Abstract
Background/Aim: The current standard for anal cancer treatment is essentially a ‘one size fits all’ approach where the dose of radiotherapy is similar whether the tumor is very small or very large. Trials are ongoing to evaluate dose de-escalation or escalation in localized disease depending on tumor size. The aim of the study was to assess results of a personalized approach involving dose stratification by stage and boost dose adjusted according to tumor early response. Patients and Methods: We retrospectively reviewed squamous cell anal cancer (SCAC) patients treated between 2011 and 2021 by long-course intensity-modulated radiotherapy (IMRT) and concomitant chemotherapy (CT); a sequential boost could be administered by IMRT or interventional radiotherapy (IRT) to obtain a total equivalent dose in 2 Gy (EQD2) of 54-60 Gy. Results: We analyzed 110 patients (61% T3-4 stage, 71% node-positive). A total of 68.2% of patients received a sequential boost, mainly by IRT; median total EQD2 to primary site was 59.3 Gy. Acute ≥G3 toxicity rate was 36.4%. Median follow-up (FUP) was 35.4 months. A total of 83% of patients achieved clinical complete response (cCR); locoregional recurrence (LRR) occurred in 20.9% and distant metastases in 6.4% of cases. A total of 12.7% patients underwent salvage surgery. A total of 25.5% of patients reported ≥G2 and 4.5% ≥G3 late toxicity. The estimated 3-year overall survival, disease-free survival and colostomy-free survival were 92%, 72% and 84% respectively; 3-year-LRR was 22%. Nodal stage was associated with poorer cCR probability and higher LRR (p<0.05). Conclusion: Our results on a large cohort of patients with locally advanced SCAC and long FUP time confirmed the efficacy of IMRT; high local control and manageable toxicity also suggest IRT as a promising method in treatment personalization.
- Anal canal cancer
- intensity-modulated radiotherapy
- interventional radiotherapy
- personalized combined treatment
Results from a large number of randomized trials have confirmed the efficacy and safety of exclusive chemoradiotherapy (CRT) as primary treatment of squamous cell anal cancer (SCAC) with 3-year overall survival (OS) rates ≥75%, and colostomy-free survival (CFS) rates of 61%-76% (1-6). Abdominoperineal surgical resection (APR) is, however, reserved for the management of non-responsive cases or disease recurrence. Radiation treatment of the anal cancer is challenging due to complexity of the target volume and multiple surrounding normal tissues (bowel loops, bladder, external genitalia, perineal skin, bone marrow).
Intensity modulated radiation therapy (IMRT) can provide highly targeted irradiation with potential dose reduction to critical structures, reducing the likelihood of acute gastrointestinal and cutaneous toxicities ≥G3 and hematologic events ≥G2, as seen in the RTOG 0529 trial (7). IMRT has also enabled the use of an integrated simultaneous boost (SIB) strategy to treat macroscopic primary tumor, clinically involved lymph nodes and elective target volumes at different dose levels (8, 9). As an additional boost modality, interventional radiotherapy (IRT - brachytherapy) represents a further technique to allow overdosing on the site of residual tumor sequentially to CRT treatment (10). Therefore, it seems plausible that this will result in better clinical outcomes of both tumor control and normal tissues complications, and this is why IMRT is the most widely employed technique for radiotherapy of anal canal cancer (11).
The aim of this retrospective analysis was to report the results after a long experience and follow-up of patients with SCAC treated at our Institution by IMRT since 2011, in terms of acute and late toxicities, tumor response and survival outcomes.
Patients and Methods
Patients affected by histologically documented anal cancer and treated in our Center from May 2011 to January 2021 were consecutively and retrospectively analyzed. For study purposes, inclusion criteria were histologically proven squamous anal carcinoma, age ≥18 years, treatment with IMRT in a curative intent, informed consent to treatment. Conversely, we excluded patients previously irradiated on the pelvis and patients not eligible for radiotherapy with curative intent (i.e. due to a high burden of metastatic disease, general clinical condition, etc.).
Every patient was evaluated at diagnosis with clinical history, physical examination, and laboratory tests. Multiparametric magnetic resonance imaging (MRI) and trans-anal ultrasonography (US) were performed for locoregional staging. A chest-abdomen computed tomography (CT) or a fluorodeoxyglucose-positron emission tomography (FDG PET), whenever possible, were acquired for systemic evaluation (10). Disease was clinically staged according to the American Joint Committee on Cancer (AJCC) TNM classification (2010-7th edition).
All cases were discussed in the frame of the institutional multidisciplinary tumor board, both at the time of diagnosis and at post-treatment re-evaluation. In case of advanced lesions leading to frank impairment of continence, at risk of occlusion or fistulation due to vaginal involvement, a defunctioning stoma was placed.
External beam radiotherapy and concomitant chemotherapy. Patients were candidate to concurrent chemotherapy according to the following schedule: 5-flourouracil (5-FU) continuous venous infusion of 1000 mg/m2 over 96 hours and mitomycin-C (MMC) of 10 mg/m2 during the first and last weeks of radiation therapy (FUMIR) (6).
All patients were treated in the supine position. A radiopaque marker was placed at the level of anal verge as caudal limit for contouring. To reduce organ motion, patients were instructed to drink 500 ml of water 30 minutes before simulation and each treatment session.
The gross tumor volume (GTV) included primary tumor (GTV-T) and involved lymph nodes (GTV-N). The GTV was contoured based on the co-registration of simulation CT with MRI images and FDG PET, when available. A margin of 20 mm was applied to the GTV-T and adapted to anatomical structures to originate the clinical target volume (CTV). The elective nodal CTV encompassed pelvic lymph nodes (presacral, bilateral inguinal, obturator, internal and external iliac nodes), mesorectum (only its lower 5 cm in case of no gross disease within the mesorectum), ischio-rectal fossa in case of direct infiltration, common iliac or lumbo-aortic nodal stations in case of positive lymph nodes at that level. Organs at risk (OARs) were contoured; dose volume constraints were adopted from RTOG 0529 trial and National Comprehensive Cancer Network guidelines (7, 11).
External beam radiation therapy (EBRT) was delivered using IMRT technique with a SIB: 45 Gy (1.8 Gy daily) were prescribed on elective nodal planning target volume (PTV) while different dose levels were prescribed on gross disease PTVs. Tumor PTV was planned to receive 45 Gy (1.8 Gy daily) in case of cT1, 50 Gy (2 Gy daily) in case of cT2, 55 Gy (2.2 Gy daily) in case of locally advanced disease (cT3-T4); in case of positive nodes, 50 or 55 Gy were administered in 25 fractions to nodal PTV according to their dimensions. Dosimetric parameters for planning followed the recommendations of the International Commission on Radiation Units and Measurements (ICRU) report No.83 (13). Daily Electronic Portal Imaging (EPI) and/or Cone-Beam CT were performed to verify patient positioning and OARs filling.
Clinical and laboratory evaluations were performed at least weekly by radiation oncologists during the course of treatment for clinical toxicity assessment according to common toxicity scale for adverse events (CTCAE v4.0) (14).
Timing. Three to four weeks after the end of CRT, patients were re-evaluated by digital rectal examination (DRE) and pelvic MRI; according to initial clinical stage and early primary tumor response, a radiotherapy boost was administered via external beam radiotherapy or Image Guided IRT (15, 16). The MRI was performed according to the MITHRA protocol with applicator into the anus in order to reproduce the same distortion of the anus that will occur at the time of IRT when the needle guide template is inserted (15).
Interventional radiotherapy (IRT–brachytherapy). After external beam radiotherapy, IRT recommendation was placed according to primary tumor baseline clinical stage and early response to treatment assessed by DRE and pelvic MRI. The following were considered exclusion criteria for the procedure: insertion of the applicator in the anal canal not feasible; involvement of the rectum (>12-13 cm cranial from the anal margin); involvement by CTV of more than half of the anal canal circumference; psychiatric disorders and/or MRI contraindications; progressive disease after radiochemotherapy.
The IRT procedure was performed in the lithotomy position either after administration of spinal anesthesia or under sedation. The template was inserted and fixed to the skin either by sutures or by adhesive stripes, and needles were positioned according to the pre-plan indications retrieved from imaging (MRI and US). Following the needles insertion, a CT scan was acquired and therefore a definite post-implantation treatment (post-plan) was obtained. Patients were kept in the very same position throughout the procedure by using a dedicated patient transport system. Needles were placed in accordance with the Paris system, however additional manual optimization was performed. The high-dose-rate (HDR) boost dose was delivered using a Microselectron with a source of Iridium-192. The IRT procedure was typically performed once or twice with one week interval. The total dose was evaluated case by case, in order to reach a total equivalent dose in 2 Gy fractions (EQD2) ranging from 54 to 60 Gy (EBRT + IRT). Treatment indication and doses to primary tumor by both external beam and interventional radiotherapy are summarized in Figure 1.
Personalized IRT boost according to initial clinical stage and response to primary chemoradiotherapy. CR: Complete response; ERT: external beam radiotherapy; IRT: interventional radiotherapy; PR: partial response.
Follow-up. For patients with a clinical complete response, follow-up was carried out every 2-4 months for the first 2 years and every 6 months thereafter up to 5 years. Additionally, trans-anal US, chest-abdomen CT or FDG PET were performed when clinically indicated. Patients with persistent disease but no evidence of progression were managed with close follow-up for up to 26 weeks from the start of chemoradiotherapy (17); if a trend toward response was observed, the observation period could be extended. When signs or symptoms of disease relapse occurred, further investigations were prompted. Biopsy to confirm recurrence was performed when APR was planned.
Endpoints. The following outcomes were evaluated: 3-year-overall survival (OS), toxicity, treatment compliance, clinical complete response (cCR), colostomy free survival (CFS), loco-regional recurrence (LRR) and disease-free survival (DFS). OS was calculated from the date of diagnosis to the date of death from any cause or the last documented date of clinical follow-up.
Acute (from CRT start to 6 months after the end of treatment) and late toxicities (>6 months after treatment completion) were scored using the CTCAE v4 (14).
Treatment compliance was estimated in terms of treatment interruptions and overall treatment time (OTT).
cCR was defined as the absence of any sign of residual disease within the irradiated volume at clinical examination. Complete response achieved more than 26 weeks after CRT was defined as late cCR (17).
Local and regional failures were considered for loco-regional control; disease recurrence was defined as local if occurring within the anal canal and/or anal margin and/or mesorectum, regional if involving local draining lymph nodes. LRR included both patients who failed to achieve cCR and failures occurring after initial cCR; it was defined as the interval between the date of diagnosis and that of local and/or regional recurrence.
CFS events included all post-treatment colostomies carried out either as surgical salvage for persistent/recurrent disease or to alleviate late effects of radiation as well as pre-treatment colostomies. For the first circumstance, CFS was calculated as the interval from the date of diagnosis to the day of colostomy, for the latter as the interval from colostomy reversion to the last follow-up. DFS was calculated as the interval between the date of diagnosis and date of local/regional recurrence or distant recurrence.
Statistical analysis. Survival endpoints, such as OS, CFS and DFS were estimated by Kaplan-Meier method, variables potentially associated were tested via Cox regression multivariate model. LRR was estimated by the cumulative incidence method; predictors of LRR were assessed using logistic regression. Statistical analysis was performed using SPSS Statistics for Windows, Version 23.0 (IBM SPSS Statistics for Windows, Version 23.0, IBM Corp., Armonk, NY, USA).
Results
Patient baseline and treatment characteristics. Among 117 consecutive patients, one-hundred and ten met the inclusion criteria and were analyzed; patients and tumor characteristics are summarized in Table I. They were mostly women (n=80, 72.7%) with a median age of 64.3 years (range=39-89.0). Sixty-seven (60.9%) were staged cT3-4 and 78 (70.9%) had clinically positive lymph nodes. In six patients, anal cancer was diagnosed after a local excision resulting in microscopic or macroscopic residual tumor; these were then classified as Tx. Seven patients (6.4%) were defined as M1 due to radiological evidence of non-regional lymph nodes (n=5) or distant sites (n=2), with a low distant disease burden in any case.
Patient and disease characteristics of the entire study cohort (n=110).
One-hundred eight patients (98.2%) received concomitant CT, of whom 8 (7.4%) received schedules other than FUMIR owing to metastatic stage, age, or comorbidities: cisplatin and 5-FU (n=4), 5-FU continuous infusion (n=3), carboplatin and paclitaxel (n=1).
Radiotherapy was delivered with a median dose to the tumoral GTV of 55 Gy (range=41.8-61.2). Seventy-five patients (68.2%) received a sequential boost, mainly by IRT (n=53, 71.6%), with a median dose of 8 Gy (range=3.5-28); thus, median total EQD2 dose to primary site was 59.3 Gy (range=50.0-73.6) for the entire population considering an alfa/beta of 10.
Treatment compliance and toxicity. Median OTT for CRT was 37 days (range=31-71) while median OTT comprehensive of the sequential boost, when performed, was 76 days (range=31-225). Treatment was temporarily interrupted for >5 days in 34 patients (30.9%) for toxicity, while in 3 cases (2.7%) a planned interruption was performed for compliance purposes. Acute ≥G3 toxicity occurred in 36.4% of patients (n=40) of cutaneous (n=29), hematological (n=14) or gastrointestinal (n=6) type. Twenty-eight patients (25.5%) experienced late adverse effects ≥G2: cutaneous (n=1), subcutaneous (n=5), gastrointestinal (n=20), urological (n=1), other (e.g. sexual dysfunction; n=10). Of these, 5 patients had G3 late toxicity (3 gastrointestinal, 2 subcutaneous). Characteristics of CRT and treatment compliance and toxicity are summarized in Table II.
Treatment characteristics, compliance and toxicity for the entire study cohort.
Treatment response. Median follow-up time was 35.4 months (range=4.8-116.4). Ninety-one patients (83%) achieved cCR after a median time of 5.8 months (range=2.2-13.5). Of these, 28.6% (n=26) were late responders and their median time to cCR was 8.35 months (range=6.87-13.47). Twenty-three patients (20.9%) experienced persistent loco-regional disease or recurrence at a median interval from diagnosis of 9.7 months (range=4.4-52.3). We did not observe a significant correlation between disease stage at diagnosis and time to complete response (CR) (B=0.115, 95% CI=−0.394 to 0.625, p=0.654). We also did not observe a significant correlation between time to CR and LRR (B=−1.289, 95% CI=−3.170 to 0.591, p=0.177). Figure 2 shows locoregional outcomes of patients after CRT completion.
Flow-chart of locoregional outcomes of patients after CRT completion. APR: Abdominoperineal resection; cCR: clinical complete response.
Colostomy failure. Twenty-eight patients required a diverting colostomy before starting treatment; of these, 14 (50%) were successfully reversed after treatment completion (median colostomy duration=12.5 months). Overall, 26 patients (23.6%) had colostomy at the last follow-up: specifically, 16 patients for persistent or recurrent disease, while 10 patients could not have their colostomy removed, even though they were disease-free, for patient’s refusal or poor expected functionality.
Overall survival, distant metastases, and outcomes analysis. Overall, 97 patients were alive at the time of the analysis. Seven patients (6.4%) developed distant metastasis, of which 3 also experienced locoregional recurrence. Of the 13 patients who died, two patients died for metastatic disease, seven for locoregional disease and the remaining four for other causes. Figure 3 summarizes locoregional and distant failure patterns. Estimated 3-year-OS, 3-year-DFS and 3-year-CFS were 92.1% (95% CI=89.2-95%), 71.7% (95% CI=66.9-76.5%) and 84% (95% CI=80.3-87.9%), respectively; 3-year-LRR was 22% (95% CI=21.9-22.1%). Kaplan-Meier estimates of OS, CFS, and DFS and the cumulative incidence of LRR are illustrated in Figure 4. In a multivariate regression analysis, nodal stage was associated with a reduced probability of cCR (HR 0.68, 95% CI=0.53-0.86, p=0.002), after adjusting for age and T stage. Nodal stage was also associated with a higher risk of LRR (HR=1.56, 95% CI=1.07-2.28, p=0.021), after adjusting for age, sex, T stage and M stage.
Patterns of local and distant failures.
Overall survival (A), disease-free survival (B), locoregional recurrence (C) and colostomy-free survival (D) Kaplan-Meier estimates for the entire study cohort.
Discussion
Combined chemoradiotherapy is standard treatment for squamous anal cancer. In our institution IMRT has been a well-established treatment technique for anal cancer for about 10 years now; these are the mature results of a mono-institutional retrospective large cohort of 110 anal cancer patients treated in a homogeneous manner with a median follow-up time of about 3 years.
Data from historical randomized trials (RTOG98-11 and ACT II) reported a grade 3+ acute skin and hematologic toxicity rate of 48% and 26% respectively (18,19). In our experience, toxicity rates are comparable to other IMRT treatment series and, more importantly, demonstrate better tolerance than historical three-dimensional conformal radiation therapy (3DCRT) cohorts despite a dose escalation on the GTV. We identified rates of grade 3+ acute dermatologic, hematologic, and gastrointestinal (GI) toxicity of 26%, 12.7%, and 5% respectively, which is comparable to IMRT RTOG 0529 trial in which a 23% of cutaneous, 58% hematologic and 21% GI events were reported (7, 20).
A distinctive feature of our cohort is that it offers a view of locally advanced disease, (60.9% were staged cT3-T4) and lymph node extension (70.9% had positive lymph node disease), with a stage II-III percentage of 88.1%.
Consistent with post-hoc analysis of the ACT II trial (17) post-treatment surveillance showed a slow clearance of anal cancer disease up to 26 weeks after starting treatment with a non-neglectable percentage of late responders as recorded by De Meric; in their experience 95% of patients achieved a cCR in 5 months (median) over a wide range of time, from 2 to 15 months (21). In our population we recorded a cCR rate of 83% in the entire cohort; median time for cCR was 5.8 months (range=2.20-13.47). Remarkably among them 28.6% (n=26) were late responders (beyond 26 weeks) and their median time to cCR was 8.35 months (range=6.87-13.47). One potential explanation for this great proportion of late responders could be the high number of large and locally advanced tumors; however, we did not observe a significant correlation between disease stage at diagnosis and time to CR. Frequently, at early follow-up assessments digital rectal examination is not sufficient to discriminate between post-treatment scar tissue or oedema and residual/relapsed disease; moreover, post-actinic fibrosis can also complicate instrumental assessment of the pelvic region. To avoid misclassifying slow tumor regression as persistent disease we opted to continue observation over time.
We did observe favorable long-term outcomes with 3-year of OS, DFS, CFS of 92.1% (95% CI=89.2-95%), 71.7% (95% CI=66.9-76.5%) and 84% (95% CI=80.3-87.9%), respectively. These results are consistent with the results of previous studies, whether they used 3DCRT or IMRT. Patients treated on RTOG 9811 had 5-year DFS of 68% and OS of 78% (18). Recently published data from RTOG 0529 IMRT phase II trial reported 2-year OS, DFS and CFS of 86%, 76% and 84% respectively (22).
In the current study, LRR was reported in 20.9% of cases; most recurrences (65%) took place within the first year, with an even greater percentage (91%) occurring within two years. This is consistent with data obtained from other studies such as ACT II, which showed that <1% of relapses occurred after 3 years post-treatment. We did not observe a significant correlation between time to CR and LRR rate; therefore, we can safely assume also late CR confers a gain in terms of local control.
Recent studies have reported that LRR are a major site of failure and that predictive factors for recurrence include male sex, high nodal stage and failure to complete radiotherapy as planned (23). Lymph node status has a significant impact on prognosis, as demonstrated by an Italian retrospective analysis on 987 patients by Caravatta et al. which showed that node-positive patients have a significantly lower probability of CR than patients with uninvolved lymph nodes and lymph node involvement (regardless of T-stage) is associated with a lower local control rate (p<0.001) (24). Our multivariate analysis confirmed that nodal stage is associated with statistically significant reduced probability of CR (aHR 0.68) and higher risk of LRR (aHR=1.56).
Three-year CFS was 84% resulting even better compared to literature data, although based on a smaller population; in fact, RTOG 9811 showed a 5 years CFS of 71.9% (18).
23.6% of our patients had colostomy at the time of follow-up, including those carried out as surgical salvage for persistent/recurrent disease as well as pretreatment colostomies never reversed after CRT. It is important to underline that within our population there was a high percentage (25%) of patients who required a derivative ostomy just before the beginning of treatment due to the presentation of the disease and a ostomy reconversion rate of 50% and a median ostomy duration of 12.5 months; these confirmed previous data from a sub-analysis of the ACT II trial, which showed a stoma reversal in 48% of patients (25).
Despite the known variation in local control rates according to tumor size and the potential decrease in adverse effects with de-escalation, the optimal dose of radiotherapy according to stage of disease is still a subject of research. In the IMRT and image-guided radiotherapy era, dose escalation continues to be investigated, especially for patients with locally advanced disease. Tumor control probability models suggest that lower doses may be sufficient for small tumors, while higher doses, at least 50-55 Gy, may be necessary for more advanced tumors (T3-4 or N1). A review of IMRT data on anal cancer identified a linear quadratic dose-response model, suggesting that for IMRT-treated patients a >5 Gy increase in total dose may improve local control rates by >10% (26). Despite potential gains in treatment efficacy associated with dose escalation, dose escalation also conditions the occurrence of late toxicities, especially the risk of fecal incontinence for dose levels >56 Gy (27).
The current approach for anal cancer treatments is essentially a ‘one size fits all’ where the dose of radiotherapy is similar whether the tumor being treated is very small or very large (10, 11). Trials are currently ongoing to evaluate the de-escalation or dose escalation in localized disease depending on tumor size at diagnosis. The aim of the ongoing Personalising Anal Cancer Radiotherapy Dose (PLATO) trial, sponsored by the Cancer Research Foundation of the United Kingdom, is to define the optimal treatment approach with different treatment intensification schedules according to risk classes (28). PLATO ACT IV trial randomized patients with intermediate-risk neoplasms (cT1-T2, ≤4 cm, N0) to standard-dose or reduced-dose CRT; short-term results confirm so far that dose de-escalation is feasible with comparable tumor response rates and better tolerance compared to standard dose (29). The ongoing ACT V trial will assess the outcomes of dose escalation for patients with cT3-T4 disease.
Our HIT-ART approach fits precisely into this scenario in that it involves dose stratification by stage and the total dose is further adjusted according to early response (Figure 1). The total dose is selected on a case-by-case basis to achieve a total EQD2 dose between 54 and 60 Gy (EBRT + IRT). Specifically, the dose of EBRT is selected according to the clinical T stage at diagnosis; then, based on the early tumor response assessment by MRI one month after the end of primary EBRT, the indication for IRT boost adapted to both initial clinical stage and the response to primary chemoradiation is defined. As an example, for a cT3 neoplasm undergoing primary therapy up to 55 Gy by EBRT, in the case of an incomplete response a dose escalation with additional 4 Gy by IRT is provided, whereas in the case of complete response an IRT boost is not indicated. On the contrary, in a cT2 tumor (>2 cm) treated with a lower EBRT dose (50 Gy) an IRT boost will always be delivered, with a single fraction (4 Gy) in the case of a complete response and two fractions (8 Gy) in the case of an incomplete response. The strength and clinical benefit of this approach are that dose modulation (de-escalation and escalation) is tailored on the basis of tumor response assessed by MRI after EBRT. Also, the peculiarity lies in the possibility to adopt IRT to deliver additional dose to the residual tumor.
In fact, the good toxicity profile and oncological outcomes of this population, carrying a significant tumor burden, could be at least partially attributed to the large use of IRT (n=53). Since IRT boost is adapted to the residual tumor and no CTV to PTV margin is needed, smaller volumes of healthy tissues are exposed to the prescribed dose compared to external beam radiotherapy boost (30). Anal dilatation by means of the spacer can further reduce the exposure of uninvolved tissues by displacing them from the high-dose region (31). Moreover, the dosimetric characteristics of IRT allow to deliver high heterogeneous dose, biologically favorable, inside the target volume with a rapid dose fall-off at the periphery (32). However, adequate procedural skills and planning, careful selection of patients and a non “one size fits all” approach are recommended (33). In fact, as highlighted in Figure 1 our treatment schedule is based on a personalized dose strategy focusing on two main aspects, namely initial clinical stage and response to primary chemoradiotherapy, with the aim to adapt the dose delivered by IRT according to the individual response.
The limitations of this study are essentially related to its retrospective design. Moreover, data related to patients smoke habit and human papilloma virus (HPV) status were missing in the majority of the cohort, which could bring additional information about the role of risk factors and help stratify the population.
We reported 25.5% ≥G2 late adverse effects, which were cutaneous, subcutaneous, gastrointestinal, urological, or sexual. These data suggest the importance of identifying strategies for better OARs preservation and late toxicities management. As several aspects of long-term function and quality of life (QoL) have been identified as factors to be investigated (e.g., sleep disorders) (34), anal cancer specific QoL questionnaires are being developed and validated and should be administered to patients over the course of follow-up visits (35-37). Unfortunately, our study lacks patient reported outcomes measures (PROMs), especially in terms of fecal continence; the opportunity to investigate this aspect, together with sexual function and sleep disorders is certainly interesting and challenging in the context of dose escalation strategy.
Conclusion
Data confirm that IMRT is associated with favorable acute and late toxicity rates and excellent long-term rates of tumor control and colostomy-free survival compared to historical 3DCRT series, and thus serve to support the continued utilization of IMRT as the preferred treatment technique for patients with anal cancer.
Our HIT-ART approach involves dose stratification by stage and the total dose is further adjusted according to early response). In addition, recent improvements in image guidance and intensity modulation even for IRT have made it possible to deliver high doses via HDR with a limited toxicity profile. Integrating this approach with other information such as biological tumor markers along with recording and verifying patient perspectives on late toxicity could allow identification of optimal intervention to further improve outcomes.
Footnotes
Authors’ Contributions
SM, LT, and MAG conceptualized and supervised the study. Data curation and formal analysis were performed by SM, SM, and RB. SM, BF, SM, GC, LT, and MAG validated data. VDL, BB, and VF provided resources. All Authors have revised the manuscript for intellectual content and approved the final version to be published.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received December 1, 2023.
- Revision received January 25, 2024.
- Accepted February 12, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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