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
Convegno Nazionale AIOM Giovani 2018 News in Oncology
STAGE
Adjuvant Therapy for Colon Cancer
II III
Low risk High risk
Follow up Fluoropyrimidine (not in MSI-H)
FOLFOX or XELOX
Or consider FOLFOX or
XELOX Or consider
Fluoropyrimidine in MSS
Or consider Fluoropyrimidine
AIOM Guidelines 2017
Adjuvant Therapy for Colon Cancer Stage III
Stage III CRC pts fit for fluropyrimidine+oxaliplatin
Adjuvant chemo (fp+oxa)
cured by surgery 50%
alone
cured by surgery 25%
and chemo
relapsed despite 25%
surgery and chemo
Courtesy of C. Antoniotti Adapted from Meyerhardt et al, ASCO Ann Meet 2017
Neurotox in MOSAIC: How much?
Andrè et al, JCO 2009
• 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
Chapter One:
We Have an IDEA
Less is
IDEA Collaboration
What is the IDEA Collaboration?
Prospective
Pooled Analysis
6 Phase III Trials
For Patients with
Stage III Colon Cancer
Study Design
Stage III Prior surgey
R 1:1
3 months
6 months
Investigator’s choice
FOLFOX or CAPOX
IDEA: Who?
Trials (Group)
N Patients (N=12834)
Stage Tumor
Location
Treatments Additional trial-specific
comparison
Median follow-up
time, m
TOSCA 2402 III
II High-Risk
Colon FOLFOX4 CAPOX
FOLFOX4+Be v vs FOLFOX alone
62
SCOT 3983 III
II High-Risk
Colon Rectum
mFOLFOX6 CAPOX
None 37
IDEA France 2010 III Colon mFOLFOX6
CAPOX
None 51
C80702 2440 III Colon mFOLFOX6 3 y of
celecoxib vs placebo
35
HORG 708 III
II High-Risk
Colon FOLFOX4 CAPOX
None 48
ACHIEVE 1291 III Colon mFOLFOX6
CAPOX
None 37
Total N Pts (Stage III):
12834
Rationale for Non-inferiority Margin
Piaggio, et al, Jama 2012
IDEA Consensus (Oncology and Patient Advocates) 12% relative risk increase (upper 95% CI)
Non-Inferiority Margin: DFS HR=1.12
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 StageResults: Adverse Events
Grothey et al., NEJM 2018
But also: Neutropenia, Febrile Neutropenia, Thrombocytopenia, Nausea, Mucositis, Fatigue and Hand-foot syndrome
Qian Shi, et al, ASCO 2017
Results – DFS
Results – DFS
Grothey et al, NEJM 2018 3 years DFS 74.6% vs 75.5%
HR: 1.07
95% CI (1.00- 1.15) P for not inferiority=0.11
Chapter Two:
Dissecting an IDEA
Preplanned Analysis
Two preplanned analysis:
• Regimen
• T/N
Results – Preplanned Analyses: T/N
Grothey et al, NEJM 2018
Favors 6m Favors 3m
Preplanned Analysis - Regimen
Qian Shi, et al, ASCO 2017
FOLFOX vs CAPOX
Grothey et al, NEJM 2018
Patients are not stratified for regimen
Results – Preplanned Analyses: T/N
Grothey et al, NEJM 2018
Favors 6m Favors 3m
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 < 1.12Chapter Three:
Finding an IDEA
Results – Subgroup Analyses: Risk Groups
Grothey et al, NEJM 2018
Stratification: high vs low risk
Are high and low risk pts are balanced between the two treatment arms?
SCOT trial TOSCA trial
IDEA France
What is IDEA message?
IDEA recommendations
Grothey et al, NEJM 2018
IDEA recommendations
Grothey et al, NEJM 2018
NCCN Guidelines
NCCN Guidelines v2.2018
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.
Chapter Four:
A new IDEA
Role of Time
Gao et al. BMC 2018 Turner et al. J Am Co Sur 2018
Stage III
N=18491 Stage III
N=72057
Role of MMR Status, Histology and BRAF Status
Zaanan et al. Jama Oncol 2018; Soliman et al. Dis Colon Rectum 2018; Andrè JCO 2015
Liquid biopsy in Stage III
Tie et al, ASCO 2018 Stage III
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.
DYNAMIC-III trial
- 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.
