1. Rectal Cancer
Scott Hebert, md
9/12/16

2. Incidence Fourth most frequently diagnosed cancer in US
Second leading cause of death in US
2016 estimates 39,220 new cases rectal ca in us (23k men, 16k women)
Overall decrease of about 4% per year from
Despite observed improvements, the SEER CRC registry found that incidence is increasing in patients younger than 50. An estimated increased rate of colon and rectal cancer expected to increase 90% and 124% for 20 to 34 year olds by 2030.

3. Risk Assessment
~20% of colorectal cancers are associated with familial clustering. All patients with colorectal cancer should be questioned about family history
FAP
Lynch- most common form of genetically determined colorectal cancer – DNA mismatch repair. Two different test performed: immunohistochemical stain for MMR protein expression or analysis of microsatellite instability (MSI)- BRAF gene mutation indicated if MLH1 expression is downregulated)
Approach to testing: all patients with newly diagnosed colorectal cancer vs all patients <70 and pts > 70 who meet Bethesda guidelines.
The latter associated with 35% reduction on testing, but 4.9% cases of Lynch syndrome missed.

4. TNM Staging

5. Pathology Gross description of tumor Grade
Depth of penetration and extension in to adjacent tissues ( T)
Number of lymph nodes evaluated
Number of positive lymph nodes ( N)
Presence of distant mets including involvement of non regional nodes
Status of proximal, distal and circumferential margins ( CRM)
Neo adjuvant treatment
Lymphovascular invasion ( LVI)
Perinerual invasion (PNI)
Number of tumor deposits

6. Margins R0: Completion resection with all margins negative
R1: Incomplete resection with microscopic involvement of margin
R3: Incomplete resection with gross residual tumor

7. Circumferential Resection Margin
It is important in segments of colon that are partially or not encased by peritoneum.
CRM= Closest radial margin between deepest penetration of the tumor and the edge of resected soft tissue around the rectum or from the edge of the lymph nodes. Measured in mm
Positive CRM is 1 mm from the closest transected margin
Strong predictor of OS and local recurrence
Example: one study looked at 150 pts where 10% of R0 and 62% of R1/R2 resections had local recurrence
NCCN, Mawdsley S, et al

8. Lymph nodes
At least 10
Literature lacks consensus, but 2 studies for rectal cancer support 14 and >10 nodes as a minimum to accurate identify stage II disease
Based on SEER database, OS survival improved with greater number of LN retrieved in Stage I and II disease
Dependent upon number of nodes depends on age, neo adjuvant treatment

9. Perineural Invasion Associated with worse prognosis
Stage II: Multivariate analysis of rectal cancer: 5yr disease free survival is 29% vs 82% without PNI
Stage III: Meta-analysis 12,661 patients: PNI = OS HR = 2.07, DFS HR 2.23

10. Extranodal Tumor Deposits
Satellite nodules in the perirectal fat without evidence of residual LN tissue, but are within the lymphatic drainage of primary tumor.
Not counted as LN replaced by tumor
Associated with decreases OS and DFS
Study: pN0= 91.5% 5 yr survival vs 37.0% pN0 with satellite nodule

12. Presentation and Treatment of Non Metastatic Disease

13. Polypoid Cancer
Malignant rectal polyp: cancer invading through the muscularis mucosa and submucosa
Carcinoma in situ- not penetrated into submucosa, no LN involvement
Favorable features: grade 1 or 2 lesions without angiolymphatic invasion and with neg resection margin
Unfavorable features: grade 3 or 4, angiolymphatic invasion, positive margins
Pedunculated or sessile polyps:
-Favorable histologic features: can offer observation, but with a discussion about increased risk of recurrence.
-Unfavorable histologic features or fragmented margins: rectal surgery with transanal excision or transabdominal resection to include lymphadenectomy.

15. Rectal Cancer Defined as lesion within 12 cm of the anal verge
Close to other pelvic structures
Stable position for radiation
Treatment thoughts: Curative or palliative, Functional results of treatment (maintaining or restoring bowel function/ continence, preservice gu function), Minimizing impact on quality of life, Reducing risk of recurrence
Should be a multimodality approach with medical onc, surgical onc, rad onc, path

16. Clinical Evaluation/Staging
H&P
Total colonoscopy
Proctoscopy
CEA
CT C/A/P
Assessment of performance status
Endorectal us, MRI: Peop assessment fo depth of tumor and LN mets
PET: to evaluate equivocal findings on CT or contrast contraindication

17. Surgical Approach Polypectomy Transanal excision
Trans anal endoscopic microsurgery (TEM)
Trans abdominal resection
-Low anterior resection
-Proctectomy with TME and coloanal anastamosis
-Abdominoperineal resection

18. Transanal Excision
T1, N0
Small ( <3cm), well to moderately differentiated, with in 8 cm from anal verge, limited to <30 % circumference
If adverse features, more radical resection
Pros: morbidity and mortality, speed post operative recovery
Cons: absence of lymph nodal staging
2015 Meta-analysis: TEM may achieve superior oncologic outcomes compared to transanal excision. Limited data suggests TEM has superior outcomes in stage I disease compared to radical resection

19. Transabdominal resection
Sphincter sparing, organ preserving procedures preferred
Preopchemo RT helps is downsizing and decreasing tumor bulk
Total mesorectal excison (TME) involves en bloc resection of mesorectum including lymphatic and vascular structures, fatty tissue and mesorectal fascia only sparing autonomic structures.
Distal tumors:
Total mesorectal excision and coloanal anastamosis.
No need to dissect iliac chain unless suspicious

20. Transabdominal resection
Mid and upper rectum:
Low anterior resection extended 4-5 cm distal to the tumor
Colorectal anastomosis vs colostomy
Wide TME
Abdominoperineal resection with TME
direct invasion of anal sphincter/levator muscles or when margin neg surgery would cause loss of anal sphincter

21. Transabdominal resection
Laparoscopic surgery:
CLASICC trial: 5 yr follow up.
COREAN trial: 3yr follow up. Stage II or III low to mid rectal cancer
Both trials with no significant difference in OS, DFS in laparoscopically assisted vs open resection
Reviews, meta-analyses, smaller trials consistently find laparoscopic approach to be safe and feasible.

23. Radiation Therapy Decreased local recurrence, increase toxiticity
T3 N0 disease
ChemoRT preoperatively and chemotherapy postoperatively vs
Chemotherapy followed by chemoRT followed by resection

24. Preoperative vs post operative radiation
Pre operative radiation preferred
Advantages
Reducing tumor volume may facilitate resection and increase the likelihood of sphincter sparing procedure- this conclusion is not supported by 2 meta-analyses of randomized trials involving preoperative chemoRT in treatment of rectal cancer
Surgery naïve tissue is best responsive to radiation due to better oxygenation
Can avoid radiation induced injury to small bowel from post-surgical adhesions
Preop rad that includes structures to be resected increases likelihood that anastomosis with healthy colon can be performed
Disadvantages
Possibility of over treating early stage tumors
Post op RT is recommended only for upstaged Stage I after surgery

26. Concurrent chemotherapy with radiation
ChemoRT preoperatively after clinical staging Vs
Postoperatively after surgical staging
Pre- or postoperative chemoRT Benefits: sensitization and systemic control of disease
Preoperative chemoRT: increase rates of pathologic complete response and sphincter preservation

27. Concurrent chemotherapy with radiation
Study: T3-4 rectal ca randomly assigned preoperative RT alone or preoperative concurrent chemoRT with 5-FU/LV
Result: no difference in OS or sphincter preservation
ChemoRT more likely to have pathologic complete response and grade 3/4 tox, less likely to have local recurrence
Phase III trial: T3-4 rectal ca: 5FU/LV + preoperative RT vs preoperative RT alone
Prelim result: chemo+RT reduced tumor size, pTN stage, lymphatic, vascular and PNI rates.
Mature results: no significant difference in OS with addition of 5-FU based chemo pre or postoperatively
Multiple studies came to similar conclusion

28. Type of chemo with RT
Bolus 5-FU/LV vs infusional 5-FU/LV with concurrent postoperative RT
Results: no significant difference in OS and DFS. Increased tox in bolus 5-FU

29. Capecitabine
Study: Stage II or III rectal, 5-FU +/- oxaliplatin vs cape +/- oxaliplatin
Result: no difference in DFS, OS, pathologic response, sphincter saving, or surgical downsizing.
Another trial suggests improved 3 yr DFS in capecitabine

30. Addition of oxaliplatin
STAR-01 trial: 5-FU+oxali+RT vs 5-FU/RT
Result: No difference in outcome. Increased toxicity with oxaliplatin. Primary endpoint of OS ongoing.
ACCORD trial: capecitabine/RT vs CapeOx/RT
Result: increased rate of minimal disease at surgery. No improvement in DFS or OS at 3yrs
German CAO/ARO/AIO-04 trial: oxali/5-FU/RT vs 5/FU/RT
Result: higher rate of pathologic response in oxaliplatin arm. DFS 75.9% oxali group, 71.2 control group
Based on results, NCCN does not recommended to add to chemoRT at this time

31. Addition of targeted agents
EXPERT-C trial: CapeOx -> capecitabine/RT->surgery->CapeOx vs same + weekly cetuximab
Result: improved OS in pts with KRAS WT.
Phase II SAKK 41/07: KRAS WT treatment with capecitabine/RT vs capecitabine/RT + panitumumab
Result: primary endpoint pathologic near complete + complete tumor response: 53% with panitumumab, 32% control. Increased grade 3+ toxticity with panitumumab
Phase II study: preop cape, ox, bev, RT followed by surgery and adjuvant FOLFOX/Bevacizumab
Result: 5 yr OS and relapse free survival 80 and 81%. Significant toxiticities observed. Low compliance rate
Currently, NCCN does not endorse bevacizumab, cetuximab, panitumumab, irinotecan or oxaliplatin with concurrent RT for rectal cancer.

32. Induction Chemotherapy
Spanish GCR-3 randomized phase II trial: CapeOx before chemoRT vs after surgery
Result: similar pathologic response, induction chemotherapy was less toxic and better tolerated
Phase II trial: chemoRT and surgery with or without FOLFOX induction
Result: no difference in results. Induction with higher toxticity
AVACROSS study: safety and efficacy: CapeOx -> Cape/bev/RT -> surgery vs same + bevacizumab
Result bevacizumab arm was well tolerated and pathologic complete response rate of 36%
Added to the 2015 guidelines of acceptable options

33. Preoperative Chemotherapy without chemoRT
Small, single center, phase II pilot trial with stage II or III rectal ca: induction of FOLFOX/bevacizumab->chemoRT in patients with stable or progressive disease and resection in all patients.
Results: all 32 patients had R0 resection and 4yr DFS was 84%
Ongoing PROSPECT trial asking if chemo alone is effective in patients with at least 20% tumor regression following neoadjuvant treatment

34. Adjuvant Chemotherapy
All patients with stage II/III disease following neoadjuvant chemoRT and surgery if not received neoadjuvant chemo regardless of surgical results.
EORTC Radiotherpay group trial: preoperative chemoRT vs 5-FU adjuvant chemo + chemoRT
Result: improvement in DFS, no improvement in OS
Other trials failed to show DFS or OS
ECOG E3201 phase III: pre or postoperative chemoRT with adjuvant 5-FU/LV + FOLVOX vs adjuvant 5-FU/LV + FOLFIRI
Study cut short, but FOLFOX safely used

35. Adjuvant Chemotherapy
ADORE trial: neoadjuvant -> adjuvant 5-FU/LV vs neoadjuvant FOLFOX
Result: FOLFOX DFS at 3yrs 71.6% vs adjuvant 5FU/LV 62.9%
CAO/ARO/AIO-04 trial: Oxali + 5-FU in neoadjuvant and adjuvant tx improves 3 yr DFS 75.9 and , respectively
NCCN continues to support use of adjuvant therapy