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Surgical Oncology (2007) 16, 65–70

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�Corresponding auE-mail address: c

(C. Kelly).

REVIEW

Chemotherapy in metastatic colorectal cancer

Claire Kelly�, Jim Cassidy

Department of Medical Oncology, Beatson Oncology Centre, Dumbarton Road, Glasgow G11 6NT, UK

SummaryThis article aims to provide the reader with a broad overview of the currentchemotherapeutic options available for the treatment of patients with metastaticcolorectal cancer. The review includes discussion of both well established andexperimental therapies.& 2007 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65Fluoropyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

5-Fluorouracil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Capecitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Newer cytotoxics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Irinotecan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Oxaliplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Downstaging of liver metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Sequencing of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Treating elderly patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68Targeted therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68Cetuximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

The future? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

nt matter & 2007 Elsevier Ltd. All rights reserved..2007.04.006

thor. Tel.: +0141 211 2000.laire.kelly@northglasgow.scot.nhs.uk

Introduction

Colorectal cancer is the second leading cause of cancermortality in the UK. In 2001, there were approximately34,500 new cases and 16,200 deaths from colorectal cancer[1]. Following a complete surgical resection, patients face a40–50% chance of disease relapse [2]. With the exception of

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a small proportion of patients who will have diseaseamenable to further curative surgical resection, recurrencewill be incurable and result in death.

Fluoropyrimidines

5-Fluorouracil

Up until the early 1990s, metastatic colorectal cancer wasconsidered untreatable. The majority of patients wereoffered supportive care only and median survival for thesepatients was 6 months. The first chemotherapeutic agent tobe used with any success was the intravenous fluoropyr-imidine 5 Fluorouracil in combination with folinic acid(5FU/FA). 5FU inhibits thymidylate synthase which is a keyenzyme in the synthesis of pyrimidines, thus reducingpyrimidines available for DNA replication.

A number of randomised controlled trials comparing 5FU/FA with best supportive care have demonstrated animprovement in quality of life and median survival from 6months to 1 year in favour of chemotherapy [3]. The sideeffects of 5FU/FA treatment are generally well toleratedand include fatigue, nausea, diarrhoea and mucositis.Despite the longevity of 5FU/FA use in clinical practice,there is a lack of consensus regarding the optimumregime and duration of therapy. This has led to considerablevariability in standard practice. In the UK infusional regimes,which have been shown to have a better response ratewith less toxicity, have generally been the standard ofcare. In the USA, bolus regimes are more popular as thisavoids the inconvenience and expense of protracted venousinfusion.

Capecitabine

The development of the oral fluoropyrimidines capecitabineand tegafur with uracil (UFT) may help address theinconsistencies in the administration of this class of drug.Capecitabine is a fluoropyrimidine carbamate precursor of5FU. It is catalysed by a number of enzymatic steps to 5FU.The enzyme involved in the final conversion to 5FU,thymidine phosphorylase, is found at higher levels in tumourcells than normal cells, thereby giving higher doses to thetumour and reducing systemic exposure to 5FU. Tegafurworks in a similar manner. Clinical application of theseagents in the Western world has concentrated mainly oncapecitabine, which is given twice daily for 14 days followedby a week break.

There have been two large randomised clinical trials ofcapecitabine versus intravenous 5FU, both of which showeda greater tumour response rate with capecitabine than bolus5FU. Time to progression and overall survival were similarfor both treatments but, perhaps most importantly, cape-citabine showed clinically meaningful benefits in term oftolerability when compared with 5FU. Capecitabine resultsin significantly less diarrhoea, febrile neutropaenia andstomatitis than 5FU but is associated with a higher incidenceof hand–foot syndrome and asymptomatic hyperbilirubinae-mia [4,5].

Newer cytotoxics

Modern standard treatment for colorectal cancer has movedon from monotherapy with fluoropyrimidines to combinationchemotherapy. The newer cytotoxic drugs oxaliplatin andirinotecan have improved further the median survival ofpatients.

Irinotecan

Irinotecan is a camptothecin derivative that acts as atopoisomerase I inhibitor. Topoisomerases are nuclearenzymes, which help unwind DNA prior to replication andhence relieve torsional stress in the DNA molecule. Inhibi-tion of these enzymes results in DNA strand breaks, failure ofreplication and subsequent cell death. The topoisomerase Ienzyme is overexpressed in colorectal cancer making it anattractive drug target.

Irinotecan is metabolised in vivo to the more activecompound SN38. This compound is excreted in bile andundergoes enterohepatic circulation. The main dose limitingtoxicity of this drug is diarrhoea, which is probably relatedto the high doses of SN38 in the colon.

The first phase III trials of irinotecan involved patientswho had relapsed after first-line treatment with 5FU/FA.The study by Cunningham et al. compared irinotecan withbest supportive care [6], whilst the study by Rougier et al.[7] compared irinotecan to continuous infusion of 5FU. Inboth trials irinotecan improved overall survival, progression-free survival, and quality of life. Once it had been proventhat irinotecan prolonged survival in patients whose diseaseis refractory to 5FU, the next logical step was to combine itwith 5FU in first-line treatment.

Three major studies have compared irinotecan/5FU(known as FOLFIRI) with 5FU alone as first line therapy[8–10]. All of these trials showed an improvement inresponse rate of about 20% with the combination arm. Timeto progression was significantly longer in the irinotecangroups and this translated into a significant increase inoverall survival of 2–3 months. Grades 3 and 4 toxicity,particularly diarrhoea, was generally greater in the patientsreceiving irinotecan but quality of life was not compromisedas a result of this. In clinical practice patients receivingirinotecan combination chemotherapy are educated aboutthe importance of prompt treatment for diarrhoea andprescribed antidiarrhoeals to commence immediately shoulddiarrhoea occur. A study investigating the efficacy ofprophylactic antidiarrhoeal treatment failed to show anybenefit from this treatment approach [11].

Oxaliplatin

Oxaliplatin is a third-generation platinum compound inwhich the platinum atom is complexed with 1,2-diaminocy-clohexane. Like other platinum agents oxaliplatin formsintra- and interstrand platinum-DNA crosslinks. This inhibitsDNA replication and transcription and results in cell death.Early work in vitro with this drug showed synergy with 5FUand this has translated into clinical practice, whereoxaliplatin and 5FU are given in combination.

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Figure 1 Median survival correlates with the availability of allthree active drugs.

Chemotherapy Colorectal cancer 67

The combination of oxaliplatin and 5FU is referred to asFOLFOX. In the literature the schedule and doses of the twodrugs are referred to by a number (FOLFOX4, FOLFOX6, etc.)For the purposes of this review the term FOLFOX has beenused generically to mean the combination, without refer-ence to the schedule. The initial phase III studies of FOLFOX(oxaliplatin/5FU) versus 5FU alone differed in the schedulesof 5FU administered but all showed similar results [12–14].

The response rates with 5FU monotherapy were inkeeping with historical data at 16–22%, while the FOLFOXdoublet achieved a response rate in the order of 50%. Theprogression-free survival was improved from 6 to 8–9 monthsin favour of the combination but this did not translate into astatistically significant survival benefit, although a trend toimproved survival was seen. A possible explanation for thelack of survival advantage is that a number of patients fromthe 5FU monotherapy arm crossed over to the oxaliplatinarm at disease progression. Furthermore, a number ofpatients received irinotecan at disease progression. Whenthese studies were planned there was no standard second-line chemotherapy treatment and therefore the studydesigns did not take account of these options.

FOLFOX chemotherapy is associated with higher incidenceof neutropaenia, diarrhoea and peripheral sensory neuro-toxicity when compared with 5FU alone, but in general thisis not associated with a decrease in quality of life [13]. Thedose limiting toxicity in clinical practice tends to beperipheral neurotoxicity which is cumulative and, in gen-eral, is reversible on cessation of the drug, but in some casesmay result in persistent loss of function.

Downstaging of liver metastases

Because of the lack of survival advantage FOLFOX was notinitially approved by the FDA or NICE for treatment ofmetastatic colorectal cancer. The exception to this was inthe case of those patients with potentially resectable livermetastases that might be downstaged by chemotherapy.Fifty percent of all patients with colorectal cancer willpresent with liver metastases at some time during follow-up. Surgical resection is the only option for long-termsurvival for these patients but primary surgical resection isan option in only 15% of such patients at presentation. UsingFOLFOX chemotherapy to downstage irresectable livermetastases has been shown to be beneficial in 13% ofpatients. The 5-year survival of patients with irresectabledisease which is rendered operable following chemotherapyis 33–50%. This is in keeping with patients who haveresectable disease from the outset [15,16]. It is now routineclinical practice to attempt to downstage initially inoper-able liver lesions with FOLFOX with the aim of improvinglong-term survival.

Sequencing of treatment

From the initial Phase III studies of oxaliplatin and irinotecanit is apparent that, when given in combination with 5FU,both of these drugs increase time to progression whencompared to 5FU alone. This therefore raises the questionof which order treatments should be given in. A largerandomised trial, N9741, randomised previously untreated

patients to FOLFOX, FOLFIRI or IROX (a combination ofoxaliplatin and irinotecan). The trial was closed temporarilydue to an imbalance of early deaths in the FOLFIRI arm. Thedose of irinotecan was reduced and the trial completedrecruitment. For all end points (time to progression,response rate and overall survival), oxaliplatin was superiorto both FOLFIRI and IROX [17]. With the exception ofneurotoxicity, there was significantly greater toxicity in theFOLFIRI arm. Of note 60% of the patients who receivedFOLFOX received second line irinotecan while only 24% ofpatients on the FOLFIRI arm received second-line oxalipla-tin. This could explain the difference in overall survival, butalso suggests that either the poorer response rate or toxicityof FOLFIRI meant that patients were not fit for second-linetreatment.

As mentioned earlier oxaliplatin was not initially ap-proved for use as first line treatment unless the intentionwas to try to downstage hepatic metastases. On the basis ofthis and other trials it became apparent that although theinitial Phase III trials did not show a statistically significantoverall survival advantage when compared with 5FU alone,the median overall survival was similar to, if not betterthan, FOLFIRI. On this basis oxaliplatin has now beenapproved for use in the first-line treatment of metaststiccolorectal cancer.

Although the N9741 trial found in favour of oxaliplatin asfirst-line treatment, pooled analysis of trials involvingFOLFOX and FOLFIRI suggests that median survival correlateswith exposure to all three active drugs (Fig. 1). The GERCORstudy compared FOLFIRI versus FOLFOX or the reversesequence in previously untreated patients. The responserate, progression-free survival and overall survival weresimilar in the two groups (55%, 8.5 and 21 months,respectively). Of interest is the observation that 21% ofthe patients initially treated with FOLFOX underwenthepatic resection following treatment, while only 9% ofpatients treated with FOLFIRI were downstaged significantlyenough for surgery [18].

Given that the GECOR study has suggested that thesequence of oxaliplatin and irinotecan does not affectoutcome and that in the N9741 study more patients wereable to proceed to second-line treatment if they hadreceived FOLFOX first, standard clinical practice in the UK

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is to offer patients FOLFOX first line followed by FOLFIRI atprogression.

As capecitabine has been shown to have similar efficacyto infusional 5FU as monotherapy, the next logical step incombination treatment is to substitute capecitabine for5FU. The recently presented XELOX trial randomisedpatients to receive either XELOX (oxaliplatin and capecita-bine) or FOLFOX. The response rate, progression-freesurvival and overall survival were the same in both groupsbut the side effect profiles differed with more febrileneutropaenia in the FOLFOX arm and more hand–footsyndrome in the XELOX arm [19]. This is useful clinically asit allows an element of choice for the patient and physician.If compliance is felt to be an issue then FOLFOX may be thetreatment of choice, whereas XELOX is an outpatienttreatment that avoids hospital admission.

Treating elderly patients

Historically elderly patients have often not been offeredchemotherapy treatment because of the perception thatthey do not benefit and that the side effects of treatmentare more severe and adversely affect quality of life. Tworecently published studies have shown that patients over theage of 70 treated with XELOX derive similar benefit in termsof response rate, progression-free survival and overallsurvival, and the toxicity profile is comparable to that seenin younger patients [20,21]. Providing elderly patients areotherwise fit, age in itself is not a contraindication tochemotherapy.

Targeted therapy

The approach to treatment of colorectal cancer is changing.The median overall survival in metastatic disease hasimproved with newer cytotoxic drugs and a patient treatedwith all three agents can have a life expectancy approaching2 years. This timeframe appears to be the ‘‘wall’’ whichconventional chemotherapy alone cannot breach. Novelapproaches to cancer treatment have been developed withthe aim of further improving survival (Fig. 2).

Figure 2 Achievements and goals in the treatment ofadvanced colorectal cancer.

The traditional cytotoxic chemotherapy drugs are un-selective in the cells they kill and hence toxicity is related todamage to any rapidly replicating cells. Alopecia, diarrhoeaand neutropaenia are the most common examples of toxicityas a result of unselective cell kill. The aim in new drugdevelopment is to create targeted therapies, which causemaximal interference to tumour cell growth with minimalnormal cell toxicity.

Bevacizumab

Tumours cannot grow beyond 1–2mm3 unless new vascula-ture is created allowing delivery of oxygen and nutrients.Cancer cells secrete various growth factors, which inducenew capillary formation in a process called angiogenesis.Vascular endothelial growth factor (VEGF) is understood tobe a major contributor in this process. Bevacizumab is amonoclonal antibody, which binds to VEGF inhibiting itsaction. In a large phase III trial comparing the combinationof bevacizumab and FOLFIRI with FOLFIRI plus placebo, themedian overall survival was 20.3 months in the bevacizumabarm compared with 15.5 months in the placebo arm. Themedian time to progression 10.6 months versus 6.2 monthsand the response rate was 44.8% versus 34.8% in favour ofbevacizumab [22].

The recently reported TREE study has shown similarresults when bevacizumab is added to oxaliplatin-containingchemotherapy. In this study there were two cohorts ofpatients. The first cohort was randomised to receive one ofthree chemotherapy regimes with infusional, bolus or oraladministration of 5FU in combination with oxaliplatin,without bevacizumab (TREE1). The second cohort wasrandomised to the same three regimes with the additionof bevacizumab (TREE2). The primary end point in this studywas incidence of Grade 3/4 toxicity on each arm during thefirst 12 weeks of treatment with the secondary end pointsbeing median overall survival, progression-free survival andresponse rate. The addition of bevacizumab caused morehypertension, bowel perforation and impaired wound heal-ing as predicted from earlier studies. The median survivalfor the chemotherapy regimes combined was 24.4 monthswith bevacizumab and 18.2 with placebo [23].

At the present time the licensed indication for bevacizu-mab in the UK is in combination with FOLFIRI or 5FU/LV inthe first line treatment of metastatic colorectal cancer.Recent NICE and SMC guidance has concluded that the cost-effectiveness estimate for the routine use of bevacizumab inits licensed indication was not compatible with the best useof NHS resources. Currently, access to bevacizumab isrestricted to patients who are eligible to enter a clinicaltrial involving the drug.

Cetuximab

Another potential target is the epidermal growth factorreceptor (EGFR). This is a transmembrane protein with anintracellular tyrosine kinase domain. When the ligand bindsthe activity of the tyrosine kinase induces a signallingcascade, which results in transcription of genes involvedin proliferation, metastasis and angiogenesis. EGFR is

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commonly overexpressed in colorectal cancer cells andthere is therefore a rationale for targeting this receptor.

Cetuximab is a monoclonal antibody, which competitivelybinds to the EGFR. This prevents the active ligands, EGF andtransmembrane growth factor a, from binding and inducingthe proliferative cascade. Binding of cetuximab alsopromotes internalisation of the receptor thus reducing theavailable binding sites.

In preclinical work cetuximab has been shown to bemainly cytostatic as opposed to cytotoxic, but it has beenshown to be synergistic with chemotherapy particularlyirinotecan.

The BOND study randomised patients to receive eithercetuximab alone or cetuximab with irinotecan. The patientsall had disease, which was refractory to irinotecan, i.e.disease which had progressed while receiving irinotecan orwithin 3 months of completing treatment with irinotecan.The rationale for this came from earlier work whichsuggested that cetuximab may reverse resistance toirinotecan. The response rate was 22.9% in the combinationarm compared with 10.8% in the monotherapy arm. The timeto progression was 4.1 months versus 1.5 months in favour ofthe combination. The median overall survival was 8.9months versus 6.9, which was not statistically significantbut these data need to be viewed with caution as thepatients in the monotherapy arm were allowed the additionof irinotecan at disease progression [24].

The most common side effects with cetuximab arediarrhoea and an acneform rash, which in its severe formcan be painful and debilitating. There is a definitecorrelation between the development grade 2 and higherskin rash and response to treatment and this appears to bean EGFR class effect. Currently there is some debate as tothe importance of the expression of EGFR on the tumourcells of an individual patient. There have been documentedcases of response to cetuximab in patients with EGFRnegative tumours [25]. More work remains to be done in thisarea.

Cetuximab was recently appraised by NICE and SMC andthe committees concluded that routine use of cetuximab forits licensed indication would not be a cost-effective use ofNHS resources.

There are a number of ongoing randomised clinical trialsinvolving bevacizumab and cetuximab in colorectal andother cancers in both the adjuvant and metatatic setting.The body of evidence involving the use of these two agentswill accumulate over the next few years and may wellchange future practice.

The future?

The promising early results with cetuximab and bevacizu-mab have led to the development of other targetedtherapies. Small molecule EGFR inhibitors such as gefitiniband erlotinib have been assessed in phase I and II trials.Combinations with chemotherapy have shown that irinote-can-based combinations are more toxic in terms ofdiarrhoea and it is unlikely that these combinations will beinvestigated further. Oxaliplatin-containing regimens have abetter toxicity profile and a recently reported phase-twostudy combined capecitabine, oxaliplatin and erlotinib. The

response rate was 69% with a median overall survival rate of14.7 months. Toxicity was reduced with a lower startingdose of capecitabine [26].

With the advent of targeted agents comes the possibilityof ‘‘multitargeting’’—blocking more than one target withthe aim of increasing response. The BOND2 study comparedcetuximab and bevacizumab with or without irinotecan inpatients who had failed prior irinotecan therapy. Theresponse rate was higher for the arm containing all threeagents but the response rate in the doublet antibody armwas 20%—somewhat remarkable in a group of patients whohad chemotherapy refractory disease [27]. Further studiesare underway to further evaluate the potential of multi-targeting.

The development of affymetrix gene chip arrays has ledto the identification of thousands of genes involved in thepathogenesis of colorectal cancer. We are now moving awayfor the idea of colorectal cancer as a homogeneous diseasetoward an era where it might be possible to profile thecancer of an individual patient and tailor treatmentaccordingly. We may be able to recognise patterns whichconfer resistance to a particular agent and therefore avoidit, or patterns which suggest a poor prognosis and intensifychemotherapy at the outset. New targets will be identifiedwith agents developed to modulate their activity andimprove outcome.

The availability of all these new active agents raises anumber of strategic questions—which treatment for whichperson, how long should treatment last, what is acceptabletoxicity and how will it all be paid for? Clinical trials arecurrently underway to answer some of these questions and itis likely that treatment options and clinical practice willchange rapidly over the next few years.

References

[1] CancerStats: Cancer Research UK 2005.[2] Obrand DI, Gordon PH. Incidence and patterns of recurrence

following curative resection for colorectal carcinoma. Diseaseof the Colon and Rectum 1997;40:15–24.

[3] Scheithauer W, Rosen H, Kornek GV, Sebasta C, DepischD. Randomised comparison of combination chemotherapy plussupportive care with supportive care alone in patients withmetastatic colorectal cancer. British Medical Journal1993;306(6880):752–5 [Mar20].

[4] Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M,et al. Comparison of oral capecitabine versus intravenousfluorouracil plus leucovorin as first line treatment in 605patienst with metastatic colorectal cancer: results of arandomised phase III study. Journal of Clinical Oncology 2001;19(8):2282–92 [Apr 15].

[5] Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, BoyerM, et al. Xeloda Colorectal Cancer Study Group. OralCapecitabine compared with intravenous fluorouracil plusleucovorin in patients with metastatic colorectal cancer:results of a large phase III study. Journal of Clinical Oncology2001;19(21):4097–106 [Nov1].

[6] Cunningham D, Pyrhonen S, James RD, Punt CJ, Hichish TF,Heikkila R, et al. Randomised trial of irinotecan plus supportivecare versus supportive care alone after fluorouracil failurefor patients with metastatic colorectal cancer. Lancet 1998;352(9138):1413–8 [Oct 31].

[7] Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K,Labianca R, et al. Randomised trail of irinotecan versus

ARTICLE IN PRESS

C. Kelly, J. Cassidy70

fluorouracil by continuous infusion after fluorouracil failure inpatients with metastatic colorectal cancer. Lancet 1998;352(9138):1407–12 [Oct 31].

[8] Douillard JY, Cunningham D, Roth AD, Navarro M, James RD,Karasek P, et al. Irinotecan combined with fluorouracilcompared with fluorouracil alone as first line treatment formetastatic colorectal cancer: a multicentre randomised trial.Lancet 2000;355(9209):1041–7 [Mar 25].

[9] Saltz LB, Cox JV, Blanke C, Rosen LS, Ferenbacher L, Moore MJ,et al. Irinotecan plus fluorouracil and leucovorin for metastaticcolorectal cancer. Irinotecan Study Group. New EnglandJournal of Medicine 2000;343(13):905–14 [Sept 28].

[10] Kohne CH, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, LutzMP, et al. European Organisation for Research and Treatment ofCancer Gastrointestinal Group. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or withoutirinotecan in patients with metastatic colorectal cancer:European Organisation for Research and Treatment of CancerGastrointestinal Group Study 40986. Journal of ClinicalOncology 2005;23(22):4811–4 [Aug 1].

[11] Ychou M, Douillard JY, Rougier P, Adenis A, Mousseau M, DufourP, et al. Randomized comparison of prophylactic antidiarrhealtreatment versus no prophylactic antidiarrheal treatment inpatients receiving CPT-11 (irinotecan) for advanced 5-FU-resistant colorectal cancer: an open-label multicenter phase IIstudy. American Journal of Clinical Oncology 2000;23(2):143–8[Apr].

[12] Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, FocanC, et al. Phase III multicenter randomized trial of oxaliplatinadded to chronomodulated fluorouracil-leucovorin as first-linetreatment of metastatic colorectal cancer. Journal of ClinicalOncology 2000;18(1):136–47 [Jan].

[13] de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A,Cassidy J, et al. Leucovorin and fluorouracil with or withoutoxaliplatin as first-line treatment in advanced colorectalcancer. Journal of Clinical Oncology 2000;18(16):2938–47 [Aug].

[14] Grothey A, Deschler B, Kroening H, Ridwelski K, Reichardt P,Kretzschmar A, et al. Phase III study of bolus 5-fluorouracil(5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24 h 5-FUinfusion/FA+oxaliplatin (OXA) (FUFOX) in advanced colorectalcancer (ACRC). Proceedings of the American Society of ClinicalOncology 2002;22:512.

[15] Giacchetti S, Itzhaki M, Gruia G, Adam R, Zidani R, KunstlingerF, et al. Long-term survival of patients with unresectablecolorectal cancer liver metastases following infusional che-motherapy with 5-fluorouracil, leucovorin, oxaliplatin andsurgery. Annals of Oncology 1999;10(6):663–9 [Jun].

[16] Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D,et al. Rescue surgery for unresectable colorectal livermetastases downstaged by chemotherapy: a model to predictlong-term survival. Annals of Surgery 2004;240(4):644–57(October; discussion 657–8.).

[17] Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, RamanathanRK, Williamson SK, et al. A randomized controlled trial offluorouracil plus leucovorin, irinotecan, and oxaliplatin combi-

nations in patients with previously untreated metastaticcolorectal cancer. Journal of Clinical Oncology 2004;22(1):23–30 (January 1; Epub 2003 December 9).

[18] Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reversesequence in advanced colorectal cancer: a randomizedGERCOR study. Journal of Clinical Oncology 2004;22(2):229–37 (January 15; Epub 2003 December 2).

[19] Cassidy J. First efficacy and safety results from XELOX-1/NO16966, a randomised 2� 2 factorial phase III trial ofXELOX (X) vs FOLFOX4 (F)+bevacizumab (B) or placebo (P) infirst line metastatic colorectal cancer (MCRC) LBA3 31st ESMOCongress 2006.

[20] Comella P, Natale D, Farris A, Gambardella A, Maiorino L,Massidda B, et al. Capecitabine plus oxaliplatin for the first-line treatment of elderly patients with metastatic colorectalcarcinoma: final results of the Southern Italy CooperativeOncology Group Trial 0108. Cancer 2005;104(2):282–9 [Jul 15].

[21] Feliu J, Salud A, Escudero P, Lopez-Gomez L, Bolanos M, GalanA, et al. XELOX (capecitabine plus oxaliplatin) as first-linetreatment for elderly patients over 70 years of age withadvanced colorectal cancer. British Journal of Cancer 2006;94(7):969–75 [Apr 10].

[22] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hains-worth J, Heim W, et al. Bevacizumab plus irinotecan,fluorouracil, and leucovorin for metastatic colorectal cancer.New England Journal of Medicine 2004;350(23):2335–42[Jun 3].

[23] H. S. Hochster, L. L. Hart, R. K. Ramanathan, J. D. Hainsworth,E. E. Hedrick, B. H. Childs. Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab asfirst-line treatment of metastatic colorectal cancer (mCRC):Final analysis of the TREE-Study. Journal of Clinical Oncology,2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S(June 20 Supplement), 2006: 3510.

[24] Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H,Santoro A, et al. Cetuximab monotherapy and cetuximab plusirinotecan in irinotecan-refractory metastatic colorectal can-cer. New England Journal of Medicine 2004;351(4):337–45[Jul 22].

[25] Hebbar M, Wacrenier A, Desauw C, Romano O, Cattan S,Triboulet JP, et al. Lack of usefulness of epidermal growthfactor receptor expression determination for cetuximabtherapy in patients with colorectal cancer. Anticancer Drugs2006;17(7):855–7 [Aug].

[26] Meyerhardt JA, Zhu AX, Enzinger PC, Ryan DP, Clark JW, KulkeMH, et al. Phase II study of capecitabine, oxaliplatin, anderlotinib in previously treated patients with metastasticcolorectal cancer. Journal of Clinical Oncology 2006;24(12):1892–7 [Apr 20].

[27] Saltz L, Lenz H, Hochster H. Randomised phase II trial ofcetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/irinotecan in irinotecan refractory colorectal cancer. Proceed-ings of the American Society of Clinical Oncology 2005;23(Abstr 3508).