Neoadjuvant FOLFOX with Bevacizumab but without pelvic radiation for Locally Advanced Rectal Cancer

D Schrag, MR Weiser, KA Goodman, M Gonen, A Cercek, DL Reidy, WD Wong, JG Guillem, LKF Temple, P. Paty, L. SaltzMemorial Sloan-Kettering Cancer Center, New York City, New York

Abstract

Results

Background

Methods

Methods

Background: Preoperative 5FU-based chemo plus radiation therapy (XRT) is standard for U.S. patients (pts) with locally advanced rectal cancer (RC). We conducted a pilot feasibility trial of pre-op FOLFOX-bevacizumab (bev) without XRT.

Methods: Patients with clinical stage II-III RC (but not T4 tumors) who were candidates for sphincter-sparing surgery, were treated with 6 cycles of FOLFOX. Bev was included for cycles 1-4. Pts then were re-imaged and had repeat sigmoidoscopy with endorectal ultrasound (ERUS) performed by their surgeon to assess the primary tumor response. Those with stable/progressive disease were to be referred for pre-op 5FU plus XRT, followed by surgery, and those with clinical regression were to have surgery without pre-op XRT.  Post-op 5FU plus XRT was planned for any pts who did not have an R0 resection.  Post-op chemo was left to investigator discretion, however 6 cycles of FOLFOX were recommended.  The primary outcome was the R0 resection rate. Secondary outcomes were the pathologic CR rate, the 3-year disease free survival and the 3-year local recurrence (LR) rate.

Results: Of 31 pts accrued since April 2007, two were withdrawn from the study for cardiovascular toxicity (1 angina, 1 arrhythmia) after 1-2 cycles of FOLFOX-bev. Both had R0 resections. Of 29 who have completed pre-op chemo, all 29 had clinical regression and proceeded to surgery without pre-op XRT. All 29 had R0 resections. Eight of 29 (27%) have had a path CR.  One pt with 14+ nodes and a close deep margin received post-op XRT, and has since developed pulmonary metastases.  One patient with pathologic yT1N0 disease had high output ileostomy post-op but was discharged home in stable condition on day 10. He died suddenly 3 days later. Autopsy did not identify a cause. Local and distant recurrence rate data are immature; however thus far, there have been no LRs and 3 distant recurrences, all pulmonary. 26 patients remain alive and disease-free.

Conclusion: Preliminary results of this pilot trial indicate that preoperative FOLFOX-bev chemo without RT achieves a high rate of R0 resections and pathologic CR for rectal cancer patients amenable to low anterior resection. Further trials of non XRT-containing approaches are warranted. The research team thanks patient participants and Genentech who supported the study.

An investigator initiated pilot study funded by Genentech for patients with newly diagnosed clinical stage II or III rectal adenocarcinoma opened in April 2007 at MSKCC and has accrued 31 of 36 planned subjects.

Inclusion Criteria: 1) Candidate for LAR, FOLFOX and Bev; 2)Flexible sigmoidoscopy with ERUS staging by primary surgeon demonstrates uT2N1; uT2N2; uT3N0; uT3N1; or uT3N2 primary rectal tumor.

Exclusion criteria: 1) T4 tumors; 2) tumors requiring APR

Treatment schema: 6 cycles of FOLFOX, the first 4 with Bevfollowed by complete restaging. Patients with clinical progression or stable disease were to have XRT with 5FU.

Those with clinical regression were to go directly to surgery. Post-op treatment was left to MD discretion but 6 cycles of FOLFOX was suggested. No post-op Bev was provided.

Patient #Age Gender

ERUS Stage Path Stage Patient # Age Gender

ERUS Stage Path Stage

1. 30F T3N1 pCR 16. 37M T3N0 T2N1

2. 49F T3N0 T2N0 17. 26F T3N1 T3N2

3. 72M T3N1 pCR 18. 58M T2N1 pCR

4. 63M T3N1 pCR 19 53M T3N1 T2N1

5. 64M T3N0 T1N1 20 50M T2N1 T1N0

6. 54M T3N1 T2N0 21. 46F T3N0 T3N0

7. 81F T3N1 T3N2 22. 42F T3N1 T3N1

8. 56M T3N1 T3N0 23. 55M T3N0 T1N0

9. 49M T3N1 T2N1 24. 65F T3N0 T3N1

10. 68F T3N1 pCR 25. 36M T3N0 pCR

11. 33F T2N1 T3N1 26. 42F T3N1 T2N0

12. 29F T3N1 T3N0 27. 52F T3N0 T3N0

13. 47M T3N1 pCR 28. 61M T3N0 pCR

14 . 47F T3N1 T2N0 29. 41F T3N1 T2N1

15. 57F T3N1 T2N0 30. 57F T3N0 pending

• Combined modality therapy with 5FU-based chemotherapy plus radiation therapy, followed by surgery and adjuvant chemotherapy, is standard for locally advanced rectal cancer

•Pelvic radiation (XRT) decreases local recurrence (LR) rates to <10% and is better tolerated pre- than post-operatively.

•Although pelvic XRT nearly eliminates the risk of LR, it may have long term adverse effects on bowel, bladder, and sexual function as well as fertility. It can induce myelosuppression and therefore decreased tolerance of protracted chemotherapy.

•Improvements in systemic chemotherapy (FOLFOX) have increased survival for stage III colon cancer. Advances in surgical technique (total mesorectal excision –TME) have improved rates of R0 resection in rectal cancer. These advances challenge the existing care standard and prompt clinicians to question whether selected patients can be spared pelvic XRT.

ResultsPreliminary Outcomes

Event Rate N %

R0 Resection-all pts 31/31 100

R0 resection, on study 29/29 100

Had Pre-op Pelvic XRT 0/29 0

Pathologic CR 8/29 27

Deaths 1/29 3

Local Recurrence Rate 0/29 0

Distant Recurrence-all lung 3/29 10•2 pts withdrawn from study after 1-2 cycles of FOLFOX.1 for angina requiring PTCA and 1 for arrhythmia. Both R0 resections.•All patients had clinical response and none had pre-op XRT•1 sudden death 10 days post-op in pt with high output ileostomy, no cause identified on autopsy•1 small anastomotic leak successfully repaired•3 wound infections. Other typical FOLFOX adverse effects•All pts have had R0 resections.1 pt had a close radial margin.•To date, No LRs, 3 distant recurrences all pulmonary

• Because the current care standard for rectal cancer achieves an R0 resection for over 90% of patients, the study was designed with early stopping rules to discontinue the protocol if more than 1 of the 1st 7, or 2 of the first 15 patients failed to undergo an R0 resection.

•The primary study outcome is the ability to achieve an R0 resection.

•Secondary outcomes are the pathologic CR rate, the 3-year LR rate and 3-year disease free survival (DFS) and the number of patients treated with neoadjuvant FOLFOX-Bev therapy without requirement for either preoperative pelvic XRT

•Plans to continue study of this treatment approach are contingent upon achieving an R0 resection rate >90%, LR rate of <15% and a 3 year DFS rate of >75%.