Current Multidisciplinary Treatment of Rectal Cancer
Charles A. Staley, M.D. Holland M. Ware Professor of Surgery
Chief, Surgical Oncology Emory University School of Medicine
Rectal Cancer
40,000 patients diagnosed each year 75% resectable at presentation Stage I 5% and II 35% Stage III 40% Stage IV, 20% synchronous disease Pattern of failure- rectal vs colon
The Rectum and Anus
Below the peritoneal reflection
Presurgical Workup
Physical exam-rectal exam Full colonoscopy Endoscopic Ultrasound CT abdomen and pelvis Chest xray CBC, electrolytes, LFTs, CEA
Endoscopic Ultrasound
Accuracy 90.9% CT 75% Sensitivity 98.3% Specificity 75% MRI coil equal to EUS
T1-4 N0-1
PET Scans
Not helpful for primary tumor staging Sensitivity for nodal disease- 29% Helpful in local recurrence and
distant metastases 90% sensitivity, 76% specificity Predictor of disease after radiation
therapy - lacking
Abdominal Perineal Resection
Permanant colostomy/Proctectomy 1995-1999 30-67% APR Preoperative radiation Sphincter preserving surgery After 2000 10% APR
APR issues
Urinary Incontinence Perineal Wound Infections Quality of Life Impotence Stoma Problems
Improvements in LR and Survival
Total Mesorectal Excision
Total Mesorectal Excision 1979 by Heald et al Sharp dissection of mesorectum Preservation of ANS 2.7-7.3% LR Dutch TME trial- 1996, 1861 pts. RT + TME vs TME alone LR 2.4% vs 8.2%, OS no difference Benefit of radiotherapy
Postoperative Chemoradiation
GITSG- Superior survival and local recurrence rates in chemoradiation arm compared to surgery alone
NCCTG- Compared post op XRT to chemoradiation. Survival and local recurrence improved in chemoradiation arm.
1990 NIH recommends chemoradiation for stage II and III disease
Transanal excision of rectal tumor T1 Tu
Early Tumors 5%- Transanal Excision
Tumor and nodal factors 6-8 cm from anal verge, not fixed <3cm tumors, <1/3 circumference Well differentiated No lymphovascular invasion No mucinous tumors T1 6-11% + nodes, T2 12-20% + nodes
Local Excision of Rectal Tumors
90 patients accrued- LR 3% all salvaged, 3 yr DFS 87%
T3-Radial margins
Author +margin APR% %LR/+margin Hall 17% 41% 15% Ng 28% 32% 53% Kapiteijn 20% 30% unk Too high APR% and positive margins
Preoperative Chemoradiation-Advantages
RT more effective in well vascularized tumor bed.
Risk of seeding tumor cells at surgery avoided RT field size smaller Complications lower-bowel injury Sphincter preservation, better functional
outcomes
Disadvantages-Overtreatment, perineal wounds
Proctectomy with stapled anastomosis(low anterior resection)
Proctectomy(coloanal anastomosi
German Rectal Cancer Study Group
823 pts. Pre vs Post chemoradiation T3, T4, or N1, 50.4 Gy, 5-FU infusional chemo Survival 76% vs 74%, path CR 10% Local failure 6% pre vs 13% post P=0.006 Grade 3 or 4 toxicity 27% pre vs 40% post
P=0.001 Sphincter preservation 39% pre vs 19% post Pre improves local control, toxicity, and
sphincter preservation, but overall survival unchanged.
Sphincter Preservation in Rectal Cancer
No study has ever shown an increased cancer recurrence or decreased survival rate in appropriate patients undergoing continence-preserving procedures vs APR.
ECOG 1297 Trial Design
R E G I S T E R
Pre - Operative Chemoradiation
50.4 Gy /28 Fx +
PVI 5-FU (225mg/m2/d) +
Oxaliplatin q 2w x3 (2 hr infusion)
.
Oxaliplatin Dose Escalation
Dose Level Dose of
Oxaliplatin (mg/m2)
1 55
2 70
3 85
Surgery (6-8 wk Interval)
Post - Operative Chemotherapy
5 -FU 500 mg/m2 q 1 week x 6
x 4 cycles
Leucovorin 500mg/m2 q 1 week x 6
Start 21-42 days post-op
ECOG 1297
ECOG 1297
21 patients enrolled Emory, Dana Farber, UPENN, NW All had R0 resections 84% sphincter preservation 26% path CR, 21% microscopic Total 47%
R E G I S T E R
Pre - Operative Chemoradiation
50.4 Gy /28 Fx +
Capecitibine (825mg/m2/d (bid)
+ Oxaliplatin (85mg/m2) q 2w x3 (2 hr infusion)
+ Bevacizumab*
.
Bevacizumab Dose Escalation
Dose Level Dose of
Bevacizumab (mg/kg)
1 2.5
2 3.5
3 5.0
Surgery (6-8 wk Interval)
Post - Operative Chemotherapy
FOLFOX Plus Bev
ECOG 3204
ECOG 3204
23 patients Toxicity neutropenia, leucopenia,
diarrhea grade 3 38% 6 patients had delay in adjuvant therapy 94% completed therapy 33% path CR Significant early and late wound
complications
NSABP R-04
NSABP final results
1608 pts 2004-2010 No difference in 3yr LR, 5 yr DFS, or
5 yr OS CVI 5-FU vs Cape Oxaliplatin added no benefit but
increased toxicity
EORTC- PETACC-6 Trial-Interim report 2008-2011, T3,T4, N pos 1094 pts, F/U 31 months 3 year DFS 74.5% vs 73.9% Addition of oxaliplatin to cape does not
improve DFS
Adj chemotherapy for pts with pCR
1999-2012 53pts(15.5) of 342 pts- pCR T3/T4 no difference in groups 63% of pCRs had adj chemo No pCR pt had LR, only 2 M1 Dx No difference in DFS/OS between those
with or without adjuvant therapy
ADORE Trial- Randomized Phase II Study 2008-2012, 321 pts Stage II/III, preop chemo/XRT Adj FOLFOX vs FL Med F/U 38 months, adverse events NS 3 yr DFS 71.6% FOLFOX 3 yr DFS 62.9% FL Stage III, pN1,N2, min regressed tumors
benefit more from FOLFOX
T1 N0
T2 N0
T3, T4 N0, N1, N2
M1
Local Excision
Preop chemo/XRT, Surgery
Preop chemo/XRT, Surgery, adjuvant chemotherapy
Preop Systemic chemotherapy, XRT, Surgery, Systemic Chemotherapy
Summary
Conclusions
EUS provides optimal staging Local excision T1 for path favorable tumors T3 or any +nodes preop chemo/XRT Cape/XRT standard preop therapy Adj chemo FOLFOX superior to FL Adj chemo may not be indicated for pCRs Novel Chemo/XRT strategies will hopefully continue to improve CR and sphincter preservation
Xu, W. et al. Clin Cancer Res 2007;13:1625-1629
Models
C 5FU STA 5FUSTA IR IR/5FU IR-STA IR-5Fu-STA
Day -14 to 0 Day 1 to 38 Ganetespib
Day -14, -11, -7, -4 Ganetespib Cycle 1
Ganetespib Cycle 2
Capecitabine BID Monday through Friday
Radiotherapy (50.4Gy) 5.5 to 6 weeks
Biopsy Pre-treatment and D-3
Study Schema
Completed dose levels 1 through 4 Paired biopsies on all patients. No unexpected toxicities.
– Only grade 3 toxicity observed was a self-limiting diarrhea (lasted for 2 days)
Patients Treated Patie
nt Age/R
ace Gend
er Dose level EUS Path Surgery
1 39/AA F 1 (60mg/m2) T3N1 (2 LN)
T2N1 (1 LN) APR
2 52/C M 1 T3N0 T2N0 LAR 3 71/C F 1 T3N1 T0N0 LAR 4 62/AA F 2(80mg/m2) T3N1 T3N0 LAR 5 70/C M 2 T3N2a T2N0 APR 6 58/C F 2 T3N0 T3N0 LAR 7 61/AA F 3
(100mg/m2) T3N2 T2N0 LAR
8 44/C M 3 T3N0 P P 9 64/C M 3 T3N0 P P
Proposed Randomized Phase II Trial
Stage II or III Rectal Cancer
Capecitabine and XRT
Ganetespib (Dose TBD on days 1, 8, 15, 29, 36) +Capecitabine and XRT
Primary endpoint: Evaluate TRG (reference 20% TRG 0,1* with standard chemoXRT) DFS at 2 years Secondary endpoints: pCR, toxicity, QOL, Correlative assays Sample size 120 patients (improvement of TRG to 35%)- *Dworak 1997
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