1. What is the most appropriate therapy for a 50 year old patient with T3N+ rectal cancer and isolated surgically resectable liver Metastases? – Systemic chemotherapy->surgery (Omission of chemoXRT).
Cathy Eng, M.D., F.A.C.P.
Associate Professor
Associate Medical Director, Colorectal Center
Director of Network Clinical Research, GI Med Onc
Co-Chair, SWOG Rectal Committee
March 28, 2014
Department of GI Medical Oncology

2. Disclosures
Please note we are colleagues at MDACC and work in a collegial fashion
Pls also note that there is no surgical oncologist that is part of this debate which would be highly unusual
SWOG PI for the PROSPECT Trial

3. Current Generalized Standard Treatment Paradigm for Rectal Cancer
Diagnosis of rectal Cancer
T1N0
TAE vs TME
Diagnostic Studies: EUS/MRI
≤ T2N0
TME
≥T3N0,
TxN+
Preop CXRT
TME
Adjuvant Chemotherapy M+
Multidisciplinary
Treatment

4. Classic Pivotal Trials

5. Preoperative Radiation and Total Mesorectal Excision (TME)
(Dutch Colorectal Cancer Group)
Local Failure
Preop RT (5x5)
(N=897)
Surgery alone
(N=908)
2-yr Recurrence Rate
2.4%
8.2%
Distance from verge cm cm
<5 cm
1.3%
1.0%
5.8%
3.8%
10.1%
10%
Type of resection
Low anterior
APR
1.2%
4.9%
7.3%
TNM stage
I (30%)
II (28%)
III (34%)
0.5%
1.5%
4.3%
0.7%
5.7%
15%
Kapiteijan et al: N Engl J Med Aug 30;345(9):

6. Dutch TME trial: Long term results Impact on Local Recurrence
N=129 pts
Local recurrences were not uncommon after 3 yrs:
TME: 9/87 (10%)
XRT/TME :13/42 (31%)
Radiotherapy may be merely postponing local recurrence
3 yrs: 10% vs. 31%
Peeters et al, Ann Surg (5):

7. Cumulative Distant Recurrence Cumulative Distant Recurrence
No impact of XRT + TME on distant recurrence or overall survival Dutch Rectal Cancer Study Group
Cumulative Distant Recurrence
Overall Survival
N=222
N=201
P=0.39
P=0.26
Cumulative Distant Recurrence
Overall Survival
Peeters et al, Ann Surg (5):

8. Neoadjuvant Chemoradiotherapy for Rectal Cancer: CAO/ARO/AIO-94
Randomi ze
5-FU/XRT
Surgery
5-FU
Control Arm
Surgery
5-FU/XRT
5-FU
Primary endpoint: DFS
Sauer et al NEJM, 2004:

9. CAO/ARO/AIO-94: Cumulative Incidence of Local Relapse (Med
CAO/ARO/AIO-94: Cumulative Incidence of Local Relapse (Med. Follow-up: 40M)
.14
.12
13%
.10
Post-op CRT
.08
Locoregional Recurrences
.06 6%
.04
.02
p = 0.006
Pre-op CRT
0.00 10 20 30 40 50 60
Months
Sauer et al., N Engl J Med 2004; 351:

10. Update of CAO/ARO/AIO-94: Median Follow-Up 11 Yrs.
Sauer et al: JCO 2012

11. Can we omit chemoXRT therapy?

12. Rationale for Omitting XRT: Impact of T and N Stage on OS and Local Relapse
A pooled analysis of 5 phase III randomized trials (NCCTG , NCCCTG , INT 0114, NSABP R-01 and R-02, N=3791)
Patients were placed in three categories:
Intermediate (T1-2N1 and T3N0)
Moderately high (T1-2N2, T3N1, and T4N0)
High (T4/N1 or N2).
The authors concluded that in the intermediate-risk patient population, those receiving bimodality therapy of surgery and chemotherapy had 5-year OS rates comparable to trimodality therapy
Gunderson et al: JCO 22(10): May 15, 2004

13. Pooled Analysis: 5-yr OS and Local Relapse
Table I: Percent Overall Survival (pooled analysis data)
Surg/chemo/XRT
Surg/chemo
T1-2N1
78-83%
85%
T3N0
74-80%
84%
Table II: Percent Local Relapse (pooled analysis data)
Surg/chemo/XRT
Surg/chemo
T1-2-N1
5-6% 5%
T3N0
5-10%
11%
Gunderson et al: JCO 22(10): May 15, 2004

14. Salient Points of Chemoradiation
Radiation therapy is associated with acute and chronic toxicities
pCR has not improved with additional chemo at risk of acute toxicities
Induction chemotherapy followed by chemoXRT is non-inferior with improved adherence and OS in small phase II studies.
Stage and location of the tumor may allow selective use of chemoradiation therapy to be considered.
Improved radiographic techniques

15. Review of the case as presented:
Any metastatic potentially surgically resectable patient should be part of a multidisciplinary discussion.
The location of the primary tumor is not mentioned.
Radiation therapy may have a potential role for palliative purposes (urgency, pain, or bleeding).

16. Salient Points of the Actual Case
Each case should be individualized.
Is the patient symptomatic?
What does the flexible sigmoidoscopy indicate?
Near obstruction? Narrowing?
What does the MRI/EUS indicate?
N1 or N2 disease
N2 would suggest higher risk of local recurrence
A “yes” to one of the above may result in the need for consideration of XRT

17. Rationale for Consideration of Omitting chemoXRT:
Toxicities associated with therapy
Sexual, urinary, bowel dysfunction, and myelosuppression
Improved surgical technique: TME
Overstaging pts radiographically
EUS vs. MRI
Differences in outcome based on location
Mid-high lying tumors may not necessarily benefit from neoadjuvant radiation therapy
Delay in surgical resection
No differences in OS excl. Swedish trial
Will provision of modern chemotherapy with the benefit of TME result in improved OS?

18. Chemotherapy alone may impact the primary rectal tumor

19. Case 2: 45 y/o F T3N1M1 with liver and lung mets
8-10 cm from the anal verge
Courtesy of Dr. Rodriguez-Bigas

20. Palliative chemotherapy is started:
FOLFIRI/bev x 18 cycles with PD of the liver
FOLFOX/BEV 10 cycles
Gr. 3 neuropathy
5-FU/Leucovorin/BEV stable disease
Courtesy of Dr. Rodriguez-Bigas

21. MSKCC Pilot Study Schrag D et al. JCO 2014;32:513-518
©2014 by American Society of Clinical Oncology

22. MSKCC Pilot Data: mid-high lying tumors
Single institution (N=32)
AJCC stage II/III pts (excluding T4)
Induction FOLFOX/Bev x 6 cycles
CR: TME
PR: chemoXRT/TME
Primary outcome: R0
Median follow-up: 52M
R0 = 30
8 of 32 (25%; 95% CI, 11% to 43%), post op death (N=1)
Outcome:
LRR (N=0, 95% CI, 0% to 11%)
4-yr DFS was 84% (95% CI, 67% to 94%).
Distant failures (N=3)
Schrag et al: JCO 2014

23. PROSPECT Protocol Concept Summary
Objective: To determine if selective use of CMT is non-inferior to preoperative CMT for management of locally advanced rectal cancer that is amenable to sphincter sparing TME
Hypothesis: Treatment with neoadjuvant FOLFOX followed by selective use of neoadjuvant 5FUCMT for patients with locally advanced rectal cancer who are candidates for curative intent sphincter sparing surgery with TME is not inferior to neoadjuvant 5FUCMT followed by surgery and FOLFOX

24. PROSPECT Study Schema (Phase II/III)
Response >=20%
TME
FOLFOX x 6
“Selective Arm”
Response<20%
FOLFOX x 6
Restage
5FU/Cape-RT
TME
FOLFOX x 2
RANDOMIZE: 1:1
5FU/Cape-RT
TME
FOLFOX x 8
“Standard Arm”
Objective: To determine if selective use of chemoRT
is non-inferior to standard preop chemoRT
PI’s: Fichera and Schrag 24 72

25. Study Endpoints Primary Outcomes: Randomized Phase II Component
R0 Resection Rate
Time to local recurrence (TLR)
Phase III Component: Co-primary endpoints
Disease free survival (DFS)
Secondary Outcomes:
Pathologic complete response rate (CR)
Overall survival
Quality of life (QOL)
Clinician and patient reported treatment toxicity
Molecular correlates of response to neoadjuvant therapy

26. Inclusion Criteria Tumor located at 5-12 cm from the anal verge
Candidate for sphincter sparing surgery according to TME experienced surgeon
Baseline Clinical staging: T2N1, T3N0, T3N1
Physical exam by primary surgeon
Proctoscopy
MRI or ERUS (MRI preferred)
CT scan of C/A/P

27. Conclusions:
Radiation therapy is associated with both acute and chronic toxicities
Radiation therapy does not appear to be needed in all cases of rectal cancer
Standard chemoXRT may result in unnecessary delay to surgical resection
Multidisciplinary discussion is warranted
Consider enrolling your patient with mid-high lying rectal tumors in the PROSPECT trial which may change the paradigm of care.