Inflammatory Bowel Diseases, Therapy and Cancer · 7 0 10 20 30 40 0 10 20 30 Eaden JA, et al. Gut...

Dienstag 20ten Juni 2013

Forschung zur Praxis

BHH S1, Kursraum 5/6

Source: MGH Crohn’s

and colitis center

Inflammatory Bowel Diseases, Therapy and Cancer

Pascal Juillerat, MD, MSc

2

Chronische Entzündliche

Darmerkrankungen

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Darmerkrankungen

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Darmerkrankungen

5 Terzic, GE 2010; 138: 2101

IBD und kolorektales Karzinom

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Läsionen bei CED : DALM, dysplasia-associated lesion or mass

AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease. Gastroenterology 2010;138:738–745

Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010

Hochgradige

Dysplasie

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0

10

20

30

40

0 10 20 30

Eaden JA, et al.

Gut 2001

AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia

in Inflammatory Bowel Disease. Gastroenterology 2010;138:738–745

Kolonkarzinom

Risiko (%)

18%

2%

8%

Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and

management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010


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0

10

20

30

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0 10 20 30

Eaden JA, et al.

Gut 2001

AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia

in Inflammatory Bowel Disease. Gastroenterology 2010;138:738–745

Kolonkarzinom

Risiko (%)

18%

2%

8%

Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and

management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010

Rutter et al,

GE 2006

Jess, et al GE 2006 & 2012


9

Richtlinien für Kolorektal Karzinom screnning in chronisch Entzündlichen

Darmerkrankungen

Patienten mit Kolitis (Crohn oder Colitis ulcerosa)

• Erste nach (Dauerkrankung) :

8-10 Jahre (pankolitis)

15-20 Jahre (linksseitige Kolitis)

• Interval (v.a. bei pankolitis) :

1x/ 2-3 Jahre 2te Decade

1x/ 1-2 Jahre 3te Decade, 4te, …

• 1x/ Jahr start bei der PSC Diagnose

Farraye AGA Technical review GE 2010, Josh Korzenik MGH

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Primär Sklerosierende Cholangitis (PSC) 1-3%

• Aber > 80% von PSC Patienten haben CED !

• häufiger mit Colitis ulcerosa

• Unhabängig von der Erkrankungsaktivität

• Meistens assoziert mit einer leichten Pancolitis.

= (oft > 50%) asymptomatische ,

chronische Entzündung der Gallenwegen.

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PSC - Therapie

• UDCA 13-15mg/kgKG: Besserung der Laborwerte, aber keine Evidenz

für die Symptome, Gallensteine oder Transplantation-freie

Überlebensrate.

“aber kann benützt werden in früheren Stadien” – europäische Guidelines

• Hochdosiert (> 25 mg/kgKG) – Verschlechterung !

• nicht mehr empfohlen für die Prävention vom colorectalen Karzinom

5-ASA Therapie .

Eaton et al, Am J Gastroenterol 2011; 106 (9): 1638-45

EASL guidelines. Journal of Hepatology 2009; 51: 237–267

Lindor et al, Hepatology 2009; 50:808-14

Lindor et al, NEJM 1997

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Darmerkrankungen

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Darmerkrankungen

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Ms CH - IBD history

• 57yo F, with Crohn’s colitis, diagnosed in 2002

• Initially treated with prednisone, then tried : – Asacol (partial response and finally a RASH)

– Imurek - HEPATITIS

– MTX- PANCREATITIS (unusual ?)

– Ciproxin: myositis, Penicilin : hives.

• In remission > 1 year on infliximab stopped due to Breast cancer in nov. 2009.

• Maintained in remission since then on chemotherapy

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Current IBD situation

HPI :

• She has minimal symptoms: feels “bloated”.

• 1BM/d no mucus or blood.

• Harvey Bradshaw Index :0

Lab values (Jan 26) : ESR 17, CRP 4.6, isolated incr. ALT 34.

Normal CBC and Renal function

(previously : ESR 8, CRP 0.3, ALT 31)

Colonoscopy (January 2011) + pathology:

- Mild to moderate active colitis of the descending colon and sigmoid.

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Summary

• 14 months after stopping Infliximab due to breast cancer

• Mild to moderate active colitis (Endo, histo, biologicallly)

• Treatment options are limited :

– 1) Solid tumor Risk of recurrence in the setting of immunosuppression.

– 2) Numerous drug intolerances ( pancreatitis - very rare for MTX, Rashes on 5ASA and antibiotics, Hepatitis on Imuran).

• OPTIONS ?:

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Options

• (A) Sulfasalazine ?

• (B) Rifaximine ?

• (C) Remicade or other anti-TNF agents ?

• (D ) MTX low dose ?

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Options

• (A) Sulfasalazine ?

• (B) Rifaximine ?

• (C) Remicade or other anti-TNF agents ?

• (D ) MTX low dose ?

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Anti-TNFs and neoplasia

• What the inherent risks of cancer with antiTNFs ?

• Which situations are at :

–« No » risk …

–Moderate risk - risk /benefit

– high risk ?

• If restart, when ?

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General considerations

• Role of TNF alpha :

Risk of development/

progression of malignancy

• Moreover, studies in murine models of colitis showed that these

mechanisms are TNF-dependent and appear critical to

maintaining tumors in a dormant state.

-1- Lyse tumor cells.

-2- Natural killer cell and CD8

lymphocyte-mediated tumor cell

death.

Carswell EA, et al Proc Natl Acad Sci USA, 1975;72: 3666- 3670.

Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ,

Smyth MJ, Schreiber RD. Adaptive immunity maintains

occult cancer in an equilibrium state. Nature, 2007;450: 903-907

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What kind of situations do we have to face ? IBD

patient with :

• Standard +/- history of cancer

• Pre - malignant conditions (Barrett, Polyps)

• Established dysplasia (Cervical dysplasia)

• Past history of malignancy (other than basal cell

carcinoma and resected squamous cell Ca)

• Malignant disease

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patient with :







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LYMPHOMA

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Meta-analysis of Lymphoma

Anti-TNFs and Thiopurines

• 8905 patients – 21178 person years of observation

• 13 Non-Hodgkin lymphoma identified in 6 of 26 studies

with Infliximab and adalimumab (RCT, cohorts, case series)

• Compared to the rates found in the SEER registry

(Surveillance Epidemiology & End Results database) and

one metanalysis from Kandiel et al : IBD patients with

6MP/AZA only.

Clin Gastro Hep 2009; Siegel C, et al: Risk of Lymphoma Associated With Combination Anti–Tumor Necrosis

Factor and Immunomodulator Therapy for the Treatment of Crohn’s Disease: A Meta-Analysis

Kandiel et al, Gut 2005;54:1121–1125.

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Meta-analysis of Lymphoma

Anti-TNFs and Thiopurines

• 8905 patients – 21178 person years of observation

• 13 Non-Hodgkin lymphoma identified in 6 of 26 studies

with Infliximab and adalimumab (RCT, cohorts, case series)

• Compared to the rates found in the SEER registry

(Surveillance Epidemiology & End Results database) and

one metanalysis from Kandiel et al : IBD patients with

6MP/AZA only.

NHL rate per

10 000 py

IRR 95% CI

SEER all age 1.9

AZA /6MP alone * 3.6

Anti-TNF vs SEER 6.1 3.23 1.5-6.9

Anti-TNF vs AZA /6MP alone 6.3 1.7 0.5-7.1

In both, the meta-analysis and SEER – Male patients have a higher rate !

Clin Gastro Hep 2009; Siegel C, et al: Risk of Lymphoma Associated With Combination Anti–Tumor Necrosis

Factor and Immunomodulator Therapy for the Treatment of Crohn’s Disease: A Meta-Analysis

Kandiel et al, Gut 2005;54:1121–1125.

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Meta-Analysis of Overall Risk of Lymphoma in Patients With

Inflammatory Bowel Disease on Thiopurine Therapy : DDW 2013

Kotlyar D., et al. DDW2013, abstract Su1147

• David Kotlyar, James D. Lewis, Laurent Beaugerie, Ann Tierney, Colleen M. Brensinger,

Edward V. Loftus, Javier P. Gisbert, Wojciech Blonski, Manuel

Van Domselaar, Maria Chaparro, Sandipani Sandilya, Gary R. Lichtenstein

• 13 Publication selected (European & American Studies).

RESULTS : Standard Incidence Rate (SIR) = 2.85 (95% CI: 2.13-3.74). Results between

referral centers and population studies showed a significant difference (p=0.0004).

(6.47 (3.76-10.4) vs. 2.24 (1.56-3.12)

Thiopurines treated IBD pts with 3-fold increased risk of

lymphoma as compared to the general population

> 2400 IBD patients treated for year for 1 case of Lymphoma !

1/ 440 Patients treated with Thiopurines will dev. Lymphoma !

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Lymphoma & Thiopurines : Summary

Siegel et al, Clin. Gastroenterol Hepatol 2009

* Kandiel et al, Gut 2005;54:1121–1125.. Cesame Study : Beaugerie Lancet 2009; 374: 1617-25

- Lymphoma – 5-6 times increased

Kandiel A, et al. Gut 2005;54:1121–5 - Metanalysis

General population – Risk : 1 / 12’000

IBD – Thiopurine : 5-6 / 12’000

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29

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Lymphoma & Thiopurines : Summary

Siegel et al, Clin. Gastroenterol Hepatol 2009

* Kandiel et al, Gut 2005;54:1121–1125.. Cesame Study : Beaugerie Lancet 2009; 374: 1617-25

- Lymphoma – 5-6 times increased

CAVE: Hepatolspenic T-cell Lymphoma

in young (<30 yo ) male patients

combining Thiopurines and Anti-TNFs.

Kandiel A, et al. Gut 2005;54:1121–5 - Metanalysis

General population – Risk : 1 / 12’000

IBD – Thiopurine : 5-6 / 12’000

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Hepato-splenic T cell Lymphoma: Update

• 20 cases reported between 2002 and Aug. 2009

– All received AZA and Anti-TNFS (all IFX, 4 also Adal.)

– Age, (range ) : 22 (12-58), only 3 over 35 yo.

– Subtypes : 17 CD, 3 UC

– Gender : Males 19/20 (93%)

– # of infusions before diagnosis : 1 to 24, 9 between 1 and 3.

– Outcome : Died 16 , unknown 4

Kotlyar et al Clin Gastro Hep 2011;9:36–41

Deepak P. Am J Gastroenterol 2013; 108:99-105

Kotlyar et al Clin Gastro Hep 2011;9:36–41

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2

Hepatosplenic T Cell Lymphoma Associated with Infliximab Use in Young Patients Treated for Inflammatory Bowel Disease: Update. Mackey, Ann; Green, Lanh; Leptak, Christopher; Avigan, Mark Journal of Pediatric Gastroenterology & Nutrition. 48(3):386-388, March 2009. DOI: 10.1097/MPG.0b013e3181957a11

TABLE 1 . Select clinical and demographic data of AERS cases of alpha/beta and gamma/delta T cell lymphoma associated with infliximab use or infliximab/adalimumab use from marketing in 1998 to June 30, 2008+ (n = 15)

Hepato-splenic T cell Lymphoma

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REAL RISK ???

• Estimation from Prof. J. Lewis (DDW 2013):

Hazard ratio per 100’00 person –year: 11.2 (OVERestimation from CESAME and Kasier-Permanent registry, because ist suggest that

HSTLC= 30% of the Lymphomas developed under thiopurines in male IBD patients )

Beaugerie L. et al. Lancet 2009; 374: 1617-25

Herrington L. et al Pharmacoepidemiologic Drug Saf.2012; 21: 49-52

Transportation Risk of death per 100’000 person -year

Commercial Plane 0.15

Car 11

Additional Risk from

talking on Cell Phone

+ 1.3

Motorcycle 450

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Cancer

http://www.google.ch/imgres?imgurl&imgrefurl=http://www.bhmpics.com/view-cancer_animal-1920x1200.html&h=0&w=0&sz=1&tbnid=Hc2elPMfVOwlqM&tbnh=177&tbnw=284&prev=/search?q=cancer&tbm=isch&tbo=u&zoom=1&q=cancer&docid=OJYG1EUsl_rtlM&hl=de&ei=_TTCUeaSBIm1O_T2gNgD&ved=0CAEQsCU

http://www.google.ch/url?sa=i&rct=j&q=&source=images&cd=&cad=rja&docid=A-nbZZeZJjNoJM&tbnid=Syiv7aaT6SSqcM:&ved=0CAUQjRw&url=http://www.gentledentaljersey.co.uk/mouth-cancer/&ei=FjXCUa3pN4GvPJ6QgLAD&bvm=bv.48175248,d.bGE&psig=AFQjCNEgYVp7j3B7qMm5cy3cFmWkiQ-wBA&ust=1371768437183877

http://www.google.ch/url?sa=i&rct=j&q=&source=images&cd=&docid=pKKA4DaUruu9PM&tbnid=ES3OYYGddD0r7M:&ved=0CAUQjRw&url=http://www.realitatea.net/cancerul-ar-putea-fi-vindecat-cu-ajutorul-virusului-hiv-testele-pe-oameni-au-inceput-deja_1070979.html&ei=aDXCUaK1O4O8PefcgJAL&bvm=bv.48175248,d.bGE&psig=AFQjCNEgYVp7j3B7qMm5cy3cFmWkiQ-wBA&ust=1371768437183877

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Risks of Cancer ? – in RCT

• Past studies have highlighted the potential for an increased risk

of malignancy in patients receiving anti-TNF therapy

• In Rheumatoid Arthritis : OR 3.3 (95%CI, 1.2-9.1)

• (Metanalysis from RCTs : Bongartz T et al, JAMA 2006)

• But, in Inflammatory Bowel Disease : no increased risk of

malignancies (Peyrin-Biroulet L et al, CGH 2008)

• However, difficult to prove a link between exposure and tumor development.

underlying disease (RA or IBD) predispose them to cancer.

37


• New meta-analysis in Rheumatoid Arthritis

• (Metanalysis from RCTs : Pharmacoepidemiology and Drug Safety,

2011; 20: 119–130)




• underlying disease (RA or IBD) predispose them to cancer.

38


• New meta-analysis in Rheumatoid Arthritis

• (Metanalysis from RCTs : Pharmacoepidemiology and Drug Safety,

2011; 20: 119–130)




• underlying disease (RA or IBD) predispose them to cancer.

anti-TNFs: Other drugs or placebo:

130 /15 418 (0.84%) vs 48/ 7486 (0.64%)

Relative risk : 0.99 (95%CI 0.61–1.68)

Conclusion: Reassuring for short-term risk,

long-term risk assessment = observational studies /

registries.

39

Risks of Cancer – in registries

• Danish registry : 691 patients (90% CD) on IFX (3 infusion/pt)

• From 1999 to 2005. Median F/u: 29.1 months (range, 0.1–72.1 mo).

Cancer

• 4 patients (all having CD) vs 5.9 expected (based on standardized

incidence ratio).

Caspersen S, Munkholm P, et al . Infliximab for inflammatory

bowel

disease in Denmark 1999-2005: clinical outcome and follow-

up

evaluation of malignancy and mortality. Clin Gastroenterol

Hepatol, 2008;6: 1212-1217.

40

Cancer & Anti-TNFs

TREAT registry - Incidence rate ratio per 100’000 py.

• 6273 pts enrolled: 3396 received IFX (14184 pt-yrs)

Lichtenstein et al, Am J Gastroenterol 2012; 107:1409–1422.

“malignancy in the TREAT registry will be the subject of a separate publication”

IRR

IFX pts

IRR Non-

IFX pts

Relative

risk

95% CI

All cancer (except. Non Melanoma)

0.42 0.45 0.76 0.54-1.07

Non melanoma

Skin cancers*

0.16 0.18 0.81 0.38-1.73

Lymphoma 0.05 0.06 0.74 0.24-2.29

41

1.46 1.85

5.4

7.06

1.29 1.1 1.09

0

2

4

6

8

10

12

14

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Risk of NM Skin Cancers & Melanoma - Thiopurine

Long et al: GASTROENTEROLOGY 2012;143:390–399

Peyrin-Biroulet L , Gastroenterology 2011 ; 141 : 1621 – 28

Singh,et al. Gastroenterology 2011 ; 141 : 1612 –20 .

NMSC Melanoma

42

1.46 1.88

2.17

1.29 1.14

2.57

0

2

4

6

8

10

12

14

16

REF -IBD Long Singh Peyrin-Biroulet

REF - IBD Long Peyrin-Biroulet

Risk of NM Skin Cancers & Melanoma - Anti-TNFs

Long et al: GASTROENTEROLOGY 2012;143:390–399

Peyrin-Biroulet L ,et al. Am J Gastro 2012 ; 141 : 1621 – 8 (Letter) .

Singh,et al. Gastroenterology 2011 ; 141 : 1612 –20 .

NMSC Melanoma

43

0.73

5.19

7.06

0

2

4

6

8

10

12

never former current

Risk of NM Skin Cancers – Thiopurine

Peyrin-Biroulet L , Khosrotehrani K , Carrat F et al. Increased risk for nonmelanoma skin cancers in patients who receive

thiopurines for infl ammatory bowel disease . Gastroenterology 2011 ; 141 : 1621 – 28.

CURRENT EXPOSURE !

Study from Long et al: While this study could not attribute the increased risk of NMSC to specific durations

of immunosuppression, length of therapy may be an important component of NMSC risk

44

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Risks of Cancer – in multicenter studies

Biancone et al, IBD 2011;17:758–766 :Cancer in Crohn's Disease patients

treated with infliximab: A long-term multicenter matched pair study.

Biancone L, Orlando A, Kohn A, et al. Gut. 2006;55:228–233.

• 12 referral center in Italy – two publication

from 1999 to 2004 & 1999 to 2008.

• F/u time 74 months (range 12–114)

CD-IFX: 8/221; 3.61% versus CD-C: 9/221; 4.07%

No specific histotype of cancer appeared associated

with infliximab use.

46

Conclusion

• Standard IBD patient +/- history of cancer

The risk is almost always outweighted by the benefits of

the treatment!

• Risk: Lymphoma & Non Melanoma Skin Cancers

• Solid tumors ? (other than basal cell carcinoma and resected squamous cell Ca),

Exceptions? : particulary anxious patients with a strong family hx

...

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patient with :







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• Recommendations from the British Society of

Rheumatology:

Established dysplasia

Established dysplasia (Cervical dysplasia)

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Rheumatology:

Pre-malignant conditions

50








patient with :

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• No study has specifically asked whether TNF blockade

increase the risk of recurrent cancer in patient with previous

malignancy,

• Consequently, it is unclear if whether treatments with anti-

TNF agents should be avoided in these patients.

Rely on expert opinion

Past history of malignancy

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Rheumatology:

• WGOC UEGW 2008

CI : Current or recent malignancy, without advice from an oncologist


From AGA consensus on the use of Biologics; Gastroenterology 2007

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• Data from the British society of Rheumatology

Biological register

• 154 patients with previous malignancy and RA

• Six cases = 4% vs 1.6% (=158/9844), OR 2.5 (1.2-5.8)

• Three cases in patients with > 10 years free of disease


Watson K, Dixon, WG, Hyrich KL, Lunt M, Symmons, DPM,

Silman AJ. Influence of anti-TNF therapy and previous malig-

nancy on cancer incidence in patients with rheumatoid

arthritis

(RA): results from the BSR biologics register (BSRBR).

Rheumatology, 2006;45:I10.

54

The general answer remains no.

Because 10 years is arbitrary…

• Or in patients who had a real benefit obtained or

expected with anti-TNFs.


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patient with :


• Pre - malignant conditions

• Established dysplasia

• Past history of malignancy


Risk / severity AntiTNF use

56


patient with :


• Pre - malignant conditions

• Established dysplasia

• Past history of malignancy


Risk / severity AntiTNF use

If 10 yrs

free

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All patients treated with Thiopurines

• Annual dermatological

examination (eoy)

• Sun block and hat

• Evaluate also for Anti-

TNF monotherapy,

after a short trial (6mo)

• Inform the patient from

the risk

• Risk –benefit balance

of long term therapy

• Discontinue ineffective

medication unless othe

justification (e.g.

preventing antibody

formation)

58

One of my sources …

Danke !

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Options

• We discussed the following remaining options (in order of preference):

• (A) Sulfasalazine - had shown some effect in mild to moderate CD

colitis and for IBD associated arthralgies.

• (B) Rifaximine - antibiotics not reimbursed for CD, but recent trials

showed a good efficacy (around 60%), also less sides effects as it is not

absorbed by the gut.

• (C) Remicade or other anti-TNF agents - taking the risks considering

the benefit of being in remission (not worth considering right now because she

is almost asymptomatic)

• (D ) MTX low dose - because pancreatitis is a rare but not

unknown side effect for MTX, and MTX has good antineoplasiques effects.

However, it remains the less likely candidate.

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