Dept. Surgery, Colorectal unit, University Hospital, Uppsala, Sweden RAPIDO Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation Lars Påhlman Dept. Surgery, Colorectal unit, University Hospital, Uppsala, Sweden

Rectal cancer treatment MRI staging Stage Irradiation Good; No Bad; 5 x 5 Gy Ugly; Chemo-rad or 5 x 5 ?

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

Advanced Rectal Cancer Standard 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 trial Inclusion 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 trial Inclusion criteria Good quality MRI (T 3 c/d), T4 a/b EMVI + N2 N+ (outside the fascia plane) MRF +

At leased one of the criteria's The RAPIDO trial At 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 trial Endpoints DFS at 3 years (Main endpoint) 880 patients (DFS 50 60 %) Toxicity + postop. complications pCR OS, Local recurrence rate QoL

Experimental arm previous experience The RAPIDO trial Experimental 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 trial Experimental arm What are we treating ? Local tumour Systemic growth disease Surgery Radioth. Chemoth.

Possible concerns The RAPIDO trial Surgery difficult after > 20 weeks Progressive disease during the delay

Local recurrence rate Trial / level Local recurrence RT - RT + p value SRCT < 5 cm 27 % 10 % 0.003 TME < 5 cm 11 % 12 % 0.53 CRO 7 < 5 cm 11 % 5 % < 0.001 SRCT 6 - 10 cm 26 % 9 % < 0.001 TME 6 - 10 cm 15 % 4 % < 0.001 CRO 7 6 - 10 cm 10 % 5 % < 0.001 SRCT > 10 cm 12 % 8 % 0.3 TME > 10 cm 6 % 4 % 0.15 CRO 7 > 10 cm 6 % 1 % < 0.001

Swedish Rectal Cancer Registry

Dutch TME - trial Overall survival; eligible patients (n=1809) TME alone 64.2% vs 63.4% p = 0.87 RT + TME

CRO7 - Overall survival All patients % 100 90 80 70 60 50 Preop. RT Postop. RT 40 p = 0.07 30 20 10 1 2 3 4 5 Years

Polish trial Trial design Preop. chemorad. 25 x 2 Gy Preop. radiotherapy 5 x 5 Gy R a n d o m i s t L o c a l R e u r S u r v i a l S p h i n c t e r s v

Polish Trial Local Recurrences 20 Chemo-radiation 15 16% 10 5 x 5 Gy 11% 5 p = 0.23 1 2 3 4 5 Years

Polish Trial - Overall Survival eligible patients (n=312) Years 5 4 3 2 1 100 80 60 40 20 0,0 chemoradiation 5 x 5 Gy p = 0.82

Short - course radiotherapy Still an important option Better than chemo-rad. ? Polish trial ! Australian trial ? Stockholm III !!!!

Ongoing trial in Sweden Stockholm III Trial Ongoing 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 Cancer Conclusion with 5x5 Gy Delayed surgery is feasible Delayed surgery gives down –sizing / staging ! Delayed surgery will not increase complication rates