oral abstract discussion rectal cancer · rectal cancer patients receiving neoadjuvant therapy...
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Oral Abstract DiscussionRectal cancer
Abstracts # 62 VOLTAG Study and # 556 CAO/ARO/AIO-12
Ali Shamseddine,MD,FRCP
Professor of Clinical Medicine
Director GI&GU Cancer Programs
NK Basile Cancer Institute, AUBMC
Disclosure
• Advisory Boards:Roche, Sanofi, Pharmamed,MSD,Bayer,Lilly,Janssen,
Pierre Fabre,Merck
• Research Grants:Roche, Sanofi, Novartis,GSK, Merck, BMS
• Educational Materials and Honoraria:Roche, Sanofi,MSD,Amgen, Merck,Pierre Fabre
Current Outcome for Stage II/III Rectal Cancer
•5 year local relapse rate 5-10%
• pCR rates < 20%
•Deaths occur from distant metastatic disease
- Good local control (TME and RT)- Neoadjuvant chemoRT (reduced toxicity)
- Surgery still required for most patients
- 5 year DFS ~ 65%- 5 year OS ~ 75%
Sauer R, et al. N Engl J Med 2004;351:1731-40Roh M, et al. J Clin Oncol 2009;27:5124-30Allegra CJ, et al. J Natl Cancer Inst 2015 Sept 14;107(11)
Hypothesis: Can Chemoradiation Modulate Microenviroment in MSS Rectal Cancer Patients?
Can we convert noninflamed tumors to become inflamed?
Increase number of antigen-specific T cells or
increase antigen presentation
Chemoradiation
Bring T cells in contact with cancer cells
Accelerate or remove brakes on T cell response with the use of
check point inhibitors
MSS (>95% of CRC)
Increases tumor infiltration with dendritic, CD+ T cells, Treg cells
Releases of neoantigens and inflammatory cytokines
Kim JM, et al. Ann Oncol. 2016;27(8):1492-1504. Hegde PS, et al. Clin Cancer Res. 2016;22(8):1865-1874Weichselbaum RR, et all. Nature Reviews 2017.
Stimulates PD-L1 production and immune- suppressive activity MDSCs
Hypothesis: Can Chemoradiation Modulate Microenviroment in MSS Rectal Cancer Patients?
Can we convert noninflamed tumors to become inflamed?
Increase number of antigen-specific T cells or
increase antigen presentation
Chemoradiation
Bring T cells in contact with cancer cells
Accelerate or remove brakes on T cell response with the use of
check point inhibitors
MSS (>95% of CRC)
Increases tumor infiltration with dendritic, CD+ T cells, Treg cells
Releases of neoantigens and inflammatory cytokines
Kim JM, et al. Ann Oncol. 2016;27(8):1492-1504. Hegde PS, et al. Clin Cancer Res. 2016;22(8):1865-1874Weichselbaum RR, et all. Nature Reviews 2017.
Stimulates PD-L1 production and immune- suppressive activity MDSCs
Abstracts :TPS3620 (NSABP FR-2) & TPS3622 ( The Ave-Rec Trial) ASCO 19
VOLTAGE Study
-Design:
-Primary endpoint: pCR by ICA using TRG score
-Secondary end point: pCR by LA, ORR, RFS, OS, Safety, RCPT, RRR
-Patients and statistical method: Cohort A1 (MSS) 37 pts to achieve 30% pCR(10%) , Cohort A2 (MSI) 5 pts, exploratory
-Results: Cohort A1 pCR (TRG 0) 11/37 (30%) , 3/37 (8%) (TRG1) with MPR 14/37 (38%)
-VOLTAGE study for advanced T/N stage: MPR 42% in T3/or N+ and for stage III (44%) compared to stage II (37%)
-PD-L1 expression and elevated CD8/eTreg ratio performed on biopsy before CRT and not after CRT may be better predictive of CPI benefit
ChemoRT Nivolumab x5 Surgery Adj Chemo
Rectal Cancer(cT3-T4,any N M0,(<12cm)
Translational Research
WGS, immune cell infiltration, HLA Haplotyping, T cell receptor and Enteric bacteria
Interpretation of the study outcome
• A positive study for the primary end point
But several questions should be answered in future trials
• Can we achieve the same results with different approach?
• What is the best modality of radiation therapy (SCRT vs LCCR) in combination with CPI?
• Weather adding CPI to LCCR or delaying surgery beyond 8 weeks after LCCR contributes to increasing pCR ?
• What is the best tool to measure the effect of CPI after LCCR, is it TNM and TRG or immunoscore and LNR?
Total Neoadjuvant Therapy (TNT)A Multicenter Phase II Trial
Gracia-Aguilar J.Lancet Oncol 2015;16:957-66Marco MR, et al. Dis Colon Rectum 2018:61:1146-1155
Disease-free survival was significantly associated withstudy group, ypTNM stage, and pathological complete response
(p = 0.004)
Median F/U 59 mo(Range, 9-125 mo)
OS in Rectal Cancer
Swedish Trial13 year follow up
Flkesson J, et aj. J Clin Oncol 2005
908 pts P= 0.008
38%
30%
OS at 3yA: 73% P=0.046B: 65%
AB
Bujko K et al. Ann of Oncol 2016;27:834-842
POLISH II Trial
541 pts
Tumor response takes time after completion of neoadjuvant therapy (CRT)
(OSTRiCh Consortium)Probst CP,et al. JACS 2015;221(2):430-440
National Cancer Data Base
Prognostic Value of Clinical vs Pathologic Stage in Rectal Cancer Patients Receiving Neoadjuvant Therapy
Delitto D, et al. JNCI Natl cancer Inst, 2018;110(5)
P=0.18P=0.12
P=0.44P=0.22
P<.001P=0.26
P<.001P=0.79
NCDB 2004-2014/ 44,320 pts with Rectal Cancer
Survival in Rectal Cancer is Driven by Post Therapy Pathologic Stage
Immunoscore in Patients with Rectal cancer
Anitei MG,et al. Clin Cancer Res 2014;20(7):1891-9
Tumor immune infiltrates in biopsies before surgery are predictive of response to chemoradiation
Abstract # 556CAO/ARO/AIO-12
• PhaseII,randomized for stage II&III rectal cancer: ↑pCR 15-25%
• Other end points: treatment compliance, toxicity, pathologic downstagingTRG, surgical complications, R0 and sphincter sparing surgery rates, CRM negativity, locoregional and distant recurrence, OS and QOL beside translational research
306 pts
156 pts 150 pts
Chemotherapy→CRT→SurgeryFOLFOX x 3 TME, W18
A B
CRT→Chemotherapy→SurgeryFOLFOX x 3 TME, W18
Pick the-winner
Randomisation
Up to 12 cm from anal verge⬧<6 cm : cT3 ⬧6-12 cm: cT3c-d, cT4 and N+
If the Compliance to Adjuvant Chemotherapy is Suboptimal, Why not to Give it Preoperatively?
• 27% of eligible patients with LARC never start adjuvant chemotherapy
• Delaying adjuvant chemotherapy beyond 12 weeks post-op will have a negative impact on outcome, any additional 4 weeks delay will result in 14% increase in mortality
• <50% receive the full dose and course without interruptions or delays owing to postoperative complications, delayed recovery, or interference caused by the need for a temporary ostomy closure (5-FU dose is <30% of the planned)
• No impact on OS in all randomized trials using preoperative CRT followed by TME followed by adjuvant chemotherapy
Khrizman P, et al. J Clin Oncol 2013;31(1):30-38
Adjuvant Chemotherapy in Rectal CancerMeta-analysis of Individual Patient Data
1196 patients,4 European randomized controlled phase III trials comparing observationwith adjuvant chemotherapy after preoperative chemoradiation and surgery
OSHR 0.97P=0.775
I-CNR-RT trial
CHRONICLE trial
PROCTOR-SCRIPT trial
EORTC 22921 trial
Patients at 10-15cmDFS : HR 0.59
P=0.005Distant recurrence
HR 0.61P=0.025
Breugom AJ.Lancet Oncol 2015;16:200-07
Which factors influence the choice of local or systemic therapy?
CRM+
T3 >5mm
or T4
T3 low lying tumour or
T4
N+
EMVI+
Local recurrence Distant recurrence
Abstract # 556CAO/ARO/AIO-12
Group A Group B
pCR* 17% P=0.210 25% P< 0.001
Compliance to CRT 78% 91%
CRT G3&4 toxicity 37% 27%
Full dose of XRT 91% 97%
Concomitant 5-FU 78% ( mean 90 ± 27% ) 87% ( mean97 ± 15% )
Concomitant OX 76% ( mean 87 ± 28% ) 93% ( mean 97 ± 14% )
Completed 3 cycles of OXCompleted 3 cycles of FU
92% ( mean 94 ± 17% )
93% ( mean 96 ± 14% )
85% ( mean 87 ± 28% )
90% ( mean 91 ± 26% )
Results
*Statistical calculation: each group versus 15% expected after standard CRT
Abstract#556CAO/ARO/AIO-12
• The study is positive for the primary end point with a TNT sequence that fulfilled the predefined trial hypothesis of an increased pCR rate of 25% as compared to historical pCR after preoperative chemoXRT alone set at 15%, whereas the inverse sequence did not. No increase on toxicity or surgical complications with a better compliance with CRT and less compliance with chemotherapy , but longer F/U is needed (limitation for survival) BUT:
• In group B , increasing pCR may be due to delaying surgery up to 90 days compared to group A with average 45 days(other factors: patient cohort, lack of central pathology review and of random assignment)
• The routine use of oxaliplatin with radiation is not recommended and may be contributing to increasing toxicity and decreased compliance with chemotherapy in group B
• To identify who will benefit from adding oxaliplatin to 5-FU with radiation ( patient < 60y as in 04 trial beside excluding stage II patients)
• What about SCRT vs LCCR in TNT?
Discussion
CAO/ARO/AIO-04 Trial
• Not a standard of care although fulfilled the primary end point DFS (P=0.038)
• Increased grade 3&4 GI toxicity during neoadjuvantchemoXRT 21%(OX) vs 15%(FU) with diarrhea 12% vs 8%
• 21% and 22% of patients did not initiate adjuvant chemotherapy
• 36% of patients in both arms had G 3&4 toxicity
• Minimal improvement in resection rate 95% in both with pCR 17% (OX) vs 13 (FU) NS
Forest plots of comparison between short-term versus long-term treatments on other outcomes. (a) death
rate; (b) recurrence rate; (c) complications; (d) distant metastasis
BUT
Short Course Radiation vs Chemoradiation
Chen et al. Journal of Cancer Research and Therapeutics - Volume 14 - Supplement Issue 1 - 2018
Surgery
Postoperativedoublet
chemotherapy
PreoperativeSCRT or LCCRfollowed by
chemotherapy
PreoperativeRT or CRT
Node positive
A suggested risk-adapted therapeutic strategy
Age <75 years
Good PS
CRM+
T3 low lyingtumour
T3c/d (>5mm)T4
Dependent on
pathology
On-going Clinical Trials (TNT)
• Short course (RAPIDO Trial)
• Chemo alone with elimination of RT (BACCHUS Trial)
• Selective elimination of RT (PROSPECT and FAVORE Trials)
• Selecive elimination of surgery (OPERA trial)
• Testing new agents with RT ( NRG GI-002 Trial)
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