EPA for prevention and treatment of bowel cancer

Professor Mark HullLeeds Institute of Biomedical & Clinical SciencesUniversity of Leeds and Leeds Teaching Hospitals

Bowel (colorectal) cancer

• Third most common cancer in men and women• Second commonest cause of cancer-related death• Treatment is sub-optimal and aggressive

– Bowel surgery– Chemotherapy– Radiotherapy

• But………..bowel cancer is preventable

Natural history of colorectal cancer

CRC liver metastasis

adenocarcinoma (cancer)adenoma (polyp)

benign malignant

5-10 years 0-5 years

1o CRC prevention strategies• Screening (stool testing, endoscopy)• Surveillance• Lifestyle/behaviour modification

– weight– diet– alcohol– smoking– awareness/early diagnosis

• Chemoprevention

Cancer chemoprevention

‘The use of natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer’

Sporn 1976

The ideal CRC chemoprevention agent

• Effective– Colorectal cancer– Other malignancies– Other conditions (improved life-expectancy)

• Safe and well tolerated• Easy to use• Inexpensive

Candidate CRC chemoprevention agents

• omega-3 fatty acids• aspirin• other anti-inflammatories eg. ibuprofen • statins• metformin• calcium ± vitamin D• folate

Drug re-purposing

• The application of known drugs to a new disease• Advantages

– Well–established with excellent safety profile– Effectiveness against more than one condition– Inexpensive (off-patent)

• Disadvantages– Clinical testing can outstrip understanding of MOA– Off-patent (regulatory problems)

Aspirin goes ‘prime-time’

Colorectal cancer (CRC) prevention

CRC liver metastasis

adenocarcinoma (cancer)adenoma (polyp)

benign malignant1o and 2o chemoprevention 3o chemoprevention

seAFOod Trial The EMT2 Trial

aspirin

Omega-3 fatty acids (O3FAs)

• Found in highest quantities in oily fish (salmon or mackerel)• Two main long-chain O3FAs – EPA and DHA • 2 g daily dose = eating 10-12 portions of oily fish per week• ‘nutraceuticals’

– Concentrated (80-90%) EPA, DHA or EPA/DHA mix– Encapsulated– 2 g possible in 4-5 capsules– Minor gastrointestinal side-effects only (approx 5%)

• Large amount of experimental evidence that O3FAs have anti-cancer activity

Evidence that dietary O3FA intake reduces CRC risk is not convincing

• “Limited, but suggestive, evidence that dietary fish intake reduces CRC risk”• 35 cohort studies

• Approx. 50% have reported decreased risk

• >50 case-control studies • Meta-analysis of cohort studies

• RR for CRC 0.98 (0.88-1.09) in relation to O3FA intake

2nd Expert report WCRF/AICR 2007 and WCRF/AICR CUP 2011Br J Nutr 2012;108:1550-6

Strong pre-clinical evidence that O3FAs have CRC chemopreventative efficacy

• Chemical carcinogenesis models (15 rat/2 mouse)– 4-20% (v/w) fish oil in chow– 20-50% reduction in tumour incidence– 30-70% reduction in aberrant crypt focus/tumour

multiplicity

• ApcMin/+ and ApcD716 mouse models– 1-12% (v/w) fish oil in chow– 40-80% reduction in adenoma multiplicity

• Usually EPA/DHA mix• EPA = DHA

– 6 single w-3 PUFA studies– 1 direct comparison (ApcMin/+)

Gut 2012;61:135-49

Human biomarker studies of O3FA therapy

Gut 2012;61:135-149

Study(author/year)

DesignPatient group

N ω-3 PUFA daily dose Treatment Duration

Primary outcome

Mucosal PUFA content

Results

Anti 1992 R, DB, PC‘sporadic’ adenoma

24 7.7 g FO1 12 wk PI ↑EPA & ↓AA 62% ↓PI

Bartoli 1993 R, DB, PC‘sporadic’ adenoma

40 2.5-7.7 g FO1 30 days PI Dose dependent ↑EPA/DHA & ↓AA

Dose dependent 40-70%↓ PI

Bartram 1993 DB crossover trialHealthy volunteer

12 4.4 g FO2 4wk +4 wk PI ω-3 PUFA ω-6 PUFA↓( NS)

16%↓ PI & 35%↓ mucosal PGE2

Anti 1994 R, DB, PC ‘sporadic’ adenoma

60 2.5-7.7 g FO1 30 days PI Dose dependent ↑EPA/DHA & ↓AA

Dose independent 50-70%↓ PI

Huang 1996 R, DB, PCDukes A/B CRC or severely dysplastic polyp

27 7.2 g FO3 6 months PI ↑EPA/DHA & ↓AA 71%↓PI (only in patients with high baseline PI)

Gee 1999 R, PC, single blindAwaiting CRC surgery

51 2.4 g FO4 7-21 days pre- and 8-12 wk post- surgery

PI ↑EPA/DHA↑ ω-3 : ω-6 ratio

No effect on PI at surgery or 12wk post-op

Cheng 2003 R, C, open labelPrevious CRC/adenoma

41 Dietary advice +/- 500 mg FO5

2 years PI/AI Not assessed PI↔, 50%↑AI, 50%↑ Bax, COX2 ↔

Courtney 2007 R, single blind‘sporadic’ adenoma

30 EPA 2 g as FFA 3 months PI/AI ↑EPA/DHA & ↓AA 20%↓PI7x↑ AI

West 2009 R, DB, PC‘sporadic’ adenoma

152 EPA 1 g or2 g as FFA 6 months PI/AI ↑EPA/DHA & ↓AA 13%↓PI57%↑ AI (NS)

FO1 = 54%EPA/46% DHA as ethyl estersFO2 = 48%EPA/44%DHA, as triglyceridesFO3 = 55%EPA/30%DHA/15% other ω-3 PUFAsFO4 = 58% EPA/42%DHAFO5 = 20%EPA/80%DHA

-25

-20

-15

-10

-5

0

5

10

15

P = 0.0122

9.7 [-2.6; 22.0]

-12.6 [-24.7; -0.6]

-22.4 [-39.6; -5.1]

Δ No. of polyps (%)

Net changePlacebo EPA-FFA

EPA is chemopreventive in humans

Gut 2010;59:918-25

• double-blind randomised placebo-controlled trial of EPA 2g daily• 58 patients with familial adenomatous polyposis undergoing surveillance

The seAFOod (Systematic Evaluation of Aspirin and Fish Oil) polyp prevention trial

• Double-blind randomised placebo-controlled trial• 2 x 2 factorial design

– EPA 2 g daily (either FFA or TG) – aspirin EC 300 mg daily

• treatment for 12 months• NHS Bowel Cancer Screening Programme patients• Multiple polyp patients needing repeat colonoscopy at 1 year• No alteration of routine clinical practice• Tissue biobank• 51 sites in England• 550/755 (73%) recruited – recruitment end June 2016• Results available end of 2017

seAFOod Polyp Prevention Trial

placeboplacebo

placeboEPA 2g

aspirin 300mg placebo

aspirin 300mg EPA 2g

Different formulations of EPA

• 99% EPA-FFA 500 mg gastro-resistant capsules• 90% EPA-TG 574 mg soft-gel capsules (Igennus)• EPA-FFA dose equivalence

– 5 capsules 90% EPA-TG = 4 capsules 99% EPA-FFA– differences

• no gastro-resistant coating• small amount of AA

• Trial biobank to compare EPA bioavailability– RBCs, plasma, rectal mucosa

• So far…………no difference in adverse events or dropout

Pre-clinical evidence of EPA activity against CRC liver metastasis

EPA

DHA

AA

DPA

0

2

4

6

8

10

12

% P

UFA

co

nte

nt

CONTROL 2.5% EPA-FFA 5% EPA-FFA

0

1

2

3

4

5

Liv

er

we

igh

t (g

)

P<0.05

0

2000

4000

6000

8000

0

200

400

600

800

Tis

sue

PG

E2 (

pg

/mg

)

Tissu

e PG

E3 (p

g/m

g)

CONTROL 2.5% EPA-FFA 5% EPA-FFA

Br J Pharmacol 2012;166:1724-37

P=0.04

0

20

40

60

80

100

% B

rdU

-po

siti

ve

cel

ls

CONTROL 2.5% EPA-FFA 5% EPA-FFA

CONTROL 2.5% EPA-FFA 5% EPA-FFA

• A Phase II randomised double-blind placebo controlled trial of EPA 2 g daily in patients awaiting liver resection for liver metastasis

• ‘window trial’ - variable treatment period before surgery• Trial designed to test

• Safety and tolerability• Markers of tumour growth after surgical removal• Incorporation of EPA into tumour tissue• Survival after the trial had finished

The EPA for Metastasis Trial (EMT)

Gut 2014;63:1760-1768

Overall survival

Months

Per

cen

t su

rviv

al

0 6 12 18 24 30 36 420

25

50

75

100

Placebo

EPA

No. at risk

p=0.0985

Tumour fatty acid levels

PUFA Placebo (n=37)a EPA-FFA (n=37)a % difference from placebo

P value

EPA (C20:5w3) 1.30% (±0.10) 1.82% (±0.11) +40% 0.0008

DPA (C22:5w3) 1.25% (±0.08) 1.76% (±0.09) +41% <0.0001

DHA (C22:6w3) 2.89% (±0.12) 2.56%(±0.11) -11% 0.0465

AA (C20:4w6) 12.82% (±0.53) 12.03% (±0.45) -6% 0.2579

AA:EPA ratio 11.35 (±0.72) 7.58 (±0.53) -33% <0.0001

EPA

%

0

1

2

3

4

EPA-FFAplacebo

DPA

0

1

2

3

4

5

EPA-FFAplacebo

AA

%

0

5

10

15

20

25

EPA-FFAplacebo%

Gut 2014;63:1760-1768

• Compatible with tissue plasma membrane incorporation

• Rapid incorporation (2-3 weeks) but prolonged ‘washout’ over 3-4 months

• Is it explained by O3FA exposure during the critical peri-operative period?

• Decreased tumour growth and/or anti-cachexia mechanism?

Prolonged effect of short-term EPA-FFA therapy

• A Phase III randomised double-blind placebo controlled trial of EPA 2 g daily in patients awaiting surgery for liver metastasis

• treatment started before surgery then continuing for minimum 2 yr FU• Trial designed to test whether EPA provides survival benefit (30%

improvement)• 450 participants• 8 sites with high-volume liver surgery units• Leeds and Sheffield expected to contribute at least one third of patients• Measurement of EPA incorporation in patient samples• Start Oct 2015 – recruitment start Oct 2016• Results due 2020

The EMT2 trial

• RCT evidence that EPA has chemoprevention activity• seAFOod Trial will determine whether EPA ‘works’ in large

number of patients at risk of future CRC• Hint that EPA provides benefit in advanced CRC patients• EMT2 trial in patients with CRC liver metastasis just opening• Many open questions

– Optimal dose and timing?– Is it tissue EPA incorporation that matters?– EPA, DHA or both?– How does EPA have anti-cancer activity?

EPA for prevention and treatment of CRC

Acknowledgements (in no particular order!)

• patients• Co-Investigators• Collaborators• Trial staff• funders