radiotherapy for rectal cancer -...

Karin HaustermansDepartment of Radiation Oncology

Radiotherapy for rectal cancer

• RT with TME surgery?

• Neoadjuvant or adjuvant RT?

• 5 x 5 Gy or long-course CRT?

• RT with new drugs?

•Selection of patients?

OU T L I N E

Swedish Rectal Cancer TrialPreop RT Surgery P - value

Local Failure 12 % 27 % < 0.001

5-Yr Survival 58 % 48 % 0.04

NEJM, 1997

TME-Trial: RT+TME vs. TME

Local Failure at 5 years:

RT+TME: 5.6% TME: 10.9% p < 0.001

Kapiteijn E et al.,N Engl J Med 2001;345: 638-46 Peeters K et al., Ann Surg 2007;246:693-701

Influence of CRM on LR

Preop RT (%)

Surgery (%) P-value

CRM ≤ 2 mm 15.5 23.3 NS

CRM > 2 mm 3.6 8.5 <0.001

CRM > 10 mm 1.1 1.1 NS

Late toxicity Dutch Trial• Faecal incontinence

– 39% in non-irradiated patients vs 62 % in irradiated patients (p<0.001)

• Sexual activity in male patients – 66% in non-irradiated patients vs 57 % in

irradiated patients (p=0.05) • Sexual activity in female patients

– 53% in non-irradiated patients vs 39 % in irradiated patients (p=0.02)

• No differences in QoL

Trial Design

Randomise

Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases

Adjuvant chemotherapy given as per local policy

PRE POST

Pre-operative RT 25Gy / 5F

Surgery

Pathology

Surgery

Pathology

CRM-ve CRM+ve

Post-op CRT 45Gy / 25F

+ concurrent 5FU

No RT

LR by treatment (ITT)

Number at risk

Pre 674 501 365 247 156 76

Post 676 511 363 246 141 55

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5Time(Years)

LR rate (%)

N Events 3yr LR 5yr LR PRE 674 23 5% 5% POST 676 61 11% 17%

HR(95%CI)=2.47(1.61, 3.79) p<0.0001

DFS by treatment (ITT)

Time(Years) 0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5

Pre 674 475 337 230 147 70

Post 676 482 326 231 129 50

DFS rate (%)

N Events 3yr DFS 5yr DFS PRE 674 112 80% 75% POST 676 146 75% 67%

HR(95%CI)=1.31 (1.02, 1.67) p=0.03

• RT with TME surgery? YES! But some subgroups may not benefit

• Neoadjuvant or adjuvant RT?



• Selection of patients?

0 2 4 6 8 10 12 14 16 18 20 22 Weeks

OP

5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 120h-infusion 120h-infusion

RT: 50.4 Gy

Arm II:

5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 500 mg/m2/d 120h-infusion 120h-infusion i.v.-bolus

RT: 50.4 + 5.4 Gy Boost

Arm I:

5-FU 5-FU 5-FU 5-FU 500 mg/m2/d I.v.bolus

OP

Sauer R et al., N Engl J Med 2004; 351:1731-40

CAO/ARO/AIO-94

0.3

0.2

0.0

0.1

0 2412 4836 60

p = 0.006

6%

Months

Cum

ulat

ive

Inci

denc

e

Preop. RCT

Postop. CRT 13%

Local Relapse

Preop CRT: + • Downstaging • Compliance • Local control • Toxicity • Sphincter


Pre vs. Postop. RCT: CAO/ARO/AIO-94

Postop. CRT CAO/ARO/AIO-94 UICC- I 18 %

UICC-II 29 %

UICC-III 40 %

UICC-IV 7 %

Missing 6 %

MSMMP

Risk of “Overtreatment”

Pathological Stage



• Neoadjuvant or adjuvant RT? Neoadjuvant! But need for improved staging (MRI)




RT

RTCT

Polish trial

Bujko et al, Radiother Oncol 2004

316 pts

surgery

5x5 Gy 50.4 Gy + CT P n=148 n=138

Sphincter- preserved 61% 58% 0.57

T-Category ypT0 1% 16% <0.001 ypT1 2% 9% ypT2 37% 37% ypT3-4 60% 38% N-Category ypN0 52% 68% 0.007 ypN1 48% 32%

CRM + 13% 4% 0.017 Bujko et al. Radiother Oncol 2004;72:15-24

Preoperative 5x5 Gy

Preoperative RCT

Bujko et al., Br J Surg 2006;93:1215-23

p=0.8

p=0.17

9.0%

14.2%

Preoperative 5x5 Gy

Preoperative RCT

An intergroup trial (TROG, AGITG, CSSANZ, RACS)

T3NxM0 5 x 5 Gy 5-FU CRT P-value

Number of pts. 163 163

3-year LR rates 7.5% 4.4% 0.24

5-year M1 28% 31% 0.85

5-year OS 74% 70% 0.56

RTOG 3-4 late tox 7.6% 8.8% 0.84

Ngan et al., JCO 2012

For distal tumors (< 5 cm), six of 48 SC patients and one of 31 LC patients experienced local recurrence

Preoperative R(C)T

Preoperative 5x5Gy

(+) Biologic effective dose

Combination with CT

Downsizing

Acute toxicity

Late toxicity

Compliance

Costs

++

(+)(+)++



• 5 x 5 Gy or long-course CRT? Risk-adapted! If downsizing required: CRT or wait



RANDOMIZE

Pre-op RT Pre-op RT + 5FU/LV x2

Pre-op RT Pre-op RT + 5FU/LV x2

Surgery Surgery Surgery Surgery

Post-op 5FU/LV x4

Post-op 5FU/LV x4

Rectal cancer T3/T4 NX M0 (UICC 1987) by DRE or EUSConsidered resectable, WHO PS 0-1, Age ≤ 80 y

Accrual : 1011 patients April 1993 - April 2003

Bosset et al, Lancet Oncology 2014

DFS

OS

Oxaliplatin

STAR-01 ACCORD 12 CAO/ARO/AIO-04

NSABP-R-04 PETACC-6

year of randomisation

11/2003-08/2008

11/2005-7/2008

7/2006-2/2010

7/2004-8/2010

11/2008-09/2011

number of patients

747 598 1265 1608 1094

preoperative regimen

50,4 Gy + fluorouracil

225mg/m² (CI)vs.


225mg/m² (CI) + OX 60mg/m²

weekly

45 Gy + CAPb.i.d. 800mg/m²

vs.50 Gy + CAP

b.i.d. 800mg/m²+ OX 50mg/m²

weekly


1000mg/m² d1-d5, d29-d33

vs.50,4 Gy +

fluorouracil 250mg/m² d1-d14, d22-d35 + OX 50mg/m² d1,8,22,29

45 Gy + 5,4-10,8Gy + fluorouracil

225mg/m² (CI) or CAP 825mg/m²

b.i.d.vs.

45 Gy + 5,4-10,8Gy + fluorouracil

225mg/m² (CI) or CAP 825mg/m²

b.i.d. + OX 50mg/m² weekly

45 Gy + optional boost 5,4 Gy +

CAP b.i.d. 825mg/m²

vs.45 Gy + optional boost 5,4 Gy +

CAP b.i.d. 825mg/m²

+ OX 50mg/m² d1,8,15,22,29

cumulative dose OX preop

360 mg/m² 250mg/m² 200mg/m² 250mg/m² 250mg/m²

primary endpoint OS pCR DFS pCR, sphincter saving surgery,

downstaging

DFS

STAR-01 ACCORD 12 CAO/ARO/AIO-04

NSABP-R-04 PETACC-6

G3-4 preop toxicity

8% vs. 24% (p<0,001)

10.9% vs. 25.4% (p<0,001)

20% vs. 23%

6,6% vs. 15,4% (p<0,0001)

15,1% vs. 36,7%

surgical toxicities

80% vs. 83% 20.9% vs. 18.1% 44% vs. 47%

NA 38% vs. 41%

full dose RT 92% vs. 84% 100% vs. 87% 96% vs. 94%

NA 97% vs. 94%

Dose modification CT

90% vs. 80% received ≥ 80% of fluorouracil and 66% received all OX cycles

50% vs. 59%

21% vs. 15%

From 84% to 97% of pts received >80% of the ideal CT dose

91% vs. 63% received <90%

Toxicity data of randomized trials with oxaliplatin

Gerard et al, JCO 2012

ACCORD 12

(years)

0 1 2 3 4 5 6

0

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60

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90

100

O N Number of patients at risk : Treatment arm124 547 468 347 129 24 0121 547 430 322 131 22 1

Cape+RTCape+Oxali+RT

Disease-‐free survival: primary analysis (ITT) follow up 31 months (2.6-‐5.6 years)

Cox model adjusted for stratification factors (except center) HR = 1.04 (0.81-‐1.33) P = 0.78 3-‐year DFS: 74.5% Cape 73.9% Cape+Oxali

Giralt J. et al., Radiother Oncol 2005;74:101-8

Rectal Cancer: Rationale to combine CRT with EGFR-Inhibition:

EGFR - EGFR +

pCR: 8/35 pCR: 2/52 29% 4% p=0.006

N Preoperative Regimen pCR

FFCD 762 RT RT/5FU

3.7% 11.7%

EORTC 1011 RT RT/5FU

5% 11%

Bertolini et al. 40 RT/5-FU/Cetuximab 8%

Horisberger et al. 50 RT/irinotecan/capecitabine/cetuximab 8%

Machiels et al. 35 37

RT/5-FU RT/Cetuximab/Capecitabine

11% 5%

Rodel et al. 103 60

RT/capecitabine/oxaliplatin RT/capecitabine/oxaliplatin + cetuximab

16% 9%

RCT: mean pCR= 12% RCT+ cetuximab: mean pCR= 7.5%

Molecular mechanisms?

Biomarkers?

Pooled pCR = 22%

SELECTION!

RAPIDO trial

• Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation trial

• Randomized multicentre Phase III study

Pts with primary high risk rectal cancer N = 885

Arm A = control ! Long course chemo-RT (5 weeks) àSurgery à(adjuvant chemo)

Arm B = exp ! 5 x 5Gy ! 6 cycles of capecitabine + oxaliplatin àSurgery

Brachytherapy

• Danish Colorectal Cancer Group• Dose-escalation randomized phase III trial

Jakobsen et al. IJROBP 2012

Pts with resectable T3 and T4 tumours; CRM ≤ 5mm on MRI

Standard CRT (50,4 Gy in 28 fx) N = 123 (T3: 102; T4: 21)

Standard CRT + HDR brachy boost (10 Gy in 2 fx) N = 120 (T3: 102; T4: 18)

Endorectal BT as boost

Brachytherapy

Jakobsen et al. IJROBP 2012

TRG 1 and 2

Post-op complications

Grade 3 toxicity

T3 tumours

• Higher radiation dose increases the rate of major response (TRG1-2) by 50% in T3 tumours

• Endorectal boost is feasible, with no significant increase in toxicity or surgical complications




• RT with new drugs? Scheduling and intensification requires further study


Selection of patients!

Quality of surgery: definitions

Complete mesorectum:

No defect deeper than 5 mm Smooth circumferential margin

Quality of surgery: definitions

Incomplete mesorectum:

Defects down onto muscularis Irregular circumferential margin

0

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90

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5Time (years)

LR r

ate

(%

)LR by plane of surgery

Events N 3yr LR 5yr LR Mesorectal plane 22 596 4% 8% Intramesorectal plane 22 382 8% 9% Muscularis propria plane 16 141 15% 21%

p=0.0019

Fokas et al, JCO 2014

Organ preservation

Organ preservation is appealing…

• Avoidance of • significant postoperative mortality and morbidity• long-term urinary, sexual, and fecal dysfunction• temporary or definitive stoma

• Increasing quality of life

… and oncological outcome seems good…

Maas et al, JCO 2011

Watch-and-wait outcome

Habr-Gama et al, Ann Surg 2004

DFSOS

Habr-Gama series Resectable cancer, <7cm from anal vergecCR + observation (n=71) vs. pCR (n=22)

5y OS 100% vs. 88% 5y OS 92% vs. 83%

Stage 0 has excellent prognosis, irrespective of treatment strategy




• RT with new drugs? Scheduling and intensification requires further study

• Selection of patients? YES! Before and during …

SU M M A R Y

Thank you!

radiotherapy for rectal cancer -...

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