Anal cancer: leading the way
Authors: Angelita Habr-Gama, Guilherme Pagin São Julião, Rodrigo Oliva Perez
Journal: The Lancet Oncology (2017)

More than 40 years ago, anal cancer researchers provided one of the most important contributions to the field of gastrointestinal oncology.1Nigro ND Vaitkevicius VK Considine Jr, B Combined therapy for cancer of the anal canal: a preliminary report.Dis Colon Rectum. 1974; 17: 354-356Crossref PubMed Scopus (781) Google Scholar 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.1Nigro ND Vaitkevicius VK Considine Jr, B Combined therapy for cancer of the anal canal: a preliminary report.Dis Colon Rectum. 1974; 17: 354-356Crossref PubMed Scopus (781) Google Scholar 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.2Benson 3rd, AB 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: 449-454Crossref PubMed Scopus (63) Google Scholar 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.3Allal 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: 1588-1594Crossref PubMed Scopus (87) Google Scholar 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.4Habr-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: 711-718Crossref PubMed Scopus (1245) Google Scholar 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.5Renehan 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: 174-183Summary Full Text Full Text PDF PubMed Scopus (472) Google Scholar, 6Perez RO Complete clinical response in rectal cancer: a turning tide.Lancet Oncol. 2016; 17: 125-126Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar In The Lancet Oncology, Robert Glynne-Jones and colleagues,7Glynne-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)30071-2Summary Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 8James 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: 516-524Summary Full Text Full Text PDF PubMed Scopus (478) Google Scholar 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.9Deniaud-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: 1259-1273Summary Full Text Full Text PDF PubMed Scopus (107) Google Scholar 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. We declare no competing interests. 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 trialMany patients who do not have a complete clinical response when assessed at 11 weeks after commencing chemoradiotherapy do in fact respond by 26 weeks, and the earlier assessment could lead to some patients having unnecessary surgery. Our data suggests that the optimum time for assessment of complete clinical response after chemoradiotherapy for patients with squamous cell carcinoma of the anus is 26 weeks from starting chemoradiotherapy. We suggest that guidelines should be revised to indicate that later assessment is acceptable. Full-Text PDF Open Access