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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 3  |  Page : 74-78

Long-term outcomes of locally advanced rectal cancer after neoadjuvant chemoradiotherapy: A bi-national colorectal cancer audit study


1 Division of Cancer Surgery; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne; Sir Peter MacCallum Department of Oncology, Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia
2 Division of Cancer Surgery; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
3 Division of Cancer Surgery; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne; Sir Peter MacCallum Department of Oncology, Department of Surgery, The University of Melbourne, Parkville; BiNational Colorectal Cancer Audit, Colorectal Surgical Society of Australia and New Zealand, Hawthorn, Victoria, Australia

Date of Submission08-Aug-2019
Date of Decision30-Aug-2019
Date of Acceptance23-Sep-2019
Date of Web Publication24-Oct-2019

Correspondence Address:
Dr. Joseph C Kong
Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria - 3000
Australia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/WJCS.WJCS_16_19

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  Abstract 


Background: There is a great interest in predicting the pathological complete response (pCR) to facilitate patient selection for a “watch and wait” protocol, sparing locally advanced rectal cancer patients from surgical related morbidity and mortality. However, there is a high risk of tumor regrowth with the current assessment of clinical complete response, highlighting the need for a better predictive marker of pCR. Objective: The aim of this study was to assess the short- and long-term outcomes according to tumor response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Design: Retrospective analysis of a prospectively maintained bi-national database. Settings: Multicenter bi-national database. Patients and Methods: This was a retrospective study of a prospectively maintained bi-national colorectal cancer audit database. Inclusion criteria were T3-4 and/or N1-2 rectal cancer patients receiving long course chemoradiotherapy followed by surgery. The primary outcome measure was pathological tumor response. Main Outcome Measures: The primary outcome measure was rate of pathological response and associated local and distant recurrence. Sample Size: There were 929 consecutive locally advanced rectal cancer patients identified within the database. Results: A total of 929 patients were included, with a pCR rate of 29.6% (275 patients). Non-responding tumors had a higher circumferential resection margin positive rate of 20% (33 of 165 patients) compared to partial responding tumors of 5.1% (24 of 475 patients). Local recurrence rates in accordance to tumor regression grade (pCR, partial and no response) were 2.2%, 4.4%, and 4.7% (P = 0.254) respectively, with distant recurrence rates of 2.9%, 4.1%, and 8.1% (P = 0.03) respectively. Independent predictors of pCR were early stage disease on pre-treatment imaging (OR 2.12 95% CI 1.24–3.63, P = 0.005), a rural setting (OR 3.15 [95%] CI 1.63–6.06, P < 0.001) and private insurance (OR 2.06 [95%] CI 1.45–2.93, P < 0.001), with an inverse association to metastatic disease (OR 0.22 [95%] CI 0.1-0.5, P < 0.001). Conclusions: Early-stage tumors had the greatest likelihood of attaining a pCR with a lower risk of local and distant recurrence than partial or non-responding tumors. Limitations: This study is limited by the retrospective nature of the analysis and the lack of data auditing to ensure accuracy of data is maintained. Conflict of Interest: None.

Keywords: Rectal cancer, recurrence, pathological response


How to cite this article:
Kong JC, Guerra GR, Lee A, Warrier SK, Lynch A C, Heriot AG. Long-term outcomes of locally advanced rectal cancer after neoadjuvant chemoradiotherapy: A bi-national colorectal cancer audit study. World J Colorectal Surg 2019;8:74-8

How to cite this URL:
Kong JC, Guerra GR, Lee A, Warrier SK, Lynch A C, Heriot AG. Long-term outcomes of locally advanced rectal cancer after neoadjuvant chemoradiotherapy: A bi-national colorectal cancer audit study. World J Colorectal Surg [serial online] 2019 [cited 2020 Aug 5];8:74-8. Available from: http://www.wjcs.us.com/text.asp?2019/8/3/74/269821




  Introduction Top


Achieving pathological complete response (pCR) after neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer has garnered interest over the last decade given the significant correlation with improved 5-year overall (OS) and disease-free survival (DFS).[1] With this knowledge, rectal cancer patients with T3-4 or N1-2 disease have in select cases been managed by a “watch and wait” approach, a term coined for patients who are deemed to achieve a clinical complete response (cCR). This allows the patient to avoid immediate surgery and instead receive intense surveillance to detect tumor regrowth.[2]

However, cCR has a tumor regrowth risk of 30.8% as revealed in a recent systematic review of nine observational studies. Furthermore, it was estimated that only 83.8% of patients with tumor regrowth were amenable to salvage surgery.[3] Hence, there is an opportunity to assess independent pathological factors for pCR using the bi-national colorectal cancer audit (BCCA) database to estimate which patients are more likely to achieve a pCR before neoadjuvant therapy. Moreover, data is scarce on the differing rates of local and distant recurrence in patients with pCR, partial, or no response to therapy.

This study aims to determine the rate of pCR across Australia and New Zealand and to identify independent pre-neoadjuvant CRT predictors of response and the associated local and distant recurrence rates post resection.


  Patients and Methods Top


This is a retrospective study of a prospectively maintained bi-national colorectal cancer audit database across Australia and New Zealand. All data, including patient follow-up, were voluntarily entered by more than 200 participating surgeons. All consecutive rectal cancer patients between January 2007 and December 2016 were identified. The inclusion criteria were locally advanced rectal cancer, long-course neoadjuvant CRT, and pathological response data. Patients who underwent short-course CRT were excluded.

The primary outcome measures were set as the independent predictors of pCR, defined as no viable cancer cells on the pathological evaluation of the resected specimen, including nodes. Contrastingly, partial response was defined as single or groups of cancer cells or residual cancer outgrown by fibrosis, and no response was defined as minimal fibrosis with extensive residual cancer. The secondary outcome measures were the rate of pCR in urban vs rural patients, public vs private, and the local and distant recurrence rate for each defined tumor response category.

All categorical data were analyzed using Pearson's Chi-square or Fisher's exact test, and continuous data using the Student's t-test. Multivariate logistic regression analysis was performed to identify independent predictors for pCR, no response, and distant recurrence. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp. and a P value <0.05 was considered significant.


  Results Top


A total of 929 consecutive locally advanced rectal cancer patients received neoadjuvant therapy followed by surgery with curative intent. Of the included patients, the pCR rate was 29.6% (275 patients), and 18.5% (172 patients) had nonresponding tumors.

There was a significantly higher rate of pCR in patients treated in a rural than an urban hospital (49% vs 28.5%) and in privately insured than public patients (35.7% vs 26.2%) as shown in [Table 1]. In tumors without a response to neoadjuvant CRT, a higher circumferential resection margin (CRM) positive rate of 20% (33 of 165 patients) was identified compared to a rate of 5.1% (24 of 475 patients) in partial responding tumors. The local recurrence rate in accordance to tumor regression grade (pCR, partial and no response) was 2.2%, 4.4%, and 4.7% (P value = 0.254), respectively, with distant recurrence identified at a rate of 2.9%, 4.1%, and 8.1% (P value = 0.03), respectively. Also, there was an increasing risk of local and distant recurrence with high overall tumor stage, lymph node involvement, and CRM positivity [Table 2].
Table 1: Patient and tumor characteristics according to tumor response to neoadjuvant chemoradiotherapy

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Table 2: The rate of local and distant recurrence according to the tumor characteristics and circumferential resection margin positivity

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Independent predictors of pCR were early-stage tumor on pretreatment imaging (OR 2.12 95% CI 1.24–3.63, P value = 0.005), rural setting (OR 3.15 95% CI 1.63–6.06, P value <0.001), and private insurance (OR 2.06 95% CI 1.45–2.93, P value <0.001) as shown in [Table 3]. An inverse association of pCR was identified with metastatic disease (OR 0.22 95% CI 0.1–0.5, P value <0.001). Furthermore, this was associated with a high likelihood of no response to neoadjuvant CRT, with an OR of 2.11 (95% CI 1.32–3.35, P value = 0.002). Finally, an independent predictor of distant recurrence was lymph node positivity, with an associated OR of 4.57 (95% CI 2.33–9.94, P value <0.001).
Table 3: Independent predictors of pathological complete response and no response to neoadjuvant chemoradiotherapy

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  Discussion Top


The pCR rate from the bi-national (Australia and New Zealand) colorectal cancer database was 29.6%, corresponding to a similar finding reported by other authors.[4],[5] Furthermore, independent pathological predictors of pCR were early-stage tumor and absence of metastatic colorectal cancer, with the presence of distant disease portending a higher likelihood of the tumor demonstrating no response. In the nonresponding tumor cohort, a higher CRM positivity rate was encountered; however, this did not translate to a higher local recurrence rate.

There has been a progressive paradigm shift away from radical surgery in patients who are deemed to have achieved a cCR, sparing patients from surgically related major complications including death. This concept was first conceived by Habr-Gama et al., and was recently published in an updated series of 90 patients managed using the “watch and wait” approach with the longest median follow-up to date of 60 months.[6] They identified a tumor regrowth rate of 31%, of which 89% (25 patients) were amenable to salvage oncological resection with 5-year cancer-specific overall survival of 91% and disease-free survival of 68%.[6] Subsequently, several trials have reported the feasibility and oncological safety of this approach, with the main concern surrounding the risk of tumor regrowth.[7],[8]

Therefore, there has been a great interest in improving the selection of patients for a “watch and wait” approach upon completion of neoadjuvant CRT, using a combination of modalities including clinical assessment, imaging, and laboratory testing.[9],[10],[11] Others have focused on pretreatment pathological factors to predict the likelihood of achieving a pCR,[12],[13] including those identified in this study, specifically mrT1-2 stage and the absence of metastatic liver or lung disease. This will guide clinicians better: informing them of discussions on the expected long-term prognosis of patients and the potential for advocating less radical surgery in a highly selected group with a projected lower life expectancy, or in those deemed to be high-risk surgical patients.[14],[15],[16]

Unexpected findings included patients with private health insurance and those managed in a rural hospital setting having a higher probability of attaining a pCR. A large national database from the United States found a similar correlation with private health insurance, which they attributed in part to the ability to access best current treatment.[12],[13] However, across Australia and New Zealand, patients have a similar standard of care, whether public or private, as health care is accessible to the entire population. There is likely to be other factors not captured in this study, which may better explain this finding, including chemoradiation compliance and the interval between completion of CRT and surgery.[17]

This study is unique because of the inclusion of local and distant recurrence posttreatment and assessment of the implications of not attaining a pCR, which has demonstrated poorer recurrence-free survival.[18] The consequence of no response to neoadjuvant CRT from an Australasian database showed a higher rate of CRM positivity and an increase in distant recurrence, but not local recurrence when compared to good responders. It is well accepted that attaining a pCR equates to an improved prognosis and lower recurrence rate as shown in a recent meta-analysis.[3] Therefore, randomized controlled trials such as the FORWARC study (NCT01211210) of mFOLFOX6 with or without radiation in the neoadjuvant treatment of locally advanced rectal cancer is crucial to increase the response rate and improve the outcomes of those that would otherwise fail conventional therapy.[19]

There were several limitations identified in our study. First was the retrospective nature of this study, although the majority of the known pretreatment predictors of pathological response were prospectively entered, making it less likely to miss other significant variables. Second, as this is a voluntary database, there is no independent audit to ensure compliance with the entry and accuracy of the data. Third was the lack of long-term outcome measures associated with the pathological response after neoadjuvant CRT.


  Conclusion Top


In conclusion, this study has provided an insight into the projected risk of tumor recurrence for locally advanced rectal cancer patients after neoadjuvant CRT based on their pathological tumor response. Furthermore, it has identified that early-stage tumors are more likely to achieve a pCR, with lower rates of local and distant recurrence, which may guide the improved selection of patients for a “watch and wait” management approach.

Financial support and sponsorship

Royal Australasian College of Surgeons Foundation for Surgery, Colorectal Surgical Society of Australia and New Zealand Foundation.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Kong JC, Guerra GR, Warrier SK, Ramsay RG, Heriot AG. Outcome and salvage surgery following “watch and wait” for rectal cancer after neoadjuvant therapy: A systematic review. Dis Colon Rectum 2017;60:335-45.  Back to cited text no. 3
    
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Wilkins S, Haydon A, Porter I, Oliva K, Staples M, Carne P, et al. Complete pathological response after neoadjuvant long-course chemoradiotherapy for rectal cancer and its relationship to the degree of T3 mesorectal invasion. Dis Colon Rectum 2016;59:361-8.  Back to cited text no. 4
    
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Habr-Gama A, Gama-Rodrigues J, Sao Juliao GP, Proscurshim I, Sabbagh C, Lynn PB, et al. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: Impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys 2014;88:822-8.  Back to cited text no. 6
    
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Lai CL, Lai MJ, Wu CC, Jao SW, Hsiao CW. Rectal cancer with complete clinical response after neoadjuvant chemoradiotherapy, surgery, or “watch and wait”. Int J Colorectal Dis 2016;31:413-9.  Back to cited text no. 8
    
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Perez RO, Habr-Gama A, Gama-Rodrigues J, Proscurshim I, Julião GP, Lynn P, et al. Accuracy of positron emission tomography/computed tomography and clinical assessment in the detection of complete rectal tumor regression after neoadjuvant chemoradiation: Long-term results of a prospective trial (National Clinical Trial 00254683). Cancer 2012;118:3501-11.  Back to cited text no. 10
    
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Kim IY, You SH, Kim YW. Neutrophil-lymphocyte ratio predicts pathologic tumor response and survival after preoperative chemoradiation for rectal cancer. BMC Surg 2014;14:94.  Back to cited text no. 11
    
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Lorimer PD, Motz BM, Kirks RC, Boselli DM, Walsh KK, Prabhu RS, et al. Pathologic complete response rates after neoadjuvant treatment in rectal cancer: An analysis of the national cancer database. Ann Surg Oncol 2017;24:2095-103.  Back to cited text no. 12
    
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Al-Sukhni E, Attwood K, Mattson DM, Gabriel E, Nurkin SJ. Predictors of pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer. Ann Surg Oncol 2016;23:1177-86.  Back to cited text no. 13
    
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Issa N, Murninkas A, Powsner E, Dreznick Z. Long-term outcome of local excision after complete pathological response to neoadjuvant chemoradiation therapy for rectal cancer. World J Surg 2012;36:2481-7.  Back to cited text no. 14
    
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Belluco C, De Paoli A, Canzonieri V, Sigon R, Fornasarig M, Buonadonna A, et al. Long-term outcome of patients with complete pathologic response after neoadjuvant chemoradiation for cT3 rectal cancer: Implications for local excision surgical strategies. Ann Surg Oncol 2011;18:3686-93.  Back to cited text no. 15
    
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Kundel Y, Brenner R, Purim O, Peled N, Idelevich E, Fenig E, et al. Is local excision after complete pathological response to neoadjuvant chemoradiation for rectal cancer an acceptable treatment option? Dis Colon Rectum 2010;53:1624-31.  Back to cited text no. 16
    
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Foster JD, Jones EL, Falk S, Cooper EJ, Francis NK. Timing of surgery after long-course neoadjuvant chemoradiotherapy for rectal cancer: A systematic review of the literature. Dis Colon Rectum 2013;56:921-30.  Back to cited text no. 17
    
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Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, et al. Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: Initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol 2016;34:3300-7.  Back to cited text no. 19
    



 
 
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