Review Article Effect of Neoadjuvant Chemoradiotherapy with Capecitabine versus ...downloads.hindawi.com/journals/grp/2016/1798285.pdf · 2019. 7. 30. · Review Article Effect of

Review ArticleEffect of Neoadjuvant Chemoradiotherapy withCapecitabine versus Fluorouracil for Locally AdvancedRectal Cancer: A Meta-Analysis

Guo-Chen Liu,1 Jun-Ping Yan,2 Qing He,3 Xin An,4 Zhi-Zhong Pan,5 and Pei-Rong Ding5

1Department of Gynecologic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine, Guangdong 510060, China2Department of Laboratory Medicine, Guangdong No. 2 Provincial People’s Hospital, Guangdong, China3Department of General Surgery, People’s Hospital of Yuxi City, Yunnan, China4Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China,Guangdong, China5Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China,Guangdong 510060, China

Correspondence should be addressed to Zhi-Zhong Pan; [email protected] and Pei-Rong Ding; [email protected]

Received 2 April 2016; Accepted 30 June 2016

Academic Editor: Carlos Fernandez-Martos

Copyright © 2016 Guo-Chen Liu et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A meta-analysis was carried out to compare the efficacy and safety of capecitabine plus radiation with 5-fluorouracil (5-FU) plusradiotherapy (RT) as neoadjuvant treatment in locally advanced rectal cancer (LARC). We searched the Cochrane database, Ovid,Medline, Embase, ISI databases, and Chinese Biomedical Literature Database between January 1998 and October 2014. Trials ofcapecitabine compared with 5-FU plus RT as neoadjuvant treatment for LARC were considered for inclusion. RevMan softwarewas used to analyze these data. Nine trials were included in this meta-analysis, which covered a total of 3141 patients. The meta-analysis showed that capecitabine group had statistically significant better pCR rates (OR, 1.34; 95% CI, 1.10–1.64; 𝑃 = 0.003), Tdownstaging rates (OR, 1.58; 95% CI, 1.22–2.06; 𝑃 = 0.0007), N downstaging rates (OR, 2.06; 95% CI, 1.34–3.16; 𝑃 = 0.001), lessdistant metastasis (OR, 0.63; 95% CI, 0.44–0.88; 𝑃 = 0.007), and lowered leucocytes (OR, 0.25; 95% CI, 0.11–0.54; 𝑃 = 0.0005), butwith higher incidence of hand-foot syndrome (HFS) (OR, 4.43; 95%CI, 1.59–12.33;𝑃 = 0.004). Capecitabine wasmore efficient than5-FU in terms of tumor response in neoadjuvant treatment for patients with LARC and favourably low toxicity with the exceptionof HFS.

1. Introduction

Neoadjuvant chemoradiotherapy with fluoropyrimidine isthe standard treatment for locally advanced rectal cancer(LARC), as supported by results of the randomized phaseIII study conducted by the German Rectal Cancer StudyGroup [1]. 5-FU combined with leucovorin (LV) is the mostcommonly administered concurrent chemotherapy. Modi-fications of perioperative fluorouracil treatment have beeninvestigated in many Phase II and Phase III trials in anattempt to improve overall survival and disease-free survivalrate. Compared to bolus 5-FU and pelvic radiotherapy (RT),patients who received concurrent RT with protracted 5-FU

infusion had an improved period of time to relapse and post-operative survival in both preoperative [2–4] and postopera-tive chemoradiotherapy [5, 6].Therefore, protracted infusion5-FU is accepted as the standard regimen for concurrentchemoradiotherapy for rectal cancer at many institutions.However, protracted 5-FU infusion requires an indwellingvenous catheter, which is associated with increased compli-cations (infection, bleeding, thrombosis, and pneumothorax)[7] and patients’ discomfort.

Capecitabine, an orally administered fluoropyrimidine,was shown to have antitumor activity in metastatic colorectalcancer, and it is also more convenient to use [8]. In severalrandomized trials, capecitabine had been shown to be at least

Hindawi Publishing CorporationGastroenterology Research and PracticeVolume 2016, Article ID 1798285, 10 pageshttp://dx.doi.org/10.1155/2016/1798285

2 Gastroenterology Research and Practice

equivalent in efficacy to 5-FU in metastatic colorectal cancer(mCRC) [9, 10]. Capecitabine is preferentially convertedto 5-FU in tumor tissue through a three-step enzymaticpathway with the participation of thymidine phosphorylase.X-ray irradiation was found to induce the synthesis ofthymidine phosphorylase, providing a rationale that theusage of capecitabine combined with RT might be associatedwith an improved therapeutic index in patients with cancer[11].

Up to now, only two randomized trials [12, 13] and severalretrospective studies [14–20] had compared capecitabineversus 5-FU/LV in neoadjuvant chemoradiotherapy regimensfor patients with LARC; however, in terms of pathologiccomplete response (pCR) rate and toxicities, the results ofthese studies were not consistent. Therefore, we carried outa meta-analysis to determine the difference in efficacies andtoxicities of these two regimens when used as treatmentcombination with RT in patients with LARC.

2. Methods

2.1. Literature Search. The Cochrane database, Ovid, Med-line, Embase, ISI databases, and Chinese Biomedical Litera-tureDatabasewere searched from January 1998 up toOctober2008. The following Mesh search headings were used: “rectalneoplasms”, “neo-adjuvant therapy”, “chemoradiotherapy”,“capecitabine”, and “fluorouracil”. All relevant OncologyMeetings Proceedings (ASCO, AACR, and ASCO GI) andbibliographies of references and reviews were also identified.Furthermore, we searched the reference lists of retrievedrelevant articles in order to broaden the scope, and allabstracts, studies, and citations scanned were reviewed too.There were no language restrictions.

2.2. Inclusion and Exclusion Criteria. Trials meetings whichhave the following two criteria were included: (1) comparedcapecitabine to 5-FU (with or without LV) as neoadjuvanttreatment for LARC and (2) illustrated at least one of theoutcome measures: tumor response rate, sphincter preser-vation rate, or adverse effects of treatment/toxicity. Whentwo studies were reported by the same institution, either theone with better quality or the most recent publication wasincluded in this analysis.

Studies were excluded from the analysis if the outcomesof interest were not reported or it was impossible to calculatethese from the published results.

2.3. Data Extraction. Two researchers assessed all abstractsidentified by the above search strategies for subject relevance,respectively. The full publications of all possibly relevantabstracts were obtained and formally assessed for inclu-sion. Two reviewers independently extracted the followinginformation from each included study: first author, yearof publication, characteristics of study population, studydesign, pathological response to chemoradiation, sphincterpreservation, and adverse effects. Adverse effects of treat-ment/toxicities (grade 3 or 4) datawere collected according toNational Cancer Institute Common Toxicity Criteria (NCI-CTC v4.0).

2.4. Statistical Methods. Statistical analyses were carried outusing Review Manager Version 5.0 software (Nordic Co-chrane Centre, Copenhagen, Denmark). We calculated theodds ratio (OR) for dichotomous data with 95% confidenceintervals (CIs) for all analyses. Two techniques were usedto calculate the pooled OR estimates: the Mantel-Haenszelmethod [21], which assumes a fixed-effects model, and theDerSimonian-Laird method [22], which assumes a random-effects model. If there was no heterogeneity, the fixed-and the random-effects models provided similar results,and we chose fixed-effects model. When heterogeneity wasfound, the random-effects model was considered to be moreappropriate, although both models might be biased. Anestimation of disease-free survival based on Kaplan-Meierplots was performed by DigitizeIt software 2.06 (Bormann,[email protected]).

Statistical heterogeneity between studies was assessed bythe chi-squared test with significance set at a 𝑃 value of 0.10and the quantity of heterogeneity measured using the 𝐼2statistic. Negative values of 𝐼2 were put equal to zero, so that𝐼2 lay between 0% and 100%. A value of 0% indicates noobserved heterogeneity, and larger values show increasingheterogeneity. Publication bias was assessed by use of a funnelplot [23].

3. Results

3.1. Description of Studies. Figure 1 showed the process usedto select potentially relevant studies for inclusion; 114 recordswere identified by the primary computerized literaturesearch. However, after screening the titles and abstracts, weexcluded 95 studies which were either case series, reviewarticles (𝑛 = 40), or irrelevant to the current study (𝑛 = 55).The full texts of the retrieved 19 manuscripts were clearlyread, and the reference lists were checked. After excluding 4articles including other regimens and 6 studies which did notinclude both 5-FU and capecitabine simultaneously, finally,we included the remaining 9 trials in the meta-analysis [12–20], having covered a total of 3141 patients. Among thesepatients, 1541 pts were found to be treated with capecitabineand 1600 pts with 5-FU as neoadjuvant chemotherapy regi-men. It should be noted that one trial [13] alone out of the9 trials contributed almost one-half of the patients includedin the present meta-analysis. The characteristics of the ninestudies included in this paper were shown in Table 1, twoof them were prospective studies [12, 13] with a combinedtotal of 2000 subjects, and 7 were retrospective studies whichcovered a total of 1141 patients [14–20].

It should be noted that the NSABP-R-04 protocol [13]was a two-step study, (1) from September 2004 to October2005, 293 patients were randomly assigned in the two-armportion of the study (capecitabine versus 5-FU) and (2) fromOctober 2005 to August 2010, additional 1315 patients wererandomly assigned into four-arm study: 330 patients to RTplus 5-FU, 329 patients to RT plus 5-FU and oxaliplatin,326 patients to RT plus capecitabine, and 330 patients toRT plus capecitabine and oxaliplatin. The author did notmention the pCR rates of patients received capecitabine/5-FU monotherapy plus RT. However, in this protocol, there

Gastroenterology Research and Practice 3

Table1:Ch

aracteris

ticso

fthe

nine

studies

inclu

dedin

thispaper.

Trials

Year

Type

ofstu

dyNum

ber

ofpts

Num

bero

fpts

Doseo

fmedicine

Doseo

fRT

Timeinterval&

Results

Cape

5-Fu

Cape

DI(mg/m

2/w

)5-Fu

DI(mg/m

2/w

)pC

RSSS

SDOS

DFS

LR

Hofh

einz

etal.

[12]

2012

RCT

392

197

195

2500

mg/m

2/day

days

1–1

4repeated

day 2

2

(2cycle

sbefore

andaft

erRT

)1650

mg/m

2/day

(duringRT

)

10113

500m

g/m

2/day

days

1–5

repeated

day 2

2(2

cycle

sbefore

andaft

erRT

)225m

g/m

2/day

(duringRT

)

966

50.4Gy/25

Fr4–

6weeks

✓✓

✓✓

✓✓

O’Con

nelletal.

[13]

2014

RCT

1,608

802

806

1650

mg/m

2/day

5days/w

eeks

1–5

8250

225m

g/m

2/day

5days/w

eeks

1–5

1125

T3N0:

50.4Gy/25

Fr;

T4/N

+:55.8Gy/25

Fr

6–8weeks

✓✓

✓M

MM

Chen

etal.[15]

2012

Retro

7447

271700

mg/m

2/day

5days/w

eeks

1–5

8500

350m

g/m

2/day

5days/w

eeks

1,5

700

45–

50.4Gy/25

Fr,

6weeks

✓✓

✓M

MM

Chan

etal.[14]

2010

Retro

102

3468

1650

mg/m

2/day

5days/w

eeks

1–5

8250

20mg/kg/day

days

1–4,22–25

N/A

50Gy/25

Fr8weeks

✓✓

✓✓

✓✓

Yerushalmiet

al.[20]

2006

Retro

8943

461650

mg/m

2/day

5days/w

eeks

1–5

8250

180m

g/m

2/day

5days/w

eeks

1–5

900

50Gy/25

Fr7–7.5

weeks

(median)

✓✓

✓M

MM

Das

etal.[16]

2006

Retro

178

8989

1650

mg/m

2/day

5days/w

eeks

1–5

58pts;

1650

mg/m

2/day

7days/w

eeks

1–5

31pts

9399

300m

g/m

2/day

5days/w

eeks

1–5

1500

52.5Gy/25

FrN/A

✓✓

✓✓

✓✓

Kim

etal.[17]

2007

Retro

278

133

145

1650

mg/m

2/day

7days/w

eeks

1–5

11550

400m

g/m

2/day

3days/w

eeks

1,5

480

50Gy/25

Fr6weeks

✓✓

✓M

MM

Ramanietal.

[19]

2010

Retro

196

9997

1650

mg/m

2/day

5days/w

eeks

1–5

8250

1000

mg/m

2/day

days

1–4,22–26

1600

50.4–

54Gy/25

Fr6–

8weeks

✓✓

✓✓

✓✓

Kim

etal.[18]

2006

Retro

224

97127

1650

mg/m

2/day

days

1–14repeated

day 2

2

9240

500m

g/m

2/day

5days/w

eeks

1,5

1000

50.4Gy/25

Fr6weeks

✓✓

✓M

MM

RCT,rand

omized

clinicaltria

l;retro

,retrospectiv

estudy

;num

bero

fpts,num

bero

fpatients;cape,capecitabine;R

T,radiotherapy;LR,

localrecurrence;pC

R,pathologicalcompleter

espo

nse;SSS,sphinctersaving

surgery;OS,overallsurvival;DFS

,dise

ase-fre

esurvival;SD

,surgicald

ownstaging

;DI,do

seintensity

;RR,

riskratio

;CI,confi

denceinterval.

&:tim

eintervalbetweenradiotherapy

andsurgery.


Records identified through database searching

Additional records identified through other sources

Records after duplicates removed

Records screened Records excluded

Full-text articles assessed for eligibility

Studies included in qualitative synthesis

Studies included in quantitative synthesis

(meta-analysis)

Other chemotherapy regimens

Do not include both 5-Fu and

included n = 4

capecitabine n = 6

Full-text articles excluded (n = 10)

(n = 9)

(n = 9)

(n = 19)

(n = 95)

(n = 114)

(n = 114)

(n = 0)(n = 265)

Figure 1: The Quality of Reporting of Meta-Analyses (QUOROM) statement flow diagram.

was no significant detrimental effect on pCR rates whenneoadjuvant chemotherapy was combined with oxaliplatin ornot (𝑃 = 0.42). Therefore, all 1608 patients were included inthe analysis for pCR rates.

3.2. Tumor Response. Tumor response rates were reportedin all trials. All 9 trials reported pCR rates (Figure 2); thefixed-effect pooled estimate including 2785 patients evaluatedfor OR showed a statistically significant increased OR forcapecitabine (OR, 1.34; 95% CI, 1.10–1.64; 𝑃 = 0.003). Theinclusion of the two RCTs only to this analysis led to an RRof 1.20 (95% CI, 0.98–1.47; 𝑃 = 0.07) (Figure 3). Seven trials[12–15, 18–20] reportedTdownstaging (the reduction of the T

stage by at least one level after neoadjuvant chemoradiation);random-effect pooled estimate demonstrated an increasedOR for capecitabine (OR, 1.58; 95%CI, 1.22–2.06;𝑃 = 0.0007)(Figure 4). However, there were heterogeneities betweenthese trials (𝐼 = 53%, 𝑃 = 0.05). Four trials [12, 15, 18, 19]reported N downstaging (the reduction of the N stage by atleast one level after neoadjuvant chemoradiation); random-effect pooled estimate demonstrated an increased OR forcapecitabine as well (OR, 2.06; 95% CI, 1.34–3.16; 𝑃 = 0.001)(Figure 5).

3.3. Type of Surgical Resection. Data on the rate of sphincter-sparing resection were available for all the 9 trials; no


Review: capecitabine versus 5-FUComparison: 01 capecitabine versus 5-FUOutcome: 01 pCR rates of capecitabine or 5-FU

Study Capecitabine 5-FU OR (fixed) Weight OR (fixed)or subcategory n/N n/N 95% CI % 95% CIDas et al. 5.06 1.92 [0.86, 4.32]Kim et al. 5.04 2.21 [1.02, 4.83]Yerushalmi et al. 3.16 2.06 [0.76, 5.61]Kim et al. 6.87 1.51 [0.73, 3.15]Chan et al. 3.72 1.21 [0.43, 3.42]Ramani et al. 6.09 1.17 [0.51, 2.67]O’Connell et al. 64.16 1.21 [0.94, 1.55]Chen et al. 3.89 0.51 [0.15, 1.78]Hofheinz et al.

19/8920/9013/43

20/1247/34

14/99161/779

6/4710/73

11/8912/105

8/4614/12412/6812/97

138/7776/274/74 2.01 2.78 [0.83, 9.30]

Total (95% CI) 14071378 100.00 1.34 [1.10, 1.64]Total events: 270 (capecitabine), 217 (5-FU)

0.1 0.2 0.5 1 2 5 10Capecitabine

Test for overall effect: Z = 2.93 (P = 0.003)

7.66, dfTest for heterogeneity: 𝜒2 = = 8 (P = 0.47), I2 = 0%

5-FU

Figure 2: Forest plot of odds ratio (OR) for pCR rate of all trials.

Review: capecitabine versus 5-FUComparison: 01 capecitabine versus 5-FUOutcome: 02 RCTStudy Capecitabine 5-FU RR (fixed) RR (fixed)or subcategory n/N n/N 95% CI 95% CI

O’Connell et al. 161/779 97.21 1.16 [0.95, 1.43]Hofheinz et al. 10/73

138/7774/74 2.79 2.53 [0.83, 7.72]

Total (95% CI) 852 851 100.00 1.20 [0.98, 1.47]Total events: 171 (capecitabine), 142 (5-FU)

0.1 0.2 0.5 1 2 5 10Favours treatment Favours control


1.82, df = 1 (P = 0.18Test for heterogeneity: 𝜒2 = ), I2 = 45.1%

Weight%

Figure 3: Forest plot of relative risk (RR) for pCR rate of RCTs only.

Review: capecitabine versus 5-FUComparison: 08 T downstaging Outcome: 01 T downstaging Study Capecitabine 5-FU OR (fixed) OR (fixed)or subcategory n/N n/N 95% CI 95% CIKim et al. 55/90 16.74 2.45 [1.38, 4.37]Yerushalmi et al. 33/43 5.88 3.30 [1.32, 8.23]Chan et al. 20/34 12.49 1.00 [0.43, 2.31]Ramani et al. 38/43 4.89 1.23 [0.35, 4.39]O’Connell et al. 44/209 39.27 0.99 [0.61, 1.58]Chen et al. 30/43 5.91 2.14 [0.79, 5.81]Hofheinz et al. 40/73

41/10523/4640/6837/43

43/20214/2729/74 14.81 1.88 [0.98, 3.62]



Test for overall effect: Z = 3.41 (P = 0.0007)10.46, df = 6 (P = 0.11),Test for heterogeneity: 𝜒2 = I2 = 42.7%

Weight%

Figure 4: Forest plot of odds ratio (OR) for T downstaging rate.

statistically significant difference was demonstrated betweenthe two regimens (OR, 1.09; 95% CI, 0.92–1.28; 𝑃 = 0.31)(Figure 6).

3.4. Recurrence. Four trials [12, 14, 16, 19] provided datafor disease-free survival; however, Kaplan-Meier plots of

disease-free survival were only available in 3 trials [12, 14, 19],including 690 patients (capecitabine, 𝑛 = 330; 5-FU, 𝑛 = 360).The meta-analysis of the pooled data demonstrated that the3-year disease-free survival was in favour of capecitabine-based regimens (HR, 0.65; 95% CI, 0.44–0.96, 𝑃 = 0.03;Figure 7). 16.2% (68/419) patients in capecitabine group and


Review: capecitabine versus 5-FUComparison: 09 N downstagingOutcome: 01 N downstaging

Study Capecitabine 5-FU OR (fixed) OR (fixed)or subcategory n/N n/N 95% CI 95% CIKim et al. 57/83 22.37 3.19 [1.38, 7.38]Ramani et al. 44/52 16.52 1.52 [0.49, 4.71]Chen et al. 15/27 20.28 1.66 [0.61, 4.47]Hofheinz et al. 42/74

63/7250/5629/4351/72 40.83 1.85 [0.93, 3.67]





Weight%

Figure 5: Forest plot of odds ratio (OR) for N downstaging rate.

Review: capecitabine versus 5-FUComparison: 05 surgeryOutcome: 01 Sphincter saving versus sphincter not savingStudy Capecitabine 5-FU OR (fixed) OR (fixed)or subcategory n/N n/N 95% CI 95% CIDas et al. 5.13 1.50 [0.77, 2.94]Kim et al. 2.28 2.75 [1.15, 6.56]Yerushalmi et al. 3.81 1.15 [0.50, 2.64]Kim et al. 4.12 1.98 [0.98, 4.03]Chan et al. 4.40 0.83 [0.36, 1.93]Ramani et al. 2.25 1.59 [0.59, 4.30]O’Connell et al. 69.35 1.00 [0.82, 1.22]Chen et al. 2.85 0.59 [0.19, 1.90]Hofheinz et al. 5.81 0.73 [0.34, 1.56]

Total (95% CI)

69/8924/3623/43

110/12413/3453/62

462/77934/4753/73

1287

62/8924/5723/46

99/12429/6837/47

463/78022/2758/74

1312 100.00 1.09 [0.92, 1.28]Total events: 841 (capecitabine), 817 (5-FU)



11.79, dfTest for heterogeneity: 𝜒2 = ), I2 = 32.1%= 8 (P = 0.16

Weight%

Figure 6: Forest plot of odds ratio (OR) for sphincter-sparing resection rate.

Chan et al.Hofheinz et al.Ramani et al.

Study or subgroup SE

−0.0726−0.5621−0.3011

0.550.250.42

13.2% 0.93 [0.32, 2.73]0.57 [0.35, 0.93]0.74 [0.32, 1.69]

0.65 [0.44, 0.96]

64.1%22.7%

100.0%

Weight IV, random, 95% CIHazard ratio

IV, random, 95% CIHazard ratio

0.10.01 1 10 100Favours [capecitabine] Favours [5-FU]

Total (95% CI)


Heterogeneity: 𝜏2 = 0.00; 𝜒2 = 0.79, df = 2 (P = 0.67), I2 = 0%

log [Hazard ratio]

Figure 7: Forest plot of hazard ratio (HR) for 3-year disease-free survival.

23.8% (107/449) in 5-FU group had distant recurrence, andthere was significant difference (OR, 0.63; 95% CI, 0.44–0.88; 𝑃 = 0.007, Figure 8). However, there was no significantdifference in the local recurrence rate between the two groups(OR, 0.88; 95% CI, 0.47–1.65; 𝑃 = 0.69, Figure 9).

3.5. Toxicity. With regard to toxicity, we chose the most fre-quently reported side-effects (at least mentioned in four tri-als) to obtain reliable comparisons between capecitabine and5-FU regimen. Thus, toxicity was not evaluated completelyand the reported results must be interpreted with caution.

The adverse events included lowered hemoglobin, loweredleucocytes, lowered platelets, nausea, vomiting, diarrhea,mucositis, hand-foot syndrome, and radiation dermatitis.The most frequent toxicity was diarrhea in patients receivingeither capecitabine (87/1204) or 5-FU (95/1252) combinedwith RT (Table 2).

Grade 3 or worse lowered leucocytes (reported by 7 trials[12, 14–19]) were significantly less prominent in patientsreceiving capecitabine and RT (OR, 0.25; 95% CI, 0.11–0.54;𝑃 = 0.0005) (Figure 10). Moreover, after excluding the onlytrial [17] in which capecitabine group had more patients with


Review: capecitabine versus 5-FUComparison: 10 metastasisOutcome: 01 metastasisStudy Capecitabine 5-FU OR (fixed) OR (fixed)or subcategory n/N n/N 95% CI 95% CIDas et al. 14.58 0.76 [0.32, 1.77]Chan et al. 12.40 0.55 [0.20, 1.55]Ramani et al. 20.62 0.63 [0.30, 1.34]Hofheinz et al. 52.40 0.60 [0.38, 0.97]Total (95% CI)

14/8919/6820/97

54/195449

11/896/34

14/9937/197





Weight%

Figure 8: Forest plot of odds ratio (OR) for metastasis rate.

Review: capecitabine versus 5-FUComparison: 06 local recurrenceOutcome: 01 local recurrenceStudy Capecitabine 5-FU OR (fixed) OR (fixed)or subcategory n/N n/N 95% CI 95% CIDas et al. 9.14 2.05 [0.37, 11.47]Chan et al. 18.02 0.65 [0.12, 3.38]Ramani et al. 9.57 0.48 [0.04, 5.43]Hofheinz et al.

4/892/341/99

12/197

2/896/682/97

14/195 63.26 0.84 [0.38, 1.86]Total (95% CI) 449419 100.00 0.88 [0.47, 1.65]Total events: 19 (capecitabine), 24 (5-FU)




Weight%

Figure 9: Forest plot of odds ratio (OR) for local recurrence rate.

Review: capecitabine versus 5-FUComparison: 04 detailed toxicityOutcome: 02 lowered leucocytesStudy Capecitabine 5-FU OR (fixed) Weight OR (fixed)or subcategory n/N n/N 95% CI (%) 95% CIDas et al. 3.20 1.00 [0.06, 16.24]Kim et al. 29.34 0.06 [0.00, 0.99]Kim et al. 6.06 1.65 [0.27, 10.03]Chan et al Not estimableRamani et al. Not estimableChen et al. 10.12 0.11 [0.00, 2.32]Hofheinz et al. 51.28 0.17 [0.05, 0.60]

Total (95% CI)

1/890/97

3/1330/340/990/47

3/197

696

1/8910/1272/1450/680/972/27

16/195




6.81, dfTest for heterogeneity: 𝜒2 = = 4 (P = 0.15), I2 = 41.3%

Figure 10: Forest plot of odds ratio (OR) for lowered leucocytes rate.

lowered leucocytes, the difference was more obvious (OR0.08; 95%CI, 0.02 to 0.30;𝑃 = 0.0002) with less heterogeneity(𝑃 = 0.48). However, the frequency of hand-foot syndrome(reported by all trials) appeared higher in the capecitabineand RT group (OR, 4.43; 95% CI, 1.59–12.33; 𝑃 = 0.004)(Figure 11). A sensitivity analysis showed that several adverseeffects were not statistically different between capecitabine

and 5-FU, such as lowered hemoglobin [12, 14–19], loweredplatelets [12, 16–20], nausea [12–15, 18, 19], vomiting [12, 13, 15,18, 19], mucositis [12, 14, 16, 19], and radiation dermatitis [12–16, 18, 20], whereas, with respect to severe diarrhea (reportedby 7 trials [12–20]), the findings of major heterogeneitybetween these trials (𝐼 = 64.5% and 𝑃 = 0.004) restricteda valid interpretation of the pooled estimates.


Table 2: Toxic (grade 3 or worse∗) effects in trials comparing capecitabine with 5-Fu.

Toxicity Number of trials Number of cases OR (95% CI) Test of homogeneity P valueCape 5-Fu 𝐼

2 (%) P valueLowered hemoglobin 7 6/696 5/748 1.13 (0.36, 3.54)# 24.6 0.27 0.83Lowered leucocytes 7 7/696 31/748 0.24 (0.11, 0.54)# 28.9 0.23 0.0005Lowered platelets 6 0/658 4/699 0.30 (0.05, 1.88)# 0 0.99 0.2Nausea 6 10/906 4/905 2.30 (0.79, 6.70)# 0 0.51 0.13Vomiting 6 7/1038 2/1049 3.04 (0.72, 12.75)# 0 0.66 0.13Diarrhea 9 87/1204 95/1252 0.92 (0.67, 1.24)§ 66.7 0.002 0.57Mucositis 4 1/419 4/449 0.33 (0.05, 2.10)# 0 0.64 0.24Hand-foot syndrome 9 17/1204 3/1252 4.43 (1.59, 12.33)# 0 0.48 0.004Radiation dermatitis 7 26/972 32/1010 0.85 (0.51, 1.44)§ 49.3 0.08 0.55RR, risk ratio; cape, capecitabine; CI, confidence interval.#Fixed-effect model.§Random-effects model.∗National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Review: capecitabine versus 5-FUComparison: 04 detailed toxicityOutcome: 08 hand-foot syndromeStudy Capecitabine 5-FU OR (fixed) OR (fixed)or subcategory n/N n/N 95% CI 95% CIDas et al. Not estimableKim et al. 9.31 18.11 [1.01, 325.60]Yerushalmi et al. 10.74 3.28 [0.13, 82.77]Kim et al. Not estimableChan et al. Not estimableRamani et al. Not estimableO’Connell et al. 68.64 1.98 [0.49, 7.98]Chen et al. Not estimableHofheinz et al. 11.30 9.09 [0.49, 170.03]Total (95% CI)

0/896/971/43

0/1330/340/99

6/4650/47

4/1971204

0/890/1270/46

0/1450/680/97

3/4580/27

0/1951252 100.00 4.43 [1.59, 12.33]

Total events: 17 (capecitabine), 3 (5-FU)




Weight%

Figure 11: Forest plot of odds ratio (OR) for hand-foot syndrome rate.

3.6. Evaluation of Publication Bias. A funnel plot of the stud-ies used in themeta-analysis reporting on capecitabine versus5-FU as chemotherapy plus RT used as neoadjuvant treat-ment for patients with LARC was shown in Figure 12. Therewas no evidence of publication bias (all studies were equallydistributed round the vertical axis).

4. Discussion

This meta-analysis compared the efficacy and safety of ca-pecitabine plus radiation with 5-FU plus RT as neoadjuvanttreatment in LARC. In the light of its favourable efficacyand low toxicity, the analysis showed that capecitabine wassuperior to 5-FU in neoadjuvant treatment for patients withLARC. Capecitabine plus RT might be regarded as standardneoadjuvant treatment in patients with LARC considering itsadvantage.

The previous work by Meta-Analysis Group in Cancerproved continuous intravenous infusion (CIV) 5-FU is supe-rior to bolus 5-FU in terms of tumor response based on other

Review: capecitabine versus 5-FUComparison: 01 capecitabine versus 5-FUOutcome: 01 pCR rates of capecitabine or 5-FU

0.1 0.2 0.5 1 2 5 10

0.0

0.2

0.4

0.6

0.8

SE(lo

g O

R)

OR (fixed)Figure 12: Funnel plot of studies included in this meta-analysis.

studies of advanced colorectal cancer [24]. Capecitabinemimics CIV 5-FU in its pharmacologic action in vivo; it hasshown equivalent efficacy to CIV 5-FU plus leucovorin on


metastatic colorectal cancer, but without the use of venouscatheter and better patient tolerability. Both the two includedRCT trials confirmed the equivalence of CIV 5-FU andcapecitabine in neoadjuvant chemoradiotherapy regimensfor patients with LARC. However, regarding outcome andtoxicity evaluation, heterogeneities still remained betweendifferent studies.

This meta-analysis brought together all currently avail-able data comparing capecitabine with 5-FU plus RT used asneoadjuvant treatment for patients with LARC.

Meta-analysis of all studies showed a significantly betterpCR, Tdownstaging,Ndownstaging, when radiation therapyis combined with capecitabine instead of 5-FU for the neo-adjuvant treatment of LARC. As far as the adverse eventswere concerned, there appeared to be higher rate of hand-foot syndrome and lower rate of lowered leucocytes in thecapecitabine arm. However, the type of surgical resectionand other adverse events (lowered hemoglobin, loweredplatelets, nausea, vomiting, diarrhea,mucositis, and radiationdermatitis) were not statistically different between these tworegimens. Since the data on diarrhea, radiation dermatitiswere different between the pooled trials; they should beinterpreted with caution.

Only four trialsmentioned long-term survivorship; inter-estingly, in all studies, capecitabine showed reduction indistant metastases and noninferiority in both DFS and OS,suggesting greater systemic efficacy than with 5-FU, in accor-dance with the X-ACT study comparing capecitabine withbolus fluorouracil plus folinic acid for adjuvant treatment ofstage III colon cancer. This could be partly explained bythe higher pCR rates of capecitabine group. As proved byother trials [25], patients with a pCR after chemoradia-tion have a significantly better long-term outcome than dothose with residual disease, although this could be influ-enced by adjuvant treatment; additional evidence will berequired to assess the long-term prognosis of capecitabineand 5-FU in the preoperative combined-modality therapy ofLARC.

Hand-foot syndrome is predominant in capecitabinetreatment group but could be easilymanagedwith vitamin B6administration and supportive care without interrupting theRT schedule. Interestingly, in the trial of Hofheinz et al., thosepatients who developed HFS enjoyed better DFS and overallsurvival than those who did not develop in both capecitabinegroup and the overall study population [12].

Our study had several limitations, and the efficiency ofthismeta-analysismight have been affected by several factors.First of all, because of the possibility that not all relevantstudies were identified by computerized searching, it wasnecessary to combine the electronic material with manualresearch and personal contact with authors. Unfortunately,efforts on this were not very productive. Secondly, only twoRCTs were included in this meta-analysis, and the numberof patients in NSABP-R-04 accounts for almost one-half;the small sample sizes of the retrospective trials includedmight affect the conclusion. Thirdly, the usage of oxaliplatinmay also influence the pCR rate in the NSABP-R-04 trial.Finally, varying doses and application of capecitabine and 5-FU might influence the results.

In conclusion, as a convenient oral fluoropyrimidine,capecitabine seemed to be at least as good as continuous5-FU and was an acceptable alternative in the neoadjuvantchemoradiation treatment of patientswith LARC. It was asso-ciated with improvement tumor response rate and favourablylow toxicity with the exception ofHFS. Based on these results,we would recommend the use of capecitabine combined withpelvic radiation as a neoadjuvant treatment for LARC.

Competing Interests

The authors have declared no competing interests.

Authors’ Contributions

Guo-Chen Liu, Jun-Ping Yan, and Qing He contributedequally to this work.

Acknowledgments

The authors thank Kun Zhao for his input on text modifica-tion.This work was supported by Nature Science Foundationof China [Grant no. 81101591].

References

[1] R. Sauer, H. Becker,W. Hohenberger et al., “Preoperative versuspostoperative chemoradiotherapy for rectal cancer,” The NewEngland Journal of Medicine, vol. 351, no. 17, pp. 1731–1810, 2004.

[2] T. A. Rich, J. M. Skibber, J. A. Ajani et al., “Preoperative infu-sional chemoradiation therapy for Stage T3 rectal cancer,” Inter-national Journal of Radiation Oncology, Biology, Physics, vol. 32,no. 4, pp. 1025–1029, 1995.

[3] N. A. Janjan, C. N. Crane, B. W. Feig et al., “Prospective trial ofpreoperative concomitant boost radiotherapy with continuousinfusion 5-fluorouracil for locally advanced rectal cancer,”International Journal of Radiation Oncology Biology Physics, vol.47, no. 3, pp. 713–718, 2000.

[4] C. H. Crane, J. M. Skibber, E. H. Birnbaum et al., “The additionof continuous infusion 5-FU to preoperative radiation ther-apy increases tumor response, leading to increased sphincterpreservation in locally advanced rectal cancer,” InternationalJournal of Radiation Oncology Biology Physics, vol. 57, no. 1, pp.84–89, 2003.

[5] M. J.O’Connell, J. A.Martenson,H. S.Wieand et al., “Improvingadjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curativesurgery,” The New England Journal of Medicine, vol. 331, no. 8,pp. 502–507, 1994.

[6] H. P. Kalofonos, A. Bamias, A. Koutras et al., “A randomisedphase III trial of adjuvant radio-chemotherapy comparingIrinotecan, 5FU and Leucovorin to 5FU and Leucovorin inpatients with rectal cancer: a Hellenic Cooperative OncologyGroup Study,” European Journal of Cancer, vol. 44, no. 12, pp.1693–1700, 2008.

[7] I. Di Carlo, E. Pulvirenti, M. Mannino, and A. Toro, “Increaseduse of percutaneous technique for totally implantable venousaccess devices. Is it real progress? A 27-year comprehensivereview on early complications,”Annals of Surgical Oncology, vol.17, no. 6, pp. 1649–1656, 2010.


[8] R. J.Mayer, “Should capecitabine replace infusional fluorouraciland leucovorin when combined with oxaliplatin in metastaticcolorectal cancer?” Journal of Clinical Oncology, vol. 25, no. 27,pp. 4165–4167, 2007.

[9] E. Van Cutsem,M. Findlay, B. Osterwalder et al., “Capecitabine,an oral fluoropyrimidine carbamate with substantial activity inadvanced colorectal cancer: results of a randomized phase IIstudy,” Journal of Clinical Oncology, vol. 18, no. 6, pp. 1337–1345,2000.

[10] P. M. Hoff, R. Ansari, G. Batist et al., “Comparison of oralcapecitabine versus intravenous fluorouracil plus leucovorin asfirst-line treatment in 605 patients with metastatic colorectalcancer: results of a randomized phase III study,” Journal ofClinical Oncology, vol. 19, no. 8, pp. 2282–2292, 2001.

[11] J. Dunst, T. Reese, T. Sutter et al., “Phase I trial evaluating theconcurrent combination of radiotherapy and capecitabine inrectal cancer,” Journal of Clinical Oncology, vol. 20, no. 19, pp.3983–3991, 2002.

[12] R.-D. Hofheinz, F. Wenz, S. Post et al., “Chemoradiotherapywith capecitabine versus fluorouracil for locally advanced rectalcancer: a randomised, multicentre, non-inferiority, phase 3trial,”The Lancet Oncology, vol. 13, no. 6, pp. 579–588, 2012.

[13] M. J. O’Connell, L. H. Colangelo, R. W. Beart et al., “Ca-pecitabine and oxaliplatin in the preoperative multimodalitytreatment of rectal cancer: surgical end points from nationalsurgical adjuvant breast and bowel project trial R-04,” Journalof Clinical Oncology, vol. 32, no. 18, pp. 1927–1934, 2014.

[14] A. K. Chan, A. O. Wong, and D. A. Jenken, “Preoperative ca-pecitabine and pelvic radiation in locally advanced rectalcancer—is it equivalent to 5-FU infusion plus leucovorin andradiotherapy?” International Journal of Radiation Oncology,Biology, Physics, vol. 76, no. 5, pp. 1413–1419, 2010.

[15] C.-F. Chen, M.-Y. Huang, C.-J. Huang et al., “A observationalstudy of the efficacy and safety of capecitabine versus bolusinfusional 5-fluorouracil in pre-operative chemoradiotherapyfor locally advanced rectal cancer,” International Journal ofColorectal Disease, vol. 27, no. 6, pp. 727–736, 2012.

[16] P. Das, E. H. Lin, S. Bhatia et al., “Preoperative chemoradiother-apy with capecitabine versus protracted infusion 5-fluorouracilfor rectal cancer: amatched-pair analysis,” International Journalof Radiation Oncology Biology Physics, vol. 66, no. 5, pp. 1378–1383, 2006.

[17] D. Y. Kim, K. H. Jung, T. H. Kim et al., “Comparison of 5-fluor-ouracil/leucovorin and capecitabine in preoperative chemora-diotherapy for locally advanced rectal cancer,” InternationalJournal of Radiation Oncology Biology Physics, vol. 67, no. 2, pp.378–384, 2007.

[18] J.-S. Kim, J.-S. Kim, M.-J. Cho, W.-H. Yoon, and K.-S. Song,“Comparison of the efficacy of oral capecitabine versus bolus5-FU in preoperative radiotherapy of locally advanced rectalcancer,” Journal of Korean Medical Science, vol. 21, no. 1, pp. 52–57, 2006.

[19] V. S. Ramani, A. Sun Myint, A. Montazeri, and H. Wong, “Pre-operative chemoradiotherapy for rectal cancer: a comparisonbetween intravenous 5-fluorouracil and oral capecitabine,” Col-orectal Disease, vol. 12, no. 2, pp. 37–46, 2010.

[20] R. Yerushalmi, E. Idelevich, Y. Dror et al., “Preoperative chem-oradiation in rectal cancer: retrospective comparison betweencapecitabine and continuous infusion of 5-fluorouracil,” Journalof Surgical Oncology, vol. 93, no. 7, pp. 529–533, 2006.

[21] D. L. Demets, “Methods for combining randomized clinicaltrials: strengths and limitations,” Statistics in Medicine, vol. 6,no. 3, pp. 341–348, 1987.

[22] R. DerSimonian and N. Laird, “Meta-analysis in clinical trials,”Controlled Clinical Trials, vol. 7, no. 3, pp. 177–188, 1986.

[23] M. Egger, G. D. Smith, M. Schneider, and C. Minder, “Bias inmeta-analysis detected by a simple, graphical test,” The BritishMedical Journal, vol. 315, no. 7109, pp. 629–634, 1997.

[24] P. Piedbois, P. Rougier, M. Buyse et al., “Efficacy of intra-venous continuous infusion of fluorouracil compared withbolus administration in advanced colorectal cancer,” Journal ofClinical Oncology, vol. 16, pp. 301–308, 1998.

[25] M. Maas, P. J. Nelemans, V. Valentini et al., “Long-term out-come in patients with a pathological complete response afterchemoradiation for rectal cancer: a pooled analysis of individ-ual patient data,”TheLancetOncology, vol. 11, no. 9, pp. 835–844,2010.

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Documents

Review Article Effect of Neoadjuvant Chemoradiotherapy with Capecitabine versus ...downloads.hindawi.com/journals/grp/2016/1798285.pdf · 2019. 7. 30. · Review Article Effect of