Hong Kong Med J 2016 Dec;22(6):546–55 | Epub 31 Oct 2016
DOI: 10.12809/hkmj154788
ORIGINAL ARTICLE
Clinical outcome of neoadjuvant chemoradiation in locally advanced rectal cancer at a tertiary hospital
William WK Yeung, FRCR, FHKAM (Radiology)1; Brigette BY Ma, FHKCP, MD (CUHK)1; Janet FY Lee, FHKAM (Surgery), MD (CUHK)2; Simon SM Ng, FHKAM (Surgery), MD (CUHK)2; Michael HY Cheung, FRCS, FHKAM (Surgery)3; WM Ho, MRCP, FHKAM (Medicine)1; Maverick WK Tsang, FRCR, FHKAM (Radiology)1; Simon Chu, FRCS, FHKAM (Surgery)2; Daisy CM Lam, MB, BS, FRCR1; Frankie KF Mo, PhD1
1 Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
2 Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
3 Department of Surgery, North District Hospital, Sheung Shui, Hong Kong
 
Corresponding author: Dr William WK Yeung (wilyeung@netvigator.com)
 
 
 Full paper in PDF
 
Abstract
Objectives: To review the clinical outcome of locally advanced rectal cancer treated with neoadjuvant chemoradiation followed by definitive surgery with or without adjuvant chemotherapy and to elucidate the prognostic factors for treatment outcome.
 
Methods: This historical cohort study was conducted at a tertiary public hospital in Hong Kong. All patients who had undergone neoadjuvant chemoradiation for locally advanced rectal cancer in our department from November 2005 to October 2014 were recruited. Local recurrence–free survival, distant metastasis–free survival, disease-free survival, and overall survival of patients were documented.
 
Results: A total of 135 patients who had received neoadjuvant chemoradiation during the study period were reviewed. There were 130 patients who had completed neoadjuvant chemoradiation and surgery. The median follow-up time was 35.1 months. The 3- and 5-year local recurrence–free survival, distant metastasis–free survival, disease-free survival, as well as overall survival rates were 91.8% and 86.7%, 73.9% and 72.1%, 70.1% and 64.6%, as well as 86.5% and 68.4%, respectively. The rate of pathological complete response was 13.8%. The T and N downstaging rate was 49.2% and 63.1%, respectively. The rate of conversion from threatened circumferential resection margin to clearance of margin was 90.6%. Of the 42 cases that were initially deemed to require abdominal perineal resection, 15 (35.7%) were converted to sphincter-sparing surgery.
 
Conclusions: The treatment outcome of neoadjuvant chemoradiation for locally advanced rectal cancer was comparable with overseas data in terms of local control rate and overall survival. This strategy may increase the chance of achieving a clear surgical margin by downstaging the tumour, especially in patients who presented with threatened circumferential margin.
 
 
New knowledge added by this study
  • This is a local study from a tertiary oncology centre on the clinical outcome of neoadjuvant chemoradiation in the treatment of locally advanced rectal cancer.
Implications for clinical practice or policy
  • Neoadjuvant chemoradiation is effective in downstaging advanced rectal cancers, especially those with threatened circumferential resection margin, facilitating definitive surgery to achieve a clearance of the final pathological margin.
 
 
Introduction
According to the Hong Kong Cancer Registry,1 there were 1797 new cases of rectal/anal cancer in 2013. The incidence rate per 100 000 persons was 25.0 (crude rate) and 13.3 (age-standardised rate). The total number of deaths from rectal/anal cancer was 597, and the mortality rate was 8.3 (crude rate) or 3.7 (age-standardised rate) per 100 000 persons. In Hong Kong, colorectal cancer is the first most common cancer in incidence and the second in mortality rate for both sexes.
 
Conventional treatment of rectal cancer is mainly surgery. In locally advanced cancer, adjuvant therapy with concurrent chemoradiation has been shown to improve local control and disease-free survival (DFS) in phase III clinical trials.2 3 4 5 The major indication for adjuvant chemoradiation is pathological T3 or T4 and/or regional nodal disease without distant metastasis.
 
Preoperative radiotherapy with or without concurrent chemotherapy has been shown to reduce the local recurrence rate of locally advanced rectal cancer.6 7 8 9 10 11 12 Preoperative radiotherapy comprises a short or long course.
 
Short-course preoperative radiotherapy was given in 5 Gy per fraction for five fractions over 1 week, followed by surgery about 1 week after completion of radiotherapy. Since the introduction of total mesorectal excision (TME), the local recurrence rate has been significantly reduced. In the new era of TME surgery, a Dutch rectal trial confirmed that a short course of preoperative radiotherapy, followed by TME surgery, was also beneficial in reducing local recurrence rate from 8.2% to 2.4% over 2 years compared with TME surgery alone in locally advanced rectal cancer.13 14
 
Long-course preoperative radiotherapy involves a conventional fractionation of 1.8 Gy per fraction, five fractions per week, up to a total dose of 45 to 50 Gy. It is given with concurrent chemotherapy consisting of mostly a fluoropyrimidine-containing regimen. Surgery is usually performed approximately 4 to 10 weeks after completion of chemoradiation.
 
A randomised German trial (CAO/ARO/AIO 94)10 compared preoperative long-course chemoradiation with postoperative chemoradiation. At a median follow-up of 4 years, no significant difference was reported in the 5-year overall survival (OS). Nonetheless, treatment compliance, grade 3/4 acute and late toxicity profile, tumour and nodal downstaging, and rates of pelvic recurrence all favoured the preoperative chemoradiation arm. In addition, the sphincter preservation rate in the 194 patients with low-lying tumours declared by the surgeon prior to randomisation requiring an abdominoperineal resection (APR) was enhanced with preoperative treatment (39% vs 19%; P=0.004).
 
Since 2005, our hospital has adopted a treatment policy of long-course neoadjuvant (or preoperative) chemoradiation (nCRT) for selected cases of locally advanced rectal cancer. The objective of this study was to review the clinical outcome of these patients with locally advanced rectal cancer treated with nCRT in our department from November 2005 to October 2014 and to elucidate the prognostic factors for treatment outcome retrospectively.
 
Methods
Eligible patients included those without distant metastasis and who were staged preoperatively on radiological grounds with T3 or T4 disease and/or having nodal involvement. There might have been other extra specific reasons for recommending nCRT, including threatened circumferential resection margin (CRM), sphincter-sparing surgery, avoidance of pelvic exenteration, and unresectability (Table 1). Patients were required to be medically fit and agree to the nCRT.
 

Table 1. Other reasons for recommending neoadjuvant chemoradiation
 
The nCRT scheme adopted in our department consisted of the following.
 
Radiotherapy
Simulation procedure was done in an immobilised prone position with full bladder, using simulation computed tomography (CT) scan. The three-dimensional conformal radiotherapy planning was performed on the simulation CT scan imaging, using three coplanar fields with shielding conformal to the target volume. The radiotherapy was given in two phases. Phase 1 included the whole pelvis. A total dose of 45 Gy was delivered at 1.8 Gy per day, five fractions per week over 5 weeks. Phase II included only the gross tumour and the enlarged pelvic nodes with margins. A booster dose of 5.4 Gy was administered in the same fractionation as phase 1.
 
Chemotherapy
Concurrent chemotherapy was given in the first and fifth weeks of radiation. It comprised an intravenous (IV) bolus of 5-fluorouracil (5-FU; 400 mg/m2) and leucovorin (20 mg/m2) on days 1 to 4.
 
The surgery was scheduled about 4 to 10 weeks after completion of nCRT. Adjuvant chemotherapy with four cycles of 5-FU and leucovorin was administered to most patients. In some selected cases with pathological node-positive disease following surgery, four cycles of capecitabine and oxaliplatin (‘XELOX’ regimen) were given.
 
In this study, clinical data were collected retrospectively from the medical records of all patients who had undergone nCRT for locally advanced rectal cancer in the Department of Clinical Oncology at the Prince of Wales Hospital, Hong Kong from November 2005 to October 2014. The surgery was performed either at Prince of Wales Hospital or the referring hospital. There was variation in practice for pretreatment staging method, re-staging on completion of nCRT (follow-up CT scan was arranged to exclude distant metastasis at least 2 weeks after nCRT; optional magnetic resonance imaging [MRI] was considered at least 4 weeks after nCRT), and follow-up among different hospitals. The patients’ demographic information, tumour characteristics, and treatment details were retrieved. The initial type of surgery recommended by the referring surgical team at presentation and any extra specific reasons (intentions) for referral for nCRT were reviewed. The final pathology at the definitive surgery (the pathological T and N staging, the tumour size, any pathological complete response [pCR], the resection margins), the treatment-related toxicity (radiation- or chemotherapy-related, surgical complications), recurrence (local, regional, distant relapse), and disease status at follow-up were reviewed.
 
The key study endpoints included loco-regional recurrence–free survival, distant metastasis–free survival, DFS, and OS. Other secondary endpoints included the rate of pCR, tumour downstaging (T and N staging), conversion of threatened CRM to clearance of margins (R0), conversion to sphincter-sparing surgery for lower rectal cancers, conversion from a potential pelvic exenteration to non-exenterating surgery, and the rate of conversion from unresectable to resectable tumour. For toxicity endpoints, the rate of grade 3 or above acute toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, and the rate of grade 3 or above late radiation toxicity according to the Toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer, and perioperative complications as represented by rate of 30-day postoperative mortality and morbidity (delayed wound healing, anastomotic complication, reoperation) were also assessed.
 
Statistical analysis
Descriptive statistics were used to report the incidence rates of secondary endpoints that were calculated directly. The survival rates and time-to-event rates were estimated with the Kaplan-Meier method. Univariate analysis based on the proportional hazard model was performed to investigate the relationship between different outcome (survival) and prognostic factors. The hazard ratio and the corresponding 95% confidence interval were shown. The prognostic factors included pretreatment T stage, pretreatment N stage, histological grade, threatened CRM, completion of nCRT, time from nCRT to surgery, pathological T stage, pathological N stage, pathological group stage, pCR, pathological margin, number of involved nodes, and completion of adjuvant chemotherapy. For those significant prognostic factors, multivariate analysis using Cox regression with stepwise selection was performed.
 
This study was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee with informed consent waived. The principles outlined in the Declaration of Helsinki have also been followed.
 
Results
A total of 135 patients who had received nCRT in our department from November 2005 to October 2014 were reviewed, of whom 130 had completed nCRT and surgery with or without adjuvant chemotherapy. Of the five patients who did not have surgery, two refused surgery after nCRT and three progressed after nCRT without undergoing surgery.
 
Patient characteristics are shown in Table 2. The mean age was 60.9 (standard deviation [SD], 9.23) years. The male-to-female ratio was 3.2:1. For the pretreatment stage, 80% and 20% were T3 and T4 respectively, while 13.8%, 40.0% and 45.4% were N0, N1 and N2 stage, respectively. For the overall group stage, the incidences of stage IIA, IIB/C, and III were 8.5%, 6.1%, and 85.4%, respectively. A total of 65.4% cases had threatened CRM at pretreatment imaging.
 

Table 2. Patient characteristics (n=130)
 
Of the 130 patients who had surgery, 128 (98.5%) completed nCRT. For the radiotherapy-related toxicities, the combined incidence of grade 3 or above acute toxicity to the skin, bowel, and urinary toxicity was 6.2%. Similarly, the radiotherapy-related grade 3 or above late toxicity to the bowel and urinary tract was 6.2%. For chemotherapy-related grade 3 or above acute toxicity, the incidences of neutropenia, anaemia, and thrombocytopenia were 14.6%, 1.5%, and 1.5%, respectively. The most common non-haematological grade 3 or above acute toxicities were hand-foot-mouth syndrome (0.8%), mucositis (1.5%), and diarrhoea (0.8%). Adjuvant chemotherapy was given to 103 (79.2%) patients, of whom 92 (89.3%) received the regimen of IV bolus 5-FU and leucovorin. With regard to surgical complications, 22 (16.9%) patients had delayed wound healing (>30 days after operation), six (4.6%) had anastomotic complication, and six (4.6%) required reoperation. There was no 30-day postoperative mortality reported (Table 3).
 

Table 3. Toxicity and treatment compliance
 
Of the 130 cases, 124 (95.4%) underwent TME surgery and 114 (87.7%) had laparoscopic surgery. The mean time from the date of completion of nCRT to surgery was 7.2 (SD, 4.8) weeks. Comparing the type of surgery recommended before starting nCRT and those finally carried out after nCRT, the rate of anterior resection/low anterior resection increased to 65.4% from 50.8%, and the rate of APR/pelvic exenteration decreased to 27.7%/3.8% from 32.3%/12.3% respectively. The overall rate of surgical conversion was reported in several clinical contexts: (1) percentage achieving a R0 resection, (2) percentage undergoing sphincter-sparing surgery, and (3) percentage avoiding pelvic exenteration. First, of the total number of patients who were found to have threatened CRM before treatment, 90.6% finally achieved a R0 resection. Of the 42 patients who were initially deemed on presentation to require an APR, 35.7% underwent sphincter-sparing surgery. In a subgroup of the 15 patients who had received nCRT with the intention of sphincter preservation, 86.7% (n=13) underwent sphincter-sparing surgery rather than APR. Among these 13 cases with successful sphincter-sparing surgery, one had pCR and all had clear resection margins. They remained alive and free of loco-regional and distant recurrence at the end of this study. Of the 16 patients who were initially assessed to require pelvic exenteration, 62.5% (n=10) underwent non-exenterating surgery. There were six patients in whom tumour was deemed unresectable and who were referred for nCRT to improve resectability. Complete resection with negative margins was subsequently achieved in four (66.7%) of the six patients while the other two had a positive margin in the palliative surgery.
 
The final pathological staging in the surgical specimen is reported (Table 4). The rates of pCR and clear resection margin were 13.8% and 89.2%, respectively. The rate of T downstaging was 49.2% and that for N stage was 63.1% (Table 3).
 

Table 4. Surgical and pathological outcomes
 
The median follow-up time was 35.1 months. Of the 130 patients, local recurrence, loco-regional recurrence, distant metastasis, disease recurrence, and death occurred in 10 (crude rate, 7.7%), 15 (11.5%), 30 (23.1%), 34 (26.2%), and 23 (17.7%) patients, respectively. The Kaplan-Meier estimates of the 3-year local recurrence–free survival, regional recurrence–free survival, loco-regional recurrence–free survival, distant metastasis–free survival, DFS, and OS were 91.8%, 92.6%, 87.9%, 73.9%, 70.1%, and 86.5%, respectively. The respective 5-year survival rates were 86.7%, 85.3%, 81.0%, 72.1%, 64.6%, and 68.4%. The corresponding Kaplan-Meier curves for local recurrence-free survival and OS is also shown in the Figure (the curves for loco-regional recurrence–free survival, distant metastasis–free survival, and DFS are shown in the Appendix).
 

Figure. (a) Local recurrence–free and (b) overall survival curves
 

Appendix. (a) Loco-regional recurrence–free, (b) distant metastasis–free, and (c) disease-free survival curves
 
Analysis of prognostic factors
The variables (factors including age and gender were tested but not significant in univariate model) in the univariate analysis included the pretreatment T stage, pretreatment N stage, histological grade, presence of threatened CRM, completion of nCRT, time from nCRT to surgery (continuous variable), pathological T stage, pathological N stage, pathological group stage, pCR, pathological margin, number of involved nodes (continuous variable), and completion of adjuvant chemotherapy. Those significant prognostic factors were studied by multivariate analysis.
 
In the multivariate analysis, the pathological clear margin, completion of nCRT, and the number of involved nodes were significantly associated with local recurrence–free survival. The number of involved nodes, pathological clear margin, and time from nCRT to surgery were significantly associated with loco-regional recurrence–free survival. The number of involved nodes, the pretreatment T4, pathological stage III/IV, and completion of adjuvant chemotherapy were significantly associated with distant metastasis–free survival. The number of involved nodes, pathological stage III/IV, and completion of adjuvant chemotherapy were significantly associated with DFS. Finally, the number of involved nodes, the pretreatment T4, and pathological stage III/IV were significantly associated with OS (Table 5).
 

Table 5. Significant prognostic factors for various survival categories in both univariate and multivariate analysis
 
Discussion
Although the current study was retrospective, survival data were comparable with figures reported in international studies. In the major randomised trials, 5-year local recurrence rate in the arm with preoperative short-course radiotherapy was in the range of 11% to 14%, and OS was in the range of 42% to 76%.6 7 8 9 In the randomised trials that had an arm with nCRT, the 4- or 5-year local recurrence rates were 5.7% to 15.6% and the OS were 66.2% to 76%.10 15 16 17 18 In this study, the 5-year local recurrence rate and loco-regional recurrence rate was 13.3% and 19%, respectively. These were close to the reported figures from randomised studies.10 15 16 17 18 The 5-year OS in this study was 68.4% and is comparable with international studies.10 15 16 17 18
 
The pCR rate was 13.8% in this study, again comparable with randomised trials10 15 16 17 18 and reviews.19 Together with the favourable downstaging effects, the completion resection rate was high (89.2%). This is the primary aim of nCRT in advanced rectal cancer. The role of nCRT in sphincter preservation for low-lying tumours has been a controversial issue in some randomised trials,10 11 15 16 and critical reviews.20 21 In a German study,10 among the 194 patients with tumours that were determined by the surgeon before randomisation to require an APR, a statistically significant increase in sphincter preservation was achieved among patients who received nCRT compared with those who received postoperative chemoradiation (39% vs 19%; P=0.004). Although long-course nCRT is expected to result in tumour downsizing, a Polish trial11 did not find that long-course chemoradiation was superior to short-course preoperative radiotherapy in reducing the APR rate. The possible explanations for this finding include the possibility that the degree of downsizing was not sufficient to alter the surgical approach, due to surgeon’s concern about residual microscopic disease despite an apparently good response after nCRT, or the surgeons had made their clinical decision based on the pretreatment staging information. In our study the overall rate of conversion from APR to sphincter-sparing surgery was 35.7% and was comparable with that (39%) in the German trial10; and for the subgroup of patients with an intention to spare the sphincter, the conversion rate was even higher, up to 86.7%, with a good clinical outcome.
 
The extent of extramural tumour spread and lymph node and CRM status are powerful predictive factors for local recurrence, distant metastases, and OS in patients with rectal cancer.22 23 24 25 26 27 28 From our study, it was evident that the number of involved nodes in the final pathology was an independent factor in OS, DFS, local or loco-regional recurrence–free survival, and distant metastasis–free survival. For local or loco-regional recurrence, the pathological clear margin, the completion of nCRT, and the time from nCRT to surgery were independent prognostic factors. Although in this study there was an attempt to find the optimal cut-off time for surgery after the completion of nCRT, this was not possible because of the small sample size. Increasing the time interval from completion of nCRT to surgery was associated with a detrimental effect on loco-regional recurrence (hazard ratio=1.348).
 
In this study, completion of adjuvant chemotherapy was a prognostic factor for distant metastasis. This implies that adjuvant chemotherapy might be important in reducing distant metastasis. It remains controversial whether adjuvant chemotherapy should be given after nCRT and surgery. A 2x2 factorial randomised trial (EORTC trial 22921)29 30 31 32 that assessed the value of preoperative chemo-radiotherapy versus preoperative radiotherapy and postoperative chemotherapy versus no postoperative chemotherapy in patients with cT3-4 disease could not demonstrate any prolonged progression-free or OS from adjuvant chemotherapy in patients with resectable T3-T4 rectal cancer. Its follow-up report of 785 eligible patients who underwent R0 resection showed that patients with a good prognosis (ypT0-2) seemed to benefit from adjuvant chemotherapy, especially if the tumour was located in the mid-rectum.33 Nonetheless, an updated analysis of the EORTC 22921 trial18 recently failed to confirm the benefit of adjuvant chemotherapy for ypT0-2 patients after a median follow-up of 10.4 years. In the I-CNR-RT phase III randomised trial,34 there was no benefit of adjuvant chemotherapy (6 cycles of 5-FU and folinic acid) compared with observation only after nCRT. The result may be partly attributed to the low compliance to complete the planned number of chemotherapy cycles. The British Chronicle trial35 is unique in comparing XELOX postoperatively against observation alone in locally advanced rectal cancer treated with nCRT. After a median follow-up of 44.8 months, there was no statistically significant benefit of adjuvant XELOX in the 3-year DFS rate. A Korean study reported the results of ADORE phase II study in which 321 patients of ypT3-4/ypN0 or ypTx/ypN1-2 after nCRT with 5-FU alone were randomised to receive adjuvant chemotherapy with 5-FU or FOLFOX.36 37 After a median follow-up of 38.2 months, the 3-year DFS rate was better in the FOLFOX arm (P=0.047). Although adjuvant treatment of patients with rectal cancer remains controversial, the National Comprehensive Cancer Network guidelines recommend 5-FU–based chemotherapy with oxaliplatin as the preferred adjuvant treatment for all patients with rectal cancer, who receive neoadjuvant 5-FU–based chemoradiation, regardless of surgical pathology results. The recently reported German CAO/ARO/AIO-04 trial also revealed the benefit of adding oxaliplatin to both neoadjuvant and adjuvant treatment with significant improvement in DFS of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with conventional 5-FU–based combined modality regimen.38
 
There were limitations to this study. The data were collected retrospectively and there was no blinding during data collection. It is possible that potential confounding factors like smoking and co-morbidity were inadequately controlled for. Toxicity data were not collected systematically and thus could be underreported. If the data can be collected prospectively, a tailor-made toxicity form will be designed and more toxicity can be captured. The median follow-up time was relatively short. Magnetic resonance imaging is now a standard staging tool in rectal cancer. The use of MRI as initial staging was only 66.1% in this cohort. Therefore, pretreatment staging might not accurately reflect the true staging at presentation. In this study, there was limited reporting of late toxicity of radiation such as sexual and sphincter dysfunction. The full extent of the late toxicity of radiation requires longer follow-up. Due to the small sample size, the adjustment of the potential confounding factors for survival was a limitation of the study.
 
Conclusions
The treatment outcome following nCRT for locally advanced non-metastatic rectal cancer in our experience was comparable with overseas data in terms of local control rate and OS. The high conversion rate from having a threatened circumferential margin to clear resection margin, and the high T and N downstaging rates, suggest that this approach is effective in facilitating surgery to obtain complete surgical clearance. In the subgroup with an intention of sphincter preservation, the conversion rate from APR to sphincter-sparing surgery was high. The rate of acute toxicities was within expectations and manageable and there were no treatment-related deaths.
 
Acknowledgements
Although not named in the author list, we thank the other colleagues who contributed to the treatment of this group of patients and those who helped with data collection.
 
Declaration
All authors have disclosed no conflicts of interest.
 
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