Perioperative Treatment of Locally Advanced Rectal...
Transcript of Perioperative Treatment of Locally Advanced Rectal...
PERIOPERATIVE TREATMENT OF LOCALLY ADVANCED RECTAL CANCER
Rob Glynne-Jones
Mount Vernon Cancer Centre, Middlesex, UK
Preoperative short course radiotherapy SCPRT (5 X 5 Gy)
Preoperative long course chemoradiotherapy CRT (25-28 X 1.8Gy Gy)
3 OPTIONS FOR RADIOTHERAPY
IN LOCALLY ADVANCED RECTAL CANCER
(Post-op CRT as adjuvant )
Induction - Pre RT (Short-course(SCPRT) or chemoradiation (CRT)
Concurrent - With RT (CRT)
Consolidation - Post CRT or SCPRT if waiting 6 to 12 weeks before surgery
Neoadjuvant alone without RT
5 OPTIONS FOR CHEMOTHERAPY IN
LOCALLY ADVANCED RECTAL CANCER
Post-op adjuvant
The rationale for short course/
chemoradiationfor rectal cancer
The limitations
of short course/ chemoradiation
for rectal cancer
How to select patients
suitable for short
course/long course
chemoradiation
The role of postop adjuvant
chemotherapy after CRT and after surgery
alone
You will be able to tailor the treatment to the individual
patient
THE AIM OF THIS E-MODULE
IS TO EXPLAIN
The evidence base
Preoperative assessment/indications for treatment
Surgery alone
Preop RT -SCPRT (5x5Gy) or chemoradiation?
The radiotherapy
The chemotherapy/what drugs
Interval to surgery
Acute and late effects
TOPICS
APER - 65% perineal recurrence
Anterior resection - 50% anastomotic/central recurrence
Both associated with high proportion of failures in posterior pelvis
Similar to Dutch TME data (den Dulk, Kusters etc..)
HISTORICAL SURGERY/PRE TME
Landmark retrospective review:
Thomas A, et al., Rectal Cancer 1969
830 patients treated 1951-1960
HISTORICAL PERSPECTIVE
5 Year Survival
Dukes A 79%
Dukes B 25%
Dukes C 6%
5X5Gy in Europe (Stockholm Trials/ Swedish Rectal Cancer Trial)
Post-operative CRT in USA
EVIDENCE BASE
S alone
IMPACT ON OVERALL SURVIVAL OF
6 METHODS OF TREATMENT IN RECTAL
CANCER POOLED ANALYSIS
S+RT
Gunderson LL, et al., J Clin Oncol 2004;22(10):1785-1796. Reprinted with permission. © (2004) American Society of Clinical Oncology. All rights reserved
And then came TME
Radiotherapy extrapolated to SCPRT and TME/preoperative CRT (German
Trial CAO/ARO/AIO-94/Dutch TME/CR07 trial)
EVIDENCE BASE
PRE- VS. POST-OPERATIVE
CHEMORADIATION CAO/ARO/AIO-94
0.3
0.2
0.0
0.1
0 2412 4836 60
P=0.006
Months
Locoregional Recurrences
Post
Pre
13%
6%
Acute G3/4 adverse events
27% vs. 40% (p=0.001)
Long-term G3/4
adverse events
14% vs. 24% (p=0.01)
There is a standard
for chemoradiation
From N Engl J Med, Sauer R, et al., Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer;351:1731-39.
Copyright © 2004, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Included Stage I, Stage II and Stage III patients
Higher RT dose (55.8Gy) mandated in postoperative arm
PRE- VS. POST-OPERATIVE
CHEMORADIATION CAO/ARO/AIO-94
Median time to recurrence
19 vs 31 months
5/22 local recurrences i.e. 23% after 5 years
LONG-TERM DATA ON LOC REC
FROM GERMAN STUDY
Rolf S, et al., J Clin Oncol 2012; 30:1926-1933. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.
Is this simply a compliance issue?
No RT - local recurrence 29.6%
Inadequate RT 21.2%
Adequate RT 6.8% (p =0.0001)
FIETKAU R, IJROBP 2007
Fietkau R, et al., Int J Radiat Oncol Biol Phys. 2007;67:1008–19
PRE- VS. POST-OPERATIVE
CHEMORADIATION CAO/ARO/AIO-94
Rolf S, et al., J Clin Oncol 2012; 30:1926-1933. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.
At two years, local recurrence was 2.4 percent in the group assigned to
radiotherapy and surgery and 8.2 percent in the group assigned to surgery alone
(P<0.001)
DUTCH TME TRIAL
KAPITEIJN, NEJM 2001
From Kapiteijn E, et al., N Engl J Med. 2001 30;345:638-46 Copyright ©2001 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society
At two years, overall survival was 82.0 percent in the group assigned to
radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone
(P=0.84)
DUTCH TME TRIAL
KAPITEIJN, NEJM 2001
From Kapiteijn E, et al., N Engl J Med. 2001 30;345:638-46 Copyright ©2001 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society
MRC CR07 NCIC C016 TRIAL
n = 1350
Clinically operable adenocarcinoma of the rectum
<15 cm from anal verge
Adjuvant chemotherapy given per local policy
PREOP
SCPRT
SELECTIVE
POSTOP CRT
Pre-operative RT
25Gy / 5F
Surgery
Pathology
Surgery
Pathology
CRM-ve CRM+ve
Post-op CRTNo CRT
Sebag-Montefiore D, et al., Lancet 2009;373(9666):811-20
POLISH TRIAL – BUJKO K, ET AL.,
RADIOTHERAPY AND ONCOLOGY 2004
Short course pre-op RT Pre-op CRT 50.4 + 5FU/LV
Immediate surgery
Surgery
6-8 week interval
cT3/T4, resectable, not involving levators,
palpable on DRE, <75 yrs
Planned operation recorded
N=316
Bujko K, et al., Radiother Oncol. 2004;72:15–24
TROG AGIT LSSANZ RACS TRIAL
NGAN, JCO 2012
cT3 resectable
Short course pre-op RT Pre-op CRT 50.4 + 5FU/LV
Immediate surgery
Surgery
6-8 week interval
N=326
Ngan SY, et al., J Clin Oncol. 2012 Nov 1;30(31):3827-33
SCPRT VERSUS CRT:
NO DIFFERENCE IN LOCAL CONTROL
14.4% vs 18.6%
P = 0.17
Polish Trial (Bujko 2006)1 TROG-01 Trial (Ngan 2012)2
7.5% vs 4.4%
P = 0.24
1. Bujko K, et al., Br J Surg 2006;93(10):1215–1223; Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd;
2. Ngan SY, et al., J Clin Oncol. 2012 Nov 1;30(31):3827-33. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.
SCPRT VERSUS CRT:
EQUIVALENCE IN OVERALL SURVIVAL
1. Bujko K, et al., Br J Surg 2006;93(10):1215–1223; Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd;
2. Ngan SY, et al., J Clin Oncol. 2012 Nov 1;30(31):3827-33. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.
Anorectal and sexual function is worse after preoperative radiotherapy and TME
compared with TME alone: Results from many randomised studies
Peeters K, J Clin Oncol 2015;25:6199
Dahlberg M, Dis Colon Rectum 1998;41:543
Stephens RJ, J Clin Oncol 2010;28:4233
Marijnen CAM, J Clin Oncol 2005;23:1847
Lundby L, Lancet 1997;350:564
Lange MM, Br J Surg 2007;94:1278
LARS SCORE
Chen TY-T, et al. Clinical Colorectal Cancer, Vol. 14, No. 2, 106-14 ª 2015 The Authors. Published by Elsevier Inc. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Major LARS found in 38% of patients, but only 27% after surgery alone
After surgery alone longer rectal remnant had better function
In contrast, 80% reported major LARS after preoperative CRT and surgery
And length of remnant made no difference
Bondeven P, et al., Eur J Surg Oncol 2015;41(11):1493-9
LOW ANTERIOR RESECTION
SYNDROME
RECTAL STUMP: MR
No Radiotherapy
Radiotherapy
Bondeven P, et al., Eur J Surg Oncol. 2015 Nov;41(11):1493-9
SEVERE LATE TOXICITY SCPRT
VERSUS SCRT
SCPRT CRT
Polish Study
Severe late toxicity – G3/G4 10% 7%
TROG 01.04
Severe late toxicity – G3/G4 9% 13%
THE EVIDENCE BASE FOR SCPRT
OR CHEMORADIATION IS NO LONGER
STATE-OF–THE ART FOR MODERN MDT
Courtesy of Barnet MDT
CRM status
Extramural Vascular Invasion (EMVI)
Involvement of levators
cT substage (cT3c and cT3d)
cN status
RELEVANT FACTORS WHICH CAN
BE IMAGED IN ORDER OF IMPORTANCE
MRI RISK STRATIFICATION
Courtesy of Prof Vicky Goh, Dept of Radiology, Guys and Thomas‘ NHS Hospitals trust, London, UK
Render resectable cancers resectable
If ≥1 mm predicted CRM/distance to mesorectal fascia (MRF) then shrink
tumour to give margin >2 mm (R0 resection)
(can be defined by MRI – i.e. tumour outside / breaching / close to MRF)
1. BORDERLINE/UNRESECTABLE
CANCERS
TRUS for early T1 cancers (for anatomical detail)
MRI for all cancers for CRM,EMVI, levator assessment, cTsubstage and
cNodal status
CT scan for all cancers (to image distant metastases)
PET/CT for extensive EMVI (very high risk of metastatic disease)
Colonoscopy to rule out synchronous tumours in colon
EUA often if very low at dentate line
RECOMMENDED STAGING
PROCEDURES
3 mm, 16 cm – 18 cm FOV, 4–6 NSA,
256 x 256 matrix, TR >3,000,
TE 80–100, ETL 16
In plane resolution 0.6 mm x 0.6 mm
MRI IS NOW STANDARDISED
Brown G, et al., Br J Radiol 2005;78:245-251
Courtesy of Prof Gina Brown
67% 5-year DFS for patients with a clear CRM predicted by MRI, versus 47%
for patients with a predicted involved CRM (p=0.003)
Local recurrence for MRI-involved CRM
HR 3.50 (95% CI, 1.53-8.00; P <0.05)
MRI-involved CRM - the only preoperative staging parameter that remained
significant for OS, DFS, and LR on multivariate analysis
CIRCUMFERENTIAL RESECTION
MARGIN STATUS (CRM) PREDICTED BY MRI
Taylor FG, et al., J Clin Oncol. 2014;32(1):34-43
MERCURY DATA
Taylor FG, et al., Magnetic Resonance Imaging in Rectal Cancer European Equivalence Study Group. J Clin Oncol. 2014 Jan 1;32(1):34-43
Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved
.
CIRCUMFERENTIAL RESECTION
1 MM MARGIN AND TREATMENT
CRM +ve 139
CRM -ve 1107
CR07 short course
5x5 Gy RT vs. none1
0 1 2 3 4 5 6 70
20
40
60
80
100
Ove
rall
surv
ival (
%)
Follow- up (years)
Mawdsley et al 2005
Luna Perez 2005
CRM -ve
CRM +ve
CRM -ve
CRM +ve
Chemoradiotherapy2,3
HR 2.91 (1.74-4.88)
HR 1.56 (0.6-4.04)
1. Sebag-Montefiore D, et al. ASCO 2006. Abstract 3511; 2. Reprinted from Int J Radiat Oncol Biol Phys, 63(3), Mawdsley S, et al. Can histopathologic assessment of
circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival? 745-52; Copyright 2005 with
permission from Elsevier; 3. Luna Perez P, et al. J Surg Oncol. 2005;90:20–5. Copyright © 2005 Wiley-Liss, Inc.; 4. Reprinted from Clin Cancer Res Copyright 2007,
2007;13(22 Pt 1):6617-23 Gosens M, et al, Circumferential Margin Involvement Is the Crucial Prognostic Factor after Multimodality Treatment in Patients with Locally
Advanced Rectal Carcinoma, with permission from AACR.
4
DUTCH TME TRIAL (NAGTEGAAL
2002) – UNIRRADIATED GROUP (N= 656)
Dutch TME study 3 year local recurrence
+CRM < or = 2 mm 16%
CRM >2 mm 5.8% p=0·0001
Nagtegaal ID, et al., Pathology Review Committee; Cooperative Clinical Investigators. Am J Surg Pathol. 2002 Mar;26(3):350-7
CRM of >2 mm is cutoff though the risk
of recurrence is likely to represent a
continuum with larger margins giving
lower risk of recurrence
A CRM of 2 mm or less impacts on the prognosis of tumours located 6-15 cm
above the anal verge
ENDRESETH BJS 2009 CRM
Bernstein TE, et al., Br J Surg 2009;96:1348–57. Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd
OVERALL CR07 DATA
(BOTH ARMS)
CR07 3 year local recurrence
+CRM (<1 mm) 17%
-CRM 6% p=0.0011
CR07 – PERCENTAGE OF PATIENTS
WITH + CRM OVER TIME
Quirke P, et al., MRC CR07/NCIC-CTG CO16 Trial Investigators; NCRI Colorectal Cancer Study Group. Lancet. 2009;373(9666):821-8
Open access funded by Medical Research Council. Copyright © 2009 Elsevier Ltd
WE CAN JUDGE THE QUALITY OF
THE SURGERY
Courtesy of Prof Phil Quirke
RANDOMISED TRIALS SCPRT
(5X5GY)
TrialMRI
mandated
EUS
mandated
TME
mandated
Good
Quality TME
Median no
of nodes
resected
Swedish
RectalNo No No ?No
Not stated
Dutch TMENo No Yes 50% 7
Polish No No ? ? 9
CR07No No No 50% 11
TROG-0104If US not
possibleYes No ? Not stated
RANDOMISED TRIALS PREOP CRT
TrialMRI
mandated
EUS
mandatedTME
Good
Quality TME
Median no
of nodes
resected
German
(Sauer 2004)No Yes ? No data
Collected but
not stated
EORTC
22921No No 38% No data 7 after CRT
FFCD 9203 No No No data No dataNot stated
NSABP R03 No ? No No dataNot stated
Polish No No ? No data 8
TROG-0104 some Yes ? No data Not stated
EBRT (IMRT/IGRT)
Contact
Brachytherapy
SABR
TECHNICAL ADVANCES IN RT
Immobilisation/precision
Intensity-modulated radiation therapy
(IMRT)
Image guided radiation therapy
(IGRT)
IMRT Rectum
Prone position
Seven 6 MV co-planer beams
Beam angles:
0°40°85°160°200°275°315°
Low rectal cancers within 7 cm of anal verge
Need to be palpable to finger
Regarded as candidates for APER
Routinely offered CRT in Brazil
Habr Gama set out to avoid APER with set doses/field sizes/ meticulous
follow-up
ANGELITA HABR GAMA SET OUT
TO AVOID SURGERY AND SELECTED
http://iwwd.org/news/
Sceptical surgeons who see a CCR and then operate need to submit their
data too
INTERNATIONAL WATCH & WAIT
DATABASE (IWWD)
SO WHAT ARE THE INDICATIONS FOR SCPRT/CRT
Chemoradiation is going to shrink the cancer
And interval +/- filled with chemotherapy
SCPRT (5x5Gy) and delay filled with chemotherapy prior to surgery may be
an alternative
EVIDENCE BASE
To reduce the risk of local recurrence
To compensate for inexperienced surgeon
If the surgeon finds other reasons for which he is not convinced that an R0
resection can be achieved
To treat lateral pelvic lymph nodes
A perforation which has now healed
To help to achieve sphincter sparing?
Frail, aged or unsuitable for radical surgery because co-morbidity
2. RESECTABLE CANCERS
OVERVIEW OF NCCN GUIDELINES
FOR RECTAL CANCER – V2.2016
NCCN Guideliens Version 2. 2016 – Rectal Cancer. Available at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed May 2016
Adjuvant treatment (6 mo perioperative treatment preferred
Primary treatment Neoadjuvant therapyClinical stage
T3, N0 or T any, N1–2 or T4
and/or locally unresectable or
medically inoperable
Chemo/RT
• Capecitabine/long-course RT or infusional 5-FU/long-course RT (category 1 and preferred for both) OR
• Bolus 5-FU/ leucovorin/long-course RT
Transabdominal resection
• FOFOX (preferred) or CapeOx (preferred)
• OR
• FLOX or 5-FU/ leucovorin or capecitabine
Surveillance
Resection contraindicated
Active chemotherapy regimen for advanced disease
RT
• Short-course RT (not recommended for T4 tumours)
Transabdominal resection
Resection contraindicated
Active chemotherapy regimen for advanced
disease
Chemotherapy
• FOLFOX (prefereed) or CapeOx (preferred) OR
• 5-FU/leucovorin or capetiabin
Surveillance
OR
OR
Capecitabine/RT (preferred) or
infusional 5-FU/RT (preferred) or bolus 5-
FU/leucovorin/RT
“ As in colon cancer stage III (and ‘high-risk’ stage II), adjuvant chemotherapy can be given, even if the level of scientific evidence for sufficient benefit is much lower than in colon cancer [33, 34, 35] [II, B].”
From a practical point of view, rectal cancers could be divided into four groups:
1. Very early (some cT1)
2. Early (cT1-2, some cT3)
3. Intermediate (cT3- some cT4a)
4. Locally advanced (cT3crm +, some cT4a, all cT4b)
Glimelius B, et al., Ann Oncol. 2013;24 Suppl 6:vi81-8
ESMO
Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up: Glimelius B, et al., Ann Oncol. 2013;24 Suppl 6:vi81-8.
By permission of Oxford University Press
TME NORTHERN EUROPE: GOOD
QUALITY MESORECTAL PLANE: NO RT
Study EligibleGood Quality
MesorectalLocal Recurrence Actuarial
Swedish Rectal
Cancer Trial 1997
(574)
T any N any <10% 150/557 27% >30%
CR07 overall
(592) Quirke 2009T any N any 51% 59/592 10% 11%
Dutch TME (180)
Nagtegaal 2005T any N any 56% Not stated 8.7% at 2 years
CR07 (301)
Quirke 2009T any N any
100% (MRI not
routinely used)27/301 9% 7% at 3 years
Mercury* (122)
Taylor 2011T3a/b N any crm- 70% 4/122 3%
3.3% at 5 years
* NB: MRI directed
Ext. Iliac A .
Sup. Vesical A
Obturator N
Ext. iliac V
Int.Iliac A .
Ureter
Head
Pelvic plexus
LATERAL NODE DISSECTION OF
RIGHT SIDE PELVIC WALL
Courtesy of Dr Hirofumi Ota, Japan
FREQUENCY OF LATERAL LYMPH
NODE INVOLVEMENT IN RECTAL CANCER
Ueno 2005 LPLND R0
resection T3/T4% Positive
Distance to anal margin 6.1 -8 cm 10.5%
4.1- 6 cm 12.9%
2.1-4 cm 26.1%
2 cm or less 41.7%
TOTAL 237 17.3%
WHAT HAPPENS IF A COMPLETE
CLINICAL RESPONSE AFTER CRT
OR SCPRT IS OBSERVED?
“Half of your patients don’t need surgery!”Rodrigo Perez
CHEMOTHERAPY
BRAZILIAN DATA: 22/28 SALVAGED
183 patients
CRT
93 surgery90 cCR
17 early regrowth 73 sustained response
62 FUP
11 late recurrence
8 salvage 3 unresectable
14 salvage 3 unresectable
Habr-Gama IJROBP 2014
Prospective since 2009
21/192 patients (11%) with CCR included in wait and see policy (how many
not?)
6/21 cT2 and 1 cT1! Patients expressed a strong preference to avoid surgery
All but 4 (17/21) received FOLFOX ‘adjuvant’ chemotherapy post CRT
Meticulous follow-up including MRI
Mean follow-up only 25 months
Only 1 endoluminal recurrence at 22 months
DUTCH DATA:
MAAS M, ET AL., J CLIN ONCOL 2011
Watch-and-wait seems safe for small early node negative low tumours with
standardised CRT and meticulous follow-up
Limits some potential risks and harms of radical surgery – particularly for
frail or elderly patients
There is a risk of eventual local tumour regrowth
No randomised trials
Still patient driven
No guarantee of same results for more advanced T3/T4 N+ cancers in
mid/upper rectum
Limit to specialist centres?
WATCH-AND-WAIT CONCLUSIONS
Author
(Year)Nr
Patient
selection
Poor risk
featuresTreatment
R0 RESECTION
RATE
pCR
Rate
Ishii et al.
(2010)26
T3-4 any N,
within 12 cm of
anal verge
T4:12%
CRM NRIFL 100% 3.8%
Cercek et al.
(2010)6 T2-3, N1
T4: 0%
CRM NRFOLFOX 100% 33%
Fernandez-
Martos et al.
(2014)
46T3 midd rectum,
no CRM+
T4:0%
CRM:0%CAPOX-BEV 95,6% 20%
Uehara et al.
(2013)32
T3c-d-T4, N2,
CRM+
T4a: 28%
T4b: 31%
CRM: NR
CAPOX-BEV 84,3% 12,5%
Schrag et al.
(2014)32
T2N1, T3 any N,
No N2, No lower
third
T4:0%
CRM:0% FOLFOX-BEV 100% 25%
TRIALS OF NEOADJUVANT CT
WITHOUT RT IN LOCALLY ADVANCED
RECTAL CANCER
Sclafani F, Cunningham D. Future Oncol 2014;10:2243-2257
NACT AND THEN CRT IN MRI
DEFINED HIGH RISK RECTAL
CANCER (EXPERT AND EXPERT-C)
Clinical Response after NACT ITT population n=269 %
Complete response 11 4.1
Partial response157 58.4
Stable disease 76 28.3
Progressive disease 3 1.1
Unassessable/not known 22 8.2
NACT is feasible and does not compromise delivery of CRT
High response rates and few progress in phase II single arm or
randomised phase II
But…. still should be considered experimental
Requires validation in randomised phase III trials in patients with MRI defined
high risk rectal cancer
NACT
WE ALREADY USE IMAGING BIOMARKERS WHICH ARE ROBUST ENOUGH TO MAKE DECISIONS
or SCPRT + chemo
MRI
Glynne-Jones R, et al., Oncology, 2014;28 (8):667-77
Extensive EMVI
Disease breaching/outside the mesorectal fascia
IN FUTURE – SELECTION FOR
NEOADJUVANT CHEMOTHERAPY
Good evidence for fluoropurimidine’s benefit in Stage III (stage II QUASAR)
Good evidence for Oxaliplatin stage III
Small benefit for 5FU in stage II
No benefit in OS for Stage II for oxaliplatin
Benefit in elderly over 70 years?
Virgin Histopathology (uncorrupted by RT/CRT)
Need 12 nodes for decision-making
ADJUVANT CHEMOTHERAPY
IN COLON CANCER
OVERALL SURVIVAL HIGH RISK
STAGE II IN MOSAIC (TOURNIGAND 2012)
Tournigand C, et al., J Clin Oncol. 2012;30 :3353-60. Reprinted with permission © 2012 American Society of Clinical Oncology. All rights reserved.
Good evidence for fluoropurimidines after surgery alone and LPLND
(Japanese data)
Benefit for over 70 years in stage II (QUASAR)?
No evidence for 5FU after CRT
No large phase III trial evidence for adjuvant Oxaliplatin - excluded from
landmark randomised studies?
Chronicle / Adore trial/PETACC6/AIO discordant
ADJUVANT CHEMOTHERAPY
IN RECTAL CANCER
Good evidence for fluoropurimidines after surgery alone and LPLND
(Japanese data)
ADJUVANT CHEMOTHERAPY
IN RECTAL CANCER
META-ANALYSIS
Meta-analysis Group of the Japanese Society for Cancer of the Colon
and Rectum and the Meta-analysis Group in Cancer
DFS is improved after
adjuvant CT
Using oral 5FU
P=0.002
Even in Dukes’ A
Sakamoto J, et al., J Clin Oncol 2004;22:484-92. Reprinted with permission © 2004 American Society of Clinical Oncology. All rights reserved.
GITSG 7175 – 4-arm trial
Survival benefit at 8 years for CRT - chemo reducing DM (20% vs. 30%) and
RT decreasing LR (16% vs. 25%)
NSABP R-01 – 3-arm trial
Chemo improved 5 yr OS (60 vs. 37%) – RT decreased LR (16% vs. 25%) but
no OS
NSABP R-02 – Chemo vs. CRT (gender specific design)
RT decreased LR (8% vs. 13%) but no OS impact
POSTOP STUDIES SHOWING
BENEFIT OF CHEMO
IMPACT ON OVERALL SURVIVAL
OF 6 METHODS OF TREATMENT IN RECTAL
CANCER POOLED ANALYSIS
S alone
Gunderson LL, et al., J Clin Oncol 2004;22(10):1785-1796. Reprinted with permission. © (2004) American Society of Clinical Oncology. All rights reserved.
S+RT
SUBSET analysis
198/3239 = 6% overall
198/968 = 20% of rectal cancer
Reprinted from Lancet, 371(9623), Gray R, McConkey RT, Adjuvant chemotherapy for rectal cancer – Authors' reply, 1503,
Copyright 2008, with permission from Elsevier.
10 year OS 51.8% vs 48.4%
(HR 0.91- 95% CI 0.77–1.09; p=0.32)
EORTC 22921 –
OVERALL SURVIVAL
Reprinted from the Lancet Oncology, Bosset JF, et al., Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal
cancer: long-term results of the EORTC 22921 randomised study, Vol 15(2), 184-190, Copyright 2014, with permission from Elsevier
Only 1/21 trials received preoperative CRT
Only 2/21 received SCPRT
META-ANALYSIS
Reduction in risk of disease recurrence (25%) with adjuvant
chemotherapy compared to observation (HR=0.75, CI: 0.68-0.83)
Level 1 evidence for fluoropurimidines after surgery alone (Japanese data)
Benefit for over 70 years in stage II (QUASAR)?
But… level of benefit may be smaller
No evidence for 5FU after CRT in individual trials
No large phase III trial evidence for adjuvant Oxaliplatin - excluded from
landmark studies?
Chronicle trial / Adore trial
ADJUVANT CHEMOTHERAPY IN
RECTAL CANCER
NB: pathological stage II no significant difference
THE ADORE PHASE II TRIAL:
DISEASE FREE SURVIVAL
Hong YS, et al., Lancet Oncol. 2014;15:1245–53. Reprinted from The Lancet Oncology. Copyright 2014, with permission from Elsevier.
Consistent HR for chemo after CRT if randomised post CRT
We need more accurate risk stratification
So MRI is essential (mrTRG)
Consider postop histology rather than preop
ypN+/ ypEMVI+ high risk
Start chemotherapy asap after surgery
Start with modified doses (pelvic RT) to achieve better compliance?
CONCLUSIONS
CAPECITABINE
Disease-free survival
Reprinted from The Lancet Oncology, 13(6), Hofheinz RD, et al., 579-88, Copyright 2012, with permission from Elsevier.
PHASE III TRIALS – INVESTIGATING
OXALIPLATIN
Trial EligibilityFluoropyrimidine
Platform
CAO/ARO/AIO-04<12 cm from anal verge
T3/T4 cN0/N+ TRUS, CT and/or MRI
5FU 1000 mg/2 X 5 days
1-5 + 29-33
NSABP R04
N=1606
<12 cm; resectable stage II, III TRUS or MRI
– CT if T4/ N1-2
PVI 5FU vs.
capecitabine
FFCD
N=598
Palpable; resectable; T3/4 N0-2; T2 distal
anterior
Capecitabine in both
arms
STAR – 01
N=747
Resectable stage II, III (c stage) <12 cm
from anal vergePVI 5FU in both arms
PETTAC 6
N=1090
Stage II or III resectable or expected to
become resectable <12 cm from anal verge
Capecitabine in both
arms
Median follow-up of 50 months
At 3 years, cumulative incidence of local recurrences after R0/1 resection was
2·9% in the oxaliplatin group versus 4·6% in control group
THE GERMAN CAO/ARO/AIO-04
TRIAL
Rödel C, et al., Lancet Oncol. 2015;16(8):979-89.
Reprinted from The Lancet Oncology, Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German
CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial, Copyright (2015), with permission from Elsevier.
At 3 years, the cumulative incidence of distant recurrences 18·5% in the oxaliplatin
group 22·4% in the control group
THE GERMAN CAO/ARO/AIO-04
TRIAL
Median follow-up of 50 months
Rödel C, et al. Lancet Oncol. 2015;16(8):979-89.
Reprinted from The Lancet Oncology, Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German
CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial , Copyright (2015), with permission from Elsevier.
3 year DFS 75·9% in the investigational group vs. 71·2% in the control group
(hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03).
THE GERMAN CAO/ARO/AIO-04
TRIAL
Median follow-up of 50 months
Rödel C, et al., Lancet Oncol. 2015;16(8):979-89.
Reprinted from The Lancet Oncology, Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German
CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial, Copyright (2015), with permission from Elsevier.
UNKNOWN WHETHER THESE BENEFITS RELATE TO THE ADDITION OF PREOPERATIVE OR POSTOPERATIVE OXALIPLATIN, OR BOTH
After SCPRT (5x5Gy)
WHAT IS THE OPTIMAL INTERVAL
TO SURGERY?
No downstaging
SCPRT normally recommended to be followed by surgery within 1-7 days
An “ideal” SCPRT schedule, delivers 5 X 5 Gy from Monday to Friday with
surgery the following Monday or Tuesday – i.e. an interval of less than 10 days
AFTER SCPRT
But Short-course RT induces tumour downstaging if surgery is performed
after an interval of 4-8 weeks
STOCKHOLM III TRIAL
Pettersson D, et al., Br J Surg 2015;102(8):972-8
R
A
N
D
O
M
I
S
A
T
I
O
N
SCPRT 5X5 GY
Standard CRT
RAPIDO TRIAL
N = 885 PATIENTS
CapOx + 6
Capecitabine: 825 mg/m2
Oxaliplatin: 130 mg/m2
T4
EMVI+
N2
CRM+
T
M
E
Primary endpoint 3 year DFS
Nilsson PJ, et al., BMC Cancer. 2013;13:279
After SCPRT (5x5Gy)
After long course CRT
WHAT IS THE OPTIMAL INTERVAL
TO SURGERY?
Longer intervals up 15 weeks
Associated with an increased chance of a pCR (Sloothak, Kalady)
HYPOTHESIS
Cumulative complete pathological response (pCR) rate
But no increase in negative CRM!
Sloothaak DA, et al., Dutch Surgical Colorectal Audit. Br J Surg. 2013;100(7):933-9. © 2013 British Journal of Surgery Society Ltd.
Published by John Wiley & Sons Ltd
HYPOTHESIS
TIMING OF RECTAL CANCER
RESPONSE TO CRT
Single-arm Simon’s two-stage minimax design
Reprinted from The Lancet Oncology 2015,16(8); 957-966, Garcia-Aguilar J, et al., Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in
locally advanced rectal cancer: a multicentre, phase 2 trial. Copyright 2015, with permission from Elsevier
Radiotherapy was given 5 days per week for 5 weeks for a total of 45 Gy with a minimum boost of 5.4 Gy.Fluorouracil was given as a 225 mg/m2 per day continuous infusion for 7 days/week during radiation therapy for 5-6 weeks, depending on the number of radiation boosts given. mFOLFOX6 was given in 2-week cycles of leucovorin 200 mg/m2 or 400 mg/m2 and oxaliplatin 85 mg/m2 in a 2-h infusion, bolus fluorouracil 400 mg/m2 on Day 1, and a 46-h infusion of fluorouracil 2400 mg/m2. *Interim assessments were done by proctoscopic examination; total mesorectal excision was done if the patient had stable or progressive disease.
TUMOUR RESPONSE – PCR
Cohort 1 (60)
SG1
Cohort 2 (67)
SG2
Cohort 3 (67)
SG3
Cohort 4 (65)
SG3
pCR 11 (18%) 17 (25%) 20 (30%) 25 (38%)
Post CRT
ChemoNone
2 cycles
FOLFOX
4 cycles
FOLFOX
6 cycles
FOLFOX
Interval to
surgery8 weeks 11 weeks 15 weeks 19 weeks
N0/N+ 75%/25% 75%/25% ? ?
Garcia-Aguilar J, et al., The Lancet Oncology 2015;16(8): 957-966
TOXICITY/COMPLIANCE
Cohort 1 (60)
SG1
Cohort 2 (67)
SG2
Cohort 3 (67)
SG3
Cohort 4 (65)
SG3
Post CRT
ChemoNone 2 cycles FOLFOX
4 cycles
FOLFOX
6 cycles
FOLFOX
Interval to
surgery8 weeks 11 weeks 15 weeks 19 weeks
Treatment
interruptions7% 35% 40%
Dose
reductions2% 13% 35%
Garcia-Aguilar J, et al., The Lancet Oncology 2015;16(8): 957-966
TOXICITY/COMPLIANCE
Cohort 1 (60)
SG1
Cohort 2 (67)
SG2
Cohort 3 (67)
SG3
Cohort 4 (65)
SG3
Post CRT
ChemoNone
2 cycles
FOLFOX
4 cycles
FOLFOX
6 cycles
FOLFOX
Interval to
surgery8 weeks 11 weeks 15 weeks 19 weeks
Pelvic Fibrosis
(1-10)2.4 3.4 4.4
3.9
p=0.0001
Technical
difficulty (1-10)4.6 4.9 5.1 4.8 (p=0.8)
Garcia-Aguilar J, et al., The Lancet Oncology 2015;16(8): 957-966
Medical Oncology trials EXPERT, EXPERT C, SPANISH (Fernandez-Martos)/
RAPIDO use systemically active chemotherapy outside chemoradiation
Radiation Oncology trials ACCORD 12, STAR-01, CAO/ARO/AIO-04, NSABP
R04 use oxaliplatin as radiosensitiser (non systemic doses)
CURRENTLY –
DIFFERENT PHILOSOPHIES
Induction - Pre RT (Short-course(SCPRT) or chemoradiation (CRT)1
Preoperative long course chemoradiotherapy CRT (25-28 X 1.8Gy Gy)
Consolidation - Post CRT or SCPRT if waiting 6 to12 weeks before surgery2
3 PREOP OPTIONS FOR
CHEMOTHERAPY AND RT IN LOCALLY
ADVANCED RECTAL CANCER
1. Expert C, Fernandez-Martos, Cercek; 2. Garcia-Aguilar J, FOLFOX, Bujko K, RAPIDO –Nordic Countries/Holland
Preoperative CRT better than postop
SCPRT=CRT for resectable cancers
SCPRT/CRT improves local recurrence but not DFS or OS
If CRM threatened on MRI needs response so CRT
Low rectal cancers (below the levators) often have threat to CRM and may
have LPLN
CURRENT WISDOM
THANK YOU