8 Giornata Onco-ematologica Varesina

Transcription

1 Azienda Ospedaliera Sant Antonio Abate di Gallarate 8 Giornata Onco-ematologica Varesina Le esperienze di eccellenza del DIPO di Varese Metastasi epatiche da tumore del colon-retto: terapia medica in funzione dei fattori di rischio Salvatore Artale Divisione di Oncologia Medica Ospedale di Gallarate

2 Azienda Ospedaliera Sant Antonio Abate di Gallarate Wich patients should we to treat with Neoadjuvant therapy?

3 La Terapia Medica in Funzione del rischio Key Points Outcome in unselected/selected patients synchronous-metachronous CLM* clinical risk score Outcomes of neoadjuvant chemotherapy for synchronous-metachronous CLM * Colorectal liver metastases

4 Resection of metastases depends on the tumor response rate in selected pts Folprecht et al. Ann Oncol 2005

5 Selected pts Resec.Rate 33-56% Non selected pts Resec.Rate2-36%

6 Selected pts

7 SELECTED PATIENTS

8 Phase II/III studies in unresectable liver metastases (non selected patients) Authors (year) Regimen N Pts RR % R0/RR % Van Cutzem (2009) FOLFIRI/CTXmab 35 WT Bokemeyer (2009) FOLFOX/CTXmab 61 WT 77 4,3 60 4,7 Douillard (2011) FOLFOX4/ Panitmab 61 WT Masi (2010) FOLFOXIRI BEVA

9 Phase II studies in selected patients Authors (year) Alberts (2004) Pozzo (2005) Regimen N Pts RR % R0/RR % FOLFOX FOLFIRI Garufi 2009 Folprecht (2010) Gruenberger (2008) FOLFIRINOX/ CTXmab FOLFOX6- FOLFIRI CTXmab XELOX BEVA 43 WT 67 WT Wong (2011) CAPEOX BEVA

10 Resectable mcrc liver metastases Uncertainties Borderline resectable Initially unresectable surgical skills Nordlinger et al. EJC 2007

11 La Terapia Medica in Funzione del rischio Key Points Outcome in unselected/selected patients synchronous-metachronous CLM* clinical risk score Outcomes of neoadjuvant chemotherapy for synchronous-metachronous CLM * Colorectal liver metastases

12 Synchronous-metachronous CLM Patients who have synchronous metastases represent a group of patients with the shortest disease free interval and have been shown to be at increased risk for recurrence after metastatic resection.. Scheele J et al. W J Surg 1995

13 Synchronous-metachronous CLM: definitions Uncertainties Synchronous hepatic lesions that are discovered before primary tumor resection * liver metastases diagnosed before colorectal resection or at the time of laparotomy ** liver metastases detected on radiographic imaging in the perioperative period or within*** 1 month after resection of the primary tumor lesions diagnosed up to 3 months from the detection of the primary lesion as a synchronous deposit **** liver metastases diagnosed at the same time or within 3 months of their primary tumor ***** Metachronous *Reddy S. K. et al. Ann Surg Oncol 2009 **Capussotti L. et al. Ann Surg Oncol 2007 ***Allen P. et al. J Gastroint Surgery 2003 ****Tzai MS et al. Ann Surg Oncol 2007 ***** Rees M et. al. Ann of Surg 2008 liver metastases discovered more than 1 month after resection of the primary tumor * liver metastases discovered more than 3 months after resection of the primary tumor ** *Allen P. et al. J Gastroint Surgery 2003 ** Adam R et al. Ann of Surg 2010

14 Uncertainties: chemotherapy for resectable Synchronous CLM A Survival Analysis of the Liver-First Reversed Management of Advanced Simultaneous Colorectal Liver Metastases LiverMetSurvey-Based Study Annals of Surgery 2012 Axel Andres, MD, Christian Toso, MD, PhD, Rene Adam, MD, PhD, Eduardo Barroso, MD, Catherine Hubert, MD, Lorenzo Capussotti, MD, Eric Gerstel, MD, Arnaud Roth, MD, Pietro E. Majno, MD, and Gilles Mentha, MD

15 No differences in terms of DFI and OS After preoperative chemotherapy Brouquet A et al. Am Coll of Surg 2010

16 Certainties: chemotherapy for Unresectable Synchronous CLM Several restrospective studies show no benefits for primary tumor resection on survival *. moreover, waiving immediate colorectal resection allows for an earlier start to systemic chemotherapy, which prolongs survival and creates a possibility of downsizing metastatic disease to resectable ** *Ahmed et al. JCO 2008 **Tebutt et al. Gut 2003 *Ruo et al. J Am Coll Surg 2003 **Benoist et al. Br J Surg 2005 *Scoggins et al. J Surg Oncol 1999

17 Uncertainties: chemotherapy for resectable Synchronous CLM

18 Long-term survival in patients with synchronous CLM after Hepatic Resection Retrospective studies *DFS/OS synchronous = DFS/OS metachronous Capussotti et al % 5-year survival Bockorn et al % 5-year survival Minagawa et al % 5-year survival Lee et al % 5-year survival DFS: disease free survival; OS: overall survival

19 N pts 70 syncronous 57 delayed In the delayed group,39 pts received chemotherapy before liver resection Treatment with neoad. therapy or patient response to it did not correlate with survival

20 Factors associated with survival in patients with synchhronous CLM Capussotti et al. Ann of Surg Oncol 2007

21 Certainties INITIALLY UNRESECTABLE DISEASE 184 pts Adam et al. JCO 2009

22 Possibility of cure? Cured patients = 5 years or more DFI after the last hepatectomy or last resection of extrahepatic disease 16% Adam et al. JCO 2009

23 POSSIBILITY OF CURE? multivariate analysis Three variables as independent predictors of cure: P= maximum size of metastases at diagnosis less than 30 mm number of metastases at hepatectomy three o fewer Complete pathologic tumor response (5-years surv rate of 76% after hepatectomy) Adam et al. JCO 2009

24 La Terapia Medica in Funzione del rischio Key Points synchronous-metachronous CLM* clinical risk score Outcomes of neoadjuvant chemotherapy for synchronous-metachronous CLM * Colorectal liver metastases

25 clinical risk score

26 * Colorectal liver metastases Retrospective analysis

27 135Pts Lee W et al. Langenbecks Arch Surg 2008

28 P= P= Lee W et al. Langenbecks Arch Surg 2008

29 Retrospective analysis

30 Fong Y et al. Ann of Surgery 1999

31 Am Coll of Surg 1999

32

33 Stat.significance was defined P value of <05 Of the assessed scoring system, only the MSKCC score and the Iwatsuki Score provided a statistically significant stratification of patients with regard to survival

34 Summary In the patients with synchronous CLM, data from multivariate analysis of restrospective studies suggest the following prognostic factors to select patients who could really benefit from time-test strategy with neoadjuvant chemotherapy before liver resection: T4 staging > 3 liver metastases The Fong clinical risk score shows that the following criteria could be used in a preoperative scoring system as a predictor of outcome: disease free interval from primary to metastases <12 months number of hepatic tumors >1 largest hepatic tumor >5 cm carcinoembryonic antigen level > 200 ng/ml,

35 Limitations of avalaible data The vast majority of the data reported comes from restrospective analyses of non randomized studies. Most studies took into consideration surgical series analyzed over a prolonged period of time, leading to biases related to the the variability of surgical approaches, chemotherapy regimens and selection criteria applied

36 La Terapia Medica in Funzione del rischio Key Points clinical risk score Outcomes of neoadjuvant chemotherapy for synchronous-metachronous CLM * Colorectal liver metastases

37

38

39 Xelox or FOLFOX4 treatment

40 Prospective study

41 24.7 months 8.8 months 3.0 months

42 Outcomes of neoadjuvant chemotherapy for resectable CLM 3278 pts from 23 randomized and non randomized studies 80% of pts < 4 livermets 20% > 4 livermets median maximum size of the largest lesion was 4 cm Terence C et al Ann Surg Oncol 2010

43 Outcomes of neoadjuvant chemotherapy for resectable CLM RR were reported in 14 studies Median rate of OR was 64% Terence C et al Ann Surg Oncol 2010

44 Outcomes of neoadjuvant chemotherapy for resectable CLM DFS results were reported in 12 studies/os in 13 studies mdfs was 21 months mos 46 months Terence C et al Ann Surg Oncol 2010

45 Limitations of avalaible data restrospective analysis of non randomized studies in most of the cases. In the Chua systematic review only 4 series have studied patients with liver-only metastases and used an optimal preoperative chemotherapy regimen based on irinotecan or oxaliplatin. The issue of single, metachronous, primarily resectable liver metastases was not addressed in any series In the particular case of the EORTC study, it is unclear whether the improved patient survival was a result of the neoadjuvant or adjuvant component of the therapy

46 Definition Certainties: chemotherapy for metachronous CLM

47 Certainties: chemotherapy for metachronous CLM

48 Certainties: chemotherapy for metachronous CLM Adam R et al. Ann of Surg.2010

49 Overall Survival Adam R et al. Ann of Surg.2010

50 Overall Survival OS in patients with tumors 5 cm or more in size and minum follow-up period of 2 months posthepatectomy Adam R et al. Ann of Surg.2010

51 Conclusions prospective randomized controlled trials evaluating the optimal timing of hepatectomy relative to chemotherapy for synchronous CLM are needed. avalaible data suggests initial chemotherapy for patients with resectable synchronous colorectal liver-only metastases in the following poor-risk categories: T4 staging > 3 liver lesions disease free interval from primary to metastases <12 months single liver metastasis > 5 cm The Fong clinical risk score demonstrated that patients with number of hepatic tumors >1 displayed poorer outcome. In the latter case in the absence of prospective data, could be taken into consideration a prehepatectomy chemotherapy also in patients with number of lesions > 2

52 Despite advances in survival with chemotherapy, surgical resection of hepatic metastases is still considered the only curative option for patients with liver metastases. However, even after a successful resection, the majority of patients will experience disease recurrence.

53

54 Overall Survival is independent from response rate to Bevacizumab Probabilità di sopravvivenza Probabilità di sopravvivenza Responder IFL/Avastin (n=180) IFL/placebo (n=143) Non responder IFL/Avastin (n=222) IFL/placebo (n=268)) HR=0.60 HR=0.75 Sopravvivenza (mesi) Grothey et al, JCO 2008

55 A PHASE II CLINICAL TRIAL OF BEVACIZUMAB IN COMBINATION WITH MODIFIED FOLFOX 6 FOLLOWED BY ONE YEAR OF MAINTENANCE WITH BEVACIZUMAB ALONE IN PATIENTS WITH INITIALLY NOT OR BORDERLINE RESECTABLE COLORECTAL LIVER METASTASES (THE CLMO-001 TRIAL/ML25625)

56 A PHASE II CLINICAL TRIAL OF BEVACIZUMAB IN COMBINATION WITH MODIFIED FOLFOX 6 FOLLOWED BY ONE YEAR OF MAINTENANCE WITH BEVACIZUMAB ALONE IN PATIENTS WITH INITIALLY NOT OR BORDERLINE RESECTABLE COLORECTAL LIVER METASTASES (THE CLMO-001 TRIAL/ML25625) Study design 1 1. Preoperative treatment phase Before surgery, patients will be treated with the combination therapy mfolfox-6 + bevacizumab for 5 cycles (cycles 1-5), followed by one cycle (cycle 6) of mfolfox-6 alone (without bevacizumab) and will be evaluated for response. 2. Stop treatment for surgery Liver resection is planned 3weeks after the discontinuation of the first 6 courses of chemotherapy, resulting in a gap of 5weeks, at the most, between surgery and the last bevacizumab dose. 5 weeks after surgery, patients will restart chemotherapy + bevacizumab programme.

57 Alternative study design 1 1. Preoperative treatment phase Before surgery, patients will be treated with the combination therapy mfolfox-6 +bevacizumab for 5 cycles (cycles 1-5), followed by one cycle (cycle 6) of mfolfox-6 alone without bevacizumab) and will be evaluated for response. 2.Stop treatment for surgery Patients, who at the end of the preoperative treatment phase will be evaluated from the Surgeon suitable for a TWO-STAGE HEPATECTOMY, will undergo a first hepatic metastasectomy 3 weeks after the discontinuation of the first 6 courses of chemotherapy, resulting in a gap of 5 weeks between surgery and the last bevacizumab dose, and a second liver resection 6 weeks after the first. 5 weeks after the second surgery, the patient will restart the chemotherapy + bevacizumab programme.

58 Azienda Ospedaliera Sant Antonio Abate di Gallarate Thank you for your attention