The Royal Marsden

Treatment of

lower GI cancers

Dr Nicholas van As

The Royal Marsden

Question 1: localised anal cancer is treated with?

1. Chemotherapy

2. Radiotherapy

3. Surgery

4. Chemo-radiotherapy

2

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Question 2: Rectal cancel with threatened resection margin?

1. Treatment with chemotherapy followed by surgery

2. Treatment with 1 week of radiotherapy then surgery

3. Surgery alone

4. Combined chemotherapy and 6 weeks of radiotherapy

3

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Question 3: 5year cancer free survival for Dukes C colon cancer treated with surgery is?

4

1. 20%

2. 50%

3. 70%

4. 90%

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Question 4: 5year cancer free survival for Dukes C colon cancer treated with surgery and chemotherapy is?

5

1. 20%

2. 50%

3. 70%

4. 90%

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Question 5: CyberKnife…

1. Is a precision surgical instrument

2. Is a linear accelerator mounted on a robotic arm

3. Can treat cancers with no side effects

4. Had a starring role in “The return of the Jedi”

6

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Anal cancer

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Anatomy8

82 yr old male, cT3N3 SCC anal verge

10

Anal SCC cT3N0 post CRT completed 24.07.2008

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Rectal Cancer

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Rectal Cancer: Radiotherapy

Why?

When?

How?

Mesorectal fascia

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Nagtegaal, I. D. et al. J Clin Oncol; 26:303-312 2008

Schematic representation of the CRM; the margin is marked with black ink

CRM

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Radiotherapy in Colorectal Cancer.Brian DP O’Neill, Diana M Tait.The Multi-Disciplinary Management of Colorectal Cancer. Cambridge University Press 2007, in press.

The MERCURY Study Group. Diagnostic accuracy of magnetic resonance imaging in predicting surgical resection margin status: prospective observational study. BMJ. 2006 Oct 14;333(7572):779.

Background

O'Neill BD, Brown G, Heald RJ, Cunningham D, Tait DM.Lancet Oncology. 2007 Jul;8(7):625-33.

? Treatment

O'Neill BD, Brown G, Heald RJ, Cunningham D, Tait DM.Lancet Oncology. 2007 Jul;8(7):625-33.

Pathological Complete Response

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Chemotherapy for lower GI cancer

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TNM system

Primary tumor (T)

Regional lymph nodes (N)

Distant metastasis (M)

Staging of CRC

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Staging of CRC: Dukes staging system

A Mucosa

B Into or through M. propria

C1 Into M. propria, + LN

C2 Through M. propria, + LN

D distant metastatic spread

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Adjuvant Chemotherapyfor Colorectal Cancer

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Adjuvant therapy increases the chance of survival: evidence in 20,898 patients

Sargent, et al. JCO 2009

Stage II CC

1.0

0.8

0.6

0.4

0.2

0

OS estim

ate

p=0.026

0 1 2 3 4 5 6 7 8

Follow-up time (years)

Surgery alone8-year OS rate (95% CI): 66.8%(63.7% to 70.0%)

Surgery + FU-based chemotherapy8-year OS rate (95% CI): 72.2%(69.3% to 75.2%)

OS estim

ate

Stage III CC

p<0.0001

Surgery alone8-year OS rate (95% CI): 42.7%(39.9% to 45.7%)

Surgery + FU-based chemotherapy8-year OS rate (95% CI): 53.0%(50.2% to 55.9%)

0 1 2 3 4 5 6 7 8

Follow-up time (years)

1.0

0.8

0.6

0.4

0.2

0

ASCO 2008 ASCO 2007

Oxaliplatin in Adjuvant Therapy

QUASAR: OS in Dukes’B

QUASAR Collaborative Group, Lancet 2007

Survival – Dukes stage B

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FOLFOX /XELOX improves OS compared to 5FU by

3- 4.6 % for stage III disease

Peripheral neuropathy 92 % any grade , 15% residual at 4 yrs-MOSAIC

No role for irinotecan in adjuvant therapy to date

Adjuvant capecitabine non inferior to 5FU

OS benefit for stage II disease with 5FU was 3.6% in QUASAR study

5FU based chemotherapy may be detrimental in dMMR stage II patients

MMR and MSI need further evaluation in randomised studies

Role of targeted agents remains to be confirmed

Conclusions

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Advanced Colorectal Cancer

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– FOLFIRI as first line therapy and irinotecan alone in subsequent therapy

– FOLFOX as first line or subsequent therapy

– Raltitrexed not recommended for patients with advanced colorectal cancer

– Capecitabine or UFT/LV is recommended as an option for the first line treatment of metastatic colorectal cancer

– Combination chemotherapy plus cetuximab for 16 weeks is approved and funded for liver only non resectable metastatic disease

NICE guidance in treatment of advanced colorectal cancer

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Treatment of advanced CRC

5-FU mono-therapy

5-FU/ leucovorin

Combination of 5-FU/ LV

with either irinotecan or

oxaliplatin

Sequential use of

irinotecan, oxaliplatin and

infused 5-FU/LV

1980s

1990

1994

2000

2002

5-9 months

11months

12-14 months

15-17 months

18-21

months

Median survival

Best supportive care

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Access to 3 drugs – fluoropyrimidine, oxaliplatinand irinotecan

Updated analysis Grothey et al JCO 2005

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Angiogenesis

Cancer cell signalling

Targeted therapy

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Angiogenesis is involved throughout tumour formation, growth and metastasis

Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25

Stages at which angiogenesis plays a role in tumour progression

Premalignantstage

Malignanttumour

Tumourgrowth

Vascularinvasion

Dormantmicrometastasis

Overtmetastasis

(Avasculartumour)

(Angiogenicswitch)

(Vascularisedtumour)

(Tumour cellintravasation)

(Seeding indistant organs)

(Secondaryangiogenesis)

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VEGF and other signals promote the angiogenic switch in tumours

Adapted from Bergers G, et al. Nature 2002;3:401–10

Small tumour (1–2mm)

• Avascular

• Dormant

Larger tumour

• Vascular

• Metastatic potential

Angiogenic switchResults in overexpressionof pro-angiogenic signals,such as VEGF

Pooled analysis of OS by treatment group for patients with KRAS wt tumors

CT

Number of patientsCT + cetuximab398 356 177 128 65 0

447 395 159 112 48 0

CI, confidence interval; CT, chemotherapy; PFS, progression-free survival

Probability of overall

survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

180 6 12 24 60

30 36 42 48 54

296313

246227

8367

2118

42

Time (months)

KRAS wtHR [95% CI]: 0.81 [0.69–0.94]

p=0.0062FOLFIRI / FOLFOX4 + cetuximab: (n=398) median 23.5 monthsFOLFIRI / FOLFOX4: (n=447) median 19.5 months

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EGFR inhibitor-induced rash

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Correlation of rash and survival in cetuximabtreated patients

Study: 9923 0141 BOND

Saltz (2001)1 Saltz (2004)2 Cunningham Van Cutsem Xiong (2004)5 Kies (2002)6

(2004)3 (2004)4

1. Saltz et al. Proc ASCO 2001; 2. Saltz et al. J Clin Oncol 2004; 3. Cunningham N Engl J Med 2004; 4. Van Cutsem et al. EORTC/NCI Geneva 2004;

5. Xiong H et al. J Clin Oncol 2004. 6. Kies et al. Proc ASCO 2002.

CRC CRC CRC CRC Pancreatic SCCHN

No reaction Grade 2Grade 1 Grade 3

Survival (m

onths)

16

14

12

10

8

6

4

2

0

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Biological agents – current status

HURWITZ

↑RR ↑PFS ↑ OS with IFL, ↑PFS with CAPOX not FOLFOX

Bevacizu

mab

E3200

FOLFOX ↑RR ↑PFS ↑OS

Bevacizu

mab

Cetu

xim

ab

BOND/EPIC

↑RR ↑PFS No ∆ in OS with Irinotecan

Panitumumab v BSC

↑PFS compared to BSC

Panitu

mumab

Cetu

xim

ab

NCIC CO.17

↑OS compared to BSC

First line Second line Last line

Cetu

xim

ab

CRYSTAL

CPFS with FOLFIRI

↑OS

MEDIAN SURVIVAL IN EXCESS OF 24 MONTHS

COIN

No change in PFS or OS

PRIME

↑PFS , NO CHANGE OS

Panitu

mumab

Metastatic colon cancer patients (100%)

Non curable Potentially

Down-sizable

12%63%

Non - resectable 75% Resectable 25%

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Stage IV Colon CancerStage IV Colon Cancer

Potentially curable Not curable

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Cyberknife

45

46

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Citroen Robot 2005

48

49

50

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Conclusions-Advanced Disease

• Combination chemotherapy is recommended for those

patients of adequate performance status

• Cetuximab is approved for k-ras wild type non resectable

liver only metastases

• Patients with oligo-metastatic disease should be

discussed at MDT and considered for consolidation local

therapy

• Future trials should be aimed at enriched patient

populations likely to benefit from targeted therapy based

on biomarker driven research

• Ultimate goal is to deliver individualised treatment

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Royal Marsden GI Unit

– Integrated multidisciplinary team approach

– Patient driven care-support groups /focus groups/patient

advocates

– Extensive portfolio of Clinical trials –investigator led and

pharmaceutical sponsored

– National and international collaborations

– Commitment to translational research -new state of the art

molecular pathology labs to be based at Sutton

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Thank you

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