In this study results of our single institution retrospective analysis of 98 consecutively treated patient with SCCA treated in 10 years’ time are described.
The reported 3-and 5 year OS of 78.6% and 71.4% are comparable to that reported in both randomized and other retrospective studies (5, 6, 17, 18). The ACT I trial reported a 3-year OS of 65% in their CRT group consisting of 292 patients clinically staged as T2N0 or higher (17). In the Accord 03, a 5-year OS of 71% - 74.5% was reported in 307 patients with tumors > 4 cm and/or N+ disease treated with CRT (18). The Montpellier study found a 5-year OS of 74% in 193 patients treated with CRT, and Mitra et al. reported a 4-year OS of 85.8% in 99 patients in all disease stages, treated with CRT (5, 6). The relatively low OS in the ACT I may be attributed to the inclusion of only more advanced stages of disease as well as stage migration over the years (inclusion ended in 1994, MRI and PET CT scans were not widely available at that time). The 4-year OS reported by Mitra et al. is higher than the 3-year OS reported in our study. Although the study populations, treatment period, median age, disease stage distributions are all comparable, this difference might be attributable to chance and limited numbers.
Our reported DFS of 79.6% and LRC of 81.6% at 3 and 5-years compares favorably to the 3-year DFS of the ACT I of 61% and the 5-year DFS of the Montpellier study of 68% (5, 17). This is likely attributable to inclusion of higher stages and lack of imaging in the ACT I study. The Accord 03 reported an overall relapse free rate of 71.4% and a LRC of 72% - 87.6% (18). Mitra et al. reported 83.5% patients were disease-free at the end of follow-up (6). As with OS however we must again consider that the ACT I trial included more advanced disease stages, and is relatively old, likely attributing to a worse DFS. Compared to the Accord 03, the Montpellier study, and Mitra et al. our DFS is better. The Accord 03 included more advanced disease stages which might negatively affect DFS and LRC and it excluded patients with comorbidities and aged 80+ which should have positively affected outcomes. In the present series 90% of relapses occurred within the first 24 months with the latest relapse at 30 months after treatment. Currently, patients receive a standard of 5-years of follow-up. Considering that in 10 years of curative anal carcinoma treatment all relapses have occurred within three years perhaps a shorter follow-up length is to be discussed with patients (19, 20).
CFS in our study was as high as 81.6%. Of the 18 patients with a colostomy 11 were operated as salvage surgery for relapsed disease. these results are like those reported in the other studies. Where the ACT I reported a CFS of 76.4% in their CRT group, the Accord 03 reported CFS of 69.6% - 82.4%, the Montpellier study reported 66% CFS, and Mitra et al. reported the highest CFS at 85% (5, 6, 17, 18). In the ACT I patients only received elective RT and were evaluated after 6 weeks, those with <50% tumor response were considered for salvage. This practice most likely attributed to a higher rate of colostomies.
Concerns were raised when the RT technique was changed from 3D to more conformal IMRT and VMAT techniques regarding potential regional misses and increased numbers of recurrences. Analyzing the time trend however did not show any significant differences in DFS in our study (78% vs 81% before and after 2014), further supporting that technique does not affect the primary outcome. Changing the technique from 3D to IMRT/VMAT caused an increase in early reported grade 3 diarrhea and grade 2 urgency. Part of the increase in diarrhea may be attributable to the change from iv 5-FU week 1 and five to oral capecitabine twice daily for the whole treatment period. Severe late incontinence grade 3 dropped from 5.6 to 1.6% with an increase in reported incontinence grade 1-2 from 27.8–56.5%. The increase in reported toxicity both early and late is likely also attributable to changes in reporting practices in our clinic, with the advent of the electronic patient file in 2011 and the addition of required toxicity forms since the start of 2018. The decrease in severe toxic effects was the expected effect of switching to IMRT techniques (8, 10, 11).
A significant portion (23%) of our patients were aged 75 and over. Tumor stage did not significantly differ from the under 75 group. Since metastatic disease occurs relatively late in the disease course and the primary tumor can give considerable complaints adequate local treatment is warranted, also in older patients. Due to older patients frequently being excluded from studies, results and outcomes within the geriatric population are often not as clear. For this reason, we analyzed the OS and LRC between patients aged 75 years and older, and those younger than 75.The portion of older patients in our study (23%) is comparable to the portion of older patients with the diagnosis of anal cancer in the Netherlands which is reported to be 28.5% in 2020 (1). This suggests that older patients are indeed also referred for treatment. Only one patient refused the chemotherapy part of the treatment and frequently MMC was omitted. Older patients had a 5 year OS of 60.8% compared to 74.6% in younger patients, however this was not statistically significant, nor was there a significant difference in LRC. Although a lack of significant difference in OS is unexpected (21), this outcome is most probably due to a to small sample size.
Our study has several limitations. It is a single center retrospective analysis and included patients treated with CRT and with radiotherapy alone. Also the necessity to interpret patient-doctor communication to a toxicity grade is a limitation although reporting in the patient files was quite elaborate. Although radiation techniques changed over time the dose prescribed remained the same. All patients were treated by a team of 2 radiation oncologists and 1 medical oncologist with their residents guarantying consistent treatment choices, techniques and reporting of toxicities.
Whether or not intensification of treatment is useful to improve outcomes remains to be investigated. The Accord 03 study demonstrated that intensifying treatment with either induction chemotherapy or a higher radiotherapy dose did not further improve outcomes (18) whereas the Mitra et al. study reported outcomes comparable, if not marginally better, than our findings but did so with a lower radiotherapy dose (6). Further studies to address find the optimum dose of radiotherapy to balance disease outcome with toxicity are warranted (10, 22). Results from the ongoing PersonaLising Anal cancer radioTherapy dOse trial (PLATO), incorporating the ACT3, ACT4 and ACT5 trials are eagerly awaited.