preliminary results of the mrc cr07 / ncic co16 randomized trial
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Preliminary Results of the MRC CR07 / NCIC CO16 Randomized Trial. Short course pre-op vs selective post-op chemo-RT for rectal cancer Local Recurrence after Rectal Cancer Resection is Strongly Related to the Plane of Surgical Dissection 2006 ASCO abstracts 3511, 3512 - PowerPoint PPT PresentationTRANSCRIPT
Preliminary Results of the MRC CR07 / NCIC CO16 Randomized Trial
Short course pre-op vs selective post-op chemo-RT for rectal cancer
Local Recurrence after Rectal Cancer Resection is Strongly Related to the Plane of Surgical Dissection
2006 ASCO abstracts 3511, 3512
Discussant: Al B. Benson III, MD, FACPNorthwestern University Feinberg School of Medicine
Advances in Rectal CancerStaging, Radiation, Surgery
• Endorectal Ultrasound (ERUS)
• Preoperative Chemoradiation
• Sphincter Preservation
• Total Mesorectal Excision (TME)
• Circumferential Resection Margin (CRM)
• Adequate Lymph Node Dissection
Adjuvant radiation therapy
PreoperativePotential downstagingImproved probability of
sphincter-sparingDecreased operative
seedingLower chronic toxicityPotential overtreatmentIncreased surgical
morbidity
PostoperativeAccurate staging and
selection of adjuvant therapy
Increased radiation morbidity
Advantages of different preoperative regimens
European approachShort course – high dose
– immediate surgery No change in path
staging Lower cost Better compliance Dose equivalent to 30-
33 Gy Expect 66% reduction
in local recurrence
American approachProlonged course – high
dose – delayed surgery
Better surgical tolerance
More tumor regression Expect >80%
reduction in local recurrenceWithers HR and Haustermans K, 2004; Int J Rad Onc Biol Phys 58(2):597-602.
Advances in Rectal CancerAdvances in Rectal CancerStaging, Radiation, Surgery
• Endorectal Ultrasound (ERUS)
• Preoperative Chemoradiation
• Sphincter Preservation
• Total Mesorectal Excision (TME)
• Circumferential Resection Margin (CRM)
• Adequate Lymph Node Dissection
Trial Design
Randomise
Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases
Adjuvant chemotherapy given as per local policy
PRE POST
Pre-operative RT25Gy / 5F
Surgery
Pathology
Surgery
Pathology
CRM-ve CRM+ve
Post-op CRT45Gy / 25F
+ concurrent5FU
No RT
MRC CR07 / NCIC C016
Large Study: 1,350 patients
Completion of a Pre-op vs Post-op Trial
50% patients: T3 N0
Adjuvant tx: 1,090 patients (81%) CRM: 13%
LR by treatment (ITT)
Number at risk
Pre 674 501 365 247 156 76
Post 676 511 363 246 141 55
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5Time(Years)
LR
rat
e (%
)
N Events 3yr LR 5yr LRPRE 674 23 5% 5%POST 676 61 11% 17%
HR(95%CI)=2.47(1.61, 3.79) p<0.0001
Local Recurrence: Pre-op vs Post-op
Pre-op Surgery S + RT Survival
Meta-analysis 22% 12.5% S + RT 45%S 42%
Swedish Trial (25 Gy, 5 tx) 27% 12% S + RT 58%S 48%
Dutch (TME) Trial 8.2% 2.4%
German 50.4 Gy - 54 6% 76%
CR07 25 Gy / 5 tx 5% 72%
Local Recurrence: Pre-op vs Post-op (cont.)
Post-op Surgery S + RT Survival
Meta-analysis 22.9% 15.3%
German Trial (50.4—54.0 Gy, 5 tx) 13% 74%
Intergroup 0114 50.4 -- 54 9-13% 53-67%
Intergroup 0144 50.4 -- 54 4.6-8% 67-72%
CR07 (45 Gy) 17% 61.7%
LR by distance from the anal verge
3yr 5yr 3yr 5yr HR (95%CI)
Distance from anal
verge
Events/N PRE PRE POST POST
0-5cm 29/444 6% 7% 10% 17% 2.0
(0.97,4.15)
>5-10cm 39/674 5% 5% 10% 16% 2.14
(1.14,4.02)
>10-15cm 15/204 1% 1% 16% 19% 4.94
(1.79,13.64)
LR by CRM positivity
3yr 5yr 3yr 5yr HR (95%CI)
CRM Events/N PRE PRE POST POST
CRM-ve 58/1093 3% 4% 10% 14% 2.91
(1.74,4.88)
CRM+ve 18/139 16% 16% 23% 31% 1.56
(0.60,4.04)
All patients
84/1350 5% 5% 11% 17% 2.47
(1.61,3.79)
LR by TNM Stage
3yr 5yr 3yr 5yr HR (95%CI)
TNM Stage Events/N PRE PRE POST POST
I 4/315 0% 0% 3% 6%
12.19
(1.64,90.41)
II 16/370 2% 2% 8% 12%
3.47
(1.29,9.35)
III 56/526 9% 10% 17% 25%
2.02
(1.20,3.42)
Plane of surgery n=1,119 (83%)
•Mesorectal plane 596 53%
•Intramesorectal plane 382 34%
•Muscularis propria plane 141 13%
LR by CRM and plane
Events N 3yr LR 5yr LR
CRM -veMesorectal plane 18 537 3% 8%Intramesorectal plane 17 331 7% 8%Muscularis propria plane 11 113 12% 17%
CRM +veMesorectal plane 4 50 9% 19%Intramesorectal plane 5 45 14% 21%Muscularis propria plane 5 27 26% 36%
INT 0114: Total Local Recurrence – 5 Yr. 14% – Overall (17% at 7 yrs) 8% – T1,2N+ 9% – T3N0 18% – T3N+ 24% – T4 any N RR of 2.1 between low risk (T1,2N+ or T3N0) and high risk (T3N+ or T4 any N) –
P < 0.0001
Total mesorectal excision = improvement in circumferential margins
Ability to obtain margins is surgeon dependent
Hospital volume improves results
Ability to obtain margins is stage dependent
Stage <1 mm margin
A
B
C1
C2
D
1.1%
21.2%
38.6%
50%
47.9%
(Birbeck et al, Ann Surg 2002;235, 449-457)
Risk of local failure vs. Risk of local failure vs. margin margin
after TMEafter TME AdamsAdams <1 mm <1 mm
marginmargin>1 mm >1 mm marginmargin
74%74%10%10%
HidaHida Positive Positive marginmarginNegative Negative marginmargin
50%50%17% 17%
BirbecBirbeckk
Positive Positive marginmargin<1 mm <1 mm marginmargin>1 mm >1 mm marginmargin
58%58%28%28%10%10%
Preoperative radiation and mesorectal Preoperative radiation and mesorectal resection (Dutch Colorectal Cancer resection (Dutch Colorectal Cancer
Group)Group)Local Local
FailureFailurePreop RTPreop RT
Local FailureLocal FailureSurgery Surgery alonealone
OverallOverall 2.4%2.4% 8.2%8.2%
Distance from Distance from vergeverge10-15 cm10-15 cm5-10 cm5-10 cm<5 cm<5 cm
1.3%1.3%1.0%1.0%5.8%5.8%
3.8%3.8%10.1%10.1%10%10%
Type of resectionType of resectionLow anteriorLow anteriorAPRAPR
1.2%1.2%4.9%4.9%
7.3%7.3%10.1%10.1%
TNM stageTNM stageIIIIIIIIIIII
0.5%0.5%1.5%1.5%4.3%4.3%
0.7%0.7%5.7%5.7%15%15%
Summary
Local recurrence rate is significantly reduced with pre-op RT compared to post-op RT
Results after post-op chemo/RT are especially poor for Stage III and CRM-positive patients
Study included patients not usually considered for RT
* Stage I (315/1211 pts)* Upper rectal tumors (204/1322 pts)
- small numbers but LRR is surprisingly high
Summary (cont.)
Distant metastases rate is similar suggesting some impact on survival secondary to LR
Many patients did not receive optimal TME (523/1119 pts) with a significant effect on LR
Additional data:* Preoperative staging methods* LR rate by CRM +/- and LN +/- * Number of LNs sampled
Summary (cont.)
Strategies for evaluation and treatment of rectal cancer:
* Define individual patient risk* Staging: ERUS, MRI/CT prior to tx* Recommend pre-op chemo/RT for pts at risk for LR* TME* Quality assurance of radiation, surgery, pathology* Risk of recurrence can continue > 5 years
- Surveillance strategies
Questions Which subsets of pts may not need RT?
Which pre-op RT schedule?: short course v. prolonged course
* Define importance of downstaging* Define impact of pCR on survival
Define optimal chemo/RT and adjuvant chemotherapy* i.e., optimize survival
Monitor acute/chronic toxicities
Tumor biology
Prognostic Significance of Tumor Regression after Preoperative Chemoradiation
CAO / ARO / A10-94
Path % pts 5-year DFS %
No tumor 10.4 86> 50% regression 52.2< 50% regression 13.8No regression 15.3 63
75
385 ptsRT: 50.4 Gy + 5-FU
Rodel, JCO 2005; 23:8688-8696
Response No. of Patients %
Pathologic response 32*
Complete response 8 25
ypT1 0 0ypT2 6 19ypT3 18 56Node negative 23 72R0 resection 30 94
NOTE. Clinical T4 at entry, n = 5; pathologic complete response, n = 2.* At phase II dose. 90% CI, 13% to 41%.
CALGB 89901: Efficacy
JCO 2006; 24(16):2557-2565
NSABP R - 04(October 2005)
Randomization
Group 1 Group 2 Group 3 Group 4
CVI 5FU CVI 5FU+ Oxali
Cape Cape +Oxali
All patients receive pelvic radiation therapy
E5204 Schema (Postoperative Systemic Therapy)
Randomize
mFOLFOX6
mFOLFOX6 +Bevacizumab
12 Cycles
All patients receive preop chemoradiation
Stage II or IIIRectal cancer
n = 2,100
Capecitabine /Oxaliplatin(50 mg/m²)RT (45 Gy)
PETACC-6 (EORTC)
Capecitabine / RT (45 Gy)
TME
TME
Capecitabine
Capecitabine /Oxaliplatin
N = 1,1001° Endpoint = 3-year DFS