Anal Squamous Cell Cancer Research Articles

A systematic review on the role of interventional radiotherapy for treatment of anal squamous cell cancer: multimodal and multidisciplinary therapeutic approach.

Aim was to compare the efficacy of interventional radiotherapy (IRT) boost vs. external beam radiotherapy (EBRT) boost after chemoradiation (CCRT) in patients with anal cancer (AC). The P.I.C.O. framework was: in patients with AC [P], is IRT boost [I] superior to EBRT boost [C] in terms of local control (LC), cancer specific survival (CSS), overall survival (OS), distant meta-static free Survival (DMFS), colostomy free survival (CFS) and toxicity [O]? 651 patients were analyzed. The median 5-year locoregional control rates was 87.8% in the IRT boost group versus 72.8% in the EBRT boost group. The 5-year cancer-specific survival rate was 91% in the IRT boost group versus 78% in the EBRT boost group. 5-years overall survival was 74.6% in IRT boost versus 67.7% in the EBRT boost. 5-years disease metastasis-free survival rate was 92.9% in IRT boost group vs. 85.6% for the EBRT boost group. Cancer-free survival rate was 76.8% in the IRT group vs. 63.1% in the EBRT boost group. Acute toxicity above grade 2 was less common in the IRT boost group while chronic toxicity was similar between both groups. IRT boost after CCRT could lead to better outcomes than EBRT boost in treating AC.

Simple imaging biomarker predicts survival in anal squamous cell cancer treated with curative intent: a UK cohort study

Simple imaging biomarker predicts survival in anal squamous cell cancer treated with curative intent: a UK cohort study

Treatment of Stages I-III Squamous Cell Anal Cancer: A Comparative Effectiveness Systematic Review.

To assess the effectiveness and harms of initial treatment strategies for stages I-III anal squamous cell cancer (SCC). We searched Medline®, Embase®, and CENTRAL®, between January 1, 2000- March 2024, for randomized controlled trials and nonrandomized studies of interventions comparing initial treatment strategies. Individual study risk of bias (RoB) and overall strength of evidence (SOE) were evaluated for a prespecified outcome list using standardized methods. We identified 33 eligible studies and extracted data. Six were deemed low/moderate RoB. Compared with radiotherapy (RT) alone, chemoradiotherapy (CRT) with 5-fluorouracil (FU) and mitomycin C (MMC) probably shows a benefit in locoregional failure (LRF), disease-specific (DSS), and colostomy-free survival (CFS) (moderate SOE) yet may result in greater overall and acute hematologic toxicity, with no difference in late harms (low SOE). CRT with 5FU+MMC may show a benefit in LRF, DSS, and CFS rates compared with 5FU alone (low SOE). CRT with 5FU+cisplatin vs 5FU+MMC probably results in no differences in several effectiveness outcomes or overall acute or late harms, and probably increases hematologic toxicity with MMC (moderate SOE). Compared with CRT using capecitabine+MMC, CRT with capecitabine+MMC+paclitaxel may improve OS, DSS, and CFS, yet cause more acute harms (low SOE). Evidence was insufficient for remaining comparisons. CRT with 5FU+MMC or 5FU+cisplatin is likely more effective yet incurs greater acute hematologic toxicity than RT alone or single-agent CRT. Adding paclitaxel to capecitabine+MMC may increase treatment efficacy and toxicity. Evidence is insufficient comparing post-treatment surveillance strategies and patient-reported outcomes, highlighting research opportunities.

HPV status and immunohistochemical analysis of p16, p53 and PD‑L1 expression as prognostic biomarkers in patients with squamous cell anal cancer receiving definitive radiotherapy/chemoradiotherapy.

Anal squamous cell carcinoma (SCC) treated with definitive radiotherapy (RT)/chemoradiotherapy (CRT) has shown high success rates, yet challenges such as treatment resistance and recurrence persist. The present study aimed to investigate the associations between immunohistochemical (IHC) evaluation, treatment response and prognosis in anal SCC. A retrospective cohort analysis included 42 patients with anal SCC treated at a single institution between 2006 and 2022. Human papillomavirus (HPV) status was determined, and the IHC analysis of p16, p53 and PD-L1 expression was conducted using formalin-fixed, paraffin-embedded biopsies. A complete response to RT/CRT was observed in 71.4% of patients. Recurrence occurred in 38.1% of cases, of which 7.1% had local-regional recurrence (LRR), 14.3% had distant recurrence (DR), and 16.7% had both LRR and DR. HPV positivity (71.4%) was significantly associated with p16 positivity. Lack of complete response was associated with HPV-negative status, p16-negative status, increased recurrence and DR. In addition, recurrence was significantly associated with p53-positive status, and p53 positivity was significantly associated with increased LRR. PD-L1 positivity, defined as a combined positive score (CPS) ≥1% was found in 73.8% of the patients, and exhibited significant associations with HPV positivity and p16 positivity. PD-L1 CPS ≥ 1% was also associated with an increased LRR. Univariate analysis revealed that age <65 years, a complete response and HPV positivity were associated with increased 5-year overall survival (OS), while a complete response, HPV positivity and p53-negative status were associated with increased 5-year disease-free survival (DFS). Multivariate analysis identified that age <65 years and HPV positivity are independent prognostic factors for 5-year OS, and a complete response and p53-negative status are independent prognostic factors for 5-year DFS. In conclusion, these findings suggust that the identification of HPV status and poor prognostic biomarkers at diagnosis may be used to guide personalized treatment strategies, with the combination of immunotherapy with standard CRT potentially providing improved outcomes.

Efficacy and Toxicity of (Chemo)Radiation Therapy in HIV+ Patients with Squamous Cell Anal Cancer, a Subgroup Analysis of the National Multicenter Cohort FFCD-ANABASE

The influence of human immunodeficiency virus (HIV) infection on clinical outcomes in patients receiving (chemo)radiation therapy (RT) for squamous cell carcinoma of the anus (SCCA) is debated. The objective of this study was to compare efficacy and safety according to HIV status in patients with SCCA treated with C/RT. Between January 2015 and April 2020, 488 patients with a known HIV status (17.6% HIV+) were treated with radiation therapy for SCCA and included in the FFCD-ANABASE multicentric prospective cohort. Clinical outcomes including overall survival (OS), locoregional recurrence-free survival, colostomy-free survival, response rate at 4 to 6 months, cancer-specific survival, relapse-free survival, and severe acute and late toxicity were compared between HIV+ and HIV- patients. The median follow-up was 35.8 months. HIV+ patients were younger (P < .01) and predominantly male (P < .01). Intensity modulated radiation therapy was performed in 80.7% of patients, and 80.9% received concurrent chemotherapy. A higher proportion of HIV+ patients received induction chemotherapy compared with HIV- patients. No statistically significant difference in overall treatment time or severe acute and late toxicities was found between HIV+ and HIV- patients. In univariate analyses, OS (HR = 2.1 [CI 95% 1.2;3.5], P = .007), locoregional recurrence-free survival (HR = 1.7 [1.1;2.7], P = .02), and colostomy-free survival (HR = 1.7 [1.1;2.6], P = .01) were significantly shorter in HIV+ patients than in HIV- patients. Response rate, cancer-specific survival, and relapse-free survival were not significantly different. The recurrence site was significantly different according to HIV status. In the multivariate analysis, prognostic factors for OS were a World Health Organization performance status of ≥1 for the whole population, as well as HIV+ status for the subgroup of women. HIV+ patients treated with chemo-RT for SCCA have poorer clinical outcomes, especially women. No difference was found in toxicity according to HIV status with intensity modulated radiation therapy technique.

Anal dysplasia and anal cancer screening practices among liver transplant centers in the United States: Results of an online survey.

Solid organ transplant recipients are at an increased risk for anogenital Human Papillomavirus (HPV)-related disease, including anal high-grade squamous intraepithelial lesions (HSIL) and anal squamous cell cancer (ASCC). Guidelines for ASCC screening in transplant recipients are limited. Our aim was to understand current practice of ASCC screening in adult liver transplant (LT) candidates and recipients at transplant centers across the United States. We surveyed medical directors of 113 LT centers across the United States which had publicly available contact information. The survey evaluated center perceptions on cancer and HPV disease risk in transplant populations, ASCC screening, barriers and facilitators for ASCC screening and HPV vaccination practices. We received 26/113 (23%) responses, of which 24 were complete and included in the analysis. Eleven of 24 (46%) centers reported screening for ASCC and 3/24 (12.5%) centers reported having formal guidelines. Centers who perform ASCC screening were more likely to perform transplants in people living with HIV and were more aware of the burden of HPV disease in transplant populations. All respondents believed that additional data on the impact of screening on ASCC incidence would support screening decisions. Increased access to specialists for screening/high-resolution anoscopy was also perceived as a facilitator. Only 7/24 (29%) centers regularly evaluated HPV vaccination status of their patients. This national survey of LT centers reveals non-standardized ASCC screening practices, and identified data, educational and resource needs to improve prevention of ASCC in this population.

Adequacy and Acceptability of the Self-Collected Anal Pap Smear in People Living With Human Immunodeficiency Virus in the Infectious Diseases Clinic.

Background Anal Pap smears are imperative to screening for human papillomavirus (HPV)-associated anal squamous cell cancers, particularly in patients living withhuman immunodeficiency virus (HIV) given a higher incidence of disease. Self-collection of specimens may be favored by patients and more feasible to collect, increasing screening. Methods This was a single-center observational cohort study at a single academic medical center Infectious Diseases clinic from October to December 2021. We aimed to improve compliance of anal Pap collection documentation of "self-collected" versus "physician-collected" as well as verify if self-collected specimens (SCS) were adequate for interpretation equivalent to physician-collected specimens (PCS). Additionally, we aimed to evaluate patient and provider satisfaction with self-collected anal Paps. Results Sixty anal Pap smears were available for evaluation. The rate of documentation of the collection method (self-collected vs. physician-collected) was 88% during the intervention. A total of 75% of patients opted for self-collection, and 35/45 (78%) of these samples were adequate for interpretation. There was no difference in the adequacy of specimen (the ability of a cytopathologist to interpret the specimen) between the SCS and PCS. Conclusion Limited prior data suggest self-collected anal Pap specimens are adequate for interpretation only slightly less often than PCS. In our small cohort, there was no statistically significant difference between collection methods. Satisfaction with self-collection of specimens was high for both patients and providers. Additional validation in more diverse/larger clinical settings may be helpful to support this practice.

Oncologic Outcomes of Salvage Abdominoperineal Resection for Anal Squamous Cell Carcinoma Initially Managed with Chemoradiation.

Background: Abdominoperineal resection (APR) has been advocated for persistent or recurrent disease after failure of chemoradiation (CRT) for anal squamous cell cancer (SCC). Treatment with salvage APR can potentially achieve a cure. This study aimed to analyze oncological outcomes for salvage APR in a recent time period at a comprehensive cancer center. Methods: A retrospective review of all patients who underwent APR for biopsy-proven persistent or recurrent anal SCC between 1 January 2007 and 31 December 2020 was performed. Patients with stage IV disease at the time of initial diagnosis and patients with missing data were excluded. Univariate analysis was used with a chi-square test for categorical variables, and non-parametric tests were used for continuous variables. Kaplan-Meier survival analysis was performed to evaluate disease-specific (DSS), post-APR local recurrence-free (RFS), and disease-free survival (DFS). Results: A total of 96 patients were included in the analysis: 39 (41%) with persistent disease and 57 (59%) with recurrent SCC after chemoradiation had been completed. The median follow-up was 22 months (IQR 11-47). Forty-nine patients (51%) underwent extended APR and/or pelvic exenteration. Eight (8%) patients developed local recurrence, 30 (31%) developed local and distant recurrences, and 16 (17%) developed distant recurrences alone. The 3-year DSS, post-APR local recurrence-free survival, and disease-free survival were 53.8% (95% CI 43.5-66.5%), 54.5% (95% CI 44.4-66.8%), and 26.8% (95% CI 18.6-38.7%), respectively. In multivariate logistic regression analysis, positive microscopic margin (OR 10.0, 95% CI 2.16-46.12, p = 0.003), positive nodes in the surgical specimen (OR 9.19, 95% CI 1.99-42.52, p = 0.005), and lymphovascular invasion (OR 2.61 95% CI 1.05-6.51, p = 0.04) were associated with recurrence of disease. Gender, indication for APR (recurrent vs. persistent disease), HIV status, extent of surgery, or type of reconstruction did not influence survival outcomes. Twenty patients had targeted tumor-sequencing data available. Nine patients had PIK3CA mutations, seven of whom experienced a recurrence. Conclusions: Salvage APR for anal SCC after failed CRT was associated with poor disease-specific survival and low recurrence-free survival. Anal SCC patients undergoing salvage APR should be counseled that microscopic positive margins, positive lymph nodes, or the presence of lymphovascular invasion in the APR specimen are prognosticators for disease relapse. Our results accentuate the necessity for additional treatment strategies for the ongoing treatment challenge of persistent or recurrent anal SCC after failed CRT.

Reduction of elective lymph node volume in radiotherapy of early anal squamous cell cancer: a comparative study between two Swedish university hospitals.

Anal squamous cell cancer (ASCC) in early stages (T1-2N0M0) is treated with chemoradiotherapy with a 3-year overall survival (OS) exceeding 90%. In Swedish guidelines, it has been optional to include the external iliac and presacral lymph node (LN) stations in radiotherapy (RT) treatment fields in early ASCC. Two Swedish hospitals treating ASCC (SU: Sahlgrenska University Hospital; UU: Uppsala University Hospital) have chosen different approaches since 2010. This study included consecutive patients with early ASCC (T1-2N0M0) treated between 2010 and 2017 at both sites (SU n = 70; UU n = 46). Data were retrieved from medical records and RT charts. At SU, the external iliac and presacral LN stations were included in elective LN irradiation in 96.8% (n = 60) and 95.2% (n = 59) patients compared to 2.4% (n = 1) and 29.3% (n = 12) at UU. The mean elective LN volume was 2,313 cc (interquartile range [IQR] 1,951-2,627) in the SU cohort compared to 1,317 cc (IQR 1,192-1,528) in the UU cohort, p < 0.0001. No case of regional LN recurrence was seen in either cohort. Disease specific survival (DSS) at 5 years was 95.7% (confidence interval [CI] 90.1-100.0) in the SU cohort and 97.8% (CI 93.2-100.0) in the UU cohort (p 0.55). OS at 5 years was 84.5% (CI 76.1-93.0) in the SU cohort and 82.6% (CI 69.6-89.1) in the UU cohort (p 0.8). We found no differences in regional recurrence, DSS or OS between the cohorts treated with different elective LN volumes. In this population-based study, reduction of RT volume in early ASCC did not lead to inferior outcome.

Deep Learning in High-Resolution Anoscopy: Assessing the Impact of Staining and Therapeutic Manipulation on Automated Detection of Anal Cancer Precursors.

High-resolution anoscopy (HRA) is the gold standard for detecting anal squamous cell carcinoma (ASCC) precursors. Preliminary studies on the application of artificial intelligence (AI) models to this modality have revealed promising results. However, the impact of staining techniques and anal manipulation on the effectiveness of these algorithms has not been evaluated. We aimed to develop a deep learning system for automatic differentiation of high-grade squamous intraepithelial lesion vs low-grade squamous intraepithelial lesion in HRA images in different subsets of patients (nonstained, acetic acid, lugol, and after manipulation). A convolutional neural network was developed to detect and differentiate high-grade and low-grade anal squamous intraepithelial lesions based on 27,770 images from 103 HRA examinations performed in 88 patients. Subanalyses were performed to evaluate the algorithm's performance in subsets of images without staining, acetic acid, lugol, and after manipulation of the anal canal. The sensitivity, specificity, accuracy, positive and negative predictive values, and area under the curve were calculated. The convolutional neural network achieved an overall accuracy of 98.3%. The algorithm had a sensitivity and specificity of 97.4% and 99.2%, respectively. The accuracy of the algorithm for differentiating high-grade squamous intraepithelial lesion vs low-grade squamous intraepithelial lesion varied between 91.5% (postmanipulation) and 100% (lugol) for the categories at subanalysis. The area under the curve ranged between 0.95 and 1.00. The introduction of AI to HRA may provide an accurate detection and differentiation of ASCC precursors. Our algorithm showed excellent performance at different staining settings. This is extremely important because real-time AI models during HRA examinations can help guide local treatment or detect relapsing disease.

DOP04 Screening and management of fistula cancers in patients with perianal fistulising Crohn’s Disease: an expert consensus

Abstract Background Fistula cancer is a rare and often devastating diagnosis in patients with perianal fistulising Crohn’s disease (CD). Fistula cancer management is a complex process requiring multi-disciplinary effort. However, given the low incidence and subsequent lack of data and clinical trials in the field, there is little to no guidance on screening and management of fistula cancer. To inform clinical practice, we developed consensus guidelines on fistula cancer in perianal fistulising Crohn’s disease by multidisciplinary experts from the international TOpCLASS consortium. Methods We performed a systematic review of the literature by standard methodology, using the Newcastle-Ottawa quality assessment tool. Data were retrieved from articles according to these domains: epidemiology and risk factors, clinical presentation, diagnostics, staging, and treatment. We developed consensus statements using a Delphi consensus approach. Participants included gastroenterologists, surgeons, radiologists, and pathologists. We performed two rounds of voting: (1) online survey followed by statement edits and (2) hybrid meeting with discussion until over 80% consensus was achieved for each statement. Results Of 550 articles identified, 99 were eligible, and 80 articles were included. The overall quality of evidence was low. Seven statements were accepted in the final consensus (Table 1). Patients with longstanding (&amp;gt;10 years) perianal fistulising CD should be considered at small but increased risk of developing fistula cancer, including anal squamous cell cancer (SCC) and anorectal carcinoma. Risk factors for anal SCC, including human papilloma virus (HPV), should be considered. Clinical signs and symptoms of fistula cancers are non-specific, and several case reports included asymptomatic patients. New or refractory/progressive perianal symptoms should prompt evaluation for fistula cancer. There was no consensus on timing or frequency of screening in patients with asymptomatic perianal fistula. Regarding diagnostics, multiple modalities may be required, including repeated exam under anesthesia with biopsy. Multidisciplinary team efforts were deemed central for the management of fistula cancers. Conclusion Clinicians managing patients with perianal fistulising CD should be aware of the risk of fistula cancers, including anal SCC and anorectal carcinoma. Our expert consensus recommends consideration of patient factors including duration of fistulas, HPV status, and perianal symptoms, and gives guidance on diagnostic modalities and treatment considerations. Multidisciplinary coordination of care is paramount, and more studies in the field are needed.

High-tailored Anal Canal Radiotherapy (HIT-ART): Outcomes of a 10-Year Single Center Clinical Experience.

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. 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. 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). 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.

S173 Deep Learning and High-Resolution Anoscopy: Assessing the Impact of Staining and Overcoming the Impact Therapeutic Anal Manipulation in the Automated Detection and Differentiation of Anal Squamous Cell Cancer Precursors

S173 Deep Learning and High-Resolution Anoscopy: Assessing the Impact of Staining and Overcoming the Impact Therapeutic Anal Manipulation in the Automated Detection and Differentiation of Anal Squamous Cell Cancer Precursors

HPV Infection and Immunohistochemical Analysis of P16, P53, and PD-L1 Expression as Prognostic Biomarkers in Squamous Cell Anal Cancer Patients Receiving Definitive Radiotherapy/Chemoradiotherapy

The treatment of anal squamous cell carcinoma (SCC) with definitive radiotherapy (RT)/chemoradiotherapy (CRT) has a high likelihood of success; nevertheless, treatment resistance and recurrence rates cannot be ignored. Therefore, we aimed to identify the relationship between immunohistochemical (IHC) evaluation, treatment response, and prognosis. This retrospective study included 42 patients with anal SCC treated with definitive RT/CRT at a single institution between 2006 and 2020. Detection of high-risk HPV-DNA and IHC analysis of p16, p53, and PD-L1 expression was performed from diagnostic formalin-fixed, paraffin-embedded (FFPE) biopsies. Positive staining was accepted as >5% in tumor cells for p16 and p53 expression in addition to ≥1% combined positive score (CPS) [(PD-L1 positive tumor, lymphocyte, macrophage count/total viable cell count) x100] for PD-L1 expression. Thirty patients (71.4%) had a complete response to definitive RT/CRT. Recurrence was observed in 16 (38.1%) patients, with 3 (7.1%) having locoregional recurrence (LRR), 6 (14.3%) having distant metastases (DM), and 7 (16.7%) having both LRR and DM. Twenty-four (57.1%) patients were alive. Thirty (71.4%) patients were HPV+, while 12 (28.6%) were HPV-. There was a significant correlation between HPV+ and p16+ status (p<0.001). HPV- status was associated with the male gender (p = 0.001). HPV- and p16- status were significantly associated with a lack of complete response to definitive RT/CRT (p<0.001, p<0.001, respectively). Furthermore, there was a significant relationship between lack of complete response and increased recurrence (p = 0.016) and distant metastases (p = 0.015). Ten of the 16 patients with recurrence were p53+; a significant correlation was found between recurrence and p53+ status (p = 0.006). Similarly, p53+ status was associated with increased LRR (p = 0.014). PD-L1 CPS ≥ 1% was found in 31 (73.8%) patients. PD-L1 positivity was significantly correlated with HPV+ (p = 0.026) and p16+ (p = 0.013) status. All 10 (23.8%) patients with LRR were PD-L1+; PD-L1 CPS ≥ 1% was associated with poor local control (p = 0.031). In univariate analysis, age [<65] (p = 0.049), complete response (p = 0.015), and HPV+ status (p = 0.010) were related to increased 5-year (y) overall survival (OS); complete response (p = 0.001), HPV+ status (p = 0.025) and p53- status (p = 0.010) were associated with increased 5-y disease-free survival (DFS). In multivariate analysis, age [<65] (p = 0.010) and HPV+ status (p = 0.002) were significant prognostic factors for 5-y OS, whereas complete response (p = 0.007) and p53- status (p = 0.038) were significant prognostic factors for 5-y DFS. Patients with HPV- status and/or poor prognostic biomarkers should be identified at diagnosis. Thus, better outcomes can be achieved with different treatment options, such as combining immunotherapy and standard CRT.

The Association of Chemoradiation Induced Lymphopenia with Racial Disparity and Its Prognostic Impact on Survival for Anal Cancer

While the association between chemoradiation induced lymphopenia (CIL) and poor overall survival (OS) is established in multiple solid malignancies, it has not been studied in anal cancer. Racial and socioeconomic disparities as potential predictors of lymphopenia have not been reported. We hypothesize that race and socioeconomic status is associated with increased incidence of severe CIL, which can predict worse overall survival for patients with anal cancer. A cohort of 75 patients treated with definitive chemoradiation (CRT) for squamous cell anal cancer from January 2014 to December 2020 was reviewed. Total lymphocyte counts (TLC) at baseline and TLC nadir at 1 month post-CRT were analyzed. Logistic regression was used to identify associations between race, gender, ethnicity, median household income by zip code, marital status, baseline hematopoietic cell counts, and post-CRT Grade 3+ lymphopenia (TLC <0.5k/μL). Kaplan-Meier method and Cox regression model were used to perform survival analysis. Of the 75 patients identified, mean age was 66.9 years and median follow-up time was 37.1 months. There were 63 females, 53 non-Hispanic whites, 22 minorities (12 Blacks, 9 Hispanics, 1 Asians) Radiation dose ranged from 41.4 Gray to 56 Gray. At 1 month post CRT, 85.3% developed lymphopenia (G1 9.3%, G2 26.7%, G3 37.3%, G4 12.0%). On multivariate logistic regression, non-white race demonstrated a trend to have more Grade 3+ lymphopenia (OR = 3.5, p = 0.07). On univariate Cox regression, poorer overall survival was associated with race (HR 3.7, p = 0.04), baseline white blood count (HR 1.3, p = 0.04), baseline hemoglobin (HR 0.6, p = 0.04), and post-CRT Grade 3+ lymphopenia (HR 5.8, p = 0.03). On multivariate Cox regression, only post-CRT Grade 3+ lymphopenia was associated with worse OS (HR 7.5, p = 0.049). 5-year OS significantly differed between patients with and without post-CRT Grade 3+ lymphopenia (62.3% vs 94.7%, P = 0.01). Lymphopenia is commonly observed after chemoradiation for anal cancer. Racial disparity is associated with severe lymphopenia induced by chemoradiation, which is a robust predictor of poor survival in anal cancer. More attention to lymphopenia induced by chemoradiation for anal cancer is needed, particularly in racial minorities.

Atezolizumab plus tiragolumab in combination with chemoradiotherapy in localized squamous cell carcinoma of the anal canal: TIRANUS (GEMCAD-2103) trial.

TPS3624 Background: Radical chemoradiotherapy (CRT) is the standard of care in patients with localized anal squamous cell carcinoma; however, around 30% of patients do not achieve a complete clinical response (CCR) and require savage surgery. Approximately 84% of anal carcinoma is associated with high risk types of human papilloma virus (HPV), primarily HPV 16 that generates high frequencies of tumor-infiltrating lymphocytes and inflammatory responses that have been linked with upregulation of PD-L1 (up to 74% of patients with squamous cell anal cancer). Additionally, poliovirus receptor (PVR) expression has been described in several squamous cell carcinomas, and has been correlated with PD-L1 expression and poorer prognosis, suggesting dual inhibition of PVR and PD-L1 as a potential mechanism of overcome the resistance to immune checkpoint monotherapy. Moreover, CRT induces the generation of tumor-neoantigens and could act in synergy with immunotherapy in this setting. The trial hypothesizes that the addition of atezolizumab (anti-PD-L1) and tiragolumab (anti-TIGIT) to chemoradiotherapy may lead to enhanced and more durable responses. Methods: TIRANUS is a Phase II, single-arm, open-label, non-randomized, multicenter clinical trial of atezolizumab and tiragolumab in concomitance with standard CRT as definitive therapy in treatment-naïve, localized squamous cell carcinoma of the anal canal. Patients receive atezolizumab (1200mg) plus tiragolumab (600 mg) for 2 cycles (Q3W) in concomitance with the 6 weeks of CRT (cisplatin: 60 mg/m² on days 1 and 29; 5-FU: 1000 mg/m² per day on days 1-4 and 29-32; radiotherapy: 1.8 Gy per day / total dose 54 Gy). After the concomitant phase, patients receive atezolizumab (1200mg) and tiragolumab (600 mg) Q3W for 6 additional cycles (consolidation phase). The primary endpoint is CCR rate, defined as the percentage of patients who achieve radiological complete response (CR), disappearance of all lesions according to RECIST 1.1 criteria (locally assessed) and no presence of residual disease assessed by biopsy at the end of consolidation phase (week 26). Secondary endpoints include Locoregional failure rate (LFR), Disease-free survival (DFS), Colostomy-free survival (CFS), Overall survival (OS), quality of life, safety and the determination of immune biomarkers potentially predictors of response in blood and tumor samples. Using a precision analysis by Clopper-Pearson method (asymptotic 95% confidence interval) and an expected CCR rate of 85%, a total of 45 evaluable patients are needed to obtain a precision estimation of ±10.4%. Accrual started in February 2023. EudraCT: 2021-005887-24 Clinical Trial identifier: NCT05201612. Clinical trial information: NCT05661188 .

Burden of chronic health conditions (CHCs) among people with HIV (PWH) and non-AIDS defining cancers (NADC): A report from the center for AIDS research (CFAR) network of integrated clinical systems (CNICS).

12089 Background: Advances in anti-retroviral therapy (ART) have led to improved life expectancy of PWH and a growing population of PWH who are at an increased risk of NADC. While the risk of CHCs in HIV uninfected cancer survivors is well known, the burden of morbidity (CHCs) borne by PWH-NADC remains unstudied and can adversely influence long-term survival. Methods: We utilized CNICS data for PWH ≥18y from 1995- 2018. CNICS data are harmonized across 8 academic sites, comprising patient-level clinical, morbidity, and outcomes data in the ART era. We included individuals with the five most common NADCs: anal squamous cell cancer, non-small cell lung cancer (NSCLC), prostate cancer, classic Hodgkin lymphoma (cHL), and hepatocellular cancer (HCC). For controls, we conducted a 1:2 matching (age at CNICS entry, year of CNICS entry, sex) for each NADC subgroup to select PWH and no NADC at last follow-up. Comorbidities diagnosed after cohort entry are validated in CNICS and were graded using the Common Terminology Criteria for Adverse Events into grade 1 (mild) through grade 4 (severe/life-threatening). Results: We included 693 PWH-NADC and 1,345 non-cancer PWH controls in this study. The NADC distribution was anal cancer (n = 195, 28%), NSCLC (n = 155, 22%), prostate cancer (n = 144, 21%), cHL (n = 124, 18%), and HCC (n = 75, 11%). Mean age at CNICS entry was 45y for cases and controls (SD: 10.4). At a median follow-up of 12.5y for cases and 9.5y for controls, the prevalence of all-grade and grade ≥3 CHCs was higher in PWH-NADC compared with controls (94% vs. 88%, and 25% vs. 14%, respectively [p &lt; 0.01]). PWH-NADC had a higher prevalence of all-grade HTN (87% vs. 80%), CKD (49% vs. 46%), hyperlipidemia (56% vs. 50%), DM (26% vs. 18%), VTE (4% vs. 1%), MI (12% vs. 5%), and CHF (7% vs. 3%) compared with controls (p-value for all &lt; 0.01). In Cox regression including type of NADC, age at CNICS cohort entry, ART use, race/ethnicity, NADCs were associated with increased risk of new-onset grade 3 or 4 CHCs (HR 2.94, p &lt; 0.01). When examining specific CHCs, all NADCs were associated with increased risk of new-onset grade 3 DM ([anal cancer HR 2.34, HCC HR 5.02, NSCLC HR 3.89, cHL HR 2.77, and prostate cancer HR 1.88], p-value for all &lt; 0.01). Additionally, NSCLC was associated with increased risk of G3-4 MI (HR 2.79, p = 0.04), and prostate cancer with G3-4 CHF (HR 6.19, p &lt; 0.01). Conclusions: In this large multi-institutional study, 25% of PWH-NADC had developed severe/life-threatening CHCs at last follow up. Occurrence of NADC among PWH was associated with increased hazards of developing grade ≥3 morbidities. The specific types of CHCs observed in PWH with NADC subtypes could be used to inform risk-based anticipatory surveillance and risk reduction strategies.

Immunotherapy in Anal Cancer

The incidence and mortality of squamous cell carcinoma of the anus has been gradually increasing globally over the last few decades. The evolution of different modalities, including immunotherapies, has changed the treatment paradigm of metastatic anal cancers. Chemotherapy, radiation therapy, and immune-modulating therapies form the backbone of treatment of anal cancer in various stages. Most anal cancers are linked to high-risk human papilloma virus (HPV) infections. HPV oncoproteins E6 and E7 are responsible for an anti-tumor immune response triggering the recruitment of tumor-infiltrating lymphocytes. This has led to the development and utilization of immunotherapy in anal cancers. Current research in anal cancer is moving forward to discover ways to incorporate immunotherapy in the treatment sequencing in various stages of anal cancers. Immune checkpoint inhibitors alone or in combination, adoptive cell therapy, and vaccines are the areas of active investigations in anal cancer in both locally advanced and metastatic settings. Immunomodulating properties of non-immunotherapies are incorporated to enhance immune checkpoint inhibitors' effectiveness in some of the clinical trials. The aim of this review is to summarize the potential role of immunotherapy in anal squamous cell cancers and future directions.

Temporal increase in the incidence of anal squamous cell carcinoma in Kentucky and factors associated with adverse outcomes.

Anal squamous cell cancer (ASCC) incidence in Kentucky is increasing at an alarming rate. In 2009, the incidence surpassed the US national average (2.66 vs. 1.77/100,000 people), and currently, Kentucky ranks second by state per capita. The reasons for this rise are unclear. We hypothesize individuals with ASCC in Kentucky have some unique risk factors associated with worse outcomes. Individuals with ASCC in a population-level state database (1995-2016), as well as those treated at two urban university-affiliated tertiary care centers (2011-2018), were included and analyzed separately. We evaluated patient-level factors including demographics, tobacco use, stage of disease, HIV-status, and HPV-type. We evaluated factors associated with treatment and survival using univariable and multivariable survival analyses. There were 1698 individuals in state data and 101 in urban center data. In the urban cohort, 77% of patients were ever-smokers. Eighty-four percent of patients had positive HPV testing, and 58% were positive for HPV 16. Seventy-two percent of patients were positive for p16. Neither smoking, HPV, nor p16 status were associated with disease persistence, recurrence-free survival, or overall survival (all p > 0.05). Poorly controlled HIV (CD4 count <500) at time of ASCC diagnosis was associated disease persistence (p = 0.032). Stage III disease (adjusted HR = 5.25, p = 0.025) and local excision (relative to chemoradiation; aHR = 0.19, p = 0.017) were significantly associated with reduced recurrence-free survival. The rate of ASCC in Kentucky has doubled over the last 10 years, which is outpacing anal SCC rates in the US with the most dramatic rates seen in Kentucky women. The underlying reasons for this are unclear and require further study. There may be other risk factors unique to Kentucky.

Anal Cancer: The Past, Present and Future

Anal cancer is a rare cancer that accounts for about 2% of all gastrointestinal tract malignancies. Among anal cancer, squamous cell cancer is the most common malignancy. The incidence of all stages of anal squamous cell cancer has been increasing. Human papillomavirus infection and immunosuppression are major risk factors for anal cancer. The management of anal cancer has evolved over the past several decades and continues to do so. Chemoradiation therapy remains the mainstay for treatment for most patients with early-stage disease, whereas systemic therapy is the primary treatment for patients with metastatic disease. Patients with persistent disease or recurrence following chemoradiation therapy are treated with salvage surgery. Access to novel cytotoxic combinations and immunotherapy has improved the outcomes of patients with advanced disease. This review provides an overview of advances in the management of anal cancer over the past two decades. This paper reviews the epidemiology, risk factors, pathology, diagnosis, and management of localized and advanced anal squamous cell cancer, highlights current knowledge gaps in the management of anal cancer, and discusses future directions.