Merkel Cell Polyoma Viral Load and Intratumoral CD8+ Lymphocyte Infiltration Predict Overall Survival in Patients With Merkel Cell Carcinoma

Introduction: Merkel cell carcinoma (MCC) is linked to the presence of clonally integrated Merkel cell polyomavirus (MCPyV) in up to 80% of the cases. The aim of the study was to determine the prognostic value of baseline MCPyV viral load and lymphocytic infiltration.Methods: MCPyV DNA prevalence, integration status and viral load were determined by specific quantitative real-time PCR in surgical specimens obtained from 49 patients with MCC treated with (n = 22, 45%) or without postoperative radiotherapy (RT). CD8+ tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) status were assessed using immunohistochemistry. MCPyV characteristics and immune marker expression were correlated with clinicopathological factors and overall survival (OS).Results: Median age at diagnosis was 74 (range, 42–100); 51% of the patients were female. One-, three, and five-year OS rates were 83.8, 58.6, and 47.1%, respectively. A positive MCPyV status was associated with female gender (p = 0.042). Tumor localization (head/arms vs. trunk) positively correlated with PD-L1 status (p = 0.011) and combined CD8/PD-L1 expression (p = 0.038). Overall CD8+ infiltration was inversely associated with N-stage (p = 0.048). Stromal TILs correlated significantly with both PD-L1 expression (p = 0.010) and N-stage (p = 0.037). A high viral load (>median) was significantly associated with worse OS (p = 0.029) and high intratumoral CD8+ infiltration with improved OS for the entire cohort (p = 0.045).Conclusion: These data provide important insight on the role of MCPy DNA viral load and TILs in the context of PD-L1 in patients with Merkel cell carcinoma. Future clinical studies should aim to explore the effect of PD-1/PD-L1 immune-checkpoint inhibitors in combination with existing radiotherapy approaches

Stereotactic body radiotherapy of adrenal metastases-A dose-finding study

Optimal doses for the treatment of adrenal metastases with stereotactic radiotherapy (SBRT) are unknown. We aimed to identify dose-volume cut-points associated with decreased local recurrence rates (LRR). A multicenter database of patients with adrenal metastases of any histology treated with SBRT (biologically effective dose, BED10 ≥50 Gy, ≤12 fractions) was analyzed. Details on dose-volume parameters were required (planning target volume: PTV-D98%, PTV-D50%, PTV-D2%; gross tumor volume: GTV-D50%, GTV-mean). Cut-points for LRR were optimized using the R maxstat package. One hundred and ninety-six patients with 218 lesions were included, the largest histopathological subgroup was adenocarcinoma (n = 101). Cut-point optimization resulted in significant cut-points for PTV-D50% (BED10: 73.2 Gy; P = .003), GTV-D50% (BED10: 74.2 Gy; P = .006), GTV-mean (BED10: 73.0 Gy; P = .007), and PTV-D2% (BED10: 78.0 Gy; P = .02) but not for the PTV-D98% (P = .06). Differences in LRR were clinically relevant (LRR ≥ doubled for cut-points that were not achieved). Further dose-escalation was not associated with further improved LRR. PTV-D50%, GTV-D50%, and GTV-mean cut-points were also associated with significantly improved LRR in the adenocarcinoma subgroup. Separate dose optimizations indicated a lower cut-point for the PTV-D50% (BED10: 69.1 Gy) in adenocarcinoma lesions, other values were similar (73.2 Gy (adenocarcinoma: 69.1 Gy) should be considered

Neoadjuvant Chemoradiotherapy for Oral Cavity Cancer: Predictive Factors for Response and Interim Analysis of the Prospective INVERT-Trial

Background To study neoadjuvant chemoradiotherapy (nCRT) and potential predictive factors for response in locally advanced oral cavity cancer (LA-OCC). Methods The INVERT trial is an ongoing single-center, prospective phase 2, proof-of-principle trial. Operable patients with stage III-IVA squamous cell carcinomas of the oral cavity were eligible and received nCRT consisting of 60 Gy with concomitant cisplatin and 5-fluorouracil. Surgery was scheduled 6-8 weeks after completion of nCRT. Explorative, multiplex immunohistochemistry (IHC) was performed on pretreatment tumor specimen, and diffusion-weighted magnetic resonance imaging (DW-MRI) was conducted prior to, during nCRT (day 15), and before surgery to identify potential predictive biomarkers and imaging features. Primary endpoint was the pathological complete response (pCR) rate. Results Seventeen patients with stage IVA OCC were included in this interim analysis. All patients completed nCRT. One patient died from pneumonia 10 weeks after nCRT before surgery. Complete tumor resection (R0) was achieved in 16/17 patients, of whom 7 (41%, 95% CI: 18-67%) showed pCR. According to the Clavien-Dindo classification, grade 3a and 3b complications were found in 4 (25%) and 5 (31%) patients, respectively; grade 4-5 complications did not occur. Increased changes in the apparent diffusion coefficient signal intensities between MRI at day 15 of nCRT and before surgery were associated with better response (p=0.022). Higher abundances of programmed cell death protein 1 (PD1) positive cytotoxic T-cells (p=0.012), PD1+ macrophages (p=0.046), and cancer-associated fibroblasts (CAFs, p=0.036) were associated with incomplete response to nCRT. Conclusion nCRT for LA-OCC followed by radical surgery is feasible and shows high response rates. Larger patient cohorts from randomized trials are needed to further investigate nCRT and predictive biomarkers such as changes in DW-MRI signal intensities, tumor infiltrating immune cells, and CAFs

Histopathological Analysis of Nodal Disease After Chemoradiation Reveals Viable Tumor Cells as the most Important Prognostic Factor in Head and Neck Squamous Cell Carcinoma

BACKGROUND In head and neck squamous cell carcinoma (HNSCC), salvage neck dissection (ND) is required after primary chemoradiation in case of residual nodal disease. Upon histopathological examination, viability of tumor cells is assessed but little is known about other prognostic histopathological features. In particular, the presence of swirled keratin debris and its prognostic value is controversial. The aim of this study is to examine histopathological parameters in ND specimens and correlate them with patient outcome to determine the relevant parameters for histopathological reporting. MATERIALS AND METHODS Salvage ND specimen from a cohort of n = 75 HNSCC (oropharynx, larynx, hypopharynx) patients with prior (chemo) radiation were evaluated on H&E stains for the following parameters: viable tumor cells, necrosis, swirled keratin debris, foamy histiocytes, bleeding residues, fibrosis, elastosis, pyknotic cells, calcification, cholesterol crystals, multinucleated giant cells, perineural, and vascular invasion. Histological features were correlated with survival outcomes. RESULTS Only the presence / amount (area) of viable tumor cells correlated with a worse clinical outcome (local and regional recurrence-free survival, (LRRFS), distant metastasis-free survival, disease-specific survival, and overall survival, p < 0.05) in both the univariable and multivariable analyses. CONCLUSION We could confirm the presence of viable tumor cells as a relevant negative prognostic factor after (chemo) radiation. The amount (area) of viable tumor cells further substratified patients with worse LRRFS. None of the other parameters correlated with a distinctive worse outcome. Importantly, the presence of (swirled) keratin debris alone should not be considered viable tumor cells (ypN0)

Dental extraction, intensity-modulated radiotherapy of head and neck cancer, and osteoradionecrosis : A systematic review and meta-analysis

Objective: To seek evidence for osteoradionecrosis (ORN) after dental extractions before or after intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC). Methods: Medline/PubMed, Embase, and Cochrane Library were searched from 2000 until 2020. Articles on HNC patients treated with IMRT and dental extractions were analyzed by two independent reviewers. The risk ratios (RR) and odds ratios (OR) for ORN related to extractions were calculated using Fisher's exact test. A one-sample proportion test was used to assess the proportion of pre- versus post-IMRT extractions. Forest plots were used for the pooled RR and OR using a random-effects model. Results: Seven of 630 publications with 875 patients were eligible. A total of 437 (49.9%) patients were treated with extractions before and 92 (10.5%) after IMRT. 28 (3.2%) suffered from ORN after IMRT. ORN was associated with extractions in 15 (53.6%) patients, eight related to extractions prior to and seven cases related to extractions after IMRT. The risk and odds for ORN favored pre-IMRT extractions (RR = 0.18, 95% CI: 0.04-0.74, p = 0.031, I2 = 0%, OR = 0.16, 95% CI: 0.03-0.99, p = 0.049, I2 = 0%). However, the prediction interval of the expected range of 95% of true effects included 1 for RR and OR. Conclusion: Tooth extraction before IMRT is more common than after IMRT, but dental extractions before compared to extractions after IMRT have not been proven to reduce the incidence of ORN. Extractions of teeth before IMRT have to be balanced with any potential delay in initiating cancer therapy. Keywords: Dental care; Dental management; Oropharyngeal cancer; Osteoradionecrosis prevention; Radiation toxicit

Detailed patient-individual reporting of lymph node involvement in oropharyngeal squamous cell carcinoma with an online interface

Purpose/ObjectiveWhereas the prevalence of lymph node level (LNL) involvement in head & neck squamous cell carcinomas (HNSCC) has been reported, the details of lymphatic progression patterns are insufficiently quantified. In this study, we investigate how the risk of metastases in each LNL depends on the involvement of upstream LNLs, T-category, HPV status and other risk factors.Materials/MethodsWe retrospectively analyzed patients with newly diagnosed oropharyngeal HNSCC treated at a single institution, resulting in a dataset of 287 patients. For all patients, involvement of LNLs I-VII was recorded individually based on available diagnostic modalities (PET, MR, CT, FNA) together with clinicpathological factors. To analyze the dataset, a web-based graphical user interface (GUI) was developed, which allows querying the number of patients with a certain combination of co-involved LNLs and tumor characteristics.ResultsThe full dataset and GUI is part of the publication. Selected findings are: Ipsilateral level IV was involved in 27% of patients with level II and III involvement, but only in 2% of patients with level II but not III involvement. Prevalence of involvement of ipsilateral levels II, III, IV, V was 79%, 34%, 7%, 3% for early T-category patients (T1/T2) and 85%, 50%, 17%, 9% for late T-category (T3/T4), quantifying increasing involvement with T-category. Contralateral levels II, III, IV were involved in 41%, 19%, 4% and 12%, 3%, 2% for tumors for tumors with and without midline extension, respectively. T-stage dependence of LNL involvement was more pronounced in HPV negative than positive tumors, but overall involvement was similar. Ipsilateral level VII was involved in 14% and 6% of patients with primary tumors in the tonsil and the base of tongue, respectively.ConclusionsDetailed quantification of LNL involvement in HNSCC depending on involvement of upstream LNLs and clinicopathological factors may allow for further personalization of CTV-N definition in the future

Need for adjuvant radiotherapy in oral cancer: depth of invasion rather than tumor diameter

PURPOSE The 8th edition of the TNM Cancer Staging Manual incorporates depth of invasion (DOI) into the pathologic tumor classification for oral squamous cell carcinoma (OSSC). While deep invading tumors with small tumor diameters (TD) have been categorized as early stage tumors in the 7th edition, they are now upstaged, potentially influencing the decision to initiate adjuvant radiotherapy (RT). METHODS OSCC patients surgically treated with curative intent between 2010 and 2019 were consecutively included. Tumors were staged based on TD only (according to the 7th edition TNM Cancer Staging Manual), then restaged based solely on DOI. RESULTS Of the 133 included patients, 58 patients (43.6%) had a different pT-stage when using DOI instead of TD for staging (upstaging in 23.3%). Overall survival (OS) was significantly worse in patients who were upstaged with DOI. In addition, stratification by adjuvant RT showed significant worse OS in upstaged patients without receiving adjuvant RT. CONCLUSIONS DOI seems to be an import indicator for adjuvant RT in OSCC-patients

Prospective assessment of stress and health concerns of radiation oncology staff during the COVID-19 pandemic

Introduction and background The COVID-19 pandemic has required rapid and repetitive adjustment of radiotherapy practice, hospital-level and department-level organization and hygiene measures. To prospectively monitor and manage stress levels and health concerns, employees of a radiation oncology department were invited to participate in weekly online surveys during the first year of the pandemic. Materials and methods Starting March 31st, 2020, cross-sectional online surveys were distributed to all employees of the Department of Radiation Oncology, University Hospital Zurich. The survey included questions about the profession, the work setting, the global stress level as well as the health concerns during the past work week. Stress levels and health concerns were assessed on a 10-point scale. SurveyMonkey® was used to conduct the survey. Distribution was performed via email. Participation was anonymous and voluntary. Results Between March 2020 and February 2021, 50 weekly surveys were distributed to 127 employees on average and resulted in 1,877 individual responses. The average response rate was 30%. The mean global stress level varied significantly by profession, ranging from 2.7 (±2.5) points for administrative staff to 6.9 (±2.3) points for radiation therapy technicians (p < 0.001). The mean global stress level was highest with 4.8 (±2.9) points for in-hospital work with direct patient contact. Health concerns were highest regarding family and friends with 4.0 (±3.1) points on average. Changes of the stress level varied in correlation with infection waves. Conclusion Weekly online surveys for prospective assessment of stress levels and health concerns were successfully conducted during the first year of the COVID-19 pandemic, indicating their feasibility and value to monitor profession and workplace specific stress patterns and to allowed for tailored interventions. The physical and mental health of frontline healthcare workers in radiation oncology should remain a top priority for departmental leadership beyond the COVID-19 pandemic

FDG-PET/CT for oral focus assessment in head and neck cancer patients

OBJECTIVES To compare oral and maxillo-mandibular inflammatory foci on standard oral radiographs (OPT, periapical radiograph) with available fluorine-18-labelled fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) data and to discuss whether additional metabolic information derived from FDG-PET/CT can support oral care specialists when performing oral focus examinations. MATERIALS AND METHODS Data from 23 patients with head and neck cancer who underwent FDG-PET/CT and panoramic and periapical radiography in close succession before first-line radiotherapy and/or chemotherapy were included in this exploratory retrospective study. Periapical lesions and marginal periodontal inflammation on FDG-PET/CT scans and standard oral radiographs were analysed and compared with regard to metabolic activity on FDG-PET/CT in comparison to recorded clinical symptoms and radiological scores. Additionally, inflammatory maxillo-mandibular pathologies were analysed using FDG-PET/CT. RESULTS The maximum standardised uptake value (SUV$_{max}$) in FDG-avid marginal periodontal sites could not be conclusively associated with the radiologically recorded severity of marginal bone loss, but a potential positive correlation was identified. No association was found either between the metabolic activity of periapical lesions and their extent, as recorded on standard oral radiographs, or regarding clinical symptoms (percussion test). Most maxillo-mandibular pathologies did not show increased FDG uptake. CONCLUSIONS FDG-PET/CT provided additional metabolic information that can help clinicians identify lesions with increased inflammatory activity. The incorporation of available oral FDG-PET/CT findings into the primary oral focus assessment may allow for more accurate oral focus treatment. CLINICAL RELEVANCE FDG-PET/CT provides valuable metabolic information for oral care specialists. The detection of inflammatory oral processes using FDG-PET/CT facilitates treatment