Neoadjuvant therapy of rectal cancer

Neoadjuvant Therapy in Rectal
Cancer
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Colorectal Cancer Meeting
Zagazig 06/04/2017

Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma
• The content of this presentation does not relate to any product of a
commercial interest
Speaker Disclosures:

Basic Facts:
• 2nd & 3rd most common cancer in females & males.
• 1.4 million new case and 694000 deaths.
• Males > Females.
• Lowest rates in Africa & South Central Asia.
• Low SES  30% increased risk.
• Rising incidence < 50 years  Left sided colon & rectal,
symptomatic & advanced  Poor outcome, yet better
than right sided colon cancer.
• Sporadic > Hereditary.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7.
Ahnen DJ, Wade SW, Jones WF, et al. The increasing incidence of young-onset colorectal cancer: a call to action. Mayo Clin Proc
2014; 89:216.

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:

Cuthbert Dukes 1932: Nodes as a prognostic factor

Local Recurrence: Better Insight:
Circumferential
Margins
Number Local Recurrence
Rate
P
> 2 mm 987 3.3% < 0.0001
1 – 2 mm 100 8.5% 0.02
< 1 mm 227 13.1 0.08
Int. J. Radiation Oncology Biol. Phys., Vol. 55, No. 5, pp. 1311–1320, 2003

MURCERY Trial:
Fiona et al. JCO. 2014:1(32). 34-46.

Accuracy in staging early rectal cancer
Presented By Julio Garcia-Aguilar at 2017 Gastrointestinal Cancers Symposium

Limitations of the TNM – T3 category forms 80% of rectal cancers

Total Mesorectal Excision (TME):
• Removal of peri-rectal
tissues involving lateral &
circumferential margins of
mesorectal envelop.
Dis Colon Rectum. 2013 May;56(5):535-50.

Total Mesorectal Excision (TME):
N Engl J Med. 2001;345:638 – 646.
Adjuvant
Radiation
Therapy
 LR =
2.4%

Adjuvant Chemoradiation in Stages II
& III Rectal Cancer:
• GITSG.
• NCCTG.
• NSABP R-01.
N Engl J Med 1986; 315:1294.
FJ Natl Cancer Inst 1988; 80:21.
N Engl J Med 1991; 324:709.
Adjuvant
Fluoroupyremidine
X 2 months
CRT – 6 Weeks
Adjuvant
Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months

Neoadjuvant Therapy:
The German Study: A Shifting Concept
N Engl J Med 2004;351:1731-40.

Radiation + Chemotherapy are MANDATORY in
Gastrointest Cancer Res 1:49-56. ©2007 by International Society of Gastrointestinal Oncology

The Use of Capecitabine:
The Cancer Journal • Volume 13, Number 3, May/June 2007
EQUIVALENT

Adding Oxaliplatin:
Curr Opin Oncol 2012, 24:441–447
• ++ Toxicity & -- Compliance.
• Did not improve:
1. R0 RR.
2. pCR.
3. Sphincter Preservation

The PETACC-6 RCT 
Adding Oxaliplatin:

PETACC-6: Early analysis at 31 months shows no major differences between arms 
Adding Oxaliplatin:

Adding EGFR Inhibition:

Adding VEGF Inhibition:

Adding EGFR/VEGF Inhibition:
No Significant Added Benefit over
Chemotherapy & Higher G 3 & 4
Adverse Events.

Indications:
1. T3 – T4 Lesions: The only definitive indication.
2. cT3N0: Should be treated (understaging).
3. Depth of Extramural Invasion:
– T3 lesions (>5 mm)  ++ LNs involvement  Higher
Cancer Specific Mortality (54% Versus 85%).
– Selection of high risk T3 for treatment.
– Approved outside US.
4. T1 – 2 lesions with Positive Nodes.
5. Low situated lesions.
6. Invasion of mesorectal fascia.
Br J Cancer 2000; 82:1131
www.uptodate.com (September 2015)

Treatment Outcome:
Complete
Response
cCRpCR
• 15 – 30%.
• Small & Less
Advanced Lesions
• 10 – 12 Weeks.
• Involution to flat scar.
• DRE & Endoscopy.
• Imaging:
• Endorectal US
• PET-CT
• MRI.
• ypT0N0
Martin R. et al. Surg Oncol Clin N Am 23 (2014) 113–125

Treatment Outcome in Relation to pCR:
German Study:

Grade Regression Fibrosis
0 No All cells are viable
1 Minor < 25% fibrosis
2 Moderate 26 – 50%nFibrosis
3 Good >50%
4 Total No Viable Cells
Tumor Regression Grade:
Grade 10 – year
DM
P 10 – Year DFS P
0 - 1 39.6%
0.005
63%
0.0082 - 3 29.3% 73.6%
4 10.5 % 89.5%
J Clin Oncol 32:1554-1562. © 2014

Impact of Pathological CR:
British Journal of Surgery 2012; 99: 918–928
Can we Avoid Surgery?

Can we Avoid Surgery?
JCO. VOLUME 29 􏰉 NUMBER 35 􏰉 DECEMBER 10 2011
21 Patients
pCR
Neoadjuvant CRT
For Stages II & III
Wait & See
MRI, Endoscopy &
Biopsy
Median Follow up
=25 months
1 Patient  LR
 Surgery
20 Pts, Stages II & III
 NAT  pCR
Median Follow up
=35 months
2 – Year DFS: 91%
2 – Year OAS: 93%

The International Watch & Wait Database (IWWD) for Rectal Cancer
Presented By Maxime Valk at 2017 Gastrointestinal Cancers Symposium

Watch & Wait in Rectal Cancer

Cause of death

Take home messages

Adjuvant Therapy in Rectal Cancer;
Mandatory or Not?

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

German CAO/ARO/AIO-04 Study: Adjuvant FOLFOX has better DFS, not OS than 5FU after pre-op ChemoRT

• Adjuvant Chemotherapy?
• Oxaliplatin – Based?
Rectal Cancer:

Problems with Adjuvant Chemotherapy:
Modern Adjuvant Chemotherapy Rectal Trials:
• EORTC 22921 (Bosset, Lancet Oncology, 2014).
• Italian (Sainato, Radiother Oncol 2014)
• Chronicle (Glynne, Jones, Ann Oncol, 2014)
• PROCTOR/SCRIPT (Bregoum, Ann Oncol, 2014)
Meta-analyses  NOT POSITIVE:
• Bregoum (Lancet Oncol, 2015)
• Bujiko (EJSO, 2015)
NEGATIVE

Parameter HR P
OAS 0.97 0.775
DFS 0.91 0.230
Distant Recurrence 0.94 0.523
Problems with Adjuvant Chemotherapy:
• 4 Major Trials: 1198 Patients.
• All received preoperative therapies.
• Overall  No Gain even.
Parameter HR P
DFS 0.59 0.005
Distant Recurrence 0.61 0.025
• Rectal Tumors  10 – 15 cm above AV:
Bregoum et al. Lancet Oncol 2015; 16: 200–07

• No one can indicate not to be given.
• To add CRT if not received before and risk of
LR is high.
• Only patients with preoperative CRT and low
risk of Recurrence can be spared.
• Data are extrapolated from colon cancer 
Oxaliplatin based therapy.
• Impact of pCR.
Adjuvant Chemotherapy:
Pragmatic Conclusions:
As Presented by Glimelius in ASCO GI 2016

Problems with Current Practice:
CRT
5.5 Weeks 6 wks
TME
1 – 2 weeks
4-6 wks Adjuvant Cth
18 weeks
• Delayed.
• Reduced.
• Omitted
CRT TME
Neodjuvant
Chemoth.
Neodjuvant
Chemoth.
CRT TME
Adopted from Deborah Schrag’s Presentation at 2015 ASCO Annual Meeting

Total Neoadjuvant Paradigm:
Brown 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
• 35 Pts Completed Treatment.
• pCR = 33%.
Perez et al. ASCO 2014, Abstract 3050

Near total neoadjuvant therapy

Questions: Total Neoadjuvant: Yes/No?
Adjuvant Cth: Yes/No?
Long versus Short Course?

PROSPECT: N1048 is ongoing Selective Use of Pelvic XRT 
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:
• Clinical Trial whenever possible.
• Careful assessment.
• Chemosensitization by 5-FU or Capecitabine is
enough.
• Upfront chemotherapy is appealing  Total &
Near Total NAT should be encourgaed  pCR.
• TME IS THE STANDARD SURGICAL APPROACH
(STAGES II & III).
• Postoperative chemotherapy should be discussed
and considered for high risk patients  DFS.

Neoadjuvant therapy of rectal cancer

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