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