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Purpose: Patient-reported outcome (PRO) and National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) data for patients with squamous cell carcinoma of the anus (SCCA) treated with modern radiation therapy (RT) are lacking. The primary aim of this study was to report bowel and bladder PRO and NCI-CTCAE for patients with SCCA 1 year after RT. Methods and Materials: From 2015 to 2020, we included patients in a prospective Danish national study. Data were collected before treatment (PT) and 1 year after treatment (1Y) using NCI-CTCAE version 4.0, as well as European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and CR29. We evaluated the combined PRO scores according to the European Organisation for Research and Treatment of Cancer scoring guidelines, and classified changes according to score difference from PT to 1Y as no change (0-5), minor (5-10), moderate (11-20), and major (>20). Raw scores were reported as frequencies of each of the scores: Not at all, a little, quite a bit, and very much. Results: Of the 270 patients, 81% had complete data sets, including PT and 1Y answers. Functional mean scores were equal to a matched normal population cohort at PT and 1Y. From PT to 1Y, C30 scores were stable despite minor improvements in global health status/quality of life (7.3), emotional functioning (9.3), insomnia (8.0), and appetite loss (7.8). For questionnaire CR29, bowel and bladder symptoms and sore skin improved with minor change (6.2), and buttocks, anal, or rectal pain improved with moderate change (18.3). Flatulence worsened moderately (12.6), and fecal incontinence had minor worsening (7.8). Agreement between PROs and NCI-CTCAE was generally only fair to moderate, especially for quantitative symptoms, such as pain (κ = 0.25). Conclusions: For patients with SCCA who underwent definitive RT, only a few patients had high scores (indicating quite a bit or very much frequency of bother) regarding bowel and bladder symptoms.

Background First‐line platinum‐based therapy for advanced squamous cell carcinomas of the anal canal (SCCA) implies a risk of substantial side effects, and data on second‐line treatment options are limited. Paclitaxel and Capecitabine are a well‐known regimen with a moderate toxicity profile, but its efficacy has not been evaluated. Methods We conducted a retrospective study using Danish Hospital Registers of patients treated with Paclitaxel and Capecitabine for inoperable, recurrent, or advanced metastatic SCCA in Denmark, between January 2000 and July 2018. Results A total of 52 patients met the eligibility criteria. Median age was 60.7 years (range 42–83). Efficacy was observed, with an overall response rate in patients receiving first‐line (N = 28) and second‐line (N = 23) Paclitaxel and Capecitabine of 39.3% (2 with complete responses) and 17.4%, respectively. Median progression‐free survival (PFS) was 4.5 months (95% CI 3.3–5.9) and 3.8 months (95% CI 2.4–5.5) with OS of 6.7 months (95% CI 5.9–8.5) and 5.9 months (95% CI 3.9–14), respectively. Performance status ≥2 and neutrophil to lymphocyte ratio ≥4 were significantly associated with a short PFS. Conclusion This study recognizes Paclitaxel and Capecitabine as a potential regimen for advanced SCCA, when recommended first‐line therapy is not feasible or as a potential second‐line treatment after failure of platinum‐based chemotherapy., Paclitaxel and Capecitabine is recognized for advanced anal cancer when recommended first‐line therapy is not feasible or as second‐line treatment after failure of platinum‐based chemotherapy.

Simple Summary The 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. Abstract 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.

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 &lt, 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.

BACKGROUND AND PURPOSE: Chemoradiotherapy (CRT) is the standard therapy for localized anal cancer (AC), but this treatment is associated with substantial toxicity. However, there is a lack of prospectively collected toxicity and patient reported outcome (PRO) data from larger cohorts. The purpose was to prospectively collect and determine agreement between physician assessed toxicity (CTCAE) and PRO during and after CRT and to compare IMRT, VMAT and proton-based planning in a subgroup of patients.MATERIAL AND METHODS: Patients, treated with CRT for AC, were included between 2015 and 2017. NCI-CTCAE v.4.0, EORTC QLQ-C30 and CR29 data were collected baseline, mid-therapy, end-of therapy and 2-4 weeks posttherapy. Treatment planning with 5- or 6-fixed field IMRT, 2 and 3 arc VMAT, and 3- and 4-field proton plans were compared.RESULTS: One-hundred patients were included. Both CTCAE and PROs related to acute toxicity reached a maximum at end of therapy. Incidences of PROs were markedly higher with only slight to fair agreement to CTCAE, (κ 13-37). Comparative planning revealed dosimetric equality of IMRT and VMAT plans, but superiority of proton plans.CONCLUSIONS: The high incidence of PRO scores and weak agreement to CTCAE suggest that PROs are important tools complementary to CTCAE in evaluating patient symptoms during and after CRT. Proton therapy has the potential to lower radiation doses to most organs at risk.

Highlights • Mesorectal-only RT for early rectal cancer requires dedicated planning guidelines. • A multi-centre study was conducted to identify planning objectives. • Robust optimisation objectives for organs at risk are presented., Background and purpose Organ preservation strategies are increasingly being explored for early rectal cancer. This requires revision of target volumes according to disease stage, as well as new guidelines for treatment planning. We conducted an international, multicentre dose planning study to develop robust planning objectives for modern radiotherapy of a novel mesorectal-only target volume, as implemented in the STAR-TReC trial (NCT02945566). Materials and methods The published literature was used to establish relevant dose levels for organ at risk (OAR) plan optimisation. Ten representative patients with early rectal cancer were identified. Treatment scans had mesorectal target volumes as well as bowel cavity, bladder and femoral heads outlined, and were circulated amongst the three participating institutions. Each institution produced plans for short course (SCRT, 5 × 5 Gy) and long course (LCRT, 25 × 2 Gy) treatment, using volumetric modulated arc therapy on different dose planning systems. Optimisation objectives for OARs were established by determining dose metric objectives achievable for ≥90% of plans. Results Sixty plans, all fulfilling target coverage criteria, were produced. The planning results and literature review suggested optimisation objectives for SCRT: V10Gy

Chemotherapy resistance remains a challenge in the clinical management of metastatic colorectal cancer (mCRC). Here, early changes in cell-free circulating tumour DNA (ctDNA) levels were explored as a marker of therapeutic efficacy. Twenty-four mCRC patients were enrolled and treated with FOLFIRI based first-line therapy. Blood samples collected pre-treatment, at day 7, 14, 21, 60 and at progression were analysed for cell-free DNA (cfDNA) and ctDNA levels using digital droplet PCR. A subset of samples were additionally analysed by targeted sequencing. Patients with high pre-treatment ctDNA or cfDNA levels (≥75th centile) had significantly shorter progression free survival (PFS) than patients with lower levels. Despite an overall decline in ctDNA levels from pre-treatment to first CT-scan, serial analysis identified seven patients with temporary increases in ctDNA consistent with growth of resistant cells. These patients had shorter PFS and shorter overall survival. Targeted sequencing analyses of cfDNA revealed dramatic changes in the clonal composition in response to treatment. Our study suggests that increasing ctDNA levels during the first cycles of first-line FOLFIRI treatment is a predictor of incipient progressive disease and poorer survival. Thus, we demonstrate the importance of monitoring ctDNA levels as early as one week after treatment onset to enable early detection of treatment failure.

To determine overall survival and baseline prognostic variables in a cohort of patients with metastatic colorectal cancer receiving a FLIRI-based stop-and-go treatment strategy.Clinical information was collected from patient files in consecutive patients treated with palliative combination chemotherapy using a stop-and-go strategy from September 2007 until June 2011. The primary outcome was overall survival. Cox regression analysis was used to examine the effect of prognostic variables on survival. Baseline variables were performance status, primary tumor site, status of primary tumor (resected or unresected), synchronous metastases,1 metastatic site, liver-only metastases, alkaline phosphatase (300 U/l), lactate dehydrogenase (300 U/l), platelets (400 × 10(9)/l), and leucocytes (10 × 10(9)/l).We included 314 patients (median age 64.5 (57-70) years). Median overall survival was 20.9 (95 % confidence interval (CI), 19.1-223.4) months with a median follow-up of 21.3 months (interquartile range (IQR) 13-34.8). Independent prognostic markers of decreased survival were PS 1 and 2 vs. 0 hazard ratio (HR) 1.47 (95 % CI 1.14-1.91, p = 0.003) and HR 2.06 (95 % CI 1.19-3.56, p = 0.01), colon as the primary tumor site HR 1.43 (95 % CI 1.09-1.88, p = 0.009), unresected primary tumor HR 2.22 (95 % CI 1.61-3.07, p 0.001), and elevated leucocytes (10 × 10(9)/l) HR 1.53 (95 % CI 1.12-2.09, p = 0.007).Overall survival in metastatic colorectal cancer using a FLIRI-based stop-and-go strategy in an unselected consecutive cohort proved comparable to RCTs from the same period. Baseline prognostic markers of poorer prognosis were PS 1 or 2, colon as primary tumor site, unresected primary tumor, and leucocytes10 × 10(9)/l. These variables are all easy accessible in daily clinical practice.

The purpose of this study is to identify treatment-related factors prognostic of survival in a cohort of patients with metastatic colorectal cancer (mCRC) receiving a palliative, stop-and-go chemotherapy regimen. Consecutive patients receiving first-line treatment with biweekly FLIRI plus bevacizumab were included. The outcome was overall survival. Cox regression analysis was used to identify predictors of outcome. We analysed reduction in chemotherapy dosage (no vs. ≤25 or >25 % reduction), bevacizumab administrated to

Introduction Women with a history of preeclampsia have increased risk of cardiovascular disease later in life. However, it is unclear if early gestational age at preeclampsia onset is associated with higher cardiovascular disease risk. This study aimed to test the association between gestational age at preeclampsia onset (including the early-onset/late-onset preeclampsia distinction) and subclinical atherosclerosis and arterial stiffness in age-matched women 12 years after index pregnancy Material and methods Eligible participants were identified in two Danish registries. Main outcome measures were carotid plaque presence, carotid intima-media thickness, aortic pulse wave velocity, and augmentation index adjusted for heart rate Results Twenty-four women with previous early-onset preeclampsia, 24 with previous late-onset preeclampsia and 24 with previous normotensive pregnancies were included after matching on age (+/- 2 years) and time since delivery (+/- 1 year). In all outcome measures, the early-onset group had the highest percentage or mean value. In the adjusted analysis, the early-onset group significantly differed from the late-onset group in all outcome measures except aortic pulse wave velocity. The early-onset group also had significantly higher carotid intima-media thickness (average and left) compared to the normotensive group. Noteworthy, gestational age at preeclampsia onset as a continuous variable was significantly associated to both carotid plaque presence and carotid intima-media thickness (average and right) Conclusions Gestational age at preeclampsia onset is negatively associated with markers of subclinical atherosclerosis 12 years after delivery. Potentially, gestational age at preeclampsia onset might be helpful in directing cardiovascular disease prevention after preeclampsia. This article is protected by copyright. All rights reserved.

Objectives: To evaluate the clinical performance of a rapid point-of-care test, Triage PLGF (Alere, San Diego) in the diagnosis of preeclampsia. Study design: For the reference range 2212 plasma samples were collected from 595 subjects with normotensive pregnancies, between week 17 of gestation and delivery. In the case-control part, two cohorts of women with preeclampsia (80 women) were matched for maternal age, gestational age (GA) at sampling and parity with normotensive women who delivered at 37 weeks or more. Results: The areas under the receiver operating characteristic curves (GA < 35 weeks) were 1.0 and 0.994 (cohort 1 and 2, respectively). The clinical sensitivity of the Triage PLGF test for the pooled GA range of 21 ≤ GA < 35, using a GA dependent cut-off, was 1.0 for both cohorts with specificities of 1.0 and 0.940. Conclusions: The Triage PLGF test distinguishes well between preterm pregnancies with and without preeclampsia. © 2011 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.

Objectives Circulating placental growth factor (PlGF) is a potential biomarker for preeclampsia. Prior studies show its limited precision in predicting or diagnosing preeclampsia, underscoring a common problem in biomarker data analyses in general – that large studies are needed to overcome clinical heterogeneity and to provide sufficient statistical power. Attaining such sample sizes often requires aggregation of cohorts. Different studies may use disparate platforms for laboratory analyses, complicating data merging. Here, we assessed whether PlGF concentrations could be merged across studies using inter-platform standardization. Methods Of 16516 pregnancies from 23 cohorts, 12,804 had at least one PlGF concentration (gestational age >20 weeks), analyzed using one of four platforms: R&D Systems, Alere-Triage, Roche-Elecsys or Abbott-Architect. Two merging algorithms, using Z -Score or Multiple of Median (MOM) transformations, were applied. A single Best Reference Curve (BRC), based on merged non-case PlGF concentrations, was constructed. Case-identification performance of the BRC for PlGF was compared to platform-specific curves. Results PlGF concentrations from different analytical platforms were merged ( Z -scores marginally better than MOMs) and, overall, BRC case-identification rates out-performed platform-specific curves. Conclusions Laboratory measurements from different platforms can be standardised and merged to give reference curves from aggregated PlGF datasets. This method allows for analysis of PlGF as a diagnostic marker for preeclampsia and is generalisable to other medical questions, thereby extending the scope of individual studies to answer a variety of important medical questions. Disclosures O. Burke: None. S. Benton: None. P. Szafranski: None. P. von Dadelszen: None. C. Buhimschi: None. I. Cetin: None. L. Chapell: None. F. Figueras: None. A. Galindo: None. I. Herraiz: None. C. Holzman: None. C. Hubel: None. U. Knudsen: None. C. Kronborg: None. H. Laivuori: None. T. McElrath: None. M. Moertl: None. J. Meyers: None. R.B. Ness: None. L. Oliviera: None. G. Olson: None. L. Poston: None. C. Ris-Stalphers: None. J.M. Roberts: None. E. Schistermann: None. E. Steegers: None. H. Stepan: None. O. Lapaire: None. D. Schlembach: None. S. Timmermans: None. V. Tsatsaris: None. J.A. van der Post: None. S. Verlohren: Consultant, Research Support Recipient, Commercial Interest: Roche Diagnostics, ThermoFisher, Novartis. P.M. Villa: None. D. Williams: None. H. Zeisler: None. C. Zhang: None. C.W. Redman: None. A. Staff: None.