Chemoradiotherapy for Rectal cancer Dr. A. Sun Myint Lead Clinician GI Tumour Group Clatterbridge Centre for Oncology Association of Coloproctology of Great Britain and Ireland M62 Coloproctology Course - March 23 rd 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 RadiotherapyPre operative Chemoradiotherapy Post operative ChemotherapyAdvance /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)

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 RTSURGERY Pre-op Chemo/RT SURGERY Pre-op RTSURGERY 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 Rectal cancer trial Pre-op RTSURGERY Ad Chemo Pre-op CRTSURGERY Ad Chemo JP Gerard et al ASCO 2005 T3/T4 rectal cancer n=733

FFCD Rectal cancer trial Pre-op Chemo/RT Pre-op RT Local recurrence 8.0% 16.5% JP Gerard et al ASCO 2005

FFCD 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 % 17.1% FFCD % 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 Post operative Chemo-RT Sauer et al N Engl J Med (2004) 351;

German pre op. vs. post operative chemoradiotherapy for rectal cancer Pre op n=405 Post op n=394 Local recurrence 6% 13% P= Survival 76% 74% P=0.08 Sauer et al N Engl J Med (2004) 351;

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;

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 RADIOTHERAPYRADIOTHERAPY

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-FU 1 1 O’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– 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 tumour 2 1 Miwa M et al. Eur J Cancer 1998;34:1274–81 2 Sawada N et al. Clin Cancer Res 1999;5:2948–53

Irradiation upregulates TP TP (units/mg protein) Days after X-ray irradiation * * * * * * * * * *p<0.05 5Gy 2.5Gy Control Sawada N et al. Clin Cancer Res 1999;5:2948–53

capecitabine enhances activity of radiation in WiDr xenografts, Tumour inhibition (%) * Sawada N et al. Clin Cancer Res 1999;5:2948–53 5Gy Xeloda Xeloda + 5Gy 5-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 age65 years ECOG 0/1 (%)54 / 41 T3 / T4 (%)48 / 52 (57% N1–3) Day Gy radiotherapy 1.8Gy / fraction 825mg/m 2 twice daily Continuous (days 1–37) Dunst J et al. Proc Am Soc Clin Oncol 2003;22:277 (Abst 1113)

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

Patients (%) DiarrhoeaLocalPain Hand-footNausea erythemasyndrome 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 events

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*) SURGERYSURGERY 5-FU continuous infusion throughout radiotherapy (50.4Gy*) Objectives –DFS –recurrence rate –pCR –safety

Chemoradiation using Oxaliplatin combination

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

CORE: European study Radiotherapy 45Gy / 25 fractions capecitabine 825mg/m 2 twice daily Monday to Friday Oxaliplatin 50mg/m 2 weekly Day  CORE: Capecitabine, Oxaliplatin, Radiotherapy and Excision

Chemoradiotherapy using Irinotecan combination

RICE - NWCCOG study Radiotherapy 45Gy / 25 fractions capecitabine 825mg/m 2 twice daily Monday to Friday IRINOTECAN 60mg/m2 weekly Day 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 RADIOTHERAPYRADIOTHERAPY ARISTOTLE

Reducing Toxicity from CRT

Toxicity Chemoradiotherapy is more toxic than radiotherapy alone To reduce toxicity:- Preoperative rather than post op Radiation volume Dose, fractionation and time Radiation 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 :

Lyon R96-02 Trial Results EBRT EBRT + Boost L R 3% 1% Morbidity43%38% LR Survival88%92% JP Gerard et al J Clin Oncol 2004 :

HDR Rectal Brachytherapy

20mm 5mm

Pre op HDR Brachytherapy Pathology T0N029% Micro37% Residual34% 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 SurgeryT1/T2/T3 / N+ (clear CRM) Pre op chemo RTr CRM <1mm (sphincter preservation) Post op chemo RTp CRM<1mm (node +ive) Radical RTT1/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