Rectal cancer debate:
Adjuvant chemotherapy following neoadjuvant chemoradiotherapy (CRT)
Ahmed Zeeneldin, MDConsultant Medical Oncology
KAMC Jeddah Oncology CenterMarch, 2016
NO
Outline
Current treatment of non-metastctic rectal CA
Why adjuvant Ctx is used in LARC? Comment on evidence that advocate
use of adjuvant Ctx in LARC Studies against use of adjuvant Ctx
in LARC Conclusions and my view
Current Treatment of M0 rectal CA
T N M NACRT
S(TME)
Adj
CTT1 N
0M0
Local
- + -
T2 N0
M0
Local
- + -
T3 N0
M0
LA + + +?
T4 N0
M0
LA + + +?
Any N+
M0
LA + + +?
Why adjuvant Ctx is used in LARC? Justifications RCT Pooled analysis of 5 key trials Cochrane Metanalysis of 21 RCTs
Justifications for adj CT
Still ,30% metastasis rate
Aim: Eliminate CTCs and micro mets
NSABP R-01Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer
J Natl Cancer Inst. 1988 Mar 2;80(1):21-9.
NSABP R-01 results
Benefits limited to Males and Young age RT only reduced LR
Comment NSABP R-01 (1988)
Recruited 1977-1986 Not TME No NA CRT
Impact of treatment on survival
Results according to riskDFS OS LR Mets
LR T1-2N0
~90% ~90% <5% ~10%
IR T1-2N1T3No
65-75%
75-80%
<10% 15-20%
MHR T1-2N2T4N0T3N1
50-60%
60-70%
<15% 30-40%
(V)HR
T3N2T4N1-2
30-35%
35-45%
15-25%
40-50%
Comment Pooled analysis
Recruited 1977-1986 Not TME No NA CRT Chemotherapy arms included postop
CRTCT Still some risk groups (VHR)
Up to 25% LR Up to 50 Mets
a systematic review 1975-March 2011
21 RCTs :11 west and 10 Japan Randomization
Surgery adj CT vs Surgery observation
Of ~16,000 patients with CRC, ~10,000 patients with rectal CA
Cochrane Database Syst Rev. 2012 Mar 14;3:CD004078.
OS HR 0.83 (17% MORTALITY REDUCTION)
Levels of evidence
OS stage II
OS stage III
DFS HR 0.75 (25% REDUCTION)
DFS stage II
DFS stage III
Western trials of adjuvant chemotherapy
Study Authro/y site C# R# (C)RT S arms
EORTC Bosset 2006 R 0 1000 (50)50% all 4 NART vs NACRT->O vs aCT
NSABP Fisher 1988 R 0 600 No all 3 O vs aCRT vs aRT
GTSG Thomas 1988 R 0 200 No all 4 O vs aCT vs aRT vs ACRT
NCCTG Krook 1991 R 0 200 No all 2 aRT vs ACRT
Austrian Kornek 1996 R 0 60 No all 2 O vs aCT
Italian Cafiero 2003 R 0 220 No all 2 aRT vs ACRT
GOG Grage 1981 CR 67 67 No all 2 O vs aCT
Swedish Hafström 1990 CR 201 99 No all 2 O vs aCT
NACCP Taal 2001 CR 700 300 No all 2 O vs aCT
R= rectum, c= colon, CRT chemoradio, O= observation,a= adjuvant
Japanese trials of adjuvant chemotherapy
Study Authro/y site C# R# (C)RT S arms
CCCSGJ Sakamoto 1999 R 0 1000 No all 3 O vs aCT
JFMTC 7-2 Yasutomi 1997 R 0 700 No all 2 O vs aCT
JFMTC 7-1 Kodaira 1998 R 0 800 No all 2 O vs aCT
JFMTC 15-2 Watanabe 2004 R 0 440 No all 3 O vs aCT
JFMTC 15-1 Sakamoto 2007 R 0 440 No all 2 O vs aCT
Hamaguchi 2011 Hamaguchi 2011 R 0 270 No all 2 O vs aCT
SGACCS Matsuda 1991 CR 1300 1200 No all 2 O vs aCT
TSGHCFU Ito 1996 CR 113 77 No all 2 O vs aCT
TACSG Kato 2002 CR 150 140 No all 2 O vs aCT
Koda 2009 Koda 2009 CR 124 ? No all 2 O vs aCT
R= rectum, c= colon, CRT chemoradio, O= observation,a= adjuvant
Conclusions
Adjuvant CT (5-FU based) is recommended following radical surgery
Encourage RCTs of adjuvant CT in patients receiving neoadjuvant therapy and surgery
Encourage adding modern anti-cancer agents in the adjuvant setting
Comment Cochrane metaanlysis (2012)
RCTS 1975-2011 Most not TME Only one trial used CRT Significant Heterogeneity
Preop CRT vs postop CRT
German Rectal Cancer Study Group CAO/ARO/AIO-94
N Engl J Med. 2004 Oct 21;351(17):1731-40.
Preop CRT vs Postop CRT in T3-T4 or N+
Postop CRT FU/LV
Preop CRT
FU/LV
P
pCR -- 8%pStage I (T1-2 N0)
18% 25% <0.001
Sphincter preservation
19% 39% 0.004
doubled
Local Recurrence 13% 6% 0.006
halved
Toxicity G3-4 40% 27% <0.05
Less
Tx completioncompliance
Less more
LR and Mets @ 5 years
LR and Mets @10 years
Comparable OS and DFSPostop
CRTPreop CRT
P
Mets 34% 30% NSOS@ 5 y 74% 76% NSOS@ 10 y 59.9% 59.6% NSDFS@5y 68% 65% NS
Comments
No observation arm CAO/ARO/AIO-94 Conclusions
With ~7% LR @ 10 y using Preop CRT (CI 5FU): Can LR be decreased further (?Add oxali)
With ~30% mets @ 10 y using adj bolus 5FU x 4: More effective adjuvant chemotherapy is
needed ?Add oxali
Plausible Questions in LARC Is more better?
Does adding Oxaliplatin to FP in NACRT improve results? pCR, DFS, favorable toxicity
Does adding Oxaliplatin to FP in ACT improve result? DFS, OS, favorable toxicity
Is less worse? Does elimination of adjuvant chemotherapy
worsen results? DFS, OS
Does adding Oxaliplatin to NACRT improve results?
* Unplanned exploratory p = 0.045
Comparable pCR but more toxicity (doubling of G3-4 toxicity: 8-11%25%)
STAR-01 trialJ Clin Oncol. 2011 Jul 10;29(20):2773-80.
FU-RT FU-Oxali_RT P379 368
G3-4 toxicity 8% 24% <0.001pCR 16% 16% NSDFS, OS Not
yetreported
ACCORD 12 trial
ACCORD 12 results
LR: ~9% in both arms (P>0.05)
OS & DFS: no sig. difference (P>0.05)
PETACC6
DFS @ 3y
LR and Mets @ 3 y
NSABP-R04 trial
Following surgery, pts encouraged to receive ACT
NSABP-R04 results
NSABP R-04 update
German trial CAO/ARO/AIO-04
Primary endpoint DFS @ 3y
ResultsFU-
RTFUFUOX-
RTFOLFOXP Report
edn 623 613NACRT 2012
CTx 79% 85%RT 96% 94%
Full Adjuvant CTx
83% 81% 2012
G3-4 diarrhea 8% 12% 2012G3-4 GI toxicities
12% 15%
pCR 13% 17% 0.045
2014- Lancet Oncol. 2012 Jul;13(7):679-87.
- ASCO 2014- Lancet Oncol. 2015 Aug;16(8):979-89.
FU-RTFU
FUOX-RTFOLFOX
HR P Reported
DFS@3y 71.2% 75.9% 0.79 0.03 2012DFS@5y 64.3% 68.8% 0.79 <0.
052014
OS@5y 78.3% 78% 0.96 >0.05
2014
Conclusions on NACRT
Adding Oxali No significant increase in OS in all trials
(including German 04) Increased toxicities in all trials (including
German 04) No significant increase in pCR or DFS
(except German 04) More is not better in NACRT
Does adding Oxaliplatin to FPs in ACT improve result in colon ca?
MOSAIC study: ~20% relative reduction in DFS events ~5% absolute increase in 3-y DFS
~7% in stage III (p<0.5) ~3% in stage II (p>0.5) Detrimental in old age
OS improved only in stage II
Does adding Oxaliplatin to FPs in ACT improve result in rectal ca?
ADORE 3-y results (both yII + yIII) DFS OS
FU FOLFOX HR P3y DFS 63% 72% 0.66 0.0473y OS 86% 95% 0.46 0.036
DFS@ 3 years y-III vs y-III
Stage y-III Stage y-II
FU-RTFU
FUOX-RTFOLFOX
HR P Reported
DFS@5y 64.3% 68.8% 0.79 <0.05
2014
OS@5y 78.3% 78% 0.96 >0.05
2014
German trial CAO/ARO/AIO-04
PETACC 6
DFS @ 3y
LR and Mets @ 3 y
Why PETACC6 is negative for DFS
Cape
CAPOX
∆
Did not get Adjuvant Ctx
23% 38% -15%
Did not get full adjuvant Ctx
32% 47% -14%
Cape dose <90%
35% 54% -19%
Conclusion Conflicting data regarding adding
Oxaliplatin to adjuvant FP in rectal caStudy DFS OS complian
ceEligibili
tyADORE Improved Improved ?? y-II/IIICAO/ARO/AIO-04
Improved Did not improve
high c-II/III
PETACC 6 Did not improve
Did not improve
Low c-II/III Following NACRT, if pathologic stage is II/III: FOLFOX improves DFS and OS (in stage III)
Patients with Clinical stage II/III, following CRT, FOLFOX improves DFS and CapeOX did not
No OS improvement with FOLFOX or CapeOX
Does elimination of ACT worsen outcome in LARC? 4 RCTS
EORTC 22921: FU/LV vs Observation
I-CNR-RT trial: FU/LV vs Observation
PROCTOR-SCRIPT: FU/LV or Cape vs Observation
Chronicle : Capeox vs observation
One metaanalysis
I-CNR-RT trial
Radiother Oncol 2014 Nov;113(2):223-9.
ResultsObservation FU/LV P
n 310 3245 Y OS Similar similar >0.055 y DFS Similar similar >0.05Mets 21% 19.6% >0.05Did not start planned CTx
28%
Dutch (PROCTOR-SCRIPT) trial
Closed prematurely due to slow accrual
Ann Oncol. 2015 Apr;26(4):696-701.
resultsObservati
onAdj CT
HR P
N 221 2165y OS 79.2% 80.4
%0.93
0.73
DFS 0.80
0.13
5 Y LR Rec
7.8% 7.8% NS
5 Y Mets
38.5% 34.7%
0.39
Chronicle trial
Closed prematurely due to slow accrualAnn Oncol. 2014 Jul;25(7):1356-62.
Results
Observation
XELOX
HR P
N 59 543 Y DSF 71% 78% 0.8
00.56
3 Y OS 89% 88% 1.18
0.75
Completed 6 cycles
----- 48%
Dose reductions
----- 39%
G3/4 toxicities ----- 40%Ann Oncol. 2014 Jul;25(7):1356-62.
EORTC 22921
Results at 5 years
PFS
Overall survival
Chemotherapy after NACRT
Conclusion
None of the trials that compared ACT to observation was positive
Question: Maybe the difference is small and it will
show in a mentanalysis? Lets see!
4 Studies having 1196 patients
Patient characteristics
OS HR 0.97 p=0.775
DFS HR 0.91 p= 0.23
Mets HR 0.94 p= 0.523
Cumulative incidence of distant recurrences
All were Stage y-II, y-III
Conclusions and my viewIN LARC (T3-4 or N+) No preop CRT:
Adjuvant CTX is indicated in All cases Regimen: CapOX/FOLFOX or FLOX
Conclusions and my view IN LARC (T3-4 or N+) Preop CRT
Adjuvant CTx is indicated in: High rectal tumors (10-15 CM from AV):
Pathologic stage y-II & y-III Regimen: (CapeOx/FOLOFOX in y-III, ?? FU/Cape in y-
II) Mid or low rectal tumors
Pathologic stage y-III (i.e. pN+) Regimen: CapeOx/FOLOFOX
High-risk y-II (all pT4 and pT3 + high risk features) Regimen: ?? FU/Cape
High-risk features in RC-CRM <= 2 mm-LVI-Poorly differentiated-Inadequate # LNs (<12)-Non-TME surgery-R1 resection that cannot be re-operated
Conclusions and my view IN LARC (T3-4 or N+) Preop CRT
Adjuvant CTx is NOT indicated in: Pathologic stage (y-0) i.e. pCR Pathologic stage (y-I) i.e. pT1-2
particularly low-risk Pathologic stage (y-II) i.e. pT3
particularly low-risk High-risk features in RC-CRM <= 2 mm-LVI-Poorly differentiated-Inadequate # LNs (<12)-Non-TME surgery-R1 resection that cannot be re-operated