Download Memorial Sloan-Kettering Cancer Center Protocol 07

Is Radiation Consistently
Necessary for Mid-High Rectal
Cancers?
Assigned Viewpoint: No
Great Debates Symposium
New York City, NY
Deb Schrag MD
Dana Farber Cancer Institute
Harvard Medical School
March 28th 2014
Background:
Why Question Use of Neoadjuvant XRT?
• Current standard of care for all Stage II-III rectal cancer is
tri-modality therapy—has been so since 1990
• In 2004, German study (Sauer NEJM) demonstrated
superiority of preoperative rather than post operative XRT
in terms of QOL/local recurrence—drift to preop rx in USA
• Neoadjuvant XRT may be overtreatment in some cases
• Pelvic radiation causes short and long-term morbidity
• Chemo, surgery and imaging techniques have each
improved since tri-modality paradigm established
• Landmark Dutch TME trial showed that XRT marginally
improves LR rates, but not survival
The Plural of Anecdote Doesn’t=Data, but
Does Raise Provocative Questions
• Patients with stage IV rectal cancer
• Start with palliative chemo RT?
• Start with palliative resection?
• Start with systemic chemotherapy?
• High response rate and conversion to resectability-omitting the preop XRT
• Chemotherapy without XRT
• Stage II-III RC in Prostate and GYN Cancer survivors
• Women seeking fertility preservation
• Men and women concerned about sexual health
Challenges Arising from Neoadjuvant
ChemoXRT Rectal Treatment Paradigm
• Rectal patients succumb to metastatic dx
• Met Rectal patients previously treated with pelvic XRT
don’t tolerate sustained myelosuppressive Rx well
• Node+ pts often drop out of post op adjuvant rx
• Node- pts may get unnecessary rx
• Met Rectal pts seem to get less chemo, end up having
slightly inferior survival than colon pts
• Why not spare the marrow for when its really needed?
Motivating Pilot Study Experience
• 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 30 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
Personal Viewpoint on Stage II/III Rectal
Cancer Treatment:
• All patients with T4 rectal cancer require XRT
• Patients with T2-T3 rectal cancer proximal to ~12 cm on
proctoscope can safely be managed without preop XRT
• Patients with T2-3 distal rectal cancer requiring an APR
should receive preop Chemo XRT
• Patients with T2-3 rectal cancer who are candidates for
Low Anterior Resection (typically ~5-12cm from anal
verge) should be encouraged to enroll in PROSPECT!
PROSPECT
N1048-CALGB81001-ACOSOGZ6052
Full protocol available on CTSU Website (www.ctsu.org)
Endorsed by SWOG, ECOG, NCIC, RTOG, NSABP
An NCI Cooperative Group Phase II/III Trial of Neoadjuvant FOLFOX with
Selective Use of Combined Modality Chemoradiation for
Locally Advanced Rectal Cancer Patients Undergoing Low
Anterior Resection with Total Mesorectal Excision
PROSPECT: N1048
• Objective:
• To determine if selective use of
neoadjuvant XRT is a safe alternative
strategy to routine use of XRT for
management of locally advanced rectal
cancer that is amenable to sphincter
sparing TME
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
PROSPECT: Study Schema
“Standard Arm”
RANDOMIZE 1:1
5FUCMT*
Response 20%
TME
TME
Chemo per
primary MD
Chemo per
primary MD
FOLFOX x 6
“Selective Arm”
5FUCMT*
Response <20%
TME
Chemo per
primary MD
*5FUCMT = infusional or oral 5FU + radiation therapy
PROSPECT: 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 (Pcr)
• Overall survival (OS)
• Quality of life (QOL)
• Clinician and patient reported treatment toxicity
• Molecular correlates of response to neoadjuvant therapy
• Adverse Event (AE) Profiles
• Rates of receiving 5FUCMT
PROSPECT: Inclusion Criteria
• Biopsy proven rectal adenocarcinoma at age 18+
• Distal end of tumor located 5-12 cm from anal verge
• 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
PROSPECT:
Exclusion Criteria
• Clinical T4 tumors
• Clinical N2 disease
• 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
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
• Evaluate if rectal tumor decreased by  20%
• Re-evaluation in selective arm:
• Proctoscopy
• Physical 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
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
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
• Regimen is at the discretion of the primary MD
PROSPECT:
Statistical Design
• The primary goal is to compare selective to routine use
of pre-op 5FUXRT with respect to the co-primary
endpoints of Disease Free Survival (DFS) and time to
local recurrence (TLR)
• DFS and TLR will be considered jointly to determine
whether selective or routine use of 5FUXRT is preferred
• The selective 5FUXRT arm will be favored if it has either
• superior DFS compared to the treat-all arm
• non-inferior DFS AND non-inferior TLR
Conclusions
• Neoadjuvant chemotherapy strategies are an
investigational approach for patients with resectable
rectal CA amenable to sphincter sparing TME
• XRT is a mainstay of Rx for a curable cancer 5-12 cm
from the anal verge: selective approach appropriate
on a trial
• Patients with threatened margins are inappropriate
candidates for selective use of XRT
• Induction FOLFOX for pts
• who can’t have XRT due to prior therapy
• with stage IV disease amenable to R0 resection
• With suspected metastatic disease
THANK YOU
• Questions?
Please Contact Study Team Members
with any suggestions or concerns
Study Component
Alliance Protocol Coordinator
Contact Information
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PI
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Statistics
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Surgical Oncology
Radiation Oncology
Medical Oncology
Radiology
Pathology
Correlative Science
Quality of Life
PROCTCAE
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