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.