Is Radiation Consistently Is Radiation Consistently Necessary for Mid-High Rectal Necessary for Mid-High Rectal

Cancers?Cancers?

Assigned Viewpoint: No Assigned Viewpoint: No Great Debates SymposiumGreat Debates Symposium

New York City, NYNew York City, NY

Deb Schrag MDDeb Schrag MD

Dana Farber Cancer InstituteDana Farber Cancer Institute

Harvard Medical SchoolHarvard Medical School

March 28March 28thth 2014 2014

Background: Background: Why Question Use of Neoadjuvant XRT?Why Question Use of Neoadjuvant XRT?

• Current standard of care for all Stage II-III rectal cancer is Current standard of care for all Stage II-III rectal cancer is tri-modality therapy—has been so since 1990tri-modality therapy—has been so since 1990

• In 2004, German study (Sauer NEJM) demonstrated In 2004, German study (Sauer NEJM) demonstrated superiority of preoperative rather than post operative XRT superiority of preoperative rather than post operative XRT in terms of QOL/local recurrence—drift to preop rx in USAin terms of QOL/local recurrence—drift to preop rx in USA

• Neoadjuvant XRT may be overtreatment in some casesNeoadjuvant XRT may be overtreatment in some cases

• Pelvic radiation causes short and long-term morbidityPelvic radiation causes short and long-term morbidity

• Chemo, surgery and imaging techniques have each Chemo, surgery and imaging techniques have each improved since tri-modality paradigm establishedimproved since tri-modality paradigm established

• Landmark Dutch TME trial showed that XRT marginally Landmark Dutch TME trial showed that XRT marginally improves LR rates, but not survivalimproves LR rates, but not survival

The Plural of Anecdote Doesn’t=Data, but The Plural of Anecdote Doesn’t=Data, but Does Raise Provocative QuestionsDoes Raise Provocative Questions

• Patients with stage IV rectal cancerPatients with stage IV rectal cancer• Start with palliative chemo RT?Start with palliative chemo RT?• Start with palliative resection?Start with palliative resection?• Start with systemic chemotherapy?Start with systemic chemotherapy?

• High response rate and conversion to resectability--High response rate and conversion to resectability--omitting the preop XRTomitting the preop XRT

• Chemotherapy without XRTChemotherapy without XRT• Stage II-III RC in Prostate and GYN Cancer survivorsStage II-III RC in Prostate and GYN Cancer survivors• Women seeking fertility preservationWomen seeking fertility preservation• Men and women concerned about sexual healthMen and women concerned about sexual health

Challenges Arising from Neoadjuvant Challenges Arising from Neoadjuvant ChemoXRT Rectal Treatment ParadigmChemoXRT Rectal Treatment Paradigm

• Rectal patients succumb to metastatic dxRectal patients succumb to metastatic dx

• Met Rectal patients previously treated with pelvic XRT don’t Met Rectal patients previously treated with pelvic XRT don’t tolerate sustained myelosuppressive Rx welltolerate sustained myelosuppressive Rx well

• Node+ pts often drop out of post op adjuvant rxNode+ pts often drop out of post op adjuvant rx• Node- pts may get unnecessary rxNode- pts may get unnecessary rx

• Met Rectal pts seem to get less chemo, end up having Met Rectal pts seem to get less chemo, end up having slightly inferior survival than colon ptsslightly inferior survival than colon pts

• Why not spare the marrow for when its really needed?Why not spare the marrow for when its really needed?

Motivating Pilot Study ExperienceMotivating Pilot Study Experience

• Single center phase II pilot at MSKCC administered 6 cycles Single center phase II pilot at MSKCC administered 6 cycles of induction FOLFOX+Bev to patients with clinical T2N1, of induction FOLFOX+Bev to patients with clinical T2N1, T3N0, T3N1 rectal cancer who were candidates for LAR at T3N0, T3N1 rectal cancer who were candidates for LAR at presentation presentation

• XRT planned if no response or any positive marginXRT planned if no response or any positive margin

• Of 30 participants, none required preoperative XRTOf 30 participants, none required preoperative XRT

• With more than 4 years median follow up:With more than 4 years median follow up:• 1 post-op death, 2 cancer deaths1 post-op death, 2 cancer deaths• No local recurrencesNo local recurrences• 4 recurrences, all with metastases to lung4 recurrences, all with metastases to lung

JCO Jan 2014

Personal Viewpoint on Stage II/III Rectal Personal Viewpoint on Stage II/III Rectal Cancer Treatment: Cancer Treatment:

• All patients with T4 rectal cancer require XRTAll patients with T4 rectal cancer require XRT

• Patients with T2-T3 rectal cancer proximal to ~12 cm on Patients with T2-T3 rectal cancer proximal to ~12 cm on proctoscope can safely be managed without preop XRTproctoscope can safely be managed without preop XRT

• Patients with T2-3 distal rectal cancer requiring an APR Patients with T2-3 distal rectal cancer requiring an APR should receive preop Chemo XRTshould receive preop Chemo XRT

• Patients with T2-3 rectal cancer who are candidates for Patients with T2-3 rectal cancer who are candidates for Low Anterior Resection (typically ~5-12cm from anal Low Anterior Resection (typically ~5-12cm from anal verge) should be encouraged to enroll in PROSPECT!verge) should be encouraged to enroll in PROSPECT!

PROSPECTPROSPECT

N1048-CALGB81001-ACOSOGZ6052N1048-CALGB81001-ACOSOGZ6052

Full protocol available on CTSU Website (www.ctsu.org)Full protocol available on CTSU Website (www.ctsu.org)Endorsed by SWOG, ECOG, NCIC, RTOG, NSABPEndorsed by SWOG, ECOG, NCIC, RTOG, NSABP

An NCI Cooperative Group Phase II/III Trial of Neoadjuvant FOLFOX with An NCI Cooperative Group Phase II/III Trial of Neoadjuvant FOLFOX with Selective Use of Combined Modality Chemoradiation for Selective Use of Combined Modality Chemoradiation for

Locally Advanced Rectal Cancer Patients Undergoing Low Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection with Total Mesorectal ExcisionAnterior Resection with Total Mesorectal Excision

PROSPECT: N1048PROSPECT: N1048

• Objective:Objective: • To determine if selective use of To determine if selective use of

neoadjuvant XRT is a safe alternative neoadjuvant XRT is a safe alternative strategy to routine use of XRT for strategy to routine use of XRT for management of locally advanced rectal management of locally advanced rectal cancer that is amenable to sphincter cancer that is amenable to sphincter sparing TMEsparing TME

PROSPECT: Study DesignPROSPECT: Study Design

• A phase II/III NCI Cooperative Group study:A phase II/III NCI Cooperative Group study:

• Randomized phase II of 366 patients with early Randomized phase II of 366 patients with early stopping rule if failure to complete R0 resections stopping rule if failure to complete R0 resections or if an unacceptably high rate of Local or if an unacceptably high rate of Local RecurrencesRecurrences

• Phase III component built in and will include 644 Phase III component built in and will include 644 additional patients if stopping criteria are not metadditional patients if stopping criteria are not met

Chemo per primary MDTME5FUCMT*

Chemo per primary MDTME

“Selective Arm”

Response 20%

“Standard Arm”

PROSPECT: Study Schema

Response <20%

RA

ND

OM

IZE

1:1

5FUCMT* TMEChemo per primary MD

FOLFOX x 6

*5FUCMT = infusional or oral 5FU + radiation therapy

PROSPECT: Study EndpointsPROSPECT: Study EndpointsPrimary Outcomes:Primary Outcomes:• Randomized Phase II ComponentRandomized Phase II Component

• R0 Resection RateR0 Resection Rate• Time to local recurrence (TLR)Time to local recurrence (TLR)

• Phase III Component: Co-primary endpointsPhase III Component: Co-primary endpoints• Time to local recurrence (TLR)Time to local recurrence (TLR)• Disease free survival (DFS)Disease free survival (DFS)

Secondary Outcomes:Secondary Outcomes:• Pathologic complete response rate (Pcr)Pathologic complete response rate (Pcr)• Overall survival (OS)Overall survival (OS)• Quality of life (QOL)Quality of life (QOL)• Clinician and patient reported treatment toxicityClinician and patient reported treatment toxicity• Molecular correlates of response to neoadjuvant therapyMolecular correlates of response to neoadjuvant therapy• Adverse Event (AE) Profiles Adverse Event (AE) Profiles • Rates of receiving 5FUCMT Rates of receiving 5FUCMT

PROSPECT: Inclusion CriteriaPROSPECT: Inclusion Criteria• Biopsy proven rectal adenocarcinoma at age 18+Biopsy proven rectal adenocarcinoma at age 18+

• Distal end of tumor located 5-12 cm from anal vergeDistal end of tumor located 5-12 cm from anal verge

• Candidate for sphincter sparing surgery according to Candidate for sphincter sparing surgery according to TME experienced surgeon at presentationTME experienced surgeon at presentation

• Standard treatment would be combined modality Standard treatment would be combined modality neoadjuvant chemoradiation followed by curative TMEneoadjuvant chemoradiation followed by curative TME

• Baseline Clinical staging: T2N1, T3N0, T3N1Baseline Clinical staging: T2N1, T3N0, T3N1• Proctoscopy by primary surgeonProctoscopy by primary surgeon• MRI or ERUS (MRI preferred)MRI or ERUS (MRI preferred)• CT scan of Chest/Abdomen/PelvisCT scan of Chest/Abdomen/Pelvis

PROSPECT: PROSPECT: Exclusion CriteriaExclusion Criteria

• Clinical T4 tumorsClinical T4 tumors

• Clinical N2 disease Clinical N2 disease • Defined as >=4 pelvic nodes >10mm in diameterDefined as >=4 pelvic nodes >10mm in diameter

• Not a candidate for either 5FUCMT or oxaliplatinNot a candidate for either 5FUCMT or oxaliplatin

• Tumor within 3mm of mesorectal fascia on MRI or CTTumor within 3mm of mesorectal fascia on MRI or CT

• Undiverted symptomatic bowel obstructionUndiverted symptomatic bowel obstruction

• ECOG Performance Status of 3 or 4ECOG Performance Status of 3 or 4

• Prior pelvic radiationPrior pelvic radiation

Staging/Restaging EvaluationStaging/Restaging Evaluation• Baseline staging is identical in both armsBaseline staging is identical in both arms

• Restaging in selective arm is more intensiveRestaging in selective arm is more intensive• Opportunity to give XRT if poor response to FOLFOXOpportunity to give XRT if poor response to FOLFOX• Evaluate if rectal tumor decreased by Evaluate if rectal tumor decreased by 20% 20%

• Re-evaluation in selective arm:Re-evaluation in selective arm:• Proctoscopy Proctoscopy • Physical exam by primary surgeonPhysical exam by primary surgeon• MRI of Pelvis or ERUS (same test as at baseline)MRI of Pelvis or ERUS (same test as at baseline)

• If response of primary tumor is:If response of primary tumor is:• <20%, then gets 5FUXRT<20%, then gets 5FUXRT20%, then straight to OR for TME20%, then straight to OR for TME

Radiation in the Intervention Arm is Radiation in the Intervention Arm is Used Used SelectivelySelectively

• Criteria for Delivery of XRT in Selective Arm:Criteria for Delivery of XRT in Selective Arm:

• Preoperative 5FUCMT is to be administered if:Preoperative 5FUCMT is to be administered if: • Evidence of clinical progression during pre-op FOLFOX Evidence of clinical progression during pre-op FOLFOX • Restaging reveals rectal tumor response is an estimated <20% Restaging reveals rectal tumor response is an estimated <20% • Unable to tolerate FOLFOXx6 at or above dose level-2Unable to tolerate FOLFOXx6 at or above dose level-2• Patient withdraws consentPatient withdraws consent

• Postoperative 5FUCMT is recommended if:Postoperative 5FUCMT is recommended if:• TME pathology is T4 TME pathology is T4 • TME pathology has any positive margin (R1 or R2 resection)TME pathology has any positive margin (R1 or R2 resection)• Surgeon’s self assessment is that TME was incompleteSurgeon’s self assessment is that TME was incomplete• Surgical/Path QA report indicates incomplete TMESurgical/Path QA report indicates incomplete TME

Treatment ConsiderationsTreatment ConsiderationsBalancing Consistency vs. FlexibilityBalancing Consistency vs. Flexibility

• RadiationRadiation• IMRT is allowedIMRT is allowed• Short course radiotherapy is Short course radiotherapy is notnot allowed allowed

• SurgerySurgery• Surgeon must be willing to submit photos of the first TME specimen for credentialing Surgeon must be willing to submit photos of the first TME specimen for credentialing

• Laparascopic and robotic assisted approaches Laparascopic and robotic assisted approaches areare allowed allowed

• Sensitizing Chemotherapy with Radiation Sensitizing Chemotherapy with Radiation • May give capecitabine or infusional 5FU May give capecitabine or infusional 5FU

• Postoperative ChemotherapyPostoperative Chemotherapy• FOLFOX is suggested, but regimen may be tailored to patient’s tolerance of FOLFOX is suggested, but regimen may be tailored to patient’s tolerance of

preoperative treatmentpreoperative treatment• Regimen is at the discretion of the primary MDRegimen is at the discretion of the primary MD

PROSPECT: PROSPECT: Statistical DesignStatistical Design

• The primary goal is to compare selective to routine use of The primary goal is to compare selective to routine use of pre-op 5FUXRT with respect to the co-primary endpoints of pre-op 5FUXRT with respect to the co-primary endpoints of Disease Free Survival (DFS) and time to local recurrence Disease Free Survival (DFS) and time to local recurrence (TLR)(TLR)

• DFS and TLR will be considered jointly to determine DFS and TLR will be considered jointly to determine whether selective or routine use of 5FUXRT is preferredwhether selective or routine use of 5FUXRT is preferred

• The selective 5FUXRT arm will be favored if it has eitherThe selective 5FUXRT arm will be favored if it has either• superior DFS compared to the treat-all arm superior DFS compared to the treat-all arm • non-inferior DFS AND non-inferior TLRnon-inferior DFS AND non-inferior TLR

ConclusionsConclusions• Neoadjuvant chemotherapy strategies are an Neoadjuvant chemotherapy strategies are an

investigationalinvestigational approach for patients with resectable approach for patients with resectable rectal CA amenable to sphincter sparing TMErectal CA amenable to sphincter sparing TME

• XRT is a mainstay of Rx for a curable cancer 5-12 cm from XRT is a mainstay of Rx for a curable cancer 5-12 cm from the anal verge: the anal verge: selective selective approach appropriate on a trial approach appropriate on a trial

• Patients with threatened margins are inappropriate Patients with threatened margins are inappropriate candidates for selective use of XRTcandidates for selective use of XRT

• Induction FOLFOX for ptsInduction FOLFOX for pts• who can’t have XRT due to prior therapywho can’t have XRT due to prior therapy• with stage IV disease amenable to R0 resectionwith stage IV disease amenable to R0 resection• With suspected metastatic diseaseWith suspected metastatic disease

THANK YOUTHANK YOU

• Questions?Questions?

Study Component Study Component Contact InformationContact Information

Alliance Protocol CoordinatorAlliance Protocol Coordinator jtaylor1@uchicago.edu jtaylor1@uchicago.edu

PIPI deb_schrag@dfci.harvard.edudeb_schrag@dfci.harvard.edu

StatisticsStatistics Sargent.Daniel@mayo.eduSargent.Daniel@mayo.edu

Shi.Qian@mayo.eduShi.Qian@mayo.edu

Surgical OncologySurgical Oncology afichera@surgery.bsd.uchicago.eduafichera@surgery.bsd.uchicago.edu

weiser1@mskcc.orgweiser1@mskcc.org

Radiation OncologyRadiation Oncology hmamon@lroc.harvard.eduhmamon@lroc.harvard.edu

Medical OncologyMedical Oncology saltzl@mskcc.orgsaltzl@mskcc.org

mcwilliams.robert@mayo.edumcwilliams.robert@mayo.edu

RadiologyRadiology gollubm@mskcc.orggollubm@mskcc.org

PathologyPathology wendy.frankel@osumc.eduwendy.frankel@osumc.edu

Correlative ScienceCorrelative Science solitd@mskcc.orgsolitd@mskcc.org

Quality of LifeQuality of Life

PROCTCAEPROCTCAE

templel@mskcc.orgtemplel@mskcc.org

basche@mskcc.orgbasche@mskcc.org

Please Contact Study Team Members with any suggestions or concerns