Rectal Cancer MOTP Half Day September 9, 2008 Yoo-Joung Ko

Outline Rectal Anatomy Evidence Importance of Quality of TME Unique aspects of a rectal primary Evidence Post Op Combined Modality Pre Op Pre Op vs Post Op Importance of Quality of TME Controversies Colon CA What regimen do? How long should we treat? Who should we treat?

Rectal Anatomy Pelvic size/structures: M vs. F Portion of Rectum Left upper valve of Houston cm from anal verge Right middle valve of Houston upper 1/3 middle 1/3 lower 1/3 15 Peritoneum 10 Ampulla of Rectum Left lower valve of Houston 6 20. Rectum: Anatomy The rectum is approximately 15 cm long and can be divided into the upper, middle, and lower thirds. Rectal cancer is localized by reference to the anal verge, dentate line, or anorectal ring. Pelvic size/structures: M vs. F Anal verge Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1197.

Rectal Cancer: Unique Aspects Below the peritoneal reflection Different surgical approach Total mesorectal excision (TME) Risk of local recurrence Significant morbidity

Rectal Cancer Staging False + T3 False + LN Transrectal U/S 10% 30% CT scan 20% MRI

Post Op Combined Modality

Advantages of Postoperative Treatment Accurate pathologic staging Less likely to overtreat Shorter delay to definitive therapy ie surgery Potentially less surgical morbidity No complicated by prior XRT-chemo

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 JAMA 1990: 264:1444-1450

NCCTG Intergroup Trial (postop trial) 2x2 study design: PVI 5-FU during XRT better significant decrease in relapse (47% to 37%, p=0.01) reduction in distant metastases (40% to 31%, p=0.03) no difference in local failure rate MeCCNU: no benefit NEJM 1994

Bolus 5FU-Leucovorin-Levamisole Tepper, JCO 1997 Intergroup 0114 CT – CRT - CT Bolus 5FU II III Bolus 5FU-Levamisole R Bolus 5FU-Leucovorin Bolus 5FU-Leucovorin-Levamisole CP1050909-25

Intergroup 0114 1696 patients with resected stage II/III rectal cancer Similar toxicity, similar efficacy – no difference in DFS or OS Local Recurrence rate 14-18% 5year OS – 61-65% Tepper, JCO 1997

PVI5FU – XRT+PVI5FU – PVI5FU b5FU/LV/LEV – XRT+5FU/LV – b5FU/LV/LEV Intergroup 0144 b5FU – XRT+PVI5FU – b5FU II III PVI5FU – XRT+PVI5FU – PVI5FU R b5FU/LV/LEV – XRT+5FU/LV – b5FU/LV/LEV Smalley, JCO2006

Intergroup 0144, n=1917 Overall survival in the three arms is shown here with arm A (PVI only during XRT) in white; arm B (consistent PVI throughout therapy) in orange; and arm C biochemically modulated bolus 5-FU alone in yellow. Stratified cox model analysis of these 3 arms yielded a p value of 0.14 Less hematologic toxicity with bolus FU

Preoperative Radiotherapy

Preoperative Therapy Lack of surgical staging Potential overtreatment minimized by better imaging XRT better tolerated (tissues better oxygenated) Sphincter preservation Less small bowel irradiation ?early irradication of micrometastatic disease

Preop RT (25 Gy in 5 fractions) Swedish Rectal Cancer Study Decrease LR and improves OS Preop RT (25 Gy in 5 fractions) R LR 11%, 5yr OS 58% Immediate surgery TME not uniform High local recurrence rates in both arms No chemotherapy hypofractionation LR 27%, 5yr OS 48% (NEJM 1997)

TME + Preop RT (25 Gy in 5 fractions) Dutch Colorectal Group (NEJM 2001) No OS benefit at 2 yrs TME + Preop RT (25 Gy in 5 fractions) R LR 2.4%*, 2yr OS 82% TME alone Evaluate preop therapy in addition to TME No survival benefit at 2 years No chemotherapy Hypofractionation LR 8.2%, 2yr OS 82% *62% rate of fecal incontinence with XRT

Preoperative vs Postoperative XRT

German Rectal Cancer Study Group, Adjuv. vs. neoadjuv. CRT (CAO/ARO/AIO-94) 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 500 mg/m2/d 120h-infusion 120h-infusion i.v.-bolus S Arm I: RT: 50.4 + 5.4 Gy Boost 5-FU 5-FU 5-FU 5-FU 500 mg/m2/d I.v.bolus 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 120h-infusion 120h-infusion S Arm II: 2 prior US studies comparing Preop and Postop closed due to poor accruel RT: 50.4 Gy 0 2 4 6 8 10 12 14 16 18 20 22 Weeks Sauer NEJM 2004

Intent-to-treat Analysis (Med. Follow-up: 40 mts) Overall Survival Intent-to-treat Analysis (Med. Follow-up: 40 mts) Overall Survival 1.0 Postop CRT .9 74% Overall Survival .8 Preop CRT 74% .7 Primary endpoint .6 10 20 30 40 50 60 Months

Chronic Toxicity (Grade 3/4) Analysis per protocol Postop. RCT 14.8 % 11.8 % 3.4 % 22.7 % Preop. RCT 9.5 % 4.0 % 2.2 % 9.6 % Gastrointestinal Anastomosis Bladder All Toxicities n.s. 0.006 0.04

Sphincter Preserving Surgery ITT Analysis Postoper. RCT Preoper. RCT n= 394 n = 405 85 109 17/85 (20%) 43/109 (39%) Pre-randomiz: “APR Necessary“ More distal tumors in the preop arm Sphincter preserved p = 0.004

12% 6% Cumulative Incidence of Local Relapses Intent-to-treat Analysis (Med. Follow-up: 40 mts) 60 50 40 30 20 10 .14 .12 .10 .08 .06 .04 .02 0.00 Months 12% Postop CRT Locoregional Recurrences 6% p = 0.006 Preop CRT

Cumulative Incidence of Metastases Intent-to-treat Analysis (Med. Follow-up: 40 mts) 60 50 40 30 20 10 .4 .3 .2 .1 0.0 Months Distant Metastases 32% Postop CRT 32% Preop CRT

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 NO effect on overall survival 18% in postop arm were overstage (ie initially T3/T4 but really T1/2)

Local recurrence after rectal cancer resection is strongly related to the plane of surgical (PoS) dissection and is further reduced by pre-operative short course radiotherapy Preliminary results of the MRC CR07/NCIC C016 randomised trial Phil Quirke on behalf of the trial investigators and the UK NCRI colorectal cancer study group

Trial Design POST PRE Adjuvant chemotherapy given as per local policy Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases Randomise POST PRE Pre-operative RT 25Gy / 5F Surgery Pathology (Pos) Surgery CRM-ve CRM+ve Pathology (PoS) CRM-ve CRM+ve No RT Post-op CRT 45Gy / 25F + concurrent 5FU Adjuvant chemotherapy given as per local policy

CRO7/NCIC CO.16 Equivalence study Pre-op (n=674) Selected post-op (n=676) p value Surgery: Anterior resection APR 60% 31% 63% NS Anastomotic leak 8% 7% CRM positivity 10% 12% T/N staging More T3 5y Local recurrence (1o endpt) 5% 17% HR=2.47 p<0.0001 Distant metastases N=98 N=106 3y DFS 80% 75% 0.03 3y OS (early for this endpoint) 81% 79% 0.07

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% To place these results in context, compared to a few recently-reported high-profile analyses, the preoperative CR07 patients fared as well as those in the German trial administering more prolonged radiation and somewhat better than those evaluated in the large meta-analysis and in the Swedish study that also included 25 Gy short-course radiation.

Pre-op vs Post-op (cont.) Local Recurrence: Pre-op vs Post-op (cont.) Post-op Surgery S + RT Survival 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% The postoperative CR07 patients, however, did not fare as well – particularly compared to the two US Intergroup postoperative chemoradiation adjuvant trials, nor to the postoperative radiation group in the German trial. Of note, all three of these previously-reported trials administered higher dose radiation.

CO.16 - Summary Local recurrence rate is significantly reduced with pre-op RT compared to post-op RT Results after post-op chemo/RT poor comared to other trials and are especially poor for Stage III and CRM-positive patients Study included patients not usually considered for RT * Stage I (315/1211 pts) Many patients did not receive optimal TME (523/1119) pts

High efficacy of short-course schedule also has been confirmed by the MRC CR07 randomized trial (ASCO Meeting 2006 ) 1350 patients Routine pre-op 5 x 5 Gy + TME vs TME + selective post-op chemoradiation for those with involvement of circumferential resection margin (CRM+)

The MRC C-07 study 1350

MRC CR07 trial: 5-year results Routine pre-op Selective post-op 5 x 5 Gy chemoradiation Local recurrence 5% 17% p<.001 Disease-free surv. 75% 67% p=.03 Overall surv. 72% 62% p=.07

Prognosis QOL of surgery Complete TME Incomplete TME

MCR- C07 study: Quality of TME Surgery Excellent : 53% Average : 34% Bad: 13%

MCR- C07 study: Quality of TME Surgery and CRM+ Excellent : 9% Average : 12% Bad: 19%

Controversies

Optimizing Preoperative Chemoradiation

Can we replace PVI-5FU with Capecitabine With RT Can we replace PVI-5FU with Capecitabine With RT? What about Oxalilatin with RT?

NSABP R-04 Oxaliplatin 50mg/m2 IV weekly X 5

Postoperative/Post CRT – Adjuvant Chemotherapy In Whom? Which Regimen? For How Long? Postoperative/Post CRT – Adjuvant Chemotherapy

Unanswered Questions Remain In Whom? Clinical stage versus Pathologic stage Downstaged to pathologic CR (ypCR)… Which regimen? 5FU/LV versus Capecitabine versus FOLFOX For How Long? 4 months versus 6 months

Which Regimen?

PETACC-6: T3,4 or N+ Rectal Cancer R0-resectability certain XRT 5 x 5 Gy XRT 45 Gy +/- 5.4 Gy Boost with Cape or FU R0-resectability uncertain XRT 45 Gy +/- 5.4 Gy Boost with Cape or FU T M E Cape 6 mos. 5-FU bolus (NCI consensus/ previous German trial) XRT 45 Gy +/- 5.4 Gy Boost with XELOX XELOX 4 – (6) mos. German protocol from previous trial (AIO/ARO/CAO-94)

ECOG 5204 Phase III Trial (NCIC CRC.4) mFOLFOX6 X 12 Stage II/II Preop CRT (Cape, FU) -NSABP R04 IF preop oxali: 9 cycles mFOLFOX6 + 3 cycles 5FU/LV R mFOLFOX6 + Bev X 12 Accrual: 2100 planned

Is there a current standard? Concurrent Preop long-course XRT Continuous infusion 5FU* Capecitabine being studied Adjuvant Chemotherapy Consider in all pts who receive CRT ? Group who doesn’t need post op therapy - ? Path CR 5FU/LV X 4 cycles is a standard Capecitabine may be an option FOLFOX is a reasonable option particularly in higher risk How do we define risk? Minimum duration of 4 months

Conclusions Unique aspects of rectal cancers Preop Chemoradiation reduces local recurrences and may improve OS Longer radiation with infusional FU standard Optimal preop staging critical Surgical TME techinque important Postop chemotherapy important Optimal chemotherapy and duration of treatment not yet defined

In Whom?

Who is high risk? Prognostic data from Sauer trial may help (Rodel, JCO 2005) in absence of definitive data to define risk in patients having had pre-op chemo rads

Prognostic factors – Pretreatment cT/cN? cT2 (n=16) cT3 (n=268) cT4 (n=24) Disease-free Survival 1.0 .8 .6 .4 .2 20 40 60 80 100 Months cN+ (n=213) cN0 (n=154) p=0.92 p=0.34

Prognostic factors – ypT/ypN Disease-free survival after R0-resection (n=344) 1.0 ypT1 1.0 ypT0 ypNO .8 .8 ypT2 ypN1 ypT3 .6 .6 Disease-free Survival ypT4 .4 .4 ypN2 .2 .2 p=0.001 p<0.0001 20 40 60 80 100 20 40 60 80 100 Months Months

Moderate/Good Regression No/Minimal Regression TRG 0+1 (n=27) Moderate/Good Regression TRG 2+3 (n=77) ypT3 ypN0 M0 R0 Submucosa T1 Muscularis propria T2 Subserosa T3 Adjacent organs T4 TRG 4 : No Viable Primary Tumour

Prognostic factors – Multivariate analysis p-Value Odds ratio Disease-Free Survival: ypT category 0.016 1.48 ypN category <.0001 2.68 Metastases-Free Survival: ypT category 0.014 1.49 ypN category <.0001 2.59 Local Relapse-Free Survival ypN category <0.001 3.86

Summary and Conclusion cT/cN: no significant prognostic impact – room for improvement! ypT/ypN: strongest prognostic factors – treatment stratification? TRG: discrimination of pts. with identical ypTNM? Need validation!!