Non-metastatic Anal Squamous Cell Carcinoma Research Articles

A single institution retrospective study evaluating mitomycin dosing during chemoradiation in anal squamous cell carcinoma.

7 Background: Mitomycin (MMC) is used concurrently during chemoradiation (CRT) treatment for non-metastatic anal squamous cell carcinoma (SCCA). The most effective dosing of MMC is not established, and due to concerns for tolerability, many have adopted a dose-reduction strategy. This study evaluates differences in treatment response and recurrence between MMC dosing in this setting. Methods: Demographics, age, smoking history, staging, and treatment history were collected for patients with non-metastatic SCCA treated with CRT from January 2011-September 2024 at a tertiary cancer center. Chi-square analyses compared categorical variables, and ANOVA tests were used to compare treatment response and recurrence between 3 MMC doses (12mg/m 2 x 1 dose with cap of 20mg, 10mg/m 2 x 2 doses, 10mg/m 2 x 1 dose). Results: There were 124 patients, 6 of whom were excluded due to lack of follow up. Of the 118 included, 70% were female, 16% Black, 3% Hispanic/Latino, and 58% current/former smokers. Median age was 61 years (31-98). Thirty-three (28%) pts were treated with MMC 12mg/m 2 , 71 (60%) with 10mg/m 2 x2 doses, and 14 (12%) with 10mg/m 2 x1 dose. Stage I included 18% of 12mg/m2, 7% of 10mg/m 2 x2 doses, and 7% of 10mg/m 2 x1 dose; stage II included 18% of 12mg/m2, 37% of 10mg/m 2 x2 doses, and 50% of 10mg/m 2 x1 dose; stage III included 64% of 12mg/m2, 56% of 10mg/m 2 x2 doses, and 43% of 10mg/m 2 x1 dose. A total of 39.7% were treated with MMC/capecitabine and 60.3% with MMC/fluorouracil. Complete response was achieved in 91% receiving the 12mg/m 2 , 75% receiving 10mg/m 2 x2 dose, and 71% receiving 10mg/m 2 x1 dose (p=0.13, Table 1). Using logistic regression with MMC dose, stage, age, and smoking status as independent predictors, the odds of achieving complete response were lower in 10mg/m 2 x2 doses (p=0.03) and 10mg/m 2 x1 dose (p=0.03) compared to 12mg/m 2 . Local, regional, or metastatic recurrence occurred in 15% of pts receiving 12mg/m 2 , 17% of 10mg/m 2 x2 doses, and 7% of 10mg/m 2 x1 dose. No significant difference was seen in local (p=0.52), regional (p=0.93), metastatic (p=0.87), or overall recurrence (p=0.65) between the MMC doses. Conclusions: Odds of achieving complete response was greater with 12mg/m 2 dosing. Local, regional, and metastatic recurrence were similar among the different MMC dosing cohorts. Differences in tolerance and side effects should be delineated to guide individualized dosing of MMC.

Tumor tissue modified viral (TTMV)-HPV DNA as a biomarker of treatment efficacy for definitive chemoradiation in anal squamous cell carcinoma: A step towards truly personalized therapy.

10 Background: Cell-free circulating tumor tissue modified viral DNA (ctDNA) has been used as a biomarker to detect recurrence for anal squamous cell carcinoma (ASCC). However, its value in informing treatment modification during definitive chemoradiation (CRT) has yet to be explored. We evaluated ctDNA response during and at completion of definitive CRT to establish patterns of disease response and inform future studies to personalize treatment. Methods: From 11/2022 to 6/2024, 13 consecutive patients with biopsy proven, non-metastatic ASCC received definitive CRT and had ctDNA testing using a commercially available droplet digital quantitative PCR assay. ctDNA testing was done at baseline (pre-CRT), week 4 of CRT, and/or end of CRT, 1-3 months post-CRT, and every 6 months thereafter. CRT included concurrent 5FU/MMC (or capecitabine/MMC) and radiotherapy according to RTOG 0529. Treatment response assessment included: physical exam, anoscopy, and imaging with PET/CT, CT C/A/P +/- MRI abdomen and pelvis. Results: 13 patients had ctDNA testing and 11 patients had HPV-positive ASCC and tested positive for ctDNA. The 11 patients with detectable baseline ctDNA were included in this analysis. The median age at diagnosis was 63 years old. Staging included: 1- Stage IIA, 7- Stage IIB, 1- Stage IIIA, 2- Stage IIIC. 1 patient was cN0, while 11 were cN1. With a median follow-up from completion of CRT of 13 months, 4 patients have persistent or recurrent disease: 2 with distant metastases, 1 with persistent local disease (1 month post-CRT), and 1 with local and distant recurrence. Baseline value of ctDNA did not correlate to stage at diagnosis, rate of clearance during CRT, or likelihood of recurrence. 5 of 11 patients cleared ctDNA by week 4 of CRT. Of 5 patients who cleared ctDNA by week 4 of CRT, 4 remain NED and 1 developed distant metastases. Of 6 patients with persistent ctDNA at week 4 of CRT, 3 have persistent or recurrent disease- 1 local persistence 1 month post-CRT, 1 local and distant recurrence 6 months post-CRT, and 1 with distant recurrence 12 months post- CRT. Among 6 patients who cleared ctDNA by the final week of CRT, 1 patient developed recurrent disease. Among the 4 patients in the series with residual/recurrent disease, 3 of them had not cleared ctDNA by the end of CRT. Of 10 patients with ctDNA testing at 1 month post-CRT, 8 had no detectable ctDNA. 2 patients with persistent (1) or recurrent (1) ctDNA at 1 month post-CRT developed disease recurrence- 1 with distant recurrence and 1 with local and distant recurrence. Conclusions: ctDNA assessment during CRT may provide insight into disease response that can predict patterns of failure and facilitate personalized therapy- treatment intensification, deintensification, or additional testing to detect early metastatic disease. Larger studies and clinical validation are needed.

Interstitial HDR brachytherapy for anal cancer-results and quality of life.

While anal cancer is avery rare oncological diagnosis representing less than 2% of lower gastrointestinal tract cancers, the incidence has doubled in the past 20years. Radical radiochemotherapy with sequential or simultaneous boost is now the standard treatment modality. Interstitial HDR brachytherapy is one of the boost application options. Implementation of new radiotherapy techniques has resulted in improved therapeutic outcomes; however, it is still associated with acute and especially late toxicity. Gastrointestinal disorders and sexual dysfunction are the most frequent factors affecting the long-term quality of cured patients' lives. Atotal of 96patients consecutively treated between 2000 and 2022 with external beam radio-/chemotherapy and an interstitial brachytherapy boost for histologically verified nonmetastatic anal squamous cell carcinoma were evaluated. The median follow-up time was 15.4 years (range 13.4-17.3 years). The primary objective of the study was to assess local control (LC) and quality of life (QoL). The Czech versions of internationally validated EORTC questionnaires were used to evaluate life quality-the basic EORTC QOL-C30v.3 and the specific QOL-ANL27 questionnaire. Local control was 85.5% at 5years, 83.4% at 10years, 83.4% at 15years, and 83.4% at 20years, and there was no dependence on clinical stage. The most common forms of acute toxicity were cutaneous and hematological but were gastrointestinal for late toxicities. In the evaluation of quality of life, 80.5% of patients alive at the time participated. In the EORTC quality of life questionnaire C30v.3, patients rated the functional scale score as 86.2 points (standard deviation [SD] = 12.6) and the symptom score as 15.5 points (SD = 12.5). The global health score achieved 68.4 points (SD = 23.6). The most common symptoms were fatigue with 25.6 points (SD = 20.2) and diarrhea with 19.0 points (SD = 27.8). In the QOL-ANL27 questionnaire, symptom scales assessing bowel symptoms were scored 27.5 points (SD = 19) in non-stoma patients and 11.9 points (SD = 17.2) in stoma patients. In the single-item symptom scales, the highest scores were rated for frequency of urination with 26.4 points (SD = 30.8), need to be close to atoilet with 22.4 points (SD = 27.3), and self-cleaning more often with 25.3 points (SD = 31.8). In the functional scales assessing sex life and interest, men and women reported scores of 45.2 (SD = 23) and 45.5 points (SD = 19), respectively. Boost with interstitial HDR brachytherapy is an established safe method of anal cancer treatment, with excellent results and limited late toxicity. Functioning scales were rated relatively highly in QoL questionnaires, and the overall global health score was comparable to published data. Gastrointestinal difficulties, fatigue, and sexual dysfunction dominated the symptom scales in our cohort.

Recurrence-free survival prediction for anal squamous cell carcinoma after chemoradiotherapy using planning CT-based radiomics model.

Approximately 30% of non-metastatic anal squamous cell carcinoma (ASCC) patients will experience recurrence after chemoradiotherapy (CRT), and currently available clinical variables are poor predictors of treatment response. We aimed to develop a model leveraging information extracted from radiation pretreatment planning CT to predict recurrence-free survival (RFS) in ASCC patients after CRT. Radiomics features were extracted from planning CT images of 96 ASCC patients. Following pre-feature selection, the optimal feature set was selected via step-forward feature selection with a multivariate Cox proportional hazard model. The RFS prediction was generated from a radiomics-clinical combined model based on an optimal feature set with 5 repeats of nested 5-fold cross validation. The risk stratification ability of the proposed model was evaluated with Kaplan-Meier analysis. Shape- and texture-based radiomics features significantly predicted RFS. Compared to a clinical-only model, radiomics-clinical combined model achieves better performance in the testing cohort with higher concordance index (0.80 vs 0.73) and AUC (0.84 vs 0.78 for 1-year RFS, 0.84 vs 0.79 for 2-year RFS, and 0.85 vs 0.81 for 3-year RFS), leading to distinctive high- and low-risk of recurrence groups (P < .001). A treatment planning CT based radiomics and clinical combined model had improved prognostic performance in predicting RFS for ASCC patients treated with CRT as compared to a model using clinical features only. The use of radiomics from planning CT is promising in assisting in personalized management in ASCC. The study outcomes support the role of planning CT-based radiomics as potential imaging biomarker.

Surgery, chemoradiotherapy, or chemoradiation plus immunotherapy: Treatment strategies for nonmetastatic anal squamous cell carcinoma

The current standard of care for anal squamous cell carcinoma (ASCC) is definitive concurrent chemoradiotherapy (CRT). However, about a third of patients may experience treatment failure. Recently, immunotherapy has emerged as a novel strategy for metastatic ASCC patients. We evaluated the efficacy and safety of surgery, CRT alone, and CRT with immunotherapy (CRT-I) in 100 nonmetastatic ASCC patients, treated from April 2012 through May 2023, by determining survival outcomes and acute adverse events. The median (range) follow-up was 30.7 (7.6 to 134.9) months. The study cohort 3-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) rates were 80.7 %, 62.2 %, 71.1 %, and 67.6 %, respectively. The Surgery group had significantly lower rates than the CRT and CRT-I groups for 3-year PFS (33.1% vs. 65.2% vs. 92.9 %, P < 0.001), DMFS (46.7% vs. 74.6% vs. 92.9 %, P = 0.002) and LRFS (37.0% vs. 73.3% vs. 92.9 %, P < 0.001), respectively. All patients receiving CRT-I were alive at last follow-up. Of 100 patients, 26 (26.0 %) experienced severe (≥ grade 3) acute toxicity. Of 24 patients receiving CRT-I, 8 (33.3 %) had severe acute toxicity. Using immunohistochemistry, peritumoural stromal infiltration by CD8+ T cells was significantly higher after CRT-I compared to before CRT-I and to after CRT alone. The addition of immunotherapy to CRT may be an effective first-line treatment option with favourable survival outcomes and acceptable toxicity for patients with ASCC. A prospective, randomized trial assessing the efficacy of CRT combined with a PD-1 inhibitor in patients with locally advanced ASCC is in progress.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma.

To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5days, P = 0.042) than in the MF group. The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC.

Prognostic factors of long-term outcomes after primary chemo-radiotherapy in non-metastatic anal squamous cell carcinoma: An international bicentric cohort.

e15501 Background: Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with Human papillomavirus (HPV) infection. Locally-advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate prognostic factors for ASCC after curative CRT. Methods: A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at 2 centers. Complete response (CR), disease-free survival (DFS) and overall survival (OS) were analyzed by Kaplan–Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. Results: CR rate was 68% and was predictive of DFS (p &lt; 0.0001) and OS (p &lt; 0.0001), where non-CR cases were associated shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77–18.81) in univariate analysis. Median follow-up was 38 months, with 3-year DFS of 71%. Prognostic factors for DFS were cT1-T2 (p = 0.0001), N0 (p = 0.03), HIV-positive (p = 0.04), HIV-HPV coinfection (p = 0.02), and well-differentiated tumors (p = 0.03). Three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.019), and well-differentiated tumors (p = 0.003) were associated with better OS. This unsupervised analysis demonstrates clear segregation, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.66, 95% CI = 1.21–2.27, p = 0.0012) were enriched with locally-advanced disease, anal canal location, HPV-HIV coinfection, and non-CR. Conclusions: In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.

Prognostic Factors of Long-Term Outcomes after Primary Chemo-Radiotherapy in Non-Metastatic Anal Squamous Cell Carcinoma: An International Bicentric Cohort.

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with human papillomavirus (HPV) infection. The locally advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate the prognostic factors for ASCC after curative CRT. A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at two centers was performed. Complete response (CR), disease-free survival (DFS), and overall survival (OS) were analyzed by Kaplan-Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. The CR rate was 70% and was predictive of DFS (p < 0.0001) and OS (p < 0.0001), where non-CR cases were associated with shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77-18.81) in a univariate analysis. The median follow-up was 38 months, with a 3-year DFS of 71%. The prognostic factors for DFS were cT1-T2 (p = 0.0002), N0 (p = 0.035), HIV-positive (p = 0.047), HIV-HPV coinfection (p = 0.018), and well-differentiated tumors (p = 0.037). The three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.02) and well-differentiated tumors (p = 0.003) were associated with better OS. The unsupervised analysis demonstrated a clear segregation of patients in three clusters, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.74 95% CI = 1.25-2.42, p = 0.0008) were enriched with the locally advanced disease, anal canal location, HIV-HPV coinfection, and non-CR. In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.

The addition of paclitaxel in chemoradiotherapy of anal squamous cell carcinoma: a prospective randomized phase 3 trial

AIM: to compare long-term outcomes and safety of the addition of paclitaxel to chemoradiotherapy for squamous cell anal carcinoma.PATIENTS AND METHODS: A prospective phase 3 randomized trial included patients with histologically verified non-metastatic anal squamous cell carcinoma. Patients received radiotherapy 52-54 Gy (for T1-T2 tumors) and 56-58 Gy (for T3- T4 tumors) in 2 Gy daily fractions during chemotherapy with mitomycin C (10 mg/m2 i.v. day 1), capecitabine (625 mg/m2 2 times a day orally on days of radiation therapy), paclitaxel (45 mg/m2 i.v. on days 3, 10 , 17, 24, 31) during 2013-2019. In the control group patients received a similar course of RT and chemotherapy with mitomycin C (12 mg/m2 i.v. day 1 ), capecitabine (825 mg/m2 2 times a day orally on radiotherapy days). The primary endpoint was 3-year disease-free survival (DFS). Secondary endpoints included complication rate (NCI-CTCAE 4.0), complete clinical response rate at 12 weeks and 26 weeks after completion of CRT, and 3-year overall survival (OS).RESULTS: The study and control groups included 72 patients each. The median follow-up was 39.5 months. A complete clinical response at the 26-week follow-up was recorded in 64 (88.9%) patients in the study group and in 54 (75%) patients in the control group (p=0.049). There were no differences in the incidence of complications of grades 3-4 in the two groups (39/72 [54.2%] in the study group versus 35/72 [48.6%] in the control group (p=0.617)). Three-year progression-free survival in the study group was 87.1%, in the control group - 64.4% (p=0.001). Three-year overall survival in the study group was 95.5%, in the control group - 80.0% (p&lt;0.001).CONCLUSION: CRT with paclitaxel for squamous cell anal carcinoma has acceptable toxicity and may improve long-term treatment outcomes.

Impact of Time From Diagnosis to Treatment Start on the Outcomes of Patients With Nonmetastatic Anal Squamous Cell Carcinoma.

To assess the impact of time from diagnosis to treatment on the survival outcomes of patients with nonmetastatic anal squamous cell carcinoma, controlling for other clinicopathological features. Surveillance, Epidemiology, and End Results research plus database was accessed, and patients with nonmetastatic anal squamous cell carcinoma were reviewed. Factors associated with longer time to treatment were evaluated through multivariable logistic regression analysis. Kaplan-Meier survival estimates were used to examine survival differences according to time to treatment (≤2 vs. >2mo), and multivariable Cox regression analysis was used to examine factors associated with worse overall and cancer-specific survival. A total of 13,032 patients were considered eligible and they were included in this study. The following factors were associated with longer time to treatment (>2mo): male sex (odds ratio [OR]: 1.503; 95% CI, 1.292 to 1.749), and non-White race (OR for Black vs. White patients: 1.846; 95% CI, 1.488 to 2.290; OR for American Indian vs. White patients: 2.414; 95% CI, 1.197 to 4.872; OR for Asian-Pacific Islanders vs. White patients: 2.182; 95% CI, 1.440 to 3.309). Using Kaplan-Meier survival estimates, longer time to treatment was associated with worse overall survival (median OS for >2mo=109mo; for ≤2mo=164mo P <0.0001). Using multivariable Cox regression analysis, the following factors were associated with worse overall survival: older age (hazard ratio [HR]: 1.037; 95% CI, 1.034 to 1.039), male sex (HR: 1.650; 95% CI, 1.548 to 1.758), Black race (HR: 1.341; 95% CI, 1.210 to 1.487), advanced stage (HR for regional vs. localized stage: 1.596; 95% CI, 1.500 to 1.698), and longer time to treatment (HR: 1.385; 95% CI, 1.222 to 1.571). Time from diagnosis to treatment longer than 2 months is associated with worse survival outcomes among patients with nonmetastatic anal squamous cell carcinoma.

Pretreatment PET Metrics and Clinical Outcomes of Anal Cancer in Patients Living with and without HIV

<h3>Purpose/Objective(s)</h3> This study investigates the association between pre-treatment positron emission tomography (PET) metrics and clinical outcomes in anal squamous cell carcinoma (ASCC) patients treated with definitive radiation therapy (RT). We hypothesize that pre-treatment PET metrics may differentially predict clinical outcomes in ASCC patients without HIV infection (HIV-) and ASCC patients living with HIV (PLWH) with detectable or undetectable viral load (VL). <h3>Materials/Methods</h3> Patients treated with definitive RT for non-metastatic ASCC between 2005 - 2021 at a single institution were retrospectively identified, and clinical and demographic data, including HIV status and pretreatment VL, were tabulated. Pre-treatment PETs were imported to MIM, and semiautomatic gradient-based segmentation tool algorithms (PET_Edge) were used to calculate PET metrics, including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Cox proportional hazard modeling was used to investigate the association between primary tumor PET metrics and clinical outcomes, including overall survival (OS), progression free survival (PFS), and loco-regional control (LRC) <h3>Results</h3> 141 ASCC patients were identified, 49 of whom were PLWH. 12 had detectable HIV VL. The median follow-up time was 51.8 months (IQR: 0.5-191.2 months). There were 22 loco-regional failures and 24 deaths. 3- and 5- year LRC was 85.6% and 83.3%, 3- and 5- year PFS was 75.9% and 71.6%, and 3- and 5- year OS was 89.3% and 86.6% for the entire cohort. There was no significant difference in LRC, PFS, or OS between PLWH and HIV- patients (p>0.50). PLWH with detectable VL had similar LRC and PFS but trended towards worse 5-year OS than did HIV- patients (66.3% vs 89.7%, p=0.16). MTV and TLG from primary tumors were significantly associated with LRC, PFS, and OS for all patients and in sub-group analysis for HIV-, PLWH, and PLWH with undetectable VL (p<0.05). SUVmax was significantly associated with LRC, PFS, and OS for all patients, and on sub-group analysis only for HIV- patients (p<0.05). On multivariable analysis, after adjusting for stage and Charlson Comorbidity Index, MTV split at median was significantly associated with LRC (HR 3.59 (95% CI:1.21-10.6), p=0.02) and PFS (HR 3.12 (95%CI:1.48-6.56), p=0.003), and TLG split at median was significantly associated with LRC (HR 4.36 (95%CI:1.36-14.0), p=0.01) and PFS (HR 3.13 (95%CI:1.48-6.64), p=0.003). <h3>Conclusion</h3> Patients with ASCC had similar outcomes regardless of HIV status. Advanced pre-treatment PET metrics, especially MTV and TLG, may have prognostic or risk-stratification utility in HIV- patients and undetectable PLWH with ASCC, but were not as strongly associated with clinical outcomes for PLWH with detectable VL, perhaps due to small numbers of patients with detectable VL in this cohort.

Failure of Initial Curative Treatment for Non-Metastatic Anal Squamous Cell Carcinoma: From Prognostic Factors Analysis to Stratified Treatment

In squamous cell anal canal neoplasms, persistent disease or recurrence after initial chemoradiotherapy are not the rule, yet their occurrence deserves to be analyzed to better identify prognostics factors. The aim of our study was to describe the patterns of failures of the initial treatment, their subsequent evolution and to identify prognostic factors in these relapsed patients.All patients with non-metastatic anal squamous cell carcinoma initially treated with curative intent at the Centre Antoine Lacassagne between 1999 and 2019, and who presented persistent disease or recurrence were analyzed. The median follow-up was 44 months. Univariate and multivariate analyses were performed to identify prognostic factors.From our database of 528 patients, 77 patients were eligible: 25 with persistent disease and 52 with recurrence after complete response. The median overall survival was 39 months (95% CI: 25.5–52.3 months) from the date of treatment failure. In univariate analysis, prognostic factors were gender, initial lymph node status, type of failure, response to treatment's failure. In multivariate analysis, only female gender remained statistically significant (HR 0.43- P=0.016). 32% of patients with persistent disease had metastatic status. 17.3% and 5.8% of recurrences respectively occurred after three and five years of follow-up.Systematic imaging could be performed after initial treatment because of distant lesions in one third of patients with persistent disease. The follow-up should not be interrupted before five years, given the significant frequency of late recurrences. In multivariate analysis, only female gender was statistically significant. Stratified treatment based on prognostic factors could be envisaged, the details of which remain to be defined.

Effects of radical radiotherapy combined with different regimens of chemotherapy on radiation intestinal injury in patients with non-metastatic anal squamous cell carcinoma

Objective: To investigate the effects of radical radiotherapy combined with different chemotherapy regimens (fluorouracil-based versus docetaxel plus cisplatin) on the incidence of radiation intestinal injury and the prognosis in patients with non-metastatic anal squamous cell carcinoma. Methods: A retrospective cohort study was conducted to recruit non-metastatic anal squamous cell carcinoma patients who underwent chemoradiotherapy in the Sixth Affiliated Hospital of Sun Yat-sen University and Nanfang Hospital from July 2013 to January 2021. Inclusion criteria: (1) newly diagnosed anal and perianal squamous cell carcinoma; (2) completed radical radiotherapy combined with concurrent chemotherapy; (3) tumor could be evaluated before radiotherapy. Exclusion criteria: (1) no imaging evaluation before treatment, or the tumor stage could not be determined; (2) patients undergoing local or radical resection before radiotherapy; (3) distant metastasis occurred before or during treatment; (4) recurrent anal squamous cell carcinoma. A total of 55 patients (48 from the Sixth Affiliated Hospital of Sun Yat-sen University and 7 from Nanfang Hospital) were given fluorouracil (the 5-FU group, n=34) or docetaxel combined with the cisplatin (the TP group, n=21). The evaluation of radiation intestinal injury, hematological toxicity and 3-year disease-free survival (DFS) rate were compared between the two groups. The effects of chemotherapy regimen and other clinicopathological factors on the incidence and severity of acute and chronic radiation intestinal injury were analyzed. The assessment of radiation intestinal injury was based on the American Cancer Radiotherapy Cooperation Group (RTOG) criteria. Results: During radiotherapy and within 3 months after radiotherapy, a total of 45 patients developed acute radiation intestinal injury, including 18 cases of grade 1 (32.7%), 22 cases of grade 2 (40.0%) and 5 cases of grade 3 (9.1%). No patient developed chronic radiation intestinal injury. Among the 34 patients in the 5-FU group, 21 had grade 2-3 radiation intestinal injury (21/34, 61.8%), which was significantly higher than that in the TP group (6/21, 28.6%) (χ(2)=5.723, P=0.017). Multivariate analysis showed that 5-FU chemotherapy regimen was an independent risk factor for radiation intestinal injury (HR=4.038, 95% CI: 1.250-13.045, P=0.020). With a median follow-up period of 26 (5-94) months, the 3-year DFS rate of patients in TP group and 5-FU group was 66.8% and 77.9%, respectively, whose difference was not significant (P=0.478). Univariate analysis showed that the DFS rate was associated with sex, age, tumor location, T stage, N stage, and induction chemotherapy (all P<0.05), while the DFS rate was not associated with chemotherapy regimen or radiation intestinal injury (both P>0.05). Multivariate analysis revealed that age ≥ 50 years old was an independent risk factor affecting the prognosis of patients (HR=8.301, 95% CI: 1.130-60.996, P=0.038). Conclusions: For patients with non-metastatic anal squamous cell carcinoma, radical radiotherapy combined with TP chemotherapy regimen can significantly reduce the incidence of radiation intestinal injury as compared to 5-FU regimen. However, due to the short follow-up time, the effect of different chemotherapy regimens on the prognosis is not yet clear.

Intensity modulated radiotherapy in anal canal squamous cell carcinoma: Implementation and outcomes.

Concurrent chemoradiotherapy (CCRT) is the standard curative treatment option for nonmetastatic anal squamous cell carcinoma (SCC). Intensity modulated radiotherapy (IMRT) can reduce doses delivered to bowel and skin and reduce toxicities associated with conventional fields. Here, we present our institutional data on dosimetry, toxicity, and clinical outcomes with IMRT for anal cancer. We analyzed 23 patients of anal SCC treated with curative-intent CCRT/radiation therapy alone, utilizing IMRT, between August 2011 and December 2016. The standard prescription dose was 54 Gy/27Fr/5.5 weeks, delivered in two phases, and concurrent chemotherapy with 5-fluorouracil and mitomycin-C. Acute and late toxicities and dosimetric data were compiled and analyzed. The median age was 65 years. Fourteen (60.7%) patients had Stage IIIC disease. Eighteen patients received concurrent chemotherapy. No patient had any treatment breaks. Grade 3 acute perianal dermatitis was recorded in 11 (47.8%) patients. Proctitis, diarrhea, and cystitis were limited to Grade 1 in 73.9%, 47.8%, and 8.6% patients, respectively. The only late Grade 2+ toxicities were gastrointestinal toxicities in 4 (17.4%) patients. Twenty (87%) patients had complete response at 6 months. The 3-year local control, nodal control, and distant metastases-free survival were 85.9%, 86.6%, 84.7%, respectively, with 3-year disease-free survival and overall survival of 63.4% and 81%, respectively. In this report on IMRT in anal cancer from India, treatment was well tolerated with lower acute toxicity than reported in other prospective studies. Long-term results are at par with other published studies.

The impact of gender and HPV status on anal squamous cell carcinoma survival.

Anal cancer is a rare entity and the effect of gender and HPV status on survival is controversial. We aimed to evaluate the difference in overall survival (OS) according to gender and analyzed the effect of HPV status on OS. The National Cancer Database (NCDB) was queried for patients with anal squamous cell carcinoma between 2004 and 2016. We evaluated the OS based on gender and HPV status using Kaplan-Meier estimates and we used multivariate Cox regression analyses to evaluate factors associated with overall survival. A total of 6133 patients with known HPV status were included for analysis. In the non-metastatic group, male gender was associated with worse OS (HR 1.50, 95% CI 1.32-1.70; P<0.001) whereas HPV status did not affect the OS (HR 1.08, 95% CI 0.96-1.22; P=0.213). In the metastatic group, there was no difference in OS based on gender (HR 1.29, 95% CI 0.91-1.82; P=0.148), whereas HPV-negative status was associated with worse OS (HR 1.52, 95% CI 1.09-2.12; P=0.014). Females had better OS only in non-metastatic anal squamous cell carcinoma (ASCC). HPV-negative status was associated with worse OS only in metastatic ASCC.

A clinical and molecular portrait of non-metastatic anal squamous cell carcinoma

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-risk Human papillomavirus (HPV) infection. Despite improved outcomes in non-metastatic ASCC, definitive chemoradiotherapy constitutes the standard treatment for localized disease. Evidences for predictive and prognostic biomarkers are limited. Here, we performed a viral, immune, and mutational characterization of 79 non-metastatic ASCC patients with complete definitive chemoradiotherapy. HPV-16 was detected in 91% of positive cases in single infections (78%) or in coinfections with multiple genotypes (22%). Fifty-four percent of non-metastatic ASCC cases displayed mutations affecting cancer driver genes such as PIK3CA (21% of cases), TP53 (15%), FBXW7 (9%), and APC (6%). PD-L1 expression was detected in 57% of non-metastatic ASCC. Increased PD-L1 positive cases (67%) were detected in patients with complete response compared with non-complete response to treatment (37%) (p = 0.021). Furthermore, patients with PD-L1 positive tumors were significantly associated with better disease-free survival (DFS) and overall survival (OS) compared with patients with PD-L1 negative tumors (p = 0.006 and p = 0.002, respectively). PD-L1 expression strongly impacts CR rate and survival of non-metastatic ASCC patients after standard definitive chemoradiotherapy. PD-L1 expression could be used to stratify good versus poor responders avoiding the associated morbidity with abdominal perineal resection.

Chemoradiation-Related Lymphopenia and Its Association with Survival in Patients with Squamous Cell Carcinoma of the Anal Canal.

Although treatment-related lymphopenia (TRL) is common and associated with poorer survival in multiple solid malignancies, few data exist for anal cancer. We evaluated TRL and its association with survival in patients with anal cancer treated with chemoradiation (CRT). A retrospective analysis of 140 patients with nonmetastatic anal squamous cell carcinoma (SCC) treated with definitive CRT was performed. Total lymphocyte counts (TLC) at baseline and monthly intervals up to 12 months after initiating CRT were analyzed. Multivariable Cox regression analysis was performed to evaluate the association between overall survival (OS) and TRL, dichotomized by grade (G)4 TRL (<0.2k/μL) 2 months after initiating CRT. Kaplan-Meier and log-rank tests were used to compare OS between patients with versus without G4 TRL. Median time of follow-up was 55 months. Prior to CRT, 95% of patients had a normal TLC (>1k/μL). Two months after initiating CRT, there was a median of 71% reduction in TLC from baseline and 84% of patients had TRL: 11% G1, 31% G2, 34% G3, and 8% G4. On multivariable Cox model, G4 TRL at two months was associated with a 3.7-fold increased risk of death. On log-rank test, the 5-year OS rate was 32% in the cohort with G4 TRL versus 86% in the cohort without G4 TRL. TRL is common and may be another prognostic marker of OS in anal cancer patients treated with CRT. The association between TRL and OS suggests an important role of the host immunity in anal cancer outcomes. This is the first detailed report demonstrating that standard chemoradiation (CRT) commonly results in treatment-related lymphopenia (TRL), which may be associated with a poorer overall survival (OS) in patients with anal squamous cell carcinoma. The association between TRL and worse OS observed in this study supports the importance of host immunity in survival among patients with anal cancer. These findings encourage larger, prospective studies to further investigate TRL, its predictors, and its relationship with survival outcomes. Furthermore, the results of this study support ongoing efforts of clinical trials to investigate the potential role of immunotherapy in anal cancer.

Abstract A049: Socioeconomic disparities in treatment delays and survival for anal cancer patients

Abstract Background: Socioeconomic status (SES) is associated with treatment delays and survival in multiple cancers, but less data exist for anal squamous cell carcinoma (ASCC). This study investigated the association between SES and outcomes for patients undergoing definitive chemoradiation therapy for ASCC. Methods: Patients diagnosed with non-metastatic ASCC between 2005 and 2018 were retrospectively reviewed. Socioeconomic predictor variables included primary payer, race, income, employment, and partnership status. Outcomes included tumor-node (TN) stage at diagnosis, the interval from diagnosis to treatment initiation, relapse-free survival (RFS), and overall survival (OS). Age, gender, TN stage, and HIV status were analyzed as covariates in survival analysis. Results: Over the study period, 111 patients met inclusion criteria. SES was not associated with the TN stage at diagnosis. SES factors associated with treatment delays were Medicaid payer (p = 0.016) and single partnership status (p = 0.016). Compared to privately insured patients, Medicaid patients had lower two-year RFS (64.4% vs. 93.8%, p = 0.021) and OS (82.9% vs. 93.5%, p = 0.038). Similarly, relative to patients in the racial majority, racial minority patients had lower two-year RFS (53.3% vs. 93.5%, p = 0.001) and OS (73.7% vs. 92.6%, p = 0.008). Race was an independent predictor for both RFS (p = 0.027) and OS (p = 0.047). Conclusions: These results highlight the impact of social contextual factors on health. Interventions targeted at socioeconomically vulnerable populations are needed to reduce disparities in ASCC outcomes. Citation Format: Tessnim R Ahmad, Matthew Susko, Karla Lindquist, Mekhail Anwar. Socioeconomic disparities in treatment delays and survival for anal cancer patients [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A049.

PDL1 expression predicts therapeutic outcome in non metastatic anal squamous cell carcinoma (NMASCC).

4054 Background: NMASCC is a rising incidence disease with up to 30% of treatment failure to achieve complete response (CR) after standard chemoradiotherapy (CRT) leading to severe morbidity and death. Stage III-TNM, p53 mutations, HPV negativity, HIV infection are linked to treatment failure. We investigated the predictive/prognostic role of TNM, CR, HPV, PDL1 positivity and CD3/CD8 densities in NM-ASCC from a single institution. Methods: All 79 eligible consecutive NMASCC pts (available FFPE pre-treatment samples) seen from October-2009 to April-2019 having completed definitive CRT (50.4 Gy Pelvic Radiotherapy with Mitomycin-C 12mg/m2/IV/d1-5 / FU 1000mg/m2/d1-4 d29-32 (28%), Mitomycin-C/Capecitabine 825 mg/m2/bid (38%), Cisplatin 60 mg/m2/IV d1-29 and 5FU (34%) were analyzed. Mean age: 59 (range 26-87), 72% female, Stage III: 59%, HPV positive: 86% (HPV-16: 80%);14% HIV positive. IHC assessed by two pathologist for PD-L1 expression (ClonSP263) and CD3-CD8+ TILS densities (Clone 2GV6, Clone SP57). HPV-DNA assessed by PCR (BSGP5+/6+ multiplexed with beta-globin). Kaplan-Meier survival, CR, DFS, OS and Univariate analyses were performed using Cox proportional hazard model. Results: CR achieved within 6 months of treatment completion was 68%( 53pts). Median follow-up after treatment completion: 35 months (range 6 –149). As of February 2020, 82% (65 pts) are alive, no evidence of disease:(57%) 46 pts, recurrence rate: 26%(22 pts), cancer death: 18% (14 pts). PDL1+ tumors ( &gt; 1% positivity-CPS score): 56%, expression levels: 1-5% (57%,26p), &gt; 10%-100% (43%,19p). PDL1+ had a strong association with CR (p = 0.021); higher PDL1+ levels had 8-fold of CR-likelihood than PDL1 negative.(OR 8.50 vs. 1.12). Significative Spearman correlation between PDL1 tumors with CR and CD3-CD8 TILS density was observed (R = 0.43,p = 0.0017 and R = 0.36,p = 0.00094 respectively), albeit CD3-CD8 failed to reach significance as prognostic factors for either CR, DFS or OS. Only CR and PDL1 positive were strongly significantly associated to DFS (HR 0.10 [IC 95% 0.04-0.28] p &lt; 0.001 and HR 0.28 [IC 95% 0.11-0.73] p = 0.006) and OS (HR 0.12 [IC 95% 0.03-0.45] p &lt; 0.001 and HR 0.15 [IC 95% 0.03-0.68] p &lt; 0.004). Low prevalence of HPV negative, early tumors, HIV positive cases in our series probably impacted in statistical power for prognosis correlation. Conclusions: PDL1 positivity was the strongest predictive/prognostic factor in NM-ASCC. Alternative therapeutics options to standard CRT should be explored on poor-risk patients as HPV-negative, P53-mutated and PDL1 negative patients.

Optimal Radiotherapy Dose in Anal Cancer: Trends in Prescription Dose and Association with Survival.

Definitive chemoradiotherapy represents a standard of care treatment for localized anal cancer. National Comprehensive Cancer Network guidelines recommend radiotherapy (RT) doses of ≥45Gy and escalation to 50.4-59Gy for advanced disease. Per RTOG 0529, 50.4Gy was prescribed for early-stage disease (cT1-2N0), and 54Gy for locally advanced cancers (cT3-T4 and/or node positive). We assessed patterns of care and overall survival (OS) with respect to the RT dose. The National Cancer Database identified patients with non-metastatic anal squamous cell carcinoma from 2004 to 2015 treated with chemoradiotherapy. Patients were stratified by RT dose: 40-< 45, 45-< 50, 50-54, and > 54-60Gy. Crude and adjusted hazard ratios (HR) were computed using Cox regression modeling. A total of 10,524 patients were identified with a median follow-up of 40.7months. The most commonly prescribed RT dose was 54Gy. On multivariate analysis, RT doses of 40-< 45Gy were associated with worse OS vs. 50-54Gy (HR 1.68 [1.40-2.03], P < 0.0001). There was no significant difference in OS for patients who received 45-< 50 or > 54-60Gy compared with 50-54Gy. For early-stage disease, there was no significant association between RT dose and OS. For locally advanced disease, 45-< 54Gy was associated with worse survival vs. 54Gy (HR 1.18 [1.04-1.34], P = 0.009), but no significant difference was detected comparing > 54-60Gy vs. 54Gy (HR 1.08 [0.97-1.22], P = 0.166). For patients with localized anal cancer, RT doses of ≥ 45Gy were associated with improved OS. For locally advanced disease, 54Gy but not > 54Gy was associated with improved OS.