19 im resident future of rectal cancer

1. The Future of rectal cancer
April 16, 2018
Hagen Kennecke MD MHA FRCPC
Medical Oncology, Virginia Mason
Medical Director, VM Cancer Institute

2. OUTLINE
1.The problem with standard therapy
2. Identify new directions
3. NOM
4. Briefly discuss biomarkers

3. Rectal Cancer 2018
Organ Loss is standard - TME:
Permanent ostomy rate: 25%
Locoregional relapse rates: 3-8%
High systemic relapse:
5-Year DFS in modern trials: 56-74%
Late radiation toxicity:
5 Y Severe Incontinence: XRT 14% vs. no XRT 5%
Persistent 14 Years later: ED 79% vs 67, Incontinence 23% vs 10
Bosset NEJM 06, Sauer NEJM 04, Allegra 2014
Aschele ASCO 2009, Gerard ASCO 2009, Roh ASCO 2011, Khrizman 2013, Wiltink ECCO 2013

4. Radiation:
Many Treated, Few Benefit
Van Gijn 2011, Sebag-Montefiore 2009
Local Control Systemic Control

5. 5-FU Chemotherapy:
Small Benefit, Big Problem
Gerard 2006, Bosset 2006
Local Control Systemic Control

6. NCCN and Europe Clinical Practice Guidelines in Oncology
Clinical Stage Primary Treatment Adjuvant Treatment
LARC:
T3N0,
T any, N1-2,
or T4
Chemoradiation (CRT)
Chemotherapy (CT)
TotalMesorectal
Excision(TME)
Surveillance
NCCN August 2018, ESMO 2013 Glimelius Ann Onc
CT
- FOLFOX
- CapeOx
- FLOX
- 5-FU/LV
- CapeCRT
T1N0 low risk
T1 hi risk, T2N0
Transanal Excision
Transabdominal Preferred
T3ab CRM - Transabdominal Preferred**Europe different!

7. Relative Survival by Cancer:
British Columbia
67%
89%
94%
BCCA Cancer Surveillance and Outcomes
Rectal
Breast
Prostate

8. New Directions
TNT NOM
TESAR
FORWARC
The NEO Trial
PROSPECT

9. R
FOLFOX x6
TME
TME
Post-op
Rx
Post-op
Rx
Response >= 20%
Response < 20%
PROSPECT N1048: Can we avoid radiation
for non-low tumors with clear CRM?
Control:
XRT for all
Intervention:
Selective XRT
Recommend
FOLFOX
Recommend
FOLFOX
PI: D Schrag, R McWilliams, A Fichera
NCIC Study Chair: H Kennecke
1120 patients almost accrued
Ph III FORWARC Study enrolled in China, N=476

10. R
5FUXRT
TME
Routine
Surveillance
Surveillance
Q6mo x 3y
Q12mox4,5y
TESAR: Can radical surgery be avoided for
T1/2N0 rectal cancer?
TEM/TAMIS/EMR/ESD
T1 1-3cm hi risk
T1 3-5 cm
T2 <3 cm
cN0
Dutch Colorectal Cancer Group
N= 302
1⁰ Endpoint= 3 year locoregional recurrence rate
Goal= No more than 4% LRR in experimental arm

11. cT1-3ab
N0
FOLFOX x6
TEMS/
TAMIS
Surveillance
Poor path
response
T2+ or T1 bad
Path
response
T0/T1N0
The NEO Trial: Can radical surgery be
avoided for T1-T3ab rectal tumors?
Q3monthly x 3y
Q6 monthly x2y
PI: H Kennecke, C Brown
N= 60
1⁰ Endpoint= Rate of minimally invasive surgery
Goal= >65% are managed without radical surgery
Radical
Surgery:TME

12. Stage II/III
Rectal
FOLFOX x 8
TNT Study NRG GI-002: Can novel systemic
agents improve local and distant outcomes?
R
XRT +
Capecitabine Surgery
FOLFOX x 8
FOLFOX +
x 8
XRT +
Capecitabine +
Veliparib
XRT +
Capecitabine +
Surgery
Surgery
Current Arms
Future Arms
12
N= 158
1⁰ Endpoint= NAR Score
Goal= 20% improvement in DFS and 3-4% improvement in OS as predicted by NAR
PI: TJ George, G Yothers

13. Rationale for nonoperative management (NOM)
Routine: CRT → TME
• TME has toxicity
• pCR
• Occurs in 12-18% of pts
• > 90% 5-yr DFS
• cCR
• pCR associated with cCR
Maas M et al. Lancet Oncol 2010 Sep;11(9):835-44
Garcia Aguilar J et al. Ann Surg Oncol. 2012 Feb;19(2):384-91
CRT = neoadjuvant chemoradiation therapy
TME = total mesorectal excision
pCR = pathologic complete response
cCR = clinical complete response
Is an operation
always
necessary?

14. Resection
NOM
Cumulative
Disease-freeSurvival%
Habr-Gama A et al., Ann Surg 2004; 240 (4):711-7
• cCR = possible cure
• Deferral of surgery = safe
• Surgical salvage = effective
• OS = no significant difference
P= 0.09
265 resectable LOW rectal cancer patients s/p CRT
• cCR  NOM (n = 71)
• non-cCR  Resection (n = 194)
- 22 pts = pCR
What about “Watch & Wait”? Aka NOM

15. 369 TME 73 cCR
297 Non-pCR
72 pCR 73 NOM
442 LARC Patients (2006-2014) MSKCC experience
compare
Neoadjuvant chemotherapy
Rates of rectal preservation
Local control
Survival
Distant recurrence
Retrospective review
4 year estimates
Smith JD et al., Ann Surg 2012; 256:965-972
Smith JJ et al ASCO GI 2015
NOM after cCR in Locally Advanced Rectal Cancer after Neoadjuvant Therapy

16. Summary
• NOM for patients with cCR after neoadjuvant therapy:
• 73 of 442 patients managed by NOM (16.5%)
• 72% durable clinical complete response at 4 years
• 26% local tumor regrowth
• 98% local control in combination with salvage surgery
• 77% rectal preservation (56/73)
• DSS and OS similar to pCR patients

17. Clinical Complete Response (cCR)
**Clinical assessment at 8 +/- 4 weeks after CRT—MSKCC Consensus Conference January 2014 JJ Smith
Clinical Evaluation Components of Negative Exam
DRE Flat mucosa
Smooth induration/scar
No mass/nodule
Proctoscopy Normal, flat mucosa
+/- pale scar
+/- telangiectasias
No ulceration
No luminal narrowing/stenosis
Imaging No detectable tumor or LNs (imagine
not standardized)

18. Biomarkers in rectal cancer
• No biomarker driven trials (!)
• What biomarkers should we use in rectal cancer?
• Rectal vs. Colon?
• Left vs. Right
• Cancer subtypes
• Molecular Markers

19. TCGA Genomic characterization:
Rectal vs Colon Cancer
TCGA Nature 2012

20. dMMR biomarker in rectal cancer:
N=62, MDACC 1992-2012
Med age 42y
Grade high/low 89/11%
Mucinous 61%
BRAF/hypermeth 0/0%
pCR post 5FURT 28%
Stage I/II 100%
Stage III 85%
Stage IV 60%%
De Rosa July 2016

21. NET histology in rectal tumors
N=60 NETs, BCCA 2002-2011
Med age 58y
T <10mm, 10-20, >20 82/12/8%
Local excision
Surgery
94%
6%
R0/R1 55/15%
R2/Unknwn 5/25%
Local Relapse 8%
Distant Mets 8%
Stage I/II 100%
Stage III 85%
Stage IV 60%%
Tsang…Kennecke, Dis Colon Rectum 2017

22. CONCLUSIONS
• Dire need to improve rectal cancer outcomes and
care.
• Innovative studies underway:
• Pre-operative chemotherapy more often used
• Move away from tri-modality therapy for all stage II/III
• Biomarkers can be integrated into care

23. End of presentation