Chemoradiotherapy for Rectal cancer Dr. A. Sun Myint Lead Clinician GI Tumour Group Clatterbridge Centre for Oncology Association of Coloproctology of.

Chemoradiotherapy for Rectal cancer

Dr. A . Sun MyintLead Clinician GI Tumour Group

Clatterbridge Centre for Oncology

Association of Coloproctology of Great Britain and Ireland

M62 Coloproctology Course - March 23rd 2007

Background

• In the UK over 10,000 new rectal cancer

• Five year survival 50% (NBOCAP-2006)

• Nearly half will develop recurrences

• At presentation 30% T3/T4 N + MO

• Preoperative radiotherapy reduce LR

• So far, no survival advantage

Treatment Options

• Surgery TME / Training

Sub specialisation

• Radiotherapy Pre operative

Chemoradiotherapy

Post operative• Chemotherapy Advance /metastatic

Adjuvant

New agents

Options Improvements

Radiotherapy

Preoperative Radiotherapy

Short course or Long course?• Short course

• Long course


Short course or Long course?• Short course - Mobile operable tumour

• Long course - Fixed / Tethered tumour

30%( MRI defined CRM +)


Short course or Long course?• Short course - Mobile operable tumour

• Long course - Fixed / Tethered tumour

( MRI defined CRM +)

Improving Outcomes

• Add chemotherapy to radiation

• Increase radiation dose

Chemo-radiotherapy

Concurrent Chemotherapy + RT• 5FU

• 5FU / FA

• 5FU infusion + Irino / Oxaliplatin

• Capecitabine + Irino / Oxaliplatin+ EGFR

• Capecitabine + Irino / Oxaliplatin+ VEGFR

Oxaliplatin is a radiosensitiser

in HT-29 xenograft models Tumour volume

Days post-treatment

Oxaliplatin + radiation

Blackstock A et al. Int J Rad Oncol Biol Phys 2000;16:92–94

Control

Oxaliplatin 5mg/kg

Radiation only (5Gy)

160

120

80

40

001 05 09 13 17 21

Comparative tumor sterilization rate by treatment modality

Treatment

modality

pCR + pMic RO

EBRT alone 7.1% (26%) 40%

EBRT+ chemo 16.2% (31%) 60%

EBRT+ duplet 21% (60%) 90%

Is chemo-Radiotherapy better than RT alone?

EORTC Rectal cancer trial

Pre-op RT SURGERY

Pre-op

Chemo/RT

SURGERY

Pre-op RT SURGERY Adjuvant

Chemo

Pre-op

Chemo/RT

SURGERY Adjuvant

Chemo

T3/T4 rectal cancer n=1011


Pre-op

Chemo/RT

Pre-op RT

Local recurrence

8.7% 17%

(p=0.0016)

Bossett al ASCO 2005


Adjuvant

Chemo

No Adjuvant

Chemo

Survival 67.2% 63.2%

Bossett al ASCO 2005

FFCD 9203- Rectal cancer trial

Pre-op RT SURGERY

Ad Chemo

Pre-op CRT SURGERY

Ad Chemo

JP Gerard et al ASCO 2005

T3/T4 rectal cancer n=733


Pre-op

Chemo/RT

Pre-op RT

Local recurrence

8.0% 16.5%



Adjuvant

Chemo

No Adjuvant

Chemo

Survival 67% 66%


Chemo RT vs. Radiotherapy

Trials

Pre-op CRT

Pre-op RT

EORTC 22921 8.7% 17.1%

FFCD 9203 8% 16.5%

German-94 6%

Local control in T3/T4 rectal cancer

Pre-operative Radiotherapy better than

post op RT?

German pre op. vs. post operative chemoradiotherapy for rectal cancer

Preoperative

Chemo-RT

Surgery

Surgery Post operative

Chemo-RT

Sauer et al N Engl J Med (2004) 351;17 1731-01740


Pre op

n=405

Post op

n=394

Local recurrence

6% 13% P=0.0006

Survival 76% 74% P=0.08



Pre op

n=405

Post op

n=394

Acute

Toxicity

27% 40%

P=0.001

Late

Toxicity

14% 24% P=0.01


Newer agents for chemoradiotherapy

Chemoradiotherapy

• 5FU bolus

• 5FU+ FA

• Infusional 5FU

• Capecitabine• Irinotecan +Cape NWCCOG 1+ RICE

• Oxaliplatin +Cape CORE/ SOCRATES

• Triplet therapy Ir/Oxali + MdG+ VEGF

RADIOTHERAPY

Pre-operative 5-FU chemoradiation:

• 5-FU-based chemoradiation has become part of standard pre-operative therapy for rectal cancer

– effective downstaging

– 10–30% pCR rates

• Protracted infusion of 5-FU with postoperative radiotherapy improves survival versus bolus

5-FU1

1O’Connell MJ et al. N Engl J Med 1994;331:502–7

Infused versus bolus 5-FU during pelvic radiation

O’Connell MJ et al. N Engl J Med 1994;331:502–7

100

80

60

40

20

00 1 2 3 4

Years after randomisation

Overall survival (%)

Log rank p=0.005

Cox model p=0.01

Infused 5-FU (n=328)

Bolus 5-FU (n=332)

Capecitabine + radiation

capecitabine plus radiotherapy

• Infused 5-FU is cumbersome and inconvenient for patients

• Oral capecitabine simplifies chemoradiation and is highly appealing to patients

• Potential for enhanced therapeutic ratio

– capecitabine generates 5-FU preferentially in tumour via

thymidine phosphorylase (TP)1

– radiotherapy further upregulates TP in tumour2

1Miwa M et al. Eur J Cancer 1998;34:1274–812Sawada N et al. Clin Cancer Res 1999;5:2948–53

Irradiation upregulates TP

25

20

15

10

5

0

TP (units/mg protein)

0 3 6 9 12 15 18 21Days after X-ray irradiation

*

*

*

**

* *

*

*

*p<0.05

5Gy

2.5Gy

Control

Sawada N et al. Clin Cancer Res 1999;5:2948–53

120

100

80

60

40

20

0

capecitabine enhances activity of radiation in WiDr xenografts,

Tumour inhibition (%)

*

Sawada N et al. Clin Cancer Res 1999;5:2948–53

5Gy

Xeloda

Xeloda

+ 5G

y5-

FU

5-FU +

5Gy

*p<0.05

Capecitabine chemoradiation:

• Oral capecitabine is replacing 5-FU in chemoradiation

– capecitabine is highly effective and well tolerated in combination with radiotherapy

– capecitabine simplifies chemoradiation and is highly appealing to patients and clinicians alike

Chemoradiation in rectal cancer: German phase II study (n=68)

• Male / female (%) 63 / 37

• Median age 65 years

• ECOG 0/1 (%) 54 / 41

• T3 / T4 (%)48 / 52 (57% N1–3)

Day 1 8 15 22 29 35

50.4Gy radiotherapy1.8Gy / fraction

825mg/m2

twice dailyContinuous (days 1–37)

Dunst J et al. Proc Am Soc Clin Oncol 2003;22:277 (Abst 1113)

capecitabine chemoradiation:efficacy

1Dunst J et al. Eur J Cancer 2003;1(Suppl. 5):S86 (Abst 282) 2Lin E et al. Proc Am Soc Clin Oncol 2003;22:287 (Abst 1152)

Patients (%)

Dunst study1 Lin study2

Down staging 79 73

pRR 80 87

pCR 5 20

Patients (%)

Diarrhoea Local Pain Hand-foot Nausea erythema syndrome

Grade 1/2

Grade 3

Dunst J et al. Eur J Cancer 2003;1(Suppl. 5):S86 (Abst 282)

capecitabine chemoradiation: Toxicity

• No grade 4 adverse events80

60

40

20

0

NSABP R-04 rectal cancer trial

*Plus 5.4Gy for fixed tumours

Resectable rectal cancer, stage II–III

n=1600

capecitabine continuously throughout

radiotherapy (50.4Gy*)SURGERY

5-FU continuous infusion throughout

radiotherapy (50.4Gy*)

Objectives – DFS– recurrence rate– pCR– safety

Chemoradiation using Oxaliplatin combination

capecitabine/oxaliplatin chemoradiation

Patients (%)

Glynne-Jones1

(n=16) Rödel2 (n=31)

pCR 31 19

pT1 / 2N0 19 23

Resection margin

R0 88 94

R1 12 6

1Glynne-Jones R et al. Proc Am Soc Clin Oncol 2003;22:292 (Abst 1174)2Rödel C et al. J Clin Oncol 2003;21:3098–104

CORE: European study

Radiotherapy45Gy / 25 fractions

capecitabine825mg/m2 twice daily

Monday to Friday

Oxaliplatin50mg/m2

weekly

1 8 15 22 29Day

CORE: Capecitabine, Oxaliplatin, Radiotherapy and Excision

Chemoradiotherapy using Irinotecan combination

RICE - NWCCOG study

Radiotherapy45Gy / 25 fractions

capecitabine825mg/m2 twice daily

Monday to Friday

IRINOTECAN

60mg/m2 weekly

1 8 15 22 29Day

S. Gollins, S.Myint, E. Levine et al Proc Am Soc Clin Oncol 2006;24:617s (Abst 13519)

Chemoradiotherapy

• 5FU bolus

• 5FU+ FA

• Infusional 5FU

• Capecitabine• Irinotecan +Cape NWCCOG 1+ RICE

• Oxaliplatin +Cape CORE/ SOCRATES

• Triplet therapy Ir/ Oxali + cape+ EGF

RADIOTHERAPY

ARISTOTLE

Reducing Toxicity from CRT

Toxicity

• Chemoradiotherapy is more toxic than radiotherapy alone

• To reduce toxicity:-Preoperative rather than post

opRadiation volumeDose, fractionation and timeRadiation techniques

Are there any other options to reduce toxicity

from chemoradiation?

Improving Outcomes

• Add chemotherapy to radiation

• Increase radiation dose

Increasing Radiation dose• External Beam ( 45 Gy /25# /35)

• EBRT +Boost ( 50.4Gy/28#/38)

• EBRT + Contact RT boost (60-80Gy)

• EBRT + Contact HDR boost

Papillon Technique

Radical contact radiotherapy

Lyon R96-02 Trial

Results EBRT EBRT+ boost

Clinical CR ( 2% ) (24%)Path CR/micro (34%) (57%)p=.027

Sphincter (44%) (76%)p=.004

JP Gerard et al. J Clin Oncol 2004 :22 2404-2409

Lyon R96-02 Trial

Results EBRT EBRT + Boost

L R 3% 1%Morbidity 43% 38%LR Survival 88% 92%

JP Gerard et al J Clin Oncol 2004 :22 2404-2409

HDR Rectal Brachytherapy

20mm

5mm

Pre op HDR Brachytherapy

Pathology• T0N0 29%

• Micro 37%

• Residual 34%

• N+ 31%

• T. Vuong et at. I.J. Rad Onc. Bio. Phys vol60:no1 supp; 2004 abst: 1062

Pre op HDR Brachytherapy

Results• Median FU 37months• 5years Local recurrence 3%

DFS 65% OS 74% CSS 84%

• Toxicity G3 1% (30% CRT)

T. Vuong et at. I.J. Rad Onc. Bio. Phys vol60:no1 supp; 2004 abst: 1062

Comparative tumor sterilization rate by treatment modality

TREATMENT pCR (pMic) RO

EBRT alone 7.1% (26%) 40%

CT+ EBRT 13% (31%) 60%

EBRT+contact 21% (60%) NA

HDR alone 29% (66%) 97%

CT+EBRT+

HDR boost

40%? (80%) 100?

Treatment Options

• Surgery T1/T2/T3 / N+

(clear CRM)

• Pre op chemo RT r CRM <1mm

(sphincter preservation)

• Post op chemo RT p CRM<1mm

(node +ive)

• Radical RT T1/T2/ N0

Conclusions-1

• All cases with rectal cancer should be discussed at the MDT

• MRI scan is essential for pre operative assessment

• Pre operative chemoradiotherapy offers better local control than pre operative radiotherapy alone

Conclusions-2

• Pre operative chemoradiotherapy is more effective and less toxic than post operative

chemoradiotherapy

• Nearly half the patients with rectal cancer will develop recurrences; however no DFS or overall survival benefit has been shown with adjuvant chemotherapy in any of the trials published so far.

It is important to contribute to clinical

trials

Chemoradiotherapy for Rectal cancer Dr. A. Sun Myint Lead Clinician GI Tumour Group Clatterbridge Centre for Oncology Association of Coloproctology of.

Documents

rectal cancersauer et

rectal cancerdr

asco 2005t3t4 rectal

n engl j med

fu chemoradiation

fubased chemoradiation

post op rt

german pre