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Treatment results for patients with squamous-cell carcinoma of the anus, a single institution retrospective analysis

Treatment results for patients with squamous-cell carcinoma of the anus, a single institution... Background and purpose: To gain insight into the treatment outcomes for anal cancer a retrospective analysis was performed with a special emphasis on trends in outcome and toxicities over time and on treatment of elderly patients. Materials and methods: Medical records of 98 consecutive patients with squamous cell carcinoma of the anus of all stages treated with curative intent between 01-01-2009 and 31-12-2018 were analyzed with follow up until 31-12- 2020. Standard tumor and pathological lymph node dose were 59.4 Gy (median 59.4 Gy, range 59.4–70 Gy) or 60 Gy (no deviation from intended dose), elective nodal regions were treated with 45 Gy (no deviations). Radiotherapy techniques in this period evolved from 3D-conformal to IMRT and VMAT. In 23 patients electron beams were used. Results: Median age was 63 years (range 41–88), the majority of patients were female (60%). Twenty three patients were > 75 years old. The TNM stages were I, II, IIIA, and IIIB in 18%, 40%, 15% and 27%, 58% of patients had N0 status. Concurrent mitomycin C and 5-fluoruracil-based chemotherapy was given in 63 patients (64%). Five-year overall survival (OS), disease free survival (DFS), locoregional control (LRC) and colostomy free survival (CFS) were 71%, 80%, 82%, and 82% for the whole group. Results in patients > 75 years of age were not statistically different from those in younger patients. With the introduction of more conformal techniques DFS did not change and toxicities decreased. Conclusion: Real word treatment outcomes per disease stage were in line with what is reported in literature. Older patients should also be offered treatment with curative intent. Keywords: Anal carcinoma, Retrospective, Chemoradiotherapy, Treatment results Introduction and 5-fluorouracil (5-FU)-based, is given to patients with Squamous-cell carcinoma of the anus (SCCA) is one of SCCA at higher stages (larger T2 disease and/or N +) the rarer forms of cancer of the digestive tract, with only [2–5]. This results in 5  year overall survival rates rang - 330 new cases in the Netherlands in 2020, an incidence ing from 60 to 85 percent and local control rates of 61–83 rate of 1.9 per 100.000 people [1]. Sphincter sparing percent in both prospective studies and retrospective treatment consists of radiotherapy alone in early-stage analyses [1, 2, 6, 7]. Acute and long term toxicities are disease (T1N0 and small T2N0) and radiotherapy with common but reported to be lower with modern radio- concurrent chemotherapy, typically mitomycin C (MMC) therapy techniques VMAT/IMRT versus conventional 3D techniques, thereby also reducing the necessity for therapy breaks [8–12]. In case of residual or recurrent *Correspondence: k.j.neelis@lumc.nl 1 disease an abdominoperineal resection (APR) may be Department of Radiotherapy, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands used as salvage treatment in the absence of distant metas- Full list of author information is available at the end of the article tases [7]. Because of the rarity of the disease randomized © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Neelis et al. Radiation Oncology (2022) 17:81 Page 2 of 9 trials are difficult to perform. Older patients are fre - on the tumor and elective nodal regions followed by a quently excluded in clinical trials but represent up to 25% boost on the macroscopic disease, 8 fractions of 1.8  Gy of the anal cancer patient population. To gain insight into to a total dose of 59.4  Gy. In most patients this was the our institutional results in all age groups and to evaluate given dose, six patients were treated with higher doses trends in outcome and toxicities over time where both ranging from 62.2 to 70  Gy. Initially the technique used radiotherapy techniques and chemotherapy regimens was 3D conformal radiotherapy (3D), which in 2014 was changed a retrospective analysis was performed. replaced for IMRT, which further amended to VMAT medio 2016. No treatment gaps were used throughout Materials and methods the time period. Patients and work up Medical records from consecutively treated patients Chemotherapy treated between 1-1-2009 and 31-12-2018 at our insti- Concurrent chemoradiotherapy consisted of MMC tution were collected with follow up as recorded until and 5-FU-based chemotherapy. 5-FU has been given 31-12-2020. Our institution is a regional center for treat- as 1000  mg/m on days 1–4 and 29–32 of radiotherapy. ment of anal cancer patients. Those treated with pal - MMC has been given 10 mg/m on day 1 and 29 [14]. In liative intent or those who had histologically proven case of advanced age and/or severe comorbidity MMC adenocarcinoma were excluded (n = 1 and n = 5 respec- was not given. From 2017 onwards capecitabine was tively). Staging was done using Magnetic Resonance given instead of 5-FU, twice daily at 825  mg/m , start- Imaging (MRI) in 87% of cases, Computed Tomography ing day 1 and to continue until day 33 on radiation days (CT) in 55%, Positron Emission Tomography (PET) in only. From that time onward MMC was only given on 22%, conventional chest X-ray in 34%, and/or on indi- day one at a dose of 12  mg/m . Severe toxicity of 5-FU cation an ultrasound of the inguinal region in 50% with is often the result of deficient function of dihydropyrimi - cytology if possible. Histological biopsies were assessed dine dehydrogenase caused by genetic polymorphisms in and graded by the pathology departments of the referring DPYD. Therefore from May 2013 pre-emptive screening medical centers. Disease staging was done following the for DPYD genotype variants and dose reductions of 5-FU American Joint Committee on Cancer 7th edition [13]. In based chemotherapy in heterozygous DPYD variant allele case of debilitating incontinence, in three patients a tem- carriers is standard of care [15, 16]. porary colostomy was given prior to start of treatment to reinstall continence and increase the possibility of suc- Follow‑up ceeding the chemoradiotherapy treatment. The protocol During treatment patients were seen weekly by the radia- for this study was approved by Medical Ethics Commit- tion oncologist and nurses to document and treat acute tee of the Leiden University Medical Center (number toxicity. In the first-year of follow-up patients were seen G20.026). frequently until recovery of acute side effects and to evaluate response to treatment, usually at 6 weeks. Then Radiotherapy every subsequent 2  months for the remainder of year Twenty six patients with superficial T1-T2 disease < 4 cm one. In the second-year follow-up visits were scheduled limited to the peri-anal region or anal canal and N0 sta- every 3 months, in the third-year every 4 months, and for tus received only radiotherapy at 60 Gy in 30 fractions of the fourth and fifth year every 6 months. No further fol - 2  Gy, usually with a direct electron beam. CTV margin low-up was scheduled after 5 years. Imaging with MRI to around the tumor was 1  cm, in these patient no elective document treatment response was routinely performed nodal regions were treated, given dose was the prescribed 3 months after completion of radiotherapy. In case of an dose in all patients. This is a conservative approach with inconclusive result (a near complete but not total remis- limited data to support this practice [5] but with a long sion, expected to resolve in time) imaging was repeated history in our institution with good results. Patients with 8 to 10  weeks later. Further imaging with MRI, PET/CT more advanced disease (N + and/or tumor size > 4  cm or other imaging modalities was only performed on sus- or small T2 tumors that were not superficially grow - picion of either metastatic disease or a local recurrence. ing) were treated with concurrent chemoradiotherapy, On indication, depending on complaints and needs of standard dose to the elective nodal regions (perirectal, patients, e.g. pain or stool complaints, sexual disfunction inguinal, external and internal iliac, obturator and puden- or disease-related emotional instability, more or less vis- dal nodes) was 49.5  Gy in 33 fractions of 1.5  Gy, with a its could be scheduled. Treatment response and toxicity simultaneous integrated boost to macroscopic disease to were determined and evaluated during these visits. Both a total dose of 59.4 Gy in 33 fractions of 1.8 Gy. In case of relapses and metastatic disease, if present, were con- a sequential boost patients were treated with 25 × 1.8  Gy firmed histologically. Neelis  et al. Radiation Oncology (2022) 17:81 Page 3 of 9 Data collected this period, up to a maximum of 5  years follow-up, was The following data were collected from the records: Age defined as ‘late toxicity’. Only the most severely reported at diagnosis, sex, pre-treatment work-up (physical exami- grade a patient experienced of a particular toxicity was nation and medical imaging) HIV status, tumor histology recorded. Grade 3 and greater toxicities, urgency grade 2, and grade, maximum tumor size (defined as the great - and incontinence grade 2 were categorized separately. est dimension), tumor location (categorized as peri-anal, intra-anal, rectal or a combination of these), lymph node involvement, size of the largest pathological lymph node Statistical analyses and assessment (defined by its greatest dimension), HPV status (either The first day of radiotherapy was defined as day 0 for cal - immunohistochemistry or PCR technique) and DYPD culations on overall survival (OS), disease free survival mutation status. (DFS), locoregional control (LRC), Colostomy Free Sur- Radiotherapy technique and dose were retrieved from vival (CFS). Endpoints of OS, DFS, LRC, were estimated the dose report and treatment plan of each patient. If with the Kaplan–Meier method whereas Cox propor- applicable, the chemotherapy plan was retrieved. The jus - tional hazard models were used to determine the asso- tifications for any deviations from standard procedure for ciations of age, sex, stage, T-stage, maximal tumor size either radiotherapy or chemotherapy were retrieved from the patient files and correspondence. Toxicities reported in the patient files were evalu - Table 2 Prognostic factors of survival in univariate analyses ated following the CTCAE version 4.03 [17]. All toxici- HR (95% CI) P value ties during treatment and within the first 6  weeks after Overall survival treatment were defined as ‘early toxicity’. Toxicity beyond Disease stage 1.45 (1.01–2.06) 0.041 T stage 1.36 (0.87–2.13) 0.184 N stage 1.48 (1.06–2.05) 0.021 Table 1 Patient, tumor, and treatment characteristics Max. tumor size 1.01 (1.00–1.03) 0.031 Age (years) Median (range) 63 (41–88) Concurrent chemotherapy 1.50 (0.66–3.42) 0.330 Gender Male 39 (40%) Age 1.02 (0.99–1.06) 0.217 Female 59 (60%) Sex 1.27 (0.60–2.70) 0.532 HIV status Negative 94 (96%) Disease-free survival Positive 3 (3%) Disease stage 1.56 (1.03–2.38) 0.037 Unknown 1 (1%) T stage 1.05 (0.64–1.78) 0.868 T stage 1/is 19 (19%) N stage 1.66 (1.14–2.42) 0.009 2 45 (46%) Max. tumor size 1.00 (0.98–1.02) 0.937 3 29 (30%) Concurrent chemotherapy 1.17 (0.47–2.93) 0.739 4 5 (5%) Age 1.01 (0.97–1.06) 0.509 N stage 0 57 (58%) Sex 1.66 (0.69–3.98) 0.259 1 16 (16%) Locoregional control 2 16 (16%) Disease stage 1.62 (1.04–2.53) 0.033 3 9 (9%) T stage 1.17 (0.67–2.03) 0.586 TNM staging I 18 (18%) N stage 1.68 (1.13–2.51) 0.010 II 39 (40%) Max. tumor size 1.00 (0.98–1.02) 0.725 IIIa 15 (15%) Concurrent chemotherapy 1.26 (0.47–3.35) 0.650 IIIb 26 (27%) Age 1.01 (0.97–1.06) 0.608 Maximum tumor size (mm) Mean (SD, range) 46 (24, 7–140) Sex 1.67 (0.66–4.20) 0.278 Radiotherapy technique 3D, seq. boost 28 (29%) Colostomy free survival 3D, electron boost 3 (3%) Disease stage 1.48 (0.95–2.30) 0.082 Electron 23 (24%) T stage 1.30 (0.74–2.30) 0.358 IMRT, seq. boost 3 (3%) N stage 1.62 (1.07–2.46) 0.022 IMRT, electron boost 1 (1%) Max. tumor size 1.01 (0.99–1.03) 0.227 IMRT, SIB 13 (13%) Concurrent chemotherapy 1.26 (0.47–3.36) 0.644 VMAT 27 (28%) Age 0.99 (0.95–1.03) 0.533 Concurrent chemotherapy Yes 63 (64%) Sex 1.04 (0.40–2.69) 0.931 No 35 (36%) HR hazard ratio, CI confidence interval Neelis et al. Radiation Oncology (2022) 17:81 Page 4 of 9 discovery or suspected relapse which was subsequently proven with additional radiological imaging and/or biopsy. In patients without cCR the DFS and LRC was set to 0. When the cause of death was unknown the last date the patient was confirmed disease free was the end-point of DFS. CFS was defined as living without colostomy excluding temporary colostomies that had been reversed. A colostomy that was given prior to treatment and that was not reversed by end of follow-up was considered a day 0 treatment failure. Results Fig. 1 Estimated overall survival for all patients Patient and treatment characteristics A total of 98 patients treated between January 2009 and December 2018 met the inclusion criteria. Primary N-stage and concurrent chemotherapy with OS, DFS, characteristics of this study population are described in LRC, and CFS. Log-rank tests were applied to study dif- Table  1. All but one patients were tested for HIV, 3 of ferences related to period of treatment (< 2014 3D-CRT them were positive. Twenty-six patients had had a diag- and ≥ 2014 IMRT/VMAT) and age (< 75 or ≥ 75 year). nostic surgical tumor resection prior to radiotherapy, of OS was defined as any survival, DFS as survival with - which 19 were R1 and 7 were R2 resections. Eighteen of out relapse or metastatic progression, LRC as survival those 26 patients were treated with local radiotherapy duration without local or regional relapse. Date of clini- only, 30 × 2 Gy, in the other 8 patients either gross resid- cal complete remission (cCR) was defined as the date of ual disease or nodal involvement was shown upon stag- reporting cCR or the date of the MRI documenting com- ing, they were treated with chemoradiation. plete remission, whichever came first. Date of local- or regional relapse was defined as the date of first reported Fig. 2 Disease-free survival. A Disease-free survival for the whole group. B Disease free survival by disease-stage according to AJCC 7th edition; C locoregional recurrences for the whole group; D disease-free survival of patients with treatment start in 2009–2013 versus 2014–2018 Neelis  et al. Radiation Oncology (2022) 17:81 Page 5 of 9 HPV testing was performed in 28% biopsies of which Twenty-seven patients had an anal margin tumor (see 90% were positive for high risk HPV. Twelve patients had Additional file  2: Table S4) of whom 21 were treated with a diagnosis of a second malignancy before (n = 6) or in 30 × 2 Gy to the tumor only and 6 received chemoradia- the follow-up after their treatment for anal carcinoma tion with also treatment on elective nodal regions. Four (n = 6). In all patients radiotherapy was given without of these patients experienced a local relapse, 3 in T1/2N0 treatment breaks. In 6 patients a higher dose than 60 Gy locally treated patients and one in a patient with T3N2 was applied based on a clinical examination of too much disease treated with chemoradiation. residual disease nearing the end of treatment, dose By the end of their follow-up 18 patients had a colos- range 62.2–70  Gy. No dose reductions were applied e.g. tomy, of these 13 were due to salvage surgery after in case of toxicities. Sixty-three patients (all stage 2 and relapse, 2 for quality of life due to severe incontinence 3) received concurrent chemotherapy (64%). Twelve of or urgency, and 3 for other reasons (see Additional file  1: these patients received no MMC, 10 due to age > 75, 1 Table  S3 for details). Four patients had had a colostomy due to M. Crohn, and 1 due to poor renal function. In 50 prior to treatment, of which 3 still had a colostomy at end patients DYPD mutations were tested, four patients (8%) of follow-up. Five patients with a locoregional relapse had a heterozygote DYPD mutation and received a reduc- did not receive salvage surgery, 3 were inoperable due tion to their 5-FU or capecitabine dose down to 75%, one to simultaneous metastatic progression, 1 due to poor patient received both no MMC and a reduced 5-FU dose. health, and 1 refused further treatment after relapse. Three patients should have received chemoradiotherapy based on their tumor stage but were treated with radio- Univariate analyses therapy only, one patient (T2N2) refused chemotherapy, Disease stage, N-status and tumor size were associated one patient (T2N0) was medically unfit and one other with a lower OS (Table  2). Disease stage and N-status patient (T2N0) for unclear reasons. Thirty five patients were also associated with a lower DFS (Fig.  2B), tumor were treated with radiotherapy only. This includes the size however was not. Similarly, a worse LRC was also three patients mentioned above, the other patients had associated with disease stage and N-status. The CFS disease stages T1N0 (n = 18) or superficial T2N0 with however was significantly associated with N-status. Con - tumor dimensions < 4 cm (n = 14). current chemotherapy was not significantly associated During treatment, because of treatment related tox- with either OS, DFS, LRC or CFS. icity, 7 patients received adjustments to their chemo- To analyze time trends as techniques changed, 40 therapy: 5 a dose-reduction, in 2 chemotherapy was patients treated prior to 2014 (n = 31 with 3D confor- prematurely stopped. mal radiotherapy, n = 9 with electrons) were compared to those 58 patients who started after 2014 (n = 44 with Treatment outcomes IMRT or VMAT and n = 14 with electrons, Fig. 2D). Dis- Median follow-up for the cohort was 43  months (range ease stages were comparable in both groups (data not 4–133). Estimated overall survival at 3 and 5  years were shown). The group treated before 2014 had an estimated 79% and 71% (Fig.  1). An unrelated second malignancy DFS at five years of 78% compared to 81% in the group was the cause of death for 4 patients. Estimated DFS at treated from 2014 onwards. Log-rank difference between 3 years was 80% (Fig. 2A) with 4 (4%) upfront failures and these groups was 0.763. 16 (16%) relapses after complete remission. Three of the Twenty three patients (23%) were aged 75  years or four patients with residual disease after treatment were higher. Ten received radiotherapy only, nine with T1N0 salvaged with an APR (see Additional file  1: Table S3), the or T2N0 stage disease and one with tumor stage T2N2, fourth patient experienced a deteriorating health lead- this patient refused concurrent chemotherapy. Thir - ing to his death without a clear cause of death. The lat - teen patients received chemoradiotherapy for higher est relapse in our series occurred at 30  months, with 18 stage disease. MMC was frequently omitted as previ- (90%) within the first 24 months after treatment. LRC was ously described. The estimated 5-year OS in the older age achieved in 80 (82%) of patients at 3 years, with a total of group was lower (60.8% vs. 74.6% in the < 75 group) and 18 locoregional relapses (Fig.  2C). No new locoregional the locoregional recurrence was higher (26.1% vs. 18.7% relapses were observed past 30 months. In the 26 patients in the < 75 group, Fig.  3A, B). The log-rank test for OS with T1 and small superficial T2 tumors that were treated was 0.136, and for the locoregional recurrence 0.496. with 60  Gy in 30 fractions to the tumor without elec- tive nodal irradiation no isolated regional recurrences occurred. Two regional recurrences occurred simultane- Toxicities ously with distant metastases. Reported early clinical toxicity of any grade consisted of dermatitis (100% of patients), pain (98%), diarrhea (52%), Neelis et al. Radiation Oncology (2022) 17:81 Page 6 of 9 Fig. 3 Results in older patients. A Estimated overall survival of patients ≥ 75 years old versus patients aged < 75 years; B locoregional recurrences in patients ≥ 75 years old versus patients aged < 75 nausea (35%), urgency (31%), malaise (29%), edema Discussion (18%), incontinence for stools (18%), vomiting (11%), and In this study results of our single institution retrospective acute cystitis (3%). Leukopenia occurred in 7% of patients analysis of 98 consecutively treated patient with SCCA treated with concurrent CRT, anemia in 4% and neutro- treated in 10 years’ time are described. penia in 3%, two patients experienced febrile neutrope- The reported 3-and 5  year OS of 78.6% and 71.4% nia. Early toxicities grade 3 or higher consisted of grade 3 are comparable to that reported in both randomized pain in 27% and grade 3or 4 dermatitis in 22% of patients. and other retrospective studies [6, 7, 18, 19]. The ACT Other severe toxicities were diarrhea grade 3 or 4 in 5%, I trial reported a 3-year OS of 65% in their CRT group grade 3 nausea in 1%, grade 3 vomiting 1% and grade 2 consisting of 292 patients clinically staged as T2N0 or urgency in 8%. Three patients (3%) had such severe ane - higher [18]. In the Accord 03, a 5-year OS of 71–74.5% mia they required a transfusion (grade 4). was reported in 307 patients with tumors > 4  cm and/ Reported late toxicities of any grade were pain in 75% or N + disease treated with CRT [19]. The Montpellier of patients, urgency in 53%, fecal incontinence in 49%, study found a 5-year OS of 74% in 193 patients treated diarrhea in 38%, dermatitis in 37%, edema in 26% and with CRT, and Mitra et al. reported a 4-year OS of 85.8% nausea in 14%. Higher grade toxicities were 16% grade 2 in 99 patients in all disease stages, treated with CRT [6, urgency, 11% grade 3 pain, 3% ≥ grade 3 incontinence, 3% 7]. The relatively low OS in the ACT I may be attrib - grade 3 dermatitis, and 1 patient with grade 3 diarrhea. uted to the inclusion of only more advanced stages of Late fecal incontinence in the 27 patients with an anal disease as well as stage migration over the years (inclu- margin tumor was 33% with 1 patient (4%) with grade sion ended in 1994, MRI and PET CT scans were not 3 incontinence. This is comparable to that in the whole widely available at that time). The 4-year OS reported by group. Pelvic insufficiency fractures were diagnosed in Mitra et al. is higher than the 3-year OS reported in our 3 patients of which 2 were painful and self-limiting. No study. Although the study populations, treatment period, grade 5 early or late toxicity occurred. median age, disease stage distributions are all compara- Toxicities changed with the transition of 3D to IMRT/ ble, this difference might be attributable to chance and VMAT with an increase in reported acute grade 3 diar- limited numbers. rhea from 2.8 to 6.5% and grade 2 urgency from 2.8 to Our reported DFS of 79.6% and LRC of 81.6% at 3 and 11.3%, with other toxicities remaining fairly consistent 5-years compares favorably to the 3-year DFS of the ACT between both techniques. Reported late toxicity differ - I of 61% and the 5-year DFS of the Montpellier study ences between patients treated with either 3D or IMRT/ of 68% [6, 18]. This is likely attributable to inclusion of VMAT showed an increase in incontinence grade 1–2 higher stages and lack of imaging in the ACT I study. from 27.8 to 56.5% but a decrease in reported incon- The Accord 03 reported an overall relapse free rate of tinence grade 3 from 5.6 to 1.6%. Urgency grade 1 rose 71.4% and a LRC of 72–87.6% [19]. Mitra et al. reported from 30.6 to 40.3%, but grade 2 reports dropped from 83.5% patients were disease-free at the end of follow-up 27.8 to 9.7%. [7]. As with OS however we must again consider that the Neelis  et al. Radiation Oncology (2022) 17:81 Page 7 of 9 ACT I trial included more advanced disease stages, and can give considerable complaints adequate local treat- is relatively old, likely attributing to a worse DFS. Com- ment is warranted, also in older patients. Due to older pared to the Accord 03, the Montpellier study, and Mitra patients frequently being excluded from studies, results et  al. our DFS is better. The Accord 03 included more and outcomes within the geriatric population are often advanced disease stages which might negatively affect not as clear. For this reason, we analyzed the OS and DFS and LRC and it excluded patients with comorbidi- LRC between patients aged 75  years and older, and ties and aged 80 + which should have positively affected those younger than 75.  The portion of older patients in outcomes. In the present series 90% of relapses occurred our study (23%) is comparable to the portion of older within the first 24  months with the latest relapse at patients with the diagnosis of anal cancer in the Neth- 30  months after treatment. Currently, patients receive erlands which is reported to be 28.5% in 2020 [1]. This a standard of 5-years of follow-up. Considering that in suggests that older patients are indeed also referred for 10 years of curative anal carcinoma treatment all relapses treatment. Only one patient refused the chemotherapy have occurred within three years perhaps a shorter fol- part of the treatment and frequently MMC was omit- low-up length is to be discussed with patients [20, 21]. ted. Older patients had a 5  year OS of 60.8% compared CFS in our study was as high as 81.6%. Of the 18 to 74.6% in younger patients, however this was not sta- patients with a colostomy 11 were operated as sal- tistically significant, nor was there a significant difference vage surgery for relapsed disease. these results are like in LRC. Although a lack of significant difference in OS is those reported in the other studies. Where the ACT I unexpected [22], this outcome is most probably due to a reported a CFS of 76.4% in their CRT group, the Accord to small sample size. 03 reported CFS of 69.6–82.4%, the Montpellier study Our study has several limitations. It is a single center reported 66% CFS, and Mitra et  al. reported the high- retrospective analysis and included patients treated with est CFS at 85% [6, 7, 18, 19]. In the ACT I patients only CRT and with radiotherapy alone. Also the necessity to received elective RT and were evaluated after 6  weeks, interpret patient-doctor communication to a toxicity those with < 50% tumor response were considered for sal- grade is a limitation although reporting in the patient vage. This practice most likely attributed to a higher rate files was quite elaborate. Although radiation techniques of colostomies. changed over time the dose prescribed remained the Concerns were raised when the RT technique was same. All patients were treated by a team of 2 radiation changed from 3D to more conformal IMRT and VMAT oncologists and 1 medical oncologist with their residents techniques regarding potential regional misses and guarantying consistent treatment choices, techniques increased numbers of recurrences. Analyzing the time and reporting of toxicities. trend however did not show any significant differences Whether or not intensification of treatment is use - in DFS in our study (78% vs. 81% before and after 2014), ful to improve outcomes remains to be investigated. The further supporting that technique does not affect the Accord 03 study demonstrated that intensifying treat- primary outcome. Changing the technique from 3D to ment with either induction chemotherapy or a higher IMRT/VMAT caused an increase in early reported grade radiotherapy dose did not further improve outcomes [19] 3 diarrhea and grade 2 urgency. Part of the increase whereas the Mitra et al. study reported outcomes compa- in diarrhea may be attributable to the change from iv rable, if not marginally better, than our findings but did 5-FU week 1 and five to oral capecitabine twice daily for so with a lower radiotherapy dose [7]. Further studies to the whole treatment period. Severe late incontinence find the optimum dose of radiotherapy to balance disease grade 3 dropped from 5.6 to 1.6% with an increase in outcome with toxicity are warranted [11, 23]. Results reported incontinence grade 1–2 from 27.8 to 56.5%. The from the ongoing PersonaLising Anal cancer radioTher - increase in reported toxicity both early and late is likely apy dOse trial (PLATO), incorporating the ACT3, ACT4 also attributable to changes in reporting practices in our and ACT5 trials are eagerly awaited. clinic, with the advent of the electronic patient file in 2011 and the addition of required toxicity forms since the Conclusions start of 2018. The decrease in severe toxic effects was the Our 10 year cohort study shows that patients treated with expected effect of switching to IMRT techniques [9, 11, curative intent for anal cancer in our regional referral 12]. center achieve OS and DFS comparable to that reported A significant portion (23%) of our patients were aged in the literature. With the introduction of more confor- 75 and over. Tumor stage did not significantly differ from mal radiation techniques DFS remained similar with the under 75 group. Since metastatic disease occurs rela- lower toxicities. Older patients can be safely treated with tively late in the disease course and the primary tumor slightly adjusted CRT with good results. Neelis et al. Radiation Oncology (2022) 17:81 Page 8 of 9 4. Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, Supplementary Information et al. Concomitant radiotherapy and chemotherapy is superior to radio- The online version contains supplementary material available at https:// doi. therapy alone in the treatment of locally advanced anal cancer: results org/ 10. 1186/ s13014- 022- 02049-8. 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. Additional file 1. Table S3: Details of patients with a colostomy at the 5. Deniaud-Alexandre E, Touboul E, Tiret E, Sezeur A, Houry S, Gallot D, et al. end of follow-up. Results of definitive irradiation in a series of 305 epidermoid carcinomas Additional file 2. Table S4: Distribution and treatment of patients accord- of the anal canal. Int J Radiat Oncol Biol Phys. 2003;56(5):1259–73. ing to site of disease. 6. de Meric de Bellefon M, Lemanski C, Castan F, Samalin E, Mazard T, Len- glet A, et al. Long-term follow-up experience in anal canal cancer treated with Intensity-Modulated Radiation Therapy: Clinical outcomes, patterns Acknowledgements of relapse and predictors of failure. Radiother Oncol. 2020;144:141–7. Not applicable. 7. Mitra D, Hong TS, Horick N, Rose B, Drapek LN, Blaszkowsky LS, et al. Long- term outcomes and toxicities of a large cohort of anal cancer patients Author contributions treated with dose-painted IMRT per RTOG 0529. Adv Radiat Oncol. KN and YL designed and supervised the study. DK analyzed and interpreted 2017;2(2):110–7. the patient data and wrote the first draft of the manuscript. YL and FS com- 8. Koerber SA, Slynko A, Haefner MF, Krug D, Schoneweg C, Kessel K, et al. mented on several versions of the manuscript. KN was a major contributor in Efficacy and toxicity of chemoradiation in patients with anal cancer–a writing the final version of the manuscript. All authors read and approved the retrospective analysis. Radiat Oncol. 2014;9:113. final manuscript. 9. Ghareeb A, Paramasevon K, Mokool P, van der Voet H, Jha M. Toxicity and survival of anal cancer patients treated with intensity-modulated radia- Funding tion therapy. Ann R Coll Surg Engl. 2019;101(3):168–75. Not applicable. 10. Pan YB, Maeda Y, Wilson A, Glynne-Jones R, Vaizey CJ. Late gastrointestinal toxicity after radiotherapy for anal cancer: a systematic literature review. Availability of data and materials Acta Oncol. 2018;57(11):1427–37. The datasets used and/or analysed during the current study are available from 11. Kachnic LA, Tsai HK, Coen JJ, Blaszkowsky LS, Hartshorn K, Kwak EL, et al. the corresponding author on reasonable request. Dose-painted intensity-modulated radiation therapy for anal cancer: a multi-institutional report of acute toxicity and response to therapy. Int J Radiat Oncol Biol Phys. 2012;82(1):153–8. Declarations 12. Deenen MJ, Dewit L, Boot H, Beijnen JH, Schellens JH, Cats A. Simultane- ous integrated boost-intensity modulated radiation therapy with con- Ethics approval and consent to participate comitant capecitabine and mitomycin C for locally advanced anal carci- The protocol for our study was submitted for review to the LUMC ethics noma: a phase 1 study. Int J Radiat Oncol Biol Phys. 2013;85(5):e201–7. committee (G20.026, March 11, 2020) and was deemed not necessary to be 13. TNM classification of malignant tumours, 7th edition ed. Cancer UIUA, subjected to further review under the Medical Research Involving Human editor: Wiley; 2009. Subjects Act ( WMO). As such individual patient consent was not applicable. 14. Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, Consent for publication cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized Not applicable. controlled trial. JAMA. 2008;299(16):1914–21. 15. Henricks LM, Lunenburg C, de Man FM, Meulendijks D, Frederix GWJ, Competing interests Kienhuis E, et al. DPYD genotype-guided dose individualisation of fluoro - The authors declare that they have no known competing financial interests pyrimidine therapy in patients with cancer: a prospective safety analysis. or personal relationships that could have appeared to influence the work Lancet Oncol. 2018;19(11):1459–67. reported in this paper. 16. van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H, De Abreu RA, et al. Clinical implications of dihydropyrimidine dehydrogenase Author details 1 (DPD) deficiency in patients with severe 5-fluorouracil-associated toxic- Department of Radiotherapy, Leiden University Medical Center, Albinusdreef 2 ity: identification of new mutations in the DPD gene. Clin Cancer Res. 2, 2333 ZA Leiden, The Netherlands. Department of Medical Oncology, 3 2000;6(12):4705–12. Leiden University Medical Center, Leiden, The Netherlands. Netherlands Com- 17. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, prehensive Cancer Organisation (IKNL), Utrecht, The Netherlands. June 2010. https:// evs. nci. nih. gov/ ftp1/ CTCAE/ CTCAE_4. 03/ CTCAE_4. 03_ 2010- 06- 14_ Quick Refer ence_8. 5x11. pdf. Received: 21 January 2022 Accepted: 4 April 2022 18. Northover J, Glynne-Jones R, Sebag-Montefiore D, James R, Meadows H, Wan S, et al. Chemoradiation for the treatment of epidermoid anal can- cer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer. 2010;102(7):1123–8. 19. Peiffert D, Tournier-Rangeard L, Gerard JP, Lemanski C, Francois E, References Giovannini M, et al. Induction chemotherapy and dose intensification 1. IKNL. Nederlandse Kankerregistratie (NKR). retrieved via iknlnl/nkr-cijfers of the radiation boost in locally advanced anal canal carcinoma: final March 31, 2021. analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol. 2. James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, 2012;30(16):1941–8. Saunders MP, et al. Mitomycin or cisplatin chemoradiation with or 20. Frazer ML, Yang G, Felder S, McDonald J, Sanchez J, Dessureault S, et al. without maintenance chemotherapy for treatment of squamous-cell Determining optimal follow-up for patients with anal cancer following carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 x 2 chemoradiation. Am J Clin Oncol. 2020;43(5):319–24. factorial trial. Lancet Oncol. 2013;14(6):516–24. 21. Glynne-Jones R, Nilsson PJ, Aschele C, Goh V, Peiffert D, Cervantes A, et al. 3. Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, AB 3rd, et al. Long-term update of US GI intergroup RTOG 98–11 phase treatment and follow-up. Radiother Oncol. 2014;111(3):330–9. III trial for anal carcinoma: survival, relapse, and colostomy failure with 22. Dale JE, Sebjørnsen S, Leh S, Rösler C, Aaserud S, Møller B, et al. Multi- concurrent chemoradiation involving fluorouracil/mitomycin versus modal therapy is feasible in elderly anal cancer patients. Acta Oncol. fluorouracil/cisplatin. J Clin Oncol. 2012;30(35):4344–51. 2017;56(1):81–7. Neelis  et al. Radiation Oncology (2022) 17:81 Page 9 of 9 23. Henkenberens C, Meinecke D, Michael S, Bremer M, Christiansen H. Reduced radiation dose for elective nodal irradiation in node-negative anal cancer: back to the roots? Strahlenther Onkol. 2015;191(11):845–54. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Treatment results for patients with squamous-cell carcinoma of the anus, a single institution retrospective analysis

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Abstract

Background and purpose: To gain insight into the treatment outcomes for anal cancer a retrospective analysis was performed with a special emphasis on trends in outcome and toxicities over time and on treatment of elderly patients. Materials and methods: Medical records of 98 consecutive patients with squamous cell carcinoma of the anus of all stages treated with curative intent between 01-01-2009 and 31-12-2018 were analyzed with follow up until 31-12- 2020. Standard tumor and pathological lymph node dose were 59.4 Gy (median 59.4 Gy, range 59.4–70 Gy) or 60 Gy (no deviation from intended dose), elective nodal regions were treated with 45 Gy (no deviations). Radiotherapy techniques in this period evolved from 3D-conformal to IMRT and VMAT. In 23 patients electron beams were used. Results: Median age was 63 years (range 41–88), the majority of patients were female (60%). Twenty three patients were > 75 years old. The TNM stages were I, II, IIIA, and IIIB in 18%, 40%, 15% and 27%, 58% of patients had N0 status. Concurrent mitomycin C and 5-fluoruracil-based chemotherapy was given in 63 patients (64%). Five-year overall survival (OS), disease free survival (DFS), locoregional control (LRC) and colostomy free survival (CFS) were 71%, 80%, 82%, and 82% for the whole group. Results in patients > 75 years of age were not statistically different from those in younger patients. With the introduction of more conformal techniques DFS did not change and toxicities decreased. Conclusion: Real word treatment outcomes per disease stage were in line with what is reported in literature. Older patients should also be offered treatment with curative intent. Keywords: Anal carcinoma, Retrospective, Chemoradiotherapy, Treatment results Introduction and 5-fluorouracil (5-FU)-based, is given to patients with Squamous-cell carcinoma of the anus (SCCA) is one of SCCA at higher stages (larger T2 disease and/or N +) the rarer forms of cancer of the digestive tract, with only [2–5]. This results in 5  year overall survival rates rang - 330 new cases in the Netherlands in 2020, an incidence ing from 60 to 85 percent and local control rates of 61–83 rate of 1.9 per 100.000 people [1]. Sphincter sparing percent in both prospective studies and retrospective treatment consists of radiotherapy alone in early-stage analyses [1, 2, 6, 7]. Acute and long term toxicities are disease (T1N0 and small T2N0) and radiotherapy with common but reported to be lower with modern radio- concurrent chemotherapy, typically mitomycin C (MMC) therapy techniques VMAT/IMRT versus conventional 3D techniques, thereby also reducing the necessity for therapy breaks [8–12]. In case of residual or recurrent *Correspondence: k.j.neelis@lumc.nl 1 disease an abdominoperineal resection (APR) may be Department of Radiotherapy, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands used as salvage treatment in the absence of distant metas- Full list of author information is available at the end of the article tases [7]. Because of the rarity of the disease randomized © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Neelis et al. Radiation Oncology (2022) 17:81 Page 2 of 9 trials are difficult to perform. Older patients are fre - on the tumor and elective nodal regions followed by a quently excluded in clinical trials but represent up to 25% boost on the macroscopic disease, 8 fractions of 1.8  Gy of the anal cancer patient population. To gain insight into to a total dose of 59.4  Gy. In most patients this was the our institutional results in all age groups and to evaluate given dose, six patients were treated with higher doses trends in outcome and toxicities over time where both ranging from 62.2 to 70  Gy. Initially the technique used radiotherapy techniques and chemotherapy regimens was 3D conformal radiotherapy (3D), which in 2014 was changed a retrospective analysis was performed. replaced for IMRT, which further amended to VMAT medio 2016. No treatment gaps were used throughout Materials and methods the time period. Patients and work up Medical records from consecutively treated patients Chemotherapy treated between 1-1-2009 and 31-12-2018 at our insti- Concurrent chemoradiotherapy consisted of MMC tution were collected with follow up as recorded until and 5-FU-based chemotherapy. 5-FU has been given 31-12-2020. Our institution is a regional center for treat- as 1000  mg/m on days 1–4 and 29–32 of radiotherapy. ment of anal cancer patients. Those treated with pal - MMC has been given 10 mg/m on day 1 and 29 [14]. In liative intent or those who had histologically proven case of advanced age and/or severe comorbidity MMC adenocarcinoma were excluded (n = 1 and n = 5 respec- was not given. From 2017 onwards capecitabine was tively). Staging was done using Magnetic Resonance given instead of 5-FU, twice daily at 825  mg/m , start- Imaging (MRI) in 87% of cases, Computed Tomography ing day 1 and to continue until day 33 on radiation days (CT) in 55%, Positron Emission Tomography (PET) in only. From that time onward MMC was only given on 22%, conventional chest X-ray in 34%, and/or on indi- day one at a dose of 12  mg/m . Severe toxicity of 5-FU cation an ultrasound of the inguinal region in 50% with is often the result of deficient function of dihydropyrimi - cytology if possible. Histological biopsies were assessed dine dehydrogenase caused by genetic polymorphisms in and graded by the pathology departments of the referring DPYD. Therefore from May 2013 pre-emptive screening medical centers. Disease staging was done following the for DPYD genotype variants and dose reductions of 5-FU American Joint Committee on Cancer 7th edition [13]. In based chemotherapy in heterozygous DPYD variant allele case of debilitating incontinence, in three patients a tem- carriers is standard of care [15, 16]. porary colostomy was given prior to start of treatment to reinstall continence and increase the possibility of suc- Follow‑up ceeding the chemoradiotherapy treatment. The protocol During treatment patients were seen weekly by the radia- for this study was approved by Medical Ethics Commit- tion oncologist and nurses to document and treat acute tee of the Leiden University Medical Center (number toxicity. In the first-year of follow-up patients were seen G20.026). frequently until recovery of acute side effects and to evaluate response to treatment, usually at 6 weeks. Then Radiotherapy every subsequent 2  months for the remainder of year Twenty six patients with superficial T1-T2 disease < 4 cm one. In the second-year follow-up visits were scheduled limited to the peri-anal region or anal canal and N0 sta- every 3 months, in the third-year every 4 months, and for tus received only radiotherapy at 60 Gy in 30 fractions of the fourth and fifth year every 6 months. No further fol - 2  Gy, usually with a direct electron beam. CTV margin low-up was scheduled after 5 years. Imaging with MRI to around the tumor was 1  cm, in these patient no elective document treatment response was routinely performed nodal regions were treated, given dose was the prescribed 3 months after completion of radiotherapy. In case of an dose in all patients. This is a conservative approach with inconclusive result (a near complete but not total remis- limited data to support this practice [5] but with a long sion, expected to resolve in time) imaging was repeated history in our institution with good results. Patients with 8 to 10  weeks later. Further imaging with MRI, PET/CT more advanced disease (N + and/or tumor size > 4  cm or other imaging modalities was only performed on sus- or small T2 tumors that were not superficially grow - picion of either metastatic disease or a local recurrence. ing) were treated with concurrent chemoradiotherapy, On indication, depending on complaints and needs of standard dose to the elective nodal regions (perirectal, patients, e.g. pain or stool complaints, sexual disfunction inguinal, external and internal iliac, obturator and puden- or disease-related emotional instability, more or less vis- dal nodes) was 49.5  Gy in 33 fractions of 1.5  Gy, with a its could be scheduled. Treatment response and toxicity simultaneous integrated boost to macroscopic disease to were determined and evaluated during these visits. Both a total dose of 59.4 Gy in 33 fractions of 1.8 Gy. In case of relapses and metastatic disease, if present, were con- a sequential boost patients were treated with 25 × 1.8  Gy firmed histologically. Neelis  et al. Radiation Oncology (2022) 17:81 Page 3 of 9 Data collected this period, up to a maximum of 5  years follow-up, was The following data were collected from the records: Age defined as ‘late toxicity’. Only the most severely reported at diagnosis, sex, pre-treatment work-up (physical exami- grade a patient experienced of a particular toxicity was nation and medical imaging) HIV status, tumor histology recorded. Grade 3 and greater toxicities, urgency grade 2, and grade, maximum tumor size (defined as the great - and incontinence grade 2 were categorized separately. est dimension), tumor location (categorized as peri-anal, intra-anal, rectal or a combination of these), lymph node involvement, size of the largest pathological lymph node Statistical analyses and assessment (defined by its greatest dimension), HPV status (either The first day of radiotherapy was defined as day 0 for cal - immunohistochemistry or PCR technique) and DYPD culations on overall survival (OS), disease free survival mutation status. (DFS), locoregional control (LRC), Colostomy Free Sur- Radiotherapy technique and dose were retrieved from vival (CFS). Endpoints of OS, DFS, LRC, were estimated the dose report and treatment plan of each patient. If with the Kaplan–Meier method whereas Cox propor- applicable, the chemotherapy plan was retrieved. The jus - tional hazard models were used to determine the asso- tifications for any deviations from standard procedure for ciations of age, sex, stage, T-stage, maximal tumor size either radiotherapy or chemotherapy were retrieved from the patient files and correspondence. Toxicities reported in the patient files were evalu - Table 2 Prognostic factors of survival in univariate analyses ated following the CTCAE version 4.03 [17]. All toxici- HR (95% CI) P value ties during treatment and within the first 6  weeks after Overall survival treatment were defined as ‘early toxicity’. Toxicity beyond Disease stage 1.45 (1.01–2.06) 0.041 T stage 1.36 (0.87–2.13) 0.184 N stage 1.48 (1.06–2.05) 0.021 Table 1 Patient, tumor, and treatment characteristics Max. tumor size 1.01 (1.00–1.03) 0.031 Age (years) Median (range) 63 (41–88) Concurrent chemotherapy 1.50 (0.66–3.42) 0.330 Gender Male 39 (40%) Age 1.02 (0.99–1.06) 0.217 Female 59 (60%) Sex 1.27 (0.60–2.70) 0.532 HIV status Negative 94 (96%) Disease-free survival Positive 3 (3%) Disease stage 1.56 (1.03–2.38) 0.037 Unknown 1 (1%) T stage 1.05 (0.64–1.78) 0.868 T stage 1/is 19 (19%) N stage 1.66 (1.14–2.42) 0.009 2 45 (46%) Max. tumor size 1.00 (0.98–1.02) 0.937 3 29 (30%) Concurrent chemotherapy 1.17 (0.47–2.93) 0.739 4 5 (5%) Age 1.01 (0.97–1.06) 0.509 N stage 0 57 (58%) Sex 1.66 (0.69–3.98) 0.259 1 16 (16%) Locoregional control 2 16 (16%) Disease stage 1.62 (1.04–2.53) 0.033 3 9 (9%) T stage 1.17 (0.67–2.03) 0.586 TNM staging I 18 (18%) N stage 1.68 (1.13–2.51) 0.010 II 39 (40%) Max. tumor size 1.00 (0.98–1.02) 0.725 IIIa 15 (15%) Concurrent chemotherapy 1.26 (0.47–3.35) 0.650 IIIb 26 (27%) Age 1.01 (0.97–1.06) 0.608 Maximum tumor size (mm) Mean (SD, range) 46 (24, 7–140) Sex 1.67 (0.66–4.20) 0.278 Radiotherapy technique 3D, seq. boost 28 (29%) Colostomy free survival 3D, electron boost 3 (3%) Disease stage 1.48 (0.95–2.30) 0.082 Electron 23 (24%) T stage 1.30 (0.74–2.30) 0.358 IMRT, seq. boost 3 (3%) N stage 1.62 (1.07–2.46) 0.022 IMRT, electron boost 1 (1%) Max. tumor size 1.01 (0.99–1.03) 0.227 IMRT, SIB 13 (13%) Concurrent chemotherapy 1.26 (0.47–3.36) 0.644 VMAT 27 (28%) Age 0.99 (0.95–1.03) 0.533 Concurrent chemotherapy Yes 63 (64%) Sex 1.04 (0.40–2.69) 0.931 No 35 (36%) HR hazard ratio, CI confidence interval Neelis et al. Radiation Oncology (2022) 17:81 Page 4 of 9 discovery or suspected relapse which was subsequently proven with additional radiological imaging and/or biopsy. In patients without cCR the DFS and LRC was set to 0. When the cause of death was unknown the last date the patient was confirmed disease free was the end-point of DFS. CFS was defined as living without colostomy excluding temporary colostomies that had been reversed. A colostomy that was given prior to treatment and that was not reversed by end of follow-up was considered a day 0 treatment failure. Results Fig. 1 Estimated overall survival for all patients Patient and treatment characteristics A total of 98 patients treated between January 2009 and December 2018 met the inclusion criteria. Primary N-stage and concurrent chemotherapy with OS, DFS, characteristics of this study population are described in LRC, and CFS. Log-rank tests were applied to study dif- Table  1. All but one patients were tested for HIV, 3 of ferences related to period of treatment (< 2014 3D-CRT them were positive. Twenty-six patients had had a diag- and ≥ 2014 IMRT/VMAT) and age (< 75 or ≥ 75 year). nostic surgical tumor resection prior to radiotherapy, of OS was defined as any survival, DFS as survival with - which 19 were R1 and 7 were R2 resections. Eighteen of out relapse or metastatic progression, LRC as survival those 26 patients were treated with local radiotherapy duration without local or regional relapse. Date of clini- only, 30 × 2 Gy, in the other 8 patients either gross resid- cal complete remission (cCR) was defined as the date of ual disease or nodal involvement was shown upon stag- reporting cCR or the date of the MRI documenting com- ing, they were treated with chemoradiation. plete remission, whichever came first. Date of local- or regional relapse was defined as the date of first reported Fig. 2 Disease-free survival. A Disease-free survival for the whole group. B Disease free survival by disease-stage according to AJCC 7th edition; C locoregional recurrences for the whole group; D disease-free survival of patients with treatment start in 2009–2013 versus 2014–2018 Neelis  et al. Radiation Oncology (2022) 17:81 Page 5 of 9 HPV testing was performed in 28% biopsies of which Twenty-seven patients had an anal margin tumor (see 90% were positive for high risk HPV. Twelve patients had Additional file  2: Table S4) of whom 21 were treated with a diagnosis of a second malignancy before (n = 6) or in 30 × 2 Gy to the tumor only and 6 received chemoradia- the follow-up after their treatment for anal carcinoma tion with also treatment on elective nodal regions. Four (n = 6). In all patients radiotherapy was given without of these patients experienced a local relapse, 3 in T1/2N0 treatment breaks. In 6 patients a higher dose than 60 Gy locally treated patients and one in a patient with T3N2 was applied based on a clinical examination of too much disease treated with chemoradiation. residual disease nearing the end of treatment, dose By the end of their follow-up 18 patients had a colos- range 62.2–70  Gy. No dose reductions were applied e.g. tomy, of these 13 were due to salvage surgery after in case of toxicities. Sixty-three patients (all stage 2 and relapse, 2 for quality of life due to severe incontinence 3) received concurrent chemotherapy (64%). Twelve of or urgency, and 3 for other reasons (see Additional file  1: these patients received no MMC, 10 due to age > 75, 1 Table  S3 for details). Four patients had had a colostomy due to M. Crohn, and 1 due to poor renal function. In 50 prior to treatment, of which 3 still had a colostomy at end patients DYPD mutations were tested, four patients (8%) of follow-up. Five patients with a locoregional relapse had a heterozygote DYPD mutation and received a reduc- did not receive salvage surgery, 3 were inoperable due tion to their 5-FU or capecitabine dose down to 75%, one to simultaneous metastatic progression, 1 due to poor patient received both no MMC and a reduced 5-FU dose. health, and 1 refused further treatment after relapse. Three patients should have received chemoradiotherapy based on their tumor stage but were treated with radio- Univariate analyses therapy only, one patient (T2N2) refused chemotherapy, Disease stage, N-status and tumor size were associated one patient (T2N0) was medically unfit and one other with a lower OS (Table  2). Disease stage and N-status patient (T2N0) for unclear reasons. Thirty five patients were also associated with a lower DFS (Fig.  2B), tumor were treated with radiotherapy only. This includes the size however was not. Similarly, a worse LRC was also three patients mentioned above, the other patients had associated with disease stage and N-status. The CFS disease stages T1N0 (n = 18) or superficial T2N0 with however was significantly associated with N-status. Con - tumor dimensions < 4 cm (n = 14). current chemotherapy was not significantly associated During treatment, because of treatment related tox- with either OS, DFS, LRC or CFS. icity, 7 patients received adjustments to their chemo- To analyze time trends as techniques changed, 40 therapy: 5 a dose-reduction, in 2 chemotherapy was patients treated prior to 2014 (n = 31 with 3D confor- prematurely stopped. mal radiotherapy, n = 9 with electrons) were compared to those 58 patients who started after 2014 (n = 44 with Treatment outcomes IMRT or VMAT and n = 14 with electrons, Fig. 2D). Dis- Median follow-up for the cohort was 43  months (range ease stages were comparable in both groups (data not 4–133). Estimated overall survival at 3 and 5  years were shown). The group treated before 2014 had an estimated 79% and 71% (Fig.  1). An unrelated second malignancy DFS at five years of 78% compared to 81% in the group was the cause of death for 4 patients. Estimated DFS at treated from 2014 onwards. Log-rank difference between 3 years was 80% (Fig. 2A) with 4 (4%) upfront failures and these groups was 0.763. 16 (16%) relapses after complete remission. Three of the Twenty three patients (23%) were aged 75  years or four patients with residual disease after treatment were higher. Ten received radiotherapy only, nine with T1N0 salvaged with an APR (see Additional file  1: Table S3), the or T2N0 stage disease and one with tumor stage T2N2, fourth patient experienced a deteriorating health lead- this patient refused concurrent chemotherapy. Thir - ing to his death without a clear cause of death. The lat - teen patients received chemoradiotherapy for higher est relapse in our series occurred at 30  months, with 18 stage disease. MMC was frequently omitted as previ- (90%) within the first 24 months after treatment. LRC was ously described. The estimated 5-year OS in the older age achieved in 80 (82%) of patients at 3 years, with a total of group was lower (60.8% vs. 74.6% in the < 75 group) and 18 locoregional relapses (Fig.  2C). No new locoregional the locoregional recurrence was higher (26.1% vs. 18.7% relapses were observed past 30 months. In the 26 patients in the < 75 group, Fig.  3A, B). The log-rank test for OS with T1 and small superficial T2 tumors that were treated was 0.136, and for the locoregional recurrence 0.496. with 60  Gy in 30 fractions to the tumor without elec- tive nodal irradiation no isolated regional recurrences occurred. Two regional recurrences occurred simultane- Toxicities ously with distant metastases. Reported early clinical toxicity of any grade consisted of dermatitis (100% of patients), pain (98%), diarrhea (52%), Neelis et al. Radiation Oncology (2022) 17:81 Page 6 of 9 Fig. 3 Results in older patients. A Estimated overall survival of patients ≥ 75 years old versus patients aged < 75 years; B locoregional recurrences in patients ≥ 75 years old versus patients aged < 75 nausea (35%), urgency (31%), malaise (29%), edema Discussion (18%), incontinence for stools (18%), vomiting (11%), and In this study results of our single institution retrospective acute cystitis (3%). Leukopenia occurred in 7% of patients analysis of 98 consecutively treated patient with SCCA treated with concurrent CRT, anemia in 4% and neutro- treated in 10 years’ time are described. penia in 3%, two patients experienced febrile neutrope- The reported 3-and 5  year OS of 78.6% and 71.4% nia. Early toxicities grade 3 or higher consisted of grade 3 are comparable to that reported in both randomized pain in 27% and grade 3or 4 dermatitis in 22% of patients. and other retrospective studies [6, 7, 18, 19]. The ACT Other severe toxicities were diarrhea grade 3 or 4 in 5%, I trial reported a 3-year OS of 65% in their CRT group grade 3 nausea in 1%, grade 3 vomiting 1% and grade 2 consisting of 292 patients clinically staged as T2N0 or urgency in 8%. Three patients (3%) had such severe ane - higher [18]. In the Accord 03, a 5-year OS of 71–74.5% mia they required a transfusion (grade 4). was reported in 307 patients with tumors > 4  cm and/ Reported late toxicities of any grade were pain in 75% or N + disease treated with CRT [19]. The Montpellier of patients, urgency in 53%, fecal incontinence in 49%, study found a 5-year OS of 74% in 193 patients treated diarrhea in 38%, dermatitis in 37%, edema in 26% and with CRT, and Mitra et al. reported a 4-year OS of 85.8% nausea in 14%. Higher grade toxicities were 16% grade 2 in 99 patients in all disease stages, treated with CRT [6, urgency, 11% grade 3 pain, 3% ≥ grade 3 incontinence, 3% 7]. The relatively low OS in the ACT I may be attrib - grade 3 dermatitis, and 1 patient with grade 3 diarrhea. uted to the inclusion of only more advanced stages of Late fecal incontinence in the 27 patients with an anal disease as well as stage migration over the years (inclu- margin tumor was 33% with 1 patient (4%) with grade sion ended in 1994, MRI and PET CT scans were not 3 incontinence. This is comparable to that in the whole widely available at that time). The 4-year OS reported by group. Pelvic insufficiency fractures were diagnosed in Mitra et al. is higher than the 3-year OS reported in our 3 patients of which 2 were painful and self-limiting. No study. Although the study populations, treatment period, grade 5 early or late toxicity occurred. median age, disease stage distributions are all compara- Toxicities changed with the transition of 3D to IMRT/ ble, this difference might be attributable to chance and VMAT with an increase in reported acute grade 3 diar- limited numbers. rhea from 2.8 to 6.5% and grade 2 urgency from 2.8 to Our reported DFS of 79.6% and LRC of 81.6% at 3 and 11.3%, with other toxicities remaining fairly consistent 5-years compares favorably to the 3-year DFS of the ACT between both techniques. Reported late toxicity differ - I of 61% and the 5-year DFS of the Montpellier study ences between patients treated with either 3D or IMRT/ of 68% [6, 18]. This is likely attributable to inclusion of VMAT showed an increase in incontinence grade 1–2 higher stages and lack of imaging in the ACT I study. from 27.8 to 56.5% but a decrease in reported incon- The Accord 03 reported an overall relapse free rate of tinence grade 3 from 5.6 to 1.6%. Urgency grade 1 rose 71.4% and a LRC of 72–87.6% [19]. Mitra et al. reported from 30.6 to 40.3%, but grade 2 reports dropped from 83.5% patients were disease-free at the end of follow-up 27.8 to 9.7%. [7]. As with OS however we must again consider that the Neelis  et al. Radiation Oncology (2022) 17:81 Page 7 of 9 ACT I trial included more advanced disease stages, and can give considerable complaints adequate local treat- is relatively old, likely attributing to a worse DFS. Com- ment is warranted, also in older patients. Due to older pared to the Accord 03, the Montpellier study, and Mitra patients frequently being excluded from studies, results et  al. our DFS is better. The Accord 03 included more and outcomes within the geriatric population are often advanced disease stages which might negatively affect not as clear. For this reason, we analyzed the OS and DFS and LRC and it excluded patients with comorbidi- LRC between patients aged 75  years and older, and ties and aged 80 + which should have positively affected those younger than 75.  The portion of older patients in outcomes. In the present series 90% of relapses occurred our study (23%) is comparable to the portion of older within the first 24  months with the latest relapse at patients with the diagnosis of anal cancer in the Neth- 30  months after treatment. Currently, patients receive erlands which is reported to be 28.5% in 2020 [1]. This a standard of 5-years of follow-up. Considering that in suggests that older patients are indeed also referred for 10 years of curative anal carcinoma treatment all relapses treatment. Only one patient refused the chemotherapy have occurred within three years perhaps a shorter fol- part of the treatment and frequently MMC was omit- low-up length is to be discussed with patients [20, 21]. ted. Older patients had a 5  year OS of 60.8% compared CFS in our study was as high as 81.6%. Of the 18 to 74.6% in younger patients, however this was not sta- patients with a colostomy 11 were operated as sal- tistically significant, nor was there a significant difference vage surgery for relapsed disease. these results are like in LRC. Although a lack of significant difference in OS is those reported in the other studies. Where the ACT I unexpected [22], this outcome is most probably due to a reported a CFS of 76.4% in their CRT group, the Accord to small sample size. 03 reported CFS of 69.6–82.4%, the Montpellier study Our study has several limitations. It is a single center reported 66% CFS, and Mitra et  al. reported the high- retrospective analysis and included patients treated with est CFS at 85% [6, 7, 18, 19]. In the ACT I patients only CRT and with radiotherapy alone. Also the necessity to received elective RT and were evaluated after 6  weeks, interpret patient-doctor communication to a toxicity those with < 50% tumor response were considered for sal- grade is a limitation although reporting in the patient vage. This practice most likely attributed to a higher rate files was quite elaborate. Although radiation techniques of colostomies. changed over time the dose prescribed remained the Concerns were raised when the RT technique was same. All patients were treated by a team of 2 radiation changed from 3D to more conformal IMRT and VMAT oncologists and 1 medical oncologist with their residents techniques regarding potential regional misses and guarantying consistent treatment choices, techniques increased numbers of recurrences. Analyzing the time and reporting of toxicities. trend however did not show any significant differences Whether or not intensification of treatment is use - in DFS in our study (78% vs. 81% before and after 2014), ful to improve outcomes remains to be investigated. The further supporting that technique does not affect the Accord 03 study demonstrated that intensifying treat- primary outcome. Changing the technique from 3D to ment with either induction chemotherapy or a higher IMRT/VMAT caused an increase in early reported grade radiotherapy dose did not further improve outcomes [19] 3 diarrhea and grade 2 urgency. Part of the increase whereas the Mitra et al. study reported outcomes compa- in diarrhea may be attributable to the change from iv rable, if not marginally better, than our findings but did 5-FU week 1 and five to oral capecitabine twice daily for so with a lower radiotherapy dose [7]. Further studies to the whole treatment period. Severe late incontinence find the optimum dose of radiotherapy to balance disease grade 3 dropped from 5.6 to 1.6% with an increase in outcome with toxicity are warranted [11, 23]. Results reported incontinence grade 1–2 from 27.8 to 56.5%. The from the ongoing PersonaLising Anal cancer radioTher - increase in reported toxicity both early and late is likely apy dOse trial (PLATO), incorporating the ACT3, ACT4 also attributable to changes in reporting practices in our and ACT5 trials are eagerly awaited. clinic, with the advent of the electronic patient file in 2011 and the addition of required toxicity forms since the Conclusions start of 2018. The decrease in severe toxic effects was the Our 10 year cohort study shows that patients treated with expected effect of switching to IMRT techniques [9, 11, curative intent for anal cancer in our regional referral 12]. center achieve OS and DFS comparable to that reported A significant portion (23%) of our patients were aged in the literature. With the introduction of more confor- 75 and over. Tumor stage did not significantly differ from mal radiation techniques DFS remained similar with the under 75 group. Since metastatic disease occurs rela- lower toxicities. Older patients can be safely treated with tively late in the disease course and the primary tumor slightly adjusted CRT with good results. Neelis et al. Radiation Oncology (2022) 17:81 Page 8 of 9 4. Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, Supplementary Information et al. Concomitant radiotherapy and chemotherapy is superior to radio- The online version contains supplementary material available at https:// doi. therapy alone in the treatment of locally advanced anal cancer: results org/ 10. 1186/ s13014- 022- 02049-8. 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. Additional file 1. Table S3: Details of patients with a colostomy at the 5. Deniaud-Alexandre E, Touboul E, Tiret E, Sezeur A, Houry S, Gallot D, et al. end of follow-up. Results of definitive irradiation in a series of 305 epidermoid carcinomas Additional file 2. Table S4: Distribution and treatment of patients accord- of the anal canal. Int J Radiat Oncol Biol Phys. 2003;56(5):1259–73. ing to site of disease. 6. de Meric de Bellefon M, Lemanski C, Castan F, Samalin E, Mazard T, Len- glet A, et al. Long-term follow-up experience in anal canal cancer treated with Intensity-Modulated Radiation Therapy: Clinical outcomes, patterns Acknowledgements of relapse and predictors of failure. Radiother Oncol. 2020;144:141–7. Not applicable. 7. Mitra D, Hong TS, Horick N, Rose B, Drapek LN, Blaszkowsky LS, et al. Long- term outcomes and toxicities of a large cohort of anal cancer patients Author contributions treated with dose-painted IMRT per RTOG 0529. Adv Radiat Oncol. KN and YL designed and supervised the study. DK analyzed and interpreted 2017;2(2):110–7. the patient data and wrote the first draft of the manuscript. YL and FS com- 8. Koerber SA, Slynko A, Haefner MF, Krug D, Schoneweg C, Kessel K, et al. mented on several versions of the manuscript. KN was a major contributor in Efficacy and toxicity of chemoradiation in patients with anal cancer–a writing the final version of the manuscript. All authors read and approved the retrospective analysis. Radiat Oncol. 2014;9:113. final manuscript. 9. Ghareeb A, Paramasevon K, Mokool P, van der Voet H, Jha M. Toxicity and survival of anal cancer patients treated with intensity-modulated radia- Funding tion therapy. Ann R Coll Surg Engl. 2019;101(3):168–75. Not applicable. 10. Pan YB, Maeda Y, Wilson A, Glynne-Jones R, Vaizey CJ. Late gastrointestinal toxicity after radiotherapy for anal cancer: a systematic literature review. Availability of data and materials Acta Oncol. 2018;57(11):1427–37. The datasets used and/or analysed during the current study are available from 11. Kachnic LA, Tsai HK, Coen JJ, Blaszkowsky LS, Hartshorn K, Kwak EL, et al. the corresponding author on reasonable request. Dose-painted intensity-modulated radiation therapy for anal cancer: a multi-institutional report of acute toxicity and response to therapy. Int J Radiat Oncol Biol Phys. 2012;82(1):153–8. Declarations 12. Deenen MJ, Dewit L, Boot H, Beijnen JH, Schellens JH, Cats A. Simultane- ous integrated boost-intensity modulated radiation therapy with con- Ethics approval and consent to participate comitant capecitabine and mitomycin C for locally advanced anal carci- The protocol for our study was submitted for review to the LUMC ethics noma: a phase 1 study. Int J Radiat Oncol Biol Phys. 2013;85(5):e201–7. committee (G20.026, March 11, 2020) and was deemed not necessary to be 13. TNM classification of malignant tumours, 7th edition ed. Cancer UIUA, subjected to further review under the Medical Research Involving Human editor: Wiley; 2009. Subjects Act ( WMO). As such individual patient consent was not applicable. 14. Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, Consent for publication cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized Not applicable. controlled trial. JAMA. 2008;299(16):1914–21. 15. 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Journal

Radiation OncologySpringer Journals

Published: Apr 20, 2022

Keywords: Anal carcinoma; Retrospective; Chemoradiotherapy; Treatment results

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