Neoadjuvant therapy for Rectal cancer

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

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 • 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 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

11. 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

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 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

14. 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)

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

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 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)

22. Guidelines • NICE guideline, up dated 11/2011

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