Dirk Arnold Lógica de proximidade à população

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1 Doenca Contando metastatica já com 70 anos potencialmente de experiência no resecável: sector da saúde Tratamento igual para colon e para recto? 5 Hospitais Privados CUF 6 Clínicas de ambulatório CUF 6 clínicas de ambulatório localizadas perto dos hospitais Dirk Arnold Lógica de proximidade à população Instituto CUF de Oncologia Focus clínico em cuidados primários Lisboa, Portugal dirk.arnold@jmellosaude.pt Clínicas e hospitais funcionam em rede: os cuidados mais diferenciados são referenciados para os hospitais 2 Hospitais em regime de Parceria Publico Privada

2 Perioperative treatment strategy with liver metastases Van Cutsem E, Cervantes A,...Arnold D. Ann Oncol 2016

3 Parameters for potential resectability Assessment of resectability: Lethal tumor load Baseline DpR Tumor Nadir Time Modest et al., WCGC 2017

4 ackground (CELIM) Blinded assessement: CELIM trial Improving resectability in mcrc- Untreated mcrc +28% 32% fter combinationtherapy 60% Folprecht G, et al. Lancet Oncol 2010 Folprecht et al., Ann Oncol 2010

5 Blinded assessement: FIRE_3 trial FIRE-3, votes at baseline (all patients) FIRE-3, votes at best response (all patients) 100% Intention 100% Intention Not resectable Not resectable 50% Conversion possible (maybe only abd. lesions) 50% Abdominal lesions resectable (+- locoreg. therapy) Abdominal lesions resectable (+- periop. Chemo) R0-resection inlc. Locoregional therapy all lesions 50% R0-resection (with periop. Chemo) 50% R0-resection all lesions 100% R0-resection 100% 21.7% Median kappa coefficient for inter-rater reliability: % Median kappa coefficient for inter-rater reliability: 0.66 Modest et al., WCGC 2017

6 1 st line choice: ESMO Consensus Guideline OMD See figure 2 Cytroreduction (Shrinkage)** Disease control (control of progression) MOLECULAR PROFILE MOLECULAR PROFILE RAS wt RAS mt BRAF mt RAS wt RAS mt BRAF mt CT doublet + anti-egfr Combination CT + bevacizumab CT triplet + bevacizumab CT doublet + biological agent CT doublet + bevacizumab CT triplet +/- bevacizumab CT = chemotherapy; mt = mutation; wt = wild type Van Cutsem E, Cervantes A,...Arnold D. Ann Oncol 2016

7 Prediction Overall survival MDT = multidisciplinararnold D, et al. Ann Oncol. 2017;28:

8 Prognostic analysis in the anti-egfr + CT arm. Arnold et al., ESMO Oct 11th, 2016

9 German VOLFI trial: FOLFOXIRI +/- panitumumab in RAS WT mcrc ORR (%) 100 PRIMARY ENDPOINT: OBJECTIVE RESPONSE RATE , , mfolfoxiri + panitumumab N=63 FOLFOXIRI N=33 30 % 95%-CI % 95%-CI Odds ratio p ( ) mfolfoxiri + panitumumab FOLFOXIRI 10. Geissler et al., ESMO Sept 12th, 2017

10 German VOLFI trial: FOLFOXIRI +/- panitumumab in RAS WT mcrc ORR (%) SECONDARY RESECTIONS OF METASTASES ITT cohort 2 70,0 mfolfoxiri + panitumumab, (%) FOLFOXIRI (%) P value ITT (n=96) 15 (23.8) 4 (12.1) R0 10 (15.9) 3 (9.1) R1 4 (6.3) 1 (3.0) ,8 12,1 36,4 Cohort 2 (n=31) Secondary resection 14/20 (70%)* 4/11 (36.4%) R0 10/20 (50.0%) 3/11 (27.3%) R1 4 (20.0%) 1/11 (9.1%) mfolfoxiri + panitumumab FOLFOXIRI mfolfoxiri + panitumumab FOLFOXIRI *1 patient in Panitumumab arm and belonging to cohort 1 was resected 13. Geissler et al., ESMO Sept 12th, 2017

11 Which implications do these data have for our clinical practice? For the treatment of patients with left-sided RAS wt (BRAF wt) tumours.. the preferred therapy option for patients would be a chemotherapy doublet plus EGFR antibody therapy, independent of treatment goal.. MDT = multidisciplinararnold D, et al. Ann Oncol. 2017;28:

12 Which implications do these data have for our clinical practice? In patients with right-sided tumours.and cytoreduction is the goal would be a chemotherapy triplet (e.g. FOLFOXIRI) with (or without) bevacizumab. However, given the findings from the analysis of ORR here, a doublet plus EGFR antibody therapy remains an option. MDT = multidisciplinararnold D, et al. Ann Oncol. 2017;28:

13 Left colon and rectum primary, liver mets: Are there differences? In tumour biology? In treatment of metachronous metastatic disease? In treatment of synchronous disease?

14 Molecular classification of CRC Summary of associations 24% 19% 31% 26% 27% 10% 7% 56% 31% 15% 3% 51% Dienstmann R, et al. WCGIC 2014 (Abstract No. O-0025) Dienstmann et al., WCGC / ESMO GI 2016

15 CALGB/SWOG 80405: Molecular pattern per localisation CALGB/SWOG NO147 (3,392 patients) Dienstmann, et al, Ann Oncol 2017

16 Rectal and left-sided colon cancers: US series CRC with molecular profile (N=10570) Exclusions (N=8840) No Localization N=8040 Transverse CRC N=116 Rectosigmoid N=227 Metastatic N=457 Primary tumor localized (N=1730) Right colon N=273 Left colon N=125 Sigmoid N=460 Rectal Cancer N=872 Marshall J et al., ASCO GI 2017

17 IHC: Specific markers Marshall J et al., ASCO GI 2017

18 NextGenSeq: Differences Marshall J et al., ASCO GI 2017

19 HER2 expression and MSI frequency Marshall J et al., ASCO GI 2017

20 Tumour mutational burden Marshall J et al., ASCO GI 2017

21 The continuum of molecular alterations Marshall J et al., ASCO GI 2017

22 Left colon and rectum primary, liver mets: Are there differences? In tumour biology? In treatment of metachronous mcrc? In treatment of synchronous disease?

23 Left colon and rectum primary, liver mets: Are there differences? In tumour biology? In treatment of metachronous mcrc? In treatment of synchronous disease? Minor in molecular profile

24 Left colon and rectum primary, liver mets: Are there differences? In tumour biology? In treatment of metachronous mcrc? In treatment of synchronous disease? Minor in molecular profile No clinical consequences

25 Left colon and rectum primary, liver mets: Are there differences? In tumour biology? In treatment of metachronous mcrc? In treatment of synchronous disease? Minor in molecular profile No clinical consequences Of course!

26 49 y/o female patient, no comorbidities Weight loss, some blood on stool diagnostic measures Middle third rectal cancer Clinically and endoscopically: no obstruction CEA 18.4 ng/ml Histology / biopsy primary tumor: Adenocarcinoma, G2, RAS wt, BRAF mut

27 49 y/o female patient, no comorbidities Weight loss, some blood on stool diagnostic measures vein EMVI Middle third rectal cancer N+ Clinically and endoscopically: no obstruction CEA 18.4 ng/ml Histology / biopsy primary tumor: Adenocarcinoma, G2, RAS wt, BRAF wt MRI: T3a/b, CRM negative, EMVI +, N +

28 49 y/o female patient, no comorbidities Liver metastasis Weight loss, some blood on stool diagnostic measures 5 small liver lesions MDT: technically resectable PET scan: no further lesions 5 small lesions resectable at initial scan, no extrahepatic disease

29 Treatment priorities Local situation: 5y relapse rates: < 6%

30 Treatment priorities Local situation: 5y relapse rates: < 6% CRT or RT without any impact on OS

31 Treatment priorities Local situation: 5y relapse rates: < 6% CRT or RT without any impact on OS Systemic situation: Presented by:

32 Treatment priorities Local situation: 5y relapse rates: < 6% CRT or RT without any impact on OS Systemic situation: 5y relapse rates: > 75% CT improves DFS / (OS) Presented by:

33 Extramural vascular invasion (EMVI) Can be identified on MRI before and after neoadjuvant therapy: mremvi is associated with pelvic recurrence 1,3 Independently poor prognostic factor for DFS for stage II and stage III 2,3 mremvi was associated with a 4-fold increase in the risk of distance metastasis and a reduction in 3-year survival 2 Mercury Study Group 2006; Smith et al., Br J Surg 2008 Chand et al., World J Gastroenterol 2016

34 SYSTEMATIC REVIEWS Systematic review of prognostic importance of extramural venous invasion in rectal cancer Manish Chand, Muhammed RS Siddiqui, I an Swift, Gina Brown Manish Chand, Muhammed RS Siddiqui, Gina Brown, Royal Marsden Hospital, London SM2 5PT, United Kingdom Ian Swift, Croydon University Hospital, London CR7 9YE, United Kingdom Author contributions: Chand M, Siddiqui MRS, Swift I and Brown G all contributed equally to the manuscript in design and writing the manuscript; Chand M and Siddiqui MRS performed the review of literature; Siddiqui MRS analysed the data. Conflict-of-interest statement: None to declare. Data sharing statement: This study does not contain patient data; and no additional data available. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer -reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: relating to extramural venous invasion in rectal cancer. METHODS: A systematic review was conducted using PRISMA guidelines. An electronic search was carried out using MEDLINE, EMBASE, CINAHL, Cochrane library databases, Google scholar and PubMed until October Search terms were used in combination to yield articles on extramural venous invasion in rectal cancer. Outcome measures included prevalence and 5-year survival rates. These were graphically displayed using Forest plots. Statistical analysis of the data was carried out. RESULTS: Fourteen studies reported the prevalence of extramural venous invasion (EMVI) positive patients. Prevalence ranged from 9%-61%. The pooled prevalence of EMVI positivity was 26% [Random effects: Event rate 0.26 (0.18, 0.36)]. Most studies showed that EMVI related to worse oncological outcomes. The pooled overall survival was 39.5% [Random effects: Event rate (0.29, 0.51)]. Chand et al., World J Gastroenterol 2017

35 (Prognostic) factors for systemic failure No RT sc RT 5x5 Gy FP based CRT Intensified CRT (e.g. oxaliplatin) Control primary and resectability primary

36 (Prognostic) factors for systemic failure Predictive factors for systemic treatment (?) Double CT triple CT (+/- mo Ab) no CT Does the sequence matter??? No RT sc RT 5x5 Gy FP based CRT Intensified CRT (e.g. oxaliplatin) Control primary and resectability primary

37 Dirk Arnold Instituto CUF de Oncologia Lisboa, Portugal