1. Rectal Cancer: A Complete Clinical Response…Now what?
University of Virginia

2. Objectives
Outline a protocol at UVA for the non-operative management of patients with a complete clinical response following neoadjuvant chemoradiation for a locally advanced rectal cancer

3. Standard of Care (NCCN) Locally Advanced Mid/Low Rectal Cancer
Neoadjuvant chemoradiation
Radical surgery with a Total Mesorectal Excision (TME)
Adjuvant chemotherapy

4. Total Mesorectal Excision after Chemoradiation
Very good oncologic outcomes!!!
BUT…..

5. Total Mesorectal Excision after Chemoradiation
Mortality, in some series 2%
Need for stoma
APR about 30%
Low anastomosis, temporary or permanent
Sexual and bladder dysfunction
Functional problems
Bowel function
Depression, body image
Wound complications

6. Are we overtreating?

7. Less Surgery

8. Pathological complete response!!!
8-24%
Lancet 2010, Mass M.

9. 5 Year Outcomes Complete response after radical surgery
Local Recurrence
pCR 2.8%
No pCR 9.7%
Distant metastasis free survival
pCR 88.8%
No pCR 74.9%
5-year risk for local recurrence was 2·8% (95% CI 1·6–5·1) in the pCR group (12/455 patients had local recurrences) and 9·7% (8·4–11·2) in the no pCR group (202/2478; unadjusted HR 0·33, 95% CI 0·19–0·60; p<0·0001). 5-year distant- metastasis-free survival was 88·8% (84·8–91·8) for patients with pCR (38/419 had distant metastasis) and 74·9% (72·9–77·0) for patients without pCR (512/2257; unadjusted HR 0·40, 0·29–0·55; p<0·0001). 5-year overall survival was 87·6% (83·6–90·7) for patients with pCR (53 deaths in 465 patients) and 76·4% (74·4–78·3) for those without pCR (614 deaths in 2538 patients; unadjusted HR 0·51, 0·38–0·67; p<0·0001).
Lancet 2010, Mass M.

10. 5 Year Outcomes Complete response after radical surgery
pCR 2%
No pCR 10%
pCR 90%
No pCR 77%
OncoTargets and Therapy 2013, Solanki A

11. Question
For selected individuals with a complete clinical response can we forego radical surgery??

12. Annals of Surgery, October 2004

13. Protocol 265 patients, 1991-2002 Tumors <= 7 cm from the anal verge
50.4 Gy
5-FU (425 mg/m2/d) and folinic acid (20 mg/m2/d) IV for 3 consecutive days on the first and last 3 days of radiation therapy.
NO ADJUVANT CHEMOTHERAPY

14. Protocol Assessed at 8 weeks
If complete response patients followed monthly
If sustained over 12 months response they were enrolled and considered complete responders.
14 patients “recurred” in first year (16%)
71 enrolled (27% of group)

15. Incomplete response Radical Surgery

16. Local Recurrence 2/71 luminal recurrence 0/22 pelvic recurrence
Both treated locally and no recurrence
No pelvic failures
0/22 pelvic recurrence

17. Systemic Recurrence 3/71 (4.2%) 3/22 (13.6%) Mean Follow up
Observation 57.3 months (12-156)
Resected 48 months (12-83)

18. Survival Data Observation vs Resected
5 yr Disease Free Survival
Observation 92%
Resected 83%
5 yr Overall Survival
Observation 100%
Resected 88%

19. Concerns Late recurrences with radiotherapy Single institution
Determining clinical response
Correlation between clinical response and pathological response

20. But….. Reaction Made surgeons very uneasy Not ready for prime time
Used when patients are elderly, frail or with metastatic disease
But…..

21. Netherlands experience, 2011
192 patients CRT, 21 CR (11%)
Long course CRT (Oxali, CAP)
17/21 (81%) got adjuvant chemotherapy

22. JOURNAL OF CLINICAL ONCOLOGY 2011, Mass, M.
Netherlands

23. Surveillance Program Year CEA DRE Endo MRI CT for distant mets 1 4x 2x3 4 5
JOURNAL OF CLINICAL ONCOLOGY 2011, Mass, M.

24. Results Mean Follow up 25 months
1/21 developed endoluminal recurrence
Refused radical surgery and got a local excision and now disease free
20 disease free
2-year DFS is 89% OS is 100%.
Comparable to control with ypT0N0M0 after radical surgery

25. Conclusions Similar overall survival Better functional outcomes
Salvage surgery possible
Very strict criteria, so some with a ypT0N0M0 still got surgery
Adjuvant chemotherapy

26. Watch and Wait Strategy
Dalton: 50% recurred in first year. All salvaged by surgery. 2 developed mets though. But same as control
NATUREREVIEWS|GASTROENTEROLOGY&HEPATOLOGY
Minsky, 2013

27. Conclusions Highly selective non-operative therapy may be appropriate
Salvage surgery possible

28. Can we increase the number of complete responders?
Wait longer
Double complete response if you wait longer than 8 weeks
More radiation
Different chemotherapy regimens
Oxaliplatinum, Avastin
Different timing
Adjuvant chemotherapy

29. Diseases of the Colon and Rectum, 2013

30. Inclusion Criteria
Palpable tumors, no more than 7 cm from anal verge
cT2-T4, cN0-N1, cM0
High resolution MRI or 3-D Endorectal ultrasound
Chest/Abd/Pelvic CT scan

31. Treatment
54 Gy
45 Gy via 3-field approach
9-Gy boost to the primary tumor and perirectal tissue (54 Gy total).
3 cycles bolus 5-FU (450 mg/m2), 50 mg of leucovorin for 3 consecutive days every 3 weeks
After radiation, patients received 3 additional cycles of chemotherapy every 3 weeks.

32. No adjuvant chemotherapy
Inclusion criteria
Assessed at 10 weeks
Complete response based on physical exam, endoscopy and radiology (MRI or PET/CT scan)
No adjuvant chemotherapy
was given

33. Patient Demographics
Copyright © 2013 Diseases of the Colon & Rectum. Published by Lippincott Williams & Wilkins.

34. Surveillance Strategy
Copyright © 2013 Diseases of the Colon & Rectum. Published by Lippincott Williams & Wilkins.

35. Watch and Wait
Results
Copyright © 2013 Diseases of the Colon & Rectum. Published by Lippincott Williams & Wilkins.

36. Salvage Procedures Early Regrowth
Radical surgery was offered to everyone as the first line. FTLE was only done if patient refused radical surgery
Copyright © 2013 Diseases of the Colon & Rectum. Published by Lippincott Williams & Wilkins.

37. Salvage Procedures Early Regrowth
Salvage procedures seem successful
Low local re-recurrence
Systemic recurrence an issue
Follow up relatively short
Frequent assessment
critical to success!!!

38. Salvage Procedures Late Recurrences
Radical surgery was offered to everyone as the first line. FTLE was only done if patient refused radical surgery
Copyright © 2013 Diseases of the Colon & Rectum. Published by Lippincott Williams & Wilkins.

39. Salvage Procedures Late Recurrences
Salvage surgery seems successful
Low local recurrence
Systemic recurrence thus far not as big an issue
Follow up pretty good
Continuing assessment
critical to success!!!

40. Conclusions Extended Chemoradiation with 54 Gy
Initial complete response 68%!!
17% failure in first 12 month
10% failure long term
Salvage surgery likely
51% handled non-operatively!!

41. What are we doing
Last several years offering non-operative therapy to those that have a complete response and:
1. Have metastatic disease
2. Too frail for surgery
3. Refuse surgery

42. What we would like to do
Develop a UVA protocol for this patient population
Inclusion criteria
Follow up protocol
Track outcomes

43. Significant regression
Neoadjuvant XRT
8 Week Assessment
Complete Response
Enroll
Significant regression
RE-Assess in 8 weeks
Complete response?
Yes – Enroll
No - Radical Surgery
Poor response
Radical Surgery

44. Enroll Encourage adjuvant chemotherapy Follow up
Discretion of referring oncologist
Follow up
Flexible Sigmoidoscopy and exam every 3 months
CEA every 3 months
Imaging every 6 months – Alternate MRI and PET CT scan
For how long??

45. Imaging options Endorectal ultrasound PET CT Scan Pelvic MRI
Techniques (Diffusion weighted)
Combination

46. Questions and Concerns
Do we need minimal standards for neoadjuvant XRT?
Recommend or require adjuvant chemotherapy?
Define complete clinical response or just surgeon discretion?
Recommend “boost” if don’t operate?
Decide on imaging follow up
How long do we follow?

47. Thank you