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Neoadjuvant Therapy For Rectal CancerNeoadjuvant Therapy For Rectal Cancer

Dr Chris TL ChengDr Chris TL Cheng

Princess Margaret HospitalPrincess Margaret Hospital

Neoadjuvant Therapy for Neoadjuvant Therapy for Rectal CancerRectal Cancer

BackgroundBackground

Benefits of neoadjuvant therapy Benefits of neoadjuvant therapy

Selection CriteriaSelection Criteria

Staging & CRMStaging & CRM

Multidisciplinary Team (MDT) approachMultidisciplinary Team (MDT) approach

BackgroundBackground

During the 1990s, TME and postoperative During the 1990s, TME and postoperative adjuvant chemoradiotherapy (CRT) for adjuvant chemoradiotherapy (CRT) for locally advanced rectal tumors was the locally advanced rectal tumors was the gold standard treatment regimengold standard treatment regimen

High Local recurrence (LR) rates despite High Local recurrence (LR) rates despite the use of adjuvant CRTthe use of adjuvant CRT investigators decided to test neoadjuvant investigators decided to test neoadjuvant

radiotherapy (RT) or CRTradiotherapy (RT) or CRT

Short course pre-op RTShort course pre-op RT

Local Local recurrencerecurrence

SurvivalSurvival

SwedishSwedish (1997) (1997) rectal cancer trialrectal cancer trial

(pre-TME)(pre-TME)

27% to 11% 27% to 11% (p<0.001)(p<0.001)

5-yr survival5-yr survival

48% to 58% 48% to 58% (p=0.004)(p=0.004)

Dutch TME trialDutch TME trial (2001)(2001)

8.2% to 2.4% 8.2% to 2.4% (p<0.001)(p<0.001)

No differenceNo difference

Pre-op radiotherapyPre-op radiotherapy

UK Medical Research Council (MRC UK Medical Research Council (MRC CR07) & National Cancer Institute of CR07) & National Cancer Institute of Canada trial (NCIC-CTG C016)Canada trial (NCIC-CTG C016) Local recurrence at 3 yearsLocal recurrence at 3 years

Pre-op short course RTPre-op short course RT: 4.4%: 4.4%

Selective Post-op adjuvant chemoRTSelective Post-op adjuvant chemoRT: 10.6%: 10.6%

Relative risk reduction 61% (p<0.0001)Relative risk reduction 61% (p<0.0001) No difference in overall survivalNo difference in overall survival

Sebag-Montefiore D et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a

multicentre, randomised trial. Lancet. 2009 Mar 7;373(9666):811-20.

Short course preop RT on local Short course preop RT on local recurrencerecurrence

Relative risk reduction in LR Relative risk reduction in LR 57%57%

Neoadjuvant RT Vs Neoadjuvant ChemoRTNeoadjuvant RT Vs Neoadjuvant ChemoRT

Ceelen WP, Van Nieuwenhove Y, Fierens K. Preoperative chemoradiation Ceelen WP, Van Nieuwenhove Y, Fierens K. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. versus radiation alone for stage II and III resectable rectal cancer. CochraneCochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006041. DOI: Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006041. DOI: 10.1002/14651858.CD006041.pub2 10.1002/14651858.CD006041.pub2

Chemotherapy in addition to neoadjuvant Chemotherapy in addition to neoadjuvant RT improves complete responseRT improves complete response

German rectal cancer study groupGerman rectal cancer study groupNeoadjuvant CRT Vs Adjuvant CRTNeoadjuvant CRT Vs Adjuvant CRT

Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731– 40.

Overall SurvivalLocal RecurrenceLocal Recurrence

Neoadjuvant CRT has less Neoadjuvant CRT has less toxicitiestoxicities

Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731– 40.

Neoadjuvant ChemoRT is recommended for Neoadjuvant ChemoRT is recommended for locally advanced rectal cancer locally advanced rectal cancer

Local recurrence for locally advanced CA rectumLocal recurrence for locally advanced CA rectum

TME onlyTME only

TME + adjuvant chemoRTTME + adjuvant chemoRT

Neoadjuvant RT + TMENeoadjuvant RT + TME

Neoadjuvant chemoRT + TMENeoadjuvant chemoRT + TME

Reduction in local recurrence

Advantages of neoadjuvant CRTAdvantages of neoadjuvant CRT

apply to virgin, well-oxygenated tissueapply to virgin, well-oxygenated tissue more profound reduction of local recurrence more profound reduction of local recurrence

compared with postoperative CRTcompared with postoperative CRT

downstage the tumordownstage the tumor make radical resection or sphincter preserving make radical resection or sphincter preserving

surgery feasiblesurgery feasible

Selection CriteriaSelection Criteria

- T 3-4T 3-4

- N +veN +ve

- Predicted CRM ≤ 2mmPredicted CRM ≤ 2mm

Accurate pre-op staging is important Accurate pre-op staging is important for neoadjuvant therapy considerationfor neoadjuvant therapy consideration

Meta-analysis on T and N stagingMeta-analysis on T and N staging

No accurate investigation for LNNo accurate investigation for LN

EUS is operator dependent, cannot pass stenotic tumor, and EUS is operator dependent, cannot pass stenotic tumor, and can only detectcan only detect mesorectal lymph nodes mesorectal lymph nodes

Bipat et al. Rectal cancer: local staging and assessment of lymph node involvement with

endoluminal US, CT, and MR imaging--a meta-analysis. Radiology 2004 Sep;232(3):773-83.

T

N

CRM (circumferential resection margin)CRM (circumferential resection margin)

the distance from the edge of the tumor to the distance from the edge of the tumor to the margin of the resected specimen the margin of the resected specimen

a credible surrogate marker for local a credible surrogate marker for local recurrence (LR)recurrence (LR)

The prognostic value of CRM involvement The prognostic value of CRM involvement is is independentindependent of TNM classification. of TNM classification.

CRM ≤ 2mmCRM ≤ 2mm consider margin positive consider margin positive

MRI for CRMMRI for CRM

MRI recommended for CRM assessmentMRI recommended for CRM assessment

MERCURY (Magnetic resonance imaging MERCURY (Magnetic resonance imaging and rectal cancer european equivalence) and rectal cancer european equivalence) study groupstudy group MRI and histopathologic assessments of MRI and histopathologic assessments of

tumor spread equivalent to within 0.5 mmtumor spread equivalent to within 0.5 mm Accurate measurement of the depth of Accurate measurement of the depth of

extramural tumor spread extramural tumor spread

Mercury Study Group. Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study. Radiology. 2007 Apr;243(1):132-9.

Multidisciplinary TeamMultidisciplinary Team

Surgeons

Pathologists

Radiologists

Oncologists

Multidisciplinary team (MDT)Multidisciplinary team (MDT)

Discussion at the MDT meetingDiscussion at the MDT meeting Increases the proportion of patients receiving Increases the proportion of patients receiving

neoadjuvant treatment neoadjuvant treatment Improves local cancer controlImproves local cancer control Improves 5-year survivalImproves 5-year survival

Palmer G et al. Preoperative tumour staging with multidisciplinary team assessment improves the outcome in locally advanced primary rectal cancer.

Colorectal Dis. 2010 Oct 19 ePub

Radiologists:Radiologists:Standardized Standardized MRI reporting by MRI reporting by specialist specialist gasterointestinal gasterointestinal radiologistsradiologists

OncologistsOncologistsLong Vs Short Scheme CRTLong Vs Short Scheme CRT

Short schemeShort scheme Long schemeLong scheme

IntensityIntensity 5 fractions of 5 fractions of 500 cGy500 cGy

4,500 to 5,060 cGy 4,500 to 5,060 cGy daily during 4 weeksdaily during 4 weeks

Time Time before before OTOT

3-4 days 3-4 days 4-6 weeks4-6 weeks

Aim Aim Reduce local Reduce local recurrencerecurrence

Downstage tumour and Downstage tumour and secure threatened secure threatened CRMCRM

ChemotherapyChemotherapy

Addition of chemotherapy to RT improves Addition of chemotherapy to RT improves complete pathologic remission up to 38%complete pathologic remission up to 38%

Xeloda (Capecitabine): oral routeXeloda (Capecitabine): oral route

5-FU + Irinotecan/Oxaliplatin + RT5-FU + Irinotecan/Oxaliplatin + RT Downstaging 67-84%Downstaging 67-84%

Biological agentsBiological agents Bevacizumab/CetuximabBevacizumab/Cetuximab

PathologistsPathologists

Quirke’s detailed reporting system for Quirke’s detailed reporting system for rectal specimenrectal specimen Completeness of mesorectal excisionCompleteness of mesorectal excision Surgical auditSurgical audit MRI auditMRI audit

Quirke P. Training and quality assurance for rectal cancer: 20 years of data is enough. Lancet Oncol 2003;4:695–702.

Quirke P, Durdey P, Dixon MF, et al. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and

surgical excision. Lancet 1986;2:996 –9.

Re-staging after neoadjuvant CRTRe-staging after neoadjuvant CRT

After RT, both EUS and MRI offered poor diagnostic performance in the assessment of T and N stages

Mezzi G. et al. Endoscopic ultrasound and magnetic resonance imaging for re-Mezzi G. et al. Endoscopic ultrasound and magnetic resonance imaging for re-staging rectal cancer after radiotherapy.staging rectal cancer after radiotherapy.

World J Gastroenterol. 2009 Nov 28;15(44):5563-7.World J Gastroenterol. 2009 Nov 28;15(44):5563-7.

Optimal time for operationOptimal time for operation

4-6 weeks is optimal4-6 weeks is optimal Allows RT-induced tissue swelling or local Allows RT-induced tissue swelling or local

inflammation to subside. inflammation to subside. Allows time for tumor regression, which may Allows time for tumor regression, which may

improve resectability and possibility of sphincter improve resectability and possibility of sphincter preservation. preservation.

1)Lim S-BM et al. Optimal surgery time after preoperative chemoradiotherapy for locally 1)Lim S-BM et al. Optimal surgery time after preoperative chemoradiotherapy for locally advanced rectal cancers. Ann Surg 2008; 248:243–251. advanced rectal cancers. Ann Surg 2008; 248:243–251.

2)Veenhof AA et al. Preoperative radiation therapy for locally advanced rectal cancer: a 2)Veenhof AA et al. Preoperative radiation therapy for locally advanced rectal cancer: a comparison between two different time intervals to surgery. Int J Colorectal Dis. comparison between two different time intervals to surgery. Int J Colorectal Dis. 2007;22:507–5132007;22:507–513

ConclusionConclusion

For locally advanced rectal cancer:For locally advanced rectal cancer: Neoadjuvant ChemoRT Neoadjuvant ChemoRT Accurate pre-op stagingAccurate pre-op staging Multidisciplinary team (MDT) approachMultidisciplinary team (MDT) approach

Thank you!Thank you!