1. ADJUVANT CHEMOTHERAPY OF COLORECTAL CANCER Damir Vrbanec Dept. of Medical Oncology University Hospital Zagreb ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia

3. 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

4. About 70% of patients are >65 years of age. The median age at presentation is 72 years

5. At diagnosis, in 75-80% of cases, surgery represents the only currative treatment

6. 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 T3N0Stage III /T0-4N1-2/ patients represent approximately 38% of all CCs, a 5 year OS after surgery is less than 50%

10. 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

11. 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.

13. poorly differentiated tumour

14. vascular or lymphatic or perineural invasion

15. tumor presentation with obstruction or tumor parforation

17. the toxicity of chemotherapy is similar below and above age 70

18. the efficacy of adjuvant chemotherapy is similar in elderly people to that in the general population

21. 6 months of therapy was demonstrated to be equally to 12 months

22. infusional 5-FU in different schedules resulted in equal activity as bolus 5-FU/LV with less toxicity on a type 1 level of evidence

23. the two schedules of 5FU/LV (mayo Clinic for 6 months, Roswell Park for 4 cycles) showed same efficacy

24. administration of adjuvant 5FU for 6 months reduces the risk of death by 30% , which is equivalent to an additional 10-15% survival gain

27. 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

29. 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.

31. risk of permanent peripheral sensory neuropathy with oxaliplatin /15.5% all grades of peripheral sensory neuropathy at 48 months after treatment

34. In the QUASAR study there was a significant improvement in overall survival /risk reduction of 18% and 3.6% overall survival gain/

35. 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

36. The use of irinotecan currently is not considered a primary option for patients with resected stage II or III colon cancer.

37. Adjuvant studies in the era of biological therapies Angiogenesis inhibitors

42. treatment with bevacizumab cause selection of a chemotherapy-resistant subclone from which a more phenotypically aggressive tumor might be reconstituted

43. 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

44. patients treated on the adjuvant bevacizumab arm be denied further treatment with bevacizumab on relapse and thus imperil their overall survival

48. Additionalevidencesuggestingthatstage II andstage III disease are biologicallydistinctcomesfromexaminingmoleculardifferencesbetweenstage II andstage III tumorsinrelation to prognosisandresponsetotreatment.

49. Currentlythere are no data to recommendthe use ofmolecularmarkersinthedecisionmakingprocess for adjuvanttherapyofCRCs.

53. 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.

54. 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)

57. the toxicity of chemotherapy is similar below and above age 70

58. the efficacy of adjuvant chemotherapy is similar in elderly people to that in the general population

60. 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.

62. 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/

63. the validation of prognostic/predictive factors