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

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

Epidemiology Colorectal cancer Hong Kong Cancer Registry 2014

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

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;351:1731-40. Sauer et al. J Clin Oncol. 2012;30:1926-33. (German trial)

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

PRE- chemoradiation POST-chemoradiation

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

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

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;9:568-573. Habr-Gama et al. Ann Surg 2004;240:711

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

Locally advanced rectal cancer Neoadjuvant chemo-radiotherapy Total mesorectal excision

‘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

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;240:711-718. Martin et al. Br J Surg 2012;99:918.

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.)

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):711-718. 2004 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;240:711-718.

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%

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

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”3501-3511. Mass et al. Ann Surg Oncol. 2015; 22:3873-3880.

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

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

Clinical Complete Response (cCR) How? Clinical + endoscopy: 92% accuracy (Habr-Gama et al 2010) 77.8% accuracy (Kuo et al) PET-CT: sensitivity 35-100%, specificity 50-100% MRI: sensitivity 30-100%, specificity 70-100% 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: 335-345.

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: 582-589. Tulchinsky et al. Ann Surg Oncol 2015; 10:2661-2667.

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*

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: 335-345.

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

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): 822-828.

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): 822-828.

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

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

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