|Year : 2018 | Volume
| Issue : 8 | Page : 224-231
Comparison of short-course with long-course preoperative neoadjuvant therapy for rectal cancer: A meta-analysis
Ke Chen, Guoming Xie, Qi Zhang, Yanping Shen, Taoqi Zhou
Department of Radiochemotherapy, Yinzhou Hospital Affiliated to Medical School of Ningbo University, Ningbo, China
|Date of Web Publication||26-Mar-2018|
Department of Radiochemotherapy, Yinzhou Hospital Affiliated to Medical School of Ningbo University, No. 251, Baizhang East Road, Ningbo 315040
Source of Support: None, Conflict of Interest: None
Aim: This study attempted to compare the prognostic performance of short- and long-course preoperative treatments for neoadjuvant therapy of rectal cancer by meta-analysis.
Methods: Electronic databases of PubMed and Embase were searched for eligible studies updated to February 29, 2016. Studies were included based on several predefined inclusion criteria. Quality assessment was carried out according to the Cochrane Collaboration recommendations in Cochrane handbook. Outcomes such as 1–5 survival rates, death rate, recurrence rate, complication rate, and distant metastasis were evaluated. Odds ratio (OR) with the corresponding 95% confidence interval (CI) was used to calculate the pooled results. Subgroup analysis stratified by radiotherapy (RT) and chemoradiotherapy (CRT) was performed. Publication bias was detected based on Egger's test. Sensitive analysis was also performed.
Results: Eight studies were included, and they were randomized controlled trials or controlled clinical trials. The included studies involved a total of 1475 patients (short treatment: n = 665; long treatment: n = 810). No significant difference was detected in each outcome between the short- and long-course preoperative treatments. Subgroup analysis indicated that the outcome of distant metastasis was significantly higher in long-course RT, compared with the short-course RT (OR = 2.65, 95% CI: 1.05, 6.68). No significant publication bias was observed. Sensitive analysis did not show any reverse result.
Conclusion: Short- and long-course preoperative treatments seem comparable for management of rectal cancer, in terms of outcomes such as survival, recurrence, and complications. However, long-course RT might increase risk of distance metastasis, compared to short-course RT.
Keywords: Long-course preoperative treatment, meta-analysis, rectal cancer, short-course preoperative treatment
|How to cite this article:|
Chen K, Xie G, Zhang Q, Shen Y, Zhou T. Comparison of short-course with long-course preoperative neoadjuvant therapy for rectal cancer: A meta-analysis. J Can Res Ther 2018;14, Suppl S1:224-31
|How to cite this URL:|
Chen K, Xie G, Zhang Q, Shen Y, Zhou T. Comparison of short-course with long-course preoperative neoadjuvant therapy for rectal cancer: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2021 Oct 24];14:224-31. Available from: https://www.cancerjournal.net/text.asp?2018/14/8/224/202231
| > Introduction|| |
Surgery remains the most effective curative treatment against rectal cancer. Substantial evidence suggests that preoperative neoadjuvant therapy followed by surgery can reduce local recurrence rate ,, and improve survival rate ,, in comparison to surgery alone. Preoperative treatments include short-course radiotherapy (RT), short-course chemoradiotherapy (CRT), long-course RT, and long-course CRT. Among them, short-course preoperative RT of 25 Gy in 5 consecutive days and long-course preoperative CRT of 50.4 Gy in 5 weeks and 3 days with concurrent chemotherapy are applied most widely in the past years. The former is well known for its simplicity in manipulation, and the latter is noted for its superiority of local control.
Although there have been many studies comparing short- and long-course preoperative treatments for the management of rectal cancer, most of them are focusing on short-course preoperative RT and long-course preoperative CRT. Thus, we attempted to systematically compare the prognostic performance of short- and long-course preoperative treatments by meta-analysis involving both RT and CRT in each group.
| > Methods|| |
Electronic databases, PubMed and Embase, were searched from their establishment date to February 29, 2016. The key search terms were rectal cancer, short-course, and long-course. The search strategy was “rectal cancer” OR “carcinoma of rectum” OR “rectum cancer” AND “short-course” OR “short course” AND “long-course” AND “humans.”
Inclusion and exclusion criteria
Studies were included when they met with the following criteria: (1) the study had clear boundary of the short- (about 1 week, short group) and long-course (about 4–6 weeks, long group) preoperative treatments (including RT and CRT); (2) the study could provide available data to calculate the outcomes in both short group and long group such as 1-, 2-, 3-, 4-, or 5-year overall survival rate, complication rate, death rate, recurrence rate, and rate of distant metastasis. On the other hand, the following studies were excluded: (1) studies with incomplete or unavailable data for statistical analysis; (2) the studies were reviews, letters, or comments.
Data extraction and quality assessment
The databases were searched by two independent investigators using the criteria aforementioned. Then, data on indispensable information below were collected, such as first author's name, publication time, test site, age and gender composition of the participants, type of study, and number of subjects in the two groups. Disagreement between the two investigators was resolved by discussion with a third investigator. For randomized controlled trials (RCTs), the quality was assessed according to the Cochrane Collaboration recommendations in Cochrane handbook; for nonrandomized studies, the quality was assessed according to the Newcastle–Ottawa Scale.
OR with the corresponding 95% confidence interval (CI) was used to calculate the pooled results. Cochran's Q and I2 tests were used to estimate heterogeneity between studies. A random effects model was used when significant heterogeneity was indicated (P < 0.05 or I2 > 50%), and a fixed effects model was employed when heterogeneity was not significant (P ≥ 0.05, I2 ≤ 50%). Sensitivity analysis was performed by removing one of the included studies at a time and then examining its effect on OR. Publication bias was assessed by the Egger's test. Subgroup analysis stratified by different preoperative treatments, RT and CRT, was implemented to detect their influences on the overall result. R 3.12 software (R Foundation for Statistical Computing, Vienna, Austria) was used for the meta-analysis.
| > Results|| |
Selected studies in this meta-analysis
The detailed study selection process is shown in [Figure 1]. Initially, 241 studies were selected using the key searching terms defined above. After excluding repeated results (n = 28), 213 studies were retained. Next, 180 studies were excluded as they were obviously irrelevant to the topic (n = 147) or did not fulfill the inclusion criteria aforementioned after browsing the titles and abstracts (n = 33). Then, the remaining 33 studies were put through full-text reading, and 25 studies were further eliminated for not providing available data. Finally, eight studies ,,,,,,, were retained and included for the meta-analysis.
Characteristics and quality assessment of the included studies
The eight included studies were RCTs or controlled clinical trials. They were carried out in Poland, Australia, Sweden, etc., during 1998–2010 and were published during 2006–2013 [Table 1]. The included studies involved a total of 1475 patients, including 665 patients in short-course group and 810 patients in long-course group. The preoperative treatments included short-course RT, short-course CRT, long-course RT, and long-course CRT. There were no significant differences in demographic parameters (e.g., age and gender) between patients in the two groups. Based on the tumor, node, and metastasis classification, most of the patients were in the clinical stages from T2 to T4.
Quality evaluation indicated the included RCTs had a relatively high quality because risk of each item was low, especially of “blinding of participants and personnel” and “blinding of outcome assessment” [Figure 2].
|Figure 2: The results of quality assessment of the eligible studies. (a) Risk of bias summary: Judgments about each risk of bias item for each included study. (b) Risk of bias graph: Judgments about each risk of bias item presented as percentages across all included studies|
Click here to view
Comparison of short- and long-course treatments on each outcome
As shown in [Figure 3], there was no significant heterogeneity among the included studies on almost all the survival outcomes [I2 < 50%, P > 0.05, [Figure 3]a, [Figure 3]b, [Figure 3]c and [Figure 3]e except 4-year survival rate [I2 = 82.3%, P= 0.0002, [Figure 3]d. Thus, a fixed effects model was applied to assess 1-, 2-, 3-, and 5-year survival outcomes between two preoperative groups while the 4-year survival rate was assessed under a random effects model.
|Figure 3: Forest plots of comparison between short-term versus long-term treatments on survival outcomes. (a) 1-year overall survival; (b) 2-year overall survival; (c) 3-year overall survival; (d) 4-year overall survival; (e) 5-year overall survival|
Click here to view
Five studies reported 1-year survival rate, and the pooled result showed there was not any significant difference between short- and long-course preoperative treatments [OR = 0.91, 95% CI: 0.52, 1.60, P= 0.75, [Figure 3]a.
Six studies examined 2-year survival rate, and the overall OR was 1.25 [95% CI: 0.86, 1.82, [Figure 3]b, also without a significance (P = 0.25).
Five studies reported 3-year survival rate. Likewise, no significant difference between the two groups was detected [OR = 1.18, 95% CI: 0.84, 1.64, P= 0.34, [Figure 3]c.
Five studies involved 4-year survival rate. Based on the combined result, there was not a significant difference between short and long groups [OR = 1.09, 95% CI: 0.49, 2.41, P= 0.11, [Figure 3]d.
Only three studies assessed 5-year survival rate. Although long group had a higher effect size than short group [OR = 1.14, 95% CI, 0.96, 2.05, [Figure 3]e, the difference was not statistically significant (P = 0.08).
Death rate, recurrence rate, complication, and distant metastases
As no significant heterogeneity was detected on these four outcomes (I2 < 0% or P > 0.05), a fixed effects model was selected for their evaluations.
Four studies reported the death rate between two groups, and the pooled result indicated that there were no significant differences between the two groups [OR = 0.83, 95% CI: 0.58, 1.19, P= 0.32, [Figure 4]a.
|Figure 4: Forest plots of comparison between short-term versus long-term treatments on other outcomes. (a) death rate; (b) recurrence rate; (c) complications; (d) distant metastasis|
Click here to view
Six studies compared the recurrence rate between the two groups. As a result, the effect of short-course preoperative treatment was not significantly different from that of long-course [OR = 0.88, 95% CI: 0.61, 1.27, P= 0.49, [Figure 4]b.
Four studies reported the complication outcome, and the combined result suggested that there was not any significant difference between the two groups [OR = 1.22, 95% CI: 0.94, 1.60, P= 0.14, [Figure 4]c.
Only three studies examined the distant metastases. Based on the pooled result, no significant differences were observed between short and long treatment [OR = 1.10, 95% CI: 0.71, 1.71, P= 0.68, [Figure 4]d.
Further subgroup analysis revealed that there was also no significant difference between the short- and long-course treatments for all the outcomes except distant metastasis. As for distant metastasis, long-course RT had a significantly higher effect size than the short-course RT [OR = 2.65, 95% CI: 1.05, 6.68, [Table 2].
|Table 2: Subgroup analysis of each outcome stratified by radiotherapy and chemoradiotherapy|
Click here to view
Publication bias and sensitive analysis result
No significant publication bias was detected based on Egger's test (P > 0.05), suggesting a stable and reliable result.
Not any reverse result was observed after removing any single study, which also indicated a stable result of the meta-analysis.
| > Discussion|| |
The preoperative adjuvant treatments of rectal cancer include short-course RT, short-course CRT, long-course RT, and long-course CRT, among which the short-course preoperative RT and long-course preoperative CRT have been extensively compared. In the present study, we undertook a meta-analysis to compare the prognostic performance of various short- and long-course preoperative treatments. As a result, we found that there was no significant difference between the short- and long-course preoperative treatments in terms of 1–5 years overall survival rates, complication rate, death rate, recurrence rate, and the rate of distant metastasis; noticeably, subgroup analysis by RT and CRT revealed that long-course RT may increase the risk of distant metastasis as compared to short-course RT.
Many studies support the comparable performance of the two neoadjuvant approaches in terms of postoperative quality-of-life of patients subject to the two treatment approaches., Zhou et al. have compared the efficacy of short-course preoperative RT with long-course preoperative CRT in the treatment of rectal cancer by meta-analysis and demonstrated that there were no significant differences in overall survival, disease-free survival, local recurrence rate, distant metastasis rate, sphincter preservation rate, R0 resection rate, and late toxicity.
However, some studies support the superiority of long-course preoperative CRT. Sabarinath et al. recommended the application of long-course preoperative CRT to locally advanced carcinoma rectum because of its better performance in pathological complete response although this approach was associated with acceptable treatment-related toxicities. Mohiuddin et al. have also presented that long-course neoadjuvant chemoradiation has preferable survival improvements, especially for distal and advanced cancers over short-course preoperative radiation while the latter has clear advantages in patients convenience and cost of treatment. In a recent study, Ngan has systematically compared the trials involving surgery alone, short-course preoperative RT, preoperative CRT, or postoperative CRT, and they finally recommended long-course preoperative CRT for distal or bulky tumors and short-course preoperative RT when convenience has to be taken into consideration first. However, we found that long-course RT may increase the risk for distant metastasis compared to short-course RT. Combining these quotes with our results, it seems that long-course neoadjuvant treatments may have better or comparable survival benefit than short-course neoadjuvant treatment, however, might increase the risk of metastasis. Nevertheless, we still need more studies to confirm this result.
Although we performed a comprehensive analysis involving both RT and CRT to compare the difference between short and long treatment, and most outcomes did not show significant heterogeneity across the studies, there were several limitations should be discussed. Adjustments of several covariates were not taken into consideration in the meta-analysis due to incomplete data in several included studies. In addition, as only eight studies were included in this meta-analysis, subgroup analyses stratified by other confounding factors were not carried out, such as study type, tumor stage, follow-up time, and dosage. These might cause several deviations to some extent. Therefore, more RCTs containing large samples are required to give more precise conclusion.
| > Conclusion|| |
Overall, our study confirmed that short- and long-course preoperative treatments are comparable in terms of outcomes such survival, recurrence, and complication when used for the adjuvant therapy of rectal cancer. In addition, long-course RT might increase risk of distance metastasis in comparison with short-course RT.
The authors would like to express their warmest gratitude to Prof. Senxiang Yan for his instructive suggestions on the writing of this thesis. At the same time, they greatly appreciate their families' support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Påhlman L, Bohe M, Cedermark B, Dahlberg M, Lindmark G, Sjödahl R, et al.
The Swedish rectal cancer registry. Br J Surg 2007;94:1285-92.
Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al
. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-46.
Martling A, Holm T, Johansson H, Rutqvist LE, Cedermark B; Stockholm Colorectal Cancer Study Group. The Stockholm II trial on preoperative radiotherapy in rectal carcinoma: Long-term follow-up of a population-based study. Cancer 2001;92:896-902.
Cedermark B, Johansson H, Rutqvist LE, Wilking N. The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. Cancer 1995;75:2269-75.
Pahlman L, Glimelius B. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997;336:980.
Glimelius B, Grönberg H, Järhult J, Wallgren A, Cavallin-Ståhl E. A systematic overview of radiation therapy effects in rectal cancer. Acta Oncol 2003;42:476-92.
Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: A systematic overview of 8,507 patients from 22 randomised trials. Lancet 2001;358:1291-304.
Ngan SY. Preoperative treatment of locally advanced rectal cancer: Assets and drawbacks of short course and long course in clinical practice. Semin Radiat Oncol 2016;26:186-92.
Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. New Jersey, USA: Wiley Online Library; 2008.
Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997;127:820-6.
Feng RN, Zhao C, Sun CH, Li Y. Meta-analysis of TNF 308 G/A polymorphism and type 2 diabetes mellitus. PLoS One 2011;6:e18480.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
Shin JS, Jalaludin B, Solomon M, Hong A, Lee CS. Histopathological regression grading versus staging of rectal cancer following radiotherapy. Pathology 2011;43:24-30.
Pach R, Kulig J, Richter P, Gach T, Szura M, Kowalska T. Randomized clinical trial on preoperative radiotherapy 25 Gy in rectal cancer – Treatment results at 5-year follow-up. Langenbecks Arch Surg 2012;397:801-7.
Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, et al.
Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-tasman radiation oncology group trial 01.04. J Clin Oncol 2012;30:3827-33.
Krajcovicova I, Bolješíková E, Sandorova M, Zavodska A, Zemanová M, Chorváth M, et al.
Preoperative radiotherapy of locally advanced rectal cancer: Clinical outcome of short-course and long-course treatment with or without concomitant chemotherapy. Klin Onkol 2012;25:364-9.
Eitta MA, El-Wahidi GF, Fouda MA, El-Hak NG, Abo El-Naga EM. Preoperative radiotherapy in resectable rectal cancer: A prospective randomized study of two different approaches. J Egypt Natl Canc Inst 2010;22:155-64.
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006;93:1215-23.
Yeh CH, Chen MF, Lai CH, Huang WS, Lee SP, Chen WC. Comparison of treatment results between surgery alone, preoperative short-course radiotherapy, or long-course concurrent chemoradiotherapy in locally advanced rectal cancer. Int J Clin Oncol 2012;17:482-90.
Pettersson D, Glimelius B, Iversen H, Johansson H, Holm T, Martling A. Impaired postoperative leucocyte counts after preoperative radiotherapy for rectal cancer in the Stockholm III trial. Br J Surg 2013;100:969-75.
Guckenberger M, Saur G, Wehner D, Thalheimer A, Kim M, Germer CT, et al.
Long-term quality-of-life after neoadjuvant short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer. Radiother Oncol 2013;108:326-30.
McLachlan SA, Fisher RJ, Zalcberg J, Solomon M, Burmeister B, Goldstein D, et al.
The impact on health-related quality of life in the first 12 months: A randomised comparison of preoperative short-course radiation versus long-course chemoradiation for T3 rectal cancer (trans-tasman radiation oncology group trial 01.04). Eur J Cancer 2016;55:15-26.
Zhou ZR, Liu SX, Zhang TS, Chen LX, Xia J, Hu ZD, et al.
Short-course preoperative radiotherapy with immediate surgery versus long-course chemoradiation with delayed surgery in the treatment of rectal cancer: A systematic review and meta-analysis. Surg Oncol 2014;23:211-21.
Sabarinath P, Anand A, Jayakumar K, Kuriakose V. 186pneoadjuvant radiotherapy of locally advanced rectal cancer: Short-course radiation vs. long-course chemo radiation. Ann Oncol 2015;26:iX56.
Mohiuddin M, Marks J, Marks G. Management of rectal cancer: Short- vs. long-course preoperative radiation. Int J Radiat Oncol Biol Phys 2008;72:636-43.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]