Neoadjuvant therapy are we doing it right? Short course and chemoradiation Rob Glynne-Jones Mount Vernon Cancer Centre
Relevant Endpoints in rectal cancer Local recurrence Disease-free survival Overall survival Sphincter sparing Late effects (function/infertility/2 nd malignancies)
Tailored Treatment according to Risk (low/inter/high) for Local Recurrence The Good Surgery alone The Bad (Nodes/EMVI etc) 5x5 Gy / long course CRT The Ugly (Involved margin clinically or at imaging) long course CRT
Risk of local recurrence for rectal tumours as predicted by MRI Characteristics of rectal tumours predicted by MRI High Moderate a threatened (<1 mm) or breached resection margin or low tumours encroaching onto the inter-sphincteric plane or with levator involvement any ct3b or greater, in which the potential surgical margin is not threatened or any suspicious lymph node not threatening the surgical resection margin or the presence of extramural vascular invasion
Questions How many with SCPRT and immediate surgery?
Do you treat? Low risk Dukes B colon cancer patients with adjuvant chemo? High Risk Dukes C colon cancer with adjuvant chemo? What is an acceptable local recurrence rate?
Questions What is an acceptable local recurrence rate?
Bearing in mind toxicity What is an acceptable local recurrence rate at 5 years for resectable cancers? 0-4.9% 5-9.9% 10-14.9% 15% +
In decisions re SCPRT/CRT So does the risk of local recurrence trump everything else?
So? What is an acceptable local recurrence rate? What is an acceptable metastases rate?
Evidence for low rectal cancer All subset analysis 50% of patients ineortc 22921 and FFCD 9203 within 5cm 33% of patients in CR07 within 5cm
Risk factors for adverse outcome with APER (den Dulk 2007) Age T stage N stage CRM Distance from anal margin Tumour location (women with anterior tumours do worst)
Rectal cancer LOW RISK INTERMEDIATE RISK (BAD) HIGH RISK Low risk local recurrence/ Low risk metastases GOOD Clinical factors Low risk local recurrence/ moderate risk metastases Define by MRI Moderate risk of local recurrence / high risk metastases High risk of local recurrence / higher risk metastases Obesity Male /with anterior tumours Narrow pelvis Previous pelvic surgery Large bulky tumour/circumferential tumour High risk local recurrence/ High risk metastases UGLY
Rectal cancer requiring Anterior Resection Low risk local recurrence/ moderate risk metastases MRI ct3b >4mm extension into muscularis propria CRM not threatened (predicted >2mm) cn1, CT M0 INTERMEDIATE RISK Moderate risk of local recurrence/ high risk metastases MRI ct3b >4mm ct3c, cn2, V2 CRM not threatened (predicted >2mm) CT M0 High risk of local recurrence/ high risk metastases MRI ct3d, T4a (resectable) V2 CRM not threatened (predicted >2mm) CT M0 Obesity Male /with anterior tumours Narrow pelvis Previous pelvic surgery Large bulky tumour/circumferential tumour
The problem TNM doesnt work for low rectal cancer (size) T2/T4 It is more difficult to predict levator involvement MRI is more critical 15% LPLN for low tumours
Chemoradiation Short course
What can SCPRT CRT Do for us here?
SCPRT Reduces local recurrence Quick enables you get on with systemic therapy Does compensate a bit for + crm (Cheap) Late effects 2 nd malignancies
SCPRT reduces local recurrence Stockholm II Swedish Rectal Cancer Trial Dutch TME trial CR07
Polish study Bujko et al 20 15 chemoradiation Rate of Local Recurrence (%) 10 5 0,00 P=0.23 5 x 5 Gy Actuarial 4-year was 11% SCPRT- and 16% in the CTRT group, p=0.29, DFS and OS the same 0 1 2 3 4 5 Years
TROG results ASCO 2010 T3NxMo within 12 cm 50.4Gy + 225mg/m2 5FU vs 25Gy/5/5 326 patients (163 in each arm) Local rec 7.5% (SC) vs 4.4% (CRT) p=0.24 Distant DFS 72% vs 69% p=0.85 OS 74% vs 70% p=0.56 Late G3/G4 7.6% vs 8.8% p=0.84 Tox Ngan S et al., ASCO 2010
Percentage patients with CRM +ve by year CR07 25 20 70 177 Change in margin rate over time - 11% overall Percentage 15 10 205 175 200 195 166 63 5 0 1998 1999 2000 2001 2002 2003 2004 2005 Year
CR07 Development impact Programme of SCPRT
CR07 CRM LR when CRM not involved SCPRT Post-op Selective (No RT) 3.3% 8.9%
CR-07 Quality of surgery-3 year LR rates Quality of Surgery Muscular propr plane Intramesorectal plane Mesorectal plane SCPRT Selective postop CRT 10% 16%? 4% 10%? 1.3% 7% N/A Patients with MRI excluded
CR-07 Distance from anal verge 3 year LR rates Distance SCPRT Selective postop CRT >10-15 1.2% 6.2%? Patients with MRI excluded >5-10 5% 10%? 0-5cm 5% 10%?
Chemoradiation using 45-50.4Gy CRT (45-50.4Gy) is not a curative dose (except in 10-15% of cases) 45-50Gy is a microscopic dose deals with at most 30% of microscopically involved nodes 15-20% of macroscopically involved nodes
CRT Reduces local recurrence Time consuming -20 weeks to surgery you dont get on with systemic therapy Does compensate a bit for + crm (more expensive) Late effects? The same 2 nd malignancies??? The same
STOCKHOLM III Resectable Rectal AdenoCa 303 R A N D O M I S E 25 Gy in 5 F 25 Gy in 5 F 50 Gy in 25 F Surgery Surgery (delayed) Surgery (delayed) Primary endpoint: sphincter preservation rate Pettersson et al BJS 2010 Epub
Stockholm III nodal down-staging Schedule 5x 5Gy immediate surgery 5x 5Gy 6 weeks to surgery 50Gy/25# /33days and 6 weeks to surgery Node + 31% 21% 28% Ie 1/3 of patients with node positive downstaged by 5 x 5 Gy and wait
Rectal Cancer Observations Local recurrence in current trials 6-8% Even lower in good quality TME/APER Loc Rec can be reduced by SCPRT or CRT Can salvage 33% with surgery if no RT What about the 96% who don t need RT??
Node + rate in randomised Trials of Monthly 5FU/LV Chemoradiation n stage RT (Gy) CT Control % preop, % AIO/ARO 312 T3/circ/teth 50.4 FU CI 40 25 FFCD EORTC Polish Study 157 T3-4 50 FU+LV 48 32 NSABP R03 123 T3-4 50.4 FU+LV 48 33
EORTC 22921 and FFCD 9203 node positivity EORTC/FFCD RT alone CRT % reduction Combined ypn + Presumed original nodes positive Presumednode negative 307/847 (36.2%) 45.5% 45.5% 54.5% 54.5% % Reduction 20% 33% 254/839 (30.3%) 16.3%
LOREC Extramural vascular invasion Primary tumour
CRT reduces local recurrence (over RT alone and postop RT) EORTC 22921 FFCD German Trial
5FU CRT Delays active systemic chemotherapy 4-6 months Allows micrometastases to thrive and be nurtured by VEGF
Pre- vs post-operative chemoradiation CAO/ARO/AIO-94 0.3 0.2 Locoregional Recurrences P=0.006 Acute G3/4 adverse events 27% vs 40% (p=0.001) 0.1 0.0 Post Pre 0 12 24 36 48 60 Months 13% 6% Long-term G3/4 adverse events 14% vs 24% (p=0.01) Sauer R. et al., N Engl J Med 2004;351: 1731-39
Facilitates R0 resection if CRM threatened Polish study resectable (Bujko 2004) 13% to 4% Braendengen 2008 -unresectable 16% to 8% with CRT vs RT No brainer that you need CRT if you need shrinkage/response (rather than RT alone or SCPRT)
The big Problem Chemoradiation does not improve survival
Pre- vs post-operative chemoradiation CAO/ARO/AIO-94
FFCD Trial
EORTC 22921-1011 patients
Overall Survival CR07 LOREC
Long-term outcome the same
QUASAR: survival in stage II patients 100 80 60 Survival (%) 40 20 Deaths Chemotherapy (n=1622) 224 No chemotherapy (n=1617) 262 p=0.04 0 0 1 2 3 4 5 6 7 8 9 10 Time (years)
Node + rate in randomised Trials of Monthly 5FU/LV Chemoradiation n stage RT (Gy) CT Control % preop, % AIO/ARO 312 T3/circ/teth 50.4 FU CI 40 25 FFCD 375 N/A 32 EORTC 506 N/A 25 Polish Study 157 T3-4 50 FU+LV 48 32 NSABP R03 123 T3-4 50.4 FU+LV 48 33
Results of the CRT Trials (Preop Chemoradiation arm) EORTC 22921 FFCD Polish AIO Sauer NSABP R03 TROG PCR 13.7% 11.7% 16% 8% 16% No data Loc Rec 8.7% 8% 16% 6% 5% 4% DFS 56% No data 56% at 4yrs No data 64% No data OS 66% 67% 66% 74% 74% 70% CT postop 67% 52% 30% 50% No data No data
This data Suggests that in the trials 50-60% were actually cn0 EORTC 22921-9 versus 7 nodes Polish -9 versus 8 Compliance to postoperative adjuvant chemotherapy approx 50%
In decisions re SCPRT/CRT So does the risk of local recurrence trump everything else?
In LARC Local recurrence has No impact on survival pcr, ypt0 or local control do not represent a clinical benefit on their own they should not be the final endpoint of phase III clinical trials should be regarded as biomarkers.
Overall Survival Braendengen M et al., JCO 2008
Evidence Base Meta-analysis Bujko 2006 No evidence preop RT/CTRT achieves sphincter sparing surgery Cochrane Review Wong 2007 No evidence preop RT/CTRT achieves sphincter sparing surgery
Decisions re AR vs APER Not just cm between tumour and sphincter Other clinical factors So Selection of favourable tumours for AR with short margins Unfavourable tumours for APER with long margins
Sphincter sparing Surgery Sauer 2004 NEJM NB Zelen randomisation
Morbidity Sphincter and bowel function Urinary incontinence Sexual problems men and women Insufficiency fractures 100% infertility
2nd Malignancies SCPRT doubles the risk of 2 nd malignancies 5-10 years after SCPRT 9.5% versus 4.3% (Birgisson 2005) Seer Data more reassuring but non randomised. only a statistically significant increase risk of second cancers in the lung, bladder, uterus and cervix (Kendal 2007).
DUTCH TME study SCPRT increases deaths from second malignancy (13.7% versus 9.4%) at 11 years. So... think of the age of the patient?
What do we need to know? Where is the tumour? APER or Ant resection? MRI predicted CRM? Can you produce a specimen in a mesorectal plane?
Conclusions 1. 5FU-based CRT more effective (downsizing) than RT but no improvement in OS 2. SCPRT = CRT in resectable mid rectal cancer 3. Radiotherapy (SCPRT or CRT) is a locoregional treatment without effect on systemic disease 4. We need to consider surgical morbidity, late effects and 2 nd cancers in our decisions 5. Do we need to rethink need for CRT for upper rectal cancer and patients for APER? 6. We need better systemic treatments
Valentini et al.,nomograms for Predicting Local Recurrence, Distant Metastases, and Overall Survival J Clin Oncol 2011;29:3163-3172
LOREC The End
Polish study (Bujko 2006) 25Gy/5/5 vs 50.4Gy + FUFA 312 patients Acute G3/G4 3.2% vs 18.2% Late G3/G4 10.1% vs 7.1% p=0.36 Toxicity SCPRT CRT Ngan S et al., ASCO 2010
TROG results ASCO 2010 T3NxMo within 12 cm 50.4Gy + 225mg/m2 5FU vs 25Gy/5/5 326 patients (163 in each arm) Late G3/G4 7.6% vs 8.8% p=0.84 Toxicity SCPRT CRT Ngan S et al., ASCO 2010
Polish Study (Bujko 2005) 316 25Gy/5F pre-op 50.4Gy /FUFA CTRT preop SS Surgery 61% SS Surgery 58% P= 0.57
NSABP R03 Study (Roh 2009) 267 NACT + 50.4Gy /FUFA CTRT preop 50.4Gy /FUFA CTRT post-op SS Surgery 48% SS Surgery 39% P= 0.227
STOCKHOLM III Resectable Rectal AdenoCa 303 R A N D O M I S E 25 Gy in 5 F 25 Gy in 5 F 50 Gy in 25 F Surgery Surgery (delayed) Surgery (delayed) Primary endpoint: sphincter preservation rate Pettersson et al BJS 2010 Epub
pcr after 25Gy/5# Stockholm III SCPRT and wait 6 weeks pcr = 12%
The UGLY ones!
Dutch TME at 6 years ANNals of Surgery
Surgical Approaches: APR versus AR Abdominoperineal resection (APR) Used for tumors of the lower 3 rd of the rectum Necessary when marginnegative tumor resection will result in loss of anal sphincter function En bloc removal of the rectosigmoidcolon, rectum, & anus + surrounding mesentery, mesorectum, and perianal soft tissue Colostomy required Anterior Resection of the Rectum (AR) Used for tumors of the proximal 2/3 of the rectum Preserves the lower portion of the rectum & the anus Allows for normal anal sphincter function Associated lymph nodes are removed Temporary colostomy may be necessary if adjuvant chemotherapy given
What the MDT needs to know Extent of tumour (site and length) Depth of extramural spread T3a,T3b,T3c etc.. EMVI (V2) Proximity to mesorectal fascia and levators (of the primary or mesorectal deposits) Gross Lymph node involvement (within and outside mesorectum) Distant metastases Distance from anal sphincter/height of tumour
Low risk local recurrence/ moderate risk metastases MRI ct3b >4mm extension into muscularis propria CRM not threatened (predicted >2mm) cn1, CT M0 No chemotherapy required Rectal cancer requiring Anterior Resection INTERMEDIATE RISK Moderate risk of High risk of local local recurrence/ recurrence/ higher high risk metastases risk metastases MRI ct3b >4mm ct3c, cn2, V2 CRM not threatened (predicted >2mm) CT M0 FUTURE THOUGHTS? better treated with neoadjuvant chemotherapy alone up front without RT (NACT) MRI ct3d, T4a (resectable) V2 CRM not threatened (predicted >2mm) CT M0? better treated with SCPRT and chemotherapy (RAPIDO) or postop adjuvant Single agent 5FU ineffective May require FOLFOX/XELOX preo/post-op adjuvant
Rectal cancer requiring Anterior Resection LOREC LOW RISK INTERMEDIATE RISK HIGH RISK Low risk local recurrence/low risk metastases Low risk local recurrence/moderate risk metastases Moderate risk of local recurrence/ high risk metastases High risk of local recurrence/ high risk metastases High risk local recurrence/high risk metastases MRI ct2/t3a/t3b <4mm extension into muscularis propria CRM not threatened (predicted >2mm) CT M0 MRI ct3b >4mm extension into muscularis propria CRM not threatened (predicted >2mm) cn1, CT M0 MRI ct3b >4mm ct3c, cn2, V2 CRM not threatened (predicted >2mm) CT M0 MRI ct3d, T4a (resectable) CRM not threatened (predicted >2mm) CT M0 MRI ctany extension into muscularis propria, T4b CRM breached or threatened (predicted <1mm) CT M0? Mucinous Clinical factors Obesity Female>Male /with anterior tumours Narrow pelvis Previous pelvic surgery Large bulky tumour
Quirke et al 2009 CR07