Hot Topic in tema di neoplasie del Colon: Durata ottimale della chemioterapia adiuvante nei tumori del Colon

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1 Convegno Nazionale AIOM Giovani 2018 News in Oncology Hot Topic in tema di neoplasie del Colon: Durata ottimale della chemioterapia adiuvante nei tumori del Colon Daniele Rossini U.O. di Oncologia Medica Universitaria Azienda Ospedaliero-Universitaria Pisana Istituto Toscano Tumori

2 Adjuvant Therapy for Colon Cancer STAGE II III Low risk Follow up Or consider Fluoropyrimidine in MSS High risk Fluoropyrimidine (not in MSI-H) Or consider FOLFOX or XELOX FOLFOX or XELOX Or consider Fluoropyrimidine AIOM Guidelines 2017

3 Adjuvant Therapy for Colon Cancer Stage III 50% cured by surgery alone Adjuvant chemo (fp+oxa) 25% cured by surgery and chemo Stage III CRC pts fit for fluropyrimidine+oxaliplatin 25% relapsed despite surgery and chemo Courtesy of C. Antoniotti Adapted from Meyerhardt et al, ASCO Ann Meet 2017

4 Neurotox in MOSAIC: How much? Grade 3 peripheral sensory neuropathy during treatment was 12.5% (0.2% of the patients in the LV5FU2 group) 18 months: 24.1% had symptoms of any grade 0.7% reporting grade 3 symptoms. At 48 months: 15,4 % had symptoms of any grade 0.7% reporting grade 3 symptoms Andrè et al, JCO 2009

5 Chapter One: We Have an IDEA

6 Less is

7 IDEA Collaboration What is the IDEA Collaboration? Prospective Pooled Analysis 6 Phase III Trials For Patients with Stage III Colon Cancer

8 Study Design 3 months Stage III Prior surgey R 1:1 6 months Investigator s choice FOLFOX or CAPOX

9 IDEA: Who? Trials (Group) N Patients (N=12834) Stage TOSCA 2402 III II High-Risk SCOT 3983 III II High-Risk Tumor Location Colon Colon Rectum Treatments FOLFOX4 CAPOX mfolfox6 CAPOX IDEA France 2010 III Colon mfolfox6 CAPOX Additional trial-specific comparison FOLFOX4+Be v vs FOLFOX alone 62 None 37 None 51 C III Colon mfolfox6 3 y of celecoxib vs placebo HORG 708 III II High-Risk Total N Pts (Stage III): Colon FOLFOX4 CAPOX ACHIEVE 1291 III Colon mfolfox6 CAPOX 35 None 48 None 37 Median follow-up time, m

10 Rationale for Non-inferiority Margin IDEA Consensus (Oncology and Patient Advocates) 12% relative risk increase (upper 95% CI) Non-Inferiority Margin: DFS HR=1.12 Piaggio, et al, Jama 2012

11 Statistical Design Primary Endpoint: disease-free survival (DFS) Time from date of randomization (enrollment) to the earliest date of relapse, secondary colorectal primary tumor, or death due to all causes Primary Analysis Population: Modified Intent-to-treat: randomized and received any dose of treatment Pre-planned Subgroup Analyses: Regimen T/N Stage

12 Results: Adverse Events But also: Neutropenia, Febrile Neutropenia, Thrombocytopenia, Nausea, Mucositis, Fatigue and Hand-foot syndrome Grothey et al., NEJM 2018

13 Results DFS Qian Shi, et al, ASCO 2017

14 Results DFS 3 years DFS 74.6% vs 75.5% HR: % CI ( ) P for not inferiority=0.11 Grothey et al, NEJM 2018

15 Chapter Two: Dissecting an IDEA

16 Preplanned Analysis Two preplanned analysis: Regimen T/N

17 Results Preplanned Analyses: T/N Favors 3m Favors 6m Grothey et al, NEJM 2018

18 Preplanned Analysis - Regimen Qian Shi, et al, ASCO 2017

19 FOLFOX vs CAPOX Patients are not stratified for regimen Grothey et al, NEJM 2018

20 Results Preplanned Analyses: T/N Favors 3m Favors 6m Grothey et al, NEJM 2018

21 Results Recap The DFS non-inferiority of 3m oxaliplatin-based adjuvant treatment was not established in overall stage III colon cancer DFS comparison by T/N showed no differences DFS comparison by regimen showed that CAPOX is not FOLFOX HR < 1.12

22 Chapter Three: Finding an IDEA

23 Results Subgroup Analyses: Risk Groups

24 Stratification: high vs low risk Are high and low risk pts are balanced between the two treatment arms? SCOT trial TOSCA trial IDEA France

25 What is IDEA message?

26 IDEA recommendations Grothey et al, NEJM 2018

27 IDEA recommendations Grothey et al, NEJM 2018

28 NCCN Guidelines NCCN Guidelines v2.2018

29 My clinical practice in stage III Choose CAPOX T4 or N2: 6 months T3N1: 1) Plan 6 months 2) At least 3 months of CAPOX or FOLFOX If Neurotox G2-3 develops, then hold oxaliplatin.

30 Chapter Four: A new IDEA

31 Gao et al. BMC 2018 Turner et al. J Am Co Sur 2018 Role of Time Stage III N=18491 Stage III N=72057

32 Role of MMR Status, Histology and BRAF Status Zaanan et al. Jama Oncol 2018; Soliman et al. Dis Colon Rectum 2018; Andrè JCO 2015

33 Liquid biopsy in Stage III Stage III Tie et al, ASCO 2018

34 DYNAMIC-III trial Primary endpoint: To demonstrate that a chemotherapy decision based on the presence or absence of circulating tumour DNA after surgery, will be more effective than standard of care treatment.

35 Take home message - In stage III, 3 months of oxaliplatin based therapy is not inferior than 6 months. - In low risk of stage III, the oncologists can discuss potential trade-offs between side effects and efficacy of adjuvant therapy. - cfdna could be useful in the future to guide the adjuvant decision.