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