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

Department of GI Medical Oncology

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 ProfessorAssociate Medical Director, Colorectal Center

Director of Network Clinical Research, GI Med OncCo-Chair, SWOG Rectal Committee

March 28, 2014

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

Current Generalized Standard Treatment Paradigm for Rectal Cancer

Diagnosis of rectal Cancer

Diagnostic Studies: EUS/MRI

≤ T2N0

≥T3N0,TxN+

T1N0

Preop CXRT

TME

TMEAdjuvant

Chemotherapy

TAE vs TME

M+Multidisciplinary

Treatment

3

Classic Pivotal Trials

Preoperative Radiation and Total Mesorectal Excision (TME)

(Dutch Colorectal Cancer Group)Local Failure

Preop RT (5x5)

(N=897)

Local FailureSurgery alone

(N=908)

2-yr Recurrence Rate 2.4% 8.2%

Distance from verge10.1-15 cm5.1-10 cm<5 cm

1.3%1.0%5.8%

3.8%10.1%10%

Type of resectionLow anteriorAPR

1.2%4.9%

7.3%10.1%

TNM stageI (30%)II (28%)III (34%)

0.5%1.5%4.3%

0.7%5.7%15%

Kapiteijan et al: N Engl J Med. 2001 Aug 30;345(9):638-46.

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 2007 246(5):693-701

Dutch TME trial: Long term results

Impact on Local Recurrence

3 yrs: 10% vs. 31%

No impact of XRT + TME on distant recurrence or overall survival

Dutch Rectal Cancer Study Group

Cumulative Distant Recurrence

Overall Survival

P=0.39 P=0.26

Peeters et al, Ann Surg 2007 246(5):693-701

N=201

N=222

Cumulative Distant Recurrence Overall Survival

Neoadjuvant Chemoradiotherapy for Rectal Cancer: CAO/ARO/AIO-94

Randomize

Surgery5-FU/XRT

Primary endpoint: DFS

Sauer et al NEJM, 2004:

Surgery

5-FU

5-FU5-FU/XRT

Control Arm

CAO/ARO/AIO-94: Cumulative Incidence of Local Relapse (Med. Follow-up: 40M)

6050403020100

.14

.12

.10

.08

.06

.04

.02

0.00

Months

Lo

core

gio

nal

Rec

urr

ence

s

p = 0.006

Post-op CRT

Pre-op CRT

13%

6%

Sauer et al., N Engl J Med 2004; 351:1731-40

Update of CAO/ARO/AIO-94: Median Follow-Up 11 Yrs.

Sauer et al: JCO 2012

Can we omit chemoXRT therapy?

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 79-47-51, NCCCTG 86-47-51, 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

Pooled Analysis:5-yr OS and Local Relapse

Surg/chemo/XRT Surg/chemo

T1-2N1 78-83% 85%T3N0 74-80% 84%

Surg/chemo/XRT Surg/chemo

T1-2-N1 5-6% 5%T3N0 5-10% 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)

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

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).

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 diseaseN2 would suggest higher risk of local recurrence

A “yes” to one of the above may result in the need for consideration of XRT

Rationale for Consideration of Omitting chemoXRT:

Toxicities associated with therapySexual, 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?

Chemotherapy alone may impact the primary rectal tumor

Case 2: 45 y/o F T3N1M1 with liver and lung mets

8-10 cm from the anal verge

Courtesy of Dr. Rodriguez-Bigas

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

MSKCC Pilot Study

Schrag D et al. JCO 2014;32:513-518

©2014 by American Society of Clinical Oncology

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

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

PROSPECT Study Schema (Phase II/III)

Response >=20%

Response<20%

FOLFOX x 6 Restage 5FU/Cape-RT TME FOLFOX x 2

TME FOLFOX x 6

TME FOLFOX 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

PI’s: Fichera and Schrag

Study EndpointsPrimary Outcomes: Randomized Phase II Component

R0 Resection RateTime to local recurrence (TLR)

Phase III Component: Co-primary endpointsTime 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

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 surgeonProctoscopyMRI or ERUS (MRI preferred)CT scan of C/A/P

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.