Colon Cancer Update 2019 - Piedmont Healthcare

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.


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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.


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


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Decline in Colorectal Cancer Mortality Rate From 1980–82 to 2013–15

by State


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Colon Cancer: Quality of Surgery


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


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.


70%

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Trends in CRC Incidence and Mortality: 2018 ACS (rates per 100,000)


https://www.cancer.org/content/dam/cancer-org. Accessed February 2, 2019

https://www.cancer.org/content/dam/cancer-org

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Early Onset Colorectal Cancer: A Challenge and an Opportunity


• 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

https://onlinelibrary.wiley.com/doi/abs10.3322

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GI Oncology: Schema of Right and Left Colon


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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?


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Anatomic Differences between Right and Left Colon: Both contain Intra and

Retroperitoneal features, vascular supply differ.


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


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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


NCCN, Colon Cancer Guidelines, Version 4. 2018 Up to Date: January 2019.

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Micro-Satellite Instability

MSI: Demystified


https://www.researchgate.net/profile/Luc_Leyns/publication/224830481. 2/9/2019

https://www.researchgate.net/profile/Luc_Leyns/publication/224830481

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Immunohistochemistry for MMR Proteins

CRC: MLH1 and PMS2 form stable Hetero-dimer


Hempel H, Genetics in Medicine, Vol 11, Number 11, Nov 2009

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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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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);


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GI Oncology: Response Rates to PD1-Ab (Pembrolizumab-Merck)


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


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


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.


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


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


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


J Gastrointest Oncol. 2015 Dec; 6(6): 660–667. Kopetz and Clarke

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BRAF V600E Mutated CRC


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


• 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

Colon Cancer Update 2019 - Piedmont Healthcare

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