Carcinoma rettale: ruolo della radioterapia

Carcinoma rettale: ruolo della radioterapia M.A.Gambacorta Cattedra di Radioterapia Università Cattolica del Sacro Cuore-Roma

Is radiotherapy active? D 10 7 Gy Primary tumour Cells 10 10-12 Positive Nodes (macro) Cells 10 8-10 70-84 Gy 56-70 Gy Subclinical Disease Cells 10 4-5 28-35 Gy 1 cm 3 = 10 9 Whiters RH et al - IJROBP - 2004

Tumour volume: dose-response Chemotherapy equivalent to a cytoreduction by 10 2-3 Primary tumour Cells 10 10-12 Positive Nodes (macro) Cells 10 8-10 49-63 Gy 35-49 Gy Subclinical Disease Cells 10 4-5 7-14 Gy 1 cm 3 = 10 9 Whiters RH et al - IJROBP - 2004

Is Radiotherapy active? YES Is Radiotherapy effective? Survival Local control Sphincter saving Organ saving

Preop RT alone : SURVIVAL 3 Meta-analysis SBU systematic overview Biologically effective dose: > 30 Gy Glimelius B et Al - Act Oncol 2002 Colorectal CC Group - Lancet 2001

Preop RT alone Sweden trial 1110 pts Local rec. gain 29 % 12% 17% Survival gain 30 % 39 % 9% Glimelius B - Eur J Onc 2005

Total Mesorectum Excision Local recurrence 5-15% Heald RJ, Lancet 1986

after 2000 randomized trials Pre vs Post CAO/ARO/AIO 94 Short ERT Pre Chemo RT vs Post Chemo RT Winner Pre Chemo RT Duch Trial MRC C07 Long ERT EORTC 22921 FFCD 9203 Polish Trial Scandinavian ian Short RT+TME vs TME Short RT+TME vs TME Long RT vs Chemo RT Long RT vs Chemo RT Short RT vs Chemo RT Long RT vs Chemo RT Short RT Short RT Chemo RT Chemo RT = Chemo RT

after 2000 randomized trials Pre vs Post CAO/ARO/AIO 94 Pre Chemo RT vs Post Chemo RT Winner Pre Chemo RT Short ERT Duch Trial MRC C07 Long ERT Short RT+TME Significant vs TME improvement Short RT Short RT+TME of vs Cancer TME specific Short RT Survival EORTC 22921 FFCD 9203 Polish Trial Scandinavian ian Long RT vs Chemo RT Long RT vs Chemo RT Short RT vs Chemo RT Long RT vs Chemo RT Chemo RT Chemo RT = Chemo RT

Cumulativ relativ survival of Rectal cancer in Sw eden Relative survival proportion 100 90 80 70 60 50 40 30 20 10 0 RT+TME TME RT+Surgery Surgery RT+No TME No TME 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years since diagnosis By the courtesy of L.Pahlman ESTRO/ESSO/ESMO Course - 2009

Is Radiotherapy effective? Survival No But one treatment for all

Is Radiotherapy effective? Local Recurrence Preop ERT+TME vs TME Short ERT,5 Local recurrence (%),4,3,2 Stage III 11.2% vs 21.5% p < 0.001 Stage III P = 0.002 23%,1 0,0 0 2 4 6 8 16% Years since surgery Duch Trial MRC C07 Peeters KC et AL Ann Surg 2007 Sebag-Montefiore D et Al ASTRO - 2008

Is Radiotherapy effective? Local Recurrence Preop ERT vs Preop ChemoERT Long ERT EORTC 22921 FFCD 9203 Polish Trial Local Recurr RT - RTCh % 17-8 17-8 10-14 < 0.05 < 0.05 ns

Is Radiotherapy effective? Subgroup analysis Stage III CRM - 5-10 cm Dutch Trial MRC C07 yes yes yes yes yes yes Stage II 0-5 cm 10-15 cm Stage I CRM + no no no no no yes yes yes no no

Is Radiotherapy effective? Local Recurrence Circumferential Resection Margins

Nagtegaal I et Al - JCO 2008 Circumferential Radial Margins 17.500 pts

Circumferential Resection Margins 17.500 pts Nagtegaal I et Al -JCO 2008

By the courtesy of R.Beets-Tan ESTRO - 2007

Circumferential Radial Margins preradiation postradiation

Is Radiotherapy effective? Local control Preop ERT vs Postop ERT UPPSALA Trial NSABP R03 CAO/ARO/AIO 94 94 MRC C07C * 3y3 Pts 471 253 823 1350 Local control Pre Post 5y % 86-77 95-91 94-85 95-83 0.02 ns* 0.006 0.0001 Pahlman L et Al Ann SUrg - 1990 NSABP Proceding ASCO - 2004 Sauer R et Al NEJM 2004 Sebag-Montefiore et Al Proceeding ASCO - 2006

Is Radiotherapy effective? Survival Local control No Yes

Is Radiotherapy effective? Sphincter saving preradiation postradiation

Is Radiotherapy effective? Sphincter saving All resectable stages DUTCH trial Sphinc Saving RT RT+ % 67-65 ns ct3-ct4 resectable EORTC 22921 FCCD 9203 Polish Trial Sphinc Saving RT - RTCh % 51-53 52-53 57-52 ns ns ns UCSC Trial 85-90 ns Van de Velde CJ ECCO 13-2005 Bosset JF / Buiko K / Gerard JP NEJM,JCO,RO 2006 Valentini V IJROBP 2008

Surgeon s decision making background TECHNICAL SKILL: TME, TEM, TATA TEAM WORK: Specialist availability, Leadership conflicts RISK TOLERANCE: Definitive surgery trust, Clinical trial support PATIENT REQUEST: Cultural and religion constrains

Is Radiotherapy effective? 323 Pts Short RT at 1 year Activity * Physi sical * Psycological * Voiding * Defecation * Sphincter saving Score 7.5 / 14 11.9 / 16 14.5 / 30 9.3 / 14 22.6 / 35 100 Pts RTCHEM at 1 year Incomplete evacuation Urgency >3 movements Inc. flatus Inc. solid stools Wearing pad Events % 58 31 23 46 5 14 Overall health 77 * A higher score indicates more problems. Overall satisfac 81 Marijnen CAM et Al - JCO 2005 Coco C et Al IJCD - 2007

Is Radiotherapy effective? Sphincter saving Sexual functioning at 2 years RT - RT + 76 0.06 67 38.2 APR 63 45.7 Overall 67 LAR 75 38. 90 0.01 72 LAR 90 28.6 APR 72 33.2 Overall 72 0.03 0.01 Marijnen CAM et Al - JCO 2005

pt0 after RT-Chem Evidence Phase III Drug 5FU pt0 G3+ % % 14 15 36 28 24 16 Phase IIb Raltitr+oxaliplat 16 51 Phase IIb 5FU+irinotecan 51 Phase IIb 5FU+platin 7 Phase II Capecitabine 24 (8-31) 17 Phase II 5FU+oxalipatin 28 (18-31) 16 Phase II 5FU+irinotecan 28 (22-37) 28 17 (10-25) 16 (8-22) 28 (21-55)

pt0 pooled analysis 566 pts preoperative RT-chemo (97%) ct3 82%, ct4 10%, cn+ 47% median follow-up 47 months 1.6 % local rec 8.9 % metastases 94 % 5 yy cancer survival 85 % 5 yy DFS Capirci C et Al IJROBP - 2008

Organ preservation

Is Radiotherapy effective? Survival Local control Sphincter saving Organ saving No Yes Surgeon attitude Research

Tailored treatment The Good The Bad The Ugly

Study design: One for all RT-Chem S vs One for one Good no RT Bad RT-Chem S Ugly higher RT-Chemo Adaptive treatment

Adaptive Clinical by decisions response INTENSIFICATION Neoadjuvant regimen ADAPTIVE 1 Surgery procedure ADPTIVE 2 Adjuvant Chemo RT+CT Surgery cstad ycstad ypstad COVARIATE 5 ys OS univariate ct 0.018 cn 0.000 COVARIATE 5 ys OS univariate dindex 0.03 Clinical response 0.01 COVARIATE 5 ys OS univariate pt 0.010 pn 0.000 TRG 0.000

Adaptive by response UCSC 20 years experience: 736 pts ct3-4 resectable 1990-1995 1995 1996-2000 2001 01-2005 Pts 173 167 396 pt0 % 9 17 26 Local Control % 83 93 94 M+ % 33 23 16 5 yy Survival % 71 85 86

Prediction model Support vector machine Performance evaluation 1 ROC-curve 0.9 0.8 0.7 Sensitivity 0.6 0.5 0.4 0.3 Area Under the Curve (AUC) 0.2 0.1 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1-Specificity

M+ prediction Score -2-1 0 1 2 pn pn-stage tumor volume RI Volume Index Type of surgery of surgery pt pt-stage 0 1 2 100 80 60 40 20 0-20 -40 1 2 3 0 1 2 3 4 pt0n0 pt3n2 Sum of scores probability Probability of metastases -2-1 0 1 2 3 4 5 4% 68% 0.05 0.1 0.2 0.3 0.5 0.7 0.8 0.9 0.95 UCSC- Maastro - ASTRO - 2009

Clinical decisions INTENSIFICATION Neoadjuvant regimen ADAPTIVE 1 Surgery procedure ADPTIVE 2 Adjuvant Chemo RT+CT Surgery Score pt-stage Tumor volume -2-1 0 1 2 0 1 2 3 4 400 350 300 250 200 150 100 50 RI tumor distance 400 300 200 100 0-100 cstad ystad pn-stage 0 1 2 Sum of scores LR ypstad -3-2 -1 0 1 2 3 4 5 6 Probability of local recurrences 0.05 0.1 0.2 0.3 0.5 0.7 0.8 0.9 0.95 Score -2-1 0 1 2 pn-stage RI tumor volume 0 1 2 100 80 60 40 20 0-20 -40 PET Diffusion MRI Type of surgery 1 2 3 pt-stage 0 1 2 3 4 Sum of scores -2-1 0 1 2 3 4 5 M+ Probability of metastases 0.05 0.1 0.2 0.3 0.5 0.7 0.8 0.9 0.95

Results: ROC 1 0.9 0.8 0.7 0.91 +/- 0.08 0.86 +/- 0.04 0.73 +/- 0.08 0.67 +/- 0.07 Sensitivity 0.6 0.5 0.4 0.62 +/- 0.03 pcr 0.3 0.2 0.1 Post-CRT Dual PET validation (21 pts, 19% pcr) Post-CRT Dual PET (78 pts, 27% pcr) Pretreatment PET (85 pts, 16% pcr) Pretreatment NO PET validation (118 pts, 15% pcr) Pretreatment NO PET (768 pts, 19% pcr) 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1-Specificity

Results: ROC 1 0.9 0.8 0.7 0.91 +/- 0.08 0.86 +/- 0.04 0.73 +/- 0.08 0.67 +/- 0.07 Sensitivity 0.6 0.5 0.4 0.62 +/- 0.03 pcr 0.3 0.2 0.1 Post-CRT Dual PET validation (21 pts, 19% pcr) Post-CRT Dual PET (78 pts, 27% pcr) Pretreatment PET (85 pts, 16% pcr) Pretreatment NO PET validation (118 pts, 15% pcr) Pretreatment NO PET (768 pts, 19% pcr) 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1-Specificity

Clinical decisions INTENSIFICATION Neoadjuvant regimen ADAPTIVE 1 Surgery procedure ADPTIVE 2 Adjuvant Chemo cstad RT+CT ystad Surgery pcr Score pt-stage Tumor volume RI tumor distance pn-stage Sum of scores Probability of local recurrences -2-1 0 1 2 0 1 2 3 4 400 350 300 250 200 150 100 50 400 300 200 100 0-100 0 1 2 LR ypstad -3-2 -1 0 1 2 3 4 5 6 0.05 0.1 0.2 0.3 0.5 0.7 0.8 0.9 0.95 Score -2-1 0 1 2 pn-stage RI tumor volume 0 1 2 100 80 60 40 20 0-20 -40 PET Diffusion MRI Type of surgery 1 2 3 pt-stage 0 1 2 3 4 Sum of scores -2-1 0 1 2 3 4 5 M+ Probability of metastases 0.05 0.1 0.2 0.3 0.5 0.7 0.8 0.9 0.95

Clinical decisions INTENSIFICATION Neoadjuvant regimen ADAPTIVE 1 Surgery procedure ADPTIVE 2 Adjuvant Chemo RT+CT Surgery cstad ystad ypstad PET Diffusion MRI

PET response prediction Jansen MHM Int J radiat Oncol Byol Phys2009

PET response prediction Jansen MHM Int J radiat Oncol Byol Phys2009

Study design: One for one RT-Chem 1 Drg RT-Chem 2 Drgs Surgery Chem 2 Drgs

Intensificazione: IMRT De Ridder M. Int J Radiat Oncol Byol Phys 2008

GTV definition PET vs MRI Roels Int J radiat Oncol Byol Phys2009

GTV definition PET vs MRI Roels Int J radiat Oncol Byol Phys2009

BTV definition FLT vs FDG Roels S Int J radiat Oncol Byol Phys2009

BTV definition Fmiso vs FDG Roels S Int J radiat Oncol Byol Phys2009

Organ motion- rectum Anterior view Posterior view Hoogeman et Al - Radiother & Oncol - 2004

Organ morion: mesorectum Leuven UCSC - 2008

GTV definition: PET Contouring Co-registrarion Organ motion Tumor shrinking

Conclusions o Radiotherapy: effective (LC) o Tailored treatments o PET: o response & outcome prediction o GTV/BTV definition (?)

Heterogeneity Tumour Management Written guidelines Periodical meetings Common data base QA procedures