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, FACP Northwestern University Feinberg School of Medicine

Four goals of Rectal Cancer Treatment Local Control Long-term Survival Preservation of Anal Sphincter, Bladder, and Sexual Function Maintenance or Improvement in Quality of Life Additional Clinical Trial Goal Development of prognostic / predictive markers

Surgical Management Issues Total mesorectal excision (TME) Autonomic nerve preservation (ANP) Circumferential resection margin (CRM) Distal resection margin Sphincter preservation and options for restoration of bowel continuity Postoperative quality of life Balch et al World J Gastroenterol (20):

Advances in Rectal Cancer Staging, Radiation, Surgery Endorectal Ultrasound (ERUS) Preoperative Chemoradiation Sphincter Preservation Total Mesorectal Excision (TME) Circumferential Resection Margin (CRM) Adequate Lymph Node Dissection

Adjuvant radiation therapy Preoperative  Potential downstaging  Improved probability of sphincter-sparing  Decreased operative seeding  Lower chronic toxicity  Potential overtreatment  Increased surgical morbidity Postoperative  Accurate staging and selection of adjuvant therapy  Increased radiation morbidity

Advantages of different preoperative regimens European approach Short course – high dose – immediate surgery  No change in path staging  Lower cost  Better compliance  Dose equivalent to Gy  Expect 66% reduction in local recurrence American approach Prolonged course – high dose – delayed surgery  Better surgical tolerance  More tumor regression  Expect >80% reduction in local recurrence Withers HR and Haustermans K, 2004; Int J Rad Onc Biol Phys 58(2):

Advances in Rectal Cancer Staging, 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 RT 25Gy / 5F Surgery Pathology Surgery Pathology CRM-ve CRM+ve Post-op CRT 45Gy / 25F + concurrent 5FU 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 Post N Events3yr LR 5yr LR PRE % 5% POST % 17% HR(95%CI)=2.47(1.61, 3.79) p<0.0001

Local Recurrence: Pre-op vs Post-op Pre-opSurgeryS + RTSurvival Meta-analysis22%12.5%S + RT 45% S 42% Swedish Trial (25 Gy, 5 tx)27%12%S + RT 58% S 48% Dutch (TME) Trial8.2%2.4% German 50.4 Gy - 546%76% CR07 25 Gy / 5 tx5%72%

Local Recurrence: Pre-op vs Post-op (cont.) Post-opSurgeryS + RTSurvival Meta-analysis22.9%15.3% German Trial (50.4—54.0 Gy, 5 tx)13%74% Intergroup %53-67% Intergroup %67-72% CR07 (45 Gy)17%61.7%

LR by distance from the anal verge 3yr 5yr HR (95%CI) Distance from anal verge Events/NPRE POST 0-5cm29/4446%7%10%17%2.0 (0.97,4.15) >5-10cm39/6745% 10%16%2.14 (1.14,4.02) >10-15cm15/2041% 16%19%4.94 (1.79,13.64)

LR by CRM positivity 3yr 5yr HR (95%CI) CRMEvents/NPRE POST CRM-ve58/10933%4%10%14%2.91 (1.74,4.88) CRM+ve18/13916% 23%31%1.56 (0.60,4.04) All patients 84/13505% 11%17%2.47 (1.61,3.79)

LR by TNM Stage 3yr 5yr HR (95%CI) TNM StageEvents/NPRE POST I4/3150% 3%6% (1.64,90.41) II16/3702% 8%12% 3.47 (1.29,9.35) III56/5269%10%17%25% 2.02 (1.20,3.42)

Plane of surgery n=1,119 (83%) Mesorectal plane % Intramesorectal plane % Muscularis propria plane %

LR by CRM and plane Events N3yr LR 5yr LR CRM -ve Mesorectal plane % 8% Intramesorectal plane % 8% Muscularis propria plane %17% CRM +ve Mesorectal plane %19% Intramesorectal plane %21% Muscularis propria plane %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 <

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, )

Risk of local failure vs. margin after TME Adams <1 mm margin >1 mm margin 74%10% Hida Positive margin Negative margin 50%17% Birbeck Positive margin <1 mm margin >1 mm margin 58%28%10%

Preoperative radiation and mesorectal resection (Dutch Colorectal Cancer Group) Local Failure Preop RT Local Failure Surgery alone Overall2.4%8.2% Distance from verge cm 5-10 cm <5 cm 1.3%1.0%5.8%3.8%10.1%10% Type of resection Low anterior APR1.2%4.9%7.3%10.1% TNM stage IIIIII0.5%1.5%4.3%0.7%5.7%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% pts5-year DFS % No tumor > 50% regression52.2 < 50% regression13.8 No regression pts RT: 50.4 Gy + 5-FU Rodel, JCO 2005; 23:

ResponseNo. of Patients% Pathologic response32 * Complete response8 25 ypT100 ypT2619 ypT31856 Node negative2372 R0 resection3094 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):

NSABP R-04 (October 2005) Randomization Group 1 Group 2Group 3Group 4 CVI 5FU +Oxali CapeCape + 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 III Rectal cancer n = 2,100

Capecitabine / Oxaliplatin (50 mg/m²) RT (45 Gy) PETACC-6 (EORTC) Capecitabine / RT (45 Gy) TME Capecitabine Capecitabine / Oxaliplatin N = 1,100 1° Endpoint = 3-year DFS

P<0.0001