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Department of GI Medical Oncology Cathy Eng, M.D., F.A.C.P. Associate Professor Associate Medical Director, Colorectal Center Director of Network Clinical.

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Presentation on theme: "Department of GI Medical Oncology Cathy Eng, M.D., F.A.C.P. Associate Professor Associate Medical Director, Colorectal Center Director of Network Clinical."— Presentation transcript:

1 Department of GI Medical Oncology 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

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 Diagnostic Studies: EUS/MRI T2N0 T3N0, TxN+ T1N0 Preop CXRT TME Adjuvant Chemotherapy TAE vs TME M+ Multidisciplinary Treatment 3

4 Classic Pivotal Trials

5 Preoperative Radiation and Total Mesorectal Excision (TME) (Dutch Colorectal Cancer Group) Local Failure Preop RT (5x5) (N=897) Local Failure 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 APR1.2%4.9%7.3%10.1% 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 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 Peeters et al, Ann Surg (5): Dutch TME trial: Long term results Impact on Local Recurrence 3 yrs: 10% vs. 31%

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

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

9 CAO/ARO/AIO-94: Cumulative Incidence of Local Relapse ( Med. Follow-up: 40M) Months Locoregional Recurrences p = Post-op CRT Pre-op CRT 13% 6% 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 Surg/chemo/XRTSurg/chemo T1-2N178-83%85% T3N074-80%84% Surg/chemo/XRTSurg/chemo T1-2-N15-6%5% T3N05-10%11% Gunderson et al: JCO 22(10): May 15, 2004 Table I: Percent Overall Survival (pooled analysis data) Table II: Percent Local Relapse (pooled analysis data)

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: ©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 T 4 ) Induction FOLFOX/Bev x 6 cycles CR: TME PR: chemoXRT/TME Primary outcome: R 0 Median follow-up: 52M R 0 = 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% Response<20% FOLFOX x 6Restage5FU/Cape-RTTMEFOLFOX x 2 TMEFOLFOX x 6 TMEFOLFOX x 8 RANDOMIZE: 1:1 Selective Arm Standard Arm 5FU/Cape-RT Objective: To determine if selective use of chemoRT is non-inferior to standard preop chemoRT PIs: Fichera and Schrag

25 Study Endpoints Primary Outcomes: Randomized Phase II Component R0 Resection Rate Time to local recurrence (TLR) Phase III Component: Co-primary endpoints Time to local recurrence (TLR) 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.

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