1. Non-operative Management of Rectal Cancer
Dr. HO King Wa Samuel
Kwong Wah Hospital
Joint Hospital Surgical Grand Round
15 July 2017

2. Epidemiology Colorectal cancer
Worldwide
Hong Kong
Incidence
1,360,602 (9.7%)
4,979 (16.8%)
Mortality
693,933 (8.5%)
2,034 (14.7%)
According to the latest data, colorectal cancer remains one of the commonest cancers & cause of cancer deaths
Worldwide I: 4th, M: 5th
HK I: 1st, M: 2nd
WHO GLOBOCAN 2012
Hong Kong Cancer Registry 2014

3. Epidemiology Colorectal cancer
Hong Kong Cancer Registry 2014

4. Epidemiology Distribution
Caecum 14%
Ascending colon 10%
Transverse colon 12%
Descending colon 7%
Sigmoid colon 25%
Rectosigmoid junction 0.9%
Rectum 23%
Global Cancer Statistics 2011

5. Neoadjuvant Surgery Adjuvant Radiotherapy TME Chemotherapy
Indications:
≥T3 lesions
Node positive lesions
Threatened circumferential margin (CRM)
Surgery remains the cornerstone for curative treatment for mid to lower rectal cancers (TME)
The role of neoadjuvant therapy in locally advanced rectal cancer has been well established – downsizing & downstaging of tumors, reduced local recurrence
Landmark studies like the Dutch trial & German trial have proven the benefits of pre-op chemoradiotherapy
Sauer et al. N Engl J Med. 2004;351:
Sauer et al. J Clin Oncol. 2012;30:
(German trial)

6. Neoadjuvant Therapy Indications
≥T3 lesions (the only definitive indication)
Node positive lesions
Threatened circumferential margin (CRM)
Other indications are relative
T1/T2 lesions with +ve nodes: difficult to acertain LN status
Distal tumor: to convert APR to sphincter-preserving operation
Mesorectal fascia invasion: high risk of local recurrence, downstage to permit CRM-negative resection

7. PRE- chemoradiation
POST-chemoradiation

8. Neoadjuvant Therapy Components
Chemoradiotherapy x 6 weeks
Capecitabine
RT 50.4 Gy in 28 fractions
Interval to surgery
At least 6 weeks for tumor regression to take place

9. Non-operative Management ‘Watch & Wait’
Shift in philosophy towards ‘watch & wait’ strategy
A controversial & potentially paradigm-changing approach

10. Non-operative Management Conception
First conceived by Nakagawa et al in 2002
Popularized by Habr-Gama et al in 2004
Habr-Gama from Brazil
Nakagawa et al. Ann Surg Oncol. 2002;9:
Habr-Gama et al. Ann Surg 2004;240:711

11. Non-operative Management ‘Watch & Wait’
Identifiy patients with clinical complete tumor regression after neoadjuvant chemoradiotherapy (CRT)
Close surveillance
Salvage surgery if tumor regrowth
Uses clinical complete response (cCR) to predict pathological complete response (pCR)
FU to identify tumor regrowth or distant metastasis

12. Locally advanced rectal cancer
Neoadjuvant chemo-radiotherapy
Total mesorectal excision

13. ‘Watch & Wait’ Protocol for Rectal Cancer
Locally advanced rectal cancer
Neoadjuvant chemo-radiotherapy
Incomplete clinical response
Total mesorectal excision
Signs of tumor recurrence
Response assessment
Complete clinical response
‘Watch & wait’ protocol
Follow-up
Persistent cCR

14. Non-operative Management Rationale
16-27% achieved pathological complete response (pCR) after neoadjuvant CRT
To avoid complications associated with radical surgery
Pathological complete response (pCR):
Absence of neoplastic cells in the surgical resection specimen after neoadjuvant chemoradiation
Chances of recurrence low
If recurrence, salvage surgery
Clinical complete response (cCR) may not equate to pCR
pCR (along with nodal status) are prognostic factors
- Associated with improved OS & DFS
Habr-Gama et al. Ann Surg 2004;240:
Martin et al. Br J Surg 2012;99:918.

15. Complications of Surgery
Complications of radical rectal surgery
Immediate post-op complications
Temporary or permanent stoma
Faecal incontinence
Urinary dysfunction
Sexual dysfunction (impotence, retrograde ejaculation etc.)

16. Habr-Gama et al 2004 University of San Paulo, Brazil 1991-2002
265 patients with resectable distal rectal adenocarcinoma
Chemoradiation (50.4Gy + 5-FU/LV)
Outcomes
cCR  ‘Watch & wait’: 71 patients (26.8%)
Incomplete CR  radical surgery, pT0N0M0: 22 patients
Vigorous surveillance: DRE, CEA, colonoscopy, imaging
Median FU 57.3 months
Habr-Gama. Ann Surg. 240(4):
Surveillance: 10wk, then every 1-2mo in first year, then every 3mo in second year, then every 6mo in third year & beyond
Habr-Gama et al. Ann Surg 2004;240:

17. Habr-Gama et al 2004 Observation group: Resection group:
3 systemic & 2 locoregional recurrences
OS 100%, DFS 92%
Resection group:
3 systemic recurrences
OS 88%, DFS 83%

18. Non-operative Management Challenges
Correlation between clinical & pathological complete responses
Optimal follow-up schedule
Failure & subsequent management
Long-term oncological outcomes
Concerns about false negative by imaging post-CRT

19. Clinical Complete Response (cCR)
cCR as surrogate marker for pCR
But cCR = pCR?
How?
Clinical - digital rectal examination (DRE)
Endoscopic – proctoscopy, ± biopsy
Radiological - PET/CT, diffusion-weighted MRI
When?
Neoadjuvant-assessment interval
Since without surgical resection, we cannot tell whether the tumor has achieved pathological complete response or not
The next best thing is to rely on clinical signs & radiological evidence
DRE to look for rectal wall irregularites
Endoscopy for ulceration or mucosal irregularity otherwise missed by DRE, biopsy during the procedure
MRI evaluates mixed signal intensity of rectal wall & mesorectal LN involvement
Perez et al. Cancer. 2012; 118”
Mass et al. Ann Surg Oncol. 2015; 22:

20. pCR vs cCR
No reliable method to identify pCR without surgical resection
cCR does not always correlate pCR
No predictors of tumor response available
Diagnostic challenge
cCR does not always correlate with pCR. Variable definitions of cCR, quality of imagings
Sex, age, tumor location NOT predictors of response to CRT

21. Clinical Complete Response (cCR)
Habr-Gama 2004:
Response assessment, 8 weeks from completion of neoadjuvant CRT
Recent studies:
P/E, DRE, CEA
proctoscopy +/- bx
CXR, CT A+P
Author, year
Definition of cCR
Interval from last dose CRT to assessment
Renehan et al, 2016
DRE; endoscopy; MRI
> 8wk
Appelt et al, 2015
Endoscopy; MRI
6 wk
Habr-Gama et al, 2014
Clinical; endoscopy; MRI / diffusion-weighted MRI / PET-CT
10 wk
Smith et al, 2012
4-10 wk
Maas et al, 2011
6-8 wk
Limitations of clinical assessment:
tumors beyond reach of DRE
distinguish ulcer from tumor regrowth
Recent studies, assessment of cCR took place 4-12 weeks from last day of treatment. Assessment was extensive, including the same 3 components – clinical/DRE, endoscopic exam & an imaging modality
What’s different from that adopted by Habr-Gama in 2004, was the use of MRI in place of CT. Habr-Gama even explored the use of DW-MRI & PET-CT

22. Clinical Complete Response (cCR) How?
Clinical + endoscopy:
92% accuracy (Habr-Gama et al 2010)
77.8% accuracy (Kuo et al)
PET-CT: sensitivity %, specificity %
MRI: sensitivity %, specificity %
Clinical assessment been demonstrated by Habr-Gama & her team to be the most accurate assessment tool for pCR, but results not easily replicated by other scholars
PET-CT & MRI most promising
Better results with DWI-MRI
Limitations:
Heterogeneity of studies with respect to timing of imaging & surgery
-> noconclusive method for assessing cCR following CRT has been defined, need further research in the future
Kong et al. Dis Colon Rectum 2017; 60:

23. Clinical Complete Response (cCR) When?
Neoadjuvant-surgery interval >8 weeks
Higher rates of pCR
Decreased recurrence
Improved disease-free survival
cumulative incidence of pCR
interval chemoradiation / surgery
Graph:
cumulative incidence of pCR (y-axis) in relation to time interval from completion of nCRT to surgery (x-axis)
Largest interval increase seen at 8 weeks, plateaus after 12 weeks, longer interval does not improve response rate
Same implication to neoadjuvant-assessment interval?
Kalady et al. Ann Surg 2009; 250:
Tulchinsky et al. Ann Surg Oncol 2015; 10:

24. Follow-up Regular & frequent assessments
Early detection of tumor regrowth or distant metastasis
e.g. Habr-Gama 2014
Clinical
Endoscopy
Radiological
Detection of tumor regrowth majority within 12 months
months 2 4 6 8 10 12 15 18 21 24 30 36 42 48 54 60 72 …
Clinical 
CEA
Imaging*

25. Salvage Surgery Systemic review 370 patients in ‘watch & wait’ group
256 (69.2%) with persistent cCR
105 (28.4%) with local tumor regrowth
7 (1.9%) with distant recurrence but no tumor regrowth
Rate of salvage surgery for tumor regrowth: 83.8%
Rate for salvage surgery (for local or distant tumors)
4 with distant recurrence
4 unfit for surgery
3 refused surgery
Kong et al. Dis Colon Rectum 2017; 60:

26. Systemic review 9 articles reviewed
4 prospective, 4 retrospective, 1 unreported design
Oncological safety of the non-operative approach
Rate of salvage surgery
Associated prognostic impact

27. Long-term Oncological Outcomes
Neoadjuvant CRT 183 patients
Incomplete Response Radical Surgery 83 patients
Complete Clinical Response ‘Watch & Wait’ 90 patients
Sustained cCR 62 patients
Tumor Regrowth 28 patients
R0 Resection 26 patiients
No Local Re-recurrence 22 patients
Unresectable Local Re-recurrence 4 patients
Unresectable 2 patients
Long-term Oncological Outcomes
Tumor regrowth 31%
Salvage surgery 93%
Relapse after ‘watch & wait’ does not compromise care
- High proportion of patients can be salvaged with definitive surgery
- No consequent difference in distant recurrence
Non-operative Management 62 patients
Salvageable Local Failures
22 patients
Unresectable Local Failures
6 patients
Habr-Gama et al. Int J Radiation Oncol Biol Phys 2014; 88(4):

28. Long-term Oncological Outcomes
Neoadjuvant CRT 183 patients
Incomplete Response Radical Surgery 83 patients
Complete Clinical Response ‘Watch & Wait’ 90 patients
Sustained cCR 62 patients
Tumor Regrowth 28 patients
R0 Resection 26 patiients
No Local Re-recurrence 22 patients
Unresectable Local Re-recurrence 4 patients
Unresectable 2 patients
Long-term Oncological Outcomes
Overall survival after tumor regrowth 88%
Disease-free survival after tumor regrowth 79%
Relapse after ‘watch & wait’ does not compromise care
- High proportion of patients can be salvaged with definitive surgery
- No consequent difference in distant recurrence
Non-operative Management 62 patients
Salvageable Local Failures
22 patients
Unresectable Local Failures
6 patients
Habr-Gama et al. Int J Radiation Oncol Biol Phys 2014; 88(4):

29. Non-operative management not equivalent to sub-optimal cancer care
Importance of patient selection & rigorous surveillance

30. Conclusion Insufficient evidence on oncological safety
Prospective validation is needed
Limitations in assessment for complete response
Until now, not standard of care for locally advanced rectal cancer
But it remains a potential option for locally advanced rectal cancer in the future

31. Thank you