Dynamics of HMBG1 (High Mobility Group Box 1) during radiochemotherapy correlate with outcome of HNSCC patients.

PURPOSE: High Mobility Group Box 1 (HMGB1) protein has been described as a consensus marker for immunogenic cell death (ICD) in cancer. To personalize treatments, there is a need for biomarkers to adapt dose prescription, concomitant chemotherapy, and follow-up in radiation oncology. Thus, we investigated the levels of HMGB1 in plasma of patients with head and neck squamous cell carcinoma (HNSCC) during the course of radiochemotherapy and follow-up in correlation with oncologic outcome and clinical confounders. METHODS: In our pilot study, 11 patients with advanced HNSCC were treated with definitive radiochemotherapy. Blood samples were taken weekly during treatment and frequently at follow-up visits. HMGB1 levels as well as routine laboratory values were measured and clinical information was collected including tumor volume, infections, toxicity, and follow-up data. RESULTS: In total, 85 samples were analyzed. In eight patients, HMGB1 levels (baseline vs. last available sample during treatment) were increasing and in three patients HMGB1 values were decreasing toward the end of treatment. All three patients with decreasing values developed tumor recurrence. By contrast, no relapse occurred in patients that showed increasing HMGB1 levels during therapy. Moreover, a positive correlation of HMGB1 levels with tumor volumes, C­reactive protein (CRP) levels, infections, and grade three toxicity (RTOG) was observed. CONCLUSION: HMGB1 might be a promising marker to monitor ICD in HNSCC during the course of radiochemotherapy. However, HMGB1 seems to reflect complex and diverse immunogenic responses and potential confounders. Infections and treatment-associated toxicity should be considered when interpreting the dynamics of HMGB1.

PET/MRI and genetic intrapatient heterogeneity in head and neck cancers.

PURPOSE: The relation between functional imaging and intrapatient genetic heterogeneity remains poorly understood. The aim of our study was to investigate spatial sampling and functional imaging by FDG-PET/MRI to describe intrapatient tumour heterogeneity. METHODS: Six patients with oropharyngeal cancer were included in this pilot study. Two tumour samples per patient were taken and sequenced by next-generation sequencing covering 327 genes relevant in head and neck cancer. Corresponding regions were delineated on pretherapeutic FDG-PET/MRI images to extract apparent diffusion coefficients and standardized uptake values. RESULTS: Samples were collected within the primary tumour (n = 3), within the primary tumour and the involved lymph node (n = 2) as well as within two independent primary tumours (n = 1). Genetic heterogeneity of the primary tumours was limited and most driver gene mutations were found ubiquitously. Slightly increasing heterogeneity was found between primary tumours and lymph node metastases. One private predicted driver mutation within a primary tumour and one in a lymph node were found. However, the two independent primary tumours did not show any shared mutations in spite of a clinically suspected field cancerosis. No conclusive correlation between genetic heterogeneity and heterogeneity of PET/MRI-derived parameters was observed. CONCLUSION: Our limited data suggest that single sampling might be sufficient in some patients with oropharyngeal cancer. However, few driver mutations might be missed and, if feasible, spatial sampling should be considered. In two independent primary tumours, both lesions should be sequenced. Our data with a limited number of patients do not support the concept that multiparametric PET/MRI features are useful to guide biopsies for genetic tumour characterization.

Impact of MRI on target volume definition in head and neck cancer patients.

BACKGROUND: Target volume definition for curative radiochemotherapy in head and neck cancer is crucial since the predominant recurrence pattern is local. Additional diagnostic imaging like MRI is increasingly used, yet it is usually hampered by different patient positioning compared to radiotherapy. In this study, we investigated the impact of diagnostic MRI in treatment position for target volume delineation. METHODS: We prospectively analyzed patients who were suitable and agreed to undergo an MRI in treatment position with immobilization devices prior to radiotherapy planning from 2017 to 2019. Target volume delineation for the primary tumor was first performed using all available information except for the MRI and subsequently with additional consideration of the co-registered MRI. The derived volumes were compared by subjective visual judgment and by quantitative mathematical methods. RESULTS: Sixteen patients were included and underwent the planning CT, MRI and subsequent definitive radiochemotherapy. In 69% of the patients, there were visually relevant changes to the gross tumor volume (GTV) by use of the MRI. In 44%, the GTV_MRI would not have been covered completely by the planning target volume (PTV) of the CT-only contour. Yet, median Hausdorff und DSI values did not reflect these differences. The 3-year local control rate was 94%. CONCLUSIONS: Adding a diagnostic MRI in RT treatment position is feasible and results in relevant changes in target volumes in the majority of patients.

Plasma sICAM-1 correlates with tumor volume before primary radiochemotherapy of head and neck squamous cell carcinoma patients.

BACKGROUND: Biomarkers are of major interest to optimize diagnosis, prognosis and to guide treatment in head and neck cancer patients. Especially blood-based biomarkers appear promising as they can be easily collected and repeatedly analyzed during the course of radiochemotherapy. PATIENTS AND METHODS: At first, for a broad overview, multiple immune markers were evaluated in six plasma samples of three head and neck squamous cell carcinoma (HNSCC) patients at the beginning and the end of radio-chemotherapy. In this pre-selection, the soluble Intercellular Adhesion Molecule 1 (sICAM-1) appeared most promising. Thus, this marker was measured in multiple samples (n = 86) during treatment and follow-up in a cohort of eleven patients and correlated with tumor features and clinical data. RESULTS: We found a strong correlation between the initial levels of sICAM-1 in the plasma and the gross tumor volumes of the primary tumor and the involved lymph nodes. However, during the course of treatment no systematic dynamics could be identified. Toxicity or infections did not seem to influence sICAM-1 concentrations. CONCLUSIONS: sICAM-1 appears to reflect the pre-treatment total tumor burden (primary tumor and involved lymph nodes) in head and neck tumor patients. However, it does not seem to be a dynamic marker reflecting response during radiochemotherapy. Thus, if our findings are confirmed in future, sICAM-1 could be used as a staging marker: if high sICAM-1 levels but low tumor burden are found it might be reasonable to intensify staging investigations to rule out further, yet undetected, tumor sites.

Patient views on genetics and functional imaging for precision medicine: a willingness-to-pay analysis.

Purpose: Willingness-to-pay (WTP) analyses can support allocation processes considering the patients preferences in personalized medicine. However, genetic testing especially might imply ethical concerns that have to be considered. Methods: A WTP questionnaire was designed to compare preferences for imaging and genetic testing in cancer patients and to evaluate potential ethical concerns. Results: Comparing the options of imaging and genetics showed comparable WTP values. Ethical concerns about genetic testing seemed to be minor. Treatment success was the top priority irrespective of the diagnostic modality. In general, the majority of patients considered personalized medicine to be beneficial. Conclusion: Most patients valued personalized approaches and rated the benefits of precision medicine of overriding importance irrespective of modality or ethical concerns.

A study of the patients preferences in diagnostic approaches where patients were asked if they would hypothetically pay out-of-pocket money for particular procedures. However, in regard to personalized medicine (specifically selected for a single person) genetic testing especially might imply ethical concerns. A questionnaire was designed to compare preferences for imaging and genetic testing in cancer patients and to evaluate potential ethical concerns. Comparing the options of imaging and genetics showed comparable values of out-of-pocket money the patients were willing to pay. Ethical concerns about genetic testing were minor. Treatment success was the top priority irrespective of the diagnostic modality. Most patients valued personalized approaches and rated the benefits of overriding importance irrespective of modality or ethical concerns.

Retrospective analysis of recurrence patterns and clinical outcome of grade II meningiomas following postoperative radiotherapy.

BACKGROUND: Atypical meningiomas exhibit a high tendency for tumor recurrence even after multimodal therapy. Information regarding recurrence patterns after additive radiotherapy is scarce but could improve radiotherapy planning and therapy decision. We conducted an analysis of recurrence patterns with regard to target volumes and dose coverage assessing target volume definition and postulated areas of tumor re-growth origin. Prognostic factors contributing to relapse were evaluated. METHODS: The clinical outcome of patients who had completed additive, somatostatin receptor (SSTR)-PET/CT-based fractionated intensity-modulated radiotherapy for atypical meningioma between 2007 and 2017 was analyzed. In case of tumor recurrence/progression, treatment planning was evaluated for coverage of the initial target volumes and the recurrent tumor tissue. We proposed a model evaluating the dose distribution in postulated areas of tumor re-growth origin. The median of proliferation marker MIB-1 was assessed as a prognostic factor for local progression and new distant tumor lesions. RESULTS: Data from 31 patients who had received adjuvant (n = 11) or salvage radiotherapy (n = 20) were evaluated. Prescribed dose ranged from 54.0 to 60.0 Gy. Local control at five years was 67.9%. Analysis of treatment plans of the eight patients experiencing local failure proved sufficient extent of target volumes and coverage of the prescribed dose of at least 50.0 Gy as determined by mean dose, D98, D2, and equivalent uniform dose (EUD) of all initial target volumes, postulated growth-areas, and areas of recurrent tumor tissue. In all cases, local failure occurred in high-dose volumes. Tumors with a MIB-1 expression above the median (8%) showed a higher tendency for re-growth. CONCLUSIONS: The model showed adequate target volume and relative dose distribution but absolute dose appears lower in recurrent tumors without reaching statistical significance. This might provide a rationale for dose escalation studies. Biological factors such as MIB-1 might aid patients' stratification for dose escalation.

Correction to: Retrospective analysis of fractionated intensity-modulated radiotherapy (IMRT) in the interdisciplinary management of primary optic nerve sheath meningiomas.

An amendment to this paper has been published and can be accessed via the original article.

Dynamics of cell-free tumour DNA correlate with treatment response of head and neck cancer patients receiving radiochemotherapy.

PURPOSE: Definitive radiochemotherapy (RCTX) with curative intent is one of the standard treatment options in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Despite this intensive therapy protocol, disease recurrence remains an issue. Therefore, we tested the predictive capacity of liquid biopsies as a novel biomarker during RCTX in patients with HNSCC. MATERIAL AND METHODS: We sequenced the tumour samples of 20 patients with locally advanced HNSCC to identify driver mutations. Subsequently, we performed a longitudinal analysis of circulating tumour DNA (ctDNA) dynamics during RCTX. Deep sequencing and UMI-based error suppression for the identification of driver mutations and HPV levels in the plasma enabled treatment-response monitoring prior, during and after RCTX. RESULTS: In 85% of all patients ctDNA was detectable, showing a significant correlation with the gross tumour volume (p-value 0.032). Additionally, the tumour allele fraction in the plasma was negatively correlated with the course of treatment (p-value <0.05). If ctDNA was detectable at the first follow-up, disease recurrence was seen later on. Circulating HPV DNA (cvDNA) could be detected in three patients at high levels, showing a similar dynamic behaviour to the ctDNA throughout treatment, and disappeared after treatment. CONCLUSIONS: Monitoring RCTX treatment-response using liquid biopsy in patients with locally advanced HNSCC is feasible. CtDNA can be seen as a surrogate marker of disease burden, tightly correlating with the gross tumour volume prior to the treatment start. The observed kinetic of ctDNA and cvDNA showed a negative correlation with time and treatment dosage in most patients.

Retrospective analysis of fractionated intensity-modulated radiotherapy (IMRT) in the interdisciplinary management of primary optic nerve sheath meningiomas.

BACKGROUND: As optic nerve sheath meningiomas (ONSM) are rare, there are no prospective studies. Our retrospective analysis focusses on a cohort of patients with uniform disease characteristics all treated with the same radiotherapy regimen. We describe treatment decision making, radiotherapy planning and detailed neuro-ophthalmological outcome of the patients. METHODS: 26 patients with unilateral ONSM extending only to the orbit and the optic canal were evaluated for neuro-ophthalmological outcome. Radiation treatment was planned in a simultaneous integrated boost approach to gross tumor volume (GTV) + 2 mm / 5 mm to 54 Gy / 51 Gy in 1.8 Gy / 1.7 Gy fractions. Follow-up was done by specialized neuro-ophthalmologists. Visual acuity and visual field defects were evaluated after therapy as well as during follow-up. RESULTS: Interdisciplinary treatment decision for patients with ONSM follows a rather complex decision tree. Radiation treatment planning (equivalent uniform dose (EUD), maximum dose to the optic nerve) improved with experience over time. With this patient selection visual acuity as well as visual field improved significantly at first follow-up after treatment. For visual acuity this also applied to patients with severe defects before treatment. Long term evaluation showed 16 patients with improved visual function, 6 were stable, in 4 patients visual function declined. Interdisciplinary case discussion rated the visual decline as radiation-associated in two patients. CONCLUSIONS: With stringent patient selection radiotherapy for unilateral primary ONSM to 51 Gy / 54 Gy is safe and leads to significantly improved visual function. Interdisciplinary treatment decision and experience of the radiation oncology team play a major role.