Carcinoma rettale: ruolo della radioterapia

Transcription

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

2 Is radiotherapy active? D 10 7 Gy Primary tumour Cells Positive Nodes (macro) Cells Gy Gy Subclinical Disease Cells Gy 1 cm 3 = 10 9 Whiters RH et al - IJROBP

3 Tumour volume: dose-response Chemotherapy equivalent to a cytoreduction by Primary tumour Cells Positive Nodes (macro) Cells Gy Gy Subclinical Disease Cells Gy 1 cm 3 = 10 9 Whiters RH et al - IJROBP

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

5 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

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

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

8 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 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

9 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 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

10 Cumulativ relativ survival of Rectal cancer in Sw eden Relative survival proportion RT+TME TME RT+Surgery Surgery RT+No TME No TME Years since diagnosis By the courtesy of L.Pahlman ESTRO/ESSO/ESMO Course

11 Is Radiotherapy effective? Survival No But one treatment for all

12 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 < Stage III P = %,1 0, % Years since surgery Duch Trial MRC C07 Peeters KC et AL Ann Surg 2007 Sebag-Montefiore D et Al ASTRO

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

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

15 Is Radiotherapy effective? Local Recurrence Circumferential Resection Margins

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

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

18 By the courtesy of R.Beets-Tan ESTRO

19 Circumferential Radial Margins preradiation postradiation

20 Is Radiotherapy effective? Local control Preop ERT vs Postop ERT UPPSALA Trial NSABP R03 CAO/ARO/AIO MRC C07C * 3y3 Pts Local control Pre Post 5y % ns* Pahlman L et Al Ann SUrg NSABP Proceding ASCO Sauer R et Al NEJM 2004 Sebag-Montefiore et Al Proceeding ASCO

21 Is Radiotherapy effective? Survival Local control No Yes

22 Is Radiotherapy effective? Sphincter saving preradiation postradiation

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

24 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

25 Is Radiotherapy effective? 323 Pts Short RT at 1 year Activity * Physi sical * Psycological * Voiding * Defecation * Sphincter saving Score 7.5 / / / / / Pts RTCHEM at 1 year Incomplete evacuation Urgency >3 movements Inc. flatus Inc. solid stools Wearing pad Events % Overall health 77 * A higher score indicates more problems. Overall satisfac 81 Marijnen CAM et Al - JCO 2005 Coco C et Al IJCD

26 Is Radiotherapy effective? Sphincter saving Sexual functioning at 2 years RT - RT APR Overall 67 LAR LAR APR Overall Marijnen CAM et Al - JCO 2005

27 pt0 after RT-Chem Evidence Phase III Drug 5FU pt0 G3+ % % Phase IIb Raltitr+oxaliplat 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) (10-25) 16 (8-22) 28 (21-55)

28 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

29 Organ preservation

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

31 Tailored treatment The Good The Bad The Ugly

32 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

33 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 cn COVARIATE 5 ys OS univariate dindex 0.03 Clinical response 0.01 COVARIATE 5 ys OS univariate pt pn TRG 0.000

34 Adaptive by response UCSC 20 years experience: 736 pts ct3-4 resectable Pts pt0 % Local Control % M+ % yy Survival %

35 Prediction model Support vector machine Performance evaluation 1 ROC-curve Sensitivity Area Under the Curve (AUC) Specificity

36 M+ prediction Score pn pn-stage tumor volume RI Volume Index Type of surgery of surgery pt pt-stage pt0n0 pt3n2 Sum of scores probability Probability of metastases % 68% UCSC- Maastro - ASTRO

37 Clinical decisions INTENSIFICATION Neoadjuvant regimen ADAPTIVE 1 Surgery procedure ADPTIVE 2 Adjuvant Chemo RT+CT Surgery Score pt-stage Tumor volume RI tumor distance cstad ystad pn-stage Sum of scores LR ypstad Probability of local recurrences Score pn-stage RI tumor volume PET Diffusion MRI Type of surgery pt-stage Sum of scores M+ Probability of metastases

38 Results: ROC / / / / Sensitivity / pcr 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) Specificity

39 Results: ROC / / / / Sensitivity / pcr 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) Specificity

40 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 LR ypstad Score pn-stage RI tumor volume PET Diffusion MRI Type of surgery pt-stage Sum of scores M+ Probability of metastases

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

42 PET response prediction Jansen MHM Int J radiat Oncol Byol Phys2009

43 PET response prediction Jansen MHM Int J radiat Oncol Byol Phys2009

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

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

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

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

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

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

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

51 Organ morion: mesorectum Leuven UCSC

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

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

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