colon cancer update 2019 - piedmont healthcare
TRANSCRIPT
Colon Cancer Update 2019
Dr. Andrew Pippas
Medical Oncology
2/23/2019
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Disclosures
I receive no financial support or remuneration from the companies or the
products discussed in this presentation.
Colon Cancer Update 2019
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• Intake of fruits, vegetables, and high fiber diet decrease risk.
• High consumption of red meat and saturated fats increases risk.
• Alcohol (more than 30 gms/day ==2 ‘standard' drinks) increases risk.
• Diabetes increases risk by 33% above baseline. Obesity known to increase RR of death
1.55x.
• Inflammatory bowel disease: 30% of patients will develop CRC after 30 years.
• Cholecystectomy. RR –1.12x, only right sided colon cancer, due to abnormal exposure of
right bowel to biliary acids.
• Uretero-colic anastomosis. Increased risk at the site of surgery secondary to the exposure
of the colonic mucosa to urinary carcinogens.
• Pelvic/Rectal radiation. Seen in patient with prior prostate cancer treatment and prior XRT
for lymphomas.
• Smoking increases risk after 45 years, independent of pack years.
• NSAIDS/ASA reduce risk by 30%, though amount, duration and mechanism are all
unknown
Established Non-familial Risks of CRCBiom Research and Therapy: Vol 4 No 10 (2017) / 1656-1675. Gandomani HS, et al.
Colon Cancer Update 2019
http://www.bmrat.org/index.php/BMRAT/article/view/372#ref58
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>52% DECLINE IN DEATH RATE SINCE 1969
51% IN MEN SINCE 1980
56% IN WOMEN SINCE 1969
Used with Permission, Dr. Otis Brawley, Best of ASCO, 2018
Colorectal Cancer
Colon Cancer Update 2019
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Decline in Colorectal Cancer Mortality Rate From 1980–82 to 2013–15
by State
Colon Cancer Update 2019
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Colon Cancer: Quality of Surgery
Colon Cancer Update 2019
A minimum 12 lymph nodes must be pathologically
examined in an adequate colorectal cancer surgery
About half of Americans have 12 or more LNs examined.
Hispanics, Blacks and the poor have higher odds of receiving an
inadequate dissection.
Inadequate examination associated with hospital where care was
received.
Inadequate staging leads to some of the talk that colorectal cancer is
more aggressive among Blacks!!!
Rhoads et al, Cancer 2012 Jan 15;118(2):469-77
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Adjusted Colorectal Cancer Survival by Stage and Insurance Status, among White
Patients 18-64 years Diagnosed from 1999-2000, NCDB
Colon Cancer Update 2019
Stage I, Privately
Insured
Stage II, Privately Insured
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80% by 2018 Goal: Northeastern States closest. In Georgia, the colorectal screening rate is 66.4%,
slightly higher than average. Phoebe System is offering FIT testing for underinsured patients and
navigation to expedite colonoscopy. Open Access Colonoscopy Program--no office visit for fit patients
prior to procedure.
Colon Cancer Update 2019
70%
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Trends in CRC Incidence and Mortality: 2018 ACS (rates per 100,000)
Colon Cancer Update 2019
https://www.cancer.org/content/dam/cancer-org. Accessed February 2, 2019
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Early Onset Colorectal Cancer: A Challenge and an Opportunity
Colon Cancer Update 2019
• Predominantly left sided colon cancer and rectal cancer, be
poorly differentiated, have mucinous or signet features
• Familial syndromes account for 20% of these cases: a thorough
family history and work up of CRC symptoms needed.
• Most guidelines do not recommend screening asymptomatic
adults:
• The ACS updated 2018 “qualified recommendation” to begin
screening at 45.
Ahnen DJ, et al. The Increasing incidence of young-onset colorectal cancer: a call to arms. Mayo Clin Proc.2014
Feb: 89(2): 216https://onlinelibrary.wiley.com/doi/abs10.3322. May 30, 2018
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GI Oncology: Schema of Right and Left Colon
Colon Cancer Update 2019
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Colon Cancer Update 2019
Histopathology, 2013. Bettington.
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• Florida Hospital and McGill reviewed the NCDB, 2004 -2014.
• Resected non-metastatic colon cancer. Assessed 5 year overall survival, lymph nodes removed.
• N=505,000. 273,200 had RCC.
• RCC LCC
• ST 2 66% 70%
• ST 3 56% 60%
• BUT, RCC survival increased by 20% when 22 or more lymph nodes were removed; this would involve higher central venous ligation of the right side, a more complicated procedure.
• Requires validation in a prospective study.
American College of Surgeons. "Right-sided colon cancer patients have poorer survival than those with left-sided disease." ScienceDaily. 23 July 2018. <www.sciencedaily.com/releases/2018/07/180723155714.htm.
Extent of Nodal Dissection: ACS standard of 12=/> LNs. Are we
removing enough from RCC?
Colon Cancer Update 2019
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Anatomic Differences between Right and Left Colon: Both contain Intra and
Retroperitoneal features, vascular supply differ.
Colon Cancer Update 2019
YET, No difference in overall 30 day morbidity (15 vs 17.7%) or 30 Day mortality, (1.5 %) in a review of 2512 patients, laparoscopic colectomy for cancer. -Subgroup analyses higher surgical site infections (9-6%), ureteral injury, conversion open procedure, and LOS (10 vs 7 days)Cancer Treatment Communications 8(2016): 1-4. Analyzing clinical outcomes in laparoscopic right vs left colectomy in colon cancer patients using the NSQIP database. Nfonsam V, et al.
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• T3, NO MO==Observation
• Consider Folfox/Capox for Higher Risk tumors. Duration unknown as IDEA data cannot be extrapolated to the stage 2 setting despite 4 of 6 trials have high risk Stage 2 cohorts
• 3 to 6 months of oxaliplatin therapy reasonable.
NCCN, Colon cancer. Version 4, 2018
Stage 2 Colon Cancer: MSI-H, dMMR
Colon Cancer Update 2019
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Colon Cancer Update 2019
PDQ®. Coloncancer.gov Accessed Feb 9, 2019
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• META-ANALYSES 5FU based chemotherapy: ASCO in 2014-- not routinely recommended.
• Intergroup Analysis: significant improvement in DFS from 72 to 76 %,
• No OS benefit, 76 to 81 %
• Oxaliplatin added to 5FU: 2015 updated analysis of the 2004 Mosaic Trial: No overall benefit from FOLFOX(~78%).
• Yet, consider in high risk subgroups: even the definition of this varies between ASCO, NCCN, and ESMO.
• T4 tumors: extension through visceral peritoneum or invades adjacent structures
• Poorly differentiated(signet ring and mucinous tumors): Not a poor risk feature in dMMR/MSI-H
• Fewer than 12 LN removed(<13 LN, ASCO)
• LVI or perineural invasion
• Bowel obstruction or perforation
• Indeterminate or positive margins (NCCN)
STAGE 2 Colon Cancer: 2019
Colon Cancer Update 2019
NCCN, Colon Cancer Guidelines, Version 4. 2018 Up to Date: January 2019.
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Micro-Satellite Instability
MSI: Demystified
Colon Cancer Update 2019
https://www.researchgate.net/profile/Luc_Leyns/publication/224830481. 2/9/2019
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Immunohistochemistry for MMR Proteins
CRC: MLH1 and PMS2 form stable Hetero-dimer
Colon Cancer Update 2019
Hempel H, Genetics in Medicine, Vol 11, Number 11, Nov 2009
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Colon Cancer Update 2019
Science 357(6349), 409 June 8,2017
Mismatch repair deficiency
predicts response of solid
tumors
to PD-1 blockade
Dung T. Le,1,2,3 Jennifer N. Durham,1,2,3* Kellie N. Smith,1,3* Hao Wang,3*
Bjarne R. Bartlett,2,4* Laveet K. Aulakh,2,4 Steve Lu,2,4 Holly Kemberling,3 Cara Wilt,3
Brandon S. Luber,3 Fay Wong,2,4 Nilofer S. Azad,1,3 Agnieszka A. Rucki,1,3 Dan Laheru,3
Ross Donehower,3 Atif Zaheer,5 George A. Fisher,6 Todd S. Crocenzi,7 James J. Lee,8
Tim F. Greten,9 Austin G. Duffy,9 Kristen K. Ciombor,10 Aleksandra D. Eyring,11
Bao H. Lam,11 Andrew Joe,11 S. Peter Kang,11 Matthias Holdhoff,3 Ludmila Danilova,1,3
Leslie Cope,1,3 Christian Meyer,3 Shibin Zhou,1,3,4 Richard M. Goldberg,12
Deborah K. Armstrong,3 Katherine M. Bever,3 Amanda N. Fader,13 Janis Taube,1,3
Franck Housseau,1,3 David Spetzler,14 Nianqing Xiao,14 Drew M. Pardoll,1,3
Nickolas Papadopoulos,3,4 Kenneth W. Kinzler,3,4 James R. Eshleman,15
Bert Vogelstein,1,3,4 Robert A. Anders,1,3,15 Luis A. Diaz Jr.
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Colon Cancer Update 2019
Science 357(6349), 409 June 8,2017
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MISMATCH REPAIR DEFICIENCY ACROSS 12,019 TUMORS: Le DT, et al: Science,
357, 409-413 (2017);
Colon Cancer Update 2019
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GI Oncology: Response Rates to PD1-Ab (Pembrolizumab-Merck)
Colon Cancer Update 2019
Le DT et al. N Engl J Med 2015;372:2509-2520
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Immune-Checkpoint Update: ESMO 2108
Dual PD1/CTLA-4 Therapy: Improved RR with Increased Toxicities
Colon Cancer Update 2019
Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study
Michael J Overman, Ray McDermott, Joseph L Leach, Sara Lonardi, Heinz-Josef Lenz, Michael A Morse, Jayesh Desai, Andrew Hill, Michael Axelson, Rebecca A Moss, Monica V Goldberg, Z Alexander Cao, Jean-Marie
Ledeine, Gregory A Maglinte, Scott Kopetz*, Thierry André* Lancet Oncol 2017; 18: 1182–91: JCO January 20, 2018. Overman et al. Durable Clinical Benefit with Nivolumab Plus Ipilimimab in DNA mismatch repair
deficient/MSI –H metastatic Colorectal Cancer.
Dr. H-J Leinz, ESMO
FIRST- LINE MSI-H, dMMR CRC
RR: 60%CR: 7%74% of the responses lasting longer than 6 months
Objective Response Rate: 31%
Obrade 3-4 toxicities(diarrhea, nausea, fever, fatigue): 14.3% vs 26.7%
Discontinuation rates: 2.9% vs 13.3%
Objective Response Rate: 55%
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• A021502=ATOMIC
• Protocol Title: Randomized Trial of Standard Chemotherapy Alone or Combined with Atezolizumab as Adjuvant Therapy for Patients with Stage III Colon Cancer and Deficient DNA Mismatch Repair
• Assess the addition of the anti-PD-L1 antibody, atezolizumab(Genentech™) for 12 months, FOLFOX (6 months) vs FOLFOX.
• 10 FEB, 2019: Accrual 152/700.
PD-L1 Ab as Adjuvant Therapy for MMR Deficient Stage 3
Colon Cancer
Colon Cancer Update 2019
CTEP/CTSU. CTSU.org. Accessed Feb 10,2019
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N
O DFS
B
E
N OS
E
F
I
T
Time to
Reoccurrence
Adjuvant Oxaliplatin based Chemotherapy for Stage 2/3 Colon Cancer: The ≥70 year old (patient) question.
ASSENT data base of 11,953 patients on 7 clinical trials from 1997 to 2004. Data censored to removed other death from other causes.
Colon Cancer Update 2019
JCO: 2013 Jul 10: 31 McCleary NJ, et al. Ann Oncol.2015;269(4).Haller DG, et al
More recent 2015 series suggests
improvement in the DFS (0.77, p=.014) and
OS (HR, 0.78,
P=.045) for FOLFOX/CAPEOX in patients
The benefits of adjuvant
Oxaliplatin-based chemotherapy
are controversial for patients
above the age of 70 years. Patient
care in this setting needs to be
individualized, cognizant of co-
morbidities.
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• OPTIMOX 2 GERCOR( Dr deGramont), 2009: FOLFOX 7 X6, alone, with Infusional 5-FU, as MT.
• Trend to improved OS( median survival 24 months versus 20 months, p=0.42)
• YET, chemotherapy was not started until tumors had progressed back to pre-FOLFOX status.
• MRC COIN, 2011: Continuous therapy with oxaliplatin-based chemo vs 12 weeks of therapy followed by chemotherapy free interval: no improvement in MS at 19.6 months versus 18 months, yet non-inferiority boundary crossed.
• Chemotherapy-free treatment remains an option for some patients: subgroup analyses showed patients with baseline NORMAL platelet count gain the benefits of intermittent therapy; those with elevated platelets have impaired survival and should not “receive a treatment break.”
Maintenance Therapy(MT) for Stage 4 CRC
Colon Cancer Update 2019
JCO. 2009: 27(34): 5727 Lancet Oncol.2011: 12(7): 642
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2015 Meta-analysis: Eleven RCTs, 4854 Patients
Randomized to Continuous vs Intermittent Treatment
Colon Cancer Update 2019
Annals of Oncology, Volume 26, Issue 3, 1 March 2015, Pages 477–485. Berry, SR, et al.
Intermittent strategies of
delivering systemic
treatment of mCRC do not
result in a clinically
significant reduction in OS
compared with a
continuous strategy of
delivery, and should be part
of an informed discussion
of treatment options with
patients with mCRC.
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BRAF V600E Mutations in CRC:
Mutations in KRAS and BRAF result in constitutive activation of the signaling cascade resulting in
uninhibited cellular proliferation and tumor growth
Colon Cancer Update 2019
J Gastrointest Oncol. 2015 Dec; 6(6): 660–667. Kopetz and Clarke
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BRAF V600E Mutated CRC
Colon Cancer Update 2019
Cancer Discov. 2018: 8(4); 428. Corcoran RB, et al.
• Median survival < one year
• Unlike Melanoma where RR>50% to monotherapy, RR are 5% in BRAFmut
CRC.
• MSI-unstable in 15-25 % : BRAF V600E mutation results hyper-methylation
of MLH1 promoter, silencing the gene.
• NCCN, updated 2018 guidelines: Vemurafenib, EGFR inhibitor, Irinotecan
option for progressive CRC.
• BRAF+MEK(mitogen activated protein kinase) inhibitors have been studied
with variable results.
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Summary
Colon Cancer Update 2019
• Increasing CRC incidence in young adults
• Biology of the Colon: Right vs Left
• MSI: Clarified
• Immune Checkpoint therapy
• Approaches to Stage 2 CRC, elderly patients with CRC, and
maintenance therapy
• BRAF V600E disease