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The Oncologist, Vol. 11, No. 9, 1003-1009, October 2006; doi:10.1634/theoncologist.11-9-1003
© 2006 AlphaMed Press

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Special Section on Colorectal Cancer

Update on Capecitabine in Colorectal Cancer

Hans-Joachim Schmoll, Dirk Arnold

Department of Internal Medicine IV, Hematology & Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany

Key Words. Colorectal cancer • Capecitabine • Oxaliplatin • FOLFOX • CapOx • CapIri • XELOX

Correspondence: Hans-Joachim Schmoll, M.D., Ph.D., Department of Internal Medicine IV, Haematology & Oncology, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany. Telephone: + 49-345-557-2924; Fax: +49-345-557-2950; e-mail: hans-joachim. schmoll{at}medizin.uni-halle.de

Received November 25, 2005; accepted for publication August 18, 2006.


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Nonrandomized Comparisons...
 Randomized Trials
 Integrating Targeted Agents
 Discussion
 Disclosure of Potential...
 References
 
After completing this course, the reader will be able to:

  1. Discuss the potential use of oral capecitabine versus i.v. 5-FU in the treatment of colorectal cancer.
  2. Explain the evolving role of capecitabine in combination with novel, targeted therapeutics.
  3. Describe the role of capecitabine in combination with radiation therapy.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Nonrandomized Comparisons...
 Randomized Trials
 Integrating Targeted Agents
 Discussion
 Disclosure of Potential...
 References
 
In combination chemotherapy for metastatic colorectal cancer, i.v. 5-fluorouracil (5-FU) can be replaced by oral 5-FU (in the form of capecitabine or another orally available analogue) without negatively affecting overall toxicity and without remarkably reducing the efficacy of treatment in terms of response rate or overall survival. Preclinical evidence of synergy has led to promising early and successfully completed studies combining capecitabine plus oxaliplatin with bevacizumab, cetuximab, and epidermal growth factor receptor tyrosine kinase inhibitors. The use of preoperative capecitabine plus radiation is achieving good rates of pathological complete response in rectal cancer. While capecitabine is generally well tolerated, its potential toxicities need careful management and may require individual dose adaption.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Nonrandomized Comparisons...
 Randomized Trials
 Integrating Targeted Agents
 Discussion
 Disclosure of Potential...
 References
 
In first-line metastatic colorectal cancer (CRC), capecitabine (Xeloda®, Roche Ltd., Basel, Switzerland) is at least as active as bolus 5-fluorouracil (5-FU) and infusional 5-FU [1–6]. In stage III colon cancer, the X-Act trial showed that capecitabine is an active agent with a favorable toxicity profile [2, 3], is convenient to give, is well accepted by patients because it is oral rather than i.v. (Fig. 1Go) [7,8], and may reduce overall costs compared with i.v. treatments.


Figure 1
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  		Figure 1. Patients prefer oral chemotherapy to i.v. chemotherapy if efficacy is comparable [7, 8].

 
Furthermore, in the study comparing capecitabine with the Mayo Clinic (Rochester, MN) regimen (5-FU/leucovorin [LV]), time to progression was equivalent with Xeloda® and 5-FU/LV (median 4.6 months vs. 4.7 months, respectively) [6]. The median time to treatment failure was 4.2 months with Xeloda® and 3.6 months with 5-FU/LV. Median survival was also equivalent with Xeloda® and 5-FU/LV (12.9 months vs. 12.8 months, respectively).

Capecitabine has been developed in combination with both oxaliplatin and irinotecan. The pivotal phase II trial in first-line metastatic CRC combined capecitabine 1,000 mg twice a day on days 1–15 with oxaliplatin 130 mg/m2 on day 1, every 21 days [9, 10]. Capecitabine has also been combined in this way with 250 mg/m2 irinotecan given on day 1.

Grothey et al. favor a schedule that facilitates dose adjustment by dividing oxaliplatin into two 70-mg/m2 doses given on days 1 and 8 [11, 12]. A similar process is followed with irinotecan, giving 80 mg of the drug on days 1 and 8. And Scheithauer et al. in France and Austria have developed a 2-week schedule in which 3,500 mg capecitabine is given on days 1–7 and 85 mg/m2 oxaliplatin on day 1, every 14 days [13]. There have so far been no completed trials formally comparing these schedules, so it is not possible to say whether they differ in efficacy and toxicity.


   NONRANDOMIZED COMPARISONS INVOLVING CAPECITABINE COMBINATIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Nonrandomized Comparisons...
Randomized Trials
 Integrating Targeted Agents
 Discussion
 Disclosure of Potential...
 References
 
Comparisons across studies suggest that the toxicity of capecitabine plus oxaliplatin (XELOX) is generally similar to that of FOLFOX (oxaliplatin/5-fluorouracil/leucovorin) [10, 14], with the exception of a higher rate of hand-foot syndrome. There is more grade 3/4 neutropenia with the latter, but this is not reflected in a greater risk of febrile neutropenia. XELOX is also comparable with FUFOX (weekly 5-FU/folinic acid/oxaliplatin) (Table 1Go) [15].


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  		Table 1. XELOX toxicity in comparison with that of FOLFOX and FUFOX [10, 14, 15]

 
The efficacy of XELOX appears similar to that of other combinations. In the international phase II trial reported by Cassidy et al., the overall survival (OS) in 96 first-line patients treated was 19.5 months [10]. The response rates (RRs) of 35%–55% obtained with the combination of capecitabine with irinotecan (CAPIRI or XELIRI) in phase II studies are comparable with those reported with 5-FU/LV and irinotecan regimens (IFL or FOLFIRI) (Fig. 2Go) [14, 16–21]. Table 2Go provides an overview of grade 3–4 adverse events [14, 16, 18, 20]. XELIRI is associated with more neutropenia than XELOX, with approximately 20% of patients experiencing grade 3/4 events [16, 18]. However, these rates are less than with IFL or FOLFIRI [14, 20], and the incidence of febrile neutropenia reported with XELIRI was only 4% [16]. However, hand-foot syndrome, which is not seen with bolus or infusional 5-FU, is apparent in 6%–8% of patients treated with XELIRI [16, 18].


Figure 2
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  		Figure 2. Response rates: XELIRI compares favorably with 5-fluorouracil/leucovorin/irinotecan [14, 16–21]. Abbreviations: FOLFIRI, irinotecan/5-fluorouracil/leucovorin; IFL, irinotecan/bolus 5-fluorouracil/leucovorin; XELIRI, capecitabine/irinotecan.

 

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  		Table 2. Safety of XELIRI is similar to that of FOLFIRI [14, 16, 18, 20]

 

   RANDOMIZED TRIALS
Top
 Learning Objectives
 Abstract
 Introduction
 Nonrandomized Comparisons...
 Randomized Trials
Integrating Targeted Agents
 Discussion
 Disclosure of Potential...
 References
 
Several controlled trials have compared capecitabine-containing combinations with each other or with alternative regimens involving bolus or infusional 5-FU. A summary of the randomized trials with capecitabine regimens, which will be discussed in further detail in this section, include capecitabine/oxaliplatin (CapOx) versus capecitabine/irinotecan (CapIri); TREE-1 trial; CapOx versus FUFOX; the European Organization for Research and Treatment of Cancer study of FOLFIRI versus XELIRI ± cyclo-oxygenase-II inhibitor (COX II); and the adjuvant Mayo Clinic/Roswell Park (RP) versus XELOX study.

Grothey et al. undertook a multicenter, randomized phase II trial of CapIri and CapOx in 161 patients using a day-1 and -8 schedule every 3 weeks [22, 23]. Both groups received capecitabine 2,000 mg on days 1–14. Four early deaths among the first 40 patients in the CapIri arm forced a dose reduction from 100 to 80 mg/m2. There was no comparable problem in the first 40 patients treated with oxaliplatin, and the dose remained unchanged at 70 mg/m2 for the duration of the study. Subsequently, one further patient died within 60 days of receiving the reduced and relatively low dose of irinotecan, giving a 6% overall mortality for that arm of the trial. Two deaths were due to septic diarrhea and two to pulmonary embolism, reflecting what seems to be a general tendency to increased thromboembolic events with capecitabine. Early mortality in patients treated with CapOx was 1%. Diarrhea was more common with CapIri than with CapOx (grade 3–4 events in 23% of patients vs. 14%). Sensory neuropathy was more common with CapOx (6% vs. 1%), and rates of hand-foot syndrome were comparable (grade 2 events in 9% of CapIri patients and 7% of CapOx patients; and grade 3 in 0% and 1%, respectively). The RR with CapOx was 55% and with CapIri, 41%. Median OS in the two arms was >17 months with CapOx and 18.8 months with CapIri. (Crossover was permitted at the end of the study.)

In the randomized phase II TREE-1 trial, 150 first-line patients were randomized to FOLFOX6 (including oxaliplatin 85 mg/m2, LV 350 mg, 5-FU bolus 400 mg/m2, and infusional 2,400 mg/m2 over 46 hours, every 2 weeks), bFOL (oxaliplatin 85 mg/m2 on days 1 and 15; LV 20 mg/m2; and bolus 5-FU 500 mg/m2 on days 1, 8, and 15; every 4 weeks) or CapOx (oxaliplatin 130 mg/m2 day 1, capecitabine 1,000 mg/m2 orally twice daily for 14 days every 3 weeks) [24]. The overall incidence of grade 3–4 adverse events was similar on FOLFOX and bFOL arms; however, a greater number of grade 3 neutropenia occurred on the FOLFOX arm (27.8% vs. 10.5%). There were more patients withdrawn due to toxicities on the bFOL compared with the FOLFOX arm (11.1% vs. 7.9%, p value not significant). CapOx had a higher incidence of grade 3–4 nonhematologic toxicities (i.e., nausea [15.6%], vomiting [15.6%], dehydration [18.8%], diarrhea [21.9%], and hand-foot syndrome [15.6%]) than the FOLFOX and bFOL arms, and more patients were withdrawn due to toxicities on the CapOx arm than the other two arms (34.4%, p = .004, Fisher’s exact test). The protocol was amended to allow for an additional 210 patients to receive bevacizumab added to each regimen and to reduce the CapOx dose by 15%.

In the German AIO (Association of Medical Oncology of the German Cancer Society) trial, 476 patients were randomized to FUFOX (5-fluorouracil 2,000 mg/m2 24-hour infusion; folinic acid 500 mg/m2; oxaliplatin 50 mg/m2 on days 1, 8, 15, and 22; every 5 weeks) or CapOx (capecitabine 1,000 mg/m2 twice a day on days 1–14, oxaliplatin 70 mg/m2 on days 1 and 8, every 3 weeks) [25]. Grade 3–4 neuropathy was more common with FUFOX than with CapOx (25% vs. 16%). This difference was also seen in the randomized phase II study. In both the phase II and phase III studies, toxicities were comparable between the 5-FU– and capecitabine-containing arms. Comparing rates of diarrhea across these studies suggests that there may be some advantage in a fractionated day-1 and -8 schedule, as used by AIO.

RRs were in the range of 40%–50% in both arms of the AIO phase III trial and across the two arms of the TREE-1 trial. A summary of the efficacy data of these three randomized trials is provided in Table 3Go [23–25]. In addition, the Spanish TTD Group has shown identical results in a randomized phase II study [26]. The large phase III trial from Roche has very recently issued a press release stating that there has been no difference in progression-free survival between FOLFOX and XELOX, with results to be presented at the European Society of Medical Oncology (ESMO) 2006 meeting.


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  		Table 3. Response rates of capecitabine in combination in randomized trials [23–26]

 
In the Adjuvant Setting
In a phase III trial in patients with resected stage III colon cancer, we compared three arms of adjuvant chemotherapy, namely: XELOX (capecitabine 1,000 mg/m2 twice a day on days 1–14 + oxaliplatin 130 mg/m2 on day 1, every 3 weeks for eight cycles); i.v. bolus 5-FU/LV (Mayo Clinic regimen: LV 20 mg/m2 + 5-FU 425 mg/m2 on days 1–5, every 4 weeks for six cycles); and RP regimen (LV 500 mg/m2 + 5-FU 500 mg/m2 on day 1, weeks 1–6 in four 8-week cycles) [26]. Table 4Go shows the most common treatment-related grade 3–4 adverse events. XELOX compares favorably with the other arms of the study and also to the FOLFOX4 regimen from the MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study [27, 28].


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  		Table 4. Grade 3–4 adverse events by percentage of patients in the phase III adjuvant trial with XELOX and in the MOSAIC trial [26, 27]

 
Efficacy data from this phase III adjuvant trial will be available in 2008.


   INTEGRATING TARGETED AGENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Nonrandomized Comparisons...
 Randomized Trials
 Integrating Targeted Agents
Discussion
 Disclosure of Potential...
 References
 
Work is proceeding apace on evaluating 5-FU–containing regimens in combination with monoclonal antibodies or tyrosine kinase inhibitors directed against growth factors or their receptors. The combination of capecitabine with novel agents is also being actively investigated.

In inhibition of human colon cancer xenografts, there is synergy between capecitabine and bevacizumab (Avastin®, Roche Ltd.) [29, 30]. In this model, the effect of 5-FU is additive but not synergistic. The same pattern holds for combination with EGFR inhibitors (i.e., synergistic with capecitabine and additive with 5-FU) [31, 32].

XELOX (CapOx) in Combination with Novel Agents
Such data underpin the TREE-2 trial in which first-line patients are randomized to bevacizumab plus FOLFOX, bFOL, or CapOx [24, 33]. Preliminary data suggest that the combination with bevacizumab does not increase the overall toxicity of CapOx, nor does it have any impact on the rate of thrombosis. In TREE-2, it appears that the addition of bevacizumab to FOLFOX increases the RR by a greater amount than when bevacizumab is added to the other regimens in the TREE trial (i.e., an additional increase in RR of 19% when bevacizumab is added to the bFOL arm, of 11% when bevacizumab is added to the FOLFOX arm, and of 19% when bevacizumab is added to the CapOx arm). This may be the first evidence that the synergy seen in animal models is clinically relevant. Moreover, progression-free survival and overall survival were higher in all bevacizumab–containing arms, with no difference between FOLFOX and XELOX (9.9 vs 10.3 and 27.0 vs 26.0 months, respectively).

Fernando et al. have recently reported a phase II trial of XELOX plus bevacizumab [34]. As has been the case in other studies, the starting 1,000-mg/m2 twice-a-day dose of capecitabine had to be reduced because of toxicity (in this instance, in 40% of patients). However, although confined to 30 patients, this trial is notable in reporting the longest median progression-free survival (11.9 months) yet seen in metastatic CRC. The overall RR was 57%. This was achieved despite the dose reductions required for capecitabine. At the reduced dose, no patient experienced grade 2 or greater diarrhea. Enrollment continues using an 825-mg/m2 dose of capecitabine.

The early analysis of the large Roche registration trial has very recently been released in a press statement indicating that XELOX/bevacizumab is comparable to FOLFOX/bevacizumab and therefore an excellent oral substitute for the triple standard i.v. combination.

In combination with EGFR inhibitors, a 50% RR has been reported with XELOX plus gefitinib (Iressa®, Astra-Zeneca, London) and a 24% RR with XELOX plus erlotinib (Tarceva®, Roche Ltd.) [35, 36]. Data from two combination studies using XELOX plus cetuximab were reported at the 2006 annual meeting of the American Society of Clinical Oncology. In both trials, XELOX could be administered at full doses when combined with cetuximab without evidence of synergistic toxicity. Response rates are promising with 57% and 60%, respectively [37, 38]. A single-arm trial from our institution used the combination in refractory patients. Interestingly, data are impressive in showing responses even when patients have had three or more lines of previous therapy [39].

XELIRI (CapIri) in Combination with Novel Agents
There are no data so far on the combination of XELIRI with bevacizumab. However, the combination of dose-reduced XELIRI (capecitabine 800 mg/m2 twice a day, irinotecan 200 mg/m2 day 1; all every 22 days) with cetuximab was well tolerated and did not show high rates of severe diarrhea in preliminary results coming from a randomized phase II trial of the AIO Group [38]. By contrast, data coming from a phase I study showed that combination of XELIRI with gefitinib resulted in unacceptably high rates of toxicity, particularly diarrhea and thrombocytopenia [40].

Capecitabine and Radiation
The rationale for preoperative combination with radiation is greater for capecitabine than for 5-FU. In rectal cancer, use of the combination has been well tolerated and has achieved high rates of pathological complete response [41, 42]. This is also seen when combining XELOX and XELIRI with radiotherapy [41, 43]. Also, combination of capecitabine or XELOX with cetuximab or bevacizumab in chemoradiation did not result in increased toxicity, indicating the potential role of capecitabine as backbone for further combinations [44–46].

Trial NSABP (National Surgical Adjuvant Breast and Bowel Project) R-04 will randomize patients to radiotherapy plus capecitabine ± oxaliplatin or to radiotherapy plus infusional 5-FU ± oxaliplatin. Following surgery, patients will receive FOLFOX ± bevacizumab. The PET-ACC6 (Pan-European Trials in Adjuvant Colorectal Cancer) trial will compare capecitabine/radiation followed by adjuvant capecitabine 6 months after surgery, with or without oxaliplatin.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Nonrandomized Comparisons...
 Randomized Trials
 Integrating Targeted Agents
 Discussion
Disclosure of Potential...
 References
 
The fact that capecitabine is generally well tolerated makes it suitable for combination with other cytotoxics (particularly oxaliplatin), and capecitabine and XELOX appear promising as a platform on which to add novel, targeted agents. Phase III trials are ongoing in France, the U.K., and Australia.

There is some suggestion that toxicities in the U.S. may differ from those in western Europe, and expertise is required in their management. The need for dose reduction may be greater with capecitabine than with infusional 5-FU. It would be helpful for dose scheduling to be more extensively investigated preclinically.

XELIRI seems more limited in suitability for combination with novel agents, especially when diarrhea is a concern. However, combination with bevacizumab should be possible.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 Nonrandomized Comparisons...
 Randomized Trials
 Integrating Targeted Agents
 Discussion
 Disclosure of Potential...
References
 
H-J.S. has acted as a consultant for sanofi-aventis and Roche.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Nonrandomized Comparisons...
 Randomized Trials
 Integrating Targeted Agents
 Discussion
 Disclosure of Potential...
 References
 

  1. Saif MW. Capecitabine versus continuous-infusion 5-Fluorouracil for colorectal cancer: a retrospective efficacy and safety comparison. Clin Colorectal Cancer 2005;5(2):89–100.[Medline]
  2. Van Cutsem E, Verslype C, Tejpar S. Oral capecitabine: bridging the Atlantic divide in colon cancer treatment. Semin Oncol 2005;32(1): 43–51.[Medline]
  3. Scheithauer W, McKendrick J, Begbie S et al. Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial. Ann Oncol 2003;14(12): 1735–1743.[Abstract/Free Full Text]
  4. Rothenberg ML. Current status of capecitabine in the treatment of colorectal cancer. Oncology (Williston Park) 2002;16(12 suppl 14):16–22.
  5. 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(4): 566–575.[Abstract/Free Full Text]
  6. Twelves C; Xeloda Colorectal Cancer Group. Capecitabine as first-line treatment in colorectal cancer. Pooled data from two large, phase III trials. Eur J Cancer 2002;38(suppl 2):15–20.
  7. Borner MM, Schoffski P, de Wit R et al. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002;38(3):349–358.[CrossRef][Medline]
  8. Liu G, Franssen E, Fitch MI et al. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15(1):110–115.[Abstract/Free Full Text]
  9. Diaz-Rubio E, Evans TR, Tabemero J et al. Capecitabine (Xeloda) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors. Ann Oncol 2002;13(4):558–565.[Abstract/Free Full Text]
  10. Cassidy J, Tabernero J, Twelves C et al. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004 Jun 1;22(11):2084–2091.[Abstract/Free Full Text]
  11. Jordan K, Kellner O, Kegel T et al. Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers. Clin Colorectal Cancer 2004;4(1):46–50.[Medline]
  12. Grothey A, Schmoll HJ. New chemotherapy approaches in colorectal cancer. Curr Opin Oncol 2001;13(4):275–286.[CrossRef][Medline]
  13. Scheithauer W, Kornek GV, Raderer M et al. Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2003;21(7):1307–1312.[Abstract/Free Full Text]
  14. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22(1):23–30.[Abstract/Free Full Text]
  15. Schmoll HJ, Grothey A, Kroening H et al. A phase II study comparing bolus 5-fluorouracil/folinic acid (Mayo Clinic) with weekly 24h-infusion of high-dose 5-fluorouracil/folinic acid plus oxaliplatin as first-line therapy in advanced colorectal cancer. Submitted to J Clin Oncol 2005.
  16. Patt Y, Liebmann T, Diamandidis D et al. Final efficacy and safety findings from a phase II trial of capecitabine (X) plus irinotecan (XELIRI) as first-line treatment for metastatic colorectal cancer (MCRC). Proc ESMO, Ann Oncol 2004;15(S3):iii88. Abstract 328P.
  17. Bajetta E, Di Bartolomeo M, Mariani L et al. Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma. Cancer 2004;100(2):279–287.[CrossRef][Medline]
  18. Borner MM, Bernhard J, Dietrich D et al. A randomized phase II trial of capecitabine and two different schedules of irinotecan in first-line treatment of metastatic colorectal cancer: efficacy, quality-of-life and toxicity. Ann Oncol 2005;16(2):282–288.[Abstract/Free Full Text]
  19. 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(13):905–914.[Abstract/Free Full Text]
  20. 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(9209):1041–1047.[CrossRef][Medline]
  21. Tournigand C, Andre T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22(2):229–237.[Abstract/Free Full Text]
  22. Grothey A, Jordan K, Kellner O et al. Capecitabine/irinotecan (CapIri) and capecitabine/oxaliplatin (CapOx) are active second-line protocols in patients with advanced colorectal cancer (ACRC) after failure of first-line combination therapy: Results of a randomized phase II study. J Clin Oncol 2004;22(14S)(suppl):3534. [Abstract, ASCO Annual Meeting Proceedings (Post-Meeting Ed.)].
  23. Grothey A, Jordan K, Kellner O et al. Randomized phase II trial of capecitabine plus irinotecan (CapIri) vs capecitabine plus oxaliplatin (CapOx) as first-line therapy of advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 2003;22:255. Abstract 1022.
  24. Hochster HS, Welles L, Hart L et al. Safety and efficacy of bevacizumab (Bev) when added to oxaliplatin/fluoropyrimidine (O/F) regimens as first-line treatment of metastatic colorectal cancer (mCRC): TREE 1 & 2 Studies. 2005 ASCO Annual Meeting. 3515a.
  25. Arkenau H, Schmoll H, Kubicka S et al. Infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic colorectal cancer (MCRC): results of the safety and efficacy analysis. 2005 ASCO Annual Meeting. Abstract 3507.
  26. Massuti B, Gómez A, Sastre J et al. Randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (XELOX) versus oxaliplatin and 5-fluorouracil in continuous infusion (FUFOX) as first-line treatment in advanced or metastatic colorectal cancer (CRC). J Clin Oncol 2006:24(18S):165s. Abstract 3580.
  27. Schmoll HJ, Tabernero J, Nowacki M et al. Early safety findings from a phase III trial of capecitabine plus oxaliplatin (XELOX) vs. bolus 5-FU/LV as adjuvant therapy for patients (pts) with stage III colon cancer. 2005 ASCO Annual Meeting. Abstract 3523.
  28. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350(23):2343–2351.[Abstract/Free Full Text]
  29. Ignoffo RJ. Overview of bevacizumab: a new cancer therapeutic strategy targeting vascular endothelial growth factor. Am J Health Syst Pharm 2004;61(21 suppl 5):S21–S26.[Abstract/Free Full Text]
  30. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004 Jun 3;350(23):2335–2342.[Abstract/Free Full Text]
  31. Tamaka Y, Selciguchi T, Yamagisawa M et al. Antitumor activity of Capecitabine (Xeloda) in combination with erlotinib (OSI-774, Tarceva) in human tumor xenograft models. Proc Am Assoc Cancer Res 2003:44. Abstract 4678.
  32. Hidalgo M. Erlotinib: preclinical investigations. 2003 Nov;17(11 suppl 12):11–16.
  33. Hochster HS, Hart LL, Ramanathan RK. Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): final analysis of the TREE-Study. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 suppl), 2006: 3510.
  34. Fernando N, Yu D, Morse M et al. A phase II study of oxaliplatin, capecitabine and bevacizumab in the treatment of metastatic colorectal cancer. Proc Am Soc Clin Oncol 2005;23:3556a.
  35. Zeuli M, Gelibter A, Nardoni C et al. A feasibility study of gefitinib in association with capecitabine (CAP) and oxaliplatin (OXA) as first-line treatment in patients with advanced colorectal cancer (ACRC). J Clin Oncol 2004;22(14S)(suppl):3748. [Abstract, ASCO Annual Meeting Proceedings (Post-Meeting Ed.)].
  36. Meyerhardt JA, Xhu A, Enzinger PC et al. Phase II study of capecitabine, oxaliplatin and erlotinib in previously treated patients with metastatic colorectal cancer (MCRC). J Clin Oncol 2004;22 (14S) (suppl):3580. [Abstract, ASCO Annual Meeting Proceedings (Post-Meeting Ed.)].
  37. Borner M, Mingrone W, Koeberle D et al. The impact of cetuximab on the capecitabine plus oxaliplatin (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC): a randomized phase II trial of the Swiss Group for Clinical Cancer Research (SAKK). Proc Am Soc Clin Oncol 2006; 24(June 20 suppl):3551.
  38. Heinemann V, Fischer von Weikersthal L, Moosmann N et al. Cetuximab + capecitabine + irinotecan (CCI) versus cetuximab + capecitabine + oxaliplatin (CCO) as first-line therapy for patients with metastatic colorectal cancer (CRC): preliminary results of a randomized phase II trial of the AIO CRC Study Group. Proc Am Soc Clin Oncol 2006;24(June 20 suppl):3550.
  39. Grothe W, Arnold D, Peinert S et al. Cetuximab with oxaliplatin and capecitabine (CAPOX)in patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy. Proc Am Soc Clin Oncol 2005;23:3669a.
  40. Arnold D, Constantin C, Seufferlein T et al. Phase I study of gefitinib in combination with capecitabine and irinotecan for 2nd- and/or 3rd-line treatment in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 2005;23:3691a.
  41. Rich T. Capecitabine and radiation therapy for advanced gastrointestinal malignancies. Oncology (WillistonPark) 2002 Dec;16(12suppl14):27–30. 41 Kim JS, Kim JS, Cho MJ et al. Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2002 Oct 1;54(2):403–408.[CrossRef][Medline]
  42. Glynne-Jones R, Dunst J, Sebag-Montefiore D. The integration of oral capecitabine into chemoradiation regimens for locally advanced rectal cancer: how successful have we been? Ann Oncol 2006;17(3):361–371.[Abstract/Free Full Text]
  43. Arnold D, Schmoll HJ. (Neo-) adjuvant treatments in colorectal cancer. Ann Oncol 2005;16(suppl 2):ii133–140.[Free Full Text]
  44. Arnold D, Hipp M, Reese T et al. Phase I/II study of cetuximab, capecitabine and oxaliplatin (CAPOX) combined with standard radiotherapy (RTX) as neoadjuvant treatment of advanced rectal cancer (RC). Proc Am Soc Clin Oncol 2006;24(June 20 suppl):3574.
  45. Machiels JP, Sempoux C, Scalliet P et al. Phase I study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Proc Am Soc Clin Oncol 2006;24(June 20 suppl):3552.
  46. Czito B, Bendell J, Willett C et al. Preliminary results of a phase I study of external beam radiation therapy (EBRT), oxaliplatin (OX), bevacizumab (BV), and capecitabine (CAP) for locally advanced or metastatic adenocarcinoma of the rectum. Proc Am Soc Clin Oncol 2006;24(June 20 suppl):3543.



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