RAPIDORectal cancer And Preoperative Induction therapy followed by Dedicated Operation

Lars Påhlman

Dept. Surgery, Colorectal unit,

University Hospital, Uppsala, Sweden

Rectal cancer treatmentMRI staging

Stage Irradiation

Good; No

Bad; 5 x 5 Gy

Ugly; Chemo-rad or 5 x 5 ?

Advanced Rectal CancerProblems !

Local recurrences solved ! Occult metastases the problem ! Survival not improved Chemo-rad. standard of care Chemotherapy too weak !

Advanced Rectal CancerStandard of care

Chemorad. 5 weeks Time to surgery 8 weeks Recovery after surgery; 4 weeks In total > 4 months until patients

receive decent chemotherapy !!

Neoadjuvant; Rectal cancer

The RAPIDO trial

Standard of care arm:

Chemorad. Surgery Chemo 4 m

Experimental arm:

5x5 Gy Chemo 5 m Surgery

The RAPIDO trialInclusion criteria

Biopsy proven rectal cancer Staging 5 weeks prior treatment No contra indication to chemotherapy ECOG performance < 1 Written informed consent 18 years Adequate for follow up

The RAPIDO trialInclusion criteria

Good quality MRI (T 3 c/d), T4 a/b EMVI + N2 N+ (outside the fascia plane) MRF +

The RAPIDO trialAt leased one of the criteria's

T4 overgrowth to adjacent organs T4b peritoneal involvement EMVI + vascular invasion N2 > 4 nodes which looks abnormal N+ lateral nodes > 1 cm MRF + threatened mesorectal fascia

The RAPIDO trialEndpoints

DFS at 3 years (Main endpoint) 880 patients (DFS 50 60 %) Toxicity + postop. complications pCR OS, Local recurrence rate QoL

The RAPIDO trialExperimental arm previous experience

Dutch M 1 Study

50 patients M1 (75% T3/4N+)5x5 Gy + XELOX + Bevacizumab (6 cycles) + surgery

83% received all chemo (90% >4 cycles)Low/acceptable toxicity

pCR in 26% of specimens‘No progression was seen on chemotherapy’

van Dijk et al. JCO 2009: p. ASCO GI 2010. Abstract 427

The RAPIDO trialExperimental armWhat are we treating ?

Local tumour Systemicgrowth disease

Surgery Radioth. Chemoth.

The RAPIDO trial

Possible concerns

Surgery difficult after > 20 weeks

Progressive disease during the delay

Local recurrence rateTrial / level Local recurrence

RT - RT + p value

SRCT < 5 cm 27 % 10 % 0.003TME < 5 cm 11 % 12 % 0.53CRO 7 < 5 cm 11 % 5 % < 0.001

SRCT 6 - 10 cm 26 % 9 % < 0.001TME 6 - 10 cm 15 % 4 % < 0.001CRO 7 6 - 10 cm 10 % 5 % < 0.001

SRCT > 10 cm 12 % 8 % 0.3TME > 10 cm 6 % 4 % 0.15CRO 7 > 10 cm 6 % 1 % < 0.001

Swedish Rectal Cancer Registry %

10

Dutch TME - trial Overall survival; eligible patients (n=1809)

Years since surgery

86420

Cu

m S

urv

iva

l

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

64.2% vs 63.4% p = 0.87

TME alone

RT + TME

CRO7 - Overall survivalAll patients

Years

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5

Preop. RT

Postop. RT p = 0.07

%

Polish trial

Trial design

Preop. chemorad. 25 x 2 Gy

Preop. radiotherapy 5 x 5 Gy

Randomisation

Local

Recurr

Survival

Sphincter

preserv

Polish Trial Local Recurrences

Years

54321

20

15

10

5

Chemo-radiation

5 x 5 Gy

p = 0.23

16%

11%

Polish Trial - Overall Survival eligible patients (n=312)

p = 0.82

Years

543210

100

80

60

40

20

0,0

chemoradiation

5 x 5 Gy

Short - course radiotherapyStill an important option

Better than chemo-rad. ? Polish trial ! Australian trial ? Stockholm III !!!!

Stockholm III TrialOngoing trial in Sweden

3-armed trial

25 Gy / 1 week immediate surgery

25 Gy / 1 week delayed surgery

50 Gy / 5 weeks delayed surgery

Non-resectable rectal cancer

Non-resectable rectal cancer

Advanced Rectal CancerConclusion with 5x5 Gy

Delayed surgery is feasible Delayed surgery gives down –

sizing / staging ! Delayed surgery will not

increase complication rates