Multimodality Therapy of Rectal Cancer Robert D. Madoff, MD University of Minnesota

rectal cancer clinical issues colostomy or anastomosis? local or radical surgery? functional outcomes? neoadjuvant therapy?

rectal cancer therapy morbidity mortality function optimal cure rate

total mesorectal excision the rectum and its mesentery are a single fascia-enveloped unit, anatomically separate from surrounding pelvic structures surgical violation of this anatomic package leads to a positive circumferential margin, a known predictor of local recurrence

rectal cancer pathologic evaluation

circumferential resection margin Adam 1995 %

rectal cancer stage dictates therapy

rectal cancer know your enemy!

uT1

uT3 uN1

Preop Staging Review of 83 studies including 4897 patients Kwok 2000 SensitivitySpecificity T Stage EUS93%78% MRI/coil89%79% N Stage EUS71%76% MRI/coil82%83%

MRI staging circumferential margin

Prediction of Involved CRM Beets-Tan 2004

local recurrence surgeon as risk factor surgeon 50 % minimum 25 rectal cancer operations per surgeonHolm 1997

rectal cancer know your surgeon!

circumferential resection margin Adam 1995 %

rectal cancer surgery impact of technique Lehander Martling 2000 % p < * p < 0.002* * Stockholm I and II vs TME project

Combined postoperative chemotherapy and radiation therapy improves local control and survival in Stage II and III patients and is recommended. NIH Consensus Statement, 1990

rectal cancer radiation + chemo local recurrence (%) Krook 1991

rectal cancer radiation + chemo, vs. TME alone local recurrence (%) Krook 1991 Heald 1998

radiation therapy friend or friendly fire?

radiation therapy disadvantages cost convenience complications covering stomas quality of life

postop chemoradiation functional results CT/RTsurgery only (%) (%) BM / 24 hr 7 2 nighttime BMs 4614 occasional incontinence 3917 frequent incontinence 7 0 pad 4110 unable to defer BM 15' 7819 Kollmorgen 1994

short course rt long-term morbidity RT (+) (%) RT (-) (%) p dvt femoral neck / pelvic fractures sbo fistulas Holm 1996

radiation therapy controversies patient selection –who needs adjuvant therapy? timing –pre- or postoperative? technique –short or conventional course?

surgery +/- rt local recurrence %

surgery +/- rt 2-year survival % Dutch TME Trial p=0.84

rectal cancer radiation timing biology downstaging –resectability –sphincter salvage –margins sb complications functional results staging accuracy –avoids overtreatment anastomotic leak risk –covering stomas prepost

German rectal cancer study 823 patients - Stage II-III 50.4 Gy RT + Chemo OR (TME) 50.4 Gy RT + Chemo OR (TME) Sauer 2003

German rectal cancer study Sauer, NEJM 2005 Pre-OpPost-Op Leak 10% 12% Bleed 2% 3% Delayed healing 4% 6% Stricture 4% 12%* Acute toxicity 27% 40%*

Downstaging8% Sphincter Preservation39%19%* Local Recurrence6%13%* Survival76%74% German rectal cancer study Sauer, NEJM 2005 Pre-OpPost-Op * p<0.05

short vs. long course United States: Europe: Gy 6 weeks OR OR 1 week 25 Gy

short course radiation convenience cost effectiveness unsafe if given improperly ? higher rate of late toxic effects cannot give simultaneously with chemotherapy procon

short course vs. conventional radiation no data!

radiation therapy current status (USA) optimally stage patient (ERUS) conventional (long course) RT plus chemotherapy for stage II (T3), stage III (N1) or stage IV cancers postoperative chemoradiation for positive circumferential margin consider postoperative chemoradiation for understaged T3 or N1 lesions

RECTAL CANCER AS BREAST CANCER: PARADIGM FOUND?

pensa globalmente… …agisci localmente

RECTAL CANCER LOCAL EXCISION pro –low morbidity/mortality –avoids sexual/urinary/bowel dysfunction –avoids colostomy con –nodal status not pathologically assessed –involved nodes not excised –? equivalent oncologic results to radical excision

non usare un cannone per sperare ad una pulce…

…ma prima assicurati che sia proprio ad una pulce che stai sparando!

local therapy results 25 local recurrence (%) CALGB 8984 T1: local excision T2: local excision plus chemoradiation

local excision vs. radical surgery T1: local excision T2: local excision; no chemoradiation local recurrence (%) Garcia-Aguilar 2000

“Dr. Mellgren and colleagues deserve to be congratulated for their honesty…” Steele 2000

“…remarkably bad outcome… significantly worse than any previously reported…” “the University of Minnesota experience stands alone…” Steele 2000

local recurrence local excision T 1 rectal cancer 25 %

CALGB 8984 Steele 1999

TEM results superior to transanal excision!

TME VS. TMN local excision: TOTAL MESORECTAL NEGLECT!

select tumors with a low likelihood of regional metastases

risk of nodal involvement resected colorectal cancer T stagepositive nodes T10-18%avg 8% T212-38%avg 22% T336-67%avg 60% T453-88%avg 65%

risk stratification within T stage positive nodes differentiation T1 T2 well 4% 12% moderate 9%20% poor 13%48%

submucosal invasion Japanese classification

Sm 1 Sm 2 Sm 3 Kikuchi 0% 10%39% Nivatvongs 2.9%7.5%23% nodal metastasis Japanese classification

local excision is first a complete excisional biopsy

local excision pathologic exclusion criteria T stage > T1 Sm3 positive or equivocal margins poor differentiation lymphovascular invasion

SALVAGE SURGERY STATUS 29 patients unresectable hepatic mets 1 additional recurrence11 free of disease17 ( positive margin, NED 3*) Friel 2002 *follow-up 12 months

SALVAGE SURGERY AFTER LOCAL EXCISION don’t count on it!

LOCAL EXCISION primum non nocere!

It is the wise surgeon who understands that the patient takes all the risk.

local excision rules of engagement selection, selection, selection! –ERUS stage first, but reassess pathologic specimen –no “winking” at adverse histology or inadequate margins adjuvant chemoradiation for pT2 tumors mandate close follow up remember that recurrent tumors are almost always more advanced than they start, and radical salvage surgery cures only 50% of patients

local excision preoperative chemoradiation? downstages tumor –? curative in some patients may reduce risk of tumor implantation at excision site

rectal cancer therapy morbidity mortality function optimal cure rate

rectal cancer conclusions numerous treatment permutations appropriate treatment depends upon tumor stage, which should be determined before surgery surgery is technically driven; optimal results require training and experience role of local therapy remains controversial oncologic cure is the primary goal, but functional results are an important outcome