Innovative Approaches to Non-Metastatic Anal Cancer: Bridging Today and Tomorrow
Main Article Content
Abstract
Anal cancer, although rare, has seen an increasing incidence and mortality, primarily due to high-risk sexual behaviors, HIV, and low HPV vaccination coverage. This review examines current treatment strategies for non-metastatic squamous cell carcinoma of the anus, with a focus on chemoradiation therapy (CRT) and emerging therapies. The historical and scientific basis for chemoradiation therapy using 5-fluorouracil and mitomycin C (MMC) is discussed as the standard treatment, although alternatives such as cisplatin and capecitabine show promise, particularly in settings where MMC is unavailable or when access to infusion pumps is restricted. Negative data regarding treatment intensification, induction or maintenance chemotherapy, and combinations with targeted therapies that have not demonstrated significant benefits are also reviewed. Ongoing research on immune checkpoint inhibitors presents new opportunities to improve patient outcomes. Surgical interventions may be recommended for very early disease but are usually reserved for cases of recurrence or failure after CRT. Despite challenges related to immunization efforts and high-risk behaviors, advancements in CRT and the development of novel therapies offer hope for improved outcomes with reduced toxicity.
Keywords:
anal cancer, squamous cell carcinoma of the anus, chemoradiation, locoregional.
Article Details
How to Cite
FERREIRA, Artur R et al.
Innovative Approaches to Non-Metastatic Anal Cancer: Bridging Today and Tomorrow.
Medical Research Archives, [S.l.], v. 12, n. 12, dec. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6190>. Date accessed: 06 jan. 2025.
doi: https://doi.org/10.18103/mra.v12i12.6190.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63.
2. Deshmukh A, Suk R, Shiels M, et al. Recent Trends in Squamous Cell Carcinoma of the Anus Incidence and Mortality in the United States, 2001-2015. J Natl Cancer Inst. 2020;112(8):829-38.
3. Donadio M and Riechelmann R. Anal canal cancer in Brazil: why should we pay more attention to the epidemiology of this rare disease? ecancer. 2020;14:1037.
4. Wei F, Alberts C, Albuquerque A, et al. Impact of Human Papillomavirus Vaccine against Anal Human Papillomavirus Infection, Anal Intraepithelial Neoplasia, and Recurrence of Anal Intraepithelial Neoplasia: A Systematic Review and Meta-Analysis. J. Infect. Dis. 2023;228:1496–504.
5. Cicero G, Ascenti G, Blandino A, et al. Magnetic Resonance Imaging of the Anal Region: Clinical Applications. J Clin Imaging Sci. 2020; 10:76.
6. Leccisotti L, Ripani D, Manfrida S, et al. Diagnostic performance and prognostic role of FDG PET/CT performed at staging in anal cancer. Clin Transl Imaging. 2020;8(2):55–64.
7. Surveillance, Epidemiology, and End Results (SEER) Program; National Cancer Institute. Cancer Stat Facts: Anal Cancer. seer.cancer.gov/statfacts/html/anus.html. (Accessed on October 31, 2024).
8. Das P, Bhatia S, Eng C, et al. Predictors and patterns of recurrence after definitive chemoradiation for anal cancer. Int J Radiat Oncol Biol Phys. 2007; 68:794-800.
9. Gunderson L, Winter K, Ajani J, 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. J Clin Oncol. 2012;30:4344–51.
10. Garris C, Arlauckas S, Kohler R, et al. Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12. Immunity. 2018; 49:1148–61.
11. Anne N Young AN, Jacob E, Willauer P, et al. Anal Cancer. Surg Clin North Am. 2020 Jun; 100(3):629-34.
12. Gondal TA, Chaudhary N, Bajwa H, et al. Anal Cancer: The Past, Present and Future. Curr Oncol. 2023;30(3):3232-50.
13. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med. 2000;342:792-800.
14. Boman BM, Moertel CG, O'Connell MJ, et al. Carcinoma of the anal canal. A clinical and pathologic study of 188 cases. Cancer. 1984;54 (1):114-25.
15. Nigro ND, Vaitkevicius VK, Considine B. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974;17(3): 354-6.
16. Leichman L, Nigro N, Vaitkevicius VK, et al. Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med. 1985;78(2):211-5.
17. Rao S, Guren MG, Khan K, et al. Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(9): 1087-100.
18. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. Available at:
https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf. (Accessed on September 07, 2024).
19. Upadhyay L, Hartzell M, Parikh AR, et al. Recent Advances in the Management of Anal Cancer. Healthcare (Basel). 2023;11(23):3010.
20. Epidermoid anal cancer: results from the UKCCCR randomized 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.
21. Northover J, Glynne-Jones R, Sebag-Montefiore D, et al. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomized UKCCCR Anal Cancer Trial (ACT I). Br J Cancer. 2010;102:1123-8.
22. Bartelink H, Roelofsen F, Eschwege F, 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;15:2040-49.
23. Flam M, John M, Pajak T, 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. J Clin Oncol. 1996; 14(9):2527-39.
24. Crehange G, Bosset M, Lorchel F, et al. Combining cisplatin and mitomycin with radiotherapy in anal carcinoma. Dis Colon Rectum. 2007;50 (1):43-9.
25. Ajani JA, Winter KA, Gunderson L, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008;299:1914-21.
26. James R, Glynne-Jones R, Meadows H, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomized, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol. 2013;14:516-24.
27. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358 (1):36-46.
28. Fernández-Martos C, Nogué M, Cejas P, et al. The role of capecitabine in locally advanced rectal cancer treatment: an update. Drugs. 2012; 72(8):1057-73.
29. Twelves C, Scheithauer W, McKendrick J, et al. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012;23(5):1190-7.
30. Oliveira S, Moniz C, Riechelmann R, et al. Phase II Study of Capecitabine in Substitution of 5-FU in the Chemoradiotherapy Regimen for Patients with Localized Squamous Cell Carcinoma of the Anal Canal. J Gastrointest Cancer. 2016;47(1):75-81.
31. Glynne-Jones R, Meadows H, Wan S, et al. EXTRA--a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J Radiat Oncol Biol Phys. 2008;72(1):119-26.
32. Peixoto R, Wan D, Schellenberg D, et al. A comparison between 5-fluorouracil/mitomycin and capecitabine/mitomycin in combination with radiation for anal cancer. J Gastrointest Oncol. 2016;7(4):665-72.
33. Meulendijks D, Dewit L, Tomasoa N, et al. Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option. Br J Cancer. 2014;111(9):1726-33.
34. Dornellas A, Bonadio RC, Moraes PM, et al. Definitive chemoradiotherapy for squamous cell carcinoma of the anal canal (SCCAC) with cisplatin and capecitabine: A prospective cohort—preliminary results. J Clin Oncol. 2021;39,e15506-e15506.
35. Nilsson P, Svensson C, Goldman S, et al. Epidermoid anal cancer: a review of a population-based series of 308 consecutive patients treated according to prospective protocols. Int J Radiat Oncol Biol Phys. 2005;61(1):92-102.
36. Meropol N, Niedzwiecki D, Shank B, et al. Induction therapy for poor-prognosis anal canal carcinoma: a phase II study of the cancer and Leukemia Group B (CALGB 9281). J Clin Oncol. 2008;26(19):3229-34.
37. Peiffert D, Seitz J, Rougier P, et al. Preliminary results of a phase II study of high-dose radiation therapy and neoadjuvant plus concomitant 5-fluorouracil with CDDP chemotherapy for patients with anal canal cancer: a French cooperative study. Ann Oncol. 1997;8(6):575-81.
38. Ben-Josef E, Moughan J, Ajani J, et al. Impact of overall treatment time on survival and local control in patients with anal cancer: a pooled data analysis of Radiation Therapy Oncology Group trials 87-04 and 98-11. J Clin Oncol. 2010;28(34): 5061-6.
39. Peiffert D, Tournier-Rangeard L, Gérard J, 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. J Clin Oncol. 2012;30(16):1941-8.
40. Spithoff K, Cummings B, Jonker D, t al. Chemoradiotherapy for squamous cell cancer of the anal canal: a systematic review. Clin Oncol (R Coll Radiol). 2014;26(8):473-87.
41. Sebag-Montefiore D, Meadows H, Cunningham D, et al. Three cytotoxic drugs combined with pelvic radiation and as maintenance chemotherapy for patients with squamous cell carcinoma of the anus (SCCA): long-term follow-up of a phase II pilot study using 5-fluorouracil, mitomycin C and cisplatin. Radiother Oncol. 2012; 104(2):155-60.
42. Damme N, Deron P, Roy N, et al. Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas. BMC Cancer. 2010;10:189.
43. Garg M, Zhao F, Sparano J, et al. Cetuximab Plus Chemoradiotherapy in Immunocompetent Patients With Anal Carcinoma: A Phase II Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group Trial (E3205). J Clin Oncol. 2017;35(7):718-26.
44. Sparano J, Lee J, Palefsky J, et al. Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma: A Phase II AIDS Malignancy Consortium Trial. J Clin Oncol. 2017;35(7):727-33.
45. Feliu J, Garcia-Carbonero R, Capdevila J, et al. VITAL phase 2 study: Upfront 5-fluorouracil, mitomycin-C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09-02). Cancer Med. 2020;9(3):1008-16.
46. Shridhar R, Shibata D, Chan E, et al. Anal cancer: current standards in care and recent changes in practice. CA Cancer J Clin. 2015;65(2):139-62.
47. Chai C, Cao H, Awad S, et al. Management of Stage I Squamous Cell Carcinoma of the Anal Canal. JAMA Surg. 2018;153(3):209-15.
48. Chakrabarti S, Jin Z, Huffman B, et al. Local excision for patients with stage I anal canal squamous cell carcinoma can be curative. J Gastrointest Oncol. 2019;10(2):171-8.
49. Renehan A and O'Dwyer S. Initial management through the anal cancer multidisciplinary team meeting. Colorectal Dis. 2011;13:Suppl 1:21-8.
50. Glynne-Jones R, Nilsson P, Aschele C, et al. Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Eur J Surg Oncol. 2014;40(10):1165-76.
51. PLATO - Personalizing anal cancer radiotherapy dose. Available at:
https://www.isrctn.com/ISRCTN88455282 (Accessed on September 20, 2024).
52. Martin D, Rödel F, Balermpas P, et al. The immune microenvironment and HPV in anal cancer: Rationale to complement chemoradiation with immunotherapy. Biochim Biophys Acta Rev Cancer. 2017;1868(1):221-30.
2. Deshmukh A, Suk R, Shiels M, et al. Recent Trends in Squamous Cell Carcinoma of the Anus Incidence and Mortality in the United States, 2001-2015. J Natl Cancer Inst. 2020;112(8):829-38.
3. Donadio M and Riechelmann R. Anal canal cancer in Brazil: why should we pay more attention to the epidemiology of this rare disease? ecancer. 2020;14:1037.
4. Wei F, Alberts C, Albuquerque A, et al. Impact of Human Papillomavirus Vaccine against Anal Human Papillomavirus Infection, Anal Intraepithelial Neoplasia, and Recurrence of Anal Intraepithelial Neoplasia: A Systematic Review and Meta-Analysis. J. Infect. Dis. 2023;228:1496–504.
5. Cicero G, Ascenti G, Blandino A, et al. Magnetic Resonance Imaging of the Anal Region: Clinical Applications. J Clin Imaging Sci. 2020; 10:76.
6. Leccisotti L, Ripani D, Manfrida S, et al. Diagnostic performance and prognostic role of FDG PET/CT performed at staging in anal cancer. Clin Transl Imaging. 2020;8(2):55–64.
7. Surveillance, Epidemiology, and End Results (SEER) Program; National Cancer Institute. Cancer Stat Facts: Anal Cancer. seer.cancer.gov/statfacts/html/anus.html. (Accessed on October 31, 2024).
8. Das P, Bhatia S, Eng C, et al. Predictors and patterns of recurrence after definitive chemoradiation for anal cancer. Int J Radiat Oncol Biol Phys. 2007; 68:794-800.
9. Gunderson L, Winter K, Ajani J, 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. J Clin Oncol. 2012;30:4344–51.
10. Garris C, Arlauckas S, Kohler R, et al. Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12. Immunity. 2018; 49:1148–61.
11. Anne N Young AN, Jacob E, Willauer P, et al. Anal Cancer. Surg Clin North Am. 2020 Jun; 100(3):629-34.
12. Gondal TA, Chaudhary N, Bajwa H, et al. Anal Cancer: The Past, Present and Future. Curr Oncol. 2023;30(3):3232-50.
13. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med. 2000;342:792-800.
14. Boman BM, Moertel CG, O'Connell MJ, et al. Carcinoma of the anal canal. A clinical and pathologic study of 188 cases. Cancer. 1984;54 (1):114-25.
15. Nigro ND, Vaitkevicius VK, Considine B. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974;17(3): 354-6.
16. Leichman L, Nigro N, Vaitkevicius VK, et al. Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med. 1985;78(2):211-5.
17. Rao S, Guren MG, Khan K, et al. Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(9): 1087-100.
18. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. Available at:
https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf. (Accessed on September 07, 2024).
19. Upadhyay L, Hartzell M, Parikh AR, et al. Recent Advances in the Management of Anal Cancer. Healthcare (Basel). 2023;11(23):3010.
20. Epidermoid anal cancer: results from the UKCCCR randomized 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.
21. Northover J, Glynne-Jones R, Sebag-Montefiore D, et al. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomized UKCCCR Anal Cancer Trial (ACT I). Br J Cancer. 2010;102:1123-8.
22. Bartelink H, Roelofsen F, Eschwege F, 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;15:2040-49.
23. Flam M, John M, Pajak T, 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. J Clin Oncol. 1996; 14(9):2527-39.
24. Crehange G, Bosset M, Lorchel F, et al. Combining cisplatin and mitomycin with radiotherapy in anal carcinoma. Dis Colon Rectum. 2007;50 (1):43-9.
25. Ajani JA, Winter KA, Gunderson L, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008;299:1914-21.
26. James R, Glynne-Jones R, Meadows H, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomized, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol. 2013;14:516-24.
27. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358 (1):36-46.
28. Fernández-Martos C, Nogué M, Cejas P, et al. The role of capecitabine in locally advanced rectal cancer treatment: an update. Drugs. 2012; 72(8):1057-73.
29. Twelves C, Scheithauer W, McKendrick J, et al. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol. 2012;23(5):1190-7.
30. Oliveira S, Moniz C, Riechelmann R, et al. Phase II Study of Capecitabine in Substitution of 5-FU in the Chemoradiotherapy Regimen for Patients with Localized Squamous Cell Carcinoma of the Anal Canal. J Gastrointest Cancer. 2016;47(1):75-81.
31. Glynne-Jones R, Meadows H, Wan S, et al. EXTRA--a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J Radiat Oncol Biol Phys. 2008;72(1):119-26.
32. Peixoto R, Wan D, Schellenberg D, et al. A comparison between 5-fluorouracil/mitomycin and capecitabine/mitomycin in combination with radiation for anal cancer. J Gastrointest Oncol. 2016;7(4):665-72.
33. Meulendijks D, Dewit L, Tomasoa N, et al. Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option. Br J Cancer. 2014;111(9):1726-33.
34. Dornellas A, Bonadio RC, Moraes PM, et al. Definitive chemoradiotherapy for squamous cell carcinoma of the anal canal (SCCAC) with cisplatin and capecitabine: A prospective cohort—preliminary results. J Clin Oncol. 2021;39,e15506-e15506.
35. Nilsson P, Svensson C, Goldman S, et al. Epidermoid anal cancer: a review of a population-based series of 308 consecutive patients treated according to prospective protocols. Int J Radiat Oncol Biol Phys. 2005;61(1):92-102.
36. Meropol N, Niedzwiecki D, Shank B, et al. Induction therapy for poor-prognosis anal canal carcinoma: a phase II study of the cancer and Leukemia Group B (CALGB 9281). J Clin Oncol. 2008;26(19):3229-34.
37. Peiffert D, Seitz J, Rougier P, et al. Preliminary results of a phase II study of high-dose radiation therapy and neoadjuvant plus concomitant 5-fluorouracil with CDDP chemotherapy for patients with anal canal cancer: a French cooperative study. Ann Oncol. 1997;8(6):575-81.
38. Ben-Josef E, Moughan J, Ajani J, et al. Impact of overall treatment time on survival and local control in patients with anal cancer: a pooled data analysis of Radiation Therapy Oncology Group trials 87-04 and 98-11. J Clin Oncol. 2010;28(34): 5061-6.
39. Peiffert D, Tournier-Rangeard L, Gérard J, 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. J Clin Oncol. 2012;30(16):1941-8.
40. Spithoff K, Cummings B, Jonker D, t al. Chemoradiotherapy for squamous cell cancer of the anal canal: a systematic review. Clin Oncol (R Coll Radiol). 2014;26(8):473-87.
41. Sebag-Montefiore D, Meadows H, Cunningham D, et al. Three cytotoxic drugs combined with pelvic radiation and as maintenance chemotherapy for patients with squamous cell carcinoma of the anus (SCCA): long-term follow-up of a phase II pilot study using 5-fluorouracil, mitomycin C and cisplatin. Radiother Oncol. 2012; 104(2):155-60.
42. Damme N, Deron P, Roy N, et al. Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas. BMC Cancer. 2010;10:189.
43. Garg M, Zhao F, Sparano J, et al. Cetuximab Plus Chemoradiotherapy in Immunocompetent Patients With Anal Carcinoma: A Phase II Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group Trial (E3205). J Clin Oncol. 2017;35(7):718-26.
44. Sparano J, Lee J, Palefsky J, et al. Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma: A Phase II AIDS Malignancy Consortium Trial. J Clin Oncol. 2017;35(7):727-33.
45. Feliu J, Garcia-Carbonero R, Capdevila J, et al. VITAL phase 2 study: Upfront 5-fluorouracil, mitomycin-C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09-02). Cancer Med. 2020;9(3):1008-16.
46. Shridhar R, Shibata D, Chan E, et al. Anal cancer: current standards in care and recent changes in practice. CA Cancer J Clin. 2015;65(2):139-62.
47. Chai C, Cao H, Awad S, et al. Management of Stage I Squamous Cell Carcinoma of the Anal Canal. JAMA Surg. 2018;153(3):209-15.
48. Chakrabarti S, Jin Z, Huffman B, et al. Local excision for patients with stage I anal canal squamous cell carcinoma can be curative. J Gastrointest Oncol. 2019;10(2):171-8.
49. Renehan A and O'Dwyer S. Initial management through the anal cancer multidisciplinary team meeting. Colorectal Dis. 2011;13:Suppl 1:21-8.
50. Glynne-Jones R, Nilsson P, Aschele C, et al. Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Eur J Surg Oncol. 2014;40(10):1165-76.
51. PLATO - Personalizing anal cancer radiotherapy dose. Available at:
https://www.isrctn.com/ISRCTN88455282 (Accessed on September 20, 2024).
52. Martin D, Rödel F, Balermpas P, et al. The immune microenvironment and HPV in anal cancer: Rationale to complement chemoradiation with immunotherapy. Biochim Biophys Acta Rev Cancer. 2017;1868(1):221-30.