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
Perioperative treatment strategy with liver metastases Van Cutsem E, Cervantes A,...Arnold D. Ann Oncol 2016
Parameters for potential resectability Assessment of resectability: Lethal tumor load Baseline DpR Tumor Nadir Time Modest et al., WCGC 2017
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
1 12 23 34 45 56 67 78 89 100 111 122 133 144 155 166 177 188 199 210 221 232 243 254 265 276 287 298 309 320 331 342 353 364 375 386 397 408 419 430 441 1 12 23 34 45 56 67 78 89 100 111 122 133 144 155 166 177 188 199 210 221 232 243 254 265 276 287 298 309 320 331 342 353 364 375 386 397 408 419 430 441 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: 0.56 53.1% Median kappa coefficient for inter-rater reliability: 0.66 Modest et al., WCGC 2017
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
Prediction Overall survival MDT = multidisciplinararnold D, et al. Ann Oncol. 2017;28:1123 1129
Prognostic analysis in the anti-egfr + CT arm. Arnold et al., ESMO Oct 11th, 2016
German VOLFI trial: FOLFOXIRI +/- panitumumab in RAS WT mcrc ORR (%) 100 PRIMARY ENDPOINT: OBJECTIVE RESPONSE RATE 90 80 85,7 70 60 60,6 50 40 mfolfoxiri + panitumumab N=63 FOLFOXIRI N=33 30 % 95%-CI % 95%-CI Odds ratio p 20 10 85.7 74.6 93.3 60.6 42.1 77.1 3.900 (1.44-10.52) 0.0096 mfolfoxiri + panitumumab FOLFOXIRI 10. Geissler et al., ESMO Sept 12th, 2017
German VOLFI trial: FOLFOXIRI +/- panitumumab in RAS WT mcrc ORR (%) SECONDARY RESECTIONS OF METASTASES 100 90 80 70 60 50 ITT cohort 2 70,0 mfolfoxiri + panitumumab, (%) FOLFOXIRI (%) P value ITT (n=96) 15 (23.8) 4 (12.1) 0.2802 R0 10 (15.9) 3 (9.1) R1 4 (6.3) 1 (3.0) 40 30 20 10 23,8 12,1 36,4 Cohort 2 (n=31) Secondary resection 14/20 (70%)* 4/11 (36.4%) 0.1277 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
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;28:1123 1129
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;28:1123 1129
Left colon and rectum primary, liver mets: Are there differences? In tumour biology? In treatment of metachronous metastatic disease? In treatment of synchronous disease?
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
CALGB/SWOG 80405: Molecular pattern per localisation CALGB/SWOG 80405 NO147 (3,392 patients) Dienstmann, et al, Ann Oncol 2017
Rectal and left-sided colon cancers: US series CRC with molecular profile 2008 2016 (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
IHC: Specific markers Marshall J et al., ASCO GI 2017
NextGenSeq: Differences Marshall J et al., ASCO GI 2017
HER2 expression and MSI frequency Marshall J et al., ASCO GI 2017
Tumour mutational burden Marshall J et al., ASCO GI 2017
The continuum of molecular alterations Marshall J et al., ASCO GI 2017
Left colon and rectum primary, liver mets: Are there differences? In tumour biology? In treatment of metachronous mcrc? In treatment of synchronous disease?
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
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
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!
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
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 +
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
Treatment priorities Local situation: 5y relapse rates: < 6%
Treatment priorities Local situation: 5y relapse rates: < 6% CRT or RT without any impact on OS
Treatment priorities Local situation: 5y relapse rates: < 6% CRT or RT without any impact on OS Systemic situation: Presented by:
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:
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
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: http://creativecommons.org/ 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 2014. 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 0.395 (0.29, 0.51)]. Chand et al., World J Gastroenterol 2017
(Prognostic) factors for systemic failure No RT sc RT 5x5 Gy FP based CRT Intensified CRT (e.g. oxaliplatin) Control primary and resectability primary
(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
Dirk Arnold Instituto CUF de Oncologia Lisboa, Portugal dirk.arnold@jmellosaude.pt