Kolon Kanserinde Adjuvan Tedavi Prof. Dr. N. Faruk AYKAN TOD Kursu Gaziantep 24 Ekim 2003

Prognosis by Stage Stage TNM Dukes 5-yr survival I T1 N0 M0 A >90% 85% II T3/4 N0 M0 B2/3 70-80% III T2 N1/2 M0 T3 N1/2 M0 T4 N1 M0 C1 C2 C3 25-60% IV Any T/N M1 D 5-30% ESMO Guidelines 2001

Kolon Kanserinde Tedavi Primer Tedavi : Cerrahi Rezeksiyon (Hastaların % 50’si kürabl) NCI-PDQ Statement March 2002

Kanser Tedavisinde Kanıt Düzeyleri (NCI-2002) Çalışma Dizaynı Hedef Randomize, kontrollü klinik çalışmalar, metaanalizler Çift kör Şemaya göre Randomize olmayan klinik çalışmalar Olgu sunumları Popülasyon, ardışık seri Ardışık seri Ardışık olmayan olgular Total mortalite (GSK) Nedene özgül mortalite Yaşam kalitesi Dolaylı veriler Hastalıksız sağkalım Progresyonsuz sağkalım Tümör cevap oranı Source: US NCI 12-6-2002. http://www.nci.nih.gov / Cancer information PDQ

Level Of Evidence: How Is It Recorded? DESIGN END POINTS Example 1 Randomized, controlled (1) Non-blinded (ii) Overall survival (A) 1ii A Example 2 Non-randomized (2) Non-blinded (ii) Disease-free survival (Di) 2ii Di MAY BE USED FOR PRIMARY AND SECONDARY ENDPOINTS

Kolon Ca – Adjuvan KT Evre III (Dukes’ C)

Kolon Ca – Adjuvan KT Evre III (Dukes’ C) 5-FU/LEV 5-FU/FA (12 ay) (6 ay) ? 1990 1997 2004 NIH ASCO

Kolon Ca – Adjuvan KT Evre III (Dukes’ C) Cerrahi 5-FU/Lev (12 ay) > Cerrahi (1iiA) (n:304) (n:315) NCCTG 1989, INT-0035 1990 – 1995 Toplam vaka sayısı: 929 5 yıl HSK: % 45 vs % 63 p<0.0001 5 yıl GSK: % 54 vs % 65 p<0.007 Moertel CG et al: Ann Intern Med 122:321-326, 1995

Kolon Ca – Adjuvan KT Önerilen KT rejimi (1991)

Kolon Ca – Adjuvan KT Evre III (Dukes’ C) Cerrahi 5-FU/FA (6 ay) > Cerrahi (1iiA) n:158 n:151 IMPACT 1995, INT-0085 1993-1997 Toplam vaka sayısı: 309 5 yıl HSK: % 58 vs % 74 p<0.004 5 yıl GSK: % 63 vs % 74 p<0.01 O’Connell et al: J Clin Oncol, 15:246-250, 1997

Kolon Ca – Adjuvan KT Evre III (Dukes’ C) Cerrahi 5-FU/FA (6 ay) = Cerrahi 5-FU/Lev (12 ay) (1iiA) n: ? n: ? INT-0089 1996 ve 1998 Toplam vaka sayısı: 3759 5 yıl HSK: % 59 vs % 56 p:0.09 5 yıl GSK: % 66 vs % 63 p:0.09 (5-FU/FA/Lev 6 ay FU/FA’dan üstün değil !) Haller DG et al: Pro ASCO, 17:256a, 1998 (abstr.982)

Kolon Ca – Adjuvan KT Standart KT rejimleri (ASCO 1997) Mayo rejimi

Kolon Ca – Adjuvan KT Standart KT rejimleri Dublin - 2001

Adjuvant Chemotherapy For Stage III Colon Cancer The oxaliplatin MOSAIC trial of LV5FU2 vs. FOLFOX4 recruited 1123 pts/arm 40% stage II patients 3-year DFS results were presented at ASCO 2003: MOSAIC 3-year DFS Overall Stage II Stage III LV5FU2 72.9% 83.9% 65.5% FOLFOX4 77.8% 86.6% 71.8% P-value P<.01 HR=.77 - HR=.82 HR=0.76 De Gramont A, et al: Pro ASCO, abstr.1015, 2003

Oxaliplatin + 5-FU/FA Adjuvan KT NSABP C-01 : MOF ≥ Cerrahi (1988) NSABP C-02 : PortalVİ 5-FU (7 gün) ≥ Cerrahi (1990) NSABP C-03 : 5-FU/FA (12 ay) > MOF (1993) NSABP C-04 : 5-FU/FA (6 ay) = 5-FU/Lev (12 ay) (1996) NSABP C-05 : 5-FU/FA (6 ay) = 5-FU/FA/INFα-2a NSABP C-06 : UFT/FA vs 5-FU/FA (6 ay) NSABP C-07 : OXA/5-FU/FA vs 5-FU/FA

Irinotecan Adjuvant Clinical Development Programme: Main Trials In Stage III Colon Cancer Regimen Pts Endpoints ACCORD 2 CPT-11+LV5FU2 LV5FU2 400 3-yr DFS Safety Overall survival PETACC-3 (V-307) CPT-11+ inf 5-FU/FA (LV5FU2 or AIO) Inf 5-FU/FA 2333 Translational res QUASAR II CPT-11+ capecitabine Bolus 5-FU/FA 3450

Adjuvan KT’de infüzyonal 5-FU PETACC-2 çalışması LV5FU2, AIO 5-FU/FA* *: Mayo klinik şeması

Irinotecan/5-FU/FA Adjuvan KT’de PETACC-3 çalışması CPT-11/5-FU/FA* 5-FU/FA* *: De Gramont, AIO şeması

PETACC-3 (V-307) Group A1 (AIO, every wk) 2 hours CPT-11 Folinic acid 500 mg/m²   2 hours 5-FU IV 2000 mg/m2 24 hours   CPT-11 80 mg/m2 60min Group A2 (LV5FU2, every 2 wks) Folinic acid 200 mg/m² 5-FU bolus 400 mg/m2   2 hours 5-FU IV 600 mg/m2 22 hours D1 & D2 D1   CPT-11 180 mg/m2 60min

Xeloda® as adjuvant treatment for colon cancer: X-ACT study Open-label, randomised, multicentre, phase III trial Recruitment of 1,956 Dukes’ C colon cancer patients is on target for completion in 2001 Xeloda 1,250mg/m2 twice daily, days 1–14 every 21 days x 8 versus 4-weekly Mayo Clinic regimen x 6 Disease-free survival as 1° endpoint 2° endpoints: overall survival, safety, quality of life, health economics, measurement of biochemical markers in selected centres 19. Xeloda® as adjuvant treatment for colon cancer: X-ACT study A phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), is evaluating Xeloda as adjuvant treatment for Dukes’ C colon cancer. This large, global trial is being conducted in 27 countries with the recruitment of 1,956 patients undergoing surgery for colon cancer and is on target for completion in 2001. Patients are randomised to receive either eight cycles of intermittent Xeloda 1,250mg/m2 twice daily for 14 days followed by a 7-day rest period or six cycles of 4-weekly Mayo Clinic regimen. The primary objective of the trial is to demonstrate at least equivalent disease-free survival with Xeloda compared with Mayo Clinic regimen. In addition, overall survival, safety, QoL and health economics will be assessed. The activity of the biochemical markers thymidine phosphorylase, dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase will be measured in tumour tissue samples collected during surgery at selected centres and these will be evaluated in relation to treatment outcome.

Kolon Ca – Adjuvan KT Evre II (Dukes’ B)

Kolon Ca – Adjuvan KT Evre II (Dukes’ B) Cerrahi 5-FU/FA (6 ay) ≥ Cerrahi (1iiDi) % 2 HSK avantajı; NSABP ve Meta-analiz 1999 Riskli sub-gruplar; Perforasyon Tam Obstrüksiyon Anöploidi Yüksek S-faz fraksiyonu 18q delesyonu MSS Kontrollü klinik çalışma !

Irinotecan Adjuvant Clinical Development Programme: Other Studies CALGB C89803 Irinotecan + bolus 5-FU/FA weekly vs bolus 5-FU/FA weekly 1263 patients, includes stage II + III and PS-2 patients 3-yr DFS, safety, overall survival, translational research AERO Irinotecan + LV5FU2 vs 5-FU/FA (Mayo Clinic or LV5FU2) 600 patients with stage II and III rectal cancer 5-yr DFS, safety, overall survival PETACC-4 Irinotecan + 5-FU/FA (TTD, LV5FU2, AIO) vs 5-FU/FA 1976 patients with stage II colon cancer 5-yr DFS, safety, overall survival, translational research