Rectal Cancer: Classic Hits

Rectal Cancer: Classic Hits Charles M. Friel, MD Associate Professor of Surgery Section of Colon and Rectal Surgery University of Virginia September 28, 2016 None Disclosures 1

Objectives Review the Classic hits from the literature on the treatment of rectal cancer..over my lifetime and some other stuff too. Colon and Rectal Cancer Estimated 2015 133,000 new cases 49,000 deaths 40,000 Rectal Cancers 15,000 Deaths 2

Colon vs Rectal Cancer Different lymphatic drainage Anatomic differences Is the biology different?? Rectal Anatomy 3

Lymphatic Drainage Rectal lymphatics drain upward toward the IMA Case Presentation 52 year old man comes to the office with a biopsy proven adenocarcinoma 10 cm from the anus 4

1970 s 1970 s 5

Rectal Cancer 1970 s Surgery only real option Very little or no pre-operative evaluation Most likely get an APR Outcomes, even when curative were poor Survival in 40% Local recurrence very high 1970 s Radical resection Conventional approach Blunt dissection Emphasis on distal margin 5-10 cm distal margin APR most common procedure 6

Zollinger Atlas of Surgery - 1993 1970 s Localized disease Surgery could be curative Local recurrence up to 50% Stage I: 5-10% Stage II: 25-30% Stage III: upto 50% 7

Local Control A real problem Some people die of local disease without systemic disease Aggressive local control should improve quality of life and may even impact survival Why is local control a problem for rectal cancer 8

Why is local control a problem for rectal cancer Pelvis A Deep Hole 9

Why is local control a problem for rectal cancer Unlike colon cancer, local recurrence is a huge problem for rectal cancer!!!!! 10

1970 s Other Approaches Radiation Began a host of single institutional reports that radiation therapy may be beneficial 11

Gastrointestinal Tumor Study Group - GITSG Gastrointestinal Tumor Study Group - GITSG Question: Can we control cancer recurrence with: Chemotherapy Radiation Combined chemo and radiation 12

GITSG-1985 Postoperative Adjuvant Therapy Accrural 1975-1985 Goal 530 patients Randomized 227 Control Chemotherapy Radiation Combined chemoradiation 13

Disease Free Combined 70% Control 45% Survival Combined 56% Control 36% P=.07 14

GITSG Accrual stopped early because it was clear that patients with postoperative chemoradiation had improved outcomes GITSG Conclusions Postoperative adjuvant therapy decreases time to recurrence. Combined chemoradiation produced the best result Significantly improved local regional control with combined Less local recurrences, XRT Less distant recurrences, chemo Toxicity, while not minimal, was acceptable 15

National Surgical Adjuvant Breast and Bowel Project (NSABP)-1988 555 patients Accrural 1977-1986 Curative resection Dukes B,C Randomized to postoperative: Surgery alone Chemotherapy Radiation therapy NSABP Results Postoperative adjuvant therapy LR DM Suvival Control 25 27 43 CT 21 24 53 XRT 16 31 50 16

NSABP Results Postoperative adjuvant therapy LR DM Suvival Control 25 27 43 CT 21 24 53 XRT 16 31 50 NSABP Results Postoperative adjuvant therapy Radiation effective for local control. No impact on survival Chemotherapy effective for survival. No impact on local control 17

North Central Cancer Treatment Group - 1991 NCCTG 209 patients accrued, 1980-1986. Randomized to postoperative Radiation Chemotherapy and radiation 18

NCCTG Results Postoperative adjuvant therapy LR DM Suvival CT/XRT 14 29 53 XRT 23 46 38 NCCTG Results Postoperative adjuvant therapy Combined postoperative chemoradiation therapy improved LOCAL CONTROL SURVIVAL 19

NIH Consensus Statement 1990 Local regional control for rectal cancer is critical Stage II and Stage III patients at risk NIH Consensus Statement 1990 Stage I No adjuvant therapy Low local recurrence Excellent survival Stage II/III Combined postoperative chemo- and radiationtherapy Improved survival (marginal) Improved local control (significant) 50% reduction, but still high 20

Late 1980 s Early 1990 s Era of postoperative chemoradiation therapy for Stage II/III rectal cancer Improved local control and survival!!! Late 1980 s Early 1990 s 21

Late 1980 s Early 1990 s Next Question Can we do it better?? Pre-operative Therapy vs Postoperative therapy 22

Postoperative Pros Full pathological staging, avoids overtreatment No delay in surgical treatment?? Less complications Cons Complications lead to no treatment No down staging, no increase in sphincter preservation Radiating your anastomosis, small bowel Preoperative Pros Downstaging, shrinkage of tumors Sterilize margins, improve outcomes with bulky tumors Improved effects with better oxygenated tissus Removing irradiated tissue?? Better compliance Cons Overtreatment, poor selection Delay surgical therapy Wound healing, anastomotic leaks, surgical complications 23

Stockholm I 1995 Multicenter, 1980-1987 849 patients randomized Surgery alone Short course pre-operative radiation 25 Gy over 5 days Surgery within a week 24

Stockholm I Stockholm I 25

Stockholm I Much improved local control 16% vs 30% Increased complications Mostly wound related Increased perioperative mortality 8% vs 2% Mostly cardiovascular in patients >75 years Stockholm II 1987-1993 Adjusted radiation fields Age < 80 557 patients randomized Surgery Short course, high dose radiation followed by surgery 26

Stockholm II Pelvic recurrence Surgery - 25% Pre-op radiation 12% Survival, in patients with curative surgery Pre-op 46% Surgery 39% Stockholm II Pelvic recurrence Surgery - 25% Pre-op radiation 12% Survival, in patients with curative surgery Pre-op 46% Surgery 39% 27

Swedish Rectal Cancer Trial 1997 Improved Survival with Preoperative Radiotherapy in Resectable Rectal Cancer New England Journal 1997 28

Local Recurrence Swedish Rectal Cancer Trial Probability of Local Recurrence All Patients 1.0 0.8 Surgery alone Radiotherapy plus surgery 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 Dukes Stage A 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 Probability of Local Recurrence 1.0 0.8 0.6 0.4 0.2 Dukes Stage B 0.0 0.0 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Years Years Figure 1. Rates of Local Recurrence among All Patients Undergoing Resection, According to Dukes Stage and Treatment Assignment. The bars indicate 95 percent confidence limits 1.0 0.8 0.6 0.4 0.2 Dukes Stage C Local Recurrence Swedish Rectal Cancer Trial Probability of Local Recurrence Probability of Local Recurrence 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 0.0 0 1 2 3 4 5 6 7 8 9 Dukes Stage B Dukes Stage C 1.0 1.0 Local recurrence 11% vs 27% 0.8 0.8 favoring 0.6 radiation over 0.6 control 0.4 0.2 All Patients Surgery alone Radiotherapy plus surgery 0.0 0.0 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Years Years Figure 1. Rates of Local Recurrence among All Patients Undergoing Resection, According to Dukes Stage and Treatment Assignment. The bars indicate 95 percent confidence limits 1.0 0.8 0.6 0.4 0.2 0.4 0.2 Dukes Stage A 29

Survival Swedish Rectal Cancer Trial Probability of Survival All Patients 1.0 0.8 0.6 0.4 0.2 Surgery alone Radiotherapy plus surgery 0.0 0 1 2 3 4 5 6 7 8 9 Dukes Stage A 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 Probability of Survival Dukes Stage B 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 Years Dukes Stage C 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 Years Figure 2. Overall Survival among All Eligible Patients Undergoing Surgery, According to Dukes Stage and Treatment Assignment. The bars indicate 95 percent confidence limits. Survival Swedish Rectal Cancer Trial Probability of Survival All Patients Dukes Stage A 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 Surgery alone 0.2 Radiotherapy plus surgery Overall survival 58% vs 48%, 0.0 0.0 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Favoring radiation over control Probability of Survival 1.0 Dukes Stage B 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 Dukes Stage C 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 Years Years Figure 2. Overall Survival among All Eligible Patients Undergoing Surgery, According to Dukes Stage and Treatment Assignment. The bars indicate 95 percent confidence limits. 30

Mid 1990 s Pre-operative therapy becoming more common Still controversial Rectal Cancer What are the surgeons doing?? 31

Total Mesorectal Excision (TME) Total Mesorectal Excision 32

Total Mesorectal Excision Found tumor deposits in mesorectum up to 4 cm distal to the tumor Some drainage is downward in a retrograde fashion?? Cause of suture line recurrence and local recurrence Advocated complete mesorectal excision for rectal cancers Conventional Surgery Blunt Dissection Left mesorectum behind with lymph node metastases. NOT RECURRENCE..PERSISTENCE BAD SURGERY!!! 33

Zollinger Atlas of Surgery - 1993 Total Mesorectal Excision En bloc resection of rectum with surrounding lymphatic tissue Precise sharp dissection, keeping intact the fascia propia Complete dissection to pelvic floor, below the mesorectum Low pelvic anastomosis 34

Rectum is like a roll of Bounty 35

Rectum Mesoectum 36

Conventional Line of Dissection TME Line of Dissection Mesoectum 37

Total Mesorectal Excision Total Mesorectal Excision 38

39

TME Pelvis after specimen removed 40

Complete vs Incomplete TME Parfitt J R, Driman D K J Clin Pathol 2007;60:849-855 Bread loafing - TME Parfitt J R, Driman D K J Clin Pathol 2007;60:849-855 41

Total Mesorectal Excision Reported on 50 cases with TME 2 year follow up with no recurrences Total Mesorectal Excision Increased sphincter salvage Higher leak rates Surgical technique is critical to management of rectal cancer 42

TME Local Recurrence Selected Series Total Mesorectal Excision Surgical technique matters!!! With good surgery, is radiation necessary?? Are results reproducible?? Yes Can it be taught/learned?? 43

Can it be taught? Stockholm TME Project 1994-1997 3 workshops over 3-4 days each Live video Surgical training with Heald Specimen analysis Pathology training, circumferential radial margin 44

Stockholm TME Project 1994-1997 Surgeons from Stockholm I and II trials Stockholm TME Project Results 45

Local Recurrence Stockholm I and II, TME Project I II TME XRT 9% 6% 1.5% No XRT 21% 21% 9% Stockholm TME Project Much greater sphincter salvage 50% less local recurrence TME results and radiation effects seemed additive!!! 46

TME vs Radiation Dutch Trial TME vs Radiation Dutch Trial Multicenter, 1996-1999 1861 patients randomized to: 1. Short course XRT then TME 2. TME alone 47

Dutch Trial Local Recurrence Local Recurrence XRT/Surgery 2.4% Surgery 8.2% Rate of Local Recurrence (%) 20 10 Surgery alones (n= 875) RadiotherapyS plus surgery (n= 873) 0 0 1 2 3 4 Years NO. AT RISK RadiotherapyS plus surgerys Surgery alone 873S S 875 691S S 688 407S S 406 170S S 173 30S S 37 Figure 2. Rates of Local Recurrence in the Population of 1748 Eligible Patients Who Underwent Macroscopically Complete Local Resection, According to Treatment Group. Dutch Experience Even with TME, preoperative radiation has beneficial effect on local control At 2 years no effect on survival 80% survival in both groups is excellent Greater sphincter salvage with TME 48

Circumferential Margin Key to cure Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: Histological study of lateral tumor spread and surgical excision P. Quirke, Leeds UK Lancet, 1986. Circumferential Margin Key to cure Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: Histological study of lateral tumor spread and surgical excision P. Quirke, Leeds UK Lancet, 1986. 49

Circumferential Margins 52 patients Bread loafing to examine circumferential margins 14/52 (27%) had a positive circumferential margin 12/14 developed local recurrence Margins Distal margins, while important, are rarely the problem Rectal cancer infrequently infiltrates intramurally, 2 cm seems adequate Lymphatic spread can be up to 4 cm, partial mesorectal excision need 4-5 cm margin NEGATIVE CIRCUMFERENTIAL MARGIN 50

Early 2000 s Early 2000 s 51

Circumferential Margins Norway, 2002 Circumferential Margin Population based in Norway, 1993-97 686 TME with known circumferential margin, no radiation 7% overall local recurrence 52

Circumferential Margin Margin > 1mm (negative) Local recurrence 5% Distant metastases 12% Margin 1 mm (positive) Local recurrence 22% Distant metastases 40% Circumferential Margin 53

Positive Circumferential Margin If good TME is done Bad biology If poor TME is done Bad surgeon How do we tell?? Pathologists assess gross specimen and grade the TME quality Improves quality, ensures standardization, provides feedback 54

Putting it all together Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer German Rectal Cancer Study Group New England Journal of Medicine, 2004 German Rectal Cancer Trial 1995-2002 421 patients pre-op chemoradiation 402 patients post-op Long course, 50.4 Gy over 5 weeks TME done 55

German Rectal Cancer Trial Results No difference in 5 year survival Pre 76% Post 74% Both excellent and significant improvement from 1970 s Improved local recurrence for preoperative therapy Pre 6% Post 13% German Rectal Cancer Trial Results Significant downstaging Improved sphincter salvage Short course therapy, No downstaging Better compliance Pre 90% received full therapy Post only about 50% received full therapy Less toxicity OVERTREATMENT 18% in post group Stage I Need better pre-operative staging 56

Case Presentation 52 year old man comes to the office with a biopsy proven adenocarcinoma 10 cm from the anus Management 2016 Multidisciplinary approach Pre-operative Staging Rectal ultrasound, MRI, CT scan 57

Clinical Stage I Immediate surgery with a total mesorectal excision Negative circumferential margin 2 cm distal margin If partial mesorectal excision (upper rectal cancer) then 4-5 cm margin with no coning in on mesentery No other therapy Selective use of local resection Clinical Stage II/III Neoadjuvant chemoradiation Radical surgery with a total mesorectal excision Negative circumferential margin 2 cm distal margin If partial mesorectal excision (upper rectal cancer) then 4-5 cm margin with no coning in on mesentery Postoperative chemotherapy 58

Expectations Improved local control (<10%) Curative treatment is curative 80% Greater sphincter salvage 2013 59

2013 Multi-Institutional Co-operative trials are the key to understanding cancer and evolving treatment algorithms 60

Questions as we move forward?? Are we OVER treating?? Are all T3 cancers the same??? Are all node positive cancers the same?? Can we identify high risk groups?? Can we eliminate (selectively) Radiation?? Surgery?? Chemotherapy?? We Keep Adding it on. 61

A Complete Clinical Response Now what? Diseases of the Colon and Rectum, 2013 62

Inclusion Criteria 2006-2010 Palpable tumors, no more than 7 cm from anal verge ct2-t4, cn0-n1, cm0 High resolution MRI or 3-D Endorectal ultrasound Chest/Abd/Pelvic CT scan Treatment 54 Gy 45 Gy via 3-field approach 9-Gy boost to the primary tumor and perirectal tissue (54 Gy total). 3 cycles bolus 5-FU (450 mg/m2), 50 mg of leucovorin for 3 consecutive days every 3 weeks After radiation, patients received 3 additional cycles of chemotherapy every 3 weeks. 63

Conclusions Extended Chemoradiation with 54 Gy Initial complete response 68%!! 17% failure in first 12 month 10% failure long term Salvage surgery likely 51% handled non-operatively!! 3 Year Survival 53 months follow up Overall 94% Disease Free 75% 64

MSKCC Non Operative Study Distal Rectal Cancer MRI Staging Randomization Arm 1 Induction (INCT) FOLFOX/CapeOx (15 16 weeks) Arm 2 Consolidation (CNCT) Chemoradiation (5.5 weeks) Interval Evaluation DRE, Endoscopy, MRI (optional) Interval Evaluation DRE, Endoscopy, MRI (optional) Chemoradiation (5.5 weeks) FOLFOX/CapeOx (15 16 weeks) Restaging DRE, Endoscopy, MRI Surgery No Clinical Response Non Operative Management Complete or Near Complete Clinical Response 65

To test: PROSPECT Trial Objective Standard radiation, chemotherapy, & TME Against Chemotherapy & surgery with selective use of radiation PROSPECT Study Schema Response >=20% TME FOLFOX x 6 Selective Arm Response<20% FOLFOX x 6 Restage 5FU/Cap- CMT TME FOLFOX x 2 RANDOMIZE: 1:1 Standard Arm 5FU/Cap- CMT TME FOLFOX x 8 66

PROSPECT Trial 411 sites approved Most have not enrolled any patients We have enrolled 8 Only 10 have more than us INOVA has enrolled 2. No one else in Virginia Wake, Duke, NC Combined 2 Combined we are second behind MSK in enrollment Future Classic Hits Non-operative care will be appropriate for select individuals More chemotherapy upfront, including systemic chemotherapy More selective use of radiotherapy 67

Thank you High Resolution MRI MERCURY BMJ. 2006 Oct 14;333(7572):779. 68

High Resolution MRI MERCURY 408 consecutive patients with rectal cancer 11 hospitals, 4 countries High Resolution MRI Predicting negative CRM In patients with primary surgery or short course XRT Accuracy 91% PPV 71% NPV 94% 69

Accuracy DRE 70% MRI 92% Predicting Negative Margin DRE vs MRI T Parameter MRI Distance into muscularis propria T3a: < 1mm T3b: 1-5 mm T3c: 5-15 mm T3d: > 15 mm 70

Good Prognosis MRI Criteria Upper and Mid Rectal Cancer T1, T2 T3a,b Regardless of N component No tumor within 1 mm of MRF Lower Rectal No invasion of intersphinteric plane 71