International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationToxicity, Tolerability, and Compliance of Concurrent Capecitabine or 5-Fluorouracil in Radical Management of Anal Cancer With Single-dose Mitomycin-C and Intensity Modulated Radiation Therapy: Evaluation of a National Cohort
Introduction
Carcinoma of the anus is a rare cancer, accounting for 2.5% of all digestive malignancies 1, 2. It is increasing in frequency across the developed world and is strongly associated with oncogenic subtypes of human papillomavirus 2, 3. The vast majority of cases are anal squamous cell carcinoma (ASCC), and most patients present with a localized stage, with or without regional lymph node involvement. Treatment is directed toward achieving cure and effective local control and avoiding the requirement for a colostomy (4). Chemoradiation therapy (CRT) forms the international standard of care, achieving a 3-year local control rate of 65% to 74% (5).
Concurrent CRT with mitomycin-C (MMC) and 5-fluorouracil (5-FU) is well established as superior to radiation therapy (RT) alone or RT combined with 5-FU for ASCC 6, 7, 8. Efforts to improve outcomes, including the substitution of MMC with cisplatin and the introduction of neoadjuvant or adjuvant chemotherapy regimens, have not changed this standard of care 9, 10, 11, 12. However, no international consensus has been reached on the optimal dosing of MMC, with 2 doses administered to patients in both RTOG (Radiation Therapy Oncology Group) 8704 and RTOG 9811, in contrast to a single dose used in the ACT (anal cancer trial) I, ACT II, and EORTC (European Organization for Research and Treatment of Cancer) trials (Table E1; available online at www.redjournal.org).
Capecitabine is a tumor-activated fluoropyrimidine derivative, administered orally as a twice-daily tablet. It provides a convenient alternative to 5-FU, which requires continuous infusion and central venous access. In colorectal cancer, capecitabine is noninferior with respect to efficacy and has a comparable toxicity profile to 5-FU in both the adjuvant setting and as part of concurrent CRT 13, 14, 15, 16. With respect to anal cancer, the National Comprehensive Cancer Network, European Society for Medical Oncology, European Society of Surgical Oncology, European Society for Radiotherapy and Oncology, French Intergroup, and recent UK intensity modulated radiation therapy (IMRT) guidelines support the use of capecitabine as an alternative option to 5-FU in radical CRT 17, 18, 19, 20. However, the current evidence for capecitabine to treat ASCC has been derived from single-center studies and a number of relatively small phase II trials 21, 22, 23. Treatment parameters also varied widely across these studies, with significant variation in the use of 3-dimensional (3D)-RT or IMRT, the radiation dose, and the target volume 24, 25, 26, 27.
Within the United Kingdom, national guidance provides a framework for the standardization of IMRT delivery in the treatment of anal cancer (28). A nationwide audit was undertaken to assess the implementation of IMRT for ASCC within the UK National Health Service, including the prospective collection of toxicity and outcomes (29). We present the comparative toxicity and early outcomes data for patients treated with standardized IMRT and either capecitabine/MMC or 5-FU/MMC.
Section snippets
Setting
With the support of the Royal College of Radiologists (RCR), we sought to detail the current treatment of patients with a diagnosis of anal cancer with respect to national guidance. All 56 centers involved in the delivery of RT within the United Kingdom were approached and asked to include every patient with confirmed anal cancer treated during a 6-month period extending from February 9 to July 27, 2015. Data were obtained from 40 centers (71%).
Population and treatment
UK IMRT guidance (19) was designed in 2013,
Patient and tumor characteristics
Of the 242 cases submitted, 180 had received IMRT. Of these, 157 were treated in accordance with the UK consensus document. Ten patients were excluded from the present analysis. Of these 10 patients, 1 had confirmed anal adenocarcinoma, 4 had not received chemotherapy, and 5 had received a drug combination consisting of cisplatin alone (n = 1) or in combination with etoposide (n = 2) or 5-FU (n = 2). Figure 1 provides an overview of the process for participant selection. Of the 147 included
Discussion
A paucity of data is available relating to the toxicity of capecitabine when used as a component of CRT for anal cancer. We have presented the toxicity and tolerability data from a national cohort of patients with ASCC managed in accordance with the UK guidance using IMRT and single-dose MMC with either 5-FU or capecitabine. No treatment-related deaths occurred, and no significant difference was found between the 2 cohorts in median treatment duration, rates of complete response at 6 months, or
Conclusions
Data from the present national multicenter cohort using a standardized IMRT technique showed similar levels of grade 3/4 toxicity overall between 5-FU and capecitabine combined with MMC as CRT for ASCC. However, differences were seen in the patterns of observed hematologic and nonhematologic toxicities. Although the toxicity of CRT with MMC/5-FU has been well characterized, further studies of MMC/capecitabine are required to understand the acute toxicity profile when used with IMRT. The early
Acknowledgments
The authors are grateful to the Royal College of Radiologists (RCR), including the RCR Clinical Oncology Quality Improvement and Audit Committee, for facilitating the audit on which our report was based, and in particular, Karl Drinkwater for his support with the audit and its analysis. We are in addition grateful to colleagues based at the following centres and institutions across the United Kingdom who submitted data: Aberdeen Royal Infirmary; Beatson West of Scotland Cancer Centre, Glasgow;
References (44)
- et al.
High-sensitivity human papilloma virus genotyping reveals near universal positivity in anal squamous cell carcinoma: Different implications for vaccine prevention and prognosis
Eur J Cancer
(2015) - et al.
Chemoradiotherapy for squamous cell cancer of the anal canal: A systematic review
Clin Oncol (R Coll Radiol)
(2014) - 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 2x2 factorial trial
Lancet Oncol
(2013) - et al.
Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: A randomised, multicentre, non-inferiority, phase 3 trial
Lancet Oncol
(2012) - et al.
Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2014) - et al.
Anal cancer: French Intergroup Clinical Practice Guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SNFCP)
Dig Liver Dis
(2017) - 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) - et al.
Capecitabine with mitomycin reduces acute hematologic toxicity and treatment delays in patients undergoing definitive chemoradiation using intensity modulated radiation therapy for anal cancer
Int J Radiat Oncol Biol Phys
(2017) - et al.
Anal cancer: Developing an intensity-modulated radiotherapy solution for ACT2 fractionation
Clin Oncol (R Coll Radiol)
(2014) - et al.
Initial results from the Royal College of Radiologists' UK national audit of anal cacner radiotherapy 2015.
Clin Oncol
(2017)
Elective clinical target volumes for conformal therapy in anorectal cancer: An RTOG consensus panel contouring atlas
Int J Radiat Oncol Biol Phys
Normal tissue complication probability modelling of acute hematologic toxicity in patients treated with intensity-modulated radiation therapy for squamous cell carcinoma of the anal canal
Int J Radiat Oncol Biol Phys
Association between bone marrow dosimetric parameters and acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy
Int J Radiat Oncol Biol Phys
Modeling early haematologic adverse events in conformal and intensity-modulated pelvic radiotherapy in anal cancer
Radiother Oncol
The development of an umbrella trial (PLATO) to address radiation therapy dose questions in the locoregional management of squamous cell carcinoma of the anus
Int J Radiat Oncol Biol Phys
Cancer statistics, 2013
CA Cancer J Clin
The rising incidence of anal cancer in England 1990-2010: A population-based study
Colorectal Dis
Impaired health-related quality of life after chemoradiotherapy for anal cancer: Late effects in a national cohort of 128 survivors
Acta Oncol
Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil and mitomycin
Lancet
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
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
Mitomycin in anal cancer: Still the standard of care
J Clin Oncol
Cited by (37)
Chemoradiation for muscle-invasive bladder cancer using 5-fluorouracil versus capecitabine: A nationwide cohort study
2023, Radiotherapy and OncologyTreatment, outcome, and prognostic factors in non-metastatic anal cancer: The French nationwide cohort study FFCD-ANABASE
2023, Radiotherapy and OncologyCompliance to chemoradiation in squamous cell carcinoma of the anus
2022, Cancer Treatment Reviews
D.C.G. and R.M. contributed equally (joint senior authors).
C. Jones was funded for the duration of this work by a National Institute for Health Research Academic Clinical Fellowship in Clinical Oncology and a Wellcome Trust N4 Clinical Research Fellowship (grant 203914/Z/16/Z) held by the Universities of Leeds, Manchester, Newcastle, and Sheffield. M. Hawkins is supported by the Medical Research Council (grant MC_UU_00001/2).
Conflict of interest: R. Glynne-Jones has received grants from Roche and Merck Serono, in addition to personal fees from Roche, Amgen, Servier, Sanofi, Merck Serono, Eli Lilly, Home Nutrition, Eisai, Mundipharma, and Bristol-Myers Squibb. M. Hawkins has received personal fees from Genesis Care CPUK, Sirtex, and Eli Lilly.