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RECTAL CANCERThe (neo)adjuvant story
Mark Rother MD FRCPCMedical Oncologist
Peel Regional Cancer CenterCredit Valley Hospital
Case• 62 year old man (father of your life long best friend)
has rectal bleeding
• You get him in to see a GI specialist and a colonoscopy finds a non obstructing adenocarcinoma 6 cms from anal verge
• CT Thorax/Abd/Pelvis – No mets
• Your friend calls you for advice on the next step? He has been reading up!
• He thinks his Dad will need surgery, chemo and radiation based on his reading
• He finds it all very confusing but knows you are an expert in GI oncology and will clarify it for him and his dad.
Questions?
• More Tests- MRI? EUS? Role of PET/CT?
• Surgery- When? What type? Who should do it?
• Radiation- Before/After surgery? Long protracted or intensive short type? With chemo or without?
• Chemotherapy- What type? How long for? New drugs? Clinical trials? Must he get a PICC?
OVERVIEW
• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative Chemoradiation• Optimizing Preoperative Chemoradiation• Postoperative chemotherapy after neoadjuvant CRT • Future Approaches
OVERVIEW
• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative Chemoradiation• Optimizing Preoperative Chemoradiation• Postoperative chemotherapy after neoadjuvant CRT • Future Approaches
Rectal Cancer
• Estimated 6000 new cases per year in Canada (30% of colorectal cancer)
• Local and Systemic Relapse Risk
• Prototype of a multimodality approach– Surgery– Radiation– Chemotherapy
Definition- Rectal Cancer• Discriminating between colon and rectal cancer is
critical
• Colon is 150 cm long but rectum is about the last 12-15 cm
• Anatomically, the upper boundary of the rectum is located at the rectosigmoid junction, slightly below the sacral promontory. On clinical grounds, the peritoneal reflection is the more important landmark
• In the post-operative setting the location of the tumour relative to the peritoneal reflection should be part of the surgical and pathological report
• Identification of rectal tumours prior to surgery is generally obtained by measuring the distance between the inferior edge of the tumour and the anal verge(12-15cm)
Definition - Rectal Cancer
Adjuvant therapy
• Adjuvant therapy needs to address the local and systemic recurrence risk
• Under-treatment : pelvic recurrences and complications
• Over-treatment : therapy related complications - bowel, bladder and sexual dysfunction
Challenges in Adjuvant Therapy for Rectal Cancer
• Data from randomized trials limited.
• Debate on pre vs post op radiation and radiation dose and schedule is confusing
• Chemotherapy concurrently with XRT-What and How?
• Decisions on adjuvant chemo if received pre-op therapy.
OVERVIEW
• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative Chemoradiation• Optimizing Preoperative Chemoradiation• Postoperative chemotherapy after neoadjuvant CRT • Future Approaches
OLDER APPROACH TO RECTAL CANCER(but still commonly done)
• Surgical resection
• Pathology assessment and risk estimation
• Treatment based on TMN
• Post operative Chemoradiation
1990 NCI Consensus Statement
• Combined postoperative chemotherapy and radiation improves local control and survival in patients with stage II and III rectal cancer and is recommended:– GITSG– NCCTG-MAYO
JAMA 1990: 264:1444-1450
GITSG(227) NEJM 1985
Surgery/5FU/mCCNU/RT
LR 11% OS 56%
Surgery/5FU/mCCNU
LR 21% OS 46%
Surgery/RT LR 20% OS 43%
Surgery
LR 24% OS 32%
NCCTG(204) NEJM 1991
Surgery/5FU/mCCNU/RT LR 14% OS 58%
Surgery/RT LR 25% OS 48%
1990 NCI Consensus Statement
NCCTG Intergroup Study• 660 patients with resected stage II/III rectal
cancer
O’Connell NEJM 1994
2x2 study design:
PVI 5-FU vs bolus(with rads)
- Improved PFS (p=0.02)
- Improved OS (p=.01)
MeCCNU: no benefit
NCCTG Intergroup Trial
O’Connell NEJM 1994
CP1050909-25
R
Bolus 5FU
IIIII
Bolus 5FU-Levamisole
Bolus 5FU-Leucovorin
Bolus 5FU-Leucovorin-Levamisole Tepper et al. JCO 2002
Intergroup 0114 : Post-operative CT – CRT- CT
Tepper, J.E. et al. J Clin Oncol; 20:1744-1750 2002
Intergroup 0114 -OS by treatment arm
R
Intergroup 0144: Post operative CT – CRT - CT
b5FU – XRT+PVI5FU – b5FU
IIIII
PVI5FU – XRT+PVI5FU – PVI5FU
b5FU/LV – XRT+b5FU/LV – b5FU/LV
Smalley, JCO2006
Smalley, S. R. et al. J Clin Oncol; 24:3542-3547 2006
Intergroup 0144 - Overall survival and relapse-free survival
Advantages of Postoperative Treatment
• Accurate pathologic staging
• Shorter delay to definitive surgery
• Potentially less surgical morbidity?– Not complicated by prior XRT-chemo
Long-Term Effects of Postoperative Chemoradiation Surgery alone
Chemoradiation
# BMs/day 2 (1-7) 7 (1-20)
Nocturnal BMs 18% 46%
Continence 93% 44%
Antidiarrheals 5% 53%
OVERVIEW
• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative Chemoradiation• Optimizing Preoperative Chemoradiation• Postoperative chemotherapy after neoadjuvant CRT • Future Approaches
Preop RT(25 Gy in 5 fractions)
Immediate surgery
R LR 11%, 5yr OS 58%
LR 27%, 5yr OS 48%
Swedish Rectal Cancer Study
NEJM 1997
Preop RT + TME(25 Gy in 5 fractions)
TME alone
R
Dutch Colorectal Group (NEJM 2001)
Kapiteijn NEJM 2001
LR 5.6%
LR 10.9%
MRC CR-07 (NCIC CO-16)
Lancet 2009; 373: 821–28
Lancet 2009; 373: 821–28
MRC CR07
Lancet 2009; 373: 821–28
MRC CR07
What about Short-course XRT?• 2500 cGy in 5 fractions
• Northern Europe approach
• No concurrent chemo(5FU) radiosensitizer
• Surgery within a 1-2 weeks
• No downstaging(not for T4 or concern re CRM)
• Concerns re long term bowel function
• Studies ongoing with 6 week delay(?downstaging)-Stockholm lll
OVERVIEW
• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative Chemoradiation• Optimizing Preoperative Chemoradiation• Postoperative chemotherapy after neoadjuvant CRT • Future Approaches
Preoperative Chemoradiotherapy
•North American/Southern Europe approach
•For patients with locally advanced disease-T3/T4 or N+
•More protracted RT course 5-6 weeks(45-50.4 cGy)
•Concurrent 5FU based chemotherapy
•Followed by Surgery 4 - 6 weeks later
Bosset NEJM 2006
Bosset NEJM 2006
PolishPolish Study ResultsStudy Results• 25/5 vs Chemoradiation Therapy
• pCR 1% vs. 19%
• Similar SSS,DFS,OS
• Similar late toxicity
• Await similar design TROG study
TROG Study-ASCO 2010
OVERVIEW
• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative Chemoradiation• Optimizing Preoperative Chemoradiation• Postoperative chemotherapy after neoadjuvant CRT • Future Approaches
• INT- 0147 - terminated prematurely due to poor accrual
• NSABP R-03 - terminated prematurely due to poor accrual
• German Trial- CAO/ARO/AIO 94 - completed accrual
Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer
Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group
Volume 351:1731-1740 October 2004
• 421 receive preoperative and 402 receive postoperative
chemoradiotherapy.
• The overall five-year survival rates were 76 percent and 74 percent (P=0.80).
• The five-year incidence of local relapse 6 percent for preoperative and 13 percent in the postoperative group (P=0.006).
• Grade 3 or 4 acute toxicity occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001)
Sauer NEJM 2004
Results -Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer
Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group
Sauer NEJM 2004 Sauer NEJM 2004
Sauer NEJM 2004
Sphincter Preserving SurgeryITT Analysis
Pre-randomization:“APR Necessary“
Postoper. RCT Preoper. RCT n= 394 n = 405
85 109
17/85 (20%) 43/109 (39%)
85-17= 68 109-43= 66
Sphincterpreserved p = 0.004
APR actually done
German Rectal Study Conclusions• Preop CRT significantly improves local control
• Preop CRT improves sphincter preservation in low-lying tumours
• Preop CRT reduced acute and chronic toxicity
• Preop CRT should be the standard adjuvant treatment in cT3/4 or cN+ rectal cancer
CAVEAT •18% of tumours in the post operative group
were overstaged clinically (i.e. Stage 1 on pathology)
• Mandates excellent preoperative radiologic assessment
Accurate preoperative local tumor staging is critical in directing patient management
All modalities remain poor in assessment of regional lymph node involvement
CT still the workhorse for distant metastatic disease, complications/sequelae and surveillance
Preoperative Rectal Staging
OVERVIEW
• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative Chemoradiation• Optimizing Preoperative Chemoradiation• Postoperative chemotherapy after neoadjuvant CRT • Future Approaches
5FU as a radiosensitizer
• Improves local control, pCR (FFCD,EORTC)
• Potentially improves control at distant sites (treats micro metastasis earlier)
• PVI is the optimal schedule
Capecitabine as a Radiosensitizer?
• Mimics infusional 5FU
• Convenient versus PVI
• Intratumoral thymidine phosphorylase activity upregulated with XRT
Oral vs Infusional 5FU N PCR (%) SSS (%)
Phase2, UFT 400mg/m2/d X 5/7 – S – 5FU/LVX4 (1)
94 9% 25%
Phase1 – RP2D Capecitabine 825mg/m2 BID X 7/7 (2)
36 -- --
Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (3)
53 24% 59%
Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (4)
95 12% 74%
Matched-Pair Analysis (PVI vs Capecitabine) (5)
89/89 12%/21% 70%/78%Similar OS
1 – Fernandez, JCO2004 2 – Dunst, JCO 20023 – DePaoli, Ann Oncol 2006 4 – Kim, IJROBP 20055 – Das, IJROBP, 2006
Capecitabine versus 5-fluorouracil-based (neo-)adjuvant chemo-radiotherapy for locally advanced rectal cancer:
Long term results of a randomized phase III trial
R. Hofheinz, F. Wenz, S. Post, on behalf of the German MARGIT study
Study Design
Mar 2002-July2005Post-Op
Treatment
Post July 2005
After Publication of Sauer TrialNeoadjuvant
TreatmentArms Added
Overall survival (OS)Primary endpoint (Median Follow-up 52 mon.)
Disease free survival (DFS)Secondary endpoint (Median Follow-up 52 mon.)
NSABP-R04
1200 pts
***Capecitabine is 825 mg /m2 bid for 5/7(Rad days)
Oxaliplatin No Oxaliplatin
Capecitabine
5FU
Roh et al ASCO 2011
NSABP-R04
Roh et al ASCO 2011
NSABP-R04
Roh et al ASCO 2011
5FU-Oxaliplatin-XRT
•Over 15 phase I/II trials have demonstrated pCR rates ranging from 20-40% (compared to 10-20% expected with XRT+5-FU)
•Increased likelihood for sphincter preservation?
•More efficacious systemic therapy for micrometastases given preoperatively?
NSABP-R04
Roh et al ASCO 2011
NSABP-R04Pathologic Complete Response by Treatment
Oxaliplatin vs NoneSphincter Saving Surgery by Treatment
Oxaliplatin vs None
Roh et al ASCO 2011
STAR TRIAL
Aschele C et al. J Clin Oncol July 2011
STAR TRIAL RESULTS
5-FU CRT 5-FU/Oxal CRT p-value
Path CR 16% 16% 0.94
Gr 3-4 toxicity
Any
Diarrhea
8%
4%
24%
15%
<0.0001
<0.0001
Grade 2-3 neurosensory
0.5% 36% <0.0001
Aschele C et al. J Clin Oncol July 2011
ACCORD 12/0405-Prodige 2
Eligibility
• T3-4, N0-2, M0 resectable (or T2 distal anterior) rectal cancer, DRE accessible
CAPOX/RT50RT 50 Gy x 5 wksCAPE 800 mg/m2 BID/day*OXA 50 mg/m2 weekly
CAPE/RT45RT 45 Gy x 5 wksCAPE 800 mg/m2 BID/day*
Adjuvant chemotherapy (Center discretion)
(6 weeks)
Total Mesorectal Excision (TME)
R
*Except weekend
Gerard JP et al. J Clin Oncol 2010;28(10):1638-44.
ACCORD 12 TRIAL RESULTS
CAP/RT CAPOX/RT p-value
Path CR 14% 19% 0.11
Gr 3-4 toxicity
Any
Diarrhea
Neuropathy
11%
3%
0.4%
25%
13%
5%
<0.001
<0.001
<0.002
Standard of care remains 5-FU based neoadjuvant CRT without oxaliplatin.
Gerard JP et al. J Clin Oncol 2010;28(10):1638-44.
OVERVIEW
• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative Chemoradiation• Optimizing Preoperative Chemoradiation• Postoperative chemotherapy after neoadjuvant CRT • Future Approaches
Decline in the rates of local failure:1980-2010 The war we are winning
35
30
25
20
15
10
5
0
Loca
l fai
lure
(%)
sx only sx RT sx CTRT CTRT TME
Deline in the rates of distant failures: 1980-2010 The war we are losing
40
35
30
25
20
15
10
5
0
Dis
tant
met
asta
ses
(%)
sx only sx RT sx CTRT CTRT TME
Gunderson, L. L. et al. J Clin Oncol; 22:1785-1796 2004
(NCCTG 794751, 864751; NSABP R01, R02; INT 0114) n=3791
CT
No CT
Postoperative chemotherapy in Rectal Cancer (no preoperative treatment in these studies)
Lancet 2007 Lancet 2007; 370: 2020–29; 370: 2020–29
Recurrence free survival
Overall survival
Postoperative chemotherapy in Rectal Cancer QUASAR STUDY-Rectal Cohort(29%) n=948
Postoperative chemotherapy in Rectal Cancer
ECOG 3201
Stage II/IIRectal Cancer
Preop or Postop CRT (MD Choice)
R
5FU/LV
FOLFOX4
FOLFIRI
Closed at 225 of planned 3150
Bosset NEJM 2006
Bosset NEJM 2006
Collette, L. et al. J Clin Oncol; 25:4379-4386 2007
Who benefits from post operative 5FU?(ypT downsized)
Postoperative chemotherapy after neoadjuvant CRT
5FU/FA:-Only trend in EORTC study(negative)-Only level 1 study to date -Standard in postoperative CRT era-QUASAR,INT 0114/0144
Xeloda:-Only extrapolation from stage 3 colon cancer(X-ACT)
FOLFOX: -Only extrapolation from stage 3 colon cancer(MOSAIC,CO7)
Postoperative chemotherapy after neoadjuvant CRT • All patients should get some chemo regardless of ypT
ypN statusplan set preoperatively
• Duration should be 4 months
• Choice of Xeloda vs FOLFOX individualized
• If no downstaging- FOLFOX?
• If short-course preop-XRT – 6 months
STUDIES OF CHEMOTHERAPY IN RECTAL CANCER
Pre-op: STAR( 5FU +/- OXALIPLATIN)-Published JCO 2011
ACCORD(XELODA +/- OXALIPLATIN)- Published JCO 2010 NASBP R-04( 5FU vs. XELODA +/- OXALIPLATIN)-ASCO 2011
Post-op: SCRIPT (XELODA vs. Nil)-Closed for accrual issues CHRONICLE (XELOX vs. Nil)- Closed for accrual issues
E5204 (FOLFOX +/-AVASTIN)- Closed for accrual issues Pre and Post-op: CAO/ARO/AIO 04(5FU+/-Oxaliplatin---PRE/POST)- report 2011
PETACC-6(XELODA +/- OXALIPATIN---PRE/POST)-ongoing
Operable Rectal Cancer-Clinical Stage2/3
↓ Preop CRT/5 day rads ↓ TME surgery ↓ Randomization Observation Capecitabine CLOSED DUE TO POOR ACCRUAL
SCRIPT STUDY
CHRONICLE STUDY
CLOSED DUE TO POOR ACCRUAL
ECOG 5204 Phase III Trial (NCIC CRC.4)
Stage II/III R
mFOLFOX6 X 12
mFOLFOX6 + Bev X 12
Accrual: 2100 planned- CLOSED DUE TO ACCRUAL -2009
CAO/ARO/AIO 04
Rodel et al ASCO 2011
CAO/ARO/AIO 04
Rodel et al ASCO 2011
CAO/ARO/AIO 04
Rodel et al ASCO 2011
CAO/ARO/AIO 04
Rodel et al ASCO 2011
Conclusion
PETACC 6
ONGOING
OVERVIEW
• Introduction• Postoperative Chemoradiation• Preoperative Radiotherapy(no chemo)• Preoperative Chemoradiation• Preoperative vs Postoperative
Chemoradiation• Optimizing Preoperative Chemoradiation• Post operative adjuvant chemotherapy• Future Approaches
Newer approaches-Phase 2
Newer approaches-Phase 2
Newer approaches-Phase 2EXPERT trial
Newer approaches-Phase 2
Newer approaches-Phase 2
Newer approaches-Phase 2
Newer approaches-Phase 2
Patients with progressive orstable disease XRT + 5-FU FOLFOX + Bev
FOLFOX + Bev x 4 FOLFOX x 2
Patients with clinical regression Surgery*
Newly diagnosed clinical stage II or III rectal adenocarinoma
*Post-operative treatment atdiscretion of physician.FOLFOX x 6 recommended; nopost-operative Bev provided.
Schrag D et al. Proc ASCO 2010;Abstract 3511.
Newer approaches-Phase 2
• 31 patients with Stage II/III (no T4) rectal • 27/27 patients had regression and proceeded
to surgery with no XRT
• 27 had R0 resection and 7/27 (26%) pCR
• One pt with 14/14 nodes offered post-op XRT
Newer approaches-Phase 2
Schrag D et al. Proc ASCO 2010;Abstract 3511.
CALGB Phase II/III “PROSPECT” study
Newer approaches-Phase 2
• Accurate preoperative imaging -MRI Staging
• Multidisciplinary Tumour Board discussion
• Use of preoperative radiation with or without chemotherapy
• Surgical concept of TME resections
• Pathologists “auditing” the surgical procedure -TME quality, CRM, nodal recovery • Postoperative chemotherapy
SUMMARY APPROACH TO RECTAL CANCER-2011
Questions
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