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Accepted Manuscript
Short-course radiotherapy in the neoadjuvant treatment for rectal cancer: a
systematic review and meta-analysis
Bin Ma, Peng Gao, Yongxi Song, Xuanzhang Huang, Hongchi Wang, Qingzhou Xu,
Shan Zhao, Zhenning Wang
PII:
S1533-0028(18)30295-0
DOI:
10.1016/j.clcc.2018.07.014
Reference:
CLCC 494
To appear in:
Clinical Colorectal Cancer
Received Date: 13 June 2018
Revised Date:
23 July 2018
Accepted Date: 28 July 2018
Please cite this article as: Ma B, Gao P, Song Y, Huang X, Wang H, Xu Q, Zhao S, Wang Z, Shortcourse radiotherapy in the neoadjuvant treatment for rectal cancer: a systematic review and metaanalysis, Clinical Colorectal Cancer (2018), doi: 10.1016/j.clcc.2018.07.014.
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Title Page
Short-course radiotherapy in the neoadjuvant treatment for rectal cancer: a
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systematic review and meta-analysis
Bin Ma1, Peng Gao1, Yongxi Song1, Xuanzhang Huang1,2, Hongchi Wang1, Qingzhou
Xu1, Shan Zhao1, Zhenning Wang1*
Department of Surgical Oncology and General Surgery, the First Hospital of China
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1
2
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Medical University, Shenyang 110001, People’s Republic of China
Department of Chemotherapy and Radiotherapy, the Second Affiliated Hospital and
Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou City 325027,
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People’s Republic of China
Bin Ma and Peng Gao contributed equally to this work
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*Correspondence to: Dr Zhen-ning Wang, Department of Surgical Oncology and
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General Surgery, the First Hospital of China Medical University, Shenyang 110001,
China. Tel: +86-24-83283556; Fax: +86-24-22703578; E-mail: josieon826@sina.cn
Funding
The Special Prophase Program for National Key Basic Research Program of China
(2014CB560712); Clinical Capability Construction Project for Liaoning Provincial
Hospitals (LNCCC-A01-2014); the Doctoral Scientific Research Startup Foundation
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of Liaoning Province (201601138)
Acknowledgments
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We thank the department of Surgical Oncology of First Hospital of China Medical
University and the College of China Medical University for technical assistance.
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Disclosure
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The authors declare that they have no competing interests.
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MicroAbstract
The effects of preoperative short-course radiotherapy (PSRT) remain controversial for
rectal cancer patients. We conducted a systematic review and meta-analysis to explore
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the effects of PSRT and its optimized regimens when compared to preoperative
long-course chemoradiotherapy (PLCRT). Our results indicated that PSRT could be
the treatment of choice in comparison with PLCRT when complete respnse is not the
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primary aim.
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Abstract and Keywords
Background: We aimed to show whether preoperative short-course radiotherapy
(PSRT) could be the treatment of choice when compared to preoperative long-course
chemoradiotherapy (PLCRT).
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Methods: PubMed, Embase and Web of Science Databases were searched to conduct
our systematic review and meta-analysis. Perioperative and survival outcomes
between PSRT and PLCRT were selected as endpoints for our meta-analysis. In
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addition, Health related quality of life (HRQL) outcomes were also systematically
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reviewed between PSRT and PLCRT. Finally, we also reviewed evidence of optimized
regimens of PSRT (with delayed surgery or adding consolidation chemotherapy).
Results: PLCRT showed a better pathological complete response (pCR) rate (OR =
0.05, 95% CI = 0.02-0.18, P < 0.01), but this benefit did not translate into a higher
sphincter preservation rate (OR = 1.62, 95% CI = 0.72-3.67, P = 0.25) and other
perioperative outcomes differences. In terms of survival outcomes, adding either
PLCRT or PSRT both showed obvious advantage on local control when compared
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with surgery alone, and PSRT and PLCRT had similar long-term outcomes
irrespective of pairwise or network meta-analyses. Moreover, PSRT and PLCRT also
had no overall differences based on HRQL scores. The insufficiency on pCR of PSRT
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might be improved by delayed surgery or adding consolidation chemotherapy based
on systematic review of current evidence.
Conclusions: Our results indicated that PSRT could be the treatment of choice in
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comparison with PLCRT when pCR is not the primary aim. PSRT with delayed
evolution of neoadjuvant era.
Keywords
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surgery or adding consolidation may provide further possibilities for advancing the
Preoperative short-course radiotherapy, Preoperative long-course chemoradiotherapy,
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rectal cancer, neoadjuvant therapy, meta-analysis
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Text
Background
Chemotherapy, radiotherapy, and surgery have been the primary methods for treating
1,2
. Based on the National Comprehensive Cancer
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rectal cancer over the past decades
Network (NCCN) Clinical Practical Guidelines in Oncology 3, there are two primary
neoadjuvant regimens accepted as standard for rectal cancer patients: preoperative
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long-course radiotherapy with concomitant chemotherapy (PLCRT) and preoperative
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short-course radiotherapy (PSRT). Both treatments are effective for local control and
carry a low morbidity. PSRT is more accepted in northern Europe, whereas PLCRT
enjoys more support in the United States and the rest of Europe 4.
Whether PSRT or PLCRT is the preferred regimen has been a continuous topic of
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debate 4-7, and two famous randomized controlled trials (RCTs) comparing PSRT and
PLCRT have been performed
8,9
. Notably, a published investigation indicated that
only 55% of rectal cancer patients received “standard” PLCRT in the United States
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according to the National Cancer Data Base 10,11. This result again put this regimen of
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PLCRT under question. For patients, this situation could be partly explained by the
higher cost and lower compliance seen for PLCRT 12. Although currently PLCRT may
not require chemotherapy infusion devices, as oral xeloda is often being used,
increased 5-fold radiotherapy schedule time and associated costs in managing
additional acute toxicity were issues remained for patients received PLCRT5. For
clinicians, does this indicate that we should reappraise our current label of this as the
standard therapy? Robust evidence is needed to define the optimal, simple and
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equivalent neoadjuvant therapy pattern.
Accordingly, we aim to explore whether PSRT can be an alternative choice
compared to conventional PLCRT for rectal cancer patients through a comprehensive
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meta-analysis based on perioperative, long-term and health related quality of life
(HRQL) outcomes. In addition, we explore whether optimized PSRT regimens could
advance the future evolution of the neoadjuvant era.
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Methods
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Search strategy
Searches were conducted using PubMed, Embase and Web of Science databases (for
studies published up to August 2017) to identify all relevant studies (restricted to the
English language). The following search algorithm was used in PubMed: “(rectal)
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AND (neoadjuvant OR preoperative OR preoperatively) AND (chemotherapy OR
radiotherapy OR irradiation OR radiation OR chemoradiotherapy OR chemoradiation
OR radiochemotherapy)”. Furthermore, if multiple studies were published on the
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same patient population based on the same outcomes, only the most informative study
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was included. If multiple studies reported different outcomes based on the same
patient population, results were combined for a more comprehensive analysis. For
comparative studies with multiple-arms, data was only extracted from the arms that
matched the eligibility criteria.
Selection criteria
PICOS criteria (population, intervention, comparison, outcomes, and study design)
was used to select eligible studies: (1) population: patients who were definitely
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diagnosed with rectal cancer without metastases and received neoadjuvant treatment;
(2) intervention: PSRT (25Gy, 5fractions) or PLCRT followed by surgical resections;
(3) comparison: PSRT versus PLCRT; (4) outcomes: anastomotic leakage, bowel
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obstruction, total complications, total postoperative mortality, pathological complete
response (pCR) rate, sphincter preservation rate, acute toxicities, late toxicities,
survival or HRQL outcomes based on questionnaire; (5) studies: comparative studies
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including RCTs, prospective comparative studies (PCRS), or retrospective
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comparative studies (RCRS).
Data extraction and study quality assessment
Data extraction and study quality assessment were performed independently by two
reviewers (Bin Ma and Peng Gao). Extraction data that was consistent between the
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two reviewers were used directly for the final analyses, and disagreements between
the two reviewers were discussed with a third reviewer (Hongchi Wang) to reach a
final consensus. The Newcastle-Ottawa Scale (NOS) criterion recommended by the
13
. In addition, we appraised the risk of bias of each eligible individual study
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studies
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Cochrane Library for included trials was used to evaluate the quality of the included
by using the Cochrane risk of bias assessment tool (www. cochrane-handbook.org).
Moreover, we used the grading of recommendations assessment, development and
evaluation (GRADE) method to rate the level of outcomes (www. gradepro.org). The
extracted data was used for the following aspects: (1) direct pairwise analysis of
comparative studies based on perioperative and long-term outcomes; (2) network
analysis of RCTs (PSRT, PLCRT and surgery alone) based on long-term outcomes; (3)
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HRQL evaluation of cohort studies based on the QLQ-C30 questionnaire; (4)
systematic review of the neoadjuvant era of comparative studies based on optimized
PSRT regimens (delayed surgery or adding consolidation chemotherapy).
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Statistical methods
For the direct pairwise meta-analysis, Stata software, version 12.0 (2011) (Stata Corp,
College Station, TX, USA) was used to compare PSRT and PLCRT based on
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perioperative and long-term outcomes. Odds ratios (ORs) were used to evaluate the
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perioperative outcomes, and the hazard ratio (HR) was used to evaluate long-term
outcomes. To further explore whether PSRT can be an alternative compared with
conventional PLCRT in terms of patients’ long-term outcomes,
network
meta-analyses were conducted by the Bayesian model using the Markov chain Monte
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Carlo method of WinBUGS 1.4.3 (MRC Biostatistics Unit, Cambridge, UK) based on
RCTs of the network relationship between PLCRT, PSRT, and surgery alone
calculation model proposed by Woods et al
15
14
. The
was applied, because it possesses the
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superior feature of preserving the randomization of the RCTs and avoids potential
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selection bias, misleading results, and loss of available treatment comparisons 15. All
analyses in this study used a random-effects model, due to its conservative estimates
and being more tailored to multicenter studies in which heterogeneity is usually
present 16. Publication bias were checked by using begg’s test among studies of PSRT
versus surgery alone, PLCRT versus surgery alone and PSRT versus PLCRT 17,18. All
statistical values were reported with a 95% confidence interval (CI), and the
two-tailed P value threshold for statistical significance was set at 0.05.
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Results
Characteristics of included studies
A total of 18573 relevant studies (records from PubMed: n= 8846; records from other
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databases: n= 9727) were initially identified based on our systematic study search
strategy. After removing duplicates between multiple databases, 9326 studies
remained for screening. After screening the title and abstracts, 58 studies remained for
9,19-36
. Our study selection process is shown in Figure
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included for our meta-analysis
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further evaluation. Finally, data from 19 studies based on 14 different trials were
1. Data from eight studies based on 5 different trials were included for the direct
pairwise analysis in terms of perioperative and long-term outcomes
9,19,20,24,26,29,30,35
.
Long-term data from 7 RCTs were included for the network meta-analysis (PSRT
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versus Surgery alone, n = 4; PLCRT versus Surgery alone, n = 1; PSRT versus PLCRT,
n = 2) 9,24,28,31-34. Three trials were included for the review of HRQL outcomes 21,23,36.
In addition, three trials were summarized for the optimized regimens of PSRT
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(delayed surgery, n = 1; adding consolidation chemotherapy, n = 2) in terms of
22,25,27
. Detailed information for the included
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perioperative and long-term outcomes
studies is summarized in Table 1. In addition, the risk of bias graph of individual
studies was shown in Supplementary Figure 1.
Pairwise meta-analysis of perioperative and long-term outcomes between PSRT and
PLCRT
Based on included comparative studies between PSRT and PLCRT, the pooled results
showed both methods had similar total postoperative complications (OR = 1.19, 95%
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CI = 0.86-1.65, P = 0.30). However, patients who received PSRT had significant
lower incidence rate of total acute toxicities in comparison with that of PLCRT (OR =
0.09, 95% CI = 0.02-0.35, P < 0.01). Meanwhile, PLCRT had significant better effects
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on pCR when compared to PSRT (OR = 0.05, 95% CI = 0.02-0.18, P < 0.01),
however, this benefit of PLCRT did not translate into a higher sphincter preservation
rate in comparison with PSRT (OR = 1.62, 95% CI = 0.72-3.67, P = 0.25)
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(Supplementary Figure 2). In terms of long-term outcomes, PSRT showed similar
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tendencies of overall survival (OS), disease-free survival (DFS), local recurrence (LR)
and distant metastasis (DM) when compared with those treated with treatment of
PLCRT (OS: HR = 0.88, 95% CI = 0.68-1.14, P = 0.34; DFS: HR = 0.72, 95% CI =
0.46-1.12, P = 0.14; LR: HR = 0.75, 95% CI = 0.48-1.17, P = 0.21; DM: HR = 0.97,
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95% CI = 0.75-1.27, P = 0.84) (Supplementary Figure 3).
Notably, because of the evidence level is much higher for RCTs, hence, we
conducted subgroup analysis based on the Polish trial and TROG 01.04 trial to further
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explore the difference between PSRT and PLCRT. We found that PSRT had similar
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long-term outcomes in comparison with PLCRT (OS: HR = 0.95, 95% CI = 0.72-1.25,
P = 0.72; LR: HR = 0.89, 95% CI = 0.44-1.78, P = 0.74; DM: HR = 0.92, 95% CI =
0.69-1.21, P = 0.55). Regarding to perioperative outcomes, PSRT also had similar
incidence rate of postoperative complications irrespective of anastomosis leakage or
bowel obstruction (total: OR = 1.20, 95% CI = 0.86-1.69, P = 0.29; anastomosis
leakage: OR = 1.40, 95% CI = 0.64-3.06, P = 0.40; bowel obstruction: OR = 0.91, 95%
CI = 0.46-1.81, P = 0.78). Meanwhile, both methods showed similar postoperative
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mortality (OR = 1.26, 95% CI = 0.33-4.81, P = 0.74). Although PLCRT had
significant better effects on pCR (OR = 0.06, 95% CI = 0.02-0.19, P < 0.01), this
benefit did not translate into a higher sphincter preservation rate (OR = 0.87, 95% CI
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= 0.56-1.37, P = 0.56). However, PSRT had significant lower rate of grade 3-4 acute
toxicities (OR = 0.10, 95% CI = 0.03-0.27, P < 0.01) and similar severe late toxicities
(OR = 1.02, 95% CI = 0.48-2.16, P = 0.96) in comparison with PLRT. The results
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presented in forest plot were shown in Figure 2. The evidence level was recorded as
RCTs (Supplementary Table 1).
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“high” using GRADE in terms of perioperative and long-term outcomes based on
Network meta-analysis of long-term outcomes between PSRT, PLCRT, and surgery
alone
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To further explore the long-term efficacy between PRST and PLCRT, we conducted a
network meta-analysis between PSRT, PLCRT, and surgery alone based on published
RCTs. The network meta-analysis showed that PLCRT and PSRT have similar OS and
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DM compared to surgery alone. However, PLCRT and PSRT both showed obvious
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lower LR compared with surgery alone (PSRT: HR = 0.47, 95% CI = 0.36-0.64;
PLCRT: HR = 0.61, 95% CI = 0.33-1.15). Furthermore, the benefits of the long-term
outcomes were similar between PLCRT and PSRT based on the network
meta-analysis results (PSRT versus PLCRT, OS: HR = 0.95, 95% CI = 0.66-1.35; DM:
HR = 0.93, 95% CI = 0.67-1.30; LR: HR = 0.78, 95% CI = 0.43-1.38; Figure 3). In
addition, consistency could be observed between direct pairwise meta-analysis
evidence and network meta-analysis evidence in terms of long-term outcomes
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(Supplementary Table 2). We did not observe significant publication bias among
studies of PSRT versus surgery alone, PLCRT versus surgery alone and PSRT versus
PLCRT (Supplementary Figure 4).
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HRQL outcomes between PSRT and PLCRT
Three trials reported the HRQL between PLCRT and PSRT 21,23,36. All three used the
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
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questionnaire to evaluate quality of life in patients who received PSRT or PLCRT. The
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EORTC QLQ-C30 is a general cancer HRQL-questionnaire composed of a global
health status, 3 functional scales, 3 symptom scales and 6-single-item scales
shown in Table 2, except Wiltink et al
34
37
. As
indicated that patients received PSRT had
lower level of nausea/vomiting, other items showed no significant difference in
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HRQL between patients who received PSRT or PLCRT based on the scores of
QLQ-C30 from the original data of these three trials.
Outcomes of optimized PSRT regimens in comparison with PLCRT
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There are two primary regimens for optimizing PSRT: use with delayed surgery and
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adding consolidation chemotherapy. In this part, we qualitatively summarized
comparative studies comparing optimized PSRT regimens with conventional PLCRT.
Latkauskas et al
27
compared PSRT with delayed surgery with PLCRT. The results
showed similar perioperative and long-term outcomes except for an improved DFS in
patients who received PLCRT. Meanwhile, improved survival outcomes were
observed in treatment of PSRT followed by consolidation chemotherapy from the
results of Bujko et al
22
and Youssef et al
12
25
. Notably, all the three trials showed
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similar pCR rate between optimized PSRT regimens and PLCRT. The comparison
data between optimized regimens of PSRT and PLCRT in terms of perioperative and
long-term outcomes are shown in Table 3.
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Discussion
Over the past decades, PLCRT and PSRT have been developed in parallel and
regarded as the two main standards of care for patients with high-risk rectal cancer. In
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general, PSRT is preferred in Northern Europe and PLCRT in Southern Europe and
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America. The primary advantage of PSRT is its lower toxicities since it does not
require concomitant chemotherapy in the radiotherapy regimen, as seen in with
PLCRT. In addition, the delivery of PSRT is less expensive because it can be
administered in 5 fractions compared to the 25-28 fractions seen for PLCRT
5,7
.
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Theoretically, the main advantage of PLCRT is the downstaging effect caused by the
concomitant chemotherapy and longer interval of use before surgery, and this may
increase organ preservation chances for patients with low lying rectal cancer
4,38
. If
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PSRT could achieve similar benefits in perioperative, long-term, postoperative and
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HRQL outcomes when compared with PLCRT, delivery of PLCRT may be seen as
over-treating and PSRT would be considered the preferable alternative.
In general, the standard schedule for PSRT includes immediate surgery (7 days),
while PLCRT is more often paired with delayed surgery (6-8 weeks). Cancer cells
sterilized by radiotherapy usually require time to undergo necrosis 39, and, accordingly,
our results showed that PLCRT with delayed surgery had a significant advantage on
pCR rate compared with PSRT with immediate surgery. However, this advantage did
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not translate into a higher sphincter preservation rate for PLCRT. This builds upon
other studies showing that higher downstaging was not correlated to a higher
sphincter preservation rate 6,40, because sphincter preservation rate can be affected by
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multiple factors such as tumor stage and location, patient desire, and the surgeon’s
skill and conceptual approach of such a “conservative” treatment
41
. Hence, PSRT
with delayed surgery might improve the insufficient results seen on tumor
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downstaging in standard PSRT. Notably, the Stockholm III trial compared three arms:
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PSRT with immediate surgery, PSRT with delayed surgery and preoperative
long-course radiotherapy (PLRT) with delayed surgery
42-45
. The Stockholm III trial
published its latest results with long-term outcomes indicating PSRT with delay
surgery had similar long-term outcomes in comparison with other two methods
42
. However, PSRT with delayed surgery
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irrespective of OS, DFS, LR or DM rates
showed higher acute toxicities when compared with other two methods (PSRT: < 1%;
PSRT-delay: 7%; PLRT: 5%). In addition, PSRT showed the highest effects on tumor
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downstaging of ypStage 0-I (PSRT: 26.8%; PSRT-delay: 38.9%; PLRT: 28.9%).
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Moreover, PSRT with delayed surgery showed significant lower incidence of
postoperative complications when compared to PSRT with immediate surgery (41%
versus 53%).
Since only two RCTs to date compare PSRT and PLCRT directly, we conducted a
network meta-analysis to further explore whether both treatments could provide
similar
long-term
outcomes.
In
comparison
with
surgery
alone,
adding
radio(chemo)therapy did not improve OS and DM. The significant benefit of
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neoadjuvant therapy is still the local control it grants, irrespective of treatment pattern
changes. However, PSRT and PLCRT showed similar long-term times based on our
results. Hence, we further studied preoperative regimens which could improve
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survival time for rectal cancer patients. Notably, Myerson et al indicated that PSRT
followed by 4 cycles of FOLFOX chemotherapy achieved a favorable response and
morbidity in 76 patients
46
. A recent RCT conducted by Bujko et al indicated that
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PSRT with consolidation chemotherapy (3 cycles FOLFOX) showed an improved OS
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(73% versus 65%, P < 0.05) and similar local recurrence incidences compared with
PLCRT (22% versus 21%, P = 0.82) after a follow-up of 3-year 22. In addition, using
match pair analysis, one proceeding from the American Society for Radiation
Oncology 57th Annual Meeting demonstrated improved DFS and metastasis-free
25
.
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survival in PSRT followed by consolidation chemotherapy compared to PLCRT
Furthermore, an ongoing RCT-RAPIDO trial also exploring the PSRT followed by
consolidation chemotherapy in comparison with PLCRT will further characterize the
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efficiency of this optimized regimen of PSRT 47. We believe that PSRT followed by
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consolidation chemotherapy may be a worthy therapy needed for further exploration.
Surgery had the most negatively affects quality of life most in the early months,
and its effect was similar in both PSRT and PLCRT based on our summarized results.
This is in contrast with the idea that the higher dose per fraction and short overall
treatment time of PSRT would increase the risk for the long-term functional effects
compared with the lower doses per fraction within PLCRT. With this data, doctors can
inform patients contemplating such treatments that there is no overall difference in
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HRQL between PSRT and PLCRT strategies. In addition, this HRQL information is
critical so that patients can learn about post-treatment function and adequate support
can provide in time.
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Based on the latest guideline of NCCN 3, PSRT was a suboptimal option for cT3
and not recommended for cT4 rectal cancer patients. In addition, European Society
for Medical Oncology (ESMO) guidelines recommended that rectal cancer patients
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should be divided into early group (the “good” cancers: cT1-2; cT3 if middle or high,
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N0 (or cN1 if high), no mesorectal fasica (MRF), no extramural venous invasion
(EMVI)), intermediate group (the “bad” cancers: cT2 very low, cT3 MRF- (unless
cT3 and mid- or high rectum, N1-2, EMVI+, limited cT4aN0)) and advanced group
(the “ugly” cancers: cT3 MRF+, cT4, lateral node+) according to the recurrence risk.
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In general, the ugly cancers may require PLCRT, the bad cancers require PSRT and
the good cancers may follow radical surgery alone. Our results indicate that PSRT
could be a preoperative treatment option for mixed patients with cT3 or cT4 tumors.
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However, we still cannot draw a definite conclusion on whether PSRT and PLCRT is
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the preferred regimen for cT4 tumors from the current evidence, since we could not
obtain individualized data to further stratify patients into cT3 or cT4 subgroups in the
present study. Therefore, we recommend that future trials provide detailed results for
cT3 and cT4 patients separately. In addition, multiple survival analyses and longer
follow-up should be undertaken for cT4 patients, since the primary advantage of
radiation is local control, but chemotherapy could also potentially control distant
metastases. Moreover, the interval between preoperative treatments and surgery was
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an important factor for tumor response
48
. This deficiency of PSRT with immediate
surgery restricted non-resectable cT4 tumor downstaging and shrinkage. Hence,
optimized PSRT regimens (with delayed surgery or adding consolidation
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chemotherapy) which could improve these insufficiencies necessitate further
exploration.
A recent published meta-analysis has provided a general summary of advantages
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and adverse effects of neoadjuvant therapies based on 41,121 rectal cancer patients
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over the past decades 49. The main advantage of our present study is that we provide a
more comprehensive examination of PSRT including perioperative, long-term, and
HRQL outcomes compared with PLCRT. In addition, we conducted network analyses
to provide updated evidence between PSRT, PLCRT and surgery alone in terms of
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long-term outcomes. Furthermore, optimized regimens for PSRT were also
summarized to explore the future directions of the neoadjuvant era. Our
comprehensive analyses and summary further verified the efficiency of PSRT. There
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were some limitations in our present study which should be pointed out. In our overall
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analyses, the differences in study design, clinical stage, age, gender rate and tumor
location could not be balanced for all potential methods between studies. We observed
that the tumor location of patients in PSRT group is higher than that in PLCRT group
in studies of Yeh et al
20
and Vironen et al
35
. As high rectal cancers have a better
outcome, the overall pairwise meta-analysis might be affected by this inherent bias. In
addition, from some of the trials included in our study, the tumour stage of the trial
patients ranged from T1 to T3, and some resectable T4, which may cause bias to the
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results of our overall analysis. Moreover, the main limitation was the heterogeneities
(study type, published year, enrolled patients) of our included studies. Although we
did not pool all the included studies for our overall analyses and data from included
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studies were used into different section analyses or review, we may rely on more
large-scale prospective trials to further update our findings, especially focus on one
specific topic (such as effect of PSRT with delayed surgery). Finally, the eligibility
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criteria in terms of TN stage, tumour height, staging methodology (from digital
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examination to magnetic resonance imaging) were different in these randomized trials.
As these patients were treated over a long period of time, radiotherapy techniques
(from 2-field chimney technique to intensity modulated radiation therapy), surgical
techniques (blunt dissection to total mesorectal exicision) and postoperative care were
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different. There were variations in chemotherapy (from no chemotherapy to adjuvant
chemotherapy of different types) as well. They all have impact on survival, toxicity,
and quality of life. Hence, we may rely on individual data of prospective studies to
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Conclusions
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further explore the impact of these factors.
PSRT showed comparable perioperative, long-term, and HRQL outcomes in
comparison with PLCRT. Although PLCRT has a better pCR effect, this benefit does
not translate into a higher sphincter preservation rate. When pCR is not the primary
aim for surgeons and patients, PSRT seems to be the better option for preoperative
treatment for rectal cancer patients based on its main advantages of simplicity and
lower cost. Furthermore, optimized PSRT regimens could improve the current
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deficiencies on tumor response with PSRT with immediate surgery. Hence, optimized
PSRT-based regimens provide possibilities for the future evolution of the neoadjuvant
era.
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Clinical Practice Points
1. Based on the NCCN Clinical Practical Guidelines in Oncology, PLCRT accepted
as standard for locally advanced rectal cancer patients.
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2. A published investigation indicated that only 55% of rectal cancer patients
Data Base.
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received “standard” PLCRT in the United States according to the National Cancer
3. Whether PSRT and its optimized regimens can be alternative choices compared to
PLCRT for rectal cancer patients based on perioperative, long-term and HRQL
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outcomes remain controversial.
4. PLCRT showed a better pCR rate, but this benefit did not translate into a higher
sphincter preservation rate and other perioperative outcomes differences when
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compared to PSRT.
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5. In terms of survival outcomes, adding either PLCRT or PSRT both showed
obvious advantage on local control when compared with surgery alone, and PSRT
and PLCRT had similar long-term outcomes irrespective of pairwise or network
meta-analyses.
6. PSRT and PLCRT had no overall differences based on HRQL scores.
7. The insufficiency on pCR of PSRT might be improved by delayed surgery or
adding consolidation chemotherapy based on systematic review of current
19
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evidence.
8. Our results indicated that PSRT could be the treatment of choice in comparison
with PLCRT when pCR is not the primary aim. PSRT with delayed surgery or
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adding consolidation may provide further possibilities for advancing the evolution
of neoadjuvant era.
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Disclosure
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The authors declare that they have no competing interests.
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Ma B, Gao P, Wang H, et al. What has preoperative radio(chemo)therapy brought to localized
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30 2017.
Figure Legends
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Figure 1: Flow chart of study selection
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Figure 2: Forest plot based on RCTs between PSRT and PLCRT. A: Overall survival;
B: Local recurrence; C: Postoperative morbidity; D: Postoperative mortality; E:
Pathological complete response; F: Sphincter preservation rate; G: Grade 3-4 acute
toxicities; H: Severe late toxicities.
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Figure 3: Network analyses between PSRT, PLCRT and surgery alone in terms of
long-term outcomes. Each link represents at least 1 study and the widths of each link
are proportional to the number of studies comparing the particular arms. The size of
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each node is proportional to the total sample size. Results were presented as hazard
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ratio and its 95% confidence interval (row-defining treatment compared with
column-defining treatment).
Supplementary Figure 1: Risk of bias graph of individual studies
Supplementary Figure 2: Forest plot based on comparative studies between PSRT and
PLCRT. A: Postoperative complications; B: Acute toxicities; C: Pathological
complete response; D: Sphincter preservation rate.
Supplementary Figure 3: Forest plot based on comparative studies between PSRT and
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PLCRT. A: Overall survival; B: Disease-free survival; C: Local recurrence; D:
Distant metastasis.
Supplementary Figure 4: Publication bias among studies of PSRT versus surgery
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alone, PLCRT versus surgery alone and PSRT versus PLCRT.
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Table 1 Baseline characteristics and quality assessment of included studies
Armc
Designb
Krajcovicova*
Taiwan
Slovak
RCT
RCRS
RCRS
Republic
Vironen
Stockholm I trial
Stockholm II trial
Finland
Sweden
Sweden
PCRS
RCT
RCT
SRCT trial
Sweden
RCT
TME trial
Netherlands
RCT
& Sweden
Fan
TROG 01.04 trial
China
Australia
RCT
RCT
(QoF outcomes)
Wiltink
Netherlands
RCRS
Poland
RCT
(QoF outcomes)
Latkauskas
Lithuania
RCT
Tumor
Interval
(M/F, %)
Stage
location
T3-4N0
5.7 cm
50.4Gy, 28 fractions (5-FU + LV)
4-6 weeks
5.8 cm
25Gy, 5 fractions
7 days
7.0 cm
50.4Gy, 28 fractions (FU)
5-6 weeks
6.2 cm
25Gy, 5 fractions
3-7 days
PLCRT
157
59
66/34
PSRT
155
60
65/35
PLCRT
161
64
75/25
PSRT
162
63
72/28
PLCRT
37
60
65/35
T3-4
4.7 cm
50.4Gy, 28 fractions (5-FU + LV)
4-6 weeks
PSRT
28
67
61/39
or N1-2
5.9 cm
25Gy, 5 fractions
7 days
PLCRT
55
64
73/27
II/III
NA
45-46Gy, 23-25 fractions (5-FU + LV or Ca)
6 weeks
PSRT
96
62
66/34
25Gy, 5 fractions
5 days
PLCRT
44
65
80/20
50Gy, 25 fractions (5-FU)
4-5 weeks
PSRT
42
68
64/36
PSRT
424
69
60/40
S
425
67
57/43
PSRT
272
66
61/39
S
285
66
61/39
PSRT
573
69
59/41
S
574
69
61/39
PSRT
897
65
64/36
S
908
66
64/36
PLCRT
90
56
62/38
S
94
58
PLCRT
154
64
PSRT
143
PLCRT
85
(QoF outcomes)
Polish trial
Clinical
PSRT
306
PLCRT
PSRT
T3Nx
T3-4Nx
8.5 cm
25Gy, 5 fractions
7 days
Promon-
25Gy, 5 fractions
1-7 days
tory
-
-
Promon-
25Gy, 5 fractions
7 days
tory
-
-
Resectable
Promon-
25Gy, 5 fractions
7 days
tory
-
-
Resectable
≤15cm
25Gy, 5 fractions
≤ 10 days
≤15cm
-
-
10cm
46-50Gy, 23-25 fractions (XELOX)
4-6 weeks
-
-
7.0 cm
50.4Gy, 28 fractions (FU)
4-6 weeks
6.2 cm
25Gy, 5 fractions
3-7 days
NA
50-50.4Gy, 25-28 fractions (5-FU + LV or Ca or
5-8 weeks
Resectable
Resectable
T3-4
54/36
or N1-2
73/27
T3Nx
63
71/29
69
65/35
68
65/35
110
60
65/35
110
62
61/39
PLCRT
72
63
69/31
PSRT
68
66
63/37
5 cm
RI
PT
Yeh
Australia
RCT
Number
Regimens of preoperative treatmentd
Gender
SC
TROG 01.04 trial
Poland
Age
M
AN
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Polish trial
Patient
TE
D
Study
EP
Country
AC
C
Studiesa
LARC
Q-Af
Out-
Follow-up
comese
(months)
P, N
48
H
P, N
70.8
H
P
36
M
P
48
M
P
NA
M
N
60
M
N
106
M
N
156
H
N
144
H
N
38
M
Q
≥ 12
H
Q
58
M
Q
≥ 12
H
O
40
M
XELOX or Ca + bevacizumab)
25Gy, 5 fractions
≤ 10 days
5.7 cm
50.4Gy, 28 fractions (5-FU + LV)
4-6 weeks
5.8 cm
25Gy, 5 fractions
7 days
T3-4
≤15cm
50Gy, 25 fractions (5-FU + LV)
6 weeks
or N1-2
≤15cm
25Gy, 5 fractions
6 weeks
T3-4
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Bujko et al
Youssef#
Poland
US
RCT
RCRS
PLCRT
254
60
67/33
PSRT
261
60
70/30
PLCRT
80
NA
NA
PSRT
69
NA
NA
T3-4
T3-4Nx
≤15cm
50.4Gy, 28 fractions (FOLFOX or 5-FU + LV)
12.4 weeks
≤15cm
25Gy, 5 fractions followed by FOLFOX
12.4 weeks
NA
Long-course chemoradiotherapy (without details)
NA
25Gy, 5 fractions followed by FOLFOX
NA
O
35
H
O
49
NA
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a: Data of 19 studies based on 14 different trials were included in our systematic review and meta-analysis; b: Study design was divided into randomized controlled trial (RCT),
retrospective comparative study (RCRS) and prospective comparative study (PCRS); c: Arm of included studies contained preoperative long-course chemoradiotherapy (PLCRT);
preoperative short-course radiotherapy (PSRT); surgery alone (S); d: 5-FU: 5-fluorouracil; LV: leucovorin; Ca: capecitabine; e: We used the data of included studies to conduct
pairwise meta-analysis (P), network meta-analysis (N), quality of life evaluation (Q) and optimized PSRT regimens summary (O); f: Quality assessment (Q-A) was divided into low,
moderate and high according to Newcastle–Ottawa Scale (NOS) criterion; * PLCRT group enrolled some patients only received long-course radiotherapy without concomitant
chemotherapy; # Proceedings from the American Society for Radiation Oncology 57th Annual Meeting; M: male; F: female; LARC: locally advanced rectal cancer; NA: not
applicable.
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Table 2 Health-related quality of life outcomes after PSRT or PLCRT based on EORTC QLQ-C30 questionnaire
EORTC QLQ-C30 subscales
Polish trial
Wiltink et al
PLCRT
P value
PSRT
PLCRT
P value
PSRT
PLCRT
P value
143
154
-
111
110
-
306
85
-
78.0
63.9
NR
NR
68.5
61.1
79.9
68.2
NR
NR
68.9
61.8
0.26
0.26
NR
NR
0.31
0.44
76
74
66
77
75
57
75
73
67
76
73
61
0.78
0.76
0.69
0.72
0.58
0.22
82.6
83.3
86.3
84.1
87.7
78.9
84.5
82.5
86.9
84.0
84.6
79.6
0.56
0.73
0.85
0.90
0.27
0.90
36.4
NR
23.0
NR
NR
20.6
NR
NR
NR
35.5
NR
22.0
NR
NR
17.3
NR
NR
NR
0.62
NR
0.98
NR
NR
0.37
NR
NR
NR
34
8
28
18
36
13
23
23
33
0.67
0.03
0.73
0.64
0.62
0.88
0.34
0.19
0.20
22.5
1.3
11.1
11.6
18.5
4.6
10.8
10.6
6.8
23.8
5.9
11.2
11.8
15.4
8.5
8.6
5.8
9.5
0.59
< 0.01
0.92
0.89
0.42
0.12
0.51
0.09
0.27
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PSRT
EP
Patients
Function
Physical
Role
Emotional
Cognitive
Social
Global
Symptoms
Fatigue
Nausea/vomiting
Pain
Dyspnoea
Insomnia
Appetite
Constipation
Diarrhoea
Financial
TROG 01.04 trial
36
5
31
18
34
14
19
18
38
A higher score for functioning reflects better functioning, whereas a higher score for symptoms represents a higher level of symptoms and decreased health-related quality of life.
NR: not reported.
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EORTC: European Organization for Research and Treatment of Cancer; PSRT: preoperative short-course radiotherapy; PLCRT: preoperative long-course chemoradiotherapy;
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Table 3 Systematic review of optimized PSRT (delayed surgery or adding consolidation
chemotherapy) versus PLCRT based on perioperative and long-term outcomes
Outcomes
Latkauskas et al
Youssef et al *
Bujko et al
PSRT+delay
PLCRT
PSRT+CCT
PLCRT
PSRT+CCT
PLCRT
Would complications
35.3%
26.8%
NA
Anastomosis leakage
5.8%
6.9%
5.9%
3.9%
NA
Total complications
35.3%
26.8%
28.9%
24.7%
NA
Pathological complete response
4.4%
11.1%
16.8%
11.7%
28%
Sphincter preservatipn
69.1%
72.2%
50.0%
48.8%
NA
Acute toxicities
NA
74.9%
82.6%
NA
Late toxicities
NA
19.1%
20.3%
NA
65%
96%
89%
52%
83%
66%
21%
a
93%
93%a
87%b
69%b
Perioperative outcomes
78%
82.4%
73%
Disease-free survival
59%
75.1%
53%
Local recurrence
0%
4.2%
22%
Distant metastasis
18.8%
11.3%
NA
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Overall survival
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Survival outcomes
NA
32%
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PSRT: preoperative short-course radiotherapy (25 Gy, 5 fractions); PLCRT: preoperative long-course
chemoradiotherapy; CCT: consolidation chemotherapy; NA: not applicable;*Proceedings from the American
Society for Radiation Oncology 57th Annual Meeting; a: local control rate; b: distant metastasis-free survival;
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Significant difference was presented by bold style.
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Supplementary Table 1: Evidence level assessment in terms of perioperative and long-term outcomes between PSRT and PLCRT based on RCTs
Quality assessment
No. of
Outcomes
studies
Study
Limitations
Inconsistency
Indirectness
Imprecision
design
Other
No. of patients
Effect
PSRT
Relative
Absolute
(95% CI)
(95% CI)
HR (0.95)
19 fewer per 1000
PLCRT
consider
Quality
Importance
-ations
OS
RCT
Not serious
Not serious
Not serious
Not serious
None
218/
320
2
2
2
Mortality
pCR rate
SP rate
Acute
RCT
RCT
RCT
RCT
RCT
Not serious
Not serious
Not serious
Not serious
Not serious
toxities
2
Late
RCT
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
Not serious
toxicities
(from 120 fewer to
288/
288/
HR (0.89)
28 fewer per 1000
320
318
0.44-1.78
(from 260 more to
215/
224/
HR (0.92)
30 fewer per 1000
320
0.69-1.21
(from 136 more to
OR (1.26)
3 more per 1000
311
313
0.33-4.81
(from 9 fewer to 46
Not serious
Not serious
None
HIGH
IMPORTANT
HIGH
79 fewer)
4/
None
IMPORTANT
78 more)
5/
Not serious
Not serious
None
0.72-1.25
318
Not serious
Not serious
None
SC
Not serious
Not serious
318
M
AN
U
2
Morbidity
RCT
Not serious
TE
D
2
DM
RCT
EP
2
LR
AC
C
2
224/
RI
PT
2
IMPORTANT
HIGH
67 fewer)
123/
112/
OR (1.20)
43 more per 1000
311
313
0.86-1.69
(from 34 more to
IMPORTANT
HIGH
127 fewer)
IMPORTANT
HIGH
more)
None
3/
45/
OR (0.06)
140 fewer per 1000
310
299
0.02-0.19
(from 118 fewer to
193/
204/
OR (0.87)
32 fewer per 1000
311
313
0.56-1.37
(from 140 fewer to
CRITICAL
HIGH
147 more)
None
IMPORTANT
HIGH
68 more)
Not serious
None
8/
73/
OR (0.10)
200 fewer per 1000
310
319
0.03-0.27
(from 155 fewer to
CRITICAL
HIGH
220 more)
Not serious
None
23/
23/
OR (1.02)
1 more per 1000
293
299
0.48-2.16
(from 38 fewer to
IMPORTANT
HIGH
76 more)
PSRT: preoperative short-course radiotherapy; PLCRT: preoperative long-course chemoradiotherapy; OS: overall survival; LR: local recurrence; DM: Distant metastasis; RCT: randomized
controlled trial; pCR: pathological complete response; SP: sphincter preservation;
ACCEPTED MANUSCRIPT
Supplementary Table 2. Consistency of long-term results between direct pairwise meta-analysis and network meta-analysis
A. PLCRT versus S
OS
LR
DM
B. PSRT versus S
OS
LR
DM
C. PSRT versus PLCRT
OS
LR
DM
1.09 (0.50, 2.63)
1.22 (0.30, 4.92)
0.91 (0.38, 2.17)
M
AN
U
0.94 (0.83, 1.08)
0.46 (0.39, 0.55)
0.90 (0.79, 1.02)
TE
D
0.95 (0.72, 1.25)
0.89 (0.44, 1.78)
0.92 (0.69, 1.21)
Network meta-analysis
RI
PT
Direct pairwise meta-analysis
1.00 (0.67, 1.47)
0.61 (0.33, 1.15)
0.96 (0.66, 1.40)
SC
Treatments
0.95 (0.77, 1.14)
0.47 (0.36,0.64)
0.90 (0.73, 1.13)
0.95 (0.66, 1.35)
0.78 (0.43, 1.38)
0.93 (0.67, 1.30)
AC
C
EP
PLCRT: preoperative long-course chemoradiotherapy; PSRT: preoperative short-course radiotherapy;
S: surgery alone; OS: overall survival; LR: local recurrence; DM: Distant metastasis.
Results were presented by hazard ratio; Results with significance were presented by bold type.
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