chemoradiotherapy for rectal cancer

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

Preoperative Radiotherapy

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

• Long course - Fixed / Tethered tumour

30%( MRI defined CRM +)

Preoperative Radiotherapy

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

EORTC Rectal cancer trial

Pre-op

Chemo/RT

Pre-op RT

Local recurrence

8.7% 17%

(p=0.0016)

Bossett al ASCO 2005

EORTC Rectal cancer trial

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

FFCD 9203- Rectal cancer trial

Pre-op

Chemo/RT

Pre-op RT

Local recurrence

8.0% 16.5%

JP Gerard et al ASCO 2005

FFCD 9203- Rectal cancer trial

Adjuvant

Chemo

No Adjuvant

Chemo

Survival 67% 66%

JP Gerard et al ASCO 2005

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

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

Pre op

n=405

Post op

n=394

Local recurrence

6% 13% P=0.0006

Survival 76% 74% P=0.08

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

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

Pre op

n=405

Post op

n=394

Acute

Toxicity

27% 40%

P=0.001

Late

Toxicity

14% 24% P=0.01

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

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