Radiotherapy for rectal cancer. Karin Haustermans Department of Radiation Oncology

Radiotherapy for rectal cancer Karin Haustermans Department of Radiation Oncology

O U T L I N E RT with TME surgery? Neoadjuvant or adjuvant RT? 5 x 5 Gy or long-course CRT? RT with new drugs? Selection of patients?

Swedish Rectal Cancer Trial Preop RT Surgery P - value Local Failure 12 % 27 % < 0.001 5-Yr Survival 58 % 48 % 0.04 NEJM, 1997

TME-Trial: RT+TME vs. TME Local Failure at 5 years: RT+TME: 5.6% TME: 10.9% p < 0.001 Kapiteijn E et al.,n Engl J Med 2001;345: 638-46 Peeters K et al., Ann Surg 2007;246:693-701

Influence of CRM on LR Preop RT (%) Surgery (%) P-value CRM 2 mm 15.5 23.3 NS CRM > 2 mm 3.6 8.5 <0.001 CRM > 10 mm 1.1 1.1 NS

Late toxicity Dutch Trial Faecal incontinence 39% in non-irradiated patients vs 62 % in irradiated patients (p<0.001) Sexual activity in male patients 66% in non-irradiated patients vs 57 % in irradiated patients (p=0.05) Sexual activity in female patients 53% in non-irradiated patients vs 39 % in irradiated patients (p=0.02) No differences in QoL

Trial Design Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases PRE Pre-operative RT 25Gy / 5F Surgery Pathology Randomise POST Surgery Pathology CRM-ve CRM+ve No RT Post-op CRT 45Gy / 25F + concurrent 5FU Adjuvant chemotherapy given as per local policy

LR by treatment (ITT) 100 90 80 70 LR rate (%) 60 N Events 3yr LR 5yr LR PRE 674 23 5% 5% POST 676 61 11% 17% HR(95%CI)=2.47(1.61, 3.79) p<0.0001 50 40 30 20 10 0 0 1 2 3 4 5 Number at risk Time(Years) Pre 674 501 365 247 156 76 Post 676 511 363 246 141 55

DFS by treatment (ITT) 100 90 80 70 60 50 40 30 DFS rate (% 20 N Events 3yr DFS 5yr DFS PRE 674 112 80% 75% POST 676 146 75% 67% HR(95%CI)=1.31 (1.02, 1.67) p=0.03 10 0 0 1 2 Time(Years) 3 4 5 Pre 674 475 337 230 147 70 Post 676 482 326 231 129 50

RT with TME surgery? YES! But some subgroups may not benefit Neoadjuvant or adjuvant RT? 5 x 5 Gy or long-course CRT? RT with new drugs? Selection of patients?

CAO/ARO/AIO-94 Arm I: OP 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5 x 1000 mg/m 2 5 x 1000 mg/m 2 500 mg/m 2 /d 120h-infusion 120h-infusion i.v.-bolus RT: 50.4 + 5.4 Gy Boost Arm II: 5-FU 5-FU 5 x 1000 mg/m 2 5 x 1000 mg/m 2 120h-infusion 120h-infusion RT: 50.4 Gy OP 5-FU 5-FU 5-FU 5-FU 500 mg/m 2 /d I.v.bolus 0 2 4 6 8 10 12 14 16 18 20 22 Weeks Sauer R et al., N Engl J Med 2004; 351:1731-40

Pre vs. Postop. RCT: CAO/ARO/AIO-94 Cumulative Incidence 0.3 0.2 0.1 0.0 Local Relapse p = 0.006 Postop. CRT 13% 6% Preop. RCT 0 12 24 36 48 60 Months Preop CRT: + Downstaging Compliance Local control Toxicity Sphincter Sauer R et al., N Engl J Med 2004; 351:1731-40

Pathological Stage Postop. CRT CAO/ARO/AIO-94 M SM MP UICC- I 18 % UICC-II 29 % UICC-III 40 % Risk of Overtreatment UICC-IV 7 % Missing 6 % Sauer R et al., N Engl J Med 2004; 351:1731-40

RT with TME surgery? YES! But some subgroups may not benefit Neoadjuvant or adjuvant RT? Neoadjuvant! But need for improved staging (MRI) 5 x 5 Gy or long-course CRT? RT with new drugs? Selection of patients?

Polish trial 316 pts RT s ur g er y CT RT Bujko et al, Radiother Oncol 2004

Preoperative 5x5 Gy Preoperative RCT 5x5 Gy 50.4 Gy + CT P n=148 n=138 Sphincterpreserved 61% 58% 0.57 T-Category ypt0 1% 16% <0.001 ypt1 2% 9% ypt2 37% 37% ypt3-4 60% 38% N-Category ypn0 52% 68% 0.007 ypn1 48% 32% CRM + 13% 4% 0.017 Bujko et al. Radiother Oncol 2004;72:15-24

Preoperative 5x5 Gy Preoperative RCT 14.2% 9.0% p=0.17 p=0.8 Bujko et al., Br J Surg 2006;93:1215-23

An intergroup trial (TROG, AGITG, CSSANZ, RACS) T3NxM0 5 x 5 Gy 5-FU CRT P-value Number of pts. 163 163 3-year LR rates 7.5% 4.4% 0.24 5-year M1 28% 31% 0.85 5-year OS 74% 70% 0.56 RTOG 3-4 late tox 7.6% 8.8% 0.84 For distal tumors (< 5 cm), six of 48 SC patients and one of 31 LC patients experienced local recurrence Ngan et al., JCO 2012

Preoperative R(C)T Preoperative 5x5Gy (+) Biologic effective dose Combination with CT + + (+) Downsizing Acute toxicity Late toxicity Compliance Costs (+) + +

RT with TME surgery? YES! But some subgroups may not benefit Neoadjuvant or adjuvant RT? Neoadjuvant! But need for improved staging (MRI) 5 x 5 Gy or long-course CRT? Risk-adapted! If downsizing required: CRT or wait RT with new drugs? Selection of patients?

Rectal cancer T3/T4 NX M0 (UICC 1987) by DRE or EUS Considered resectable, WHO PS 0-1, Age 80 y RANDOMIZE Pre-op RT Pre-op RT + 5FU/LV x2 Pre-op RT Pre-op RT + 5FU/LV x2 Surgery Surgery Surgery Surgery Accrual : 1011 patients April 1993 - April 2003 Post-op 5FU/LV x4 Post-op 5FU/LV x4

DFS OS Bosset et al, Lancet Oncology 2014

year of randomisation number of patients preoperative regimen cumulative dose OX preop STAR-01 ACCORD 12 CAO/ARO/ AIO-04 11/2003-08/2008 Oxaliplatin 11/2005-7/2008 7/2006-2/2010 NSABP-R-04 7/2004-8/2010 PETACC-6 11/2008-09/2011 747 598 1265 1608 1094 50,4 Gy + fluorouracil 225mg/m² (CI) vs. 50,4 Gy + fluorouracil 225mg/m² (CI) + OX 60mg/m² weekly 45 Gy + CAP b.i.d. 800mg/m² vs. 50 Gy + CAP b.i.d. 800mg/m² + OX 50mg/m² weekly 50,4 Gy + fluorouracil 1000mg/m² d1- d5, d29-d33 vs. 50,4 Gy + fluorouracil 250mg/m² d1- d14, d22-d35 + OX 50mg/m² d1,8,22,29 45 Gy + 5,4-10,8Gy + fluorouracil 225mg/m² (CI) or CAP 825mg/m² b.i.d. vs. 45 Gy + 5,4-10,8Gy + fluorouracil 225mg/m² (CI) or CAP 825mg/m² b.i.d. + OX 50mg/ m² weekly 45 Gy + optional boost 5,4 Gy + CAP b.i.d. 825mg/m² vs. 45 Gy + optional boost 5,4 Gy + CAP b.i.d. 825mg/m² + OX 50mg/m² d1,8,15,22,29 360 mg/m² 250mg/m² 200mg/m² 250mg/m² 250mg/m² primary endpoint OS pcr DFS pcr, sphincter saving surgery, downstaging DFS

Toxicity data of randomized trials with oxaliplatin G3-4 preop toxicity STAR-01 ACCORD 12 CAO/ARO/ AIO-04 8% vs. 24% 10.9% vs. 25.4% 20% vs. (p<0,001) (p<0,001) 23% NSABP-R-04 6,6% vs. 15,4% (p<0,0001) PETACC-6 15,1% vs. 36,7% surgical toxicities 80% vs. 83% 20.9% vs. 18.1% 44% vs. 47% NA 38% vs. 41% full dose RT 92% vs. 84% 100% vs. 87% 96% vs. 94% Dose 90% vs. 80% 50% vs. 59% 21% vs. modification received 80% 15% CT of fluorouracil and 66% received all OX cycles NA 97% vs. 94% From 84% to 97% of pts received >80% of the ideal CT dose 91% vs. 63% received <90%

ACCORD 12 Gerard et al, JCO 2012

Disease- free survival: primary analysis (ITT) follow up 31 months (2.6-5.6 years) 100 90 80 70 60 50 40 30 20 Cox model adjusted for stratification factors (except center) HR = 1.04 (0.81-1.33) P = 0.78 3- year DFS: 74.5% Cape 73.9% Cape+Oxali 10 0 0 1 2 3 4 5 6 (years) O N Number of patients at risk : Treatment arm 124 547 468 347 129 24 0 Cape+RT 121 547 430 322 131 22 1 Cape+Oxali+RT

Rectal Cancer: Rationale to combine CRT with EGFR-Inhibition: EGFR - EGFR + pcr: 8/35 pcr: 2/52 29% 4% p=0.006 Giralt J. et al., Radiother Oncol 2005;74:101-8

N Preoperative Regimen pcr FFCD 762 RT RT/5FU 3.7% 11.7% EORTC 1011 RT RT/5FU 5% 11% Bertolini et al. 40 RT/5-FU/Cetuximab 8% Horisberger et al. 50 RT/irinotecan/capecitabine/cetuximab 8% Machiels et al. 35 37 RT/5-FU RT/Cetuximab/Capecitabine 11% 5% Rodel et al. 103 60 RT/capecitabine/oxaliplatin RT/capecitabine/oxaliplatin + cetuximab 16% 9% RCT: mean pcr= 12% RCT+ cetuximab: mean pcr= 7.5%

Pooled pcr = 22% SELECTION! Molecular mechanisms? Biomarkers?

RAPIDO trial Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation trial Randomized multicentre Phase III study Arm A = control! Long course chemo-rt (5 weeks) àsurgery à(adjuvant chemo) Pts with primary high risk rectal cancer N = 885 Arm B = exp! 5 x 5Gy! 6 cycles of capecitabine + oxaliplatin àsurgery

Brachytherapy Endorectal BT as boost Danish Colorectal Cancer Group Dose-escalation randomized phase III trial Pts with resectable T3 and T4 tumours; CRM 5mm on MRI Standard CRT (50,4 Gy in 28 fx) N = 123 (T3: 102; T4: 21) Standard CRT + HDR brachy boost (10 Gy in 2 fx) N = 120 (T3: 102; T4: 18) Jakobsen et al. IJROBP 2012

Brachytherapy T3 tumours TRG 1 and 2 Post-op complications Grade 3 toxicity Higher radiation dose increases the rate of major response (TRG1-2) by 50% in T3 tumours Endorectal boost is feasible, with no significant increase in toxicity or surgical complications Jakobsen et al. IJROBP 2012

Selection of patients!

Quality of surgery: definitions Complete mesorectum: No defect deeper than 5 mm Smooth circumferential margin

Quality of surgery: definitions Incomplete mesorectum: Defects down onto muscularis Irregular circumferential margin

LR by plane of surgery LR rate (%) 90 80 70 60 50 Events N 3yr LR 5yr LR Mesorectal plane 22 596 4% 8% Intramesorectal plane 22 382 8% 9% Muscularis propria plane 16 141 15% 21% p=0.0019 40 30 20 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Time (years)

Fokas et al, JCO 2014

Organ preservation Organ preservation is appealing Avoidance of significant postoperative mortality and morbidity long-term urinary, sexual, and fecal dysfunction temporary or definitive stoma Increasing quality of life and oncological outcome seems good Maas et al, JCO 2011

Watch-and-wait outcome Habr-Gama series Resectable cancer, <7cm from anal verge ccr + observation (n=71) vs. pcr (n=22) OS DFS 5y OS 100% vs. 88% 5y OS 92% vs. 83% Habr-Gama et al, Ann Surg 2004 Stage 0 has excellent prognosis, irrespective of treatment strategy

S U M M A R Y RT with TME surgery? YES! But some subgroups may not benefit Neoadjuvant or adjuvant RT? Neoadjuvant! But need for improved staging (MRI) 5 x 5 Gy or long-course CRT? Risk-adapted! If downsizing required: CRT or wait RT with new drugs? Scheduling and intensification requires further study Selection of patients? YES! Before and during

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