Annals of Oncology21(Supplement5):v93–v97,2010
doi:10.1093/annonc/mdq222 clinical practice guidelines
Advanced colorectal cancer:ESMO Clinical
Practice Guidelines for treatment
E.Van Cutm1,B.Nordlinger2&A.Cervantes3
On behalf of the ESMO Guidelines Working Group*
1Digestive Oncology Unit,University Hospital Gasthuisberg,Leuven,Belgium;2Ambroi Pare´,Hospital,Boulogne,France;3Department of Hematology and Medical Oncology,INCLIVA,University of Valencia,Valencia,Spain
incidence
In2006there were412900new cas of colorectal cancer (CRC)in Europe.This is12.9%of all cancer cas.CRC was responsible for217400deaths in Europe in2006.This reprents12.2%of all cancer d
eaths.Approximately25% prent with metastas at initial diagnosis and almost50%of patients with CRC will develop metastas,contributing to the high mortality rates reported for CRC.
diagnosis
Clinical or biochemical suspicion of metastatic dia should always be confirmed by adequate radiological imaging[usually a computed tomography(CT)scan or alternatively magnetic resonance imaging(MRI)or ultrasonography]. Fluorodeoxygluco-positron emission tomography(FDG-PET) scan can be uful in determining the malignant characteristics of tumoral lesions,especially when combined with CT scan.FDG-PET scan is especially uful to characterize the extent of metastatic dia when the metastas are potentially rectable. Histology of the primary tumour or metastas is always needed before chemotherapy is started.For metachronous metastas histopathological or cytological confirmation of metastas should be obtained,if the clinical or radiological prentation is atypical or very late after the initial diagnosis of the primary tumour. Rectable metastas do not need histological or cytological confirmation before rection becau of a low chance of eding. Evaluation of the general condition,organ function and concomitant non-malignant dias determines the therapeutic strategy for patients with metastatic CRC.determination of the treatment strategy The optimal treatment strategy of patients with metastat
ic CRC should be discusd in a multidisciplinary team.
In order to identify the optimal treatment strategy for patients with metastatic CRC,the staging should include at least clinical examination,blood counts,liver and renal function tests, carcinoembryonic antigen(CEA),CT scan of the abdomen and chest(alternatively,MRI).The general condition and performance status of the patient are strong prognostic and predictive factors.Known biochemical prognostic factors are white blood cell count,alkaline phosphata level,lactate dehydrogena,rum bilirubin and albumin.Additional examinations as clinically needed,are recommended before major abdominal or thoracic surgery with potentially curative intent.An FDG-PET can give additional information on equivocal lesions before rection of metastatic dia or can identify new lesions in the ca of planned rection of metastas.
treatment of metastatic CRC
The majority of patients have metastatic dia that initially is not suitable for rection.It is,however,important to lect patients in whom the metastas are suitable for rection and tho with initially unrectable dia in whom the metastas can become suitable for rection after a major respon has been achieved with combination chemotherapy.The aim of the treatment in the l
ast group of patients may therefore be to rever initially unrectable metastatic CRC to rectable CRC. unrectable metastatic CRC
The optimal treatment strategy for patients with clearly unrectable metastatic CRC is rapidly evolving.The treatment of patients should be en as a continuum of care in which the determination of the goal of the treatment is important: prolongation of survival,cure,improving tumour-related symptoms,stopping tumour progression and/or maintaining quality of life.
The outcome of patients with metastatic CRC has clearly improved during the last years with median survival now reaching almost24months.
河北师范大学录取分数线The backbone offirst-line palliative chemotherapy consists of afluoropyrimidine[intravenous(i.v.)5-fluorouracil(5-FU)or
*Correspondence to:ESMO Guidelines Working Group,ESMO Head Office,Via
L.Taddei4,CH-6962Viganello-Lugano,Switzerland;
E-mail:clinicalrecommendations@esmo
Approved by the ESMO Guidelines Working Group:April2002,last update March2010.
This publication supercedes the previously published version-Ann Oncol2009;20
(Suppl4):iv61-iv63
Conflict of interest:Prof.Van Cutm has reported that he has received rearch
funding from Amgen,MerckSerono,Pfizer,Roche and Sanofi-Aventis;Prof.Nordlinger
has reported no conflicts of interest;Dr Cervantes has reported that he is currently
conducting rearch sponsored by Roche,Amgen and MerckSerono and that he is
a member of the speakers’bureau for MerckSerono.
ªThe Author2010.Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights rerved.For permissions,plea email:journals.permissions@oxfordjournals by guest on February 6, fordjournals/ Downloaded from
oralfluoropyrimidines]in various combinations and schedules. Infud regimens of5-FU/leucovorin(L
V)are generally less toxic than bolus regimens.The most frequently ud regimens are a48h bolus and infud regimen of5-FU/LV every2weeks (LV5FU2regimens).The oralfluoropyrimidines capecitabine and uracil–ftorafur(UFT)/LV are an alternative to intravenous 5-FU/LV as monotherapy.The experience and databa with capecitabine is more extensive than with UFT. Combination chemotherapy with5-FU/LV/oxaliplatin (FOLFOX)or5-FU/LV/irinotecan(FOLFIRI)provides higher respon rates,longer progression-free survival and better survival than5-FU/LV[I,B].FOLFOX and FOLFIRI have
a similar activity,but a different toxicity profile:more alopecia and diarrhoea for irinotecan and more polyneuropathy for oxaliplatin[I,B].Both regimens consist of a48h administration every2weeks(q2weeks).The do of oxaliplatin in combination regimens with5-FU/LV is between 85mg/m2and130mg/m2q2weeks;there is,however,no evidence that the do at the higher range is more active. Therefore usually a do of85mg/m2is propod.Two randomized studies showed that combination chemotherapy was not superior to quential treatment in terms of overall survival,and therefore quential therapy starting with
fluoropyrimidine monotherapy remains a valid option in lected and frail patients[I,B].Nevertheless,when an objective respon is the primary goal in a specific in
view of surgical rection of metastas or when the metastas are symptomatic),combination chemotherapy remains the preferred option.There are,however,no perfect lection criteria for determining which patients are still candidates for upfrontfluoropyrimidine therapy.It is estimated that today 15%of patients are treated initially with
afluoropyrimidine alone.
The exposure to all three cytotoxics(fluoropyrimidines, oxaliplatin and irinotecan)in various quences,results in the longest survival.
The combination of capecitabine plus oxaliplatin(CAPOX; capecitabine2000mg/m2/day;day1-14q3weeks and oxaliplatin130mg/m2day1q3weeks)is an alternative to the combination of infud5-FU and oxaliplatin[I,A]bad on similar activity and safety.The original3weekly regimen of capecitabine/irinotecan(capecitabine2000mg/m2/day for2 weeks and irinotecan250mg/m2day1q3weeks)ems to be more toxic than5-FU/LV/irinotecan.This regimen is therefore less well established and less frequently ud in its original form.A do-reduced regimen ems be less toxic,while maintaining the activity(capectitabine1600mg/m2/day for2 weeks and irinotecan200mg/m2day1q3weeks).
The optimal duration of chemotherapy for metastatic CRC remains controversial.Options are afixed treatment period(3–6 months)and treatment until progression or toxicity.Treatment interruptions of combination chemotherapy or less intensive cytotoxic treatment should be considered if cumulative toxicity occurs,if the metastas are not rectable and if dia control is reached.Maintenance treatment with afluoropyrimidine alone prolongs the progression-free survival compared with a complete treatment break,after an initial period of combination chemotherapy[I,B].Reintroduction of combination chemotherapy is usually indicated in the ca of progression.
Second-line chemotherapy should be propod for patients with good performance status and adequate organ function.In patients refractory to afluoropyrimidine in monotherapy, cond-line treatment must consist of a combination with oxaliplatin or irinotecan.In patients refractory to FOLFOX or CAPOX,an irinotecan-bad regimen is propod in the cond-line treatment.Irinotecan monotherapy(350mg/m2 q3weeks)and FOLFIRI are options.There is no strong evidence that5-FU significantly increas the activity of irinotecan in this tting,but there are clear safety advantages of the FOLFIRI regimen,compared with irinotecan monotherapy.In patients refractory to FOLFIRI,FOLFOX or CAPOX is propod as cond-line treatment[I,B].
Monoclonal antibodies against vascular endothelial growth factor(VEGF)and against the epidermal g
rowth factor receptor (EGFR)in combination with chemotherapy should be considered in patients with metastatic CRC,since they improve the outcome of lected patients with metastatic CRC. Bevacizumab,an anti-VEGF antibody,should be considered in patients with metastatic CRC,as it increas the activity of an active cytotoxic regimen.It increas the survival,progression-free survival and respon rate infirst-line treatment in combination with5-FU/LV/irinotecan and in combination with5-FU/LV or capecitabine alone[I,B].Bevacizumab improves the progression-free survival in combination with
afluoropyrimidine plus oxaliplatin in thefirst-line treatment of metastatic CRC[I,B].Bevacizumab improves also the survival and progression-free survival in combination with FOLFOX in cond-line treatment[I,B].Bevacizumab has specific class-related side-effects:hypertension,proteinuria,arterial thrombosis,mucosal bleeding,gastrointestinal perforation and wound healing problems.Patients older than65years with
a history of arterial thrombotic events are at significantly higher risk for having an arterial thrombosis while being treated with bevacizumab.
There are no validated predictive molecular markers available for bevacizumab.There is no strong e
vidence for post-progression continuation of bevacizumab.Bevacizumab is usually continued in combination with a cytotoxic agent (fluoropyrimidine alone6oxaliplatin or irinotecan)until progression,toxicity or until the metastas are rectable. The anti-EGFR antibodies cetuximab and panitumumab are active as single agent in chemorefractory metastatic CRC.The activity of the anti-EGFR antibodies is confined to KRAS wild-type tumours[I,B].
It has been shown that cetuximab improves the survival of chemorefractory patients compared with best supportive care (BSC)[I,B].Panitumumab improves the progression-free survival compared with BSC in chemorefractory metastatic KRAS wild-type CRC[I,B].The panitumumab trial did not show a survival difference due to the cross-over design of the trial.The combination of cetuximab with irinotecan is more active than cetuximab monotherapy in chemorefractory patients[II,A].The combination of cetuximab and irinotecan has become the reference treatment infit chemorefractory KRAS wild-type metastatic CRC patients.
Anti-EGFR antibodies also increa the activity of a backbone reference cytotoxic regimen in earlier lines of treatment of KRAS wild-type metastatic CRC.
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Cetuximab increas the activity of a cytotoxic doublet in the first-line treatment in KRAS wild-type patients.A survival, progression-free survival and respon rate advantage has been demonstrated for the combination FOLFIRI/cetuximab compared with FOLFIRI alone in thefirst-line treatment of KRAS wild-type patients[I,B].An improved respon rate and progression-free survival of the combination of FOLFOX and cetuximab in KRAS wild-type patients has been reported,but not consistently confirmed infirst-line treatment.The progression-free survival and respon rate were improved for the combination cetuximab/irinotecan compared with irinotecan alone in the cond-line treatment of metastatic CRC[I,B].The panitumumab studies infirst-and cond-line treatment of KRAS wild-type metastatic CRC also showed an incread progression-free survival for panitumumab when combined with FOLFOX infirst-line treatment and an incread respon rate and progression-free survival when combined with FOLFIRI in cond-line treatment.No survival advantage has been shown in the trials[I,B].
There are no pha III results available of studies comparing the activity of bevacizumab and cetuximab or panitumumab in KRAS wild-type tumours.The anti-EGFR antibodies should not be com
bined with bevacizumab[I,B].
The activity of the anti-EGFR antibodies is confined to KRAS wild-type tumours and they should not be ud in KRAS mutant CRC[I,B].Approximately40%of metastatic CRCs are KRAS mutant;5%–10%of CRC are BRAF mutant.KRAS mutations and BRAF mutations are usually mutually exclusive. The activity of the anti-EGFR antibodies in chemorefractory CRC ems also to be confined to BRAF wild-type CRC.BRAF mutations have a strong prognostic value in early lines of treatment.A predictive value of BRAF mutation status for anti-EGFR antibodies in combination with cytotoxics could not be demonstrated until now in early lines of treatment.Other emerging he ligands amphi-and epiregulin)are under investigation,but the prognostic and predictive role of the markers needs validation.
The anti-EGFR antibodies induce in most treated patients an acneiform rash.Hypomagnesaemia is another class-related side-effect.Cetuximab is a chimeric antibody that gives slightly more frequent allergic reactions than the human monoclonal antibody panitumumab.
In patients prenting synchronously with a primary colon cancer and metastas and suffering from symptoms of the primary lusion,bleeding),a rection of the primary tumour should be
considered before starting chemotherapy.In patients with metastatic rectal cancer with symptoms of the primary tumour,irradiation(possibly combined with chemotherapy)of the primary tumour should be considered after discussion with the radiation oncologist in order to obtain optimal symptom control of the primary tumour.
rection of metastatic dia
Surgical rection should be considered for solitary or confined liver metastas,since it offers patients with metastatic CRC the best chance of long-term survival with actuarial5-year survival rates(following hepatic rection)ranging from30%–35%to >50%in some lected ries.Unfortunately,60%–75%of the patients will suffer a relap following rection of their hepatic metastas,with the majority occurring in the liver[II,A]. There is no role for partial palliative rection of metastas. Radiofrequency ablation,in combination with systemic treatment,is under investigation as an alternative or
a complement to surgical rection of liver metastas in cas where this is not possible or complete.
In patients with rectable liver metastas,perioperative combination chemotherapy with the FOLF
OX regimen improves the progression-free survival by7%–8%at3years[I, B].The perioperative chemotherapy is given for3months(six cycles)before and3months after the surgical rection of the metastas.In the ca that no preoperative chemotherapy can be or has been administered,postoperative adjuvant treatment with FOLFOX should be considered.There is no evidence yet that adding a biological to a cytotoxic doublet improves the outcome in rectable metastas compared with a cytotoxic doublet alone in combination with rection of the metastas. Rection of rectable lung metastas offers also25%–35% 5-year survival rates in carefully lected patients.
Initially unrectable liver metastas can become rectable after downsizing with chemotherapy and,if so,rection should be considered after multidisciplinary discussions.For patients with initially unrectable liver metastas,a strong correlation between respon rate and rection rate in the neoadjuvant treatment of metastatic CRC has been demonstrated. Pathological respon ems to be a surrogate for predicting the outcome.Thus,the strategy when treating patients with initially unrectable dia is to try to achieve high respon rates in order to convert unrectable metastas to rectable metastas.Diminution of the metastas in number only should not be considered as the majority of metastas in complete radiological remission still contain microscopic
viable tumour cells.In patients in whom the metastas have disappeared on standard imaging,microscopic dia is often still prent and a multidisciplinary discussion for the optimal strategy has to take place.Standard combination chemotherapy regimens comprising5-FU/LV in combination with either irinotecan,typically FOLFIRI,or oxaliplatin(FOLFOX)have been reported to facilitate the rection of7%–40%of patients with initially unrectable metastas depending upon the initial lection of patients.However,75%–80%of the patients experience cancer relap within2years of rection. Data emerging from randomized trials suggest that the addition of a targeted agent(bevacizumab or cetuximab)or even scarce data of pha II trials on the combination with a third cytotoxic plus or minus a targeted agent,might be even more effective, although concerns about toxicity limit the u of this triple cytotoxic regimen to highly lected cas.The combination of a doublet of cytotoxics plus cetuximab has led to higher rection rates(although still low in absolute numbers)in patients with liver limited unrectable metastatic KRAS wild-type CRC.The combination of FOLFOX/cetuximab and FOLFIRI/cetuximab has led to similar respon rates and rection rates in KRAS wild-type tumours.The combination of afluoropyrimidine/oxaliplatin/bevacizumab has led to
a non-significant trend in an incread rection rate compared with the cytotoxic backbone alone,although no increa in
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respon rate was shown.There are no data of randomized studies comparing the activity of a doublet of cytotoxics plus bevacizumab with a doublet plus cetuximab.
苏宁e购Surgery can be performed safely after4weeks from the last cycle of chemotherapy plus or minus cetuximab,and5–8weeks following chemotherapy plus bevacizumab.
Rection of the metastas should be performed as soon as the metastas are rectable,since unnecessary prolonged administration of chemotherapy may lead to a higher postoperative morbidity.The postoperative morbidity is more related to the duration of the chemotherapy than to the type of chemotherapy that is administered,although oxaliplatin and irinotecan may cau different histological changes in liver parenchyma:oxaliplatin is related to sinusoidal liver lesions and irinotecan to steatohepatitis.
The criteria for rectability of liver metastas are not standardized and have evolved over the last
years and are clearly related to the experience of the surgeon and of the multidisciplinary team.Multiple rections can also be performed,provided there is sufficient remnant liver(>30%)and surgery is not too risky due to location.Other considerations must include the prence of questionably rectable extrahepatic dia and poor biology. conclusion on strategy of treatment of metastatic CRC
In the lection of the optimal treatment options for patients with metastatic CRC,the determination of the treatment goals and strategy are crucial.The possibility of rection of liver(or lung)metastas should be considered.In view of this and also becau of the higher activity,multidrug combination regimens are propod to many patients,although for a subgroup of patients with unrectable metastas without symptoms or risk of rapid deterioration and with comorbidity a quential approach may be justified(Figures1and2).In patients who are candidates for combination therapy determination of the KRAS status of the tumour can clearly determine the lection of the best combination regimen(Figure2).隔着门缝吹喇叭的歇后语
respon evaluation
History,including the evaluation of the general condition,the side-effects of the chemotherapy and the
impact on the quality of life of the patient,physical examination,CEA if initially elevated and a CT scan of the involved regions are recommended after2–3months during palliative chemotherapy.It is recommended that the patient be re-evaluated every2–3months if chemotherapy is continued. note
Levels of evidence[I–V]and grades of recommendation[A–D] as ud by the American Society of Clinical Oncology are given in square brackets.Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.
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