Neoadjuvant therapy for Rectal cancer

Rectal cancer Improvements in management of rectal cancer in past decades Preoperative accurate tumor staging Good surgical technique (TME) Neoadjuvant / adjuvant therapy Improved pathological assessment identifying adequacy of resection

Preoperative Tumor Staging All decisions on requirement for neoadjuvant therapy are predicted on accurate tumor staging Local tumor staging of extent of tumor invasion (T) and nodal involvement (N) is important Clinical examination and contrast CT provides an estimate EUS & MRI are used for more accurate local tumor staging

EUS Especially useful in assessment of early non-invasive T1 disease Help to determine whether local excision is possible Disadvantages: Operator dependent Limited ability to assess stenotic / bulky tumors Cannot evaluate iliac, mesenteric or retroperitoneal LNs Cannot identify mesorectal fascia  prediction of CRM not possible Other prognostic factors cannot be assessed

MRI High resolution MRI with rectal coil Plane of mesorectal fascia can be seen on MRI which allows predicton of likelihood of a positive or close circumferential resection margin (CRM) Other prognostic features including extramural venous invasion, nodal status and peritoneal infiltration

Sensitivity & Specificities A meta-analysis on sensitivities and specificities of CT / EUS / MRI published in 2004 Both EUS and MRI have high sensitivities for evaluating depth of tumor invasion into muscularis propria --- 94% For evaluating LN involvement, all 3 modalities were comparable (sensitivity, specificity) CT (55%, 74%), EUS (67%, 78%), MRI (66%, 76%)

MRI prediction of CRM A prospective observational study conducted by the MERCURY Study Group published in 2006 tried to assess accuracy of MRI in predicting curative resection (clear CRM) Collected patients from 12 colorectal units in 4 European countries Using MRI with rectal coil and high resolution protocol Workshops to ensure standardization of scan techniques, image interpretation and reporting 92% specificity for a clear CRM (CI, 90-95%) Reproducible in multicenter setting

Adjuvant therapy: preop or postop? Decades ago, standard management of locally advanced rectal cancer was surgery with adjuvant radiotherapy -In 1990, NIH recommended that postop chemoradiotherapy as standard for patients with locally advanced rectal cancer (stage II or III) However complications of RT were dose limiting, treatment-related complications and treatment tolerance were factors leading to trials comparing pre-op and post-op therapies

Neoadjuvant therapy Advantages Disadvantages tumor down staging increase tumor resectability increase sphincter preservation increase sensitivity to RT in preop better oxygenated tissues avoid radiation-induced SB injury to SB trapped in pelvis by post-op adhesions less severe treatment-related toxicity and better compliance Disadvantages potential overtreating patients with early disease Major adv of post-op chemoRT = more selective use for high risk patients based on intraop findings and pathological staging of disease

Neoadjuvant therapy 2 types of neoadjuvant therapy 1) long course preoperative chemoradiotherapy using conventional doses of RT (1.8-2 Gy per fraction) over 5-6wks (for tot dose of 45-50.4Gy) with administration of concurrent 5-fluorouracil-based chemotherapy adv chemo potentiates local RT senstitization induce tumor downsizing +/- downstaging may improve rates of sphincter preservation 2) short course preoperative radiotherapy RT over 5days (5Gy/day for 5days) without chemo, followed by surgery within 10 days of first session of RT aim: sterilize resection margin

Long course chemoradiotherapy German Rectal Cancer Group RCT comparing preop vs postop chemoradiotherapy Patient enrollment from 1995 - 2002 Randomised 823 locally advanced patients (T3/T4, N+) to either pre or post-op CRT Staging by EUS&CT Neoadjuvant CRT: 50.4Gy RT in 1.8Gy daily fractions concurrent with infusional 5-FU Post-op regimen is identical except a boost of 5.4Gy TME performed in all patients according to standardized technique

German trial Results: Decreased local recurrence (6% vs 13%, p=0.006) Less acute and long term toxic effects with better compliance (27% vs 40%, p=0.001) Sphincter preservation: no stat difference between the 2 groups subgroup analysis of 194 patients who were determined by surgeon before randomization to require an APR showed a stat sig increase in sphincter preservation in those who received preop CRT No statistically significant difference in overall survival

Short course preop radiotherapy Several trials studied the effect of SCPRT vs surgery alone but many of them are in the pre-TME era Swedish Rectal Cancer Trial randomized 1168 patients in 1987-1990 to either SCPRT then surgery or surgery alone significant reduction in local recurrence (11% vs 27%, P<0.001) and increase in 5-yr survival (58% vs 48%, P=0.002) the only trial that showed improvement in survival a follow up study at a median 13yrs showed the local control and survival remained durable the difference in local recurrence may account for the improved survival

Dutch Colorectal Cancer Group Trial First study to investigate benefit of preop RT in combination with TME Randomized 1861 patients in 1996-1999 with resectable rectal cancer to receive SCPRT or no SCPRT before standardized TME surgery Adjuvant therapy was only given to patients with intraoperative tumor spillage or positive margins at pathology Results: preop RT further reduce local recurrence rate (2.4% vs 8.2% at 2yrs)

Dutch TME trial: 12yrs follow up 12 yr follow up of Dutch TME trial SCPRT decreases local recurrence rate compared to surgery alone (at 10 yrs, 5% vs 11%, p<0.0001) no effect on overall 10-year survival (48% vs 49%, P=0.86) subgroup analysis: 10-yr survival was significantly improved in TNM stage III patients with negative CRM in the SCPRT + surgery group compared to surgery alone (5% vs 17%, P<0.0001)

Medical Research Council CR07 trial Compare SCPRT vs surgery with selective postop chemoradiotherapy Multicentre RCT, recruited 1350 patients between 1998 to 2005 Randomized patients with resectable rectal cancer, assessed clinically or imaging (CT/MRI/EUS) to either SCPRT or initial surgery with selective postop chemoradiotherapy (CRM positive) Primary outcome measure was local recurence Results: Absolute difference in 3-yr local recurrence rate 6.2% Overall survival did not differ between the groups Quality of surgery also examined, local recurrence rates 4% (good) vs 13% (poor) (P=0.0039), 1% local recurrence rate at 3yrs for those with SCPRT & achieved good mesorectal plane

Long course vs short course Long-course chemoradiotherapy is the therapy of choice for patients requiring preop downsizing / downstaging but its use is debatable for other patients Few studies have directly compared the two

Polish Colorectal Study Group Small RCT of 312 patients published in 2006 Patients with T3/4 rectal cancer, staged by clinically or EUS/MRT/CT All received TME surgery Results: no sig diff in sphincter preservation rate (61.2% vs 58% in CRT group, P=0.57) more acute toxicity in preop CRT than SCPRT gp (18.2% vs 3.2%, P<0.001) more positive CRM in SCPRT group (12.9% vs 4.4%, P=0.017) no difference in local recurrence (9% vs 14.2% in CRT, P=0.170) and overall 4-yr survival rates (67.2% vs 66.2% in CRT, P=0.820)

Australian / New Zealand trial RCT of 326 patients published in 2010 Recruited patients with T3Nany rectal cancer, staged by EUS / MRI All patients received post-op adjuvant chemotherapy Results: no difference in 3-yr local recurrence (7.5% vs 4.4% in CRT, P=0.24) and 5-yr overall survival rates (74% vs 70% in CRT, P=0.56)

Adjuvant therapy after neoadjuvant Since the introduction of neoadjuvant therapy, it had led to questions on need of further adjuvant tx Support for use of adjuvant chemo came from extrapolation from colon cancer clinical trials suggest that approximately 6 months of FOLFOX is the optimal current strategy to improve survival One important question was whether the relatively brief exposure to chemo in combination with preop RT is sufficient to improve survival

EORTC trial Explored the impact of timing of chemo (preop / postop / both) on outcome It is a four-arm RCT that randomised 1011 patients in 1993-2003 with T3/T4 rectal cancer to receive preop RT +/- concurrent Chemo, followed by surgery with or without postop chemotherapy Staging of tumor by clinical, rigid proctoscopy and CT (EUS optional) Results: significant decrease in local recurrence among patients who received chemotherapy (preop 8.7%, postop 9.6%, both 7.6%) than RT alone (17.1%) no sig diff in survival between the groups that received chemo preop and those that received it postop subgroup analysis revealed patients who responded to preop CRT (tumor downstaging to ypT0-2) had a survival benefit from postop chemotherapy (5yr disease free survival 76.7% vs 65.6%, P=0.13)

Guidelines NICE guideline, up dated 11/2011 cT3a extend <1mm beyond muscularis propria cT3b 1-5mm, cT3c >5-15mm, cT3d >15mm Recommendations: Low risk operable rectal cancer -no need for any SCPRT or CRT -long-term morbidity outweighs benefits Moderate risk -Consider SCPRT then immediate surgery for patients with moderate-risk operable rectal cancer. -Consider preoperative chemoradiotherapy with an interval to allow tumour response and shrinkage before surgery for patients with tumours that are borderline between moderate and high risk. High risk -Offer preoperative chemoradiotherapy with an interval before surgery to allow tumour response and shrinkage, (rather than SCPRT) to patients with high-risk operable rectal cancer -no direct evidence on effectiveness of SCPRT -reduction in risk of a positive margin would be facilitated by tumor shrinkage, with current evidence => recommend CRT -do not offer preop CRT solely to facilitate sphincter-sparing surgery because there was no evidence that CRT would facilitate increase in sphincter preservation

NCCN guideline For T3, N0 or T any N1-2 lesions should be treated by preop CRT unless medically contraindictated Then undergo resection 5-10wks after completion of neoadjuvant therapy Post-op adjuvant chemotherapy for 6mo in total of pre & post op chemotherapy No recommendation on SCPRT

Conclusion Preop accurate staging in mandatory for decisions for neoadjuvant therapy Increase widespread use of MRI for pre-op staging Neoadjuvant therapy will reduce local recurrence even in patients who undergo optimal surgery Preop CRT remains the standard for locally advanced rectal cancers that has to be downsized / downstaged before surgery

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