JHSGR JHSGR Neoadjuvant Therapy For Rectal Neoadjuvant Therapy For Rectal Cancer Cancer Dr Chris TL Cheng Dr Chris TL Cheng Princess Margaret Hospital Princess Margaret Hospital
Feb 08, 2016
JHSGRJHSGRNeoadjuvant Therapy For Rectal CancerNeoadjuvant Therapy For Rectal Cancer
Dr Chris TL ChengDr Chris TL ChengPrincess Margaret HospitalPrincess Margaret Hospital
Neoadjuvant Therapy for Neoadjuvant Therapy for Rectal CancerRectal Cancer
BackgroundBackgroundBenefits of neoadjuvant therapy Benefits of neoadjuvant therapy Selection CriteriaSelection CriteriaStaging & CRMStaging & CRMMultidisciplinary 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 survival48% 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 onlyTME + adjuvant chemoRTTME + adjuvant chemoRTNeoadjuvant RT + TMENeoadjuvant RT + TMENeoadjuvant 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 LNEUS 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 assessmentMERCURY (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 schemeIntensityIntensity 5 fractions of 5 fractions of
500 cGy500 cGy4,500 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 route5-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 operation4-6 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!