Chemoradiation vs Surgery for rectal cancer. Dr. Chris Crane

1. 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

2. No Disclosures

3. 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.

4. Complications of Radical Rectal
Surgery
• Permanently altered bowel
function
– Often colostomy
• Urinary dysfunction from 7-68%
• Impotence 15-100%
• Retrograde ejaculation 3-35%

5. 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

6. 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

7. CXRT / Mesorectal resection- cT3 N0 pts
ypN+ 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%)

8. Can Radical Surgery Be Avoided
in Selected Rectal Cancer
Patients?

9. *Responding patients
Chemoradiation Followed by
Local Excision*

10. Local Excision of T3 tumors after
Preoperative XRT
Study # Patients % pCR/mRD % LF
(5-yr act)
Median FU
Mohiuddin, TJU,
1994
15 Downstaged 0 40
Kim, USF, 2001 17 100/0 0 19
Bonnen, MDACC,
2004
26 54/35 6 51
Lezoche, Italy 2005 46 0/23 5 55
Meadows, UF, 2006 16 56/44 21 (3 yr)
9 (with salvage)
27

11. 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

12. 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 Stage
CXRT/LE (cT2/cT3)
Modified from Table 5, Borschitz, et al Ann Surg Onc, 2008

13. 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

14. ACOSOG Z6041 Study Design
uT2
rectal
cancer
(EUS-
MRI)
CXRT
Cape (850mg/m2 bid)
oxali (50 mg/m2/wk)
54 Gy
Local
excision
T0-T2
R0:
Observation
T3 or R+:
radical
resection
F
o
l
l
o
w
<8 cm from
anal verge
<4 cm size
Primary Obj: 3 yr DFS in uT2N0
Chan, ASTRO 2010

15. ACOSOG Z6041 Study Design
uT2
rectal
cancer
(EUS-
MRI)
CXRT
Cape (650mg/m2 bid)
oxali (50 mg/m2/wk)
50.4Gy
Local
excision
T0-T2
R0:
Observation
T3 or R+:
radical
resection
F
o
l
l
o
w
<8 cm from
anal verge
<4 cm size
Primary Obj: 3 yr DFS in uT2N0
Chan, ASTRO 2010

16. Conclusions
Neoadjuvant 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

17. 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

18. 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

19. Organ Preservation Model
Locally 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

20. 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)?

21. The Message Regarding
Pre-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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