Multimodality Therapy of Rectal Cancer

Robert D. Madoff, MD

University of Minnesota

rectal cancerclinical 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 cancerpathologic evaluation

circumferential resection margin

Adam 1995

0

50

100

local recurrence survival

CRM (+)

CRM (-)

%

rectal cancer

stage dictates therapy

rectal cancer

know your enemy!

uT1

uT3uN1

Preop Staging• Review of 83 studies including 4897 patients

Kwok 2000

Sensitivity Specificity

T Stage

EUS 93% 78%

MRI/coil 89% 79%

N Stage

EUS 71% 76%

MRI/coil 82% 83%

MRI stagingcircumferential margin

Prediction of Involved CRM

Beets-Tan 2004

local recurrencesurgeon as risk factor

surgeon

50

%

minimum 25 rectal cancer operations per surgeon Holm 1997

rectal cancer

know your surgeon!

circumferential resection margin

Adam 1995

0

50

100

local recurrence survival

CRM (+)CRM (-)

%

rectal cancer surgeryimpact of technique

15 1514 16

6

9

0

25

local recurrence cancer deaths

Stockholm IStockholm IITME project

Lehander Martling 2000

%

p < 0.0001* 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 cancerradiation + chemo

25

14

0

15

30

RT RT + CT

local

recurrence

(%)

Krook 1991

rectal cancerradiation + chemo, vs. TME alone

25

6

14

0

15

30

RT RT + CT TME

local

recurrence

(%)

Krook 1991

Heald 1998

radiation therapy

friendor

friendly fire?

radiation therapydisadvantages

• cost

• convenience

• complications

• covering stomas

• quality of life

postop chemoradiationfunctional results

CT/RT surgery only

(%) (%)

BM / 24 hr 7 2

nighttime BMs 46 14

occasional incontinence 39 17

frequent incontinence 7 0

pad 41 10

unable to defer BM 15' 78 19

Kollmorgen 1994

short course rtlong-term morbidity

RT (+)

(%)

RT (-)

(%)

p

dvt 7.5 3.6 0.01

femoral neck / pelvic fractures

5.3 2.4 0.03

sbo 13.3 8.5 0.02

fistulas 4.8 1.9 0.01

Holm 1996

radiation therapy controversies

• patient selection–who needs adjuvant therapy?

• timing–pre- or postoperative?

• technique–short or conventional course?

surgery +/- rt local recurrence

27

11

8

2

0

surgery surgery/ RT

SRCT

Dutch TME Trial%

surgery +/- rt 2-year survival

82 82

0

50

100

surgery surgery/ RT

%

Dutch TME Trial

p=0.84

rectal cancerradiation timing

• biology• downstaging

– resectability– sphincter salvage– margins

• sb complications• functional results

• staging accuracy– avoids

overtreatment

• anastomotic leak risk– covering stomas

pre post

German rectal cancer study

823 patients - Stage II-III

50.4 Gy RT + Chemo

OR (TME)

50.4 Gy RT + ChemoOR (TME)

Sauer 2003

German rectal cancer study

Sauer, NEJM 2005

Pre-Op Post-Op

Leak 10% 12%Bleed 2% 3%Delayed healing 4% 6%Stricture 4% 12%*Acute toxicity 27% 40%*

Downstaging 8%

Sphincter Preservation 39% 19%*

LocalRecurrence 6% 13%*

Survival 76% 74%

German rectal cancer study

Sauer, NEJM 2005

Pre-Op Post-Op

* p<0.05

short vs. long course

United States:United States:

Europe:Europe:

45-54 Gy45-54 Gy

6 weeks6 weeks

OROR

OROR

1 week1 week

25 Gy25 Gy

short course radiation

• convenience

• cost

• effectiveness

• unsafe if given improperly

• ? higher rate of late toxic effects

• cannot give simultaneously with chemotherapy

pro con

short course vs. conventional radiation

no data!

radiation therapycurrent 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 CANCERAS BREAST CANCER:PARADIGM FOUND?

pensa globalmente…

…agisci localmente

RECTAL CANCERLOCAL 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 therapyresults

3

14

T1 T2

25

local recurrence

(%)

CALGB 8984T1: local excisionT2: local excision plus chemoradiation

local excision vs.radical surgery

T1: local excisionT2: local excision; no chemoradiation

local recurrence

(%)

Garcia-Aguilar 2000

18

47

06

0

50

100

T1 T2

local excision

radical surgery

“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 recurrencelocal excision T1 rectal cancer

1815

17

UMN 2000

MSKCC 2005

CCF 2005

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 involvementresected colorectal cancer

T stage positive nodes

T1 0-18% avg 8%

T2 12-38% avg 22%

T3 36-67% avg 60%

T4 53-88% avg 65%

risk stratification within T stage

positive nodes

differentiation T1 T2

well 4% 12%

moderate 9% 20%

poor 13% 48%

submucosal invasionJapanese classification

Sm1 Sm2 Sm3

Kikuchi 0% 10% 39%

Nivatvongs2.9% 7.5% 23%

nodal metastasis Japanese classification

local excision is first a complete

excisional biopsy

local excisionpathologic exclusion criteria

• T stage > T1 Sm3

• positive or equivocal margins

• poor differentiation

• lymphovascular invasion

SALVAGE SURGERYSTATUS

29 patients

unresectable hepatic mets 1additional recurrence 11free of disease 17

(positive margin, NED 3*)

Friel 2002*follow-up 12 months

SALVAGE SURGERYAFTER 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 excisionpreoperative 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 cancerconclusions

• 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