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