Anal Squamous Cell Carcinoma Patients Research Articles

MRI morphological characteristics of lymph nodes in anal squamous cell carcinoma

ObjectivesPre-treatment staging of anal squamous cell carcinoma (ASCC) includes pelvic MRI and [18F]-fluorodeoxyglucose positron emission tomography with computed tomography (PET-CT). MRI criteria to define lymph node metastases (LNMs) in ASCC are currently lacking. The aim of this study was to describe the morphological characteristics of lymph nodes (LNs) on MRI in ASCC patients with PET-CT-positive LNs.MethodsASCC patients treated at Skåne University Hospital between 2009 and 2017 were eligible for inclusion if at least one positive LN according to PET-CT and a pre-treatment MRI were present. All PET-CT-positive LNs and PET-CT-negative LNs were retrospectively identified on baseline MRI. Each LN was independently classified according to pre-determined morphological characteristics by two radiologists blinded to clinical patient information.ResultsSixty-seven ASCC patients were included, with a total of 181 PET-CT-positive LNs identified on baseline MRI with a median short-axis diameter of 9.0 mm (range 7.5–12 mm). MRI morphological characteristics of PET-CT-positive LNs included regular contour (87%), round shape (89%), and homogeneous signal intensity on T2-weighed images (67%). An additional 78 PET-CT-negative LNs were identified on MRI. These 78 LNs had a median size of 6.8 mm (range 5.5–8.0 mm). The majority of PET-CT-negative LNs had a regular contour, round shape, and a homogeneous signal that was congruent to the primary tumor.ConclusionsThere are MRI-specific morphological characteristics for pelvic LNs in ASCC. PET-CT-positive and negative LNs share similar morphological features apart from size, with PET-CT-positive LNs being significantly larger. Further studies are needed to determine discrimination criteria for LNM in ASCC.

Pathogenic alterations in PIK3CA and KMT2C are frequent and independent prognostic factors in anal squamous cell carcinoma treated with salvage abdominoperineal resection.

The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer-related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV-positive tumors, while HPV-negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV-positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C = 2.54, 95%CI = [1.25,5.17], P value = .010; HRPIK3CA = 2.43, 95%CI = [1.3,4.56], P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV-positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.

Anal Cancers in Previously Screened Versus Unscreened Patients: Tumor Stage and Treatment Outcomes.

Targeted screening programs for patients at high risk for anal squamous cell carcinoma have been proposed; however, the evidence in support of screening remains unclear. This study aimed to determine whether screening high-risk patients (predominantly those living with HIV) detected squamous cell carcinoma at an earlier stage compared to the routine practice of not screening. This is a cohort study. This study was conducted at a quaternary care center in Canada. Included patients were at least 18 years old with a pathologic diagnosis of invasive anal squamous cell carcinoma between 2002 and 2022. Patients diagnosed through a high-risk screening program were compared to those who did not undergo screening. The primary outcome was clinical stage at presentation, categorized as T1N0M0 vs. other. Secondary outcomes included treatments received, treatment failure, and overall survival. A total of 612 anal squamous cell carcinoma patients were included, with 26 of those patients diagnosed through a screening program. Patients with screen-detected cancers had greater odds of presenting with T1N0M0 tumors compared to unscreened patients (18 [69.2%] vs. 84 [14.3%]; adjusted odds ratio 9.95; 95% confidence interval 3.95-25.08). A propensity score matched sensitivity analysis found similar results (odds ratio 11.13; 95% confidence interval 4.67-26.52; p < 0.001). Screened patients had greater odds of treatment with wide local excision alone, as opposed to any combination of chemotherapy, radiation, and surgery (3 [12.5%] vs. 18 [3.2%]; odds ratio 4.38; 95% confidence interval 1.20-16.04). There were no statistically significant differences in treatment failure or overall survival between groups. The small number of screened patients limits the power of the analysis. Screening for anal squamous cell carcinoma amongst high-risk populations detects cancers at an earlier stage. Patients with screen-detected cancers also had a greater likelihood of being candidates for wide local excision alone, which may have spared them the morbidity associated with chemoradiotherapy or abdominoperineal resection.

Predictors of recurrence following local excision for early-stage anal squamous cell carcinoma

IntroductionThere is increasing use of local excision (LE) for definitive treatment of early-stage anal squamous cell carcinoma (ASCC) to avoid the morbidity associated with chemoradiotherapy (CRT). However, the importance of different histological variables on risk of recurrence is poorly understood. MethodsA detailed analysis of patient characteristics, histology results, recurrence patterns and salvage treatment was conducted in consecutive T1/T2N0 ASCC patients treated by LE 2010–2021 across a UK regional cancer network multi-disciplinary team (MDT). Associations between potential predictors of disease recurrence were explored using chi-squared and Kruskal-Wallis tests for categorical and continuous variables respectively. ResultsOf 621 ASCC patients discussed in the network MDT, 164 had early-stage disease (T1/T2 N0). Of these, 36 (22%) were deemed suitable for LE (median age 61 years, female to male ratio 2:1). Twenty-two LE tumours were T1; 14 were T2. There were 12 well-differentiated tumours, 21 moderate and 3 poorly-differentiated. Seven out of 36 LE patients (19.4%) developed recurrence, all of whom went on to have salvage treatment with CRT (n = 4), re-excision (n = 2) or radiotherapy (n = 1). Predictors of disease recurrence following LE were: tumour differentiation (p = 0.024), tumour depth (p = 0.033) and R1 resection margin (p = 0.034). Tumour stage and site (margin/canal) were non-significant. ConclusionLE for T1/T2 N0 ASCC of the margin or canal is a viable treatment strategy to avoid the morbidity associated with CRT and salvage treatments are still available for patients that develop recurrence. Tumour differentiation, depth and margin status are all important factors to consider when discussing management of early-stage ASCC.

Pre- and post-treatment FDG PET-CT as a predictor of patient outcomes in anal squamous cell carcinoma: A systematic review and meta-analysis.

Anal squamous cell carcinoma (ASCC) has a generally acceptable outlook in terms of survival. 18-fluorodeoxyglucose-positron emission tomography/computer tomography (FDG PET-CT) is not recommended for routine monitoring post-ASCC treatment. We examine herein if FDG PET-CT has a use in the prognostic evaluation of patients with ASCC, what FDG PET-CT metrics are of value and if a pre- or post-chemo/radiotherapy scan is more prognostic of outcomes. PubMed, EMBASE and Cochrane Central Registry of Controlled Trials were comprehensively searched until 3 May, 2023. A modified Newcastle Ottawa scale was used to assess for study bias. We present our systematic review alongside pooled hazard ratios (HR) for maximum standardised uptake values (SUV) as a predictor of overall survival (OS) and progression-free survival (PFS). Seven studies including 523 patients were included in our systematic review. Current evidence suggests that SUV maximum and median, metabolic tumour volume, total lesion glycolysis and complete and partial metabolic response may be prognostic when considering overall or progression-free survival (OS)/(PFS) along with local recurrence (LR). Pooled HR from two included studies indicate SUV max is prognostic of OS, HR 1.179, CI (1.039-1.338), P = 0.011 and PFS 1.176, CI (1.076-1.285), P < 0.01. FDG PET-CT may have a role to play in the prognostic evaluation of ASCC patients. Current evidence suggests post-treatment scanning may hold superior prognostic value at this time.

Intensity-modulated radiotherapy and cisplatin-based chemotherapy for anal cancer: long-term outcomes at a single institution.

To evaluate oncological outcomes and late toxicities in a retrospective series of patients with locally-extended anal squamous cell carcinoma (ASCC), treated with curative Intensity Modulated Radiotherapy (IMRT) and chemotherapy. ASCC patients who underwent chemo-radiotherapy with IMRT from 2010 to 2020 were included. Oncological outcomes were assessed in terms of overall survival (OS), disease-free survival (DFS), colostomy-free survival (CFS) and event-free survival (EFS). Late toxicity was detected according to CTCAE v.5.0 and RTOG late radiation morbidity scoring system. Ninety-five patients were included. Most patients (83%) received chemotherapy with oral Fluoropyrimidine plus Cisplatin. The median follow-up was 5.5years. The OS was 85.2%, 82.1% and 79.3% at 3, 5 and 8years, respectively. The DFS was 73.1%, 70%, and 65.3% at 3, 5 and 8years, respectively; 3, 5 and 8years CFS was 86.2%, 84.3% and 84.3%, respectively. The EFS was 71%, 67.9% and 63.1%, at 3, 5 and 8years, respectively. On univariable analysis, a statistically significant lower OS was found for patients with T3-T4 stage (HR = 4.58, p = 0.005) and overall treatment time (OTT) ≥ 47days (HR = 3.37, p = 0.038). A statistically significant lower DFS was reported for patients with T3-T4 stage (HR = 2.72, p = 0.008) and Serum Squamous Cell Carcinoma Antigen (SCC) value post-RT > 1.5 (HR = 2.90, p = 0.038.). Ten severe late toxicity (≥ G3) events were reported in 8 patients (8.6%). Our data confirm IMRT concomitant with a Cisplatin-based chemotherapy as an effective treatment of ASCC, ensuring acceptable long-term toxicities and good oncological outcomes.

Clinicopathological Characteristics and Outcomes of Anal Squamous Cell Carcinoma Patients With and Without HIV Infection in Sub-Saharan Africa.

In the past 20 years, the burden of anal cancer (AC) increased by 60% in the United States and over three-fold in Africa. Rates of AC have increased by 20× in people living with HIV and the highest (50×) in men with HIV who have sex with men. However, in sub-Saharan Africa (SSA) where HIV is endemic, data on clinicopathological characteristics and outcomes of patients with AC are lacking. To address this, we have investigated AC disease presentation, treatment outcomes, and its predictors in a cohort of patients who were either HIV-infected or HIV-uninfected in SSA. We conducted a retrospective cohort study of patients with anal squamous cell carcinoma (SCC) treated at Ocean Road Cancer Institute in Dar es Salaam, Tanzania from January 2014 to December 2019. Associations between the study outcomes and their predictors were analyzed using univariate and multivariate analysis models. A total of 59 patients with anal SCC were retrieved and had at least 2-year follow-up. The mean age was 53.9 (standard deviation ±10.5) years. While none of the patients presented with stage I disease, 64.4% had locally advanced disease. HIV infection was the major comorbidity (64.4%). The rate of complete remission at the end of treatment was at 49% while the 2-year overall survival (OS) and local recurrence-free survival were 86.4% and 91.3%, respectively. Despite high HIV coinfection in the cohort, AC treatment outcomes were not significantly associated with HIV status. Disease stage (P = .012) and grade (P = .030) were significantly associated with 2-year OS. Patients with anal SCC in Tanzania present mainly with locally advanced disease associated with high HIV prevalence. In this cohort, the SCC grade was independently associated with treatment outcomes unlike other factors such as HIV coinfection.

Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma.

Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. On the discovery cohort, the median age was 61years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33months, and overall survival was 45months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5years than those with two CYP2D6 copies (21%vs. 84%; p<.0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5years (56% vs. 87%; p=.02, HR=3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy.

Circulating HPV16 DNA in Blood Plasma as Prognosticator and Early Indicator of Cancer Recurrence in Radio-Chemotherapy for Anal Cancer.

Implementation of anal squamous cell carcinoma (ASCC) treatment modifications requires reliable patient risk stratification. The circulating tumor-related human papillomavirus type 16 (ctHPV16) may play a role in predicting survival or assessing treatment response. The study included 62 ASCC patients treated with chemoradiotherapy. A threshold of 2.5 was used to determine the maximum standardized uptake value (SUVmax). The ctHPV16 viral load (VL) was quantified by qPCR. In the multivariate Cox analysis, lower SUVmax (p = 0.047) and ctHPV16-positive (p = 0.054) proved to be independent prognostic factors for favorable overall survival (OS). In the subgroup with the higher SUVmax, ctHPV16 and nodal (N) status were independent prognostic factors with p = 0.022 for ctHPV16 and p = 0.053 for N. The best survival rate (95%) presented ctHPV16-positive/N-negative patients. High ctHPV16 VL tended to be slightly specific for patients younger than 63 years (p = 0.152). The decrease in ctHPV16 VL to undetectable level after the end of treatment correlated with the overall clinical response. A prognostic stratification by SUVmax, ctHPV16 and N-positive status allows consideration of more aggressive treatment in high-risk patients (those with high SUVmax, ctHPV16-negative, and N-positive) or de-intensification of therapy in low-risk patients (those with low SUVmax, ctHPV16-positive and N-negative). However, prospective clinical trials on a large group are needed.

Anal squamous cell carcinoma: Impact of radiochemotherapy evolution over years and an explorative analysis of MRI prediction of tumor response in a mono-institutional series of 131 patients.

Radiochemotherapy (RCHT) for the treatment of anal squamous cell carcinoma (ASCC) has evolved dramatically, also thanks to intensity-modulated RT (IMRT) and 3D image guidance (3D IGRT). Despite most patients presenting fair outcomes, unmet needs still exist. Predictors of poor tumor response are lacking; acute toxicity remains challenging; and local relapse remains the main pattern of failure. Between 2010 and 2020, ASCC stages I-III treated with 3D conformal radiotherapy or IMRT and CDDP-5FU or Mytomicine-5FU CHT were identified. Image guidance accepted included 2D IGRT or 3D IGRT. The study endpoints included freedom from locoregional recurrence (FFLR), colostomy free survival (CFS), freedom from distant metastasis (FFDM), overall survival (OS), and acute and late toxicity as measured by common terminology criteria for adverse events (CTCAE) version 5.0. An exploratory analysis was performed to identify possible radiomic predictors of tumor response. Feature extraction and data analysis were performed in Python™, while other statistics were performed using SPSS® v.26.0 software (IBM®). A total of 131 patients were identified. After a median FU of 52 months, 83 patients (63.4%) were alive. A total of 35 patients (26.7%) experienced locoregional failure, while 31 patients (23.7%) relapsed with distant metastasis. Five year FFLR, CFS, DMFS and PS resulted 72.3%, 80.1%, 74.5% and 64.6%. In multivariate analysis, 2D IGRT was associated with poorer FFLR, OS, and CFS (HR 4.5, 4.1, and 5.6, respectively); 3DcRT was associated with poorer OS and CFS (HR 3.1 and 6.6, respectively). IMRT reduced severe acute gastro-intestinal (GI) and severe skin acute toxicity in comparison with 3DcRT. In the exploratory analysis, the risk of relapse depended on a combination of three parameters: Total Energy, Gray Level Size Zone Matrix's Large Area High Gray Level Emphasis (GLSZM's LAHGLE), and GTV volume. Advances in radiotherapy have independently improved the prognosis of ASCC patients over years while decreasing acute GI and skin toxicity. IMRT and daily 3D image guidance may be considered standard of care in the management of ASCC. A combination of three pre-treatment MRI parameters such as low signal intensity (SI), high GLSZM's LAHGLE, and GTV volume could be integrated in risk stratification to identify candidates for RT dose-escalation to be enrolled in clinical trials.

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.

Trends in utilization of first-line palliative treatments for anal squamous cell carcinoma.

Anal squamous cell carcinoma patients often present with significant symptoms, including pain, bleeding, and obstructive symptoms. This requires palliation-directed therapy as a first-line treatment to alleviate symptoms. The proportion of patients receiving first-line palliative treatments is unknown. We aimed to study the factors associated with the use of first-line palliative treatments in stage II-IV anal squamous cell carcinoma patients. We used the National Cancer Database to identify adult patients diagnosed with stage II-IV anal squamous cell carcinoma between 2004 and 2016. We performed univariable and multivariable logistic regression analysis to determine the clinical and sociodemographic variables associated with the utilization of palliative treatment in the first-line setting, including palliative radiotherapy, chemotherapy, surgery, and pain management. Among 16,944 patients diagnosed with stage II-IV anal squamous cell carcinoma, only a small proportion of 492 (2.9%) required first-line palliative treatments to control symptoms. The majority of these patients received palliative radiotherapy (32%), followed by palliative surgery (25%), palliative chemotherapy (19%), combination therapies (14%), and pain management (10%). On multivariable analysis, higher stage disease, lower income, Medicare and Medicaid insurance, and life expectancy <6 months were associated with higher odds of use of first-line palliative therapy. First-line use of palliative treatments to control symptoms is needed in a small proportion of anal squamous cell cancer patients. It was utilized in all stages, but it was most frequently observed in patients with stage IV disease and patients with <6 months life expectancy. First-line palliative therapy was also more frequent in lower-income patients and patients with Medicare and Medicaid insurance which highlights the disparities in anal cancer management.

P-69 Anal squamous cell carcinoma (ASCC) outcomes in clinical practice: From localized to metastatic setting

Anal cancer is an infrequent neoplasm, usually diagnosed at localized stages. A multidisciplinary approach involving chemoradiotherapy (CRT) and surgery is necessary. Real-world data in both locally advanced and metastatic setting is needed to support therapeutic decisions. Patients with ASCC diagnosis between 2004 and 2022 in three tertiary care centers in Spain were reviewed. Demographic, clinical, pathological, and therapeutic variables were collected. Comparative analyses have been performed by Chi-squared tests. Survival estimates have been calculated by Kaplan-Meier method and comparations have been made using Cox proportional hazards model. 111 patients were included (45.9% males, median age 61y, 9.9% metastatic at initial diagnosis). Preferred treatment in localized stage was CRT (88.1%) with 5-fluorouracil and mytomicin-C (5FU-MMC) (55%) or 5FU-Cisplatin (33%). Response in patients treated with CRT was assessed by MRI at 3 and/or 6 months after CRT in 60.4% and 53.1% respectively. 19.6% of patients needed surgical intervention due to persistent or progressive disease after CRT. There were no significant differences between 5FU-MMC or 5FU-Cisplatin in terms of complete radiological response (45,28% vs. 51,61%; p = 0.58), need of surgical rescue (18,85% vs. 19,35%; p = 0.96), distant or localized relapse (30,18% vs. 25,80%; p = 0.67), median disease-free survival (DFS) (50,00 months vs. non reached (NR); p = 0.24) or overall survival (117,26 months vs. NR; p = 0.45). OS was significantly improved in patients who achieved a complete radiological response vs. patients who not (117,26 months vs. 29,01 months p 42,57% of all patients treated with curative intent relapsed locally (44.2%) or distant (55.8%), being regional nodes most common place of recurrence. The median OS of metastatic patients at diagnosis was 14,75 months. Considering all metastatic patients (de novo or relapsed), no significant differences in OS were found between patients who received treatment with curative intent (surgery, CRT) and patients only candidate to palliative chemotherapy 15,97 months vs. 13,11 months; p = 0.072). Median progression-free survival (PFS) of Carboplatin-Paclitaxel was 4,76 months. 62,85% of metastatic patients received a 2nd line of treatment. 48,57% of metastatic patients received immunotherapy. PD-(L)1 was only determined in 11,42% of metastatic patients. PFS of immunotherapy was 2,27 months. One patient receiving immunotherapy achieved a complete response and two patients achieved a PFS > 12 months. Other regimens used in latter lines included oxaliplatin (5,71%) and irinotecan-based (14,28%) regimens. Real world data in ASCC population reveals a complex scenario with significant heterogeneity in response to treatments and outcomes. Multidisciplinary collaboration is essential. Role of immunotherapy in ASCC patients in clinical practice is still unknown. More research is needed in the refractory setting after Carboplatin-Paclitaxel to increase OS.

Combined PET-CT and MRI for response evaluation in patients with squamous cell anal carcinoma treated with curative-intent chemoradiotherapy

ObjectivesTo assess the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) positron-emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI) for response assessment post curative-intent chemoradiotherapy (CRT) in anal squamous cell carcinoma (ASCC).MethodsConsecutive ASCC patients treated with curative-intent CRT at a single centre between January 2018 and April 2020 were retrospectively identified. Clinical meta-data including progression-free survival (PFS) and overall survival (OS) outcomes were collated. Three radiologists evaluated PET-CT and MRI using qualitative response assessment criteria and agreed in consensus. Two-proportion z test was used to compare diagnostic performance metrics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy). Kaplan-Meier analysis (Mantel-Cox log-rank) was performed.ResultsMRI (accuracy 76%, PPV 44.8%, NPV 95.7%) and PET-CT (accuracy 69.3%, PPV 36.7%, NPV 91.1%) performance metrics were similar; when combined, there were statistically significant improvements (accuracy 94.7%, PPV 78.9%, NPV 100%). Kaplan-Meier analysis demonstrated significant differences in PFS between responders and non-responders at PET-CT (p = 0.007), MRI (p = 0.005), and consensus evaluation (p < 0.001). Cox regression analysis of PFS demonstrated a lower hazard ratio (HR) and narrower 95% confidence intervals for consensus findings (HR = 0.093, p < 0.001). Seventy-five patients, of which 52 (69.3%) were females, with median follow-up of 17.8 months (range 5–32.6) were included. Fifteen of the 75 (20%) had persistent anorectal and/or nodal disease after CRT. Three patients died, median time to death 6.2 months (range 5–18.3).ConclusionCombined PET-CT and MRI response assessment post-CRT better predicts subsequent outcome than either modality alone. This could have valuable clinical benefits by guiding personalised risk-adapted patient follow-up.Key Points• MRI and PET-CT performance metrics for assessing response following chemoradiotherapy (CRT) in patients with anal squamous cell carcinoma (ASCC) were similar.• Combined MRI and PET-CT treatment response assessment 3 months after CRT in patients with ASCC was demonstrated to be superior to either modality alone.• A combined MRI and PET-CT assessment 3 months after CRT in patients with ASCC has the potential to improve accuracy and guide optimal patient management with a greater ability to predict outcome than either modality alone

Circulating tumor DNA-based molecular residual disease detection and recurrence monitoring in patients with advanced or metastatic anal squamous cell carcinoma.

6 Background: For patients with anal squamous cell carcinoma (ASCC), the current standard of care involves curative-intent definitive chemoradiation. For those that recur locally, salvage surgery maybe a consideration. ASCC, however, still lacks a non-invasive blood-based biomarker, which can be of value in this patient population for monitoring recurrence and/or response to immunotherapy later. Circulating tumor DNA (ctDNA) is a promising non-invasive tool to assess molecular residual disease (MRD) and recurrence in ASCC. Here, we evaluated real-world utility of ctDNA status to identify MRD and recurrence in ASCC patients across all stages. Methods: This is a retrospective analysis of patients with any stage ASCC receiving SOC or/and immunotherapy with immune checkpoint inhibitors. A personalized tumor-informed PCR/NGS-based assay (Signatera) was used for ctDNA detection, in the pre/on/post-treatment and surveillance setting. Results: In this study, plasma samples (n=105) were collected from 25 ASCC patients (13 females, 12 males; median age 66 years) at various timepoints for a median follow-up of 315 days (range: 59-1717), post-diagnosis; 12 patients were HPV-positive, 1 patient was HPV-negative, and 12 had unknown HPV status; 88% (22/25) of the patients had serial timepoints (≥2) available. ctDNA-positivity rates, test results, and ctDNA quantification by stage are summarized in Table. The quantitated ctDNA values (mean tumor molecules (MTM)/mL) increased in concordance with the stage of the disease, with values trending higher in stage III and IV. In addition, complete clinical outcome information was available for 22/25 patients at the time of releasing this data. Of the 96 plasma samples drawn from these patients, 68 (70%) were in the surveillance setting (post-definitive therapy). No recurrences were observed among 15 patients who cleared ctDNA on treatment and/or tested negative post-treatment, whereas, 6/7 ctDNA-positive patients were confirmed to have disease recurrence and 1 was pending confirmatory imaging. This often predated recurrence on scans. Conclusions: Measuring and monitoring MRD in patients with ASCC is feasible and has the potential to impact clinical decision making. Our study is the first to set the benchmark for the feasibility of using a tumor-informed assay in ASCC. Larger prospective studies are needed to explore the clinical utility of ctDNA status to guide disease surveillance and management of ASCC.[Table: see text]

Construction and validation of a prognostic nomogram for anal squamous cell carcinoma.

BackgroundAnal squamous cell carcinoma (ASCC) is the main subtype of anal cancer and has great heterogeneity in prognosis. We aimed to construct a nomogram for predicting their 1‐, 3‐, and 5‐year overall survival (OS) rates.MethodsPatients with ASCC, enrolled between January 1, 2010 and December 31, 2017, were identified from the SEER database. They were divided into a training group and a validation group in a ratio of 7:3. Univariate and multivariate Cox analyses were used to identify the prognostic factors for OS. Then a prognostic nomogram was established and validated by Harrell consistency index (C‐index), area under the curve (AUC) of the receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA).ResultsWe identified 761 patients in training group and 326 patients in validation group. Four prognostic factors including age, sex, AJCC stage, and radiotherapy were identified and integrated to construct a prognostic nomogram. The C‐index and AUC values proved the model's effectiveness and calibration plots manifested its excellent discrimination. Furthermore, in comparison to the AJCC stage, the C‐index, AUC, and DCA proved the nomogram to be of good predictive value. Finally, we constructed a risk stratification model for dividing patients into low‐risk, medium‐risk, and high‐risk groups, and there were obvious differences in OS.ConclusionsA prognostic nomogram was firstly established for predicting the survival probability of ASCC patients and helping clinicians improve their risk management.

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.

Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice.

Anal squamous cell carcinoma (SCC) will be diagnosed in an estimated 9,080 adults in the United States this year, and rates have been rising over the last several decades. Most people that develop anal SCC have associated human papillomavirus (HPV) infection (~85–95%), with approximately 5–15% of anal SCC cases occurring in HPV-negative patients from unknown etiology. This study identified and characterized the Kras-driven, female sex hormone-dependent development of anal squamous cell carcinoma (SCC) in the LSL-KrasG12D; Pdx1-Cre (KC) mouse model that is not dependent on papillomavirus infection. One hundred percent of female KC mice develop anal SCC, while no male KC mice develop tumors. Both male and female KC anal tissue express Pdx1 and Cre-recombinase mRNA, and the activated mutant KrasG12D gene. Although the driver gene mutation KrasG12D is present in anus of both sexes, only female KC mice develop Kras-mutant induced anal SCC. To understand the sex-dependent differences, KC male mice were castrated and KC female mice were ovariectomized. Castrated KC males displayed an unchanged phenotype with no anal tumor formation. In contrast, ovariectomized KC females demonstrated a marked reduction in anal SCC development, with only 15% developing anal SCC. Finally, exogenous administration of estrogen rescued the tumor development in ovariectomized KC female mice and induced tumor development in castrated KC males. These results confirm that the anal SCC is estrogen mediated. The delineation of the role of female sex hormones in mediating mutant Kras to drive anal SCC pathogenesis highlights a subtype of anal SCC that is independent of papillomavirus infection. These findings may have clinical applicability for the papillomavirus-negative subset of anal SCC patients that typically respond poorly to standard of care chemoradiation.

TP9.2.2Evaluating the Outcomes of anal squamous cell carcinoma (ASCC) with curative intent- a 10-year experience

Abstract Background Our 10-year experience with radical treatment of patients with ASCC. Patients and Method Data of patients with ASCC treated with curative intent were analysed between January 2011 and December 2019. Patients underwent the standard workup, treated and followed up accordingly. The outcome measures were response to radical chemoradiotherapy, recurrent disease, disease-free and overall survival. Results 117 patients were diagnosed with anal cancer. 26 ASCC patients palliatively treated, adenocarcinoma(11), melanoma(1), Paget disease(1) and carcinoid(1) were excluded. Median age of included patients was 65(38-90) years with a male to female ratio of 1:1.9. Three patients were HIV positive and 52% of the patients had AIN of varying degree of dysplasia. AJCC stages were I(16), II(18), IIIA(19), IIIB(9) and IV(15). 88.3%%(68/77) of the patients had radical chemoradiotherapy while 9 patients with tumours ≤2cm underwent wide local excision. 92.6%(63/68) of the patients treated with radical chemoradiotherapy had complete response while 7.4%(5/77) had partial response. Four patients with incomplete response underwent salvage APER. 13%(10/77) of the patients developed recurrent disease. Mean survival time was 99.82(95% CI 88.87-110.77) months with 5-year overall survival rate of 78.0%. The mean disease-free survival time was 111.82(95% CI 102.38-121;26) months. 75.3%(58/77) of the patients were alive at the end of the study with an overall mortality rate was 24.7% and disease-specific mortality was 15.6%. Conclusion ASCC responds well to radical chemoradiotherapy with favourable outcome but locoregional failure and distant metastases are still issues.

Predictors of Severe Chemoradiation-Related Lymphopenia in Patients With Anal Squamous Cell Carcinoma

Treatment-related lymphopenia may be prognostic for poorer survival in anal squamous cell carcinoma (ASCC). With current randomized trials evaluating the potential role of immunotherapy in localized ASCC, the contribution of host immunity will become increasingly important. We sought to identify clinical, tumor, and dosimetric predictors for severe lymphopenia during chemoradiation (CRT) for ASCC.Patients who underwent CRT for ASCC from 2008-2020 at two Comprehensive Cancer Centers were identified and charts were reviewed. Only those who received 5-fluorouracil and mitomycin C concurrent with IMRT to 50.4-59.4 Gy were included. Lymphopenia was graded per CTCAE v5.0 with absolute lymphocyte count (ALC) nadir < 0.2×109/L indicating grade 4 toxicity. Logistic regression was used to distinguish the effects directly attributable to radiation exposure from contextual covariates. The outcome was presence of grade 4 lymphopenia. The primary predictors of interest were iliac crest V40 and total prescription dose (TPD). It was hypothesized that higher iliac crest V40 and higher TPD would be positively associated with severe lymphopenia. PTV total volume (PTVtv) and GTVp volume were also included and interactions with dose were examined for each. Lastly, covariates included history of malignancy, age, and pre-treatment ALC. These variables were selected because literature has identified them as relevant to lymphopenia in other samples.A total of 119 patients were identified with a median age of 59 years. Forty-seven patients (39%) had T3/4 disease and 57 patients (49%) had node positive disease. Fifty-eight patients (49%) developed grade 4 lymphopenia during CRT or within 1 month of completing treatment. On multivariate analysis pre-treatment ALC (P = 0.006, OR = 0.31), GTVp volume (P = 0.010, OR = 1.23), and iliac crest V40 (P = 0.013, OR = 1.08) were predictive of grade 4 lymphopenia. History of previous malignancy was associated with reduced risk of grade 4 lymphopenia (P = 0.030, OR = 0.04). TPD and PTVtv were not independently predictive of grade 4 lymphopenia, though patients with a higher TPD and smaller PTVtv were significantly more likely to develop grade 4 lymphopenia (P = 0.038) compared to those with both high TPD and PTVtv or both low TPD and PTVtv.Severe lymphopenia is common during CRT for ASCC and certain patients are at higher risk for developing this treatment-related toxicity. Pre-treatment lymphocyte count, larger tumor volume, and dose to the iliac crests are each independent predictors of grade 4 lymphopenia. Additionally, closer observation should be employed when treating patients with higher prescription doses and smaller PTV total volumes. With ongoing efforts to incorporate immunotherapy in the treatment of ASCC, using predictors to detect patients at risk for severe lymphopenia will be increasingly important.