Squamous Cell Carcinoma Of The Anus Research Articles

P-275 Evaluation of radical chemoradiation outcomes in stage II/III anal cancer: Real-world data population

Squamous cell carcinoma of the anus (SCCA) is a rare disease accounting for 1%–2% of digestive tract tumours and 2%–4% of colon, rectal and anal tumours. The annual incidence is 1 in 100 000, is higher in women and is increasing. Five-year survival has changed little in the last two decades. In the United States, the overall 5-year survival rates for 1994–2000 were 60% for men and 78% for women (SEER data). In Europe, 5-year survival varied between 66% (Central Europe) and 44% (Eastern Europe). Combinations of 5-fluorouracil (5-FU)-based radical chemoradiation (CRT) and other cytotoxic agents [mainly mitomycin C (MMC)] have been established as the standard of care, leading to complete tumour regression in 80%–90% of patients, with locoregional failures of ∼15%. Approximately 10%–20% of patients suffer distant relapse. The aim of this study was to evaluate outcomes in stage II/III anal cancer submitted to CRT. A retrospective analysis evaluated stage II-III SCCA pts with PS ECOG 0-1 treated with CRT using fluoropyrimidine and MMC at a single Portuguese Oncology Unit between January 1st 2010 and October 30th 2020. Data cut-off was March 20th 2021. Data were obtained from pts´ clinical files and analysed with SPSSv26.0. Twenty-three pts were selected with a median (med) age of 66 years (y) [30-81], the majority being females (60.9%). Regarding initial staging, 21.7% had stage II, 17.4% stage IIIA, and 60.9% stage IIIB. 39.1% were active smokers; 56.5% were tested for HIV infection, of whom 3 were HIV positive. 78.3% had lymph node disease; 47.8% had tumours > 5 cm in size; 56.5% had ulcerated lesions (skin or endoscopically). Of the 23 pts, 2 (8.7%) were treated with capecitabine (CAP), while the others were treated with infusional 5-FU in addition to MMC. There was an imaging and endoscopic complete response (CR) in 78.3% of the pts (including both pts treated with CAP); 3 of the 5 pts without CR underwent salvage surgery. 13% had locoregional relapse and 4.3% had distant relapse. Med follow-up was 4y; the overall survival at 4y was about 75%, with an estimated med OS 8.09y [6.0-10.2]. In our cohort, CRT was associated with a higher CR rate in concordance with previous evidence. Distant relapse was slightly inferior in our population. Going forward, we will be studying prospective data on the use of CAP vs infusional 5-FU in CRT-treated patients. Given the rarity of this diagnosis and the lack of evidence on this subject, we believe our findings are of extreme importance to share.

Intensified Induction Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Anus-A Population-Based Experience from the Danish Anal Cancer Group.

Simple SummaryThe primary treatment modality for anal cancer is chemoradiotherapy, but patients with locally advanced disease (i.e., large tumors and/or involvement of regional lymph nodes) have a high risk of treatment failure. The use of chemotherapy prior to radiotherapy (induction chemotherapy) can potentially shrink the tumor and/or eradicate small cancer cells with metastatic potential, with a chance of a better outcome. With this paper, the authors present 20 years of nationwide experience with intensified induction chemotherapy in the treatment of locally advanced anal cancer, which indicates a role for further investigation in the most advanced cases.Locally advanced squamous cell carcinoma of the anus (LASCCA) has a poor prognosis with a high risk of treatment failure calling for intensified therapy. We present the long-term follow-up of a nationwide cohort of LASCCA treated with intensified induction chemotherapy (ICT). The study included patients with LASCCA (T3-4N0 or T1-4N+) treated with at least one cycle of ICT (cisplatin, ifosfamide, leucoverin, and 5-flourouracil) between 1998–2018. Data were retrospectively collected from medical records, and statistics were performed in STATA 16.1. In total, 166 patients with LASCCA were identified. Following ICT, 157 patients (95%) received primary curative treatment with either radiotherapy (70%), chemoradiotherapy (27%), or abdominal perineal resection (3%). The overall local tumor response rate after ICT was 76% with 20 (13%) achieving complete local tumor response. After the primary treatment, 123 patients (79%) obtained complete response, and 27 underwent salvage surgery due to persistent disease. The median follow-up time was 6 years, local and distant failure rates 22% and 13%, respectively. The 3- and 5-year disease-free survival rates were 70% and 67%, and the 3- and 5-year overall survival rates were 76% and 70%, respectively. Intensified ICT regimen could be a supplementary treatment option in the most advanced cases of LASCCA. Prospective randomized trials are needed to investigate this approach further.

Multi-institutional Comparison of Intensity Modulated Photon Versus Proton Radiation Therapy in the Management of Squamous Cell Carcinoma of the Anus

PurposeConcurrent chemoradiation therapy is a curative treatment for squamous cell carcinoma of the anus, but patients can suffer from significant treatment-related toxicities. This study was undertaken to determine whether intensity modulated proton therapy (IMPT) is associated with less acute toxicity than intensity modulated radiation therapy (IMRT) using photons. Materials and MethodsWe performed a multi-institutional retrospective study comparing toxicity and oncologic outcomes of IMRT versus IMPT. Patients with stage I-IV (for positive infrarenal para-aortic or common iliac nodes only) squamous cell carcinoma of the anus, as defined by the American Joint Committee on Cancer's AJCC Staging Manual, eighth edition, were included. Patients with nonsquamous histology or mixed IMPT and IMRT treatment courses were excluded. Acute nonhematologic toxicities, per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4, were recorded prospectively at all sites. Acute and late toxicities, dose metrics, and oncologic outcomes were compared between IMRT and IMPT using univariable and multivariable statistical methods. To improve the robustness of our analysis, we also analyzed the data using propensity score weighting methods. ResultsA total of 208 patients were treated with either IMPT (58 patients) or IMRT (150 patients). Of the 208 total patients, 13% had stage I disease, 36% stage II, 50% stage III, and 1% stage IV. IMPT reduced the volume of normal tissue receiving low-dose radiation but not high-dose radiation to bladder and bowel. There was no significant difference between treatment groups in overall grade 3 or greater acute toxicity (IMRT, 68%; IMPT, 67%; P = .96) or 2-year overall grade 3 or greater late toxicity (IMRT, 3.5%; IMPT, 1.8%; P = .88). There was no significant difference in 2-year progression-free survival (hazard ratio, 0.8; 95% CI, 0.3-2.0). ConclusionsDespite reducing the volume of normal tissue receiving low-dose radiation, IMPT was not associated with decreased grade 3 or greater acute toxicity as measured by CTCAE. Additional follow-up is needed to assess whether important differences arise in late toxicities and if further prospective evaluation is warranted.

CEA as a blood-based biomarker in anal cancer.

Background: The clinical utility of a blood-based biomarker in squamous cell carcinoma of the anus (SCCA) is unknown. We analyzed carcinoembryonic antigen (CEA), a commonly employed assay for patients with colorectal adenocarcinoma, as a serum biomarker for patients with biopsy-proven SCCA.Materials and Methods: Medical records from 219 patients with biopsy-proven SCCA at the University of Texas MD Anderson Cancer Center were reviewed under an IRB-approved protocol from 2013 to 2020 to assess for correlations between CEA levels and corresponding clinical and pathologic characteristics.Results: The mean CEA among subgroups by clinical status at the time of presentation to our institution was highest among those patients with metastatic SCCA to visceral organs (M-V, 20.7 ng/mL), however this finding was not statistically significant by ANOVA (p = .74). By clinical subgroup, the percentage of patients with an abnormally elevated CEA was highest in those patients with metastatic disease to lymph nodes (M-L, 41.2%) followed by recurrent/unresectable SCCA (36.8%), and metastatic SCCA to visceral organs (M-V, 35.2%), and was statistically significant between groups (Fisher’s exact test p = .02). Using RECIST criteria for tumor progression and disease response, the mean change in CEA for patients with progression was an increase in 19 ng/mL, compared to a change of –7.3 ng/mL in those with disease response (p = .004). We likewise assessed whether CEA levels were associated with survival outcomes for all patients with metastatic SCCA, and found no correlation between CEA and likelihood for survival in a ROC analysis (multivariate, age-adjusted analysis for CEA cutoff of 8, HR = 1.01, 95% CI 0.52–1.96).Conclusions: Despite interesting patterns of abnormally high CEA in SCCA patients with advanced disease, and correlation of increased CEA with disease progression (and conversely decreased CEA with disease response), CEA is not associated with survival outcomes in SCCA, and is not a clinically relevant biomarker in this disease.

The Clinical Value of Measuring Circulating HPV DNA during Chemo-Radiotherapy in Squamous Cell Carcinoma of the Anus

Simple SummaryAnal cancer is treated with high dose chemoradiotherapy; but despite this, a minor patient group experience treatment failure. Anal cancer is strongly related to human papilloma virus (HPV) infection and previous smaller studies have shown that fragments of HPV DNA can be detected in blood samples from anal cancer patients. This study measured HPV DNA in 88 patients including both small- and more advanced tumors and detected six different subtypes of HPV. During treatment with chemoradiotherapy, the level of HPV DNA decreased, and three elimination patterns with clinical relevance were identified. Fast elimination correlated to a low risk of failure, slow elimination correlated to risk of failure in the pelvis, and persistent HPV DNA after treatment correlated to a high risk of later distant failure. The results add new information to the increasing interest in research of HPV DNA in HPV related cancers and holds great clinical potential.Background and purpose: Circulating tumor DNA (ctDNA) is investigated in various cancers. In squamous cell carcinoma of the anus (SCCA) infection with human papilloma virus (HPV) is found in around 90% of cases and here, plasma HPV (pHPV) can be used as ctDNA. Preliminary data have proved the ability to detect pHPV16 and -18 in SCCA. We have developed a highly sensitive method for measurement of six relevant pHPV subtypes, to investigate the elimination pattern of pHPV during chemo-radiotherapy (CRT) for SCCA and its clinical value. Material and methods: Patients treated at Aarhus University Hospital from 2016–2020 were included. P16 status in the primary biopsy was measured and 82% of patients had P16 positive tumor. Blood samples were collected prior to treatment (PT), mid treatment (MT), end of therapy (EOT), and during follow-up (FU). An in-house multiplex digital droplet PCR method measured pHPV subtypes 16, 18, 31, 33, 51, 58. Results: Samples from 88 patients were drawn PT (n = 73), MT (n = 72), EOT (n = 64) and during FU (n = 41). Plasma HPV was detectable in 52 patients and PT pHPV levels correlated to tumor stages. Three elimination patterns were observed during CRT with correlation to outcome: fast responders with no local or distant failures (0/12); slow responders with high risk of local failures (4/20), no distant failures; persistent molecular responders with high risk of distant failures (4/13), but no local failures, p < 0.01. Conclusion: During CRT, pHPV can divide patients with SCCA into three groups with significantly different risk of failure. The use of pHPV can potentially assist in clinical treatment decision.

Treatment outcomes and prognostic factors after chemoradiotherapy for anal cancer

Background Squamous cell carcinoma of the anus (SCCA) is a rare malignancy with rising incidence, associated with human papilloma virus (HPV). Chemoradiotherapy (CRT) is the preferred treatment. The purpose was to investigate treatment failure, survival and prognostic factors after CRT. Material and methods In this prospective observational study from a large regional centre, 141 patients were included from 2013 to 2017, and 132 were eligible for analysis. The main inclusion criteria were SCCA, planned radiotherapy, and performance status (ECOG) ≤2. Patient characteristics, disease stage, treatment, and treatment response were prospectively registered. Disease-free survival (DFS), overall survival (OS), and locoregional treatment failure after CRT were analysed. Hazard ratios (HRs) were estimated with Cox`s proportional hazards model. Results Median follow-up was 54 (range 6–71) months. Eighteen patients (14%) had treatment failures after CRT; of these 10 (8%) had residual tumour, and 8 (6%) relapse as first failure. The first treatment failure was locoregional (11 patients), distant (5 patients), and both (2 patients). Salvage abdomino-perineal resection was performed in 10 patients, 2 had resections of metastases, and 3 both. DFS was 85% at 3 years and 78% at 5 years. OS was 93% at 3 years and 86% at 5 years. In analyses adjusted for age and gender, HPV negative tumours (HR 2.5, p = 0.024), N3 disease (HR 2.6, p = 0.024), and tumour size ≥4 cm (HR 2.4, p = 0.038) were negative prognostic factors for DFS. Conclusion State-of-the-art chemoradiotherapy for SCCA resulted in excellent outcomes, and improved survival compared with previous national data, with <15% treatment failures and a 3-year DFS of >80%.

De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus

Simple SummaryManagement of early-stage squamous cell carcinoma of the anus (SCCA) remains controversial. The current standard of care treatment of chemotherapy combined with radiation therapy can result in both acute and late toxicity. Alternative therapies, including radiation therapy alone or local excision, may be less toxic, but the role of these therapies in early-stage SCCA remains unclear. Additional options for reducing the intensity of therapy for early-stage SCCA include reduction of radiation dose, altering treatment volumes, modifying chemotherapy type and dosage, and using intensity-modulated radiation therapy to reduce the radiation dose to adjacent normal tissues. Multiple prospective studies are actively investigating the role of de-escalation of therapy in patients with early-stage SCCA.The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly in the elderly, with increased mortality in this age group. While the current standard of care for localized SCCA remains chemoradiation (CRT), completion of this treatment can be challenging with risks for severe acute and late toxicity. It remains unclear if full course CRT is required for the management of early-stage SCCA or if de-escalation of treatment is possible without compromising patient outcomes. Alternative therapies include radiation therapy alone or local excision for appropriate patients. Modifying standard CRT may also reduce toxicity including the routine use of intensity-modulated radiation therapy for treatment delivery, modification of treatment volumes, and selection and dosing of concurrent systemic therapy agents. Finally, we provide an overview of currently accruing prospective trials focused on defining the role of de-escalation of therapy in patients with early-stage SCCA.

What is the optimal treatment for T1N0 anal squamous cell carcinoma? Analysis of current practices in the prospective French FFCD ANABASE cohort

Introductionfor localized T1N0 squamous cell carcinoma of the anus (SCCA) standard radiotherapy (RT) may result in overtreatment and alternative strategies are debated. MethodsT1N0M0 SCCA treated between 2015 and 2020 by local excision (LE) or RT were analyzed from the French prospective FFCD ANABASE cohort. Treatment strategies, recurrence-free and colostomy-free survivals (RFS, CFS) and prognostic factors were reported. Resultsamong 1135 SCCA patients, 99 T1N0M0 were treated by LE(n = 17,17.2%), or RT (n = 82,82.8%) including RT alone (n = 65,79.2%) or chemo-RT (n = 17, 20.7%). Median follow-up was 27.2 months [0.03–54.44]. Median tumor size were 11.4 mm [0.9–20] and 15.3 mm [2–20] in the LE and RT groups respectively. Mean RT tumor dose was 59.4 Gy [18–69.4 Gy]. One patient in LE group and 9 in RT group had a pelvic recurrence, either local (60%), nodal (10%) or both (30%). RFS and CFS at 24 months were 92.2%[95%CI,83.4–96.4] and 94.6%[95%CI,86.1–98.0], at 36 months 88.1%[95%CI,77.1–94.2] and 88.5%[95%CI,77.0–94.5], in LE and RT group respectively, without any significative difference (HR = 0.57;[95%CI,0.07–4.45];p = 0.60). By univariate analysis, male gender was the only prognostic factor(HR = 5.57;95%CI, 1.76–17.63; p = 0.004). Conclusionthis cohort confirms the heterogeneity of T1N0M0 SCCA management, questioning the place of RT alone, reduced dose or RT volume, and the safety of LE.

A population-based analysis of chemoradiation versus radiation alone in the definitive treatment of patients with stage I-II squamous cell carcinoma of the anus.

The optimal management of patients with stage I-II squamous cell carcinoma (SCC) of the anus is controversial. The current study evaluates the efficacy of combined chemotherapy and radiation therapy (CRT) versus radiation therapy (RT) alone in the treatment of these patients using the Surveillance, Epidemiology, and End Results (SEER) registries. SEER 18 Custom Data registries were queried for patients with stage I-II SCC of the anus. Univariate analysis (UVA) and multivariable analysis (MVA) using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was used to account for indication bias. A total of 4,288 patients with stage I-II disease were identified, of whom 3,982 (93%) underwent CRT and 306 (7%) underwent RT. Median follow-up was 42 months. Approximately 30.8% had T1 disease and 69.2% had T2-T3 disease. The IPTW-adjusted 5-year overall survival (OS) was 76.7%, with no significant differences between the CRT and RT groups (77% vs. 73.5%, P=0.33). On multivariate IPTW-adjusted analysis, the lack of association between CRT use and OS was upheld (HR, 0.84, 95% CI, 0.65-1.08, P=0.2). On subgroup analyses, 5-year OS was 86% with CRT (n=1,216) and 84.2% with RT (n=103) (P=0.74) in stage I (T1N0) patients, while 5-year OS was 72.8% with CRT (n=2,766) and 66.4% with RT (n=203) (P=0.13) in stage II (T2-3N0) patients. CRT was associated with improved median OS in stage II patients (119 months vs. not reached, P=0.04). The current study suggests that omission of concurrent chemotherapy is not associated with inferior OS in patients with stage I SCC of the anus. However, combined chemoradiation was superior to radiation alone in patients with stage II disease. Prospective evidence is needed to optimize clinical decision-making in this patient population.

Three-dimensional (3D) magnetic resonance volume assessment and loco-regional failure in anal cancer: early evaluation case-control study

BackgroundThe primary aim was to test the hypothesis that deriving pre-treatment 3D magnetic resonance tumour volume (mrTV) quantification improves performance characteristics for the prediction of loco-regional failure compared with standard maximal tumour diameter (1D) assessment in patients with squamous cell carcinoma of the anus undergoing chemoradiotherapy.MethodsWe performed an early evaluation case-control study at two UK centres (2007–2014) in 39 patients with loco-regional failure (cases), and 41 patients disease-free at 3 years (controls). mrTV was determined using the summation of areas method (Volsum). Reproducibility was assessed using intraclass concordance correlation (ICC) and Bland-Altman limits of agreements. We derived receiver operating curves using logistic regression models and expressed accuracy as area under the curve (ROCAUC).ResultsThe median time per patient for Volsum quantification was 7.00 (inter-quartile range, IQR: 0.57–12.48) minutes. Intra and inter-observer reproducibilities were generally good (ICCs from 0.79 to 0.89) but with wide limits of agreement (intra-observer: − 28 to 31%; inter-observer: − 28 to 46%). Median mrTVs were greater for cases (32.6 IQR: 21.5–53.1 cm3) than controls (9.9 IQR: 5.7–18.1 cm3, p < 0.0001). The ROCAUC for mrT-size predicting loco-regional failure was 0.74 (95% CI: 0.63–0.85) improving to 0.82 (95% CI: 0.72–0.92) when replaced with mrTV (test for ROC differences, p = 0.024).ConclusionPreliminary results suggest that the replacement of mrTV for mrT-size improves prediction of loco-regional failure after chemoradiotherapy for squamous cell carcinoma of the anus. However, mrTV calculation is time consuming and variation in its reproducibility are drawbacks with the current technology.

Stage I Squamous Cell Carcinoma of the Anus: Is Radiation Therapy Alone Sufficient Treatment?

Simple SummaryThe optimal treatment of early stage anal cancer is unknown. This patient population was relatively under-represented on the trials, which defined radiation therapy with concurrent chemotherapy as the standard treatment for anal cancer, thus radiation therapy alone may be an effective alternative treatment. The aim of this study was to use a large national database of anal cancer patients to compare overall survival of patients treated with radiation therapy alone to those treated with radiation therapy with concurrent chemotherapy. We found that patients who received radiation therapy alone were more likely to be ≥70 years old and less likely to be female. Treatment with radiation and concurrent chemotherapy was associated with a 31% reduction in the risk of death compared to treatment with radiation alone. Our results suggest that radiation with concurrent chemotherapy should be the standard treatment for early stage anal cancer patients.The optimal treatment for stage I squamous cell carcinoma of the anus (SCCA) remains undefined. Recently, wide local excision alone was found to have comparable survival to those treated with chemoradiation (CRT). Given that local excision may be sufficient for the treatment of stage I SCCA, we hypothesized that radiation therapy (RT) alone, compared to CRT would result in equivalent overall survival (OS) in this population. We identified non-surgically treated patients with stage I SCCA from the National Cancer Database from 2004–2015. We included only patients treated either with CRT (45–59.4 Gy with chemotherapy initiated within 14 days of RT) or RT alone (45–59.4 Gy with no chemotherapy). The primary endpoint was OS between CRT and RT patients. Propensity-score matched (PSM) analysis was performed to determine the effect of concurrent chemotherapy on OS using a Cox proportional hazards model with robust standard error to account for clustering in matched pairs. We identified 3552 stage I patients treated with CRT and 287 treated with RT. Compared to patients treated with CRT, those that received RT were more likely to be ≥70 years old (33.1% vs. 19.7%, p < 0.001) and less likely to be female (63.1% vs. 71.0%, p < 0.001). The proportion of patients with a Charlson-Deyo score of 0 was similar in both groups (80.8% RT vs. 82.7% CRT, p = 0.164). The PSM cohort consisted of 287 pairs of patients with median follow-up 48.3 months (interquartile range, 24.4–85.1 months) and 151 deaths (86 RT, 65 CRT). CRT was associated with a 31% reduction in the risk of death (HR = 0.69, 95% CI 0.50–0.95, p = 0.023). We found that CRT was associated with improved OS, compared to RT alone, in patients with non-surgically treated stage I SCCA. These data suggest that de-intensification of therapy in stage I SCCA must be used with caution. However, given the retrospective nature of the data, prospective trials are required.

OC-0335: Circulating free DNA in squamous cell carcinoma of the anus: Relation to risk factors and recurrence

OC-0335: Circulating free DNA in squamous cell carcinoma of the anus: Relation to risk factors and recurrence

Stage I Squamous Cell Carcinoma of the Anus: Is Radiation Therapy Alone Sufficient Treatment?

Stage I Squamous Cell Carcinoma of the Anus: Is Radiation Therapy Alone Sufficient Treatment?

Anal squamous cell carcinoma incidentally found at hemorrhoidectomy

BackgroundAnal squamous cell carcinoma incidence is increasing nationally and, more so, in Kentucky. Squamous cell carcinoma of the anus unexpectedly identified at hemorrhoidectomy pathologic evaluation is not uncommon. We hypothesized this is occurring more frequently and sought to evaluate its impact on outcomes. MethodsThe Kentucky Cancer Registry, a premier population database, was queried for all squamous cell carcinoma of the anus cases between 2007 and 2016. Hemorrhoidal squamous cell carcinoma of the anus patients were compared with nonhemorrhoidal squamous cell carcinomas of the anus. Patient demographics, treatments, and outcomes were analyzed. ResultsOf the 722 squamous cell carcinoma of the anus cases identified, 3.05% (n = 22) were within hemorrhoidectomy specimens. Demographics were similar between hemorrhoidal squamous cell carcinoma of the anus versus nonhemorrhoidal squamous cell carcinoma of the anus. Chemoradiation was the most common treatment strategy among all patients, and there were similar rates of disease, persistence, recurrence, and survival between hemorrhoidal and nonhemorrhoidal squamous cell carcinoma. Stage I disease was more common in the hemorrhoid group compared with the nonhemorrhoid group (63% vs 27%, P < .01). ConclusionHemorrhoidal squamous cell carcinoma of the anus comprised 3.05% of our population-based cohort. Hemorrhoidal squamous cell carcinomas of the anus were more likely to receive chemoradiation compared with local excision, but there were similar oncologic outcomes. We postulate that some individuals may receive overtreatment with chemoradiation owing to imprecise labeling of hemorrhoid specimens. For this reason, we advocate for separate submission of each hemorrhoid specimen.

Screening for intra-anal squamous intra-epithelial lesions in women with a history of human papillomavirus-related vulvar or perianal disease: results of a screening protocol.

Women with a history of human papillomavirus (HPV)-related cervical, vaginal or vulvar high-grade squamous intra-epithelial lesions (HSILs) or cancer are at increased risk of developing anal squamous intra-epithelial lesions (SILs) or a squamous cell carcinoma of the anus (SCCA). Screening for intra-anal SILs with high-resolution anoscopy (HRA) in high-risk populations is a subject of debate. In this study we aimed to answer the following question: what is the prevalence of intra-anal (H)SIL in women with HPV-related vulvar and/or perianal disease using HRA for screening? A retrospective study was performed to evaluate the prevalence of intra-anal (H)SIL in women with a history of vulvar and/or perianal HSIL or (superficially invasive) squamous cell carcinoma (SCC). This study was performed between 2015 and 2018 following implementation of a protocol for intra-anal screening using HRA. Twenty-seven patients, 10 with a history of (superficially invasive) SCC (four vulvar, five perianal, one multizonal) and 17 with HSIL as the worst diagnosis (two perianal, 15 multizonal) were screened for intra-anal lesions using HRA. No anal cancer was found at screening, 6 (22%) patients were diagnosed with intra-anal HSIL and 12 (44%) patients with intra-anal low-grade SIL. We found a high prevalence of intra-anal HSIL in women previously diagnosed with vulvar and perianal HSIL. Given the clear link between HSIL and SCCA, screening for intra-anal lesions in women with HPV-related genital pathology seems warranted. Future studies should focus on the effect of HSIL treatment on the prevention of anal cancer.

Prognostic implications of advancing nodal stage in anal cancer: evaluating AJCC 8 staging changes through an NCDB analysis.

In the AJCC8, nodal staging for squamous cell carcinoma of the anus (SCCA) has been changed to a binary format (N0 or N+), and overall stage groups have been redefined. We evaluated the effect of AJCC8 nodal stage by T stage and hypothesized similar survival regardless of the extent of AJCC7-defined nodal involvement. The National Cancer Database (NCDB) was used to identify patients' SCCA. Overall survival (OS) for each T stage within the AJCC7 was compared with increasing nodal stage, as well as for the new AJCC8 overall stage groups and subsets. There were 6738 patients analyzed. The 5-year OS by AJCC8 stage was I = 81%, IIA = 78%, IIB = 64%, IIIA = 69%, IIIB = 59%, IIIC = 57% (p < 0.0001). In AJCC8 IIIA (T1-2, N+), there was no difference in 5-year OS between T1N+ or T2N+ patients (70.3% vs 68.6%, p = 0.09). A significant survival difference was demonstrated between AJCC7 N1, N2, and N3 for patients with either T1 (p = 0.0047) or T2 (p = 0.0389) disease. In the AJCC 8 IIIC (T3-4, N+) group, there was no difference in 5-year OS between T3N+ and T4N+ (58% vs 55%, p = 0.81). There was no OS difference between AJCC7 N1-3 for either T3 (p = 0.19) or T4 (0.35) disease. For earlier T stages, advancing nodal stage per AJCC7 retains prognostic implications for OS. Survival in AJCC8 stage IIIA is heterogeneous and is largely driven by burden of nodal disease in patients with T1-2 disease.

Outcome following local excision of T1 anal cancers—a systematic review

In most cases, squamous cell carcinoma of the anus (SCCA) is treated with chemo-radiotherapy preserving sphincter function and offering good long-term survival and low recurrence rates. However, chemo-radiotherapy has several side effects: dyspareunia, impotence, fecal incontinence, pain, and skin symptoms. Small/T1 tumors, without metastatic disease, can be treated with local excision alone. We aimed to systematically review the literature regarding outcome following local excision of T1 SCCA. PubMed and Embase databases were searched for studies that investigated outcome following local excision of SCCA. Twenty-three studies were included. Twenty of the studies were retrospective, and three studies included more than 100 patients. Most of the studies were published before the 1980s. Overall there was great heterogeneity and missing data across the included studies when comparing patient demographics, resection margins, definitions on tumor location, and outcome. Overall 5-year survival was 69% (95% CI 66-72) following local excision. Overall 5-year recurrence was 37% (95% CI 30-45) following local excision. No complications were reported following local excision. The current literature on outcome following local excision of T1 anal cancers consists predominantly of smaller, retrospective, and heterogenous studies. Overall 5-year survival is acceptable, but worse than following chemo-radiation therapy. However, local excision seems to have no or only few minor complications. Recurrence rates are high. Therefore, a thorough follow-up program is needed when performing local excision as primary treatment for T1 SCCA. There is an evident need for further studies.

Measurement of circulating free DNA in squamous cell carcinoma of the anus and relation to risk factors and recurrence

BackgroundMeasuring circulating-free-deoxyribonucleic-acid (cfDNA) has created a new framework for personalized treatment in oncology. The aim of this study was to analyze the relation between cfDNA and risk factors and outcome in squamous cell carcinoma of the anus (SCCA). MethodsPatients treated with radiotherapy for localized SCCA were included in Aarhus, Denmark from 2016 to 2019. Serum samples from baseline, during and after therapy, were measured for the level of cfDNA in ng per µL by a direct fluorescent assay. ResultsEighty patients were included. Samples were available at baseline (n = 73) mid-therapy (n = 74), end-therapy (n = 67) and one-year follow-up (1Y) (n = 29). P16-positivity was found in 89% (n = 55). The median level of cfDNA was higher for P16 negative tumors (1.48) compared with the P16 positive tumors (0.90, P = 0.04). Data showed a correlation between baseline cfDNA levels and Gross Tumor Volume (R2 = 0.13, P < 0.01), and increasing levels with increasing T-stage (T1 = 0.80, T2 = 0.94, T3 = 1.11, T4 = 1.3). Higher cfDNA levels were observed in patients with poor performance status (P < 0.01). The cfDNA level decreased from baseline to mid-therapy (0.92–0.78, P < 0.01) and from baseline to 1Y (0.92–0.71, P < 0.01). Baseline levels for patients with treatment failure (n = 8) were above the 25th percentile (p = 0.05) which translates into difference in disease free survival. ConclusionResults indicate an association between baseline cfDNA levels and risk factors in SCCA and a low baseline level correlates to lower risk of treatment failure. Findings contribute with new knowledge of the biological role of cfDNA in SCCA and holds potential knowledge for personalized treatment of SCCA.

Atezolizumab plus modified docetaxel-cisplatin-5-fluorouracil (mDCF) regimen versus mDCF in patients with metastatic or unresectable locally advanced recurrent anal squamous cell carcinoma: a randomized, non-comparative phase II SCARCE GERCOR trial

BackgroundModified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients.MethodsPatients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy.DiscussionAlthough the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA.Trial registrationNCT03519295.

Impact of radiotherapy duration on overall survival in squamous cell carcinoma of the anus.

Prolongation of radiotherapy (RT) in the treatment of numerous types of cancer has been shown to reduce overall survival (OS). Treatment delays are common in squamous cell carcinoma of the anus (SCCA) due to the toxicity of definitive chemoradiation (CRT). The effect of these delays on outcomes has not been well evaluated. This study investigated the effects of RT prolongation on OS in patients receiving CRT for SCCA. The National Cancer Database was queried for adult patients diagnosed with SCCA and treated with CRT from 2004-2014. Cox proportional hazard regression models examined the effect of duration of RT, measured as fractions delivered per week, on OS. Negative binomial regression assessed the effects of demographic and prognostic factors on the duration of RT. A total of 8,948 patients were included in the analysis of factors impacting treatment duration, and 6,429 patients in the OS analysis. Multivariable analysis (MVA) showed female gender, non-private insurance, treatment at a low or intermediate volume facility, Charlson/Deyo score ≥2, and advanced disease were associated with longer RT duration. Treatment with IMRT, with single agent chemotherapy, at an academic center, and in later years were associated with shorter RT duration. A decrease in fractions delivered per week was independently associated with reduced OS with a cutoff of 4.72 fractions per week (about 2 missed fractions over a 30 fraction treatment) delineating the largest differences in OS. Efforts should be made to avoid RT interruptions of any length in SCCA patients and to compensate for treatment breaks to reduce the total duration of RT.