Rectal cancer _international_perspectives_on_multimodality_management__current_clinical_oncology_
Current treatment of Rectal Cancer - prIME Oncology · German Rectal Cancer Study Group 823 pts....
Transcript of Current treatment of Rectal Cancer - prIME Oncology · German Rectal Cancer Study Group 823 pts....
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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
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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
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The Rectum and Anus
Below the peritoneal reflection
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Presurgical Workup
Physical exam-rectal exam Full colonoscopy Endoscopic Ultrasound CT abdomen and pelvis Chest xray CBC, electrolytes, LFTs, CEA
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Endoscopic Ultrasound
Accuracy 90.9% CT 75% Sensitivity 98.3% Specificity 75% MRI coil equal to EUS
T1-4 N0-1
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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
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Abdominal Perineal Resection
Permanant colostomy/Proctectomy 1995-1999 30-67% APR Preoperative radiation Sphincter preserving surgery After 2000 10% APR
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APR issues
Urinary Incontinence Perineal Wound Infections Quality of Life Impotence Stoma Problems
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Improvements in LR and Survival
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Total Mesorectal Excision
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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
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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
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Transanal excision of rectal tumor T1 Tu
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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
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Local Excision of Rectal Tumors
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90 patients accrued- LR 3% all salvaged, 3 yr DFS 87%
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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
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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
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Proctectomy with stapled anastomosis(low anterior resection)
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Proctectomy(coloanal anastomosi
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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.
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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.
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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
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ECOG 1297
21 patients enrolled Emory, Dana Farber, UPENN, NW All had R0 resections 84% sphincter preservation 26% path CR, 21% microscopic Total 47%
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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
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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
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NSABP R-04
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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
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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
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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
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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
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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
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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
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Xu, W. et al. Clin Cancer Res 2007;13:1625-1629
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Models
C 5FU STA 5FUSTA IR IR/5FU IR-STA IR-5Fu-STA
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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
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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)
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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
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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