.4 and 12.3 % achieved HATE grade G3 (pCR). Although the efficacy of NACRT regarding local tumor control was proven, RFS and OS were not significantly prolonged by NACRT. The 5-year OS rate in patients with ypStage II disease in our study was 69.1 %. This outcome was similar to that of Japanese LARC patients with pStage IIIa disease. Furthermore, the 5-year OS rate (43.8 %) of patients with ypStage IIIa in our study was similar to that of Japanese LARC patients with pStage IIIb disease . This observation demonstrated that NACRT was effective for the downstaging of LARC but did not contribute to prolongation of the OS of LARC patients. Similar to our outcome, no survival-prolonging effects regarding NACRT were demonstrated in previous reports [13, 14].
Schrag et al. reported that >25 % of patients with LARC had distant organ metastasis . We also found that 16 patients (28.1 %) exhibited recurrence in distant organs. Regarding multivariate analysis of the factors associated with postoperative distant organ recurrence, ypN+ was found to be a high-risk factor, where the RFS rate of ypN+ patients was significantly lower than that of ypN− patients. Fokas et al. reported that a higher ypN category after preoperative CRT was the strongest prognostic factor regarding multivariate analysis . There have been some other studies that have reported on other predictive factors related to recurrence after NACRT. Toiyama et al. found that C-reactive protein was a promising predictor of recurrence and prognosis in patients with rectal cancer after NACRT . Further, factors such as fibroblast growth factor receptor 2 overexpression , ALDH1 , and upregulated polo-like kinase in rectal cancer  were reported to be predictors of recurrence after NACRT. Further study will be necessary to clarify the predictive factors regarding NACRT and to facilitate improvement of long-term outcomes of NACRT.
Many predictive biomarkers concerning the antitumor effect of NACRT have been reported. Patients who responded well to chemoradiothetapy (CRT) for rectal cancer had a significantly higher number of pre-CRT lymphocytes ; sustaining a high blood lymphocyte count during NACRT was predictive of achieving a pCR in rectal cancer . In addition to this, it has been reported that predictive biomarkers for NACRT were tumor differentiation grade and B cell lymphoma 2 expression . As a negative predictive factor, Flanagan et al. reported that the increased X-linked inhibitor of apoptosis protein may be a useful indicator of NACRT resistance in rectal cancer tissues . In our study, positive predictive factors regarding the effectiveness of NACRT (≥G2) were a neutrophil rate <70 % and an NLR score <3.0, indicating that the therapeutic efficacy of NACRT may be lower if inflammation is present. As similar to our data, Krauthamer et al. reported that an NLR <5 and a serum albumin level >3.5 mg/dL may be positively related to complete pathological response after NACRT in patients with clinical stage III LARC . For improving the prognosis of LARC patients, it is necessary to select other positive biomarkers for predicting the effectiveness of NACRT by analyzing pretreatment rectal cancer specimens or blood.
In the present study, we administered oral fluoropyrimidine anticancer agents, such as 5′-DFUR, capecitabine, and S1 with radiotherapy and the pCR rate was 12.3 %. Similar results were obtained using neoadjuvant single-agent capecitabine plus radiotherapy for LARC . Recently, cytotoxic agents such as irinotecan and oxaliplatin plus fluorouracil have been administrated for combination chemotherapy regarding NACRT [27, 28]. Wong et al. reported that the efficacy of capecitabine plus irinotecan with radiotherapy and the efficacy of capecitabine plus oxaliplatin with radiotherapy were similar in a neoadjuvant setting for LARC patients. However, it remains uncertain as to whether or not the addition of a second cytotoxic agent enhances the effectiveness of fluorouracil plus radiotherapy . The ACCORD 12 trial investigated the value of two different NACRT regimens involving CAP45 (45 Gy radiotherapy plus capecitabine) or CAPOX50 (50 Gy radiotherapy plus capecitabine plus oxaliplatin). Unfortunately, there were no significant differences in clinical results such as OS and disease-free survival (DFS) at 3 years, where the authors did not recommend the administration of oxaliplatin with radiotherapy . To evaluate the best combination chemotherapy with radiotherapy, it will be essential to plan further large-scale randomized clinical studies.
In our study, adjuvant chemotherapy was introduced in only 31 (54.4 %) patients. The low introduction rate of adjuvant chemotherapy possibly resulted in no improvement in survival time. There have been several studies that have reported no benefit of adjuvant chemotherapy for LARC after NACRT. Sainato et al. reported that the addition of adjuvant chemotherapy (5-fluorouracil-folinic acid) in patients with LARC treated with NACRT did not improve 5-year OS and DFS and had no impact on the rate of distant metastasis . Rodel et al. reported that LARC patients after NACRT had a low compliance to adjuvant chemotherapy . Additionally, the ACT regimen (adriamycin, cytoxan, and taxol) had no effect in LARC patients after NACRT [31, 32]. In contrast, Hong et al. reported that adjuvant FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) improved DFS relative to fluorouracil plus leucovorin in patients with LARC after NACRT , but prolongation of OS was not demonstrated. It seems likely that improvement in prognosis, especially prolongation of OS, is difficult after the introduction of ACT after NACRT.
Recently, neoadjuvant chemotherapy (NAC) has been administered to LARC patients instead of NACRT. Schrag et al.  reported that the outcomes of LARC patients who underwent FOLFOX chemotherapy without radiotherapy in a neoadjuvant setting were not inferior to those of NACRT. In this study, all patients exhibited tumor regression, and TME and the pCR rate after chemotherapy alone were 8 of 32; the 4-year local recurrence and DFS rates were 0 and 84 %, respectively . Xiao et al. reported that although there were no pCR cases, sandwich-like NAC with bevacizumab was safe and effective for LARC . To confirm the results of NAC, a randomized trial (PROSPECT trial) has been initiated in North America . In the near future, NAC may become the main therapy for LARC after NACRT.
Our study does lack in new insights, however, the clinical outcomes for Japanese LARC patients after NACRT have not been established yet. In the future, a multicenter prospective randomized controlled study in Japan is necessary to validate the usefulness, efficacy, and prognosis of NACRT in Japanese LARC patients.
In the present study, NACRT for Japanese LARC patients was found to be an effective treatment in reducing local recurrence but did not suppress distant organ recurrence. NACRT could not prolong RFS and OS. It will be necessary to change the NACRT regimen and to further investigate preoperative multimodal therapy for LARC such as NAC.
Written informed consent was obtained from the locally advanced rectal carcinoma patients for induction of NACRT.
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