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Anal cancer: leading the way
Comment
More than 40 years ago, anal cancer researchers provided one of the most important contributions to the field of gastrointestinal oncology.1 Norman Nigro’s observation of complete pathological remission in two patients and clinical remission in one patient after neoadjuvant chemoradiotherapy founded the modern management of anal cancer.1 Since this seminal publication, organ preservation became the standard of care and is now indisputable among patients with anal carcinoma with complete clinical response to neoadjuvant chemoradiotherapy.2 Instead of undergoing abdominal perineal excision, which inevitably results in a definitive end colostomy, patients were able to preserve the anus with acceptable functional outcomes and quality of life.3 Perhaps more striking than the absence of any randomised controlled trial to show that no surgery was better than radical surgery among these patients, is the fact that identification of patients with complete response was exclusively on the basis of clinical assessment. Simple digital rectal examination became the sole method for the assessment of response among these patients without the requirement for complex, elaborate, or expensive studies to rule out the presence of microscopic disease. Despite the inherent differences between anal and rectal cancers, this approach was considered years later to be applicable to patients with very distal rectal adenocarcinomas that had a complete clinical response after being treated with a chemoradiotherapy regimen similar to that used for anal cancer.4 However, Nigro’s original findings and observational treatment approach endured slower acceptance in the clinical rectal oncology community. These rectal cancers are located centimetres away from the anus and have been only recently more widely considered for an organ-preserving strategy without immediate radical surgery after a complete clinical response.5,6 In The Lancet Oncology, Robert Glynne-Jones and colleagues,7,8 provide an additional important contribution to the understanding of in-vivo kinetics of anal tumour response to neoadjuvant chemoradiotherapy. In their post-hoc analysis of their extensive, labourious, randomised ACT II trial the authors provide definitive evidence that tumour regression is a time-dependent event. Anal cancer requires time to respond to treatment and longer intervals from chemoradiotherapy are required
to assess complete clinical response. The observation that the ideal interval to assess tumour response is 26 weeks is remarkable and a leap forward in clinical practice for the management of these patients, especially considering that this interval was formerly only 8 weeks.9 Besides the issue of timing of assessment, the present study draws attention to a very interesting observation. The study was done in multiple institutions and the tools used to assess clinical response were subjective. however, despite this, the researchers were able to consistently and safely manage these patients. Not only were patients unharmed by rather long periods of time without a definitive conclusion (complete versus incomplete response), but were not prematurely given unnecessary surgical resection. However, these same issues might represent actual limitations of the present study. The presence of multiple observers and variable tools to assess tumour response might also represent a source of bias. Ultimately, the inherent subjectivity of clinical response assessment and the variation in examiners and specific tools for assessment of response might have accounted for some complete clinical responses being incorrectly labelled as incomplete clinical response in the early intervals. Also, it remains unclear whether longer intervals (ie, longer than 26 weeks) could be used. These findings must be implemented into clinical practice to the benefit of patients with anal cancer in the very near future and represent an important milestone after Nigro’s original contribution. Furthermore, these results and the kinetics of tumour regression after neoadjuvant chemoradiotherapy and the accuracy of clinical assessment might not be unique to anal carcinoma and might again apply, at least to some extent, to rectal adenocarcinoma after neoadjuvant chemoradiotherapy. Time and future studies will tell us what are the true differences apart from the few centimetres that separate these two cancers within the lumen of the large bowel.
Steve Gschmeissner/Science Photo Library
Anal cancer: leading the way
Lancet Oncol 2017 Published Online February 10, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30073-6 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30071-2
*Angelita Habr-Gama, Guilherme Pagin São Julião, Rodrigo Oliva Perez Colorectal Surgery Division, University of São Paulo, São Paulo, Brazil (AH-G); and Gastroenterology Department, Angelita and Joaquim Gama Institute, São Paulo 04001-005, Brazil (AH-G, GPSJ, ROP)
www.thelancet.com/oncology Published online February 10, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30073-6
1
Comment
We declare no competing interests.
6
© The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license.
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Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17: 354–56. Benson AB 3rd, Arnoletti JP, Bekaii-Saab T, et al. Anal carcinoma, Version 2.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw 2012; 10: 449–54. Allal AS, Sprangers MA, Laurencet F, Reymond MA, Kurtz JM. Assessment of long-term quality of life in patients with anal carcinomas treated by radiotherapy with or without chemotherapy. Br J Cancer 1999; 80: 1588–94. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240: 711–18. Renehan AG, Malcomson L, Emsley R, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol 2015; 17: 174–83.
8
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Perez RO. Complete clinical response in rectal cancer: a turning tide. Lancet Oncol 2016; 17: 125–26. Glynne-Jones R, Sebag-Montefiore D, Meadows HM, et al. Best time to assess complete clinical response after chemoradiotherapy in squamous cell carcinoma of the anus (ACT II): a post-hoc analysis of randomised controlled phase 3 trial. Lancet Oncol 2017; published online Feb 10. http://dx.doi.org/10.1016/S1470-2045(17)30071-2. James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol 2013; 14: 516–24. Deniaud-Alexandre E, Touboul E, Tiret E, et al. Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal. Int J Radiat Oncol Biol Phys 2003; 56: 1259–73.
www.thelancet.com/oncology Published online February 10, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30073-6
More than 40 years ago, anal cancer researchers provided one of the most important contributions to the field of gastrointestinal oncology.1 Norman Nigro’s observation of complete pathological remission in two patients and clinical remission in one patient after neoadjuvant chemoradiotherapy founded the modern management of anal cancer.1 Since this seminal publication, organ preservation became the standard of care and is now indisputable among patients with anal carcinoma with complete clinical response to neoadjuvant chemoradiotherapy.2 Instead of undergoing abdominal perineal excision, which inevitably results in a definitive end colostomy, patients were able to preserve the anus with acceptable functional outcomes and quality of life.3 Perhaps more striking than the absence of any randomised controlled trial to show that no surgery was better than radical surgery among these patients, is the fact that identification of patients with complete response was exclusively on the basis of clinical assessment. Simple digital rectal examination became the sole method for the assessment of response among these patients without the requirement for complex, elaborate, or expensive studies to rule out the presence of microscopic disease. Despite the inherent differences between anal and rectal cancers, this approach was considered years later to be applicable to patients with very distal rectal adenocarcinomas that had a complete clinical response after being treated with a chemoradiotherapy regimen similar to that used for anal cancer.4 However, Nigro’s original findings and observational treatment approach endured slower acceptance in the clinical rectal oncology community. These rectal cancers are located centimetres away from the anus and have been only recently more widely considered for an organ-preserving strategy without immediate radical surgery after a complete clinical response.5,6 In The Lancet Oncology, Robert Glynne-Jones and colleagues,7,8 provide an additional important contribution to the understanding of in-vivo kinetics of anal tumour response to neoadjuvant chemoradiotherapy. In their post-hoc analysis of their extensive, labourious, randomised ACT II trial the authors provide definitive evidence that tumour regression is a time-dependent event. Anal cancer requires time to respond to treatment and longer intervals from chemoradiotherapy are required
to assess complete clinical response. The observation that the ideal interval to assess tumour response is 26 weeks is remarkable and a leap forward in clinical practice for the management of these patients, especially considering that this interval was formerly only 8 weeks.9 Besides the issue of timing of assessment, the present study draws attention to a very interesting observation. The study was done in multiple institutions and the tools used to assess clinical response were subjective. however, despite this, the researchers were able to consistently and safely manage these patients. Not only were patients unharmed by rather long periods of time without a definitive conclusion (complete versus incomplete response), but were not prematurely given unnecessary surgical resection. However, these same issues might represent actual limitations of the present study. The presence of multiple observers and variable tools to assess tumour response might also represent a source of bias. Ultimately, the inherent subjectivity of clinical response assessment and the variation in examiners and specific tools for assessment of response might have accounted for some complete clinical responses being incorrectly labelled as incomplete clinical response in the early intervals. Also, it remains unclear whether longer intervals (ie, longer than 26 weeks) could be used. These findings must be implemented into clinical practice to the benefit of patients with anal cancer in the very near future and represent an important milestone after Nigro’s original contribution. Furthermore, these results and the kinetics of tumour regression after neoadjuvant chemoradiotherapy and the accuracy of clinical assessment might not be unique to anal carcinoma and might again apply, at least to some extent, to rectal adenocarcinoma after neoadjuvant chemoradiotherapy. Time and future studies will tell us what are the true differences apart from the few centimetres that separate these two cancers within the lumen of the large bowel.
Steve Gschmeissner/Science Photo Library
Anal cancer: leading the way
Lancet Oncol 2017 Published Online February 10, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30073-6 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30071-2
*Angelita Habr-Gama, Guilherme Pagin São Julião, Rodrigo Oliva Perez Colorectal Surgery Division, University of São Paulo, São Paulo, Brazil (AH-G); and Gastroenterology Department, Angelita and Joaquim Gama Institute, São Paulo 04001-005, Brazil (AH-G, GPSJ, ROP)
www.thelancet.com/oncology Published online February 10, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30073-6
1
Comment
We declare no competing interests.
6
© The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license.
7
1 2
3
4
5
2
Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17: 354–56. Benson AB 3rd, Arnoletti JP, Bekaii-Saab T, et al. Anal carcinoma, Version 2.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw 2012; 10: 449–54. Allal AS, Sprangers MA, Laurencet F, Reymond MA, Kurtz JM. Assessment of long-term quality of life in patients with anal carcinomas treated by radiotherapy with or without chemotherapy. Br J Cancer 1999; 80: 1588–94. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240: 711–18. Renehan AG, Malcomson L, Emsley R, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol 2015; 17: 174–83.
8
9
Perez RO. Complete clinical response in rectal cancer: a turning tide. Lancet Oncol 2016; 17: 125–26. Glynne-Jones R, Sebag-Montefiore D, Meadows HM, et al. Best time to assess complete clinical response after chemoradiotherapy in squamous cell carcinoma of the anus (ACT II): a post-hoc analysis of randomised controlled phase 3 trial. Lancet Oncol 2017; published online Feb 10. http://dx.doi.org/10.1016/S1470-2045(17)30071-2. James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol 2013; 14: 516–24. Deniaud-Alexandre E, Touboul E, Tiret E, et al. Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal. Int J Radiat Oncol Biol Phys 2003; 56: 1259–73.
www.thelancet.com/oncology Published online February 10, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30073-6