1. Neoadjuvant therapy for Rectal cancer

2. 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

3. 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

4. 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

5. 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

6. 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 %
For evaluating LN involvement, all 3 modalities were comparable (sensitivity, specificity)
CT (55%, 74%), EUS (67%, 78%), MRI (66%, 76%)

7. 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

8. 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

9. 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

10. 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 Gy) 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

11. Long course chemoradiotherapy
German Rectal Cancer Group
RCT comparing preop vs postop chemoradiotherapy
Patient enrollment from
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

12. 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

13. 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 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

14. Dutch Colorectal Cancer Group Trial
First study to investigate benefit of preop RT in combination with TME
Randomized 1861 patients in 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)

15. 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)

16. 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

17. 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

18. 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)

19. 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)

20. 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

21. 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 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)

22. 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

23. 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

24. 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

25. Questions