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The Best Way to Treat Locally Advanced Rectal Cancer
Mohamed Abdulla MDProf of Clinical Oncology
Cairo University
Colorectal Cancer Master ClassApril 15 ndash 16 Istanbul Turkey
Member of Advisory Board Consultant and Speaker forbull Amgen Astellas AstraZeneca Hoffman la Roche Janssen Cilag
Merck Serono Novartis Pfizer Mundipharmabull The content of this presentation does not relate to any product of a
commercial interest
Speaker Disclosures
Basic Facts
bull 2nd amp 3rd most common cancer in females amp malesbull 14 million new case and 694000 deathsbull Males gt Femalesbull Lowest rates in Africa amp South Central Asiabull Low SES 30 increased riskbull Rising incidence lt 50 years Left sided colon amp
rectal symptomatic amp advanced Poor outcomebull Sporadic gt Hereditary
Siegel RL Miller KD Jemal A Cancer statistics 2016 CA Cancer J Clin 2016 667 Ahnen DJ Wade SW Jones WF et al The increasing incidence of young-onset colorectal cancer a call to action Mayo Clin Proc 2014 89216
Principles
Surgery is the cornerstone in management
However
Local Recurrence Following Surgery Alone
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Adjuvant Radiation Therapy
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Cuthbert Dukes 1932 Nodes as a prognostic factor
Local Recurrence Better Insight
Circumferential Margins
Number Local Recurrence Rate
P
gt 2 mm 987 33 lt 00001
1 ndash 2 mm 100 85 002
lt 1 mm 227 131 008
Int J Radiation Oncology Biol Phys Vol 55 No 5 pp 1311ndash1320 2003
CRM or LNs
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Member of Advisory Board Consultant and Speaker forbull Amgen Astellas AstraZeneca Hoffman la Roche Janssen Cilag
Merck Serono Novartis Pfizer Mundipharmabull The content of this presentation does not relate to any product of a
commercial interest
Speaker Disclosures
Basic Facts
bull 2nd amp 3rd most common cancer in females amp malesbull 14 million new case and 694000 deathsbull Males gt Femalesbull Lowest rates in Africa amp South Central Asiabull Low SES 30 increased riskbull Rising incidence lt 50 years Left sided colon amp
rectal symptomatic amp advanced Poor outcomebull Sporadic gt Hereditary
Siegel RL Miller KD Jemal A Cancer statistics 2016 CA Cancer J Clin 2016 667 Ahnen DJ Wade SW Jones WF et al The increasing incidence of young-onset colorectal cancer a call to action Mayo Clin Proc 2014 89216
Principles
Surgery is the cornerstone in management
However
Local Recurrence Following Surgery Alone
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Adjuvant Radiation Therapy
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Cuthbert Dukes 1932 Nodes as a prognostic factor
Local Recurrence Better Insight
Circumferential Margins
Number Local Recurrence Rate
P
gt 2 mm 987 33 lt 00001
1 ndash 2 mm 100 85 002
lt 1 mm 227 131 008
Int J Radiation Oncology Biol Phys Vol 55 No 5 pp 1311ndash1320 2003
CRM or LNs
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Basic Facts
bull 2nd amp 3rd most common cancer in females amp malesbull 14 million new case and 694000 deathsbull Males gt Femalesbull Lowest rates in Africa amp South Central Asiabull Low SES 30 increased riskbull Rising incidence lt 50 years Left sided colon amp
rectal symptomatic amp advanced Poor outcomebull Sporadic gt Hereditary
Siegel RL Miller KD Jemal A Cancer statistics 2016 CA Cancer J Clin 2016 667 Ahnen DJ Wade SW Jones WF et al The increasing incidence of young-onset colorectal cancer a call to action Mayo Clin Proc 2014 89216
Principles
Surgery is the cornerstone in management
However
Local Recurrence Following Surgery Alone
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Adjuvant Radiation Therapy
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Cuthbert Dukes 1932 Nodes as a prognostic factor
Local Recurrence Better Insight
Circumferential Margins
Number Local Recurrence Rate
P
gt 2 mm 987 33 lt 00001
1 ndash 2 mm 100 85 002
lt 1 mm 227 131 008
Int J Radiation Oncology Biol Phys Vol 55 No 5 pp 1311ndash1320 2003
CRM or LNs
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Principles
Surgery is the cornerstone in management
However
Local Recurrence Following Surgery Alone
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Adjuvant Radiation Therapy
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Cuthbert Dukes 1932 Nodes as a prognostic factor
Local Recurrence Better Insight
Circumferential Margins
Number Local Recurrence Rate
P
gt 2 mm 987 33 lt 00001
1 ndash 2 mm 100 85 002
lt 1 mm 227 131 008
Int J Radiation Oncology Biol Phys Vol 55 No 5 pp 1311ndash1320 2003
CRM or LNs
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Local Recurrence Following Surgery Alone
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Adjuvant Radiation Therapy
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Cuthbert Dukes 1932 Nodes as a prognostic factor
Local Recurrence Better Insight
Circumferential Margins
Number Local Recurrence Rate
P
gt 2 mm 987 33 lt 00001
1 ndash 2 mm 100 85 002
lt 1 mm 227 131 008
Int J Radiation Oncology Biol Phys Vol 55 No 5 pp 1311ndash1320 2003
CRM or LNs
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Adjuvant Radiation Therapy
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004
Cuthbert Dukes 1932 Nodes as a prognostic factor
Local Recurrence Better Insight
Circumferential Margins
Number Local Recurrence Rate
P
gt 2 mm 987 33 lt 00001
1 ndash 2 mm 100 85 002
lt 1 mm 227 131 008
Int J Radiation Oncology Biol Phys Vol 55 No 5 pp 1311ndash1320 2003
CRM or LNs
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Cuthbert Dukes 1932 Nodes as a prognostic factor
Local Recurrence Better Insight
Circumferential Margins
Number Local Recurrence Rate
P
gt 2 mm 987 33 lt 00001
1 ndash 2 mm 100 85 002
lt 1 mm 227 131 008
Int J Radiation Oncology Biol Phys Vol 55 No 5 pp 1311ndash1320 2003
CRM or LNs
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Local Recurrence Better Insight
Circumferential Margins
Number Local Recurrence Rate
P
gt 2 mm 987 33 lt 00001
1 ndash 2 mm 100 85 002
lt 1 mm 227 131 008
Int J Radiation Oncology Biol Phys Vol 55 No 5 pp 1311ndash1320 2003
CRM or LNs
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
CRM or LNs
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
MURCERY Trial
Fiona et al JCO 20141(32) 34-46
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Limitations of the TNM ndash T3 category forms 80 of rectal cancers
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Total Mesorectal Excision (TME)
bull Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop
Dis Colon Rectum 2013 May56(5)535-50
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Total Mesorectal Excision (TME)
Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646
Adjuvant Radiation Therapy
LR = 24
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Adjuvant Chemoradiation in Stages II amp III Rectal Cancer
bull GITSGbull NCCTGbull NSABP R-01
N Engl J Med 1986 3151294FJ Natl Cancer Inst 1988 8021 N Engl J Med 1991 324709
Adjuvant Fluoroupyremidine
X 2 monthsCRT ndash 6 Weeks
Adjuvant Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant Therapy The German Study A Shifting Concept
N Engl J Med 20043511731-40
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Slide 4
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Slide 3
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Slide 2
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Slide 6
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Slide 7
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Slide 9
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Slide 11
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Slide 12
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Radiation + Chemotherapy are MANDATORY in Neoadjuvant Therapy
Gastrointest Cancer Res 149-56 copy2007 by International Society of Gastrointestinal Oncology
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyThe Use of Capecitabine
The Cancer Journal bull Volume 13 Number 3 MayJune 2007
EQUIVALENT
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyAdding Oxaliplatin
Curr Opin Oncol 2012 24441ndash447
bull ++ Toxicity amp -- Compliancebull Did not improve
1 R0 RR2 pCR3 Sphincter Preservation
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
The PETACC-6 RCTltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt
Neoadjuvant TherapyAdding Oxaliplatin
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyAdding EGFR Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyAdding VEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyAdding EGFRVEGF Inhibition
Curr Opin Oncol 2012 24441ndash447
No Significant Added Benefit over Chemotherapy amp Higher G 3 amp 4
Adverse Events
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyIndications
1 T3 ndash T4 Lesions The only definitive indication2 cT3N0 Should be treated (understaging)3 Depth of Extramural Invasion ndash T3 lesions (gt5 mm) ++ LNs involvement Higher Cancer
Specific Mortality (54 Versus 85)ndash Selection of high risk T3 for treatmentndash Approved outside US
4 T1 ndash 2 lesions with Positive Nodes5 Low situated lesions6 Invasion of mesorectal fasciaBr J Cancer 2000 821131wwwuptodatecom (September 2015)
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyTreatment Outcome
Complete Response cCRpCR
bull 15 ndash 30bull Small amp Less
Advanced Lesionsbull 10 ndash 12 Weeks
bull Involution to flat scarbull DRE amp Endoscopybull Imaging
bull Endorectal USbull PET-CTbull MRI
bull ypT0N0
BIASED
NOT ACCEPTED
Martin R et al Surg Oncol Clin N Am 23 (2014) 113ndash125
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyTreatment Outcome in Relation to pCR German Study
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Grade Regression Fibrosis
0 No All cells are viable
1 Minor lt 25 fibrosis
2 Moderate 26 ndash 50nFibrosis
3 Good gt50
4 Total No Viable Cells
Neoadjuvant TherapyTumor Regression Grade
Grade 10 ndash year DM
P 10 ndash Year DFS P
0 - 1 3960005
6300082 - 3 293 736
4 105 895
J Clin Oncol 321554-1562 copy 2014
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyImpact of Pathological CR
British Journal of Surgery 2012 99 918ndash928
Can we Avoid Surgery
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Can we Avoid Surgery
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Can we Avoid Surgery
JCO VOLUME 29 1113097 NUMBER 35 1113097 DECEMBER 10 2011
21 Patients pCR
Neoadjuvant CRTFor Stages II amp III Wait amp See
MRI Endoscopy amp Biopsy
Median Follow up =25 months
1 Patient LR Surgery
20 Pts Stages II amp III NAT pCR
Median Follow up =35 months
2 ndash Year DFS 91 2 ndash Year OAS 93
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Trial Randomized Phase II ltbr gt
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has better DFS not OS than 5FU after pre-op ChemoRT
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
bull Adjuvant Chemotherapy
bull Oxaliplatin ndash Based
Rectal Cancer
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Problems with Adjuvant Chemotherapy
Modern Adjuvant Chemotherapy Rectal Trialsbull EORTC 22921 (Bosset Lancet Oncology 2014)bull Italian (Sainato Radiother Oncol 2014)
bull Chronicle (Glynne Jones Ann Oncol 2014)
bull PROCTORSCRIPT (Bregoum Ann Oncol 2014)
Meta-analyses NOT POSITIVEbull Bregoum (Lancet Oncol 2015)
bull Bujiko (EJSO 2015)
NEG
ATIV
E
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Parameter HR POAS 097 0775DFS 091 0230Distant Recurrence 094 0523
Problems with Adjuvant Chemotherapybull 4 Major Trials 1198 Patientsbull All received preoperative therapiesbull Overall No Gain even
Parameter HR PDFS 059 0005Distant Recurrence 061 0025
bull Rectal Tumors 10 ndash 15 cm above AV
Bregoum et al Lancet Oncol 2015 16 200ndash07
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
bull No one can indicate not to be givenbull To add CRT if not received before and risk of
LR is highbull Only patients with preoperative CRT and low
risk of Recurrence can be sparedbull Data are extrapolated from colon cancer
Oxaliplatin based therapybull Impact of pCR
Adjuvant ChemotherapyPragmatic Conclusions
As Presented by Glimelius in ASCO GI 2016
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Neoadjuvant TherapyProblems with Current Practice
CRT 55 Weeks 6 wks TME
1 ndash 2 weeks 4-6 wks Adjuvant Cth
18 weeksbull Delayedbull Reducedbull Omitted
CRT TME Neodjuvant Chemoth
Neodjuvant Chemoth CRT TME
bull Total Neoadjuvant Therapy Paradigm
bull Better down-staging
bull Better pCR
bull Higher R 0 Resection Rates
Adopted from Deborah Schragrsquos Presentation at 2015 ASCO Annual Meeting
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Total Neoadjuvant ParadigmBrown University Study (CONTRE)
FOLFOX X 8 Courses CRT + Cape TME
Pathologic Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
bull 35 Pts Completed Treatmentbull pCR = 33
Perez et al ASCO 2014 Abstract 3050
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Slide 12
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Near total neoadjuvant therapy
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Questions Total Neoadjuvant YesNoAdjuvant Cth
YesNoLong versus Short
Course
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr gt
Can we Omit Radiation From NAT
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
The Art for Today
bull Clinical Trial whenever possiblebull Careful assessmentbull Chemosensitization by 5-FU or Capecitabine is enoughbull Upfront chemotherapy is appealing Total amp Near
Total NAT should be encourgaed pCRbull TME IS THE STANDARD SURGICAL APPROACH (STAGES
II amp III)bull Postoperative chemotherapy should be discussed and
considered for high risk patients DFS
Thank You
Thank You
