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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2014 Nov 20;78(6):1228–1237. doi: 10.1111/bcp.12449

Incidence and relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5- fluorouracil: a meta-analysis of published trials

Roberto Iacovelli 1,2,✉, Filippo Pietrantonio 1, Antonella Palazzo 1,2, Claudia Maggi 1,2, Francesca Ricchini 1, Filippo de Braud 1, Maria Di Bartolomeo 1
PMCID: PMC4256612  PMID: 24962653

Abstract

Aim

Capecitabine is an oral fluoropyrimidine that can effectively replace infusional 5-fluorouracil (5-FU) for treatment of colorectal, gastric and breast cancer. This study aims to analyze the incidence and the relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5-FU in randomized clinical trials (RCTs).

Methods

MEDLINE and Cochrane Library were reviewed for RCTs that compared capecitabine with 5-FU for treatment of solid malignancies. The incidence and relative risk (RR) of grade 3/4 diarrhoea were estimated for each arm in the overall population and in colorectal cancer (CRC) patients

Results

Twenty-three studies and 15 761 patients were included. Among these 8303 and 7458 patients received capecitabine or 5-FU based therapies, respectively. In the overall populations severe diarrhoea was reported in 16.6% (95% CI 15.8, 17.4) and in 12.7% (95% CI 11.9, 13.4) of patients treated with capecitabine or 5-FU-based therapies, respectively. The RR was 1.39 (95% CI 1.14, 1.69, P = 0.0010). In 14 899 CRC patients, the incidence of severe diarrhoea was 17.0% (95% CI 16.2, 17.9) and 12.9% (95% CI 12.1, 13.7), respectively, with a RR of 1.46 (95% CI 1.18, 1.81, P < 0.0001). In CRC patients treated with combined chemotherapy, the RR was 1.40 (95% CI 1.07, 1.82; P = 0.01) for patients receiving oxaliplatin and 2.35 (95% CI 1.76, 3.13; P < 0.0001) for patients receiving irinotecan.

Conclusions

Treatment with capecitabine is characterized by an increased risk of severe diarrhoea, mainly in patients affected by CRC and treated with polichemotherapy. Combination treatment with irinotecan doubles the risk over 5-FU.

Keywords: 5-fluorouracil, breast cancer, capecitabine, colorectal cancer, diarrhoea, gastric cancer

Introduction

Capecitabine is an orally administered fluoropyrimidine which constitute a systemic prodrug of 5′-deoxy-5-fluorouridine (5′-DFUR). Several enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo, and both normal and tumour cells metabolize 5-FU to 5-fluoro-2′-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites are able to bind the thymidylate synthase whose products are essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Moreover, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP), interfering with RNA synthesis and causing apoptosis 1,2. Then capecitabine presents a pharmacokinetic profile that mimics a continuous 5-FU infusion.

Currently, capecitabine is approved by both the FDA and EMA for the treatment of colorectal and breast cancers. In the former indication, it may be used as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumour or as first line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Furthermore, the EMA authorized the use of capecitabine in first line treatment of advanced gastric cancer in combination with a platinum-based regimen 2,3. In colorectal cancer (CRC) capecitabine is often used by treating physicians as part of combination regimens, particularly oxaliplatin-based ones, in both the adjuvant and metastatic setting. In fact, treatment with capecitabine does not require the setting up of a central venous access and oral administration may be characterized by greater patient compliance. However, the FDA reports that the use of capecitabine instead of 5-FU/leucovorin as combinations with other agents has not been adequately studied to assure safety or preservation of the survival advantage 2.

The most common adverse events of capecitabine are hand-foot syndrome, diarrhoea, stomatitis, nausea and asthenia and, among the high grade adverse events, diarrhoea and hand-foot syndrome play a significant role as dose limiting toxicity. The increase of gastrointestinal toxicity may jeopardize quality of life, particularly in patients with CRC, and lead to reduction of treatment dose intensity.

The aim of this study was to analyze the incidence and the relative risk (RR) of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5-FU in randomized clinical trials, with focus on patients affected by CRC and treated with capecitabine or 5-FU-based combination therapies.

Methods

Definition of outcomes

Capecitabine-based treatments were considered as the experimental arms and 5-FU-based ones as the standard comparators. Absolute number of grade 3 and 4 diarrhoea events was considered as the main outcome and the analysis was conducted in order to find a significant difference between the two arms. The Common Terminology Criteria for Adverse Events (CTCAE v 4.0) were used to define severe diarrhoea, with grade 3 as an increase of ≥ seven stools per day over baseline, incontinence and a required hospitalization in the case of the severe increase in ostomy output compared with baseline and grade 4 as the presence of life-threatening consequences requiring urgent intervention 4.

Selection of studies

We reviewed MEDLINE and Cochrane Library for citations published until October 2013. The search was restricted to randomized controlled trials (RCTs) performed in humans, those that were written in English, and that compared capecitabine with 5-fluorouracil for the treatment of solid malignancies. The entry terms for the search were ‘capecitabine’ and ‘5-fluorouracil’. Only phase II or III studies that tested a capecitabine-based treatment vs. a 5-fluorouracil based treatment were included in the final analysis. If more than one publication was found for the same trial, only the most recent was considered.

Data extraction

Two authors (RI and FP) conducted the data extraction independently. It was performed according to the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) statement 5 and any types of discrepancies were resolved by consensus. The data extracted for each trial were first author's name, year of publication, trial phase, number of enrolled patients, type of treatments administered (combined or monotherapy), type and dosages of capecitabine and 5-fluorouracil combination, type of tumours, intent of treatment (adjuvant or palliative) and number of grade 3 and 4 diarrhoea events in both populations.

Statistical method

For calculating the incidence, the number of patients with grade 3 and 4 diarrhoea and the number of patients treated in each arm were extracted from the safety profile of the selected trials. The proportion of patients with diarrhoea and the derived 95% confidence interval (CI) were calculated for each study. We also calculated the RR and the CIs of events in patients assigned to the capecitabine arm compared with the control patients in the same study. To calculate the 95% CIs, the variance of a log-transformed study-specific RR was derived using the delta method 6.

Statistical heterogeneity between the trials included in the meta-analysis was assessed using Cochrane's Q statistic. This was computed by summing the squared deviations of each study's estimates from the overall meta-analytic estimate, weighting each study's contribution in the same manner as in the meta-analysis. The quantification of the heterogeneity was evaluated as described by Higgins et al. 7 and provides a measure of the degree of inconsistencies in the studies' results. The quantity I2 describes the percentage of total variation across the studies that are due to heterogeneity rather than chance. Negative values of I2 are set equal to zero so that I2 lies between 0% and 100%. A value of 0% indicates no observed heterogeneity and larger values show increasing heterogeneity.

Assumptions of homogeneity were considered invalid for P values less than 0.1. Summary incidence and RRs were calculated using random or fixed effect models, depending on the heterogeneity of the included studies. When substantial heterogeneity was not observed, the pooled estimate, calculated based on the fixed effects model, was reported using the inverse variance method. When substantial heterogeneity was observed, the pooled estimate, calculated based on the random effects model, was reported using the method described by Der Simonian et al. 8, which considers both within and between study variations 6. Publication bias was evaluated using funnel plots (plots of the study results against precision), and with tests described by Begg et al. 9 and Egger et al. 10. A two-tailed P value of less than 0.05 was considered statistically significant.

Study quality was assessed by using the Jadad seven-item scale that included the randomization, double-blinding, and withdrawals. The final score was reported between 0 and 5 11.

A sensitivity analysis was performed to assess the RRs of high grade diarrhoea in patients treated in phase III trials or not, in patients treated for colorectal cancer or for other diseases and in patients treated with combination therapies compared with capecitabine or 5-FU used as a single agent. All data were collected using Microsoft Office Excel 2007. Statistical analyses were performed using PASW statistics software (version 18) and meta-analysis was performed using RevMan software (v. 5.2.3) 12.

Results

Of the 248 citations identified by the electronic search, 204 were immediately rejected after screening because they were not related to the study subject. A total of 45 full text articles were evaluated and eight articles were excluded because of quality of life, cost-analysis or molecular studies. A total of 12 articles were eliminated because had updated versions, they were sub-analyses of main trials or not RCTs. Finally, of the 25 articles remaining two others were excluded because of the lack of data on toxicity. At the end of this selection process (Figure 1), 23 articles were considered for final analysis because of their adequate quality and relevance for inclusion in the meta-analysis 13–35. Sixteen were randomized phase III trials and eight were randomized phase II trials. A total of 19 studies were performed in patients with CRC, two in metastatic breast cancer (MBC) and the remaining three in patients affected by head and neck tumours, oesophageal and gastric cancer, respectively. Dosages for each drug are reported in Table 1.

Figure 1.

Figure 1

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PRISMA diagram; selection process for trials included in meta-analysis

Table 1.

Selected studies and main characteristics

Author Type of disease Stage Number of patients Phase of study Experimental arm Control arm Dosage of capecitabine (mg m−2 day−1) Dosage of 5-FU (mg m−2) Jadad score
Gupta et al. [13] HN LAD 153 II Cape + CDDP 5-FU + CDDP 750 weeks 2/3 750 ic days 1−3, every 21 days 1
Ducreux et al. [14] CRC Met 145 II Xeleri+ B FOLFIRI + B 2000 weeks 2/3 400 bolus + 2400 ic × 46 h, every 14 days 3
De Gramont et al. [15] CRC Adj 3451 III Xelox + B FOLFOX-4 + B 2000 weeks 2/3 400 bolus days 1 + 2 + 600 ic × 22 h days 1 + 2, every 14 days 3
Madi et al. [16] CRC Met 2445 III Xelox FOLFOX-6 2000 weeks 2/3 400 bolus + 2400 ic × 46 h, every 14 days 3
Pectasides et al. [17] CRC Met 302 III Xeleri + B FOLFIRI + B 2000 weeks 2/3 400 bolus + 2400 ic × 46 h, every 14 days 3
Hofheinz et al. [18] CRC LAD 401 III Cape + RT 5-FU + RT 2500 weeks 2/3 500 ic × 5 days, every 29 days 3
Souglakos et al. [19] CRC Met 333 II Xeleri + B FOLFIRI + B 2000 weeks 2/3 400 bolus days 1 + 2 + 600 ic × 22 h days 1 + 2, every 14 days 2
Stockler et al. [20] MBC Met 323 II Cape CMF 2000 weeks 2/3 600 bolus days 1 + 8, every 28 days 3
Cassidy et al. [21] CRC Met 2034 III Xelox ± B FOLFOX-4 ± B 2000 weeks 2/3 400 bolus days 1 + 2 + 600 ic × 22 h days 1 + 2, every 14 days 3
Ducreux et al. [22] CRC Met 306 III Xelox FOLFOX-6 2000 weeks 2/3 400 bolus + 2400 ic × 46 h, every 14 days 3
Tebbutt et al. [23] Esophagus Met 106 II Cape + TXT+CDDP 5-FU + TXT + CDDP 1600 weeks 2/3 200 ic, every 21 days 3
Skof et al. [24] CRC Met 87 II Xeliri FOLFIRI 2000 weeks 2/3 400 bolus + 2400 ic × 46 h, every 14 days 0
Jackson et al. [25] CRC Met 278 III Xeleri FOLFIRI 2000 weeks 2/3 400 bolus + 2400 ic × 46 h, every 14 days 2
Kang et al. [26] Gastric Met 316 III Cape + CDDP 5-FU + CDDP 2000 wks 2/3 800 ic × 5 days, every 21 days 2
Comella et al. [27] CRC Met 322 III Xelox L-OHP + 5-FU 2000 weeks 2/3 850 bolus, every 14 days 2
Rothenberg et al. [28] CRC Met 627 III Xelox FOLFOX-4 2000 weeks 2/3 400 bolus days 1 + 2 + 600 ic × 22 h days 1 + 2, every 14 days 3
Schmoll et al. [30] CRC Met 1886 III Xelox 5-FU Mayo 2000 weeks 2/3 425 bolus days 1–5, every 28 days 3
Díaz-Rubio et al. [29] CRC Met 348 III Xelox FUOX 2000 weeks 2/3 2250 ic × 48 h, every 7 days 3
Martoni et al. [31] CRC Met 118 II Xelox L-OHP + 5-FU 2000 weeks 2/3 250 ci, every 21 days 1
Twelves et al [32] CRC Adj 1987 III Cape 5-FU Mayo 2500 weeks 2/3 425 bolus days 1–5, every 28 days 3
Oshaughnessy et al. [33] MBC Met 95 II Cape CMF 2500 weeks 2/3 600 bolus days 1 + 8, every 28 days 3
Van Cutsem et al. [34] CRC Met 602 III Cape 5-FU Mayo 2500 weeks 2/3 425 bolus days 1–5, every 28 days 3
Hoff et al. [35] CRC Met 595 III Cape 5-FU Mayo 2500 weeks 2/3 425 bolus days 1–5, every 28 days 3
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5-FU, 5-fluorouracil; Adj, adjuvant; b, bevacizumab; Cape, capecitabine; CDDP, cisplatin; CMF, cyclophosphamide + methotrexate + 5-FU; CRC, colorectal cancer; FOLFIRI, combined therapy containing irinotecan and 5-FU; FOLFOX and FUOX, combined therapies containing oxaliplatin and 5-FU; HN, head and neck tumour; ic, infusion continued; LAD, locally advanced disease; MBC, metastatic breast cancer; Met, metastatic; TXT, docetaxel; Xeleri, combined therapy containing irinotecan and capecitabine; Xelox, combined therapy containing oxaliplatin and capecitabine.

A total of 17 260 patients were enrolled, and 15 761 were evaluable for toxicity. A total of 8303 patients received capecitabine based therapies, and a total of 7458 patients were enrolled in control arms. Capecitabine was administered as monotherapy in six studies, with cisplatin-based therapy in three studies and with oxaliplatin- or irinotecan-based therapy in seven studies.

Incidence and relative risk of severe diarrhoea in the overall population

Grade 3 and 4 diarrhoea was reported in 1378 out of 8303 patients in the capecitabine- based arms compared with 945 out of 7458 patients in the 5-FU-based arms with an incidence of 16.6% (95% CI 15.8, 17.4) vs. 12.7% (95% CI 11.9, 13.4), respectively.

The RR of grade 3 and 4 diarrhoea was 1.39 (random effect, 95% CI 1.14, 1.69, P = 0.0010) (Figure 2). No significant publication biases were detected among studies, P values from Begg's and Egger's test were 0.85 and 0.32, respectively.

Figure 2.

Figure 2

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Forest plot of relative risk (RR) of severe diarrhoea events associated with capecitabine in the overall population

When the analysis was restricted to phase III trials, the analysis was restricted to 7669 patients treated with capecitabine-containing regimens, and 6861 patients treated with 5-FU-containing ones. The RR was found to be 1.44 (random effect, 95% CI 1.15, 1.80; P = 0.002).

Incidence and relative risk of severe diarrhoea in patients with colorectal cancer

A total of 14 899 patients were affected by CRC. Among these 7853 received capecitabine-based therapies and 7046 5-FU-based ones. Grade 3 and 4 diarrhoea was reported in 1337 and 907 patients, respectively, with an incidence of 17.0% (95% CI 16.2, 17.9) vs. 12.9% (95% CI 12.1, 13.7), respectively.

The RR was 1.46 (random effect, 95% CI 1.18, 1.81, P < 0.0001) and no significant publication biases were detected among studies, since the P values from Begg's and Egger's test were 0.62 and 0.16, respectively.

When patients were selected based on the type of combination regimen, 10 241 patients were treated with oxaliplatin and capecitabine or 5-FU, 1108 patients were treated with irinotecan and capecitabine or 5-FU and 3350 received capecitabine or 5-FU as monotherapy.

In the oxaliplatin group, the incidence of grade 3 and 4 diarrhoea was 18.2% (95% CI 17.2, 19.2) for combinations with capecitabine and 13.7% (95% CI 12.7, 14.7) for combinations with 5-FU. The RR was found to be 1.40 (random effect, 95% CI 1.07, 1.82; P = 0.01) (Figure 3).

Figure 3.

Figure 3

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Forest plot of relative risk (RR) of severe diarrhoea events associated with capecitabine in colorectal cancer patients treated with (A) oxaliplatin-based, (B) irinotecan-based combination of therapies or with (C) monotherapy

In the irinotecan group, the incidence of grade 3 and 4 diarrhoea was 23.5 % (95% CI 19.9, 27.1) for combinations with capecitabine and 9.9% (95% CI 7.3, 12.5) for combinations with 5-FU. The RR was found to be 2.35 (fixed effect, 95% CI 1.76, 3.13; P < 0.0001) (Figure 3).

In the group of patients treated with fluoropyrimidines alone, the incidence of grade 3 and 4 diarrhoea was 11.4% for capecitabine (95% CI 9.9, 12.9) vs. 11.5% (95% CI 10.0, 13.0) for 5-FU. The RR was found to be only 1.13 (random effect, 95% CI 0.77, 1.66; P = 0.55) (Figure 3).

When groups were compared with each other, significant differences were found between the irinotecan and the monotherapy groups (P = 0.001) and between the irinotecan and oxaliplatin groups (P = 0.04).

Quality of studies

Randomized treatment allocation sequences were generated in all trials and, considering the nature of drugs administered, all trials were open label. Jadad's score was 3 for 16 studies and 2 or less for seven (Table 1), with a mean value of 2.4.

Discussion

The oral administration of capecitabine may be particularly attractive for patients and their treating physicians due to better compliance and no need for infusion pumps.

The comparable efficacy of capecitabine and 5-FU has been reported by several RCTs in terms of PFS and OS. Moreover, a meta-analysis based on individual patient data from six non-inferiority RCTs, reported an overall decrease of the risk of death of 6% (HR 0.94, 95% CI 0.89, 1.00; P = 0.049) in patients treated with capecitabine for stage III, stage IV colorectal or stage IV gastric cancer 36. Despite this comparable efficacy, few analyses have been done until now as regards the differential toxicity profiles of these two drugs, particularly when used as part of combination regimens. In a meta-analysis including six trials carried out in patients with CRC and treated with oxaliplatin combined with capecitabine or 5-FU, a higher incidence of high grade thrombocytopenia and hand-foot syndrome were reported in the capecitabine arms, while no difference in terms of asthenia diarrhea and other gastrointestinal side effects was reported 37. Moreover, Polk et al. reported an incidence of 3–35% and 0–20% of cardiotoxic events in a systematic review comparing subjects treated with capecitabine or 5-FU, respectively 38.

In patients treated with fluoropyrimidines, diarrhoea is one of the more common adverse events that may be exacerbated by combination with other chemotherapy agents, resulting in a deterioration of general and gastrointestinal quality of life 39. Our study reports the incidence of severe diarrhoea in patients treated with capecitabine vs. 5-fluorouracil in RCTs. Overall, we report an increased risk by 39% in patients treated with capecitabine based therapies as compared with 5-fluorouracil-based ones. This risk was higher when only phase III trials were considered (44%) and in patients affected by CRC (46%).

In patients with gastrointestinal malignancies, chemotherapy-induced diarrhoea is of special interest because it may cause a worsening of surgery- and radiotherapy-related long term effects, with deterioration of quality of life 40,41. Thus, the choice of specific chemotherapy regimens may have a role in the final compliance and quality of life of the patients. When only CRC subjects were considered in our analysis, several interesting data were found. First, patients treated with capecitabine and oxaliplatin had a significant increase in the incidence of severe diarrhoea, as compared with patients treated with infusional oxaliplatin and 5-FU-based regimens (18.2% vs. 13.7%). Furthermore, we found that capecitabine and 5-FU monotherapy did not differ in terms of such an incidence (11.4% vs. 11.5%).

When we focus on irinotecan-based therapy, we observed the most meaningful and significant increase of severe diarrhoea (23.5% vs. 9.9%) with a RR increased by 135%. This increase of toxicity may be regarded as unacceptable, as the RR was much higher than that observed for oxaliplatin-based combinations or single agent treatment.

Interestingly, the literature data report that diarrhoea is the main adverse event and dose-limiting toxicity in patients treated with irinotecan, with an incidence of 15–36% 42. Initial phase III RCTs using capecitabine and irinotecan at previously recommended doses showed an increase of diarrhoea and even toxic deaths over FOLFIRI regimen 43,44. The use of modified schedules of capecitabine and irinotecan regimen was demonstrated as feasible and effective in the phase II AIO-0604 trial. In view of this, the European guidelines, performed by the European Society of Medical Oncology (ESMO), advise about the low general use of this combination and suggest that the daily dosage of capecitabine should be reduced from 2000 to 1600 mg m−2 45.

Moreover, Haller and colleagues described geographical variations in fluoropyrimidines toxicity 46. In studies of first line metastatic CRC comparing capecitabine with 5-FU, patients in the United States were found to have a higher incidence of grade 3–4 adverse events (RR = 1.77; P < 0.001), dose reductions and treatment discontinuations compared with the rest of the world 46. As regional difference may be related to pharmacogenetic background, a correct screening for the most important and validated toxicity-associated polymorphisms is warranted when the administration of capecitabine and/or irinotecan is scheduled. Market research indicates that US-based oncologists rarely prescribe the label-recommended dose of capecitabine (1250 mg m−2 twice daily for 14 days) compared with their European colleagues preferring a starting dose of 1000 mg m−2 twice daily for 14 days 47. Moreover, regional differences in the incidence of toxicity might be explained with differences in dietary folate intake, especially given international variation in policies for folate fortification 47. Two studies have been reported where patients with higher baseline levels of serum folate had a significantly increased incidence of toxic events 48,49.

Age was also found to be a predictive factor for capecitabine-related toxicity. A report from the European Medicines Evaluation Agency describes an age-related increase in concentration of an inactive metabolite of capecitabine and 5-FU (e.g. fluoro-beta-alanine [FBAL]). This increase in FBAL concentration was thought to be due to an age-related decrease in renal function 47.

In fact a 50% decrease in creatinine clearance is associated with a 35% decrease in FBAL clearance and, subsequently, a 41% and 53% increase in FBAL, Cmax and AUC, respectively, that have been directly related to grade 3 and/or 4 diarrhoea 47,50.

The use of capecitabine as the chemotherapy backbone may particularly enhance toxicity when monoclonal antibodies are added to treatment. For example, the negative results of the MRC COIN trial were partially explained by the authors with reduced treatment tolerability and dose intensity when cetuximab was added to a standard oxaliplatin and capecitabine regimen 51. Unfortunately, no data are available about the comparison between capecitabine and 5-FU in patients receiving anti-EGFR targeted therapies.

Despite the evidence that some toxicities, such as hypertension, thyroid toxicity, hand-foot syndrome or diarrhoea related to the use of anti-VEGFR tyrosine kinase inhibitors, seem to be related with a better survival and response to therapy in other tumours 52,53. To our knowledge, there is no evidence in medical literature about the prognostic role for capecitabine-related toxicity or for any relationship between toxicity and efficacy. Therefore, every effort should be made to find the best patient dose in order to avoid worthless toxicity.

Importantly, our study may be accompanied by some limitations. First, as this is a meta-analysis based on studies and not on the patients' data, then confounding variables such as patient's comorbidities, and previous type of surgery and its outcome could not be incorporated into the analysis. Second, the management of diarrhoea may differ among centres and this may affect the appearance of severe toxicity.

In conclusion, we showed that capecitabine significantly increases the risk of grade 3–4 diarrhoea over 5-FU, mainly in patients treated with combination regimens. The risk of toxicity observed in patients receiving capecitabine and irinotecan does not support the routine use of this combination in the every day clinical practice, whenever the equally effective and corresponding 5-FU-based infusional regimen is available.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

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