- Email: [email protected]
Differences in Efficacy and Safety Between Capecitabine and Infusional 5-Fluorouracil When Combined With Irinotecan for the Treatment of Metastatic Colorectal Cancer
Original Study
Differences in Efficacy and Safety Between Capecitabine and Infusional 5-Fluorouracil When Combined With Irinotecan for the Treatment of Metastatic Colorectal Cancer Francesco Montagnani,1 Antonella Chiriatti,2 Sara Licitra,1 Camillo Aliberti,3 Giammaria Fiorentini1 Abstract Background: Capecitabine is an oral fluoropyrimidine that is shown to have similar efficacy to 5-fluorouracil (5-FU) when used both alone and in combination with oxaliplatin in the treatment of colorectal cancer (CRC). Capecitabine and irinotecan combinations (XELIRI) have been developed for the treatment of this disease but randomized comparisons with standard infusional 5-FU and irinotecan (FOLFIRI) showed conflicting results. Patients and Methods: We searched the literature for randomized controlled trials comparing XELIRI to FOLFIRI for the treatment of metastatic colorectal cancer. Odds ratios with 95% confidence intervals were used to analyze dichotomous variables. Hazard ratios for progression and death were combined with an inverse variance method based on logarithmic conversion. The fixed-effect model and Mantel-Haenszel method were used. Heterogeneity was investigated with the Q-test and I2. Sensitivity analyses were performed. Results: Only 3 studies were identified, involving a total of 450 patients. XELIRI was associated with significantly shorter progression-free survival (PFS) and increased grade 3/4 gastrointestinal toxicities such as nausea, vomiting, and diarrhea. Severe neutropenia, however, was significantly more frequent with FOLFIRI. No differences in responses and febrile neutropenia events were observed. Conclusion: Our analysis suggest that the 2 regimens are not equivalent. XELIRI remains an option for the first-line treatment of metastatic CRC but FOLFIRI should be preferred as it confers more benefits in terms of PFS and induces fewer GI toxicities. Clinical Colorectal Cancer, Vol. 9, No. 4, 243-247, 2010; DOI: 10.3816/CCC.2010.n.036 Keywords: Bevacizumab, FOLFIRI, XELIRI
Introduction Metastatic colorectal carcinoma (mCRC) represents one of the most common causes of cancer-related deaths worldwide. In 2006, there were more than 207,000 cancer-related deaths in Europe alone.1 In the past few decades, effective chemotherapy regimens have been developed with some advantage in survival time. For a long time, 5-fluorouracil (5-FU) together with the biologic modifier folinic acid (FU/LV) have been the mainstay of treatment and are 1Oncology
Unit, Department of Medicine, S. Giuseppe Hospital, AUSL 11, Empoli (Florence), Italy 2Nurse Medical School, Siena University School of Medicine, Siena, Italy 3Department of Radiology, Delta Hospital Lagosanto, Ferrara, Italy Submitted: Jan 8, 2010; Revised: Mar 17, 2010; Accepted: Apr 6, 2010 Address for correspondence: Francesco Montagnani, MD, S. Giuseppe Hospital, Azienda Unità Sanitaria Locale (AUSL) 11, Empoli Firenze 50053, Italy Fax: 39-057-170-5695; e-mail: [email protected]
still used in almost all chemotherapeutic schedules. Continuous infusion is preferred because a meta-analysis showed a superior efficacy and a lower toxicity over bolus administration.2 Irinotecan and oxaliplatin are 2 other drugs that are demonstrated to be active in the treatment of mCRC. Currently, the concomitant administrations of FU/LV and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are regarded as the standard treatments of this condition with or without the addition of the newer monoclonal antibodies cetuximab or bevacizumab.3-5 Moreover, a statistical analysis suggests that the administration of all the active drugs correlates with longer survival time.6 The administration of continuous infusion FU/LV requires central venous access devices which can lead to infections and thrombosis. Moreover, the placement and the subsequent management of these devices require important economic resources. An oral administration of 5-FU would be, for these reasons, more convenient and
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
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XELIRI in Metastatic Colorectal Cancer Figure 1 Trial Flow Chart
532 Potentially Relevant Publications 446 Excluded Because not RCT or Duplications 86 Potentially Relevant RCT Remaining 83 Excluded Because Not Comparing FOLFIRI to XELIRI 3 RCT Available for the Analysis
Abbreviations: FOLFIRI = 5-fluorouracil/leucovorin/irinotecan; RCT = randomized controlled trials; XELIRI = capecitabine and irinotecan combinations
Table 1 Characteristics of the Patients Involved in the Analysis Characteristic, n %
XELIRI (n = 230)
FOLFIRI (n = 231)
Sex
Systematic Literature Search We searched PubMed, EMBASE, and the Cochrane Register of Controlled Trials using different combinations of the terms “irinotecan,” “capecitabine,” “XELIRI,” “FOLFIRI,” and “metastatic colorectal cancer.” When possible, we limited the results to randomized controlled trials. We also looked at studies presented as abstracts in the annual meeting of the European Society of Medical Oncology and the American Society of Clinical Oncology in the past 10 years. References of the identified publications were screened. The trial schema is given in Figure 1.
129 (56.1)
148 (64.1)
Female
101 (43.9)
83 (35.9)
0
127 (55.2)
135 (58.4)
1
103 (43.9)
96 (41.6)
2
2 (0.9)
0 (0)
Colon
161 (70.0)
167 (72.3)
Design and Participants
Rectum
69 (30.0)
64 (27.7)
Three randomized phase III studies involving a total of 461 patients were identified. The principal endpoints were PFS for the BICC-C, Khöne et al trial, and objective response rate in the study of Skof et al. These last 2 trials were closed prematurely because of the approval of bevacizumab (Skof et al) and because of 8 toxic deaths (6 for XELIRI and 2 for FOLFIRI) reported by Khöne et al. We investigated PFS and responses. Overall survival was not investigated because in the 2 smaller studies the median follow-up time was too short (13 and 17 months). Patient characteristics are given in Table 1. Possible sources of selection, assessment, attrition, and detection biases were investigated to determine the quality of the studies.
Primary
A χ2 test did not find significant differences (P > .05 for all). Abbreviations: FOLFIRI = 5-fluorouracil/leucovorin/irinotecan; PS = performance status; XELIRI = capecitabine/irinotecan
better accepted by the patients. Capecitabine is an orally available prodrug that is converted to 5-FU preferentially in tumor tissues. In randomized clinical studies it was shown to be at least as effective as infusional FU/LV in the treatment of CRC in both the metastatic and the adjuvant setting, with a good toxicity profile, and with no need for the placement of central venous access devices.7-10 Combinations of capecitabine have been developed with oxaliplatin (XELOX) and irinotecan (XELIRI). It has been compared with infusional 5-FU in at least 5 randomized studies when used in oxaliplatin-based combinations, and a recent meta-analysis involving 3494 patients found that no significant differences are present with respect to progression-free survival (PFS) even though capecitabine is associated with lower response rates. On the other hand, very few studies have been conducted to compare capecitabine to infusional 5-FU/LV when used in irinotecan-based combinations and randomized studies reported conflicting results.11-13
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Patients and Methods
Male
PS
244
The XELIRI regimen has been studied in preliminary phase I and II studies and showed to be active and well tolerated. Main toxicities recorded were diarrhea, other gastrointestinal (GI) events and neutropenia. A typical capecitabine-related side effect reported was also the hand-foot syndrome.14-18 In the BICC-C study, XELIRI was directly compared with FOLFIRI. A significantly shorter PFS was noted for the capecitabinebased combination, which was also associated with higher toxicity. Specifically, almost 50% of the patients treated with the capecitabine and irinotecan combination experienced at least 1 episode of severe grade 3 or grade 4 diarrhea. Because of these findings, the XELIRI arm was considered inferior and prematurely closed after an interim analysis. However, other authors reported different results. Skof et al in a recent randomized study noted no significant differences in PFS and toxicity between XELIRI and FOLFIRI, and argued in favor of a substantial equivalence between the 2 regimens.13 The aim of the present work is to perform a systematic review of the available literature in order to better assess the efficacy and safety of the XELIRI regimen, specifically when compared with the standard FOLFIRI schedule.
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Data Extraction and Synthesis Data were retrieved from the published materials or kindly communicated by the principal investigators. The odds ratio (OR) was used to analyze dichotomous variables. The hazard ratio (HR) was combined using an inverse-based logarithmic conversion. A 95% confidence interval (CI) was used to determine the standard error (SE). The survival analysis was made considering the intent-to-treat (ITT) population.
Francesco Montagnani et al Figure 2 Standard Forest Plot of the Hazard Ratio for Progression Study
Weight
HR
95% CI
Khöne et al
20%
0.76
0.48-1.21
Skof et al
12%
0.94
0.58-1.50
Fuchs et al
68%
0.74
0.56-0.96
Outcome
100%
0.76
0.65-0.90
Z-Test = 3.23 P < .001
Progression-Free Survival
0.40
Q-Test = 0.88 P = .64; I 2 = 0%
0.60
0
1.70
HR
Values < 1 favor FOLFIRI. P value of the Z-test is 2-sided. Abbreviations: CI = confidence interval; HR = hazard ratio
The fixed-effect model and Mantel-Haenszel method (M-H) were used. The treatment effect was reported as a point estimate with a 95% CI. Heterogeneity was evaluated with the Q-test and I 2. Because of the small number of studies, the P values of the Q-tests were considered significant at a value of P < .1. Aggregate data were used for the analysis of HR for progression. The OR of toxicities, responses, and R0 resections were calculated with a 95% CI from the number of events reported and the total number of patients observed. Z-test for overall effect and the related 2-tailed P value was assessed for every analysis. Two independent reviewers extracted and interpreted the data. MIX meta-analysis (http:// www.meta-analysis-made-easy.com) and RevMan software (http:// www.ims.cochrane.org/revman) were used for the analyses without differences in the reported outcomes.
Sensitivity Analysis For the sensitivity analysis we repeated the evaluation excluding 1 of the studies, testing all of the possible combinations. We also repeated the analysis using a 20% higher SE.
Results Patients’ Characteristics and Study Quality Patient characteristics are shown in Table 1. Others characteristics, such as site and number of metastases, serum lactate dehydrogenase (LDH), and carcinoembryonic antigen (CEA) were not reported in the BICC-C trial. No study was blinded. We have concerns of performance bias in the BICC-C, and in the study reported by Khöne et al. In the Khöne et al study, the dose intensity of capecitabine was only 73.7%, compared with that of 86.8% for 5-FU. This difference is probably because of the higher rate of adverse events in the capecitabine arm, but patient compliance may also have played a role. Dose intensities in the BICC-C trial were not reported but authors stated that reductions were performed for grade > 2 toxicities. These toxicities where higher in the XELIRI arm, leading to more dose reductions and treatment delays. No differences in dose reductions and treatment delays were reported by Skof et al. Considering these observations, we believe that a moderate to high risk of performance bias is present. Correct randomization procedures were reported by Fuchs et al and Khöne et al but were unclear in the study of Skof et al in which the patients were well balanced in respect to a variety of patient characteristics including performance
Table 2 Analysis of Grade 3/4 Toxicities (n = 450) OR (95% CI)
P Value
Q-Test/I 2
Diarrhea
4.58 (2.41-8.71)
< .01
0.2/38%
Nausea
1.92 (0.81-4.55)
.05
0.39/0%
Vomiting
1.82 (0.74-4.45)
.08
0.93/0%
Neutropenia
0.62 (0.35-1.10)
.03
0.64/0%
Febrile Neutropenia
1.66 (0.49-5.60)
.29
0.79/0%
Toxicity
Values of I 2 and P value of the Q-test are reported in the right column. P value is 2-sided. Abbreviations: CI = confidence interval; OR = odds ratio
status (PS), serum LDH and CEA, site and number of metastases, and percentage of liver involvement. Overall, we believe that the risk of selection bias is low. We found no evidence of attrition and detection bias.
Progression-Free Survival and Response As shown in Figure 2, we observed a significant reduction in the risk of progression associated to FOLFIRI (HR, 0.76; 95% CI, 0.62-0.95; P < .01). No signs of heterogeneity were present. We performed the sensitivity analysis as previously described. The use of random effect did not significantly alter the results. Significance of the benefit associated with FOLFIRI was retained if the trial of Skof et al or Khöne et al were not included. If the BICC-C study was not included, a decreased HR for progression was still associated with FOLFIRI but significance was lost, probably because of the small population involved (< 200 patients [HR, 0.82; 95% CI, 0.57-1.18; P = .17]). Results retained significance, also, if the standard errors were artificially increased by 20% (HR, 0.76; 95% CI, 0.60-0.98; P < .01). Response to a chemotherapeutic treatment weakly correlates with survival in patients with CRC, to a lesser extent than PFS. Recently, it has been shown that the rate of R0 resection is a great prognostic factor with approximately 30% of patients rendered disease-free by an R0 metastasectomy experiencing long-term survival. In this regard, the rate of responses of a chemotherapeutic regimen could also be of importance as it has been shown to correlate with the rate of R0 resections.19-21 We performed an analysis of the response rate between XELIRI and FOLFIRI, but no significant differences were observed (OR, 0.78; 95% CI, 0.48-1.27; P = .18).
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XELIRI in Metastatic Colorectal Cancer Toxicity Analysis of toxicities included 450 patients. Twelve patients were not available for toxicity assessment, 9 in the 5-FU arm and 3 in the other. The OR was calculated from the reported population and the number of events (Table 2). A significant increase in severe grade 3/4 toxicity was associated with the use of capecitabine, whereas no difference was present in the events of febrile neutropenia. Events of severe grade 3/4 neutropenia were significantly lower in the capecitabine arm. A sharp difference was evident in GI toxicities between the BICC-C study and the study of Khöne et al with respect to the Skof et al trial. In the former trial, the authors observed almost no differences in these toxicities, whereas in the remaining 2 a marked increase was clearly associated with capecitabine. Even if heterogeneity was not evidenced by the Q-test and the I2, we performed a test of interaction between the population involved in the BICC-C and the Khöne et al study comparing them to that in the Skof et al trial. The results confirmed the presence of a significant difference in the rates of grade 3/4 nausea, vomiting, and diarrhea in this last study with respect to the others (P < .01 for all). We cannot explain this observation. It has been hypothesized that the tolerability of fluoropyrimidines can differ by region.22 The BICC-C is an American trial, and the majority of the patients were white. The Khöne et al and Skof et al trials were conducted in Europe and presumably involved a white population even if 1 was conducted in the center of Europe (Khöne et al) and the other in an eastern European country (Slovenia). We cannot rule out differences in patient population but given that the vast majority of patients were white with no imbalances between the 2 arms, this hypothesis seems unlikely.
Discussion To our knowledge, this is the first systematic review conducted to compare the efficacy and toxicity profile of XELIRI and FOLFIRI. Our results do not support the equivalence between the 2 regimens. Consistent with the results of the BICC-C study, XELIRI was associated with significantly shorter PFS and increased GI toxicities, but 2 considerations need to be made. First, our analysis is small and involves only 3 published studies for a total of 450 patients, with a single study accounting for more than 50% of the total weight. Second, unexplainable differences seem to be present regarding GI toxicities. In the BICC-C and the Khöne et al studies, a very high rate of GI events were reported, which led to dose reductions. Capecitabine dose intensity was lower than that of 5-FU in this last study and it is very likely that this has also happened with BICC-C. This observation could explain the lower efficacy observed for XELIRI in these 2 studies. Consistent with this hypothesis is the Skof et al trials, in which no differences in toxicity were reported: the PFS was almost identical between the 2 arms. It should be noted, however, that this hypothesis has been addressed in the BICC-C by analyzing only the patients who did not undergo dose reductions. Even in this subset, a significant improvement in PFS was associated with FOLFIRI, indicating that increased toxicities and more dose reductions could not be enough to explain the observed differences in efficacy. The results of our analysis argue in favor of a significant superiority of FOLFIRI over XELIRI, with increased PFS and lesser
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toxic events; but, because of the aforementioned considerations we believe that more data are needed. An increase in GI toxicities was evident for the capecitabinebased combinations. Possible explanations for this occurrence are related to the dosage of capecitabine and patient compliance. Whether it is very difficult to address this last point, the schedule of XELIRI was almost the same across all of the trials and was selected on the bases of preliminary nonrandomized studies. Alternative schedules could also offer comparable efficacy and lesser toxicities as some clinical reports suggest. In a recently published small single-arm trial, capecitabine and irinotecan were administered on a biweekly basis and severe diarrhea was recorded in only 15% of patients.23 However, changing dosing or scheduling could also affect the efficacy, and in the absence of randomized comparison it is not possible to draw any conclusion in this regard. In the past decade, the monoclonal antibodies cetuximab, bevacizumab, and more recently, panitumumab have been approved in combination with chemotherapy for the treatment of mCRC, after the demonstration of a small but significant benefit in survival or PFS when combined with chemotherapy. Bevacizumab is a monoclonal antibody specific for vascular endothelial growth factor–A (VEGF-A), one of the most important proangiogenic factors. In a large randomized study comparing capecitabine/oxaliplatin with infusional 5-FU/LV/oxaliplatin, bevacizumab was shown to increase the PFS of both regimens without an important effect on the toxicity. Interestingly, the greatest benefit occurred for the capecitabine-based combination.24 Only 1 randomized trial has been conducted to investigate the effect of bevacizumab added to XELIRI and no differences in response, PFS, or survival have been observed. However, this study is clearly underpowered to detect small differences. Also of note, the toxicity profile did not significantly differ significantly.25 Another report confirmed that bevacizumab does not add alarming toxicities when combined with capecitabine and irinotecan.26 The BICC-C study was designed to compare 3 different irinotecan/fluoropyrimidine combinations and was divided in a first part without bevacizumab and a second part in which bevacizumab was combined with all regimens. Although not strictly randomized, this comparison could have been of help, but unfortunately the XELIRI arm was closed at an interim analysis as previously stated. In our opinion, the addiction of bevacizumab to both of the regimens investigated in the present analysis could alter the results, possibly increasing PFS and erasing the observed difference in efficacy. However, the absence of well-conducted randomized studies makes this assumption very difficult to verify.
Conclusion We failed to demonstrate the equivalence between FOLFIRI and XELIRI. On the contrary, our results strongly argue for shorter PFS and increased GI events related to the capecitabine-based regimen, but the analysis suffers from some limitations. XELIRI remains a possible option for the first-line treatment of patients with CRC, but FOLFIRI confers a longer PFS and should be preferred until more data are available. Inclusion of monoclonal antibodies to both regimens could improve results, but data from randomized studies are lacking.
Francesco Montagnani et al Disclosures This work has been entirely funded by the Azienda Unità Sanitaria Locale (AUSL) 11 Empoli, and the Siena University School of Medicine. All authors have no relevant relationships to disclose.
13.
References
14.
1. Ferlay J, Authier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18:581-92. 2. Meta Analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16:301-8. 3. Köhne CH, van Cutsem E, Wils J, et al. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol 2005; 23:4856-65. 4. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 2000; 343:905-14. 5. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 2000; 355:1041-7. 6. Grothey A, Sargent D, Goldberg RM, et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22:1209-14. 7. Comella P, Casaretti R, Sandomenico C, et al. Capecitabine, alone and in combination, in the management of patients with colorectal cancer: a review of the evidence. Drugs 2008; 68:949-61. 8. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352:2696-704. 9. Cassidy J, Twelves C, Van Cutsem E, et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002; 13:566-75. 10. Ward S, Kaltenthaler E, Cowan J, et al. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation. Health Technol Assess 2003; 7:1-93. 11. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J Clin Oncol 2007; 25:4779-86. 12. Köhne CH, De Greve J, Hartmann JT, et al. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-
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line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol 2008; 19:920-6. Skof E, Rebersek M, Hlebanja Z, et al. Capecitabine plus Irinotecan (XELIRI regimen) compared to 5-FU/LV plus Irinotecan (FOLFIRI regimen) as neoadjuvant treatment for patients with unresectable liver-only metastases of metastatic colorectal cancer: a randomised prospective phase II trial. BMC Cancer 2009; 9:120. Rea DW, Nortier JW, Ten Bokkel Huinink WW, et al. A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer. Ann Oncol 2005; 16:1123-32. Bajetta E, Di Bartolomeo M, Mariani L, et al. Randomized multicenter phase II trial of two different schedules of irinotecan combined with capecitabine as firstline treatment in metastatic colorectal carcinoma. Cancer 2004; 100:279-87. Delord JP, Pierga JY, Dieras V, et al. A phase I clinical and pharmacokinetic study of capecitabine (Xeloda) and irinotecan combination therapy (XELIRI) in patients with metastatic gastrointestinal tumours. Br J Cancer 2005; 92:820-6. Kim TW, Kang WK, Chang HM, et al. Multicenter phase II study of oral capecitabine plus irinotecan as first-line chemotherapy in advanced colorectal cancer: a Korean Cancer Study Group trial. Acta Oncol 2005; 44:230-5. Patt YZ, Lee FC, Liebmann JE, et al. Capecitabine plus 3-weekly irinotecan (XELIRI regimen) as first-line chemotherapy for metastatic colorectal cancer: phase II trial results. Am J Clin Oncol 2007; 30:350-7. Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumor response and resection rates. Ann Oncol 2005; 16:1311-9. Simmonds PC, Primrose JN, Colquitt JL, et al. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006; 94:982-99 Wei AC, Greig PD, Grant D, et al. Survival after hepatic resection for colorectal cancer metastases: a 10-year experience. Ann Surg Oncol 2006; 13:668-76. Haller DG, Cassidy J, Clarke S, et al. Tolerability of fluoropyrimidines appears to differ by region. J Clin Oncol 2006; 24(18 suppl):149s (abstract 3514). Garcia-Alfonso P, Muñoz-Martin A, Mendez-Ureña M, et al. Capecitabine in combination with irinotecan (XELIRI), administered as a 2-weekly schedule, as first-line chemotherapy for patients with metastatic colorectal cancer: a phase II study of the Spanish GOTI group. Br J Cancer 2009; 101:1039-43. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26:2013-9. Moehler M, Sprinzl MF, Abdelfattah M, et al. Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol 2009; 15:449-56. Ardavanis A, Kountourakis P, Mantzaris I, et al. Bevacizumab added to the irinotecan and capecitabine combination for advanced colorectal cancer: a well-tolerated, active and convenient regimen. Anticancer Res 2008; 28:3087-92.
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Differences in Efficacy and Safety Between Capecitabine and Infusional 5-Fluorouracil When Combined With Irinotecan for the Treatment of Metastatic Colorectal Cancer Francesco Montagnani,1 Antonella Chiriatti,2 Sara Licitra,1 Camillo Aliberti,3 Giammaria Fiorentini1 Abstract Background: Capecitabine is an oral fluoropyrimidine that is shown to have similar efficacy to 5-fluorouracil (5-FU) when used both alone and in combination with oxaliplatin in the treatment of colorectal cancer (CRC). Capecitabine and irinotecan combinations (XELIRI) have been developed for the treatment of this disease but randomized comparisons with standard infusional 5-FU and irinotecan (FOLFIRI) showed conflicting results. Patients and Methods: We searched the literature for randomized controlled trials comparing XELIRI to FOLFIRI for the treatment of metastatic colorectal cancer. Odds ratios with 95% confidence intervals were used to analyze dichotomous variables. Hazard ratios for progression and death were combined with an inverse variance method based on logarithmic conversion. The fixed-effect model and Mantel-Haenszel method were used. Heterogeneity was investigated with the Q-test and I2. Sensitivity analyses were performed. Results: Only 3 studies were identified, involving a total of 450 patients. XELIRI was associated with significantly shorter progression-free survival (PFS) and increased grade 3/4 gastrointestinal toxicities such as nausea, vomiting, and diarrhea. Severe neutropenia, however, was significantly more frequent with FOLFIRI. No differences in responses and febrile neutropenia events were observed. Conclusion: Our analysis suggest that the 2 regimens are not equivalent. XELIRI remains an option for the first-line treatment of metastatic CRC but FOLFIRI should be preferred as it confers more benefits in terms of PFS and induces fewer GI toxicities. Clinical Colorectal Cancer, Vol. 9, No. 4, 243-247, 2010; DOI: 10.3816/CCC.2010.n.036 Keywords: Bevacizumab, FOLFIRI, XELIRI
Introduction Metastatic colorectal carcinoma (mCRC) represents one of the most common causes of cancer-related deaths worldwide. In 2006, there were more than 207,000 cancer-related deaths in Europe alone.1 In the past few decades, effective chemotherapy regimens have been developed with some advantage in survival time. For a long time, 5-fluorouracil (5-FU) together with the biologic modifier folinic acid (FU/LV) have been the mainstay of treatment and are 1Oncology
Unit, Department of Medicine, S. Giuseppe Hospital, AUSL 11, Empoli (Florence), Italy 2Nurse Medical School, Siena University School of Medicine, Siena, Italy 3Department of Radiology, Delta Hospital Lagosanto, Ferrara, Italy Submitted: Jan 8, 2010; Revised: Mar 17, 2010; Accepted: Apr 6, 2010 Address for correspondence: Francesco Montagnani, MD, S. Giuseppe Hospital, Azienda Unità Sanitaria Locale (AUSL) 11, Empoli Firenze 50053, Italy Fax: 39-057-170-5695; e-mail: [email protected]
still used in almost all chemotherapeutic schedules. Continuous infusion is preferred because a meta-analysis showed a superior efficacy and a lower toxicity over bolus administration.2 Irinotecan and oxaliplatin are 2 other drugs that are demonstrated to be active in the treatment of mCRC. Currently, the concomitant administrations of FU/LV and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are regarded as the standard treatments of this condition with or without the addition of the newer monoclonal antibodies cetuximab or bevacizumab.3-5 Moreover, a statistical analysis suggests that the administration of all the active drugs correlates with longer survival time.6 The administration of continuous infusion FU/LV requires central venous access devices which can lead to infections and thrombosis. Moreover, the placement and the subsequent management of these devices require important economic resources. An oral administration of 5-FU would be, for these reasons, more convenient and
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
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XELIRI in Metastatic Colorectal Cancer Figure 1 Trial Flow Chart
532 Potentially Relevant Publications 446 Excluded Because not RCT or Duplications 86 Potentially Relevant RCT Remaining 83 Excluded Because Not Comparing FOLFIRI to XELIRI 3 RCT Available for the Analysis
Abbreviations: FOLFIRI = 5-fluorouracil/leucovorin/irinotecan; RCT = randomized controlled trials; XELIRI = capecitabine and irinotecan combinations
Table 1 Characteristics of the Patients Involved in the Analysis Characteristic, n %
XELIRI (n = 230)
FOLFIRI (n = 231)
Sex
Systematic Literature Search We searched PubMed, EMBASE, and the Cochrane Register of Controlled Trials using different combinations of the terms “irinotecan,” “capecitabine,” “XELIRI,” “FOLFIRI,” and “metastatic colorectal cancer.” When possible, we limited the results to randomized controlled trials. We also looked at studies presented as abstracts in the annual meeting of the European Society of Medical Oncology and the American Society of Clinical Oncology in the past 10 years. References of the identified publications were screened. The trial schema is given in Figure 1.
129 (56.1)
148 (64.1)
Female
101 (43.9)
83 (35.9)
0
127 (55.2)
135 (58.4)
1
103 (43.9)
96 (41.6)
2
2 (0.9)
0 (0)
Colon
161 (70.0)
167 (72.3)
Design and Participants
Rectum
69 (30.0)
64 (27.7)
Three randomized phase III studies involving a total of 461 patients were identified. The principal endpoints were PFS for the BICC-C, Khöne et al trial, and objective response rate in the study of Skof et al. These last 2 trials were closed prematurely because of the approval of bevacizumab (Skof et al) and because of 8 toxic deaths (6 for XELIRI and 2 for FOLFIRI) reported by Khöne et al. We investigated PFS and responses. Overall survival was not investigated because in the 2 smaller studies the median follow-up time was too short (13 and 17 months). Patient characteristics are given in Table 1. Possible sources of selection, assessment, attrition, and detection biases were investigated to determine the quality of the studies.
Primary
A χ2 test did not find significant differences (P > .05 for all). Abbreviations: FOLFIRI = 5-fluorouracil/leucovorin/irinotecan; PS = performance status; XELIRI = capecitabine/irinotecan
better accepted by the patients. Capecitabine is an orally available prodrug that is converted to 5-FU preferentially in tumor tissues. In randomized clinical studies it was shown to be at least as effective as infusional FU/LV in the treatment of CRC in both the metastatic and the adjuvant setting, with a good toxicity profile, and with no need for the placement of central venous access devices.7-10 Combinations of capecitabine have been developed with oxaliplatin (XELOX) and irinotecan (XELIRI). It has been compared with infusional 5-FU in at least 5 randomized studies when used in oxaliplatin-based combinations, and a recent meta-analysis involving 3494 patients found that no significant differences are present with respect to progression-free survival (PFS) even though capecitabine is associated with lower response rates. On the other hand, very few studies have been conducted to compare capecitabine to infusional 5-FU/LV when used in irinotecan-based combinations and randomized studies reported conflicting results.11-13
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Patients and Methods
Male
PS
244
The XELIRI regimen has been studied in preliminary phase I and II studies and showed to be active and well tolerated. Main toxicities recorded were diarrhea, other gastrointestinal (GI) events and neutropenia. A typical capecitabine-related side effect reported was also the hand-foot syndrome.14-18 In the BICC-C study, XELIRI was directly compared with FOLFIRI. A significantly shorter PFS was noted for the capecitabinebased combination, which was also associated with higher toxicity. Specifically, almost 50% of the patients treated with the capecitabine and irinotecan combination experienced at least 1 episode of severe grade 3 or grade 4 diarrhea. Because of these findings, the XELIRI arm was considered inferior and prematurely closed after an interim analysis. However, other authors reported different results. Skof et al in a recent randomized study noted no significant differences in PFS and toxicity between XELIRI and FOLFIRI, and argued in favor of a substantial equivalence between the 2 regimens.13 The aim of the present work is to perform a systematic review of the available literature in order to better assess the efficacy and safety of the XELIRI regimen, specifically when compared with the standard FOLFIRI schedule.
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Data Extraction and Synthesis Data were retrieved from the published materials or kindly communicated by the principal investigators. The odds ratio (OR) was used to analyze dichotomous variables. The hazard ratio (HR) was combined using an inverse-based logarithmic conversion. A 95% confidence interval (CI) was used to determine the standard error (SE). The survival analysis was made considering the intent-to-treat (ITT) population.
Francesco Montagnani et al Figure 2 Standard Forest Plot of the Hazard Ratio for Progression Study
Weight
HR
95% CI
Khöne et al
20%
0.76
0.48-1.21
Skof et al
12%
0.94
0.58-1.50
Fuchs et al
68%
0.74
0.56-0.96
Outcome
100%
0.76
0.65-0.90
Z-Test = 3.23 P < .001
Progression-Free Survival
0.40
Q-Test = 0.88 P = .64; I 2 = 0%
0.60
0
1.70
HR
Values < 1 favor FOLFIRI. P value of the Z-test is 2-sided. Abbreviations: CI = confidence interval; HR = hazard ratio
The fixed-effect model and Mantel-Haenszel method (M-H) were used. The treatment effect was reported as a point estimate with a 95% CI. Heterogeneity was evaluated with the Q-test and I 2. Because of the small number of studies, the P values of the Q-tests were considered significant at a value of P < .1. Aggregate data were used for the analysis of HR for progression. The OR of toxicities, responses, and R0 resections were calculated with a 95% CI from the number of events reported and the total number of patients observed. Z-test for overall effect and the related 2-tailed P value was assessed for every analysis. Two independent reviewers extracted and interpreted the data. MIX meta-analysis (http:// www.meta-analysis-made-easy.com) and RevMan software (http:// www.ims.cochrane.org/revman) were used for the analyses without differences in the reported outcomes.
Sensitivity Analysis For the sensitivity analysis we repeated the evaluation excluding 1 of the studies, testing all of the possible combinations. We also repeated the analysis using a 20% higher SE.
Results Patients’ Characteristics and Study Quality Patient characteristics are shown in Table 1. Others characteristics, such as site and number of metastases, serum lactate dehydrogenase (LDH), and carcinoembryonic antigen (CEA) were not reported in the BICC-C trial. No study was blinded. We have concerns of performance bias in the BICC-C, and in the study reported by Khöne et al. In the Khöne et al study, the dose intensity of capecitabine was only 73.7%, compared with that of 86.8% for 5-FU. This difference is probably because of the higher rate of adverse events in the capecitabine arm, but patient compliance may also have played a role. Dose intensities in the BICC-C trial were not reported but authors stated that reductions were performed for grade > 2 toxicities. These toxicities where higher in the XELIRI arm, leading to more dose reductions and treatment delays. No differences in dose reductions and treatment delays were reported by Skof et al. Considering these observations, we believe that a moderate to high risk of performance bias is present. Correct randomization procedures were reported by Fuchs et al and Khöne et al but were unclear in the study of Skof et al in which the patients were well balanced in respect to a variety of patient characteristics including performance
Table 2 Analysis of Grade 3/4 Toxicities (n = 450) OR (95% CI)
P Value
Q-Test/I 2
Diarrhea
4.58 (2.41-8.71)
< .01
0.2/38%
Nausea
1.92 (0.81-4.55)
.05
0.39/0%
Vomiting
1.82 (0.74-4.45)
.08
0.93/0%
Neutropenia
0.62 (0.35-1.10)
.03
0.64/0%
Febrile Neutropenia
1.66 (0.49-5.60)
.29
0.79/0%
Toxicity
Values of I 2 and P value of the Q-test are reported in the right column. P value is 2-sided. Abbreviations: CI = confidence interval; OR = odds ratio
status (PS), serum LDH and CEA, site and number of metastases, and percentage of liver involvement. Overall, we believe that the risk of selection bias is low. We found no evidence of attrition and detection bias.
Progression-Free Survival and Response As shown in Figure 2, we observed a significant reduction in the risk of progression associated to FOLFIRI (HR, 0.76; 95% CI, 0.62-0.95; P < .01). No signs of heterogeneity were present. We performed the sensitivity analysis as previously described. The use of random effect did not significantly alter the results. Significance of the benefit associated with FOLFIRI was retained if the trial of Skof et al or Khöne et al were not included. If the BICC-C study was not included, a decreased HR for progression was still associated with FOLFIRI but significance was lost, probably because of the small population involved (< 200 patients [HR, 0.82; 95% CI, 0.57-1.18; P = .17]). Results retained significance, also, if the standard errors were artificially increased by 20% (HR, 0.76; 95% CI, 0.60-0.98; P < .01). Response to a chemotherapeutic treatment weakly correlates with survival in patients with CRC, to a lesser extent than PFS. Recently, it has been shown that the rate of R0 resection is a great prognostic factor with approximately 30% of patients rendered disease-free by an R0 metastasectomy experiencing long-term survival. In this regard, the rate of responses of a chemotherapeutic regimen could also be of importance as it has been shown to correlate with the rate of R0 resections.19-21 We performed an analysis of the response rate between XELIRI and FOLFIRI, but no significant differences were observed (OR, 0.78; 95% CI, 0.48-1.27; P = .18).
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XELIRI in Metastatic Colorectal Cancer Toxicity Analysis of toxicities included 450 patients. Twelve patients were not available for toxicity assessment, 9 in the 5-FU arm and 3 in the other. The OR was calculated from the reported population and the number of events (Table 2). A significant increase in severe grade 3/4 toxicity was associated with the use of capecitabine, whereas no difference was present in the events of febrile neutropenia. Events of severe grade 3/4 neutropenia were significantly lower in the capecitabine arm. A sharp difference was evident in GI toxicities between the BICC-C study and the study of Khöne et al with respect to the Skof et al trial. In the former trial, the authors observed almost no differences in these toxicities, whereas in the remaining 2 a marked increase was clearly associated with capecitabine. Even if heterogeneity was not evidenced by the Q-test and the I2, we performed a test of interaction between the population involved in the BICC-C and the Khöne et al study comparing them to that in the Skof et al trial. The results confirmed the presence of a significant difference in the rates of grade 3/4 nausea, vomiting, and diarrhea in this last study with respect to the others (P < .01 for all). We cannot explain this observation. It has been hypothesized that the tolerability of fluoropyrimidines can differ by region.22 The BICC-C is an American trial, and the majority of the patients were white. The Khöne et al and Skof et al trials were conducted in Europe and presumably involved a white population even if 1 was conducted in the center of Europe (Khöne et al) and the other in an eastern European country (Slovenia). We cannot rule out differences in patient population but given that the vast majority of patients were white with no imbalances between the 2 arms, this hypothesis seems unlikely.
Discussion To our knowledge, this is the first systematic review conducted to compare the efficacy and toxicity profile of XELIRI and FOLFIRI. Our results do not support the equivalence between the 2 regimens. Consistent with the results of the BICC-C study, XELIRI was associated with significantly shorter PFS and increased GI toxicities, but 2 considerations need to be made. First, our analysis is small and involves only 3 published studies for a total of 450 patients, with a single study accounting for more than 50% of the total weight. Second, unexplainable differences seem to be present regarding GI toxicities. In the BICC-C and the Khöne et al studies, a very high rate of GI events were reported, which led to dose reductions. Capecitabine dose intensity was lower than that of 5-FU in this last study and it is very likely that this has also happened with BICC-C. This observation could explain the lower efficacy observed for XELIRI in these 2 studies. Consistent with this hypothesis is the Skof et al trials, in which no differences in toxicity were reported: the PFS was almost identical between the 2 arms. It should be noted, however, that this hypothesis has been addressed in the BICC-C by analyzing only the patients who did not undergo dose reductions. Even in this subset, a significant improvement in PFS was associated with FOLFIRI, indicating that increased toxicities and more dose reductions could not be enough to explain the observed differences in efficacy. The results of our analysis argue in favor of a significant superiority of FOLFIRI over XELIRI, with increased PFS and lesser
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toxic events; but, because of the aforementioned considerations we believe that more data are needed. An increase in GI toxicities was evident for the capecitabinebased combinations. Possible explanations for this occurrence are related to the dosage of capecitabine and patient compliance. Whether it is very difficult to address this last point, the schedule of XELIRI was almost the same across all of the trials and was selected on the bases of preliminary nonrandomized studies. Alternative schedules could also offer comparable efficacy and lesser toxicities as some clinical reports suggest. In a recently published small single-arm trial, capecitabine and irinotecan were administered on a biweekly basis and severe diarrhea was recorded in only 15% of patients.23 However, changing dosing or scheduling could also affect the efficacy, and in the absence of randomized comparison it is not possible to draw any conclusion in this regard. In the past decade, the monoclonal antibodies cetuximab, bevacizumab, and more recently, panitumumab have been approved in combination with chemotherapy for the treatment of mCRC, after the demonstration of a small but significant benefit in survival or PFS when combined with chemotherapy. Bevacizumab is a monoclonal antibody specific for vascular endothelial growth factor–A (VEGF-A), one of the most important proangiogenic factors. In a large randomized study comparing capecitabine/oxaliplatin with infusional 5-FU/LV/oxaliplatin, bevacizumab was shown to increase the PFS of both regimens without an important effect on the toxicity. Interestingly, the greatest benefit occurred for the capecitabine-based combination.24 Only 1 randomized trial has been conducted to investigate the effect of bevacizumab added to XELIRI and no differences in response, PFS, or survival have been observed. However, this study is clearly underpowered to detect small differences. Also of note, the toxicity profile did not significantly differ significantly.25 Another report confirmed that bevacizumab does not add alarming toxicities when combined with capecitabine and irinotecan.26 The BICC-C study was designed to compare 3 different irinotecan/fluoropyrimidine combinations and was divided in a first part without bevacizumab and a second part in which bevacizumab was combined with all regimens. Although not strictly randomized, this comparison could have been of help, but unfortunately the XELIRI arm was closed at an interim analysis as previously stated. In our opinion, the addiction of bevacizumab to both of the regimens investigated in the present analysis could alter the results, possibly increasing PFS and erasing the observed difference in efficacy. However, the absence of well-conducted randomized studies makes this assumption very difficult to verify.
Conclusion We failed to demonstrate the equivalence between FOLFIRI and XELIRI. On the contrary, our results strongly argue for shorter PFS and increased GI events related to the capecitabine-based regimen, but the analysis suffers from some limitations. XELIRI remains a possible option for the first-line treatment of patients with CRC, but FOLFIRI confers a longer PFS and should be preferred until more data are available. Inclusion of monoclonal antibodies to both regimens could improve results, but data from randomized studies are lacking.
Francesco Montagnani et al Disclosures This work has been entirely funded by the Azienda Unità Sanitaria Locale (AUSL) 11 Empoli, and the Siena University School of Medicine. All authors have no relevant relationships to disclose.
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