Terapia neoadyuvante en cáncer de recto Estado del arte Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia

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1 Terapia neoadyuvante en cáncer de recto Estado del arte Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia

2 Temario Generalidades Adyuvancia en colon y recto FU / Capecitabina / Oxaliplatino Estado del arte Quimiorradioterapia para estadíos II & III Oxaliplatino preoperatorio Eficaz y seguro (?)

3 TNM7 Colorectal

4 Supervivencia a 5 años de cáncer colo-rectal de acuerdo con el TNM7 Estadío % de pacientes Supervivencia a 5 años N=2229; I % IIA % IIB % IIC % IIIA % IIIB % IIIC % IVA % IVB %

5 Recurrence rate (%) Colon cancer recurrence rate by time from randomisation (all patients) After 5 years, recurrence rates <1.5%/year After 8 years, recurrence rates <0.5%/year For DFS endpoint, long-term follow-up will provide few events After 5 years, follow-up for recurrence may be reduced DFS=disease free survival Year Sargent, et al. JCO 2009

6 Adjuvant therapy increases the chance of survival: evidence in 20,898 CC patients 1.0 Stage II CC 1.0 Stage III CC OS estimate p=0.026 Surgery alone 8-year OS rate (95% CI): 66.8% (63.7% to 70.0%) OS estimate p< Surgery alone 8-year OS rate (95% CI): 42.7% (39.9% to 45.7%) 0.2 Surgery + FU-based chemotherapy 8-year OS rate (95% CI): 72.2% (69.3% to 75.2%) 0.2 Surgery + FU-based chemotherapy 8-year OS rate (95% CI): 53.0% (50.2% to 55.9%) Follow-up time (years) Follow-up time (years) CC=colon cancer OS=overall survival Sargent, et al. JCO 2009

7 X-ACT: 5-year DFS and OS updated data 1.0 Capecitabine (n=1,004) 5-FU/LV (n=983) HR=0.88 (95% CI: ) p= year DFS (%) year OS (%) HR=0.86 (95% CI: ) p= DFS estimate OS estimate Absolute difference at 5 years: 4.1% Years 0.4 Absolute difference at 5 years: 3.1% Years Twelves et al. ASCO GI 2008

8 FOLFOX-4 FOLFOX4: ciclo de 14-días OX 85mg/m 2 iv 2 h LV 200mg/m 2 iv 2 h 5-FU 400mg/m 2 iv bolus 5-FU 600mg/m 2 iv 22 h LV 200mg/m 2 iv 2 h 5-FU 400mg/m 2 iv bolus 5-FU 600mg/m 2 iv 22 h d1 d2 d3 5-FU = 5-fluorouracilo; LV = leucovorin (Folinato de calcio); OX = oxaliplatino

9 Diseño del estudio MOSAIC Aimery De Gramont

10 1.0 MOSAIC FOLFOX vs. 5- FU Stage III 0.8 Propor?on Disease Free FOLFOX4 LV5FU2 =7.5% p=0.005 HR= Years Andre et al., J Clin Oncol 2009

11 FOLFOX vs. 5- FU (MOSAIC) Propor?on Alive FOLFOX4 LV5FU2 =4.2% p=0.023 HR= Years Andre et al., J Clin Oncol 2009

12 Superior DFS with XELOX Estimated probability Absolute difference at 3 years: 4.4% 3-year 4-year 5-year DFS DFS DFS XELOX (n=944) 70.9% 68.4% 66.1% 5-FU/LV (n=942) 66.5% 62.3% 59.8% Absolute difference at 4 years: 6.1% Absolute difference at 5 years: 6.3% HR=0.80 (95% CI: ) p= Years ITT population Haller et al. ECCO/ESMO 2009

13 MOSAIC Neuropatía sensorial por oxaliplatino

14 Preoperative vs Postoperative Chemoradiotherapy for Rectal Cancer Sauer R, Becker H, Hohenberger W, et al. N Engl J Med. 2004;351:

15 Background and Rationale Adjuvant radiotherapy with or without chemotherapy improves outcomes in patients with rectal cancer Unclear whether preoperative or postoperative chemoradiotherapy affords greater benefit In locally advanced disease Chemoradiotherapy improves local control and overall survival Unclear whether preoperative or postoperative chemoradiotherapy is superior Current trial conducted by German Rectal Cancer Study Group Sauer R, et al. N Engl J Med, 2004;351:

16 Summary of Study Design Locally advanced rectal cancer, T3, T4, or node positive (N = 823) Preoperative chemoradiotherapy (6 wks) Wk 0 Arm A* (n = 415) Arm B (n = 384) Wk 0 Surgery Surgery Wk 12 Postoperative chemotherapy Wk 16 Follow-up every 3 mos for 2 yrs, then every 6 mos for 3 yrs Wk 16 Postoperative cgy boost chemotherapy *Arm A: Preoperative chemoradiotherapy: 28 fractions (180 cgy/day, 5 x/wk) radiotherapy plus 5-fluorouracil (5-FU) as 120-hr continuous infusion (1000 mg/m 2 /day) in Wks 1 and 5 of RT Postoperative chemotherapy: bolus 5-FU (500 mg/m 2 5 x/wk) every 4 wks for 4 cycles Arm B: Chemotherapy: bolus 5-FU (500 mg/m 2 /day) for 5 days, every 4 wks for 4 cycles Sauer R, et al. N Engl J Med, 2004;351:

17 Main Findings Survival comparable between groups Overall survival at 5 years 76% in preoperative group vs 74% in postoperative group (P =.80) Disease-free survival at 5 years 68% in preoperative group vs 65% in postoperative group (P =.32) Preoperative treatment improved local control 5-year cumulative local recurrence incidence 6% in preoperative vs 13% in postoperative group (P =.006) Distant recurrence similar between groups Sphincter preservation rates in patients with abdominoperineal resection before randomization Higher with preoperative chemoradiotherapy (P =.004) Sauer R, et al. N Engl J Med, 2004;351:

18 Other Outcomes Greater compliance with preoperative treatment Treatment change requested by 9 patients in preoperative group vs 19 in postoperative group More patients assigned to postoperative therapy failed to complete chemoradiotherapy (< 1% vs 28%, P <.001) More short-term toxicity but less long-term toxicity among postoperative cohort Grade 3/4 acute events» 27 vs 40 events (P =.001) Grade 3/4 long-term toxicity» 14 vs 24 events (P =.01) Sauer R, et al. N Engl J Med, 2004;351:

19 Key Conclusions Compared with postoperative chemotherapy, preoperative chemoradiotherapy in patients with locally advanced rectal cancer: Improves» Local control» Treatment compliance» Rates of sphincter preservation Reduces long-term toxicity Does not improve overall survival or disease-free survival Preoperative chemoradiotherapy should be considered first-line therapy for patients with locally advanced rectal cancer Sauer R, et al. N Engl J Med, 2004;351: