Under what Circumstances would chemoradiation +/- LE be

comparable to radical surgery?

Christopher H. Crane, M.D.Program Director, GI SectionProgram Director, GI Section

Department of Radiation OncologyDepartment of Radiation Oncology

No Disclosures

GI Mucosa Limits the XRT Dose

• Many other tumors: definitive doses possible– Lung, head and neck, prostate, liver, anal ca

• Luminal GI tumors: esophageal, gastric, rectal– The tumor resides within a serial organ at risk– Limits the dose to 54Gy or so.

Complications of Radical Rectal Surgery

• Permanently altered bowel function– Often colostomy

• Urinary dysfunction from 7-68%• Impotence 15-100%• Retrograde ejaculation 3-35%

NCDB LE Special Study (1994-96)Local Recurrence – T2

5- Year

LE RR

T2 22% 15%

T2: p=0.01

You et al. Ann Surg 245(5):726-33, 2007

N=164

N=866

German Trial (CAO / ARO / AIO)Pre-operative vs Postoperative CXRT

• Significantly lower acute toxicity rate – 27% vs 40%, p=0.001

• LR improved with preoperative CXRT– 5 yr: 6% vs 13%, p=0.001

• SP higher in preoperative CXRT– 39% vs 19%, p=0.006– Subjective need for APR, not whole group

• Significantly lower late toxicity– 14% vs 24%, p=0.01

• anastamotic stricture (12% vs 4%)• Diarrhea, SBO (9% vs 15%)

Sauer, R NEJM, 351, 2004

CXRT / Mesorectal resection- cT3 N0 ptsypN+ according to ypT stage

Crane, pESTRO 2004

ypT0 in T3 NX (including clinically node +) = 4/45 = 9%

Bedrosian, J Gastroint Surg, 2004

Pathologic T Stage

Institution 1 Institution 2 Institution 3 Total

ypT0 0/27 (0%) 0/14 (0%) 1/43 (2%) 1/84(1%) ypT1 2/29 (7%) 0/12 (0%) 4/17 (24%) 6/58 (10%) ypT2 15/95 (16%) 12/97 (12%) 4/60 (7%) 31/252 (12%) ypT3 54/166 (33%) 62/164 (38%) 15/68 (22%) 131/398 (33%) ypT4 0 5/5 (100%) 2/2 (100%) 7/7 (100%)

Can Radical Surgery Be Avoided in Selected Rectal Cancer

Patients?

*Responding patients

Chemoradiation Followed by Local Excision*

Local Excision of T3 tumors after Preoperative XRT

Local Excision of T2 tumors after Preoperative XRT

Study # Patients % pCR % LF

Median FU

Lezoche, Italy 2005 54 16(30%) 5 (5 yr) 55

Meadows, UF, 2006 16 T1/T2 4(25%) 9 (3 yr) 27

ypT stage

All patients -seven studies

LR

T0 0/53 (0%)

T1 1/45 (2%)

T2 6/85 (7%)

T3 7/33 (21%)

Total 17/237 (7%)

Cumulative recurrence rates based on ypT StageCXRT/LE (cT2/cT3)

Modified from Table 5, Borschitz, et al Ann Surg Onc, 2008

Randomized Trial - T2 Rectal Cancer CXRT then TAE vs Laparoscopic Resection

• 40 pts• 50.4 Gy + PVI 5-FU (200 mg/m2)

– 20 TAE– 20 LAP Resection

• One recurrence in each group (5%)• Median FU 56 mo

Lezoche, et al Surgical Oncology, 2005

ACOSOG Z6041 Study Design

uT2 rectal cancer(EUS-MRI)

CXRTCape (850mg/m2 bid)oxali (50 mg/m2/wk)54 Gy

Local excision

T0-T2 R0: Observation

T3 or R+: radical resection

Follow

<8 cm fromanal verge<4 cm size

Primary Obj: 3 yr DFS in uT2N0

Chan, ASTRO 2010

ACOSOG Z6041 Study Design

uT2 rectal cancer(EUS-MRI)

CXRTCape (650mg/m2 bid)oxali (50 mg/m2/wk)50.4Gy

Local excision

T0-T2 R0: Observation

T3 or R+: radical resection

Follow

<8 cm fromanal verge<4 cm size

Primary Obj: 3 yr DFS in uT2N0

Chan, ASTRO 2010

ConclusionsNeoadjuvant CRT with CAPOX

• 44% pCR

• Only 5% of patients needed radical surgery

• Long term follow-up is needed for LC endpoint

• High GI toxicity rates

Chan, ASTRO 2010

Author Wound dehiscence

Transient incontinence

Kim et al 1/26 (4%) 1/26 (4%)

Ruo et al 1/10 (10%) None

Schell et al None 2/11 (18%)

Hershman et al NS NS

Bonnen et al NS NS

Stipa et al None 1/26 (4%)

Lezoche et al 11/100 (11%) 2/100 (2%)

NS, not specified; nCRT, neoadjuvant chemoradiation; LE, local excision.

Complications, CXRT / TAE

Modified from Table 3, Borschitz, et al Ann Surg Onc, 2008

•Wound complications do not appear to be a limitation•Diverting iliostomy could be perfomed

Non-operative Management in Complete Responders?

• University of São Paulo, Brazil• Pre-op Chemoradiation (50.4 Gy + FU/LV)• 265 pts

– Clinical CR = observation (n=71, 26%)• 2 endorectal failures, 5y OS 100%

– Incomplete CR / radical surgery, pCR (n=22%, 8.3%)• 2 DOD, 5y OS 88%

• Median follow-up 57.3 months

Habr-Gama, Ann Surg. 240(4):711-718, 2004

Organ Preservation ModelLocally Advanced Rectal Ca

• Clinical selection will affect success– Tumor size, nodal status, tumor grade, others

• Neoadjuvant CXRT– Endoscopic CR

• Full thickness local excision = excisional biopsy of tumor bed– ypT0, no further surgery

• Radical surgery only for non-responders: – Gross residual disease or ypT3

• What about microscopic residual disease?

Crane, Annals of Surg Onc, (3) p288-90, 2006

Response of Primary Tumor to CXRT

• Observing response of primary key to organ preserving strategy

• Predicts Control of Microscopic Mesorectal Disease

• Could predicting response help?– Only if it leads to personalized therapy– Increase the pool of responders

• Pair agents to patients– Proteomics, genomics

• Change agents during therapy (PET)?

The Message RegardingPre-op/LE

• Promising strategy, especially in responding patients

• Better long term GI and sexual function• Salvage rates of LR 50-70%

– Close FU is critical• Multidisciplinary team has to be on the

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