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Systematic review: adjuvant chemotherapy for locally advanced rectal cancer with respect to stage of disease.

1. Introduction

Colorectal cancer is a major cause of morbidity and mortality throughout the world [1]. It accounts for over 9% of all cancer incidences. It is the third most common cancer worldwide and the fourth most common cause of death [2, 3]. Rectal cancer is defined as disease occurring in the distal 12-15 cm of the large bowel, where the distal two-thirds is extraperitoneal [4]. Surgery is the mainstay treatment of resectable rectal cancer. Total mesorectal excision (TME) is the standard surgical approach to proctectomy for rectal cancer and is associated with reduced local recurrence rate and improved oncologic outcomes [5].

In locally advanced stages of rectal carcinoma, stage II (T3-4, N0, M0) and stage III (any T, N1-2, M0), surgery is often supported by combined modality therapy to further reduce the riskoflocal and distant recurrence [6]. It has been shown that preoperative chemoradiotherapy is associated with reduced local recurrence rate and it is considered as the standard of care for moderate or high-risk resectable rectal cancer [7, 8].

Although adjuvant chemotherapy is recommended for stage III and high-risk stage II colon cancer, uncertainty remains around the benefits of such chemotherapy for patients with stage II and III rectal cancer [7]. The most recent meta-analysis of 21 randomised controlled trials (RCTs), conducted by Cochrane Colorectal Cancer Group, supports the use of 5-fluorouracil (5-FU) based postoperative adjuvant chemotherapy for patients undergoing apparently radical surgery for nonmetastatic rectal carcinoma. In fact, it was reported that adjuvant chemotherapy is associated with reduction in the risk of death and risk of disease recurrence in rectal cancer [6]. However, this study did not provide adequate evidence about outcomes of adjuvant chemotherapy with respect to stage of rectal cancer.

Whether all patients with locally advanced rectal cancer should receive adjuvant chemotherapy is still controversial. Knowledge about outcomes of adjuvant chemotherapy with respect to stage of rectal cancer is required in order to be able to define a subgroup of patients who can potentially benefit from postoperative adjuvant chemotherapy. Therefore, this study aims to review trials investigating adjuvant chemotherapy with respect to stage of disease in patients with locally advanced rectal cancer who had undergone surgery for cure (stage II and stage III).

2. Methods

2.1. Search Strategy. In order to find appropriate articles about adjuvant chemotherapy in rectal cancer, Ovid Medline (1946 to February 2014), PubMed, and the Cochrane library were used as online databases.

In Medline, The keyword "adjuvant chemotherapy" and medical subject headings (MeSH) term "chemotherapy, adjuvant" were combined by OR (search A). Also, keyword "rectal cancer" and MeSH term "rectal neoplasms" were combined by OR (search B). The resulted literatures from search A and search B were combined by AND in order to narrow the results. Then, the resulted search was limited to randomized controlled trial.

In PubMed, search strategy consisted of "adjuvant chemotherapy" and "rectal cancer." Then, the resulted search was limited to randomized controlled trial.

In order to reduce the possibility of missing relevant articles, the reference lists of relevant articles were reviewed.

2.2. Study Selection. The title, abstract, and introduction sections of the obtained literatures were assessed carefully by two independent reviewers (Shahab Hajibandeh and Shahin Hajibandeh) to find relevant articles. Full texts of relevant reports were retrieved and those articles that met the inclusion criteria of the study were selected. Any discrepancies in inclusion were resolved by discussion between the reviewers. If necessary, an independent third reviewer was consulted.

2.3. Inclusion Criteria. Inclusion criteria are as follows:

(i) randomised controlled trials,

(ii) including patients with stage II or/and stage III resectable rectal cancer as population of interest,

(iii) comparing adjuvant chemotherapy with curative surgery alone as interventions of interest,

(iv) investigating overall survival (OS) or/and disease-free survival (DSF) as outcome measures,

(v) reporting survival outcomes stratified to stage II or/ and to stage III rectal cancer.

2.4. Exclusion Criteria. Exclusion criteria are as follows:

(i) previous neoadjuvant cancer therapy (radiotherapy or chemotherapy),

(ii) review articles,

(iii) nonrandomised observational studies,

(iv) case reports,

(v) case series,

(vi) clinical audits,

(vii) ongoing trials,

(viii) authors' replies,

(ix) language other than English.

2.5. Data Extraction. The data from the included articles were extracted on data extraction sheets by two independent reviewers (Shahab Hajibandeh and Shahin Hajibandeh). The extracted data included publication year, sample size, study design, patient characteristics, type of patients, type of intervention, and outcomes. Disagreements were resolved by discussion between the two reviewers. If no agreement could be reached, a third reviewer made the final decision.

2.6. Methodological Quality. The methodological quality of the included articles was assessed by two independent reviewers (Shahab Hajibandeh and Shahin Hajibandeh) using SIGN (Scottish Intercollegiate Guidelines Network) notes on methodology [9, 10] which consists of two sections and classifies each study as high quality, acceptable, or low quality. Disagreements were resolved by discussion between the two reviewers. If no agreement could be reached, a third reviewer made the final decision.

2.7. Statistical Analysis and Data Synthesis. The outcomes in our review (DFS and OS) were dichotomous variables; therefore, the odds ratio (OR), which is the odds of survival in the chemotherapy group compared to surgery only group, was calculated as the summary measure. An OR of less than one would favour the adjuvant chemotherapy. Separate analyses were performed for stage II and stage III rectal cancer. The unit of analysis in our review was the individual patient.

We assessed heterogeneity among the studies using Cochrane chi-squared ([chi square], or [Chi.sup.2]) test and quantified inconsistency by calculating [I.sup.2]. The Review Manager 5.3 was used for data synthesis. We used random effect modelling for analysis and reported the results in a forest plot with 95% confidence intervals (CI).

3. Results

Searches of electronic information sources identified 147 and 191 articles in Medline and PubMed, respectively, of which 8 studies (Glimelius et al. 2005 [11], CCCSGJ 1995 [12], Fisher et al. 1988 [13], Kato et al. 2002 [14], Kodaira et al. 1998 [15], Hamaguchi et al. 2011 [16], QUASAR2007 [17], and Sakamoto et al. 2007 [18]) were found to be eligible for this review (Figure 1 and Table 1).

3.1. Included Population. The included studies enrolled a total number of 11839 colorectal cancer patients of which 5527 patients had stage II or stage III rectal cancer. Forty seven percent of rectal cancer patients had stage II disease and 53% of them had stage III disease. A sum of 2954 (53%) rectal cancer patients received adjuvant chemotherapy and 2573 (47%) patients were treated with surgery alone. None of the included patients had received neoadjuvant chemotherapy or radiotherapy (Table 2).

[FIGURE 1 OMITTED]

3.2. Included Studies. Glimelius et al. 2005 [11] is a 4-arm multicentre RCT which included 2224 patients with stage II or stage III resectable colorectal cancer. The exclusion criteria of this study were another malignancy (except squamous cell carcinoma of the skin and cervical carcinoma stage 0), previous chemotherapy or radiotherapy, severe cardiopulmonary disease, and major laboratory abnormalities. There were 3 intervention arms (A, B, and C) in this study that received postoperative adjuvant chemotherapy. Arm A received 5FU plus levamisole, arm B received 5FU plus leucovorin, and arm C received 5FU plus leucovorin plus levamisole. Patients in control arm were treated with curative surgery only. OS was outcome measure of this study that was analysed by log-rank test.

CCCSGJ 1995 [12] is a 6-arm multicentre RCT which included 2001 patients (997 colon cancer and 1004 rectal cancer) with stage II or stage III resectable colorectal cancer. The exclusion criteria of this study were age over 75, serious complications, history of cancer therapy (surgery, radiotherapy, chemotherapy, etc.), synchronous or metachronous multiple primary carcinomas, and major laboratory abnormalities. There were 3 rectal cancer arms in this study. One of the intervention arms received intraoperative intra-arterial mitomycin C (MMC) and postoperative adjuvant MMC plus 5FU. The other intervention arm received adjuvant MMC plus 5FU. Patients in control arm were treated with curative surgery only. OS and DFS were outcome measures of this study that were analysed by Kaplan-Meier method, log-rank test, and Cox regression model.

Fisher et al. 1988 [13] is a 3-arm multicentre RCT which included 555 patients with stage II or stage III resectable rectal cancer. The exclusion criteria of this study were stage I and stage IV rectal cancer, previous cancer, second primary cancer in the colon and abnormal performance status, and hematologic profile. There were 2 intervention arms in this study. One arm received adjuvant chemotherapy with 5-FU plus semustine plus vincristine and the other arm received adjuvant radiotherapy. Patients in control arm were treated with curative surgery only. OS and DFS were outcome measures of this study.

Kato et al. 2002 [14] is a 2-arm multicentre RCT which included 289 patients with stage II or stage III resectable colorectal cancer. The exclusion criteria of this study were age over 75, anticancer therapy (chemotherapy, radiation therapy, immunotherapy, or a combined modality of these) after the surgery, synchronous or metachronous double cancer, synchronous or metachronous multiple colorectal cancer (except for intramucosal carcinoma), abnormal performance status, and major laboratory abnormalities. Patients in intervention arm received adjuvant chemotherapy with Tegafur-uracil (UFT) and patients in control arm were treated with curative surgery only. OS and DFS were outcome measures of this study that were analysed by Kaplan-Meier method and logrank test.

Kodaira et al. 1998 [15] is a 2-arm multicentre RCT which included 834 patients with stage II or stage III resectable rectal cancer. The exclusion criteria of this study were age over 70, serious complications, other surgical therapies, radiotherapy, chemotherapy or immunotherapy (alone or in combination), synchronous or metachronous multiple primary carcinomas, and major laboratory abnormalities. Patients in intervention arm received adjuvant chemotherapy with MMC plus UFT and patients in control arm were treated with curative surgery only. OS and DFS were outcome measures of this study that were analysed by Kaplan-Meier method and log-rank test.

Hamaguchi et al. 2011 [16] is a 2-arm multicentre RCT which included 276 patients with stage III resectable rectal cancer. The exclusion criteria of this study were age under 20 or above 75, abnormal performance status, and major laboratory abnormalities. Patients in intervention arm received adjuvant chemotherapy with UFT and patients in control arm were treated with curative surgery only. OS and DFS were outcome measures of this study that were analysed by Kaplan-Meier method, log-rank test, and Cox proportional hazards models.

QUASAR 2007 [17] is a 2-arm multicentre RCT which included 3239 patients with stage II or stage III resectable colorectal cancer. The exclusion criteria of this study were distant metastases, definite contraindications to chemotherapy, and prior chemotherapy. Patients in intervention arm received adjuvant chemotherapy with 5-FU plus L-folinic acid and patients in control arm were treated with curative surgery only. OS and DFS were outcome measures of this study that were analysed by log-rank methods.

Sakamoto et al. 2007 [18] is an individual patient meta-analysis that included 2091 patients with resectable rectal cancer from 5 RCTs. In this study, patients in intervention group had received adjuvant chemotherapy with UFT and patients in control group had been treated by curative surgery only. OS and DFS were outcome measures of this study. The main reason for including Sakamoto 2007 was the fact that it provided survival data stratified to rectal cancer stages from 2 RCTs (JFMC15-1, JFMC15-2 [19]) that their original reports did not provide any data stratified to stages of rectal cancer.

3.3. Outcomes

3.3.1. Disease-Free Survival. DFS is defined as time from randomization until recurrence, death without recurrence, or occurrence of a new primary cancer. All the included studies, except Glimelius et al. 2005 [11], reported DFS as outcome measure (Table 3). DFS stratified according to stages II and III rectal cancer has been reported by CCCSGJ 1995 [12], Fisher et al. 1988 [13], Kato et al. 2002 [14], Kodaira et al. 1998 [15], and Sakamoto et al. 2007 [18]. DSF reported by Hamaguchi et al. 2011 [16] was related to stage III only and QUASAR 2007 [17] reported DSF stratified to stage II only.

Stage II Disease. In CCCSGJ 1995 [12], there was statistically significant difference in DFS between chemotherapy groups and surgery only group for stage II rectal cancer (arm 1 versus surgery: 85.4% versus 62.7%, P = significant; arm 2 versus surgery: 78.8% versus 62.7%, P = significant). Fisher et al. 1988 [13] also showed significantly better DFS in chemotherapy group compared to control group (61% versus 39%, P = significant). This was consistent with results from Kato et al. 2002 [14] (87.8% versus 50%, P = significant), QUASAR 2007 [17] (82.9% versus 76.7%, P = significant), and Sakamoto et al. 2007 [18] (77.1% versus 66.4%, P = significant). However, unlike the above studies, Kodaira et al. 1998 [15] did not report statistically significant difference in DFS between chemotherapy and control groups for stage II disease (77.3% versus 67.5%, P = not significant).

Stage III Disease. In CCCSGJ 1995 [12], adjuvant chemotherapy resulted in significantly better DFS only in one of the intervention arms (arm 1 versus surgery: 53.1% versus 39.3%, P = not significant; arm 2 versus surgery: 62.9% versus 39.3% P = significant). The better DFS in chemotherapy group compared to surgery only group was also reported by Fisher et al. 1988 [13] (29% versus 25%, P = significant), Kato et al. 2002 [14] (65% versus 37.1%, P = significant), Kodaira et al. 1998 [15] (54.5% versus 40.7%, P = significant), Hamaguchi et al. 2011 [16] (68.9% versus 56.3%, P = significant), and Sakamoto et al. 2007 [18] (55% versus 46.5%, P = significant).

3.3.2. Overall Survival. OS is defined as time from randomization until death from any cause. All the included studies reported OS as outcome measure (Table 4). Glimelius et al. 2005 [11], CCCSGJ 1995 [12], Fisher et al. 1988 [13], Kodaira et al. 1998 [15], and Sakamoto et al. 2007 [18] reported OS stratified according to stages II and III disease. OS reported by Hamaguchi et al. 2011 [16] was related to stage III only. QUASAR 2007 [17] reported OS related to stage II only. Kato et al. 2002 [14] reported OS stratified to all rectal cancers but not stratified to specific stage.

Stage II Disease. Adjuvant chemotherapy resulted in better OS compared to surgery only for stage II disease in Fisher et al. 1988 [13] (80% versus 57%, P = significant), QUASAR 2007 [17] (80.9% versus 76.7%, P = significant), Sakamoto et al. 2007 [18] (82.4% versus 76.8%, P = significant), and one of the intervention arms in CCCSGJ 1995 [12] (arm 1 versus surgery: 82.2% versus 68.1%, P = significant; arm 2 versus surgery: 81.1% versus 68.1% P = not significant). However, there was no statistically significant difference in OS between two groups in Glimelius et al. 2005 [11] (81% versus 73%, P = not significant) and Kodaira et al. 1998 [15] (80.4% versus 75.9%, P = not significant).

Stage III Disease. There was statistically significant difference in OS between chemotherapy and surgery only groups for stage III disease in Hamaguchi et al. 2011 [16] (85.3% versus 72.1%, P = significant), Sakamoto et al. 2007 [18] (64.1% versus 59.2%, P = significant), and one of the intervention arms in CCCSGJ 1995 [12](arm 1 versus surgery: 54.7%versus 43.1%, P = not significant; arm 2 versus surgery: 62.3% versus 43.1% P = significant). Unlike the above studies, there was no statistically significant difference in OS between two groups in Fisher et al. 1988 [13] (37% versus 35%, P = not significant), Glimelius et al. 2005 [11](48% versus 51%, P = not significant), and Kodaira et al. 1998 [15] (53.4% versus 49.1%, P = not significant).

3.4. Methodological Quality and Risk of Bias. Based on SIGN notes on methodology checklist, the included studies had high methodological quality. In all the included RCTs, an appropriate and clearly focused question was addressed, the assignment of subjects to treatment groups was randomised, an adequate concealment method was used, the treatment and control groups were similar at the start of the trial, the only difference between groups was the treatment under investigation, and all relevant outcomes were measured in a standard, valid, and reliable way.

In terms of risk of bias, Glimelius et al. 2005 [11], CCCSGJ 1995 [12], Fisher et al. 1988 [13], Kato et al. 2002 [14], Kodaira et al. 1998 [15], Hamaguchi et al. 2011 [16], and QUASAR 2007 [17] were associated with low risk of reporting and selection bias. Because of nature of study, Sakamoto et al. 2007 [18] were associated with high risk of reporting bias but low risk of any other bias.

3.5. Odds Ratio Analysis and Outcome Synthesis

3.5.1. Stage II Disease

Disease-Free Survival. DFS was reported in 2366 patients. Odds ratio analysis showed that patients receiving adjuvant chemotherapy had better DFS than patients treated by surgery alone [OR = 0.51 (95% CI 0.39-0.67), P < 0.00001]. Moderate heterogeneity among the studies existed ([I.sup.2] = 44%, P = 0.11).

Overall Survival. OS was reported in 2637 patients. Odds ratio analysis showed that patients receiving adjuvant chemotherapy had better DFS than patients treated by surgery alone [OR = 0.64, (95% CI 0.51-0.80), P < 0.0001]. Low heterogeneity among the studies existed ([I.sup.2] = 24%, P = 0.25).

3.5.2. Stage III Disease

Disease-Free Survival. DFS was reported in 2470 patients. Odds ratio analysis showed that patients receiving adjuvant chemotherapy had better DFS than patients treated by surgery alone [OR = 0.61 (0.51-0.73), P < 0.00001]. Low heterogeneity among the studies existed ([I.sup.2] = 12%, P = 0.34).

Overall Survival. OS was reported in 2761 patients. Odds ratio analysis showed that patients receiving adjuvant chemotherapy had better DFS than patients treated by surgery alone [OR = 0.76 (0.61-0.96), P < 0.02]. Moderate heterogeneity among the studies existed ([I.sup.2] = 47%, P = 0.09).

Results of synthesis of the outcome parameters are depicted in Figure 2.

4. Discussion

Adjuvant chemotherapy is standard of care for stage III and high-risk stage II colon cancer [7]. It has been shown that 5FU based adjuvant chemotherapy can be beneficial in locally advanced rectal cancer as well [6]. However, which group of patients with locally advanced rectal cancer can benefit from adjuvant chemotherapy still remains a question.

In this review, our pooled analysis of data from seven RCTs and one individual patient meta-analysis, enrolling total number of 5527 patients, found that adjuvant chemotherapy is associated with better DFS and OS in both stage II and stage III rectal cancers. There was low to moderate heterogeneity among the studies in our analysis that can be partly explained by different chemotherapy regimens and some differences in baseline characteristics of the included studies. There was not considerable inconsistency in the direction of effect by adjuvant chemotherapy among the included studies. We used a random-effects meta-analysis to incorporate heterogeneity that cannot be explained although this is not a substitute for a thorough investigation of heterogeneity. Nevertheless, we do not believe that our results have been affected by between-study heterogeneity significantly.

Our analysis showed that for stage III rectal cancer improvement in DFS was more considerable than improvement in OS. This may be explained by the fact that marginally significant DFS advantages may not translate into OS benefit [20]. Considering that DFS is more appropriate end point than OS in stage III disease, demonstration of a clinically meaningful improvement in DFS may be adequate evidence of clinical benefit [21]. Moreover, improved survival after adjuvant chemotherapy in patients with stage III rectal cancer has been reported by prospective cohort studies [22, 23].

The included population in our analysis did not receive preoperative treatment with chemoradiation which has recently become the standard of care in patients with stages II and III rectal cancer in Europe and in the USA. However, although preoperative chemoradiotherapy inhibits local recurrence and reduces toxicity, it does not improve OS compared with postoperative chemoradiotherapy [24]. This highlights the importance of knowledge about effect of adjuvant chemotherapy on survival in rectal cancer patients despite common practice in western countries. Postoperative adjuvant chemotherapy for stages II and III rectal cancer has been recommended by National Institutes of Health (NIH) consensus conference [25] and our findings support this recommendation.

Despite a comprehensive literature search, we identified only 8 studies that provided data separately for stages II and III rectal cancer. However, considering the proven benefits of neoadjuvant chemoradiotherapy in preventing local recurrence of disease, it is unlikely to identify further studies with rectal cancer patients without preoperative chemoradiotherapy at least in western countries.

In our review, the included studies used conventional chemotherapy agents such as UFT and 5FU and none of them used modern chemotherapy agents such as oxaliplatin, irinotecan, or bevacizumab which can significantly improve the therapeutic efficacy of conventional chemotherapy [26] and improve survival [27]. Therefore, the effect of adjuvant chemotherapy on survival outcomes may be greater with modern agents.

Our review has some limitations. The included population in our review did not receive preoperative chemoradiotherapy which is currently the standard treatment for rectal cancer; therefore, the benefits of adjuvant chemotherapy for patients who already had neoadjuvant chemoradiation still remain unknown. The chemotherapy regimens used in the included studies were heterogeneous although all of them were 5FU based. Moreover, due to unavailability of original stratified data from two RCTs, one individual patient data meta-analysis, which contained relevant data, was included. Although it was a high quality study, it was inevitably associated with reporting bias. Some of the included studies were not specifically designed for stage II or stage III rectal cancers and they included patients with colon cancer as well; therefore, their stratified data were used for analysis. All of these may affect robustness of the results of our review and can subject it to bias.

5. Conclusions and Future Directions

Our study indicates that both stage II and stage III rectal cancer patients may benefit from postoperative adjuvant chemotherapy. It is associated with statistically significant improvement in disease-free survival and overall survival compared to surgery alone in both stage II and stage III cancer. There was no significant heterogeneity between the included studies in terms of eligibility criteria, outcomes, and design. This can potentially make the conclusion of our study reliable.

Considering heterogeneity between included studies in terms of chemotherapy agents and regimens, further RCTs are required to compare different chemotherapy agents and regimens in stage II and stage III rectal cancer. The future randomised trials should focus on effect of modern chemotherapy agents as adjuvant therapy in stage II and stage III rectal cancer patients who have already received neoadjuvant treatments. Moreover, future trials should include patients specifically with stage II and stage III rectal cancer to provide further evidence about benefits of adjuvant chemotherapy in these subgroups.

http://dx.doi.org/10.1155/2015/710569

Conflict of Interests

The authors declare no conflict of interests and no financial disclosures.

Authors' Contribution

Shahab Hajibandeh and Shahin Hajibandeh have equally contributed to this paper and joint first authorship is proposed.

References

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Shahab Hajibandeh (1) and Shahin Hajibandeh (2)

(1) General Surgery Department, Pilgrim Hospital, Sibsey Road, Boston, Lincolnshire PE21 9QS, UK

(2) General Surgery Department, Blackpool Victoria Hospital, 38 Whinney Heys Road, Blackpool, Lancashire FY3 8NR, UK

Correspondence should be addressed to Shahab Hajibandeh; shahab_hajibandeh@yahoo.com

Received 24 July 2014; Revised 12 January 2015; Accepted 15 January 2015

Academic Editor: Mustafa Benekli
Table 1: Main characteristics of included studies.

                       Glimelius et        CCCSGJ 1995
                       al. 2005 [11]           [12]

Study design            Multicentre        Multicentre
                            RCT                RCT

Number of                  2224                2001
patients

Stage of                II and III          II and III
rectal cancer

Intervention              Surgery             Arm I:
arm(s)                  adjuvant CT          surgery
                                             adjuvant
                                          intra-arterial
                                          + systemic CT
                                              arm 2:
                                             surgery
                                           adjuvant CT

Control arm               Surgery            Surgery

Chemotherapy              Arm 1:              Arm 1:
regimen                    5FU +            MMC + 5FU
                        levamisole       arm 2: MMC + 5FU
                          arm 2:
                           5FU +
                     leucovorin arm 3:
                           5FU +
                       leucovorin +
                        levamisole

Intention to                Yes                Not
treat analysis                               reported

Outcomes                    OS              DSF and OS

Risk of bias                Low                Low

Methodological             High                High
quality *

                     Fisher et al.   Kato et al.    Kodaira et al.
                       1988 [13]      2002 [14]        1998 [15]

Study design          Multicentre    Multicentre      Multicentre
                          RCT            RCT              RCT

Number of                 555            289              834
patients

Stage of              II and III      II and III      II and III
rectal cancer

Intervention            Arm I:         Surgery          Surgery
arm(s)                  surgery      adjuvant CT      adjuvant CT
                      adjuvant CT
                        arm 2:
                        surgery
                      adjuvant RD

Control arm             Surgery        Surgery          Surgery

Chemotherapy            5-FU +           UFT             MMC +
regimen              semustine +                          UFT
                      vincristine

Intention to              Not            Not              Not
treat analysis         reported        reported        reported

Outcomes              DSF and OS      DSF and OS      DSF and OS

Risk of bias              Low            Low              Low

Methodological           High            High            High
quality *

                     Hamaguchi et al.       QUASAR
                         2011 [16]        2007 [17]

Study design            Multicentre      Multicentre
                            RCT              RCT

Number of                   606              3239
patients

Stage of                    III           II and III
rectal cancer

Intervention              Surgery          Surgery
arm(s)                  adjuvant CT      adjuvant CT

Control arm               Surgery          Surgery

Chemotherapy                UFT           5-FU + L-
regimen                                  folinic acid

Intention to                Not              Yes
treat analysis           reported

Outcomes                DSF and OS        DSF and OS

Risk of bias                Low              Low

Methodological             High              High
quality *

                      Sakamoto et
                     al. 2007 [18]

Study design         Patient based
                     meta-analysis
                     of multicentre
                          RCTs
Number of                 2091
patients

Stage of               II and III
rectal cancer

Intervention            Surgery
arm(s)                adjuvant CT

Control arm             Surgery

Chemotherapy              UFT
regimen

Intention to              Not
treat analysis          reported

Outcomes               DSF and OS

Risk of bias              Low
                        (except
                       reporting
                         bias)

Methodological            High
quality *

CT: chemotherapy, RCT: randomised controlled trial, RD:
radiotherapy, 5-FU: 5-fluorouracil, MMC: mitomycin C, UFT:
Tegafur-uracil, OS: overall survival, and DSF: disease-free
survival, * based on SIGN notes on methodology checklist.

Table 2: Baseline characteristics of rectal cancer
patients in included studies.

                            Number of
                             patients
                   Total   Chemotherapy   Control
                               (%)          (%)

Glimelius et                   339          352
al. 2005 [11]                  (49)        (51)

CCCSGJ 1995                    516          245
[12]               761         (68)        (32)

Fisher et al.      371         187          184
1988 [13]                      (50)        (50)

Kato et al.        129          66          63
2002 [14]                      (51)        (49)

Kodaira et al.     670         331          339
1998 [15]                      (49)        (51)

Hamaguchi                      139          135
et al. 2011 [16]   274         (51)        (49)

QUASAR                         410          407
2007 [17]          817         (50)        (50)

Sakamoto et        1814        966          848
al. 2007 [18]                  (53)        (47)

Total              5527        2954        2573
                               (53)        (47)

                                          Stage II rectal cancer
                                  Male
                       Age         (%)    Chemotherapy   Control
                                              (%)          (%)

Glimelius et       64 versus 66    NR         160          163
al. 2005 [11]                                 (23)        (24)

CCCSGJ 1995        57 versus 60    NR         229          120
[12]                                          (30)        (16)

Fisher et al.      61 versus 61    240         72          67
1988 [13]                         (64)        (19)        (18)

Kato et al.        60.2 versus     NR          26          26
2002 [14]              61.4                   (20)        (20)

Kodaira et al.          NR         NR         154          162
1998 [15]                                     (23)        (25)

Hamaguchi          59 versus 58    165
et al. 2011 [16]                  (60)         NR          NR

QUASAR                                        410          407
2007 [17]               NK         NK         (50)        (50)

Sakamoto et             NR         NR         377          316
al. 2007 [18]                                 (21)        (17)

Total                   --         --         1428        1261
                                              (26)        (23)

                   Stage III rectal cancer

                   Chemotherapy   Control
                       (%)          (%)

Glimelius et           179          189
al. 2005 [11]          (26)        (27)

CCCSGJ 1995            287          125
[12]                   (38)        (16)

Fisher et al.          115          117
1988 [13]              (31)        (32)

Kato et al.             40          37
2002 [14]              (31)        (29)

Kodaira et al.         177          177
1998 [15]              (26)        (26)

Hamaguchi              139          135
et al. 2011 [16]       (51)        (49)

QUASAR
2007 [17]               NK          NK

Sakamoto et            589          532
al. 2007 [18]          (33)        (29)

Total                  1526        1312
                       (27)        (24)

                       Previous treatment

                   Chemotherapy   Radiotherapy

Glimelius et
al. 2005 [11]

CCCSGJ 1995
[12]                    No             No

Fisher et al.           No             No
1988 [13]

Kato et al.             No             No
2002 [14]

Kodaira et al.          No             No
1998 [15]

Hamaguchi
et al. 2011 [16]        No             No

QUASAR
2007 [17]               No             No

Sakamoto et             No             No
al. 2007 [18]

Total                   --             --

Table 3: Disease-free survival reported by included studies.

                                      Stage II

Study              Control         Intervention

CCCSGJ              62.7%        Arm 1      Arm 2
1995 [12]                        85.4%      78.8%
                                 P = S      P = S

Fisher et            39%                61%
al. 1988 [13]

Kato et             50.0%               87.8%
al. 2002 [14]

Kodaira et al.      67.5%               77.3%
1998 [15]

Hamaguchi et     Not Reported           Not Reported
al. 2011 [16]

QUASAR              76.7%               82.9%
2007 [17]

Sakamoto et         66.4%               77.1%
al. 2007 [18]

                             DFS

                 Statistical
Study            significance     Control

CCCSGJ
1995 [12]                          39.3%

Fisher et             S             25%
al. 1988 [13]

Kato et               S            37.1%
al. 2002 [14]

Kodaira et al.        NS           40.7%
1998 [15]

Hamaguchi et                       56.3%
al. 2011 [16]

QUASAR                S         Not Reported
2007 [17]

Sakamoto et           S            46.5%
al. 2007 [18]

                     Stage III         Statistical
Study              Intervention        significance

CCCSGJ            Arm 1      Arm 2
1995 [12]         53.1%      62.9%
                  P = NS     P = S

Fisher et                29%                S
al. 1988 [13]

Kato et                  65.0%              S
al. 2002 [14]

Kodaira et al.           54.5%              S
1998 [15]

Hamaguchi et             68.9%              S
al. 2011 [16]

QUASAR                   Not Reported
2007 [17]

Sakamoto et              55.0%              S
al. 2007 [18]

DFS: disease-free survival, S: significant, and
NS: not significant.

Table 4: Overall survival reported by included studies.

                                       OS

                                    Stage II
Study                Control      Intervention

Glimelius et           73%            81%
al. 2005 [11]
                                     Arm 1       Arm 2
CCCSGJ 1995 [12]      68.1%          82.2%       81.1%
                                     P = S       P = NS

Fisher et al.          57%            80%
1988 [13]

Kodaira et al.        75.9%          80.4%
1998 [15]

Hamaguchi et       Not Reported   Not Reported
al. 2011 [16]

QUASAR 2007 [17]      76.7%          80.9%

Sakamoto et           76.8%          82.4%
al. 2007 [18]

                                       OS
                                                       Stage III
                   Statistical
Study              significance     Control           Intervention

Glimelius et            NS            51%            48%
al. 2005 [11]
                                                    Arm 1       Arm 2
CCCSGJ 1995 [12]                     43.1%          54.7%       62.3%
                                                    P = NS      P = S

Fisher et al.           S             35%            37%
1988 [13]

Kodaira et al.          NS           49.1%          53.4%
1998 [15]

Hamaguchi et                         72.1%          85.3%
al. 2011 [16]

QUASAR 2007 [17]        S         Not Reported   Not Reported

Sakamoto et             S            59.2%          64.1%
al. 2007 [18]

                   Statistical
Study              significance

Glimelius et            NS
al. 2005 [11]

CCCSGJ 1995 [12]

Fisher et al.           NS
1988 [13]

Kodaira et al.          NS
1998 [15]

Hamaguchi et            S
al. 2011 [16]

QUASAR 2007 [17]

Sakamoto et             S
al. 2007 [18]

OS: overall survival, S: significant, and NS: not significant.

Figure 2: Forest plots of comparison of (a) stage II DFS,
(b) stage II OS, (c) stage III DFS, and (d) stage III OS.
The solid squares denote the odds ratios (ORs), the
horizontal lines represent the 95% confidence intervals
(CIs), and the diamond denotes the pooled OR. M-H, Mantel
Haenszel test.

(a)

                             Adjuvant       Surgery only
                           chemotherapy

Study or subgroup        Events   Total   Events   Total   Weight

CCCSGJ 1995                41      229      45      120    17.3%
Fisher et al. 1988         28      72       41      67     11.6%
Kato et al. 2002           3       26       13      26      3.4%
Kodaira et al. 1998        35      154      53      162    17.4%
QUASAR 2007                70      410      95      407    24.8%
Sakamoto et al. 2007       86      377     106      316    25.4%
Total (95% CI)                    1268             1098    100.0%
Total events              263              353

                         Odds ratio

Study or subgroup        M-H, random, 95% CI

CCCSGJ 1995              0.36 [0.22, 0.60]
Fisher et al. 1988       0.40 [0.20, 0.80]
Kato et al. 2002         0.13 [0.03, 0.54]
Kodaira et al. 1998      0.60 [0.37, 1.00]
QUASAR 2007              0.68 [0.48, 0.95]
Sakamoto et al. 2007     0.59 [0.42, 0.82]
Total (95% CI)           0.51 [0.39, 0.67]
Total events

Heterogeneity: [[tau].sup.2] = 0.05; [chi square] = 8.96,
df = 5 (P = 0.11); [I.sup.2] = 44% Test for overall effect:
Z = 4.78 (P < 0.00001)

(b)

                             Adjuvant       Surgery only
                           chemotherapy

Study or subgroup        Events   Total   Events   Total   Weight

CCCSGJ 1995                43      229      39      120    14.9%
Fisher et al. 1988         14      72       29      67      7.6%
Glimelius et al. 2005      30      160      44      163    14.0%
Kodaira et al. 1998        30      154      39      162    13.6%
QUASAR 2007                79      410      95      407    26.6%
Sakamoto et al. 2007       66      377      73      316    23.3%
Total (95% CI)                    1402             1235   100.0%
Total events              262              319

                         Odds ratio
Study or subgroup        M-H, random, 95% CI

CCCSGJ 1995              0.48 [0.29, 0.80]
Fisher et al. 1988       0.32 [0.15, 0.67]
Glimelius et al. 2005    0.62 [0.37, 1.06]
Kodaira et al. 1998      0.76 [0.45, 1.31]
QUASAR 2007              0.78 [0.56, 1.10]
Sakamoto et al. 2007     0.71 [0.49, 1.03]
Total (95% CI)           0.64 [0.51, 0.80]
Total events

Heterogeneity: [[tau].sup.2] = 0.02; [chi square] = 6.59,
df = 5 (P = 0.25); [I.sup.2] = 24%
Test for overall effect: Z = 3.95 (P < 0.0001)

(c)

                             Adjuvant
                            chemotherapy    Surgery only
Study or
subgroup                 Events   Total   Events   Total   Weight

CCCSGJ 1995              121      287     76       125     16.1%
Fisher et al. 1988       82       115     88       117     9.3%
Hamaguchi et al. 2011    43       139     59       135     12.5%
Kato et al. 2002         14       40      23       37      3.8%
Kodaira et al. 1998      80       177     105      177     16.6%
Sakamoto et al. 2007     263      589     284      532     41.6%

Total (95% CI)                    1347             1123   100.0%
Total events             603              635

                         Odds ratio
Study or
subgroup                 M-H, random, 95% CI

CCCSGJ 1995              0.47 [0.31, 0.72]
Fisher et al. 1988       0.82 [0.46, 1.47]
Hamaguchi et al. 2011    0.58 [0.35, 0.95]
Kato et al. 2002         0.33 [0.13, 0.83]
Kodaira et al. 1998      0.57 [0.37, 0.86]
Sakamoto et al. 2007     0.70 [0.56, 0.89]

Total (95% CI)           0.61 [0.51, 0.73]
Total events

Heterogeneity: [[tau].sup.2] = 0.01; [chi square] = 5.68,
df = 5 (P = 0.34); [I.sup.2] = 12%
Test for overall effect: Z = 5.24 (P < 0.00001)

(d)

                         Adjuvant         Surgery only
                         chemotherapy

Study or subgroup        Events   Total   Events   Total   Weight

CCCSGJ 1995                119     287       71     125    16.5%
Fisher et al. 1988          72     115       76     117    12.4%
Glimelius et al. 2005       93     179       93     189    17.2%
Hamaguchi et al. 2011       21     139       38     135    10.7%
Kodaira et al. 1998         83     177       90     177    16.8%
Sakamoto et al. 2007       213     589      222     532    26.3%
Total (95% CI)                    1486             1275   100.0%
Total events               601              590

                         Odds ratio

Study or subgroup        M-H, random, 95% CI

CCCSGJ 1995              0.54 [0.35, 0.82]
Fisher et al. 1988       0.90 [0.53, 1.54]
Glimelius et al. 2005    1.12 [0.74, 1.68]
Hamaguchi et al. 2011    0.45 [0.25, 0.83]
Kodaira et al. 1998      0.85 [0.56, 1.30]
Sakamoto et al. 2007     0.79 [0.62, 1.01]
Total (95% CI)           0.76 [0.61, 0.96]
Total events

Heterogeneity: [[tau].sup.2] = 0.04; [chi square] = 9.50,
df = 5 (P = 0.09); [I.sup.2] = 47%
Test for overall effect: Z = 2.27 (P = 0.02)
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Author:Hajibandeh, Shahab; Hajibandeh, Shahin
Publication:International Scholarly Research Notices
Article Type:Clinical report
Date:Jan 1, 2015
Words:6750
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