Hans-Joachim Schmoll is Head ofthe Department of Haematology

and Oncology and AssociateProfessor of Haematology and

Oncology & Internal Medicine atMartin Luther Halle-WittenbergUniversity Hospital in Germany.

Previously, Dr Schmoll was aProfessor of Internal Medicine, andlater Director of the Department of

Haematology/Oncology of theMedical University of Hanover. He is

on the Board of Directors of theEuropean Society for MedicalOncology and serving on the

Membership Programme Committeeof the American Society of ClinicalOncology. Dr Schmoll is also Chair

of the Gastrointestinal TumoursSection of the Association of

Medical Oncology of Germany (AIO)within the German Cancer Society.He is a founder and the Presidentof the Saxony-Anhalt Cancer Societyand Chair of the Cancer Centre atthe Martin Luther Halle-WittenbergUniversity Hospital. Dr Scholl is a

member of many scientific societies,including the European Organisation

for Research and Treatment ofCancer (EORTC) and the AmericanAssociation of Cancer Research. He

is Editor in Chief of Onkologie,Associate Editor of Cancer

Research, and an editorial boardmember for the European Journal

of Cancer, Annals of Oncology,Critical Reviews in Hematology and

Oncology and Cancer &Chemotherapy Reviews. Dr Scholl

has been awarded the 1981Johann-Georg-Zimmermann award

for Cancer Research and the 2001German Cancer Award and he hasbeen an Honorary Member of the

Hungarian Cancer Society since 2006.

a report by

Han s - J o a c h im S c hmo l l

Head, Department of Haematology and Oncology, Martin Luther Halle-Wittenberg University Hospital

Ep i d em i o l o g y

Colorectal cancer is a frequent disease in Westerncountries and ranks as second after lung cancer inmen and breast cancer in women with about 500,000new cases in Europe and 150,000 in the US. Themortality of 40–50% is high; however, in recentyears this has been steadily improving due to earlydetection and better treatment measures, in particularadjuvant chemotherapy. In advanced disease, theimproved efficacy of systemic chemotherapy leads toa substantial long-term survival by means ofneoadjuvant chemotherapy followed by radicalresection of metastases in the liver and/or lung.

On-going pre-clinical and clinical research withdrugs directed to multiple targets is using colorectalcancer as a paradigm for early investigation of newdrugs in combination with classical chemotherapyand this will hopefully create further substantialimprovement in cancer treatment in the near future.

This disease is diagnosed mostly in resectable stages;however, 35–40% of patients have clinicallydetectable metastatic disease at the time of firstdiagnosis. Owing to the relatively aggressive natureof colon cancer in a relevant fraction of patients,synchronous and metachronous metastases occur in50% of cases, resulting in an overall mortality of40–45%. In recent years the introduction of adjuvantchemotherapy with single agent 5 fluorouracil(5FU), and most recently 5FU/oxaliplatin,significantly improved the long-term survival andcure rate of patients with stage II and III disease (nolymph nodes involved and lymph node positive,respectively), leading to a substantially reducedmortality, at least in the US. However, a stage shiftwith increasingly early detection by effectivescreening programmes (e.g. Hemoccult blood testingand – more importantly – a screening-colonoscopyas part of a general early detection programme, willreduce the mortality of colorectal cancer in thefuture. Also, in advanced disease, the efficacy ofcombination chemotherapy including new targeteddrugs has improved the median survival from 1-1.5to 2-2.5 and even nearly three years in some recent

phase II studies. Some of these new developmentswill be described in the following.

Ad v a n c e s i n A d j u v a n t T r e a tmen t o fR e s e c t a b l e D i s e a s e

P e r i - o p e r a t i v e T r e a t m e n t o f C o l o n

C a n c e r

For patients with high risk stage II and III, adjuvantchemotherapy with 5FU/oxaliplatin has becomestandard. Treatment should start within 5–6 weeksafter surgery and should be given for six months.Combination chemotherapy is preferred over single-agent 5FU since the relapse rate is significantlyimproved by the addition of oxaliplatin withacceptable short and long-term toxicity. Since arelapse in this disease mostly means an incurablesituation, this event should be avoided as much aspossible and combination chemotherapy should bepreferred for most patients, as well as for olderpatients. Patients with stage II disease lacking riskfactors (e.g. obstruction, perforation, less than 12lymph nodes resected, poor grading) also mightbenefit from adjuvant chemotherapy, at least singleagent 5FU as shown in the British QUASAR trial.Despite these data, the decision for adjuvanttreatment in stage II disease without high riskfeatures can be decided on an individual basis.

Several prognostic factors have been investigated;however, currently none of them form the basis forindividual selection of patients for specific adjuvanttreatment modalities. These factors include loss ofheterozygosis, chromosome 18q, microsatellitestability or instability, insulin-like growth factor-β-receptor type II, excision repair cross-complementingrodent repair deficiency, complementation group 1(ERCC1), etc. None of these markers should becurrently used as argument for or against adjuvantchemotherapy outside clinical trials.

There is cumulative evidence that infusional 5FU,which has been the standard partner for oxaliplatin inadjuvant treatment, can be exchanged for oral 5FU,particularly capecitabine. The large Roche trials with

Sys temic Treatment in Co lorec ta l Cancer

Colorectal Cancer

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Sys temic Treatment in Co lorec ta l Cancer

4,000 patients have shown that capecitabine is anexcellent partner for oxaliplatin in early disease as wellas for adjuvant treatment, with a treatment-relatedmortality of 0.6% for FOLFOX and for XELOX.Efficacy data from this adjuvant chemotherapy trial(XELOXA trial) in high-risk stage II/III will beavailable in 2007. However, a large clinical trial inadvanced disease comparing FOLFOX with XELOX(Jim Cassidy et al., European Society for MedicalOncology Presidential Symposium 2006)demonstrated the excellent practicability andtolerability of this combination for a limited period ofsix months. Therefore, in adjuvant treatment the oralXELOX combination is favoured as standard.Currently, the role of bevacizumab (Avant trial) andcetuximab (Pan-European Trials in Alimentary TractCancer – PETACC-8 trial) is being investigated foradjuvant treatment of high risk stage II and III coloncancer; however, efficacy results are not availablebefore 2009.

P e r i - o p e r a t i v e T r e a t m e n t o f R e c t a l

C a n c e r

The standard treatment of locally advanced rectalcancer including low located tumours is neoadjuvantchemoradiation with 5FU infusion, followed byspecial rectal cancer surgery (total mesorectalexcision). There is much evidence that post-operative adjuvant chemotherapy with 5FU inaddition to pre-operative chemotherapy should alsobe a standard due to some effect on survival. For lessextended or higher located tumours, five x 25Gyradiation (one week) without chemotherapy,followed by total mesorectal excision (TME), is analternative option. Current prospective trials (theNational Surgical Adjuvant Breast and Bowel Project – NSABP – in the US and the PETACC-6trial in Europe) investigate the combination ofcapecitabine/oxaliplatin for chemoradiation asadjuvant chemo-therapy after surgery (PETACC) orthe addition of bevacizumab to 5FU/oxaliplatin(NSABP). The NSABP control arm with FOLFOXindicates that, at least in the US, adjuvant treatmentfor rectal cancer does not differ from colorectalcancer. The role of targeted drugs, e.g. bevacizumaband/or cetuximab as inhibitor of epidermal growthfactor (EGF) receptor pathway together withchemotherapy as well as radiation, are currentlybeing evaluated in phase II trials, and preliminarydata show highly interesting efficacy.

A d v a n c e d D i s e a s e

As in any other tumour type, survival of patients withadvanced disease depends on the sensitivity to thechosen chemotherapeutic drugs reflecting thebiology of the tumour, and the number of treatment

regimen or individual drugs given might influencethe course of disease. In addition, individual caseswith limited metastases to the liver and/or lung withgood response to chemotherapy are candidates forsecondary and even repeated metastatic resection,resulting in an excellent long-term outcome for 30%of these patients. Therefore, the treatment strategyfor patients with advanced disease should beprospectively planned and sequential treatments withalternative drugs should be given as much as possible,depending on the individual registration character-istics in different countries.

Most importantly, before any treatment decision, thepatient should be categorised with respect to the aimof the treatment, either ‘curative’, aiming for long-term survival or ‘palliative’. For patients with limitedmetastases and major response resectable disease,optimal combination chemotherapy should bechosen as the first-line treatment, as well as for thosepatients with fast-growing metastases and a risk forrapid development of major tumour relatedsymptoms. While for rapid and substantial reductionof tumour mass combination, chemotherapyincluding targeted drug use should be standard, forthe other patients (e.g. 30%) with slow-growingmetastases or severe co-morbidity, single agent 5FU,preferably capecitabine or uracil and ftorafur(UFT)/leucovorin, should be selected as initialtreatment. This must be followed by combinationchemo-therapy in cases of progression under first-line single agent 5FU.

The most active treatment combinations forstandard treatment from clinical trials areFOLFOX/bevacizumab, XELOX/bevacizumab,FOLFIRI/bevacizumab or FOLFOX/irinotecan,with response rates in the range of 45–65%. It is ofmajor importance that in cases of progression underthe chosen first-line combination, second-linetreatment is mandatory to maintain the possibility oflong-term survival. All these protocols have more orless comparable efficacy, but different toxicity, e.g.oxaliplatin is associated with neuropathy and noalopecia, whereas irinotecan is associated withalopecia. Therefore, an irinotecan-containingcombination can be given for a more prolongedtime, whereas an oxaliplatin combination is limiteddue to the occurrence of neuropathy after mediantreatment duration of about six months in themajority of the patients, leading to discontinuationof oxaliplatin. The selection of an oral 5FU regimen(XELOX) has many advantages for the patients overinfusional 5FU (FOLFOX or FOLFIRI) since thepatient does not need a port with pumps for twodays every two weeks. Therefore, the oral 5FU-based combination should be preferred. Thecombination of oral capecitabine plus irinotecan has

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not been sufficiently investigated and is associatedwith toxicity and should therefore not be usedoutside clinical trials.

The role of cetuximab in first-line treatment is underinvestigation, and the results of large phase III studiesfor first and second-line treatment are expected in2007. Phase II data have been promising withresponse rates from 50–80%, progression free survival(PFS) from 9–12 months and an overall survival of 30months. At least for second- and third-linetreatment, cetuximab is an excellent option. Beyondthe single agent activity of cetuximab (10%), thecombination of cetuximab plus irinotecan andprobably also oxaliplatin shows synergistic activitywith acceptable toxicity. Therefore, according to thecurrent registration label, cetuximab is mandatory forpatients failing irinotecan combination.Bevacizumab, if not given as part of the first-linetreatment combination, is able to double theresponse rate, PFS and survival in second-linetreatment, if combined with FOLFOX (andprobably also XELOX), and has therefore provenactivity even in second-line treatment. However, it

is not known whether bevacizumab, as a part ofsecond-line combination chemotherapy, is active inthose patients who had bevacizumab-containingcombination treatment as their first-line treatment.The treatment of bevacizumab beyond progressionfor second-line treatment is unproven and should notbe undertaken on a regular basis outside of the on-going clinical trials investigating this procedure.Bevacizumab is, in contrast to cetuximab, not activeas single agent, at least in colorectal cancer andtherefore only used for combination withchemotherapeutic drugs.

For third, or first-line treatment mitomycin C incombination with capecitabine is a valid option forsome patients. In particular, in cases with metastasesconfined to the liver and refractory to systemictreatment, locoregional chemotherapy or chemoem-bolisation, it is an appropriate measure with a goodresponse rate even in advanced stages.

Cu r r e n t D e v e l o pmen t i nC h emo t h e r a p y

Several new drugs have shown some activity in phase

I trials, e.g. epothelone, histone deacetylase-inhibitors, insulin-like growth factor receptor typeII-inhibitors, etc., and warrant further investigationin phase II trials and in combination with otherdrugs. In addition, the combination of drugsinhibiting different targets, and the inhibition of onetyrosine kinase pathway with different modalitiesincluding receptors as well as the intracellulartyrosine kinase domain, are highly promising.Recently, it has been shown in a phase I trial that,even for refractory colorectal cancer patients thecombination of gefitinib plus cetuximab, without theaddition of chemotherapy, yielded a response rate ofbetween 15% and 16% indicating that doubleinhibition of a relevant pathway, at least in coloncancer, is a promising treatment strategy.

The combination of different targeted drugs, inparticular those inhibiting the EGF and vascularendothelial growth factor (VEGF) 1/2/3 receptorpathway like cetuximab or panitumumab plusbevacizumab, alone or in combination withirinotecan, has shown significant activity in patientsrefractory to chemotherapy. The preliminary data

indicate a synergy if both pathways are inhibited,together with chemotherapeutic drugs. The on-going Intergroup study in US is thereforeinvestigating FOLFOX or FOLFIRI plus eitherbevacizumab or cetuximab or both. Furthermore,phase I/II trials are investigating the addition of athird drug, irinotecan, to the FOLFOX/bevacizumab/cetuximab combination. The value oforal tyrosine kinase inhibitors targeting severalpathways (e.g. EGF receptor, VEGF/EGF-receptor,platelet-derived growth factor, etc.), in combinationwith chemotherapy is currently being investigated.The potential role of further new targets includingEGF-receptor or aurora kinase inhibitor drugs arethe focus of current clinical research.

Colorectal cancer remains an excellent paradigm forthe development of new drugs, in particulartargeted drugs in combination with classicalchemotherapy, and it serves as a model for othertumour types. Hopefully the survival of patientswith advanced colorectal cancer will be significantlyincreased. There is clear hope that the number oflong-term survivors will increase substantially in thenear future. ■

Colorectal Cancer

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Colorectal cancer remains an excellent paradigm for the

development of new drugs, in particular targeted drugs in

combination with classical chemotherapy.

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