Neoadjuvant Therapy of Rectal Cancer: Pathologic Versus Clinical CR

Neoadjuvant Therapy in Rectal Cancer Complete Clinical versus Pathological Response

Mohamed Abdulla MDProf of Clinical OncologyCairo University

Member of Advisory Board Consultant and Speaker for Amgen Astellas AstraZeneca Hoffman la Roche Janssen

Cilag Merck Serono Novartis Pfizer The content of this presentation does not relate to any product

of a commercial interest

Speaker Disclosures

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


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

Total Mesorectal Excision (TME)

Removal of peri-rectal tissues involving lateral amp circumferential margins of mesorectal envelop

Dis Colon Rectum 2013 May56(5)535-50


Clinical Colorectal Cancer Vol 4 No 4 233-240 2004N Engl J Med 2001345638 ndash 646


LR = 24

Adjuvant Chemoradiation in Stages II amp III Rectal Cancer

GITSG NCCTG 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


X 2 months

Adjuvant Therapy = 6 months

Neoadjuvant Therapy The German Study A Shifting Concept

N Engl J Med 20043511731-40

German CAOAROAIO-94 11 Years Update

Sauer R et al JCO 2012301926-33

Neoadjuvant Therapy TME Trial ldquoShort Courserdquo 10 Years FU

10 - Year RTh + S S P

LR 5 11 lt 00001

OAS 48 49 086

CCSD 17 22 004

Lancet Oncol 2011 12 575ndash82

CCSD Cumulative Incidence of Cancer Specific Death

Neoadjuvant Therapy TME Trial 10-Year Subset Analysis


OAS Benefit

Neoadjuvant TherapyShort versus Long Radiation Therapy Course

Polish Trial Trans-Tasman Radiation

Oncology Group

bull Local Recurrencebull DFSbull Distant Recurrencebull OASbull Severe Late

Toxicity

EQUIVALENT

J Clin Oncol 2012 303827Br J Surg 2006 931215

Distal Tumors LC gt SC

LR = 0 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


ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no major differences between armsltbr gt


Neoadjuvant TherapyAdding EGFR Inhibition


Neoadjuvant TherapyAdding VEGF Inhibition


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 Lesions

bull 10 ndash 12 Weeks

bull Involution to flat scar

bull 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 Pathological Outcome German Study

Grade Regression Fibrosis0 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



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


2 ndash Year DFS 91 2 ndash Year OAS 93

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 R0 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 III38 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

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

Slide 12

Near total neoadjuvant therapy

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

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


What to do today

Clinical Trial whenever possible Careful assessment Chemosensitization by 5-FU or Capecitabine is enough Upfront chemotherapy is appealing Total amp Near Total

NAT should be encourgaed pCR TME IS THE STANDARD SURGICAL APPROACH

(STAGES II amp III) Postoperative chemotherapy should be discussed and

considered for high risk patients DFS

Thank You

Neoadjuvant Therapy in Rectal Cancer Complete Clinical versus

Speaker Disclosures

Principles





Total Mesorectal Excision (TME) (2)






Neoadjuvant Therapy Short versus Long Radiation Therapy Course


Neoadjuvant Therapy The Use of Capecitabine

Neoadjuvant Therapy Adding Oxaliplatin


ltbr gtPETACC-6 ltbr gtEarly analysis at 31 months shows no majo

Neoadjuvant Therapy Adding EGFR Inhibition

Neoadjuvant Therapy Adding VEGF Inhibition

Neoadjuvant Therapy Indications

Neoadjuvant Therapy Treatment Outcome

Neoadjuvant Therapy Treatment Outcome in Relation to Pathologi

Neoadjuvant Therapy Tumor Regression Grade

Neoadjuvant Therapy Impact of Pathological CR


Can we Avoid Surgery (2)

Neoadjuvant Therapy Problems with Current Practice

Total Neoadjuvant Paradigm Brown University Study (CONTRE)

The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treat

The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatm

Slide 34


Postop Adjuvant 5FU or FOLFOX for Rectal Cancer The ADORE Tria

ltbr gtGerman CAOAROAIO-04 Studyltbr gtAdjuvant FOLFOX has bet

Slide 38

PROSPECT N1048 is ongoingltbr gtSelective Use of Pelvic XRTltbr

MSKCC 07-021 Phase II Trial of Selective Radiation for Rectal

What to do today

Slide 43

Member of Advisory Board Consultant and Speaker for Amgen Astellas AstraZeneca Hoffman la Roche Janssen

Cilag Merck Serono Novartis Pfizer The content of this presentation does not relate to any product

of a commercial interest

Speaker Disclosures

Principles


However








Rate

P

gt 2 mm 987 33 lt 00001

1 ndash 2 mm 100 85 002

lt 1 mm 227 131 008








LR = 24







X 2 months



N Engl J Med 20043511731-40





LR 5 11 lt 00001

OAS 48 49 086

CCSD 17 22 004





OAS Benefit



Oncology Group


Toxicity

EQUIVALENT



LR = 0 12





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43

Principles


However








Rate

P

gt 2 mm 987 33 lt 00001

1 ndash 2 mm 100 85 002

lt 1 mm 227 131 008








LR = 24







X 2 months



N Engl J Med 20043511731-40





LR 5 11 lt 00001

OAS 48 49 086

CCSD 17 22 004





OAS Benefit



Oncology Group


Toxicity

EQUIVALENT



LR = 0 12





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43








Rate

P

gt 2 mm 987 33 lt 00001

1 ndash 2 mm 100 85 002

lt 1 mm 227 131 008








LR = 24







X 2 months



N Engl J Med 20043511731-40





LR 5 11 lt 00001

OAS 48 49 086

CCSD 17 22 004





OAS Benefit



Oncology Group


Toxicity

EQUIVALENT



LR = 0 12





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43







LR = 24







X 2 months



N Engl J Med 20043511731-40





LR 5 11 lt 00001

OAS 48 49 086

CCSD 17 22 004





OAS Benefit



Oncology Group


Toxicity

EQUIVALENT



LR = 0 12





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43







X 2 months



N Engl J Med 20043511731-40





LR 5 11 lt 00001

OAS 48 49 086

CCSD 17 22 004





OAS Benefit



Oncology Group


Toxicity

EQUIVALENT



LR = 0 12





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43


N Engl J Med 20043511731-40





LR 5 11 lt 00001

OAS 48 49 086

CCSD 17 22 004





OAS Benefit



Oncology Group


Toxicity

EQUIVALENT



LR = 0 12





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43





LR 5 11 lt 00001

OAS 48 49 086

CCSD 17 22 004





OAS Benefit



Oncology Group


Toxicity

EQUIVALENT



LR = 0 12





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43



OAS Benefit



Oncology Group


Toxicity

EQUIVALENT



LR = 0 12





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43



Oncology Group


Toxicity

EQUIVALENT



LR = 0 12





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43





EQUIVALENT





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43





















Advanced Lesions





bull ypT0N0

BIASED

NOT ACCEPTED






3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43





3 Good gt50




P 10 ndash Year DFS

P

0 - 1 3960005

6300082 - 3 293 736

4 105 895








21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43







21 Patients pCR
















bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43









bull Better pCR





Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43



Pathologic Grade



1 14 4 10

2 8 1 7

3 3 1 2







Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43





Slide 12









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43









What to do today





Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43

Thank You


Speaker Disclosures

Principles






























Slide 34




Slide 38



What to do today

Slide 43

Neoadjuvant Therapy of Rectal Cancer: Pathologic Versus Clinical CR

Health & Medicine

Transcript of Neoadjuvant Therapy of Rectal Cancer: Pathologic Versus Clinical CR