Update on Colorectal Cancer - sialliance.health.nz · Update on Colorectal Cancer Dr Christopher...

Update on Colorectal Cancer

Dr Christopher Jackson

Medical Oncologist

Southern Blood and Cancer Service

CRC Update – September 2010

2005 NZ Cancer Registrations

*Excludes basal and squamous cell skin cancers.

Source: Cancer: New Registrations and Deaths. MOH 2009

27% Breast

16% Colon & rectum

10% Melanoma of skin

8% Lung & bronchus

4% Uterine corpus

4% Non-Hodgkinlymphoma

3% Ovary

3% Myeloprolif.

2% Leukaemia

2% Pancreas

20% All Other Sites

Prostate 26%

Colon & rectum 14%

Melanoma of skin 12%

Lung & bronchus 10%

Non-Hodgkin 4% lymphoma

Myeloproliferative 4%

Leukaemia 3%

Urinary bladder 3%

Kidney 2%

Stomach 2%

All Other Sites 21%

Age standardised incidence of Colorectal Cancer

NZ, UK and Aus 2004/5

0

100

200

300

400

500

600

15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Age category

Incid

en

ce p

er

100,0

00 p

op

ula

tio

n

NZ total UK total Aus total

NZHIS 2005; Aus Institute of Health and Welfare; Cancer Research UK

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

1961

1963

1965

1967

1969

1971

1973

1975

1977

1979

1981

1983

1985

1987

1989

1991

1993

1995

1997

1999

2001

2003

2005

Year

Mo

rta

lity

pe

r 1

00

,00

0

Age standardised death rates, NZ 1961-2005

Lung

Colorectal

Breast

Prostate

Melanoma

Cervix

NZ HIS 2005


Disease-specific funding

Colorectal Cancer

5-FU / Capecitabine

Oxaliplatin

Irinotecan

Breast Cancer

FEC / FAC + G-CSF

Docetaxel / Paclitaxel

Tam / AIs

Herceptin adjuvant / advanced

Vinorelbine

Capecitabine

Cetuximab

Bevacizumab

Panitumumab

SIR Spheres

Raltitrexed Gemcitabine


Risk factors

Personal / Family history

Ulcerative colitis

Hyperinsulinism: RR 1.30

Alcohol: > 2pints/d, 4 glasses wine / d: RR 1.41

Obesity: RR 1.5 if BMI > 25

Vitamin B6 inversely related to colon cancer risk: RR 0.51

– Unclear whether supplementation or diet important

Exercise: RR 0.33-0.60

Diet – Western Diet

Red meat > 300g / week

Vitamin D, Calcium controversial

Association does not prove causation


All cancers come from polyps


Common symptoms

Change in bowel habit – loose stool

Rectal bleeding

Narrow stool

Abdominal pain

Bloating

Anaemia

Constitutional symptoms are LATE signs

Pain is uncommon

80% of rectal bleeding will be benign


Good staging critical

Colonoscopy

Biopsy

CT

MRI

PET


Incidence of colorectal cancer by stage

Stage I

24% Stage II

26%

Stage III

29%

Stage IV22%

Eligible for

adjuvant

chemotherapy


Types of surgery


Adjuvant Chemotherapy

Stage IIIStage IIStage I

Worsening Survival

No Adjuvant

TherapyAdjuvant TherapyPossible Adjuvant Therapy

Traditional view of relapse risk & adjuvant therapy


Stage I

Worsening Survival

Low Risk High RiskModerate Risk

Stage III

Defining Recurrence Risk in CRC

Actual risk is not well defined by T & N stage alone

Stage II

Stage III


Adjuvant Therapy of Colon Cancer:

An Historical Perspective

1990 5-FU/lev better than surgery alone

1994 5-FU/LV better than surgery alone

1998 5-FU/LV better than 5-FU/lev

1998 6 months = 12 months

1998 Levamisole unnecessary

1998 HDLV = LDLV

1998 Weekly = monthly

2002 LV5FU2 = monthly bolus

2003 FOLFOX > LV5FU2

2005 Capecitabine = monthly bolus

2009 Bevacizumab / Cetuximab no additional benefit


Post-operative combination chemotherapy:

Superior in Stage III Colon Cancer

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Overall survival (months)

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

HR [95% CI]

Stage II 1.00 [0.71–1.42]

Stage III 0.80 [0.66–0.98]

0.1%

4.4%

p=0.996

p=0.029


Relative toxicities of differing regimens

%Bolus 5-

FUInfused 5-FU Bolus 5-FU Capecitabine

Diarrhoea 9 4 11 13

Stomatitis 7 2 14 2

Nausea/Vomiting 3 1 3 3

PPE 0 0 <1 17

Neutropenia 16 7 26 2


Management of toxicity

Early recognition!!!

– Importance of specialist nursing

Interruption of treatment

Delay

Dose reduction

Loperamide, Codeine, Octreotide, Steroids??

Anti-biotics

Pyridoxine

Side effects of adding Oxaliplatin

NCI Gr 3 % FOLFOX4 LV5FU2(n=1108) (n=1111)

Thrombocytopenia 1.6 0.4

Neutropenia 41.0 (Gr 4: 12.2) 4.7

Febrile neutropenia 0.7 0.1

Neutropenic sepsis 1.1 0.1

Diarrhoea 10.8 6.7

Stomatitis 2.7 2.2

Vomiting 5.9 1.4

Allergy 3.0 0.2

Alopecia (Gr2) 5.0 5.0

All cause mortality 0.5 0.5


Long-term Neuropathy

0

10

20

30

40

50

60

During

Tx

6

months

1-year 2-year 3-year 4-year

Grade 1

Grade 2

Grade 3

Evaluable patients n=811

Grade 0 84.3%

Grade 1 12.0%

Grade 2 2.8%

Grade 3 0.7%


Adjuvant chemotherapy in the elderly


Pooled Analyses of fluoropyrimidine

chemotherapy in Elderly Patients n=3351

Sargent et al. NEJM 2001. 345(15): 1091-7

Individual patient data pooled from 7 adjuvant trials of surgery

vs fluorouracil-based chemo for stage II and III pts

< 70 yrs n=2845; >70 yrs n=506

No significant

interaction between

age and treatment

effect

Increased age

associated with

higher rates of

haematologic toxicity


Adjuvant chemo in elderly

André T et al. JCO 2009;27:3109-3116; QUASAR Collab Group Lancet 2007; 370:2020-29


Rectal cancer: pre-operative therapy


Pre-operative therapy

Advanced disease


Progress in the Cytotoxic Management of mCRC

FOLFOX-FOLFIRI (Tournigand)9

5-FU/LV (Saltz)1

Xeloda/UFT (Hoff/Douillard)3,4

5-FU/LV (de Gramont)2

IFL (Goldberg)5

IFL (Saltz)1

FOLFIRI (Douillard)7

FOLFOX (Goldberg)5

XELOX (Van Cutsem)8

0 252015105

IFL (Hurwitz)6

Median OS (months)

BSC 1980’s

2009

1.Saltz N Engl J Med 2000; 2. De Gramont JCO 2000; 3. Hoff JCO 2001; 4. Douillard JCO 2002; 5. Goldberg ASCO 2003; 6. Hurwitz NEJM 2004; 7. Douillard Lancet 2000; 8. Van Cutsem ASCO 2003; 9. Tournigand JCO 2004; 10. Cassidy ASCO 2007; 11 Van Cutsem NEJM 2009

FOLFIRI-Cetuximab (Van Cutsem)10

FOLFOX-Bevacizumab (Cassidy)10


10 year survival following liver resection

Tomlinson, J. S. et al. J Clin Oncol; 25:4575-4580 2007


OPTIMOX 1 Neurotoxicity FOLFOX4 vs 7

0

2

4

6

8

10

12

14

16

18

1 3 5 7 9

11

13

15

17

19

21

23

cycles

% o

f patients

FOLFOX4

FOLFOX7


Anti-VEGF

Reduces

interstitial fluid pressure

vessel density

Increases

drug delivery

Anti-VEGF antibody ‘normalises’ the tumour

vasculature

Jain R. Nature Med 2001;7:987–9; Willett CG, et al. Nat Med 2004;10:145–7;

Tong R, et al, Cancer Res 2004;64:3731–6


Bevacizumab-Related Toxicities

• Hypertension (about 10%)

• Venous Thromboembolism

• Arterial Thromboembolism (increased risk 2->4.5%)

• Bleeding

• Proteinuria

• Delayed Wound Healing

• GI Perforation (about 2%)

1Hurwitz H, et al. N Engl J Med 2004;350:2235–42 2Novotny W, et al. J Clin Oncol 2004;22 (July 15 Suppl.): Abstract 3529 3Hambleton J, et al. J Clin Oncol 2004;22 (July 15 Suppl.): Abstract 3582

4Scappaticci et al J Surg Oncol. 2005 Sep 1;91(3):173-80.

CRC Update – September 2010Ciardiello F and Tortora G. N Engl J Med 2008

EGFR pathway promotes cell survival, invasion and metastasis

Ras

RAF

MAPK

EGFR

Cell growth, proliferation,

invasion and metastases


P’mab: PFS in Mutant KRAS group

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

po

rtio

n w

ith

PF

S

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

PFS (Weeks)

36 38 40 42 44 46 48 50 52

Panitumumab + BSC (n=84)

BSC Alone (n=100)

HR = 0.99 (95% CI: 0.73–1.36)

Amado et al., ECCO 2007

7.4

weeks7.3

weeks


P’mab: PFS in WT KRAS group

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

PFS (Weeks)

36 38 40 42 44 46 48 50 52

Panitumumab + BSC (n=124)

BSC Alone (n=119)

HR = 0.45 (95% CI: 0.34–0.59)

Stratified log-rank test, p < 0.0001

Pro

po

rtio

n w

ith

PF

S

Amado et al., ECCO 2007

7.3

weeks

12.3 weeks

EGFR inhibitor-induced skin reactions

1 2 3 4 5 6 7 8 9

Post-inflammatory effectsAcne-like rash

Paronychia

Dry skin

Pruritus

Fissura

Hydrocolloid

dressing

or

Propylene

glycol +/-

salicylic acid

Anti-septic

soaks

Silver nitrate

(pyogenic

granuloma)

THERAPY SUGGESTIONS

Topical anti-acne

creams (drying

effect)

+/- tetracyclines

+/- antihistamines

Emollients

Pictures provided by S Segaert and E Van Cutsem (Leuven, Belgium).


NICE appraisal – Cost per QALY

Bevacizumab: £88,364

– Additional median survival 6 weeks; 10% addit response

Cetuximab: £58,870

– Additional 10 weeks progression-free survival in chemo-refractory group

NICE threshold: £30,000


Managing toxicity: CTCAE grading

G1: Mild

G2: Moderate

G3: IV, or hospitalisation (25% DR)

G4: Life threatening (50% DR or stop)

G5: RIP

A question of how soon, how severe,

and the treatment context

Primary and secondary prevention


Colorectal cancer – screening

4 trials examining FOBT effect on CRC mortality

Biennial testing; FOBT Colonoscopy

Age range 45-70

Cochrane meta-analysis:


Lifestyle advice – diet

JAMA 2007: Meyerhardt

1009 patients

Dietary patterns and relapse rates

Effect as strong as adjuvant chemotherapy; cumulative not exclusive

US PPP trial as supportive evidence

– Dietary intervention independent of obesity, T2DM


Lifestyle advice – exercise

668 patient cohort w stg 1-3 CRC

Pre- and post-cancer exercise levels

Highest MET level HALVES risk of CRC comapred with lowest

Brisk half hour walk = 3.3

10 min run = 10 MET Meyerhardt, J. A. et al. Arch Intern Med 2009;169:2102-2108.


Lifestyle advice – general

Hyperinsulinism: RR 1.30

Obesity: RR 1.5 if BMI > 25

– Lose weight

Alcohol: > 2pints/d, 4 glasses wine / d: RR 1.41

– Drink less

Vitamin B6 inversely related to colon cancer risk: RR 0.51

– Vitamin supplements? (or healthy diet)


Case 1 – SM

34 yo f. Noted rectal bleeding, attributed to haemorrhoids. On rectal

examination there was a palpable mass at 5cm. She has no significant

comorbidities and takes no medications, and has no family history of cancers.

CT scan shows bone and liver mets

Biopsy confirms adenocarcinoma

? Radiotherapy

? Surgery

? Chemo


Case 2 – CW

62 year old female

Emergency presentation

pT4a N0 (0/22) V1 G2 adenocarcinoma sigmoid

CEA = 9, CT scan clear

? Other staging investigations

? Benefit of chemo

? Colonoscopy

Summary


Summary

CRC 2nd most common, incidence and deaths

Early detection saves lives

Change in bowel habit needs investigation

Good staging critical

Adjuvant therapy in stage 2 & 3 benefit of 4-20%

Treatment of stage four quadruples survival time

Toxicity management requires early recognition

Aggressive multi-modal therapy in selected patients with stage 4 disease can result in cure

Several lifestyle and prevention options available

We can do better!

NZ Summary – How do we stack up?

Ease of access to colonoscopy

Screening

Rapid specialist access ? / Access to adjuvant therapy

Full access to advanced drug therapy /

Comprehensive bowel cancer programme /

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