{'fraction_non_alphanumeric': 0.035942028985507246, 'fraction_numerical': 0.02673913043478261, 'mean_word_length': 5.183243727598566, 'pattern_counts': {'":': 0, '<': 2, '<?xml version=': 0, '>': 3, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 3, 'zh_pornsignals.json': 0}}
Intensity modulated radiotherapy for anal canal squamous cell carcinoma: A 16-year single institution experience

Highlights • IMRT is associated with favorable toxicity rates for patients with anal cancer.• Outcomes were favorable for those with T3-4 tumors or lymph node involvement.• Current smokers are at a higher risk of severe dermatologic toxicity.• Overall treatment duration greater than 39 days is associated with recurrence.

The purpose of this study is to report a 16-year single institution experience utilizing IMRT for patients with ASCC with an emphasis upon long-term efficacy, toxicity, and disease and treatment-related variables associated with outcomes.

Patient population
Following institutional review board approval, patients diagnosed with ASCC between 2003 through 2019 were identified. Patients were included for analysis if they were 18 years of age or older, had biopsy confirmed ASCC, and received curativeintent IMRT. Patients with a prior history of pelvic radiotherapy were excluded.
Pre-treatment evaluation included complete history, physical examination, and laboratory evaluation. Systemic staging imaging included positron-emission tomography-CT (73%) and/or CT of the chest, abdomen, and pelvis (27%). Local staging with pelvic MRI was performed per physician discretion. Lymph node status was determined based upon imaging, with biopsy confirmation infrequently performed. Tumor Human Papillomavirus (HPV) status was determined by p16 immunohistochemistry or by in situ hybridization for high risk HPV RNA, when available.

Patient assessments
Patients underwent routine oncologic surveillance including digital rectal exam with or without anoscopy and diagnostic imaging at 3-6 month intervals. Sites of recurrence were characterized through the entirety of follow-up and not restricted to first site of recurrence.
LR was defined as recurrence or progression at the primary tumor site; LRR was defined as recurrence or progression within the primary tumor site or non-metastatic regional lymph nodes; DM sites were defined as non-regional lymph nodes or distant organs. Disease recurrence was diagnosed histologically, or when unavailable, clinically per radiographic findings. AEs were assessed and attributed prospectively by the treating physician per common terminology criteria for adverse events version 4.0 (CTCAE v 4.0). When unavailable, AEs were ascertained through retrospective chart review. Acute AEs were defined as those occurring during RT or within 3 months of treatment completion. Late AEs were defined as those occurring greater than 3 months after completion of RT.

Statistical analysis
Statistical analysis was performed using SAS version 9.4 (SAS Institute Inc., Cary NC), with p < 0.05 considered statistically significant. OS, CFS, and PFS were estimated using the Kaplan-Meier method. The cumulative incidence of LR, LRR, DM, and posttreatment colostomy (excluding 2 patients who underwent diverting colostomy prior to treatment initiation) were reported with death as a competing risk. Treatment-related AEs were reported descriptively.
The Cox Proportional Hazards model was performed to identify associations between disease and treatment characteristics and oncologic endpoints. Variables examined included American Joint Committee on Cancer Staging 8th edition clinical stage grouping, T-stage, LN status, RT dose, biologically effective dose (BED) assuming an a/b ratio of 10 Gy, chemotherapy regimen, overall treatment duration, and smoking status.

Results
A total of 127 patients were included for analysis. Baseline patient and treatment characteristics are reported in Table 1.
Eleven patients underwent colostomy, of which 2 underwent pre-treatment colostomy due to tumor-related obstruction. One patient developed a bowel obstruction mid-treatment requiring urgent colostomy and another developed a bowel obstruction in the absence of LRR 2 months after treatment and underwent colostomy. Five patients underwent salvage abdominoperineal resection due to LRR or incomplete tumor response at a median of 10 months (range 3-11 months) after RT. Two patients underwent abdominoperineal resection in the absence of LRR-1 patient due to chronic pain and anal sphincter incompetence 7 months after RT and the other was a patient with comorbid inflammatory bowel disease who underwent abdominoperineal resection as part of an inflammatory bowel disease-directed operation approximately 31 months after completion of RT.
Interesting aspects of this work include the relatively large patient cohort (n = 127), fairly homogeneous delivery of DP-IMRT (95%), mature median follow-up of 47 months (IQR: 28-   89 months), robust collection of acute and late AEs, and the availability of extensive patient, disease, and treatment characteristics which facilitated an analysis of variables associated with oncologic efficacy outcomes. Our series, in addition to the IMRT series summarized within Table 4, continue to show that IMRT is associated with a favorable toxicity profile compared to historical 3DCRT series [8,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. We identified rates of grade 3+ acute GI, dermatologic, and hematologic toxicity of 17%, 16%, and 31%, respectively. This is in reference to rates of 7-21%, 10-48%, and 3-63% in other IMRT series, and rates of 36%, 49%, and 62% identified with the use of 3DCRT in RTOG 9811. Severe late toxicities were uncommon, with rates of grade 3+ GI, GU, and chronic pain of 3%, 2%, and 1%, respectively. Patients who continued tobacco smoking during CRT had nearly 5 times the rate of acute dermatologic toxicity (34% vs. 7%, p < 0.001) compared to former or never smokers. Lerman et al. reported on the impact of tobacco smoking upon outcomes after CRT for patients with ASCC [35]. They identified that tobacco smoking had a detrimental impact upon LRR, relapse-free survival, and OS. However, tobacco smoking was not associated with the risk of grade 3 toxicity. Eifel et al. have demonstrated an association between smoking history and an increased risk of acute small bowel toxicity in women receiving pelvic radiotherapy for cervical cancer and Alsadius et al. have reported an association between current smoking and an increased risk of bowel toxicity for men receiving RT for prostate cancer. Therefore, it does seem plausible that smoking may have an adverse impact upon treatment tolerability [36,37]. Based upon these data, we suggest that utilization of IMRT may offer a reduction in GI, dermatologic, and hematologic toxicity when compared with 3DCRT, while addressing patient modifiable risk factors, such as smoking status, is also an important aspect of care.
In this analysis, prolonged overall treatment duration (>39 days) was associated with an increased risk of LRR. One argument may be that this finding is primarily reflective of a greater risk of LRR for T3-4 tumors as they are more commonly treated with regimens of !30 fractions extending >39 days, as was done on RTOG 0529. In our study, the median overall treatment duration for the total cohort was 39 days (IQR: [36][37][38][39][40][41][42] and was 38 days and 39 days for patients with T0-2 and T3-4 tumors, respectively. To assess the interactions between T-stage, LN status, and overall treatment duration, analyses were performed as bivariate models incorporat-  ing overall treatment duration and either T-stage or LN status, and as a multivariate model. In each instance, only overall treatment duration >39 days remained associated with LRR. These data are consistent with other reports evaluating the impact of overall treatment duration for patients with ASCC and are analogous to data derived from the head and neck cancer population [14,[38][39][40]. For example, prolongation of the overall treatment duration greater than 42 days was associated with worse PFS and OS per a post-hoc analysis of the United Kingdom Anal Cancer Trial II (ACT II) and overall treatment duration greater than 53 days has been associated with an increased risk of LRR and colostomy per a pooled analysis of RTOG trials by Ben-Josef et al. [38]. Similarly, a retrospective analysis by Mitra et al. has suggested its detrimental impact upon OS [14]. In contemporary practice, with few patients receiving induction chemotherapy and continued efforts to omit mid-treatment breaks, it is rare for treatment to extend beyond 53 days in the absence of severe toxicity necessitating delays. Therefore, our findings of improved outcomes for patients treated within 39 days supports a continued emphasis on a condensed overall treatment schedule. Assuming treatment commences on a Monday, no intervening holidays, and treatment limited to once per day, this would coincide with limiting treatment to 29 total fractions or less as is currently being utilized in the high-risk cohort of the UK PLATO trial (53.2-61.6 Gy in 28 fractions) [34]. A subset analysis of the RTOG 9811 trial previously reported the impact of tumor stage and LN status upon oncologic outcomes [41]. Patients with T3-4N0 or T3-4N+ disease were at the highest risk for disease relapse or death, with relatively poor disease-free survival of 43% and 27% for patients with T3N+ (IIIC) and T4N+ (IIIC) disease, respectively. These data provide a precedent for treatment intensification strategies in these cohorts [32,34,[42][43][44]. In our series, we identified excellent PFS even in high-risk subgroups with 4-year PFS of 76%, 75%, and 83% for patients with stage IIIA (T1-2N+), IIIB (T4N0), and IIIC (T3-4N+) disease, respectively, and no association between clinical stage grouping and oncologic outcomes. Similarly, we identified 4-year PFS of 78% and 74% in the subsets of patients who meet inclusion criteria for the ongoing high-risk ECOG-ACRIN Trial 2165 and UK PLATO ACT 5 trial, respectively. Apparent improvements in outcomes for patients with stage III disease in our series versus RTOG 9811 may be related to improved diagnostic imaging including PET-CT scan, which may lead to improved targeting and stage migration, lack of induction chemotherapy, shorter overall treatment duration, and improved tolerance of IMRT. As the ECOG-ACRIN Trial 2165 power analysis was based upon event rates from the RTOG 9811 trial with a projected 2-year disease-free survival of 45% in the control group, it is plausible that the study may be underpowered to detect a statistically significant improvement with the addition of maintenance nivolumab in a contemporary cohort of patients receiving high quality IMRT.
Unexpectedly, we did not identify an association between clinical stage and oncologic outcomes, with the most plausible explanation being the limited patient numbers within stage subgroups, low overall event rates, excellent outcomes even amongst highrisk subgroups, and subsequently the inadequate statistical power to identify differences amongst subgroups. However, it is an interesting finding to consider because our practice routinely uses a tailored dosing regimen based upon tumor extent with a particular focus on maintaining a condensed overall treatment duration such that patients with T3-4 tumors received a median dose of RT to the primary tumor and involved LNs of 54 Gy (IQR: 53-57 Gy) and 55 Gy (IQR: 50-58 Gy) in a median of 30 fractions (IQR: [25][26][27][28][29][30] for a BED of 64 Gy 10 over a median duration of 39 days. Additionally, 40% of patients with T3-4 tumor in our series received treatment in 28 fractions or less with daily doses ranging between 1.85 and 2.25 Gy in an attempt to further condense the overall treatment duration. This treatment scheme is most similar to that reported by Mitchell et al. which used DP-IMRT with tailored dosing based upon T-stage (median 54 Gy, range 50-58.8 Gy) and a daily fraction dose of 2-2.1 Gy [17]. Similarly to our series, they demonstrated excellent outcomes with 2-year local control of 91% for the entire cohort and local control of 71% and 80% for patients with T3 tumors and T4 tumors, respectively. Hence, we speculate that the total dose, total number of fractions, and overall treatment duration are at least partially contributing to the favorable outcomes in our series. We must also acknowledge that our cohort was predominately human immunodeficiency virus (HIV)negative (99%), and thus host immunological factors likely also contributed [45].
These data appear promising and provide continued support of the use of IMRT, although, there are some limitations. This was a retrospective series and is subject to the associated limitations. There was potential underestimation of acute and late treatmentrelated AEs related to the retrospective nature of data collection for some patients. The addition of patient-reported outcomes would also have strengthened this report, but unfortunately, were unavailable for most patients. Correlation of outcomes with tumor HPV or p16 status may have provided a further understanding of the prognostic significance of this biomarker [46], but unfortunately was unavailable for the majority of patients. Assessments of tumor and treatment characteristics associated with outcomes were limited by low event rates and potentially underpowered statistical comparisons.

Conclusion
These data demonstrate that IMRT is associated with favorable toxicity rates and excellent long-term efficacy compared with historical 3DCRT series, and thus serve to support the continued utilization of IMRT as the preferred treatment technique for patients with ASCC. Based upon these data, we speculate that oncologic efficacy may be maintained, even in high-risk subsets, by utilizing simultaneously integrated boost strategies with tailored dosing and a condensed overall treatment duration.