1. Neoadjuvant Chemotherapy for Locally Advanced Rectal Cancer
Neoadjuvant Chemotherapy for Locally Advanced Rectal Cancer? Assigned Viewpoint: PRO
Great Debates Symposium
New York City, NY
Deb Schrag MD
Dana Farber Cancer Institute
Harvard Medical School
March 27th 2015

2. CAVEAT LOCUTOR
The standard of care for locally advanced rectal cancer is chemoradiation
Neoadjuvant chemo is an investigational strategy
This is a post-prandial debate
I need to keep you awake

3. The Efficacy of neoadjuvant chemotherapy without radiation has not yet been established in the context of controlled clinical trials

4. Objective
Persuade you that a trial to compare neoadjuvant chemoradiation to neoadjuvant chemo with selective radiation is a priority
Describe the rationale for neoadjuvant chemotherapy
Describe trials evaluating neoadjuvant chemo
Pilot/Phase II experience
Phase III trials in progress

5. Current Rectal Cancer Treatment Paradigm
5-6 weeks recovery
4-6 weeks recovery
5.5 Weeks of CMT
TME Rectal Surgery
Adjuvant ChemoRx
16-19 weeks until start of systemic chemotherapy 72

6. Dutch Trial: Pre-op XRT and TME vs. TME Alone
1805 eligible pts, T1-3 (54% T1-2, 56% I-II)
Outcome
TME
Pre-op XRT
LR at 4 years
11% 6%
Rx Mortality 3% 4% OS
82%
Radiation Decreases LR Rate Even with Good Surgery
Kapiteijn NEJM

7. German Trial RCT of Pre vs. Post Op Chemo RT
Pre-Op
394
Post-op
405
P value
Local Recurrence 6%
13%
.006
Distant
Recurrence
30%
34% NS
Grade 3-4 Toxicity
27%
40%
<0.05
Overall Survival 3-yr
76%
74%
Sphincter
Preservation
39%
19%
Sauer et al: NEJM 2004
Preop ChemoRT is preferable to Postop

8. Why Question Use of Neoadjuvant XRT?
Pelvic radiation causes short and long-term morbidity
Each treatment modality has improved since the current treatment paradigm was established
Better imaging
Widespread availability of MRI to characterize T stage and Circumferential radial margin (CRM)
Better surgery
Diffusion of modern TME techniques
Better systemic chemotherapy—adjuvant FOLFOX
More screen detected rectal cancers---within stage migration to smaller tumors

9. Experience with Neoadjuvant Chemo in Stage IV Rectal Cancer and Patients with Contraindications to XRT
Patients with stage IV rectal cancer
High response rate and conversion to resectability--omitting the preop XRT
Clinical experience treatment rectal cancer without XRT in “special cases”
Stage II-III RC in Prostate and GYN Cancer survivors
Women seeking fertility/childbearing preservation
Men and women very concerned about sexual function

10. Challenges Arising from Neoadjuvant ChemoXRT Rectal Treatment Paradigm
Distant disease is the primary site of recurrence/site of death in rectal cancer
Undertreatment risk: Node+ pts don’t complete post-op systemic chemo
Overtreatment risk: Node- pts may get unnecessary rx
Myelosuppression and impaired chemo tolerance after pelvic XRT
Met rectal pts get less chemo, have inferior survival compared to met colon pts

11. Restaging post CAPOX Restaging Post Chemo/RT
UK Phase II of Induction CAPOX, then ChemoRT: MRI demonstrates high clinical response rates
Restaging post CAPOX Restaging Post Chemo/RT
(n=68) (n=68)
CR (4%) (21%)
PR 57 (84%) (77%)
SD (12%) (3%)
ORR % %
Chau et al ASCO 2005

12. Pilot Study of Neoadjuvant Chemo with Selective Use of XRT
Single center phase II pilot at MSKCC administered 6 cycles of induction FOLFOX+Bev to patients with clinical T2N1, T3N0, T3N1 rectal cancer who were candidates for LAR at presentation
XRT planned if no response or any positive margin
Of 32 participants, none required preoperative XRT
With more than 4 years median follow up:
1 post-op death, 2 cancer deaths
No local recurrences
4 recurrences, all with metastases to lung
JCO Jan 2014

13. Pilot Studies of Neoadjuvant Chemo without routine use of XRT
Study N
Cohort
Bad
Risk
Features Rx
R0 Rate
pCR%
Ishii
(2010) 26
T3-4
Any N
12% T4
IFL
100%
3.8%
Fernandez Martos
(2012) 28 T3
Middle 3rd
>2mm from MRF
Excluded
CAPOX-Bev
96.4%
14.3%
Uehara
(2013) 32
T3,T4, N2
CRM at risk
57% T4
84.3%
12.5%
Schrag
(2014)
T2N1
T3N0
T3N1
FOLFOX-Bev
25%

14. PROSPECT: N1048 Objective:
To determine if selective use of XRT is a safe alternative strategy to routine use of neoadjuvant XRT for management of locally advanced rectal cancer amenable to sphincter sparing TME

15. PROSPECT: Study Design
A phase II/III NCI Cooperative Group study:
Randomized phase II of 366 patients with early stopping rule if failure to complete R0 resections or if an unacceptably high rate of Local Recurrences
Phase III component built in and will include 644 additional patients if stopping criteria are not met
310 patients accrued to date…

16. PROSPECT: Study Schema
“Standard Arm”
5FUCMT*
TME
RANDOMIZE 1:1
Response 20%
TME
FOLFOX x 6
“Selective Arm”
5FUCMT*
TME
Response <20%
*5FUCMT = infusional or oral 5FU + radiation therapy

17. PROSPECT: Study Schema
“Standard Arm”
Chemo per
primary MD
5FUCMT*
TME
Chemo per
primary MD
RANDOMIZE 1:1
Response 20%
TME
FOLFOX x 6
“Selective Arm”
5FUCMT*
TME
Chemo per
primary MD
Response <20%
*5FUCMT = infusional 5FU or capecitabine + radiation therapy

18. Study Schema with Suggested Post-op Regimens
“Standard Arm”
5FUCMT
TME
FOLFOX x 8*
Response 20%
FOLFOX x 6*
RANDOMIZE 1:1
TME
FOLFOX x 6
“Selective Arm”
5FUCMT
TME
Response <20%
*Post-op chemo is suggested; # of cycles & regimen may be modified
(modification is not a protocol violation)

19. PROSPECT: 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)

20. PROSPECT: Inclusion Criteria
Biopsy proven rectal adenocarcinoma at age 18+
Candidate for sphincter sparing surgery according to TME experienced surgeon at presentation
Standard treatment would be combined modality neoadjuvant chemoradiation followed by curative TME
Baseline Clinical staging: T2N1, T3N0, T3N1
Proctoscopy by primary surgeon
MRI or ERUS (MRI preferred)
CT scan of Chest/Abdomen/Pelvis

21. PROSPECT: Exclusion Criteria
Clinical T4 tumors
Bulky clinical N2 disease (estimated from imaging)
Defined as >=4 pelvic nodes >10mm in diameter
Not a candidate for either 5FUCMT or oxaliplatin
Tumor within 3mm of mesorectal fascia on MRI or CT
Undiverted symptomatic bowel obstruction
ECOG Performance Status of 3 or 4
Prior pelvic radiation

22. Staging/Restaging Evaluation
Baseline staging is identical in both arms
Restaging in selective arm is more intensive
Opportunity to give XRT if poor response to FOLFOX
Re-evaluation in selective arm:
Proctoscopy/exam by primary surgeon
MRI of Pelvis or ERUS (same test as at baseline)
If response of primary tumor is:
<20%, then gets 5FUXRT
20%, then straight to OR for TME

23. Radiation in the Intervention Arm is Used Selectively
Criteria for Delivery of XRT in Selective Arm:
Preoperative 5FUCMT is to be administered if:
Evidence of clinical progression during pre-op FOLFOX
Restaging reveals rectal tumor response is an estimated <20%
Unable to tolerate FOLFOXx6 at or above dose level-2
Patient withdraws consent
Postoperative 5FUCMT is recommended if:
TME pathology is T4
TME pathology has any positive margin (R1 or R2 resection)
Surgeon’s self assessment is that TME was incomplete
Surgical/Path QA report indicates incomplete TME

24. Treatment Considerations Balancing Consistency vs. Flexibility
Radiation
IMRT is allowed
Short course radiotherapy is not allowed
Surgery
Surgeon must be willing to submit photos of the first TME specimen for credentialing
Laparascopic and robotic assisted approaches are allowed
Sensitizing Chemotherapy with Radiation
May give capecitabine or infusional 5FU
Postoperative Chemotherapy
FOLFOX is suggested, but regimen may be tailored to patient’s tolerance of preoperative treatment and MD discretion

25. Randomized Phase II Study of Neoadjuvant Chemo without XRT: Bacchus Trial (MRC UK)
Study in progress NCT
“poor prognosis”-pT3bT3c or T3d
FOLFOX/Bev vs. FOLFOXIRI/bev x6
Response assessed by PET/CT after 3 cycles of rx
Primary endpoint: pathologic CR rate at surgery

26. Neoadjuvant Chemo Phase III Trial in Progress: Sun Yat Sen Trial
FOWARC: NCT China
3 arm Phase II/III for all pre-op locally advanced rectal cancers
ChemoRT
FOLFOX then chemoRT
FOLFOX
Primary outcome is DFS at 3 years

27. Conclusions
Neoadjuvant chemotherapy strategies are an investigational approach for patients with resectable rectal CA amenable to sphincter sparing TME
Patients with threatened margins are inappropriate candidates for selective use of XRT
Induction FOLFOX merits consideration for pts
who can’t have XRT due to prior therapy
with stage IV disease amenable to R0 resection
with suspected metastatic disease
Please enroll clinical stage II/III rectal cancer patients in PROSPECT to help address this “great debate”

28. THANK YOU
Questions?