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Background: Short-course preoperative radiation (SCRT) with delayed surgery has been shown to increase pathologic complete response (pCR) rate in several trials. However, there was no clear answer on whether SCRT or long-course chemo-radiotherapy (LCRT) is more effective. Therefore we conducted this meta-analysis to evaluate the safety and efficacy of SCRT with delayed surgery versus LCRT with delayed surgery for treatment of rectal cancer.
Methods: Literatures were searched from PubMed, EMBASE, Web of science, Cochrane Library and clinicaltrials.gov up to August, 2014. Quality of the randomized controlled trials (RCTs) was evaluated according to the Cochrane’s risk of bias tool of RCT. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) System was used to rate the level of evidence. ReviewManager 5.3 was used for statistical analysis. Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated.
Results: Four RCTs were included in the present systematic review. Three RCTs, with total of 357 rectal cancer patients, were included. Meta-analyses results demonstrated there were no significantly differences in sphincter preservation rate, local recurrence rate, grade 3~4 acute toxicity, R0 resection rate and downstaging rate. Compared with SCRT, LCRT significantly increased pCR rate [RR=0.49, 95%CI (0.31, 0.78), P=0.003].
Conclusions: In terms of sphincter preservation rate, local recurrence rate, grade 3~4 acute toxicity, R0 resection rate and downstaging rate, SCRT with delayed surgery is as effective as LCRT with delayed surgery for management of rectal cancer. LCRT significantly increased pCR rate compared with SCRT. Due to risk of bias and imprecision, further multi-center large sample RCTs were needed to confirm this conclusion.
Long-course chemo-radiotherapy (45~50 Gy in 25 fractions) with delayed surgery or short-course radiotherapy (25 Gy in 5 fractions) with immediate surgery were the most frequent regimens for the treatment of localized and locally advanced resectable rectal cancer (1-4). Compared with postoperative chemo-radiotherapy, this strategy improved local control and was associated with reduced toxicity and better compliance of radiotherapy (2, 5, 6). By comparing short-course preoperative radiotherapy with selective postoperative chemo-radiotherapy, the MRC (Medical Research Council) CR07 rectal trial provided further support for the short course regimen (5). Long-course preoperative chemo-radiotherapy (LCRT) of 50.4 Gy in 6 weeks and 5 days with concurrent chemotherapy has been widely used in the last decades. This regimen’s superiority, in terms of local control, was demonstrated in the German rectal cancer trial, when compared with postoperative chemo-radiotherapy (2, 7). In fact, the optimal timing interval of surgery remains controversial. Short-course preoperative radiation with delayed surgery has been shown to increase pathologic complete response (pCR) rate and induce tumour down-staging rate in both randomized and observational studies in recent years (8-10).
To date, many studies have explore whether SCRT or LCRT is more effective neoadjuvant modality to improve outcomes for localized and locally advanced rectal cancer [11-14], but the results were heterogeneous. (11-14). On the one hand, the benefit of the short-course schedule is less expensive and more convenient, especially in centers with a long waiting list or lack of medical resources (15). On the other hand, long-course chemo-radiation might be better than the short-course irradiation schedule at increasing pathologic complete response (pCR) and R0 resection rate (15), because the tumor bulk might be reduced before surgery. Therefore we performed this systematic review and meta-analysis to fully analyze the safety and efficacy of SCRT with delayed surgery versus LCRT with delayed surgery as a modality for the management of rectal cancer.
Studies would be included in systematic review if they met the following criteria: (1) Participants: All the patients that were diagnosed as localized and locally advanced resectable rectal cancer using pathology and cytology were included in systematic review. Metastatic rectal cancer patients were excluded. All the patients did not have serious cardiopulmonary diseases and other severe underlying diseases. (2) Interventions and comparisons: Comparing the efficacy and safety of short-course radiotherapy with delayed surgery +/- adjuvant chemotherapy versus long-course radiotherapy or chemo-radiotherapy with delayed surgery +/- adjuvant chemotherapy for treatment of rectal cancer.Short-course radiotherapy was not more than one week, and long-course radiotherapy should be more than 4 weeks at least. Total dose of short-course was at least more than 20 Gy, and long-course surpassed 45 Gy. Timing interval of surgery was more than 4 weeks either SCRT or LCRT arms. (3) Outcomes: The following outcomes were evaluated: sphincter preservation rate, R0 resection rate, Downstaging (T stage decreased) rate, pCR rate, local recurrence rate and grade 3~4 acute toxicity. (4) Study design: randomized control trials (RCTs).
We excluded the following articles: (1) The design of the study was not randomized controlled trials, for example, retrospective study, case series or case report etc.; (2) The study had repeated data or did not report outcomes of interest; (3) Non-original research, such as review, comments etc.; (4) Short-course radiotherapy was more than one week, or long-course radiotherapy less than 4 weeks. Total dose of short-course was less than 20 Gy, or long-course less than 45 Gy. Timing interval of surgery was less than 4 weeks either SCRT or LCRT arms.
Eligibility assessment was performed independently in a non-blinded standardized manner by 2 reviewers. Any disagreement between two authors was resolved by discussion..
We searched related articles in PubMed (From 1966 to August 2014), EMBASE (From 1974 to August 2014), Web of Science, Cochrane Library (CENTRAL, Issue 8 of 12, Oct 2014) and clinicaltrials.gov up to August, 2014. In electronic searching, we used MeSH or Emtree terms combined free terms in all the search strategies. The following search terms were used: “rectal cancer”, “preoperative radiotherapy”, “chemoradiotherapy”, “neoadjuvant radiotherapy”, “short course” and “long course”. The whole search strategies were listed in the appendix. We also reviewed the references of included studies to look for potentially eligible articles. Furthermore, we checked abstracts that were published in major academic conferences (American Society of Clinical Oncology, European Society for Medical Oncology, American Society for Therapeutic Radiology and Oncology and European SocieTy for Radiotherapy & Oncology). No language restrictions were adopted.
Assessing risk of bias of included RCTs
Qualities of included RCTs were evaluated according to the Cochrane Collaboration's tool for assessing risk of bias of RCT (ROB tool, 5.1.0) (16). The RoB tool included seven domains: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. For each study, we made judgments about risk of bias from each of the seven domains of the tool. In all domains, an answer ‘Yes’ indicated a low risk of bias, an answer ‘No’ indicated high risk of bias, and if insufficient detail is reported of what happened in the study, the judgment would usually be ‘Unclear’ risk of bias.
Data extraction was performed completely independently by two reviewers. Reviewers were not blinded to authors or journals. Disagreements were resolved by discussion between the two review authors; if no consensus was reached, a third author would decide. Information about baseline patient characteristics, duration of follow up, and the number of events for all the outcomes, trial design, interventions and outcomes were extracted from each included study.
All statistical analyses were performed using ReviewManager 5.3 software. Risk ratio (RR) and 95% confidence intervals (CI) was calculated for count data. Chi-square test and I-square test were used for testing heterogeneity between studies. If heterogeneity was not present (P>0.10, I2<50%), fixed-effect model would be adopted for analysis, otherwise, random-effect would be employed. In the presence of heterogeneity, we explored potential sources from the following three aspects: clinical, methodological and statistical. In the case of excessive heterogeneity, descriptive analysis rather than meta-analysis was employed.
Quality of evidence
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to grade the quality of evidence and strength of recommendations (17-20). Risk of bias, limitations, the indirectness, the consistency of the results across studies, the precision of the overall estimate across studies and other considerations are six domains of the tool. For each outcome, if further research was very unlikely to change our confidence in the estimate of effect, the quality of the evidence was rated as high; if further research was likely to have an important impact on our confidence in the estimate of effect and may change the estimate, the quality was moderate; if further research was very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate, the quality was low; if the estimate was very uncertain, the quality was very low. The GRADEpro 3.6 software was used to estimate the quality of the evidence in the meta-analysis by two reviewers. If there were disagreements between the two reviewers, a third author would join to discuss and make decisions.
Study selection and characteristics of included studies
Total 502 relevant literatures were searched, 165 duplicates were removed. After reviewed the titles and abstracts of 337 of records, 330 of them was excluded due to obviously irrelevancy. 7 of full-text were obtained to further determine eligibility. We ruled out another 3 of full-text articles: 1 article due to interventions not meeting inclusion criteria; 1 article due to review; 1 article due to non-RCT. Finally, 4 studies were included in the qualitative systematic review (10, 21-23), 1 of them is an ongoing trial, no publications were reported (23); 3 trials, total 357 patients, were included in meta-analysis (10, 21, 22). The PRISMA flow diagram of studies was shown in Figure 1. The characteristics of the studies were shown in Table 1.
Risk of bias assessment
This meta-analysis included 3 RCTs: the baseline characteristics of patients were reported in all RCTs. All 3 RCTs mentioned "random"; only 1 RCT reported an adequate randomized sequence generation and allocation concealment (10), 1 RCT was unclear (21), 1 RCT was with high risk (22). 2 RCTs described the reasons of incomplete outcome data (10, 21), 1 RCT with high risk (22). All trials did not mention whether the blind method was adopted or not, however, this should unlikely affect the quality assessment results (Figure 2).
Results of meta-analysis
Sphincter preservation rate
Two trials reported the sphincter preservation rate; total 172 rectal cancer patients were included in the meta-analysis. There was no significant difference in the sphincter preservation rate between SCRT and LCRT arms [RR=1.14, 95%CI (0.86, 1.52), p=0.37]. No obvious heterogeneity was found (I2=24%, P=0.25), so the fixed effect model was employed, (Figure 3A).
R0 resection rate
Two trials, with total 127 rectal cancer patients, were included in the meta-analysis to evaluate R0 resection rate. Meta-analysis suggested that there was no significant difference between SCRT and LCRT arms [RR=0.94, 95%CI (0.84, 1.06), p=0.29], without significant heterogeneity was detected (I2=0%, P=0.81), so the fixed effect model was applicable, (Figure 3B).
Downstaging (T stage decreased) rate
Only one RCT evaluate the downstaging rate. Compared SCRT with LCRT, there was no significant difference between the two arms [RR=0.62, 95%CI (0.33, 1.16), P=0.14], (Figure 3C).
Two RCTs reported the pCR rate; total 172 rectal cancer patients were included in the meta-analysis. LCRT significantly increased the pCR rate compared with SCRT [RR=0.49, 95%CI (0.31, 0.78), P=0.003], without heterogeneity was found (I2=0%, p=0.32), so fixed effect model was adopted, (Figure 4A).
Local recurrence rate (LRR)
Only one RCT reported the local recurrence rate. There was no significant difference between SCRT and LCRT arms [RR=4.76, 95%CI (0.66, 34.53), p=0.12], (Figure 4B).
Grade 3~4 acute toxicity
Two RCTs reported the grade 3~4 acute toxicity; total 274 rectal cancer patients were included in the meta-analysis. There was no significant difference between SCRT and LCRT arms [RR=0.60, 95%CI (0.19, 1.88), P=0.38], without obvious heterogeneity was detected (I2=17%, p=0.27), so the fixed effect model was employed, (Figure 4C).
Quality of evidence
There were 6 outcomes in this meta-analysis. Sphincter preservation rate, pCR rate, local recurrence rate and grade 3~4 acute toxicity were critical outcomes; R0 resection rate and downstaging rate were both important outcomes. The quality of the evidence of each outcome was shown in table 2.
This systematic review and meta-analysis manifested that there were no obviously differences in sphincter preservation rate, local recurrence rate, grade 3~4 acute toxicity, R0 resection rate and downstaging rate between two arms. Compared with SCRT plus delayed surgery, LCRT with delayed surgery obviously increased pCR rate [RR=0.49, 95%CI (0.31, 0.78), P=0.003]. Based on the GRADE system, the evidence qualities of pCR rate and R0 resection rate were “moderate”; the evidence qualities of sphincter preservation rate, downstaging rate and grade 3~4 acute toxicity were “low”; local recurrence rate was “very low”. The main reason was risks of bias and imprecision.
Overall completeness and applicability of evidence
Most of rectal cancer patients included in this meta-analysis were clinical stage II~III and without distant metastasis. SCRT with delayed surgery would be a good choice for T3~4 and/or N+ rectal cancer patients. So the results of this meta-analysis could be applicable to the patients with localized and locally advanced rectal cancer patients (stage II~III, without distant metastasis). Based on the major findings of this systematic review, there were no significant differences in most of outcomes between the two interventions. The benefit of the SCRT is more convenient and inexpensive, especially in centers with a long waiting list or lack of medical resources (15). Furthermore, LCRT is better than SCRT at increasing pathologic complete response rate. Therefore, based on the available evidence, choose which kind of treatment strategy largely depends on the clinician’s experience, the patient's clinical features and the public health resources (14, 24, 25).
Only 3 RCTs, total 357 rectal cancer patients, were included in the meta-analysis, so the sample size was too small to detect the possible statistical difference in some outcomes, such as sphincter preservation rate, downstaging rate, local recurrence rate and grade 3~4 acute toxicity, which were with serious or very serious imprecision (19). Take grade 3~4 acute toxicity as example, the statistical power of the meta-analysis was only 0.2881, undoubtedly, it is not enough (26). In addition, there were some potential risks of biases. Firstly, though all included RCTs mentioned "random", only 1 RCT reported the method of adequate randomized sequence generation (10), 1 RCTs was unclear (21), 1 RCT with high risk (22). Secondly, only 1 RCT reported the details about the method of allocation concealment (10), 1 RCT was unclear (21), 1 RCT with high risk (22). So selection biases and attrition biases were inevitable (16).
It should be noted that clinical heterogeneity existed in individual studies. There were some possible sources of clinical heterogeneity. Firstly, though most recruited rectal cancer patients with clinical stage II~III, there was still some stage I and IV patients, and that the proportion of different clinical stage of the patients included in each study was not completely comparable, which might be an important source of heterogeneity. Secondly, the type and dose of the same chemotherapeutics, as well as route of administration in each study, was not comparable, which may introduce heterogeneity. Thirdly, TME was performed in most studies, except the study performed by Bujko et al 2013, in which local excision was adopted (22). Last but not least, duration of follow-up was different in each study. In one word, these limitations might lead to potential biases in the systematic review process. In addition, all included RCTs did not report long-term follow up results, such as overall survival, progression free survival and distant metastases recurrence rate. So we could not objectively and comprehensively evaluation the efficacy of two treatment strategies and further studies were needed to address this issue.
In conclusion, SCRT with delayed surgery is as effective as LCRT with delayed surgery for treatment of rectal cancer in terms of sphincter preservation rate, local recurrence rate, grade 3~4 acute toxicity, R0 resection rate and downstaging rate. LCRT significantly increased pCR rate compared with SCRT. Due to serious risk of bias and imprecision, this conclusion need further multi-center large sample RCTs with longer-term follow up to confirm it.
Table 1. Characteristics of trials included in systematic review
Table 2. GRADE evidence profile
Figure 1. Flow chart of the study selection process
Figure 2. (A) Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies; (B) Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
Figure 3. Meta-analysis of short-course RT plus delayed surgery vs. long-course chemo-RT plus delayed surgery. (A): Meta-analysis results of Sphincter preservation rate; (B): Meta-analysis results of R0 resection rate; (C): Meta-analysis results of downstaging rate.
Figure 4. Meta-analysis of short-course RT plus delayed surgery vs. long-course chemo-RT plus delayed surgery. (A): Meta-analysis results of pCR rate; (B): Meta-analysis results of Local recurrence rate (LRR); (C): Meta-analysis results of Grade 3~4 acute toxicity.