Cancer of the colon and rectum altogether are the third most common tumor type worldwide.
In Europe 250 000 new colon cancer cases are diagnosed each year / cancer of the colon is more frequent than rectal cancer: in high-risk population the ratio is 2:1
About 70% of patients are >65 years of age. The median age at presentation is 72 years
At diagnosis, in 75-80% of cases, surgery represents the only currative treatment
Accordingly to the AJCC TNM staging system, patients with stage II disease /T3-4N0/, who account for approximately 1/4 of patients , have relatively good prognosis after curative resection, with 5 year overall survival ranging from 72% for T4N0 to 85% for T3N0
Stage III /T0-4N1-2/ patients represent approximately 38% of all CCs, a 5 year OS after surgery is less than 50%
The aim of postoperative chemotherapy is to destroy microscopic metastasis that may be already present, and reduce the risk od recurence
Adjuvant chemotherapy for stage III colon cancer has to been show to improve progression free /PFS/ and overall /OS/, and is recommended as standard therapy
The value of adjuvant chemotherapy for patients with stage II disease is controversial.
When determining the benefit of adjuvant therapy for this group of patients, several factors should be taken into consideration, including number of lymph nodes analyzed after surgery, the prognostic features, anticipated life expectancy, and comorbid conditions.
Adjuvant treatment is recommended for stage III and “high-risk” stage II patients The patients with stage II are at high risk if they present at least one of the following characteristics :
Oralfluoropyrimidinesandcombinationtherapies Capecitabine is a prodrug of 5FU administered by oral route. Today is capecitabine considered a valid alternative to 5FU/FA in the adjuvant setting for stage III patients and was not inferior to bolus 5FU and low-dose leucovorin for disease –free survival. Capecitabine is an alternative for patients who are unlikely to tolerate 5FU, leucovorin and oxaliplatin. Another active OF is UFT, which is constituted by Tegafur and Uracil in a molar ratio of 1:4. In the NSABP-C-06 study, which enrolled 1608 patients with stage II and III, UFT/FA achived similar DFS and OS as compared to bolus 5FU/FA. capecitabine
A major change in survival of patients with advanced colorectal cancer was observed at the and of 1990s with the addition of oxaliplatin and irinotecan to infused 5FU/LV, in particular to the LV5FU2 schedule. The same combination regimens were therefore translated into the adjuvant setting.
In the QUASAR study there was a significant improvement in overall survival /risk reduction of 18% and 3.6% overall survival gain/
Therapeutic differences between adjuvant and metastatic colon cancer Adjuvant chemotherapy for cancer has generally been the adaptation of effective regimens used in metastatic setting and testing them for efficacy in the adjuvant setting. The adjuvant therapy for coloncancer has reached some rather unexpected conclusions. Irinotecan, a very effective drug in the metastatic setting, failed in the adjuvant setting despite its proven role in the management of metastatic disease. Multiple trials have repeadly failed to show additional benefits when it is combined with the older standars of 5FU/Leucovorin
The use of irinotecan currently is not considered a primary option for patients with resected stage II or III colon cancer.
Adjuvant studies in the era of biological therapies Angiogenesis inhibitors
theadditionofbevacizumab to mFF6 didnotresultinanoverallstatisticallysignificantprolongationin DFS
therewas a transientbenefitin DFS duringthe one yearthatbevacizumabwasutilized
Recently, the AVANT study, whichhasjustbeenpresentedinfull at the ASCO GI Cancersymposium 2011, suggestedthatthecombinationofbevacizumab /for 12 months/ with FOLFOX and XELOX /for 6 months/ wasossociatedwith a slight but significantdecrementinoveralsurvival De Gramont et al. J ClinOncol 29, a362, 2011
Hypotheses to explain the negative findings of the AVANT and NSABP C-08 trials
withdrawal of bevacizumab after 12 months exposure cause a supraphysiological “rebound” in which there is synthesis and release of angiogenic cytokines that increase revascularization of residual microscopic metastases, confering a more aggressive tumor phenotype, with associated consequences
treatment with bevacizumab cause selection of a chemotherapy-resistant subclone from which a more phenotypically aggressive tumor might be reconstituted
treatment with bevacizumab during the first yearalterthe vascular physiology of recurrent tumor nodules and make them more difficult to detect with conventional imaging modalities, implyingt hat the initial apparent benefit of bevacizumab on disease-free survival are artifactual
patients treated on the adjuvant bevacizumab arm be denied further treatment with bevacizumab on relapse and thus imperil their overall survival
we have lost an important aspect of the mechanism of action of bevacizumab by using an infusional rather than a bolus chemotherapy regimen
Epidermal growth factor receptor inhibitors /cetuximab/ NCCTG/Intergroup N0147 trial The fate of the utility of cetuximab in adjuvant colon cancer will rest with the results of the PETACC 8 trial which has completed recruitment and results are awaited
Molecular markers to individualize adjuvant therapy for colon cancer
AnalysisofresultsfromtheAdjuvantColoncancerEndpoints /ACCENT/ databaserevealedthatevenafterrecurrence, patientswithstage II disease live longerthanpatientswithstage III disease, suggestingthatthetwodiseasemightbebilogicallydistinct, withstage II diseasehaving more indolent natural history.
Additionalevidencesuggestingthatstage II andstage III disease are biologicallydistinctcomesfromexaminingmoleculardifferencesbetweenstage II andstage III tumorsinrelation to prognosisandresponsetotreatment.
Currentlythere are no data to recommendthe use ofmolecularmarkersinthedecisionmakingprocess for adjuvanttherapyofCRCs.
Lossofheterozygosity at chromosome 18q (LOH18Q) andthelackofmicrosatelliteinstability (MSI) are potentialmarkers for aggressiveclinicaldisease
MSI – microsatelliteinstabillity /a change inthenumberof DNA repeatsequence/ is a molecular signature ofdeficientmismatchrepair(dMMR) in tumor DNA. dMMR, manifestedby MSI, increasesthe rate ofmutationwithincellsofthecolon. Thedegreeof MSI presentin a tumor indicateseither a dMMRphenotype(MSI-high; MSI-H), or proficient MMR(pMMR) inthecaseof MSI-stable or MSI-lowtumors. Inaddition to PCR-detectionof MSI, MMR canalsobeassessedusing IHC to assay for the protein expression.
Tumor biologybasedtesting A usefulmolecular tool for treatmentdecisionforpatientswithstage II and/or stage III coloncancerwouldbe one similar to Oncotype DX breastcancerassay. Based on data fromthedevelopmentphaseassays, the 761 candidategeneswerenarrowed to Seven potentialrecurrencegenes, six-potentialbenefitgenesandfiveinternal reference genes.
Based on the gene signature, a prespecified continuous recerrence score was assigned to each patients. TherecurrencescorewasvalidatedintheQuasartrialwith a significantcorrelationbetweentheriskscore as a continuousvariableandthelikehoodofrecurrence at 3 years. HRswerealsosignificant for DFS(1.41,p=0.010) and for overallsurvival(1.33,p=0.041)
Elderly: a special population? The median age of diagnosis of CC is 72 years, and the incidence is increasing with age. Should we recomended potentially toxic and expensive 6 months therapy to 75-year or even older patients? Elderly patients />70/ with resected high risk colorectal cancer :
the life expectancy of a 70-year-old otherwise healthy individual is 8 years for men and 14 years for women
the toxicity of chemotherapy is similar below and above age 70
the efficacy of adjuvant chemotherapy is similar in elderly people to that in the general population
recent data from pooled analysis suggest caution in treating elderly patients with novel chemotherapy drugs /oxaliplatin/ in the adjuvant setting
Age doesn’t seem to be a predictive factor for benefit and tolerability of adjuvant chemotherapy, while it still represent a prognostic factor for OS, since the probability of dying for non-malignant causes increases with age. Toxicity considerations imply fluoropyrimidine monotherapy might be considered in older patients with stage III colorectal cancer.
In the adjuvant setting many questioins are still unanswered :
the role of targeted agents associated with chemotherapy
the optimal duration of adjuvant treatment: 3 – 6 months? / In Italy, the TOSCA trial is investigating whether 3 months of FOLFOX4 treatment are not inferior to 6 months /large international collaboration /IDEA/
the validation of prognostic/predictive factors
other molecular markers to individualize adjuvant therapy