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Current status and future perspectives of adjuvant therapy Maria Chiara Banzi

Current status and future perspectives of adjuvant therapy Maria Chiara Banzi U.O. Oncologia Medica ASMN-IRCCS Reggio Emilia Area Valutazione del Farmaco Agenzia Sanitaria e Sociale Regionale, RER. COLORECTAL CANCER: ITALY, CHANGES IN 18 Yrs. Prevalenza 300.000 pazienti

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Current status and future perspectives of adjuvant therapy Maria Chiara Banzi

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  1. Current status and future perspectives of adjuvant therapy Maria Chiara Banzi U.O. Oncologia Medica ASMN-IRCCS Reggio Emilia Area Valutazione del FarmacoAgenzia Sanitaria e Sociale Regionale, RER

  2. COLORECTAL CANCER: ITALY, CHANGES IN 18 Yrs Prevalenza 300.000 pazienti con pregressa diagnosi di tumore colonrettale (51% uomini) • - NEW CASES / Yr • 30.000 1995 • 55.000 2013 • - DEATHS / Yr • 18.000 1995 • 20.000 2013

  3. INCIDENCE and SURVIVAL Gender

  4. FUFA 63% CH 44% DISEASE-FREE SURVIVAL STAGE III PATIENTS 3-year FOLFOX 72% LV5FU2 65% DFS (months)

  5. ANALYSIS OF 6 ADJUVANT TRIALS MOSAIC FOLFOX NSABP C-07 FLOX NO16968 XELOX stage III CALGB 89903 IFL ACCORD 02 FOLFIRIHR stage III PETACC-3   FOLFIRI

  6. CONCLUSION MOSAIC FOLFOX NSABP C-07 FLOX NO16968 XELOX CALGB 89903 IFL ACCORD 02 FOLFIRI PETACC-3   FOLFIRI 3 0

  7. 2246 patients 249 patients André, New England Journal of Medicine 2004; 350: 2343-2351

  8. DFS: ITT 1.0 0.9 0.8 5.9% 0.7 0.6 0.5 Probability Events FOLFOX4 304/1123 (27.1%) LV5FU2 360/1123 (32.1%) HR : 0.80 [95% CI, 0.68–0.93] 0.4 FOLFOX4 LV5FU2 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 Disease-free survival (months) p=0.003 5.3% Data cut-off: June 2006

  9. DFS: STAGE II AND STAGE III PATIENTS 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR [95% CI] p-value Stage II* 0.84 [0.62–1.14] 0.258 Stage III 0.78 [0.65–0.93] 0.005 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months p=0.258 3.8% p=0.005 7.5% *Not powered for stage II Data cut-off: June 2006

  10. DFS: HIGH-RISK STAGE II PATIENTS 1.0 0.9 0.8 5.0% 7.2% 0.7 FOLFOX4 n=286 LV5FU2 n=290 0.6 Probability 0.5 3-year 5-year FOLFOX4 85.4% 82.1% LV5FU2 80.4% 74.9% HR 0.74 [95% CI: 0.52–1.06] 0.4 High-risk stage II- at least one : T4, tumor perforation, bowel obstruction, G3, venous invasion , <10 lymph nodes 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Disease-free survival (months) Data cut-off: June 2006

  11. OVERALL SURVIVAL (ITT) Δ 1.6 2.1 2.5 * HR 0.80, CI 0.68-0.93, p = .003 cut-off data 16 Jan 2007

  12. USA CHANGES IN 5 Yrs ( 2004 – 2008 ): FU + OXA • - Stage III • 39% 91% • - Stage II • 23% 79% Abrams. JCO 2011

  13. R NSABP C-07 FU B Rest 500 N=1207 LV 500 2hr X3 500 Rest FU LV 500 N=1200 ELOX 85 2hr Week 1 2 3 4 5 6 7 8

  14. JCO, Oct 2011 5yrs DFS 69.4 vs 64.2 HR 0.82 p 0.002

  15. JCO, Oct 2011 5yrs OS 80.3 vs 78.4 HR 0.88 p 0.08

  16. NSABP C 07 mFOLLOW UP 8 ys ST II 29% G 3 NEUROTOXICITY 8 % OXALIPLATIN 760 mg/mq ( MOSAIC 1020 mg/mq ) G 3- 4DIARRHEA !!! 38% BOWEL WALL INJURY 4.5% TOXIC DEATHS 1.3 % (FLOX all ages, 3.6% 70+)

  17. NO16968: XELOX ADJUVANT THERAPY IN STAGE III DISEASE RANDO MISATION n=944 XELOXcapecitabine 1000mg/m2 bid d1–14 oxaliplatin 130mg/m2 d1q3w 8 cycles Stage III chemo/radiotherapy-naiveCCPotentially curative resection ≤8 weeks n=1886 Bolus 5-FU/LVRoswell or Mayo regimen n=942 • Primary endpoint: superior 3-year DFS • Secondary endpoints include: OS, tolerability and convenience Schmoll et al. JCO 2007 Haller et al. JCO 2011

  18. XELOX: 5 Yrs DFS 3-yearDFS 4-yearDFS 5-yearDFS XELOX (n=944) 70.9% 68.4% 66.1% Estimated probability 59.8% 5-FU/LV (n=942) 66.5% 62.3% 1.0 HR=0.80 (95% CI: 0.69–0.93) 0.8 Absolute difference at 3 years: 4.5% p=0.0045 0.6 Absolute difference at 4 years: 6.1% 0.4 Absolute difference at 5 years: 6.3% 0.2 0.0 0 1 2 3 4 5 6 5Yrs OS 77.6% vs 74.2% p 0.148 ITT population Haller et al. JCO 2011

  19. ADJUVANT CHEMOTHERAPY: RECENT STUDIES WITH BIOLOGICS

  20. THE RESULTS OF BIOLOGICS BEVACIZUMAB - C-08 Negative - AVANT Negative - Quasar 2 Closed CETUXIMAB - NO 147 Negative - PETACC 8 Negative

  21. ADJUVANT THERAPY: OPEN QUESTIONS • Stage II • Elderly • Predictive and prognostic markers • DPD

  22. ADJUVANT THERAPY OPEN QUESTIONS • Stage II • Elderly • Predictive and prognostic markers • DPD

  23. AJCC CANCER STAGING 2002. COLORECTAL CANCER TNM Stage AJCC 2002 Stage Grading 5yrs DFS (Surgery +CT) IIA IIB T3,No T4,No LOW vs HIGH LOW vs HIGH 82% 79% 74% 70% IIIA IIIB IIIC T1-2,N1 T3-4,N1 any T,N2 LOW vs HIGH LOW vs HIGH LOW vs HIGH 81% 77% 53- 68% 46- 61% 27- 64% 21- 59%

  24. MOERTEL 1990 , 929 STAGE III pts : 7 Yrs OS SURGERY + 5 FU-Lev SURGERY 61% ALIVE 39% DEAD 44% ALIVE 56% DEAD 17 Pazients saved out of 100 treated ( RR death- 40%) Stage II : DFS 79% vs 71% ( NS )

  25. QUASAR: A RANDOMIZED STUDY OF ADJUVANT 5FU VS OBSERVATION IN 3239 STAGE II COLON PTS OBS CT HR p PTS 1617 1622 5 YRS DFS 73.8% 77.8%* 0.78 0.001 5 YRS OS 77.1% 80.8%* 0. 82 0.008 + 3.6% + 4.0% Lancet 2007

  26. ADJUVANT THERAPY :EVIDENCE FROM 20,898 PATIENTS Stage II Stage III 8-year OS 8-year OS 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 ∆=5.4%p=0.026 ∆=10.3%p=<0.0001 Surgery alone: 66.8% Surgery alone: 42.7% Surgery + FU-based chemotherapy: 72.2% Surgery + FU-based chemotherapy: 53.0% 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Follow-up (years) Sargent et al. JCO 2009

  27. DISEASE-FREE SURVIVAL: STAGE II AND STAGE III 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR [95% CI] p-value Stage II* 0.84 [0.62–1.14] 0.258 Stage III 0.78 [0.65–0.93]0.005 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months p=0.258 3.8% p=0.005 7.5% *Not powered for stage II ! Data cut-off: June 2006

  28. DATA EXTRAPOLATION FROM QUASAR and MOSAIC STUDIES : DFS STAGE II 5FU vs CONTROL + 4.0 % FOLFOX vs 5FU + 3.8 % FOLFOX vs CONTROL + 7.8 % NB Stage II not selected for high risk Mod. da Grothey and Sargent, JCO 2005

  29. DISEASE-FREE SURVIVAL: HIGH-RISK STAGE II 1.0 0.9 0.8 5.0% 7.2% 0.7 FOLFOX4 n=286 LV5FU2 n=290 0.6 0.5 Probability 3-year 5-year FOLFOX4 85.4% 82.1% LV5FU2 80.4% 74.9% HR [95% CI]: 0.74 [0.52–1.06] High-risk stage II- defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion , <10 lymph nodes examined; Data cut-off: June 2006 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Disease-free survival (months) Exploratory analysis

  30. The addition of Oxaliplatin did not improve either DFS or OS in patients age 70-75 years with either Stage II or Stage III cancer.

  31. Adjuvant Treatment for Stage II of Colon Cancer The updated results of the MOSAIC and C-07 trials reveal a consistent pattern showing that the addition of Oxaliplatin to 5Fu-LV enhances OS by 3% to 5% in patients with stage III disease but has no effect on the likelihood of cure in patients with stage II disease.

  32. CONCLUSION: STAGE II Benefit of Monotherapy 3-4 % in 5 yr DFS/OS Clinically meaningful? Additional benefit of Oxaliplatin No benefit in Overall Survival +5% DFS in high risk stage II Stage II should be considered for adjuvant CT, but need tools to inform decision

  33. Adjuvant: in Elderly Sargent, NEJM 2001

  34. “Postoperative 5FU improves survival in elderly patients, however data are conflicting whether Oxaliplatin added to 5FU provides survival benefits.In the absence of clinical evidence and with no ongoing prospective studies in this patient group, physicians are also guided by data from observational studies”. ASCO 2012, Daily News, McCleary, Dana Farber Cancer Institute CONCLUSION: ELDERLY

  35. CONCLUSION : STAGE III Patients < 70 years old: 12 cycles of FOLFOX 4 or mFOLFOX 6 or 8 cycles of XELOX Patients ≥70 years old : 12 cycles of LV5FU2 or 8 cycles of Capecitabine XELOX ? Andrè T, N Engl J Med,2004 Allegra CA, J Clin Oncol,2010 Haller D, J Clin Oncol,2011 Twelves C et al, N Engl J Med,2005

  36. TRIAL “ 3 vs 6” Adjuvant Therapy of Stage II and III colon carcinoma : 3 vs 6 months FOLFOX / XELOX GISCAD and Italian Intergroup

  37. ADJUVANT THERAPY: OPEN QUESTIONS • Stage II • Elderly • Predictive and prognostic markers • DPD

  38. MAIN RISK FACTORS T4 G3 N < 10-13 OCCLUSION-PERFORATION VENOUS-LYMPHATIC-PERINEURAL INVASION TS MSS GENE EXPRESSION PROFILE 18q LOH …………….

  39. % Schmoll, Ann Oncol, Oct 2012

  40. Schmoll, Ann Oncol, Oct 2012

  41. Defective MMR - Colon cancer Characterized by presence of MSI & loss of MLH1, MSH2, MSH6 or PMS2 expression ~15% of Sporadic CC, >90% loss of MLH1 Clinical Correlations: Right sided, Female, Early stage, Better prognosis Tumors: Poorly differentiated, Signet-ring-cell, dMMR cells resistant to 5-FU1,2 ( ???? ) 1Carethers, 1999; 2Arnold 2003

  42. MSI prognostic for RFS stage II CONSENSUS HR 0.27 (0.11-0.37) Tejpar, ASCO 2009

  43. MMR status is prognostic: 515 untreated stage II colon cancer in 13 RCT deficient proficient HR: 0.51 p=0.009 In MSI pts higher incidence of local and abdominal relapses after adjuvant chemotherapy with 5FU. No difference in control Sinicrope F. ASCO 2010, 3519

  44. DFS in dMMR pts, Pooled data* Stage II (N=102) Stage III (N=63) 5 yr DFS 5 yr DFS Untreated 62% Treated 67% Untreated 87% Treated 72% HR: 1.08 (0.44-2.68) p=0.86 HR: 2.80 (0.98-8.97) p=0.05 *not confirmed by recent analysis from PETACC3 and QUASAR: Schmoll , Ann Oncol Oct 2012 Sargent D. ASCO 2008

  45. PROPOSED STAGE II ALGORITHM MSI MSS MMR No Adjuvant Clinical Risk High Not High Adjuvant No Adjuvant Or Adjuvant *all decisions require discussion with patient Meropol NJ Ed Session ASCO 2010

  46. E5202: STAGE II COLON CANCER Arm A mFOLFOX6 High-risk(MSS and18q LOH) Arm B mFOLFOX6 + Bevacizumab 5mg/kg SURGERY Tumour block risk assessment based on biology (18q/MSI) Low-risk (MSI or no loss of 18q ) Observation Accrual goal= 3,125 patients

  47. Validation of a 18 gene expression classifier (ColoPrint) for predicting outcome in the T3-MSS subgroup of Stage II colon cancer patients. AbstractNo: 3510 T3–MMS : 61% Low Risk 3-years RFS : Low Risk 91% High Risk 74% (HR 2,9; p 0.001).

  48. TERAPIA ADIUVANTE Validation of the 12-gene colon cancer Recurrence Score (RS) in NSABP C07 as a predictor of recurrence in 264 Stage II and 628 Stage III pts treated with 5FU/LV or FLOX AbstractNo: 3512 12-gene RS predicted recurrence (p= .001) indipendent of T, N, MMR, G 39% LRS, 35% IRS, 26% HRS 5FU treated 5 Yrs RS: St.II: 9, 13, 18% St.III: 21, 29, 38% St.IIIC: 40, 51, 64%

  49. ADJUVANT THERAPY: OPEN QUESTIONS • Stage II • Elderly • Predictive and prognostic markers • DPD

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