Neoadjuvant therapy for Neoadjuvant therapy for Rectal cancerRectal cancer

Rectal cancerRectal cancer

• Improvements in management of Improvements in management of rectal cancer in past decadesrectal cancer in past decades

• Preoperative accurate tumor stagingPreoperative accurate tumor staging

• Good surgical technique (TME)Good surgical technique (TME)

• Neoadjuvant / adjuvant therapyNeoadjuvant / adjuvant therapy

• Improved pathological assessment Improved pathological assessment identifying adequacy of resection identifying adequacy of resection

Preoperative Tumor StagingPreoperative Tumor Staging

• All decisions on requirement for neoadjuvant All decisions on requirement for neoadjuvant therapy are predicted on accurate tumor therapy are predicted on accurate tumor staging staging

• Local tumor staging of extent of tumor Local tumor staging of extent of tumor invasion (T) and nodal involvement (N) is invasion (T) and nodal involvement (N) is important important

• Clinical examination and contrast CT provides Clinical examination and contrast CT provides an estimatean estimate

• EUS & MRI are used for more accurate local EUS & MRI are used for more accurate local tumor stagingtumor staging

EUSEUS

• Especially useful in assessment of early non-Especially useful in assessment of early non-invasive T1 diseaseinvasive T1 disease

• Help to determine whether local excision is Help to determine whether local excision is possiblepossible

• Disadvantages:Disadvantages:– Operator dependentOperator dependent– Limited ability to assess stenotic / bulky tumorsLimited ability to assess stenotic / bulky tumors– Cannot evaluate iliac, mesenteric or retroperitoneal LNsCannot evaluate iliac, mesenteric or retroperitoneal LNs– Cannot identify mesorectal fascia Cannot identify mesorectal fascia prediction of CRM prediction of CRM

not possiblenot possible– Other prognostic factors cannot be assessedOther prognostic factors cannot be assessed

MRIMRI

• High resolution MRI with rectal coilHigh resolution MRI with rectal coil• Plane of mesorectal fascia can be Plane of mesorectal fascia can be

seen on MRI which allows predicton seen on MRI which allows predicton of likelihood of a positive or close of likelihood of a positive or close circumferential resection margin circumferential resection margin (CRM)(CRM)

• Other prognostic features including Other prognostic features including extramural venous invasion, nodal extramural venous invasion, nodal status and peritoneal infiltrationstatus and peritoneal infiltration

Sensitivity & SpecificitiesSensitivity & Specificities• A meta-analysis on sensitivities and A meta-analysis on sensitivities and

specificities of CT / EUS / MRI specificities of CT / EUS / MRI published in 2004published in 2004

MRI prediction of CRMMRI prediction of CRM

• A prospective observational study conducted by the A prospective observational study conducted by the MERCURY Study Group published in 2006 tried to MERCURY Study Group published in 2006 tried to assess accuracy of MRI in predicting curative assess accuracy of MRI in predicting curative resection (clear CRM)resection (clear CRM)

• Collected patients from 12 colorectal units in 4 Collected patients from 12 colorectal units in 4 European countriesEuropean countries

• Using MRI with rectal coil and high resolution Using MRI with rectal coil and high resolution protocolprotocol

• Workshops to ensure standardization of scan Workshops to ensure standardization of scan techniques, image interpretation and reportingtechniques, image interpretation and reporting

• 92% specificity for a clear CRM (CI, 90-95%)92% specificity for a clear CRM (CI, 90-95%)• Reproducible in multicenter settingReproducible in multicenter setting

Adjuvant therapy: preop or Adjuvant therapy: preop or postop?postop?

• Decades ago, standard management of locally Decades ago, standard management of locally advanced rectal cancer was surgery with advanced rectal cancer was surgery with adjuvant radiotherapy adjuvant radiotherapy

• -In 1990, NIH recommended that postop -In 1990, NIH recommended that postop chemoradiotherapy as standard for patients chemoradiotherapy as standard for patients with locally advanced rectal cancer (stage II or with locally advanced rectal cancer (stage II or III)III)

• However complications of RT were dose However complications of RT were dose limiting, treatment-related complications and limiting, treatment-related complications and treatment tolerance were factors leading to treatment tolerance were factors leading to trials comparing pre-op and post-op therapiestrials comparing pre-op and post-op therapies

Neoadjuvant therapyNeoadjuvant therapy

• AdvantagesAdvantages– tumor down stagingtumor down staging

• increase tumor resectabilityincrease tumor resectability• increase sphincter preservationincrease sphincter preservation

– increase sensitivity to RT in preop better oxygenated increase sensitivity to RT in preop better oxygenated tissuestissues

– avoid radiation-induced SB injury to SB trapped in pelvis avoid radiation-induced SB injury to SB trapped in pelvis by post-op adhesionsby post-op adhesions

– less severe treatment-related toxicity and better less severe treatment-related toxicity and better compliancecompliance

• DisadvantagesDisadvantages– potential overtreating patients with early diseasepotential overtreating patients with early disease

• Major adv of post-op chemoRT = more selective Major adv of post-op chemoRT = more selective use for high risk patients based on intraop findings use for high risk patients based on intraop findings and pathological staging of diseaseand pathological staging of disease

Neoadjuvant therapyNeoadjuvant therapy

• 2 types of neoadjuvant therapy2 types of neoadjuvant therapy• 1) long course preoperative chemoradiotherapy1) long course preoperative chemoradiotherapy

– using conventional doses of RT (1.8-2 Gy per fraction) using conventional doses of RT (1.8-2 Gy per fraction) over 5-6wks (for tot dose of 45-50.4Gy) with over 5-6wks (for tot dose of 45-50.4Gy) with administration of concurrent 5-fluorouracil-based administration of concurrent 5-fluorouracil-based chemotherapychemotherapy

– advadv• chemo potentiates local RT senstitizationchemo potentiates local RT senstitization• induce tumor downsizing +/- downstaginginduce tumor downsizing +/- downstaging• may improve rates of sphincter preservationmay improve rates of sphincter preservation

• 2) short course preoperative radiotherapy2) short course preoperative radiotherapy– RT over 5days (5Gy/day for 5days) without chemo, RT over 5days (5Gy/day for 5days) without chemo,

followed by surgery within 10 days of first session of RTfollowed by surgery within 10 days of first session of RT– aim: sterilize resection marginaim: sterilize resection margin

Long course Long course chemoradiotherapychemoradiotherapy• German Rectal Cancer GroupGerman Rectal Cancer Group

– RCT comparing preop vs postop RCT comparing preop vs postop chemoradiotherapychemoradiotherapy

– Patient enrollment from 1995 - 2002Patient enrollment from 1995 - 2002– Randomised 823 locally advanced patients (T3/T4, Randomised 823 locally advanced patients (T3/T4,

N+) to either pre or post-op CRTN+) to either pre or post-op CRT– Staging by EUS&CTStaging by EUS&CT– Neoadjuvant CRT: 50.4Gy RT in 1.8Gy daily Neoadjuvant CRT: 50.4Gy RT in 1.8Gy daily

fractions concurrent with infusional 5-FUfractions concurrent with infusional 5-FU– Post-op regimen is identical except a boost of Post-op regimen is identical except a boost of

5.4Gy5.4Gy– TME performed in all patients according to TME performed in all patients according to

standardized techniquestandardized technique

German trialGerman trial• Results:Results:

– Decreased local recurrence (6% vs 13%, p=0.006)Decreased local recurrence (6% vs 13%, p=0.006)– Less acute and long term toxic effects with better Less acute and long term toxic effects with better

compliance (27% vs 40%, p=0.001)compliance (27% vs 40%, p=0.001)– Sphincter preservation: no stat difference Sphincter preservation: no stat difference

between the 2 groupsbetween the 2 groups• subgroup analysis of 194 patients who were determined subgroup analysis of 194 patients who were determined

by surgeon before randomization to require an APR by surgeon before randomization to require an APR showed a stat sig increase in sphincter preservation in showed a stat sig increase in sphincter preservation in those who received preop CRTthose who received preop CRT

– No statistically significant difference in overall No statistically significant difference in overall survivalsurvival

Short course preop Short course preop radiotherapyradiotherapy• Several trials studied the effect of SCPRT vs surgery Several trials studied the effect of SCPRT vs surgery

alone but many of them are in the pre-TME eraalone but many of them are in the pre-TME era• Swedish Rectal Cancer TrialSwedish Rectal Cancer Trial

– randomized 1168 patients in 1987-1990 to either SCPRT randomized 1168 patients in 1987-1990 to either SCPRT then surgery or surgery alonethen surgery or surgery alone

– significant reduction in local recurrence (11% vs 27%, significant reduction in local recurrence (11% vs 27%, P<0.001) and increase in 5-yr survival (58% vs 48%, P<0.001) and increase in 5-yr survival (58% vs 48%, P=0.002)P=0.002)

– the only trial that showed improvement in survivalthe only trial that showed improvement in survival– a follow up study at a median 13yrs showed the local a follow up study at a median 13yrs showed the local

control and survival remained durablecontrol and survival remained durable– the difference in local recurrence may account for the the difference in local recurrence may account for the

improved survivalimproved survival

Dutch Colorectal Cancer Group Dutch Colorectal Cancer Group Trial Trial • First study to investigate benefit of preop RT First study to investigate benefit of preop RT

in combination with TMEin combination with TME• Randomized 1861 patients in 1996-1999 Randomized 1861 patients in 1996-1999

with resectable rectal cancer to receive with resectable rectal cancer to receive SCPRT or no SCPRT before standardized TME SCPRT or no SCPRT before standardized TME surgerysurgery

• Adjuvant therapy was only given to patients Adjuvant therapy was only given to patients with intraoperative tumor spillage or with intraoperative tumor spillage or positive margins at pathologypositive margins at pathology

• Results:Results:– preop RT further reduce local recurrence rate preop RT further reduce local recurrence rate

(2.4% vs 8.2% at 2yrs)(2.4% vs 8.2% at 2yrs)

Dutch TME trial: 12yrs Dutch TME trial: 12yrs follow upfollow up• 12 yr follow up of Dutch TME trial12 yr follow up of Dutch TME trial

– SCPRT decreases local recurrence rate SCPRT decreases local recurrence rate compared to surgery alone (at 10 yrs, 5% vs compared to surgery alone (at 10 yrs, 5% vs 11%, p<0.0001)11%, p<0.0001)

– no effect on overall 10-year survival (48% vs no effect on overall 10-year survival (48% vs 49%, P=0.86)49%, P=0.86)

– subgroup analysis:subgroup analysis:• 10-yr survival was significantly improved in TNM 10-yr survival was significantly improved in TNM

stage III patients with negative CRM in the SCPRT + stage III patients with negative CRM in the SCPRT + surgery group compared to surgery alone (5% vs surgery group compared to surgery alone (5% vs 17%, P<0.0001)17%, P<0.0001)

Medical Research Council CR07 Medical Research Council CR07 trialtrial• Compare SCPRT vs surgery with selective postop Compare SCPRT vs surgery with selective postop

chemoradiotherapychemoradiotherapy• Multicentre RCT, recruited 1350 patients between Multicentre RCT, recruited 1350 patients between

1998 to 20051998 to 2005• Randomized patients with resectable rectal Randomized patients with resectable rectal

cancer, assessed clinically or imaging cancer, assessed clinically or imaging (CT/MRI/EUS) to(CT/MRI/EUS) to– either SCPRTeither SCPRT– or initial surgery with selective postop or initial surgery with selective postop

chemoradiotherapy (CRM positive)chemoradiotherapy (CRM positive)• Primary outcome measure was local recurencePrimary outcome measure was local recurence• Results:Results:

– Absolute difference in 3-yr local recurrence rate 6.2%Absolute difference in 3-yr local recurrence rate 6.2%– Overall survival did not differ between the groupsOverall survival did not differ between the groups– Quality of surgery also examined, local recurrence rates Quality of surgery also examined, local recurrence rates

4% (good) vs 13% (poor) (P=0.0039), 1% local recurrence 4% (good) vs 13% (poor) (P=0.0039), 1% local recurrence rate at 3yrs for those with SCPRT & achieved good rate at 3yrs for those with SCPRT & achieved good mesorectal planemesorectal plane

Long course vs short courseLong course vs short course

• Long-course chemoradiotherapy is Long-course chemoradiotherapy is the therapy of choice for patients the therapy of choice for patients requiring preop downsizing / requiring preop downsizing / downstaging but its use is debatable downstaging but its use is debatable for other patients for other patients

• Few studies have directly compared Few studies have directly compared the twothe two

Polish Colorectal Study Polish Colorectal Study Group Group • Small RCT of 312 patients published in 2006Small RCT of 312 patients published in 2006• Patients with T3/4 rectal cancer, staged by Patients with T3/4 rectal cancer, staged by

clinically or EUS/MRT/CTclinically or EUS/MRT/CT• All received TME surgeryAll received TME surgery• Results:Results:

– no sig diff in sphincter preservation rate (61.2% vs 58% no sig diff in sphincter preservation rate (61.2% vs 58% in CRT group, P=0.57)in CRT group, P=0.57)

– more acute toxicity in preop CRT than SCPRT gp (18.2% more acute toxicity in preop CRT than SCPRT gp (18.2% vs 3.2%, P<0.001)vs 3.2%, P<0.001)

– more positive CRM in SCPRT group (12.9% vs 4.4%, more positive CRM in SCPRT group (12.9% vs 4.4%, P=0.017)P=0.017)

– no difference in local recurrence (9% vs 14.2% in CRT, no difference in local recurrence (9% vs 14.2% in CRT, P=0.170) and overall 4-yr survival rates (67.2% vs P=0.170) and overall 4-yr survival rates (67.2% vs 66.2% in CRT, P=0.820)66.2% in CRT, P=0.820)

Australian / New Zealand Australian / New Zealand trial trial • RCT of 326 patients published in 2010RCT of 326 patients published in 2010

• Recruited patients with T3Nany rectal Recruited patients with T3Nany rectal cancer, staged by EUS / MRIcancer, staged by EUS / MRI

• All patients received post-op adjuvant All patients received post-op adjuvant chemotherapychemotherapy

• Results:Results:– no difference in 3-yr local recurrence (7.5% vs no difference in 3-yr local recurrence (7.5% vs

4.4% in CRT, P=0.24) and 5-yr overall survival 4.4% in CRT, P=0.24) and 5-yr overall survival rates (74% vs 70% in CRT, P=0.56)rates (74% vs 70% in CRT, P=0.56)

Adjuvant therapy after Adjuvant therapy after neoadjuvantneoadjuvant

• Since the introduction of neoadjuvant Since the introduction of neoadjuvant therapy, it had led to questions on need of therapy, it had led to questions on need of further adjuvant txfurther adjuvant tx

• Support for use of adjuvant chemo came Support for use of adjuvant chemo came from extrapolation from colon cancer from extrapolation from colon cancer clinical trials suggest that approximately 6 clinical trials suggest that approximately 6 months of FOLFOX is the optimal current months of FOLFOX is the optimal current strategy to improve survivalstrategy to improve survival

EORTC trial EORTC trial

• Explored the impact of timing of chemo (preop / postop / both) Explored the impact of timing of chemo (preop / postop / both) on outcomeon outcome

• It is a four-arm RCT that randomised 1011 patients in 1993-It is a four-arm RCT that randomised 1011 patients in 1993-2003 with T3/T4 rectal cancer to receive preop RT +/- 2003 with T3/T4 rectal cancer to receive preop RT +/- concurrent Chemo, followed by surgery with or without postop concurrent Chemo, followed by surgery with or without postop chemotherapychemotherapy

• Staging of tumor by clinical, rigid proctoscopy and CT (EUS Staging of tumor by clinical, rigid proctoscopy and CT (EUS optional)optional)

• Results:Results:– significant decrease in local recurrence among patients who significant decrease in local recurrence among patients who

received chemotherapy (preop 8.7%, postop 9.6%, both 7.6%) than received chemotherapy (preop 8.7%, postop 9.6%, both 7.6%) than RT alone (17.1%)RT alone (17.1%)

– no sig diff in survival between the groups that received chemo no sig diff in survival between the groups that received chemo preop and those that received it postoppreop and those that received it postop

– subgroup analysis revealed patients who responded to preop CRT subgroup analysis revealed patients who responded to preop CRT (tumor downstaging to ypT0-2) had a survival benefit from postop (tumor downstaging to ypT0-2) had a survival benefit from postop chemotherapy (5yr disease free survival 76.7% vs 65.6%, P=0.13)chemotherapy (5yr disease free survival 76.7% vs 65.6%, P=0.13)

GuidelinesGuidelines

• NICE guideline, up dated 11/2011NICE guideline, up dated 11/2011

NCCN guidelineNCCN guideline

• For T3, N0 or T any N1-2 lesions For T3, N0 or T any N1-2 lesions – should be treated by preop CRT unless should be treated by preop CRT unless

medically contraindictatedmedically contraindictated

• Then undergo resection 5-10wks after Then undergo resection 5-10wks after completion of neoadjuvant therapycompletion of neoadjuvant therapy

• Post-op adjuvant chemotherapy for Post-op adjuvant chemotherapy for 6mo in total of pre & post op 6mo in total of pre & post op chemotherapychemotherapy

• No recommendation on SCPRTNo recommendation on SCPRT

ConclusionConclusion

• Preop accurate staging in mandatory for Preop accurate staging in mandatory for decisions for neoadjuvant therapydecisions for neoadjuvant therapy

• Increase widespread use of MRI for pre-op Increase widespread use of MRI for pre-op stagingstaging

• Neoadjuvant therapy will reduce local Neoadjuvant therapy will reduce local recurrence even in patients who undergo recurrence even in patients who undergo optimal surgeryoptimal surgery

• Preop CRT remains the standard for locally Preop CRT remains the standard for locally advanced rectal cancers that has to be advanced rectal cancers that has to be downsized / downstaged before surgerydownsized / downstaged before surgery

QuestionsQuestions