The Role of Multiagent Chemoradiation in the Management and Prognosis of Anal Squamous Cell Carcinoma
The standard treatment for anal squamous cell carcinoma (ASCC) is multiagent chemotherapy with radiation (CRT). This is based on several randomized trials demonstrating lower recurrence and colostomy-free survival rates with multiagent CRT; however, these studies could not confirm an overall survival (OS) benefit. We hypothesized that the lack of improved OS was due to limited sample sizes and follow-up, and that multiagent CRT is associated with higher OS.
The National Cancer Database was queried for patients diagnosed with stages I, II, and II ASCC and received between 45 and 59.4 Gy of radiation between 2004 and 2015. OS of patients receiving multiagent CRT compared to monoagent CRT and radiation alone was analyzed across stages.
A total of 10,438 patients received multiagent CRT, 1163 had monoagent CRT and 446 received radiation alone. Compared to the other two groups, patients receiving multiagent CRT were younger, had fewer comorbidities, and more advanced disease (all p < 0.001). After adjusting for available confounders, multiagent CRT remained independently associated with higher OS for stages II and III ASCC. A subset analysis of patients ≥ 70 years demonstrated similar survival between monoagent versus multiagent CRT across all stages.
Multiagent CRT is associated with an OS benefit compared to monoagent CRT or radiation alone for stages II and III, but not stage I ASCC. Monoagent CRT may represent an adequate treatment for selected patients ≥ 70 years. The benefit of multiagent CRT should be balanced against treatment-related toxicities depending on disease stage and patient physiology.
KeywordsAnal squamous cell carcinoma Chemotherapy Radiation Survival
We would like to thank Timothy Ginader from the University of Iowa Biostatistics Core Alliance for his statistical support.
Each Author meets the International Committee of Medical Journal Editors (ICMJE), including:
- Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work;
- Drafting the work or revising it critically for important intellectual content;
- Final approval of the version to be published; and
- Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Compliance with Ethical Standards
None to report. The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator.
- 1.NIH. Cancer Stat Facts: Anal Cancer. https://seer.cancer.gov/statfacts/html/anus.html. Accessed 1 August 1st 2018.
- 2.Benson AB, 3rd, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK et al. Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN. 2018;16(7):852–71. doi: https://doi.org/10.6004/jnccn.2018.0060.Google Scholar
- 3.Nigro ND, Vaitkevicius VK, Considine B, Jr. Combined therapy for cancer of the anal canal: a preliminary report. Diseases of the colon and rectum. 1974;17(3):354–6.Google Scholar
- 4.Leichman L, Nigro N, Vaitkevicius VK, Considine B, Buroker T, Bradley G et al. Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. The American journal of medicine. 1985;78(2):211–5.Google Scholar
- 6.Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol. 1997;15(5):2040–9. doi: https://doi.org/10.1200/jco.19220.127.116.110.Google Scholar
- 7.Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet. 1996;348(9034):1049–54.Google Scholar
- 8.Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1996;14(9):2527–39. doi: https://doi.org/10.1200/jco.1918.104.22.1687.Google Scholar
- 9.National Cancer Database ncdbpuf.facs.org. 2018. Accessed March 2018.Google Scholar
- 10.Fritz ACP, A Jack, K Shanmugarathnam, L Sobin, DM Parkin, S Whelan. International Classification of Disease for Oncology. 3rd ed. Geneva: World Health Organization; 2000.Google Scholar
- 11.National Comprehensive Cancer Network 2017. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed May 2017.
- 12.Northover J, Glynne-Jones R, Sebag-Montefiore D, James R, Meadows H, Wan S et al. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). British journal of cancer. 2010;102(7):1123–8. doi: https://doi.org/10.1038/sj.bjc.6605605.Google Scholar
- 15.Kachnic LA, Winter K, Myerson RJ, Goodyear MD, Willins J, Esthappan J et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. International journal of radiation oncology, biology, physics. 2013;86(1):27–33. doi: https://doi.org/10.1016/j.ijrobp.2012.09.023.Google Scholar
- 16.Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson AB, 3rd et al. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(35):4344–51. doi: https://doi.org/10.1200/jco.2012.43.8085.Google Scholar
- 17.James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP 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 x 2 factorial trial. The Lancet Oncology. 2013;14(6):516–24. doi: https://doi.org/10.1016/s1470-2045(13)70086-x.Google Scholar
- 18.Peiffert D, Tournier-Rangeard L, Gerard JP, Lemanski C, Francois E, Giovannini M et al. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(16):1941–8. doi: https://doi.org/10.1200/jco.2011.35.4837.Google Scholar
- 19.Buckstein M, Arens Y, Wisnivesky J, Gaisa M, Goldstone S, Sigel K. A Population-Based Cohort Analysis of Chemoradiation Versus Radiation Alone for Definitive Treatment of Stage I Anal Cancer in Older Patients. Diseases of the colon and rectum. 2018;61(7):787–94. doi: https://doi.org/10.1097/dcr.0000000000001103.Google Scholar
- 20.Geltzeiler CB, Tsikitis VL, Kim JS, Thomas CR, Jr., Herzig DO, Lu KC. Variation in the Use of Chemoradiotherapy for Stage II and III Anal Cancer: Analysis of the National Cancer Data Base. Annals of surgical oncology. 2016;23(12):3934–40. doi: https://doi.org/10.1245/s10434-016-5431-9.Google Scholar