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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
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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 Discussant: Al B. Benson III, MD, FACP Northwestern University Feinberg School of Medicine
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 30-33 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):597-602.
Advances in Rectal Cancer 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
Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases Randomise POST PRE Pre-operative RT 25Gy / 5F Surgery Pathology Surgery CRM-ve CRM+ve Pathology Post-op CRT 45Gy / 25F + concurrent 5FU No RT Adjuvant chemotherapy given as per local policy Trial Design
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%
100 90 80 70 LR rate (%) 60 50 40 30 20 10 0 5 0 1 2 3 4 Time(Years) LR by treatment (ITT) N Events 3yr LR 5yr LR PRE 674 23 5% 5% POST 676 61 11% 17% HR(95%CI)=2.47(1.61, 3.79) p<0.0001 Number at risk Pre 674 501 365 247 156 76 Post 676 511 363 246 141 55
Local Recurrence: Pre-op vs Post-op Pre-opSurgery 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-opSurgery 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%
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 -ve Mesorectal plane18 537 3% 8% Intramesorectal plane17 331 7% 8% Muscularis propria plane 11 113 12% 17% CRM +ve Mesorectal plane450 9% 19% Intramesorectal plane5 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 (Birbeck et al, Ann Surg 2002;235, 449-457)
Risk of local failure vs. margin after TME
Preoperative radiation and mesorectal resection (Dutch Colorectal Cancer Group)
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 13.8 No regression 15.3 63 75 385 pts RT: 50.4 Gy + 5-FU Rodel, JCO 2005; 23:8688-8696
Response No. of Patients % Pathologic response 32* Complete response 8 25 ypT1 0 0 ypT2 6 19 ypT3 18 56 Node negative 23 72 R0 resection 30 94 CALGB 89901: Efficacy NOTE. Clinical T4 at entry, n = 5; pathologic complete response, n = 2. * At phase II dose. 90% CI, 13% to 41%. JCO 2006; 24(16):2557-2565
NSABP R - 04 (October 2005) Randomization Group 1 Group 2 Group 3 Group 4 CVI 5FU CVI 5FU Cape Cape + + Oxali Oxali All patients receive pelvic radiation therapy
E5204 Schema(Postoperative Systemic Therapy) Stage II or III Rectal cancer mFOLFOX6 12 Cycles Randomize mFOLFOX6 + Bevacizumab All patients receive preop chemoradiation n = 2,100
PETACC-6 (EORTC) Capecitabine / RT (45 Gy) TME Capecitabine Capecitabine / Oxaliplatin (50 mg/m²) RT (45 Gy) Capecitabine / Oxaliplatin TME N = 1,100 1° Endpoint = 3-year DFS