The first UKCCCR Anal Cancer Trial (1996) demonstrated the benefit of chemoradiation over radiotherapy (RT) alone for treating epidermoid anal cancer, and it became the standard treatment. Patients in this trial have now been followed up for a median of 13 years. A total of 577 patients were randomised to receive RT alone or combined modality therapy using 5-fluorouracil and mitomycin C. All patients were scheduled to receive 45 Gy by external beam irradiation. Patients who responded to treatment were recommended to have boost RT, with either an iridium implant or external beam irradiation. Data on relapse and deaths were obtained until October 2007. Twelve years after treatment, for every 100 patients treated with chemoradiation, there are an expected 25.3 fewer patients with locoregional relapse (95% confidence interval (CI): 17.5–32.0 fewer) and 12.5 fewer anal cancer deaths (95% CI: 4.3–19.7 fewer), compared with 100 patients given RT alone. There was a 9.1% increase in non-anal cancer deaths in the first 5 years of chemoradiation (95% CI +3.6 to +14.6), which disappeared by 10 years. The clear benefit of chemoradiation outweighs an early excess risk of non-anal cancer deaths, and can still be seen 12 years after treatment. Only 11 patients suffered a locoregional relapse as a first event after 5 years, which may influence the choice of end points in future studies.

14085 Background: Phase III trials have shown RT + 5-Fluorouracil (5-FU) + mitomycinC (MMC) as the standard treatment for patients with epidermoid anal carcinoma. The objective of this trial is to determine if capecitabine in combination with MMC has a similar outcome in terms of complete response (CR) rate and toxicity to a 5-day infusion of 5-FU. Capecitabine is a rational alternative to 5-FU as these cancers express high levels of thymidine phosphoralase. Methods: Main eligibility criteria are histologically proven anal carcinoma (epidermoid, squamous, basaloid), fit to receive capecitabine and MMC and ineligible for the ongoing phase III UK trial, ACT II. Exclusion criteria include complete local excision, prior chemoradiation, uncontrolled cardiovascular disease and known HIV+ve. All patients receive: 50.4Gy in 28F(RT) and capecitabine 1650mg/m2/day on each RT treatment day (M-F) over 6 weeks. In addition patients receive MMC 12mg/m2, day 1 only. Assessment of response is by CT scan at 4 wks post chemoradiation. Results: To date 18/30 patients have been registered. Pre-treatment characteristics are: median age 59 yrs (44–85); 7 male, 11 female; 13 Canal, 5 Margin; 5T1, 4T2, 6T3, 2T4, 1Tx; 4N+ve, 13N-ve, 1Nx. Data on 14 evaluable pts are presented here. RT compliance: 12 pts completed planned treatment, treatment was interrupted in 2 cases (chest pain 1; machine breakdown 1). Chemotherapy compliance: 10 pts completed protocol treatment, in 3 pts chemotherapy was affected due to toxicity (1 dose reduced, 2 stopped early 1 due to chest pain and 1 due to grade 3 skin and diarrhoea). One patient decided to stop treatment. Grade 3 toxicity was reported in 2 pts during treatment: dyspnoea 1, diarrhoea 1. Four weeks post chemoradition, 10 had CR, 3 had partial response and 1 pt was not assessable. Thirteen pts are alive and disease free at a median follow-up of 6 months (range 1 -13). One pt has relapsed in an inguinal node 9 months after the end of treatment following a previous CR. Conclusions: This early information suggests that this regimen can be given without interruption and with acceptable toxicity. The early response data is encouraging and the trial aims to reach target accrual by Summer 2006. Educational grant provided by Roche pharmaceuticals. [Table: see text]

In the late 1980s, the treatment of primary anal cancer in the UK moved away from surgical treatment to non-surgical treatment. This was partly due to the first UK trial in the disease [1The UKCCCR Anal Cancer Trial Working Party Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil and mitomycin C.Lancet. 1996; 348: 1049-1054Abstract Full Text Full Text PDF PubMed Scopus (720) Google Scholar], now known as ACT I. By the early 1990s, the results of the UK trial and separate trials run by the European Organisation for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) were available [2Bartelink H. Roelofson 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 randomised trial of the European organisation for research and treatment of cancer radiotherapy and gastrointestinal groups.J Clin Oncol. 1997; 15: 2040-2049Crossref PubMed Scopus (1006) Google Scholar, 3Flam M. John M. Pajak T.F. et al.Role of mitomycin in combination with fluorouracil and radiation and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomised intergroup study.J Clin Oncol. 1996; 14: 2527-2539Crossref PubMed Scopus (853) Google Scholar]. ACT I was the largest of the three trials and, like the EORTC trial, compared radiotherapy with the same radiotherapy plus 5-fluorouracil (5-FU) and mitomycin C (MMC) during the first and final week of the first radiotherapy course. The trial established chemoradiation as the treatment of choice for most patients with the disease. Subsequently, similar trials in other squamous cell carcinomas showed improved survival for patients receiving both treatment modalities synchronously. After these trials had closed, several pilot studies were conducted with the aim of testing alternative schedules with dose escalation of alternative schedules and dose escalation of either the chemotherapy or radiotherapy in order to improve prognosis. Currently, we know of six open trials in anal cancer (Table 1), each exploring a series of questions. Three trials combine 5-FU/cisplatin (CDDP) with radiotherapy, which is an effective schedule for relapsed anal cancer, and is commonly used in combination with radiotherapy for other squamous cell cancers (cervix, head and neck and oesophagus). The Fondation Française de Cancérologie Digestive (FFCD) trial randomises patients between a high-dose or low-dose radiotherapy boost. The FFCD and RTOG 9811 trials randomise patients to two courses of neoadjuvant 5-FU/CDDP before chemoradiation. The EORTC trial compares 5-FU/MMC with CDDP/MMC, and follows on from their phase II study of low-dose infusional 5-FU. All three non-UK trials include split-course radiotherapy.Table 1Ongoing trials in anal cancerTrial namePhaseRandomisation armsRadiotherapyTarget accrualDate openedRTOG-9811III5-FU+MMC+RT45 Gy in 25 fractions650October 19985-FU+CDDP alone then 5-FU+CDDP+RT10–14 Gy for T3–4 N+FFCD ACCORD-3III5-FU+CDDP alone then 5-FU+CDDP+RT then low-dose RTConcurrent 45 Gy in 25 fractions then either350October 19985-FU+CDDP alone then 5-FU+CDDP+RT then high-dose RTLow-dose 15 Gy in 8 fractions or5-FU+CDDP+RT then low-dose RT5-FU+CDDP+RT then high-dose RTHigh-dose 20–5 Gy in 11–14 fractionsACT-IIIII5-FU+MMC+RT50.4 Gy in 28 fractions600June 20015-FU+MMC+RT+maintenancePhase I=30.6 Gy in 17 fractions5-FU+CDDP+RTPhase II=19.8 Gy in 11 fractions5-FU+CDDP+RT+maintenanceEORTC-22011III5-FU+MMC+RT (2 week gap) then 5-FU+MMC+RT36 Gy in 20 fractions (2 week gap) 23.4 Gy in 13 fractions678July 2003CDDP+MMC+RT (2 week gap) then CDDP+MMC+RTEXTRAIICapecitabine+mitomycin+RT50.4 Gy in 28 fractions30June 2004Phase I=30.6 Gy 17 in fractionsPhase II=19.8 Gy in 11 fractionsMDA-2003-0874IICapecitabine+oxaliplatin+RTTX,T1=45 Gy in 25 fractions60September 2004T2=55 Gy in 30 fractionsT3–4=59 Gy in 32 fractionsCDDP, cisplatin; 5-FU, 5-fluorouracil; MMC, mitomycin C; RT, radiotherapy. Open table in a new tab CDDP, cisplatin; 5-FU, 5-fluorouracil; MMC, mitomycin C; RT, radiotherapy. When designing the second UK trial (ACT II) (Fig. 1), a primary aim was to avoid the 6-week radiotherapy gap in the previous trial, to reflect UK practice. Two centres piloted a continuous schedule of 50.4 Gy in 28 fractions, with either 5-FU/MMC or 5-FU/CDDP [4Melcher A. Brammer C. Sebag-Montefiore D. Radical chemoradiation for squamous cell carcinoma of the anus using a two phase technique with no boost.Br J Cancer. 2001; 85: 103Google Scholar, 5Osborne M. Glynne-Jones R. Makris A. Chemoradiation followed by immediate boost in squamous call carcinoma of the anus.Br J Cancer. 2000; 83: 46Google Scholar], and demonstrated its feasibility with no excess skin toxicity or loss in disease control. This schedule was adopted as the radiotherapy schedule in ACT II. A pilot study of 5-FU/MMC and CDDP with radiotherapy resulted in unacceptable toxicity [6James R.D. Cunningham D. Davidson N. et al.Chemoradiation and maintenance chemotherapy for patients with anal carcinoma: a phase II trial of the UK coordinating committee for cancer research (UKCCCR) anal cancer working party.Proceedings of ASCO. 2000; 19 ([abstract 1045])Google Scholar], and we concluded that the chemoradiotherapy schedule was close to the limit of dose intensity. 5-FU/CDDP was therefore chosen for the comparator arm. MMC and CDDP are known to be radiosensitisers, and therefore a difference in long-term outcome is not expected. However, the complete response rate and toxicity profile may differ, and these are the main outcome measures for this comparison. The question of how to prolong chemotherapy remained. Although neoadjuvant chemotherapy was an attractive option, the concern of the ACT II Trial Management Group was that the associated toxicity might interfere with delivery of the full chemoradiation schedule. For this reason, patients are randomised to additional courses of chemotherapy after chemoradiation. The ACT II pilot study indicated that few patients would be able to complete three courses of maintenance chemotherapy, and hence only two courses are recommended. Irrespective of the drug combination given during chemoradiation, 5-FU and CDDP are given as maintenance. In the ACT II, pilot inclusion of MMC as part of the maintenance schedule led to an unacceptable rate of grade 4 toxicity. As in ACT I, the trial has been well supported by UK clinicians; at the end of 2004, 380 patients had been treated from 49 UK radiotherapy centres. The ACT II Trial began recruitment in June 2001, and is on target to recruit 600 patients by July 2006. Accrual is especially encouraging considering the rarity of the disease. Analysis on early data from the trial was highly encouraging, and showed that both the chemoradiation regimen and maintenance chemotherapy could be given without interruption and had acceptable toxicity [7James R. Meadows H. for the NCRI Anal Cancer Trials Management Group The second UK phase III anal cancer trial of chemoradiation and maintenance therapy (ACT II): preliminary results on toxicity and outcome.Proceedings of ASCO. 2003; 22 ([abstract 1151])Google Scholar]. Despite advances in the treatment of anal cancer over the past two decades, important questions still remain. The Trial Management Group are aware that the entry criteria for ACT II is more stringent than for ACT I, and elderly and frail patients are being excluded. Treatment options for this group of patients are limited, and other studies are needed for these patients. Evaluation of Xeloda Treatment with Radiotherapy in Anal cancer (EXTRA), a phase II NCRN adopted trial, which started in June 2004, combines capecitabine, MMC and the ACT II radiotherapy schedule. It is hoped that the completely oral schedule will reduce hospitalisation and be simpler for patients, particularly for elderly people. The trial recruits patients unsuitable for ACT II; reasons for ineligibility include patient frailty and unsuitability for CDDP (e.g. low GFR, impaired hearing). This group of patients might be adequately treated with a reduced radiation dose; data on 16 patients treated with 30 Gy demonstrated that this is a well tolerated regimen for elderly or poor performance patients with achievable high rates of local control and survival. Longer follow-up will determine whether these encouraging results can be maintained [8Charnley N. Choudhury A. Chesser P. Cooper R.A. Sebag-Montefiore D. Effective treatment of anal cancer in the elderly with low dose chemoradiotherapy.Br J Cancer. 2005; 92: 1221-1225Crossref PubMed Scopus (37) Google Scholar]. The treatment of patients having relapsed from chemoradiation is also a challenge. Not all patients are suitable for surgery, although there have been improvements in surgical technique for those that are operable. For inoperable patients having had 5-FU/CDDP, there are no data on suitable alternative treatment schedules. This lack of data has prompted the NCRI anal cancer sub-group to develop a phase II trial protocol called Scene 1, which uses a completely oral chemotherapy combination of capecitabine and vinorelbine. If effective, this combination could be taken further as first-line therapy. Ongoing work analysing samples from 240 patients entered into ACT I includes immunohistochemical analysis. This was conducted to analyse expression of p53, bcl2, ki67, thymidylate synthase and thymidine phosphorylase. These studies will provide information on biological markers important for prognosis and response in this disease [9Mawdsley S. Anal Cancer Trial Management Group Meadows H. James R. The role of biological molecular markers in predicting both response to treatment and clinical outcome in squamous cell carcinoma of the anus.ASCO. 2004; ([abstract 183])Google Scholar]. Future plans are to continue and expand this work on samples from ACT II. Preliminary discussions on the design of ACT III have begun. It is possible that the field arrangement and field size will be refined to improve the radiotherapy schedule. A number of chemotherapy drugs are of interest, such as capecitabine, oxaliplatin and vinorelbine, as well as some very promising targeted agents, such as cetuximab and avastin. It is encouraging to see the increase in research activity in this disease since the 1980s, and we await the results of the ongoing trials with interest. The ultimate aim is that patients at all stages are offered a regimen that provides the prospect of long-term tumour control and survival.