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Introduction. The paper presents an original, used in our Institute, method of lung volume irradiation in patients with pneumonia during COVID-19 infection. Material and methods. Procedures such as the simulation of treatment and radiotherapy are performed in a treatment room. Real time radiation treatment planning is realized as 2D planning (Irreg Planning VMS) in a separate room, and the 3D (eclipse VMS) dose distribution is calculated after the treatment. During radiation exposure, a fluence map is measured. Results. A method of irradiating the lungs of patients with COVID-19 was developed, which allows to shorten the time the patient is on the treatment table and minimize contacts between the patient and staff. Conclusions. The presented procedure made it possible to minimize the time of patient’s stay in the radiotherapy department and at the same time, it retains all the required quality assurance procedures in radiotherapy treatment.

Background: Radiotherapy plays an essential role in the treatment of oropharyngeal carcinoma (OPC). The aim of this study was to assess and compare the nutritional status (NS) of patients with HPV-related (HPV+) and non-HPV-related (HPV-) OPC before and after radiotherapy (RT) or chemoradiotherapy (CRT). Methods: The analysis included 127 patients with OPC who underwent radiotherapy (RT) alone, or in combination with chemotherapy (CRT), in the I Radiation and Clinical Oncology Department of Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland. Patients were divided according to HPV status. Confirmation of HPV etiology was obtained from FFPE (formalin-fixed, paraffin-embedded) tissue material and/or extracellular circulating HPV DNA. Basic anthropometric and biochemical parameters before and after RT/CRT were compared between the HPV- and HPV+ groups. The effect of NS on survival was also analyzed. Results: In both groups, a significant decrease in all analyzed nutritional parameters was noted after RT/CRT (p < 0.01). CRT caused significant weight loss and decreases in BMI, albumin, total lymphocyte count (TLC), and hemoglobin concentration, as well as an increase in the Nutritional Risk Score (NRS) 2002, in HPV- and HPV+ patients. A significant decrease in prealbumin levels after CRT was noted only in HPV+ patients. RT caused a significant decrease in hemoglobin concentration and TLC in HPV- patients. There were no significant differences regarding other nutritional parameters after RT in either group. RT did not have negative impact on body mass index (BMI), weight, NRS, CRP, Alb, Prealb, or PNI. Overall survival (OS) and disease-free survival (DFS) were significantly better in patients with a higher BMI in the HPV- group (OS, p = 0.011; DFS, p = 0.028); DFS was significantly better in patients with C-reactive protein (CRP) < 3.5 g/dL in the HPV- (p = 0.021) and HPV+ (p = 0.018) groups, and with total lymphocyte count (TLC) >1.28/mm3 in the HPV+ group (p = 0.014). Higher NRS 2002 was an independent adverse prognostic factor for OS and DFS in HPV-, but not in the HPV+ group. Kaplan–Meier analysis showed that both OS and DFS were significantly better in HPV- patients with lower NRS 2002 scores. However, this relationship was not observed in the HPV+ group. Conclusions: Regardless of HPV status, patients with OPC can develop malnutrition during RT/CRT. Therefore, nutritional support during RT/CRT is required in patients with HPV- and HPV+ OPC.

Fibroblast growth factor (FGF)/FGF receptor (FGFR), and platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) systems, as well as some matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), are involved in various steps of angiogenesis. Data indicate that common germline variations in angiogenesis-regulating genes may modulate therapy results and cancer progression. However, whether these variants affect clinical outcome in head and neck squamous cell carcinoma (HNSCC) is unclear. Hence, we assessed the relationship between FGF/FGFR, PDGF/PDGFR, MMP, and TIMP genetic variants and treatment outcomes in HNSCC patients receiving radiotherapy (RT) alone or combined with cisplatin-based chemotherapy. In multivariate analysis, FGF2 rs1048201 CC homozygotes showed a higher risk of death (p = 0.039), while PDGFRA rs2228230 T was strongly associated with an increased risk of locoregional relapse (HR 2.49, p = 0.001) in the combination treatment subgroup. In the RT alone subset, MMP2 rs243865 TT carriers had a higher risk of locoregional recurrence (HR 2.92, p = 0.019), whereas PDGFRB rs246395 CC homozygotes were at increased risk of metastasis (HR 3.06, p = 0.041). The MMP2 rs7201 C and TIMP2 rs7501477 T were associated with a risk of locoregional failure in the entire cohort (p = 0.032 and 0.045, respectively). Furthermore, rs1048201, rs2228230, rs246395, rs243865, rs7201, and rs7201/rs7501477 were independent indicators of an unfavorable outcome. This study demonstrates that the FGF2, PDGFRA, PDGFRB, MMP2, and TIMP2 variants may contribute to treatment failure and poor prognosis in HNSCC.

Human papilloma virus (HPV) is highly frequent among patients with anal squamous cell carcinoma, but the viral load (VL) differs between patients. This study aimed to compare the rate of HPV positivity, HPV16VL, p16INK4A and p53 expression between treatment naive and recurrent anal cancer patients. HPV was genotyped via AmpliSens® HPV HCR-genotype-titre-FRT kit. HPV16 VL was determined via quantitative polymerase chain reaction-based in-house test. p16INK4A and p53 expression was tested via immunohistochemistry. The cohort comprised 13 treatment-naive and 17 recurrent anal SCC patients. High-risk HPV was detected in 87% of cases, and HPV16 (73%) was the predominant genotype. The rate of HPV positivity was higher among women and nonsmokers, and majority of HPV-positive cases were also p16INK4A-positive. All p53-negative tumors were HPV16-positive. The most predominant p53 staining pattern in the HPV-positive group was scattered type, whereas it was diffuse type in the HPV-negative group. The HPV16 VL was higher in the treatment-naive group. Further, in the treatment-naive group, cases with scattered staining pattern of p53 had higher HPV16 VL than cases with diffuse staining pattern. The opposite result was noted in the recurrent cancer group. Moreover, p16-positive cases with scattered p53 staining pattern in the treatment naive group had higher HPV16 VL than their counterparts in the recurrent cancer group. In conclusion, the HPV VL, as is the association between VL and p16INK4A /p53, is in an inversed trend in treatment naive and recurrent cancer patients, highlighting the importance of HPV VL measurement in anal SCC.

Head and neck cancer is a serious clinical and social problem. Surgery and radiotherapy play the most important role in treatment and give the chance of cure. Optimal treatment of patients with head and neck cancer should provide for the maximum destruction of cancerous tissue, saving as much healthy tissue as possible. Despite this, due to radiotherapy still almost 90% of patients develop skin symptoms. It seems that the mechanism of radiodermatitis is quite clear, but studies assume that its pathogenesis is not fully understood and there is much to be clarified. Acute and chronic dermatitis caused by radiotherapy is usually diagnosed according to clinical criteria. It seems that it would be useful to have a photographic classification that would facilitate and unify the clinical evaluation. In this article we shall summarize the current knowledge about the mechanisms of formation, risk factors, clinical classifications and methods for the prevention and treatment of acute and chronic radiation dermatitis. We have included clinical photos that depict individual stages according to the clinical classification of RTOG.

Recent findings have shown that human papillomavirus (HPV) DNA is present in the blood as a tumor-specific biomarker (circulating tumor-related HPV; ctHPV) in patients with HPV-related oropharyngeal cancer (HPV-related OPC). The molecular response (MR) in patients with HPV-related OPC can be defined as the change in the number of ctHPV copies in relation to its initial quantity. The optimal model for assessing the MR using a liquid biopsy (LB) should be based on the E6/E7 sequences of the viral genome. MR assessment can help to evaluate the intensity of ongoing treatments in relation to the tumor response. The evaluation of the residual disease at the end of therapy may also be performed by MR assessment. If a partial MR (pMR) is found, caution is indicated and a subsequent LB should be considered, due to the likelihood of disease progression. Complete radiological and clinical responses together with a complete MR (cMR) convincingly indicate a low risk of treatment failure. Moreover, molecular recurrence (Mrec) during a follow-up, confirmed in two consecutive assays, even despite the lack of any other clinical or radiological symptoms of progression, indicates patients at high risk of disease recurrence. In conclusion, MR by ctHPV assessment may hasten the early detection of disease progression, at any stage of the management of the patient with HPV-related OPC.

The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common.

Several immune and hematological parameters are associated with survival in patients with oropharyngeal cancer (OPC). The aim of the study was to analyze selected immune and hematological parameters of patients with HPV-related (HPV+) and HPV-unrelated (HPV-) OPC, before and after radiotherapy/chemoradiotherapy (RT/CRT) and to assess the impact of these parameters on survival. One hundred twenty seven patients with HPV+ and HPV− OPC, treated with RT alone or concurrent chemoradiotherapy (CRT), were included. Patients were divided according to HPV status. Confirmation of HPV etiology was obtained from FFPE (Formalin-Fixed, Paraffin-Embedded) tissue samples and/or extracellular circulating HPV DNA was determined. The pre-treatment and post-treatment laboratory blood parameters were compared in both groups. The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), and systemic immune inflammation (SII) index were calculated. The impact of these parameters on overall (OS) and disease-free (DFS) survival was analyzed. In HPV+ patients, a high pre-treatment white blood cells (WBC) count (&gt, 8.33 /mm3), NLR (&gt, 2.13), SII (&gt, 448.60) significantly correlated with reduced OS, whereas high NLR (&gt, 2.29), SII (&gt, 462.58) significantly correlated with reduced DFS. A higher pre-treatment NLR and SII were significant poor prognostic factors for both OS and DFS in the HPV+ group. These associations were not apparent in HPV− patients. There are different pre-treatment and post-treatment immune and hematological prognostic factors for OS and DFS in HPV+ and HPV− patients. The immune ratios could be considered valuable biomarkers for risk stratification and differentiation for HPV− and HPV+ OPC patients.

Severe xerostomia is noted in the majority of patients irradiated for oropharyngeal cancer. Extracellular microRNAs (miRNAs) may serve as effective tools allowing prediction of radiation-related toxicity. The aim of this study was to create an efficient prognostic miRNA-based test for severe, patient-rated xerostomia 3 months after primary treatment.This prospective study enrolled patients with oropharyngeal cancer treated between 2016 and 2018 in 3 centers in Poland. The primary endpoint was severe (grade ≥3) xerostomia as assessed by the European Organisation for Research and Treatment of Cancer HN-35 questionnaires. Initially, a group of 10 patients with severe xerostomia was randomly selected and matched with a comparative group of 10 patients without severe xerostomia. Samples were collected before radiation therapy, after receiving 20 Gy, and within 24 hours after treatment completion. Quantitative real-time polymerase chain reaction arrays (QIAGEN, Hilden, Germany) were used to quantify expression levels of 752 miRNAs in the serum at all timepoints. The resulting logistic-regression based model was validated in additional 60 patients: 30 with grade3 xerostomia and 30 without.Of 152 eligible patients, we successfully recruited 111 patients. Severe xerostomia 3 months after treatment was reported by 63 patients (56.8%). Mean dose delivered to parotid glands was higher in both the exploratory and validation cohort. The model based on miR-185-5p and miR-425-5p expression levels measured before the start of radiation therapy had an area under the curve of 0.96 (95% confidence interval, 0.88-1.00). The model based on the same miRNAs remained robust when parameters were measured after 20 Gy (area under the curve 0.90; 95% confidence interval, 0.75-1.00). These results were confirmed in the validation group. In the validation group, preradiation therapy model application yielded 73.3% sensitivity and 80.0% specificity. In the samples taken after 20 Gy, the same 2 miRNAs yielded 67.7% sensitivity and 72.4% specificity. The model including pretreatment miR-185-5p and miR-425-5p levels together with mean parotid dose yielded 90.0% sensitivity and 80.0% specificity. In the validation cohort, this model yielded 80.6% sensitivity and 55.2% specificity. The model based on miRNA levels measured after 20 Gy and mean parotid dose had 80.0% sensitivity and 100% specificity in the exploratory group. In the validation cohort its performance fell to 71.0% sensitivity and 58.6% specificity.Serum expression levels of miR-425-5p and miR-185-5p measured before the start of radiation therapy or during therapy (after 20 Gy) had significant prognostic value for the occurrence of severe xerostomia 3 months after treatment completion. The variability explained by miRNAs appears to be, at least partially, independent from that related to the dosimetric data.

Simple Summary Hypothyroidism is a common complication of therapeutic irradiation in the neck area. Several dose-response models have been proposed to predict its’ occurrence based on clinical and radiomic features. We aimed to externally validate the results of five such models in a prospectively recruited cohort of 108 patients with oropharyngeal cancer. Two of the evaluated models, published by Rønjom et al. and by Boomsma et al., had satisfactory performance. Both models are based on mean thyroid dose and thyroid volume. Three remaining models, by Cella et al., Bakhshandeh et al. and Vogelius et al., performed significantly worse. Short-term change in the level of thyroid-stimulating hormone (TSH) after radiation therapy was not indicative of hypothyroidism development in long term. We conclude that the models by Rønjom et al. and by Boomsma et al. are feasible for long-term prediction of hypothyroidism in oropharyngeal cancer survivors treated with intensity-modulated radiation therapy. Abstract We aimed to externally validate five normal tissue complication probability (NTCP) models for radiation-induced hypothyroidism (RIHT) in a prospectively recruited cohort of 108 patients with oropharyngeal cancer (OPC). NTCP scores were calculated using original published formulas. Plasma thyrotropin (TSH) level was additionally assessed in the short-term after RT. After a median of 28 months of follow-up, thirty one (28.7%) patients developed RIHT. Thyroid mean dose and thyroid volume were significant predictors of RIHT: odds ratio equal to 1.11 (95% CI 1.03–1.19) for mean thyroid dose and 0.87 (95%CI 0.81–0.93) for thyroid volume in univariate analyses. Two of the evaluated NTCP models, published by Rønjom et al. and by Boomsma et al., had satisfactory performance with accuracies of 0.87 (95%CI 0.79–0.93) and 0.84 (95%CI: 0.76–0.91), respectively. Three remaining models, by Cella et al., Bakhshandeh et al. and Vogelius et al., performed significantly worse, overestimating the risk of RIHT in this patient cohort. A short-term TSH level change relative to baseline was not indicative of RIHT development in the follow-up (OR 0.96, 95%CI: 0.65–1.42, p = 0.825). In conclusion, the models by Rønjom et al. and by Boomsma et al. demonstrated external validity and feasibility for long-term prediction of RIHT in survivors of OPC treated with Intensity-Modulated Radiation Therapy (IMRT).

Angiogenesis is essential for growth, progression, and metastasis of solid tumors. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) and angiopoietin (ANGPT)/ tyrosine kinase endothelial (TEK) signaling plays an important role in regulating angiogenesis. Very little is known about the effects of single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes on treatment outcome in head and neck squamous cell carcinoma (HNSCC). Therefore, we evaluated the association between SNPs in ANGPT1, ANGPT2, TEK, VEGF, VEGFR1, and VEGFR2 genes and five clinical endpoints in 422 HNSCC patients receiving radiotherapy alone or combined with chemotherapy. Multivariate analysis showed an association of ANGPT2 rs3739391, rs3020221 and TEK rs639225 with overall survival, and VEGF rs2010963 with overall and metastasis-free survival. VEGFR2 rs1870377 and VEGF rs699947 affected local recurrence-free survival in all patients. In the combination treatment subgroup, rs699947 predicted local, nodal, and loco-regional recurrence-free survival, whereas VEGFR2 rs2071559 showed an association with nodal recurrence-free survival. However, these associations were not statistically significant after multiple testing correction. Moreover, a strong cumulative effect of SNPs was observed that survived this adjustment. These SNPs and their combinations were independent risk factors for specific endpoints. Our data suggest that certain germline variants in ANGPT2/TEK and VEGF/VEGFR2 axes may have predictive and prognostic potential in HNSCC treated with radiation or chemoradiation.

Paragangliomas of the head and neck are a group of neoplasms which occur very rarely. Most of them are benign tumours. Tinnitus, headaches and dysfunction of the cranial nerves are typical symptoms. Some paragangliomas have metastatic abilities and they can produce catecholamines. There are some typical imaging features in CT and MRI scans which help to determine the correct diagnosis without the necessity of performing a biopsy which can be associated with a haemorrhage risk. Therapeutic management consists of the choice between an active observation, surgical procedure, as well as radiotherapy and systemic therapy in the case of malignant paragangliomas.

Purpose: There is a lack of effective diagnostic tools for early assessment of radiotherapy (RT) outcome in patients with head and neck cancer (HNC). The timely diagnosis of treatment failure may facilitate use of salvage procedures to prevent disease progression. We assessed squamous cell carcinoma antigen and CYFRA 21-1 as early markers of radiotherapy failure in patients with HNC. Methods: Between January 2009 and February 2012, 185 patients (median age 59 years) with squamous cell carcinoma were treated with curative intent with RT alone or combined with chemotherapy (ChT). Markers were estimated in the serum 2 times: before RT and after completion of treatment. Results: The median of follow-up was 40 months. Locoregional control (LRC) was 53% and locoregional failure (LRF) was 31%. When comparing LRC and LRF, there were no significant differences between markers concentration obtained before RT. After RT, CYFRA 21-1 (p = 0.018) was significantly elevated in the LRF group. Patients with CYFRA 21-1 Conclusions: CYFRA 21-1 assessed at the end of RT or ChT seems to be a prognostic marker for tumor response. A high concentration of CYFRA 21-1 after treatment increases the risk of death. CYFRA 21-1 might be suggested in the monitoring of carcinomas of HNC.

State-of-art normal tissue complication probability (NTCP) models do not take into account more complex individual anatomical variations, which can be objectively quantitated and compared in radiomic analysis. The goal of this project was development of radiomic NTCP model for radiation-induced hypothyroidism (RIHT) using imaging biomarkers (radiomics). We gathered CT images and clinical data from 98 patients, who underwent intensity-modulated radiation therapy (IMRT) for head and neck cancers with a planned total dose of 70.0 Gy (33–35 fractions). During the 28-month (median) follow-up 27 patients (28%) developed RIHT. For each patient, we extracted 1316 radiomic features from original and transformed images using manually contoured thyroid masks. Creating models based on clinical, radiomic features or a combination thereof, we considered 3 variants of data preprocessing. Based on their performance metrics (sensitivity, specificity), we picked best models for each variant ((0.8, 0.96), (0.9, 0.93), (0.9, 0.89) variant-wise) and compared them with external NTCP models ((0.82, 0.88), (0.82, 0.88), (0.76, 0.91)). We showed that radiomic-based models did not outperform state-of-art NTCP models (p &gt, 0.05). The potential benefit of radiomic-based approach is that it is dose-independent, and models can be used prior to treatment planning allowing faster selection of susceptible population.

Objective(s): The aim of this analysis was to evaluate the platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), platelets (PLT), and neutrophil level for their prognostic value in patients with metastatic renal cell carcinoma (mRCC). Materials: We retrospectively reviewed medical records of 141 patients with mRCC (2006–2016). Univariate and multivariate analyses were performed with the Cox proportional hazards regression model. The cutoff value of NLR was “elevated” as >3.68 and the PLR cutoff value was “elevated” as >144.4. Results: The median PFS and OS were shorter in elevated NLR and PLR. A higher value of PLT was associated with worse median OS and higher neutrophil level with worse OS and PFS. In multivariate analysis, higher NLR (p = 0.007) and PLR (p = 0.006) were independent prognostic factors for shorter OS together with BMI ≤30 (p = 0.004), higher Fuhrman grade (p = 0.0002), lower level of hemoglobin (p= 0.010), and ZUBROD 2 (p = 0.0002). Higher PLR (p = 0.0002) was an independent negative prognostic factor for PFS together with higher Fuhrman grade (p = 0.001), higher neutrophil level (p = 0.001), and lower lymphocyte level (p = 0.013). Conclusion: Elevated pretreatment NLR, PLR, PLT, and neutrophil count are associated with shorter OS and PFS in patients with mRCC. NLR and PLR are independent prognostic factors for OS. However, PLR and neutrophil count are independent prognostic factors for PFS.

Purpose Adenoid cystic carcinoma (ACC) is a rare neurotropic cancer with slow progression occurring in salivary glands and less frequently in other body parts. ACC is featured by hyperchromatic nuclei and various mutations in genes encoding chromatin-related machineries. The ACC treatment is mainly limited to the radical surgery and radiotherapy while the chemotherapy remains ineffective. As the knowledge about molecular basis of ACC development is limited, we investigated here the molecular features of this disease. Patients and methods This study included 50 patients with ACC. Transcript profiling of available ACC samples vs normal salivary gland tissue, quantitative real-time PCR (qRT-PCR) transcript level measurements and the immunohistochemistry (IHC) for SWI/SNF chromatin remodeling complex (CRC) subunits and androgen receptor on surgery-derived paraffin-embedded samples were performed. Results Transcriptomic study followed by Gene Ontology classification indicated alteration of chromatin-related processes, including downregulated transcript levels of main SWI/SNF CRC subunits and elevated expression of BRM ATPase-coding SMARCA2 gene in ACC. Subsequent IHC indicated broad accumulation of BRM ATPase and several SWI/SNF subunits, suggesting affected control of their protein level in ACC. The IHC revealed ectopic, heterogeneous expression of androgen receptor (AR) in some ACC cells. Conclusions Our study indicated that ACC features aberrant expression of genes controlling chromatin status and structure. We found that the balance between SWI/SNF classes is moved towards the BRM ATPase-containing complex in ACC. As BRM is known to be involved in chemoresistance in cancer cells, this observation may be the likely explanation for ACC chemoresistance. Electronic supplementary material The online version of this article (10.1007/s00432-018-2783-5) contains supplementary material, which is available to authorized users.

6069 Background: New therapeutic approaches are needed for elderly or frail head and neck squamous cell carcinoma (HNSCC) patients (pts) ineligible for standard of care treatment. NBTXR3, a crystalline solution of hafnium oxide nanoparticles may represent such an option. Injected intratumorally, NBTXR3 enters tumor cells and yields an increased cell-localized energy deposit upon exposure to radiotherapy (RT), leading to increased tumor cell death compared to the same dose of RT alone. Methods: Phase I study of NBTXR3 activated by RT in pts ≥70 years old or ≥65 years old and unable to receive cisplatin, eligible for exclusive RT with stage III or IV HNSCC of the oral cavity or oropharynx [NCT01946867]. A 3+3 dose escalation design was implemented with dose levels corresponding to 5%, 10%, 15% and 22% of baseline tumor volume, followed by an expansion phase. Pts received an intratumoral (IT) injection of NBTXR3 and intensity modulated RT (IMRT; 70 Gy/35 fractions/7 weeks). Determination of Recommended Phase 2 Dose (RP2D) and Dose Limiting Toxicities (DLT) were primary endpoints of phase I. Absence of NBTXR3 leakage and preliminary efficacy using RECIST 1.1 principles were also evaluated. Results: The dose-escalation is complete. Nineteen pts were enrolled: 3 at 5%, 3 at 10%; 5 at 15% and 8 at 22% with no observed DLT or SAE related to NBTXR3 or IT injection. One grade 1 NBTXR3-related AE (asthenia at 22%) and four IT injection-related AE (grade 2 oral pain; grade 1 tumor hemorrhage; grade 1 asthenia, and grade 1 injection site hemorrhage) were reported. RT-related toxicity was as expected with IMRT. RP2D has been determined to be 22%. CT-scan assessment between 24h and 7 weeks post-IT injection demonstrated absence of NBTXR3 leakage in the surrounding tissues. Among 13 evaluable pts treated at doses ≥10%, 9 achieved a complete response of the injected lesion. Conclusions: These results show that NBTXR3 activated by RT is safe and well tolerated at all doses with preliminary encouraging efficacy results. It thus represents a promising future treatment for frail and elderly pts with locally advanced HNSCC with limited therapeutic options. Expansion phase has started at the RP2D. Clinical trial information: NCT01946867.

Background The precise analysis of tumour markers in blood such as circulating cell-free DNA (cfDNA) could have a significant impact in facilitating monitoring of patients after initial therapy. Although high levels of total cfDNA in plasma of cancer patients are consistently demonstrated, a low sensitivity of DNA alterations is reported. Objective The major question regards the recovery of tumour-specific cfDNA such as KRAS mutated DNA and cancer-associated type 16 of human papillomavirus (HPV16). Methods TaqMan technology was used for detection of KRAS mutation, HPV16 and to quantify cfDNA in blood plasma. Results Comparison of four different column-based commercial kits shows that the cfDNA purification carried out by the Genomic Mini AX Body Fluids kit and the QIAamp Circulating Nucleic Acid kit gave us the possibility to improve the sensitivity of detection of KRAS mutation and HPV16. The optimized method was used to follow the reduction in cancer-specific cfDNA after therapy. We found that large volume extractions with low volume of DNA eluate enabled trace amounts of tumour-specific cfDNA from cancer patients to be effectively identified. Conclusions Data presented in this study facilitate detection of tumour-specific cfDNA and improve standards needed for the implementation of cfDNA technology into routine clinical practice.

Summary Background Irradiation of salivary glands during the treatment of head and neck cancer may lead to an alteration in the amount of saliva produced. Because of this, patients can suffer dryness of the mouth with oral discomfort, taste disturbance and dental decay. Aim The aim of this study is to estimate late toxicity dependence on radiotherapy method. The main goal is to investigate the correlations between the radiation doses in salivary glands and their salivary excretion fractions (SEF) measured by dynamic scintigraphy. Materials/Methods In 40 patients with pharyngeal and laryngeal cancer irradiated by IMRT or conformal 3D to a total dose of 62.5–72.0Gy, parotid SEFs were measured. Parotid dose-volume histograms were obtained from 3D computer treatment planning. SEF measurements were performed before (baseline), and 6 weeks and 6 months after radiotherapy by 185MBq 99 Tc injected intravenously and next SEF rates were analysed in relation to radiation doses accumulated. The late radiation toxicity of salivary glands was tested according to the CTC v. 3.0 and SOMA-LENT scales. The non-parametric Mann Whitney test was used for the estimation of relationships. Results Pre- and post-treatment SEFs were measured in 31 patients treated by IMRT and in 9 patients treated by 3D CRT. Six weeks after radiotherapy SEF was generally lower by 34%, and 6 months after irradiation by 29.3% in IMRT technique. In 3D CRT relatively it was lower: after 6 weeks by average 52% and after 6 months by 35.5%. Late radiation toxicity of salivary glands was observed at a similar level according to CTC and SOMA-LENT scales in both methods of radiotherapy. Conclusions The level of SEF in parotid glands measured 6 weeks after radiotherapy clearly reflects the dose-response relationship of irradiated salivary tissue; 6 months later changes of SEF are the result of partial recovery of parotids. The results of sparing salivary glands can be optimized in the future; that is, a further reduction of xerostomia can be achieved by using improved IMRT techniques and focusing on sparing major and minor salivary glands.

Summary Objectives The advantages of the circulating cell-free DNA (cfDNA) methodology are quick results and the possibility of repeated analysis. The main aim of our study was to establish the relationship of the total cfDNA with patients’ clinical characteristics and circulating HPV DNA detection in the blood of patients with head and neck squamous cell carcinoma (HNSCC). Methods The cfDNA level of 200 HNSCC patients in plasma was quantified using TaqMan-based TERT amplification. TaqMan technology was also used for HPV16/18 detection. Additionally, mutations in KRAS and EGFR were investigated. Results A higher level (p = 0.011) of the total cfDNA was found in patients with oropharyngeal squamous cell carcinoma (OPSCC) (9.60 ± 6.23 ng/ml) in comparison with other HNSCC (7.67 ± 4.44 ng/ml). The level of cfDNA in patients with clinical N2–N3 disease (9.28 ± 6.34 ng/ml) was (p = 0.015) higher than in patients with a clinical N0–N1 disease (7.50 ± 3.69 ng/ml). It was also higher in patients with stage IV (9.16 ± 6.04 ng/ml) compared with stages I–III of cancer (7.26 ± 3.63 ng/ml) (p = 0.011). Analysis of HPV16/18 in plasma revealed that 14% of patients were HPV-positive, the majority of whom had the type HPV16 (96.4%). CfDNA level was comparable in HPV-positive and HPV-negative HNSCC patients, as well in the OPSCC subgroup. Somatic mutations in EGFR and KRAS were not found. Conclusions A high level of cfDNA is specific for patients with OPSCC. HPV detection in cfDNA does not depend on the cfDNA concentration. Our results prove the diagnostic potential of plasma-based HPV cfDNA tests for the early detection and monitoring of HPV-positive HNSCC.

Brain metabolism after surgery and postoperative radiotherapy (pRT) because of primary brain tumors was assessed by proton magnetic resonance spectroscopy ((1)H-MRS) in vivo. The study was designed to reveal the impact of pRT on normal brain tissue metabolism, which may potentially help in delineating the target volumes for reirradiated patients.Spectra of 43 patients ages 16-63 years treated with pRT for primary glial tumors in the Center of Oncology Maria Curie Memorial Institute Branch in Gliwice were analyzed. The control group consisted of spectra acquired for 30 healthy volunteers. All patients were treated with 3D conformal techniques using 6-20 MV photons to total doses of 60 Gy. Spectra were acquired from the control region before pRT and from three uninvolved regions 9-12 months after the end of pRT. Voxels were located in the region of low (6 Gy), medium (29-39 Gy), and high radiation dose ( approximately 60 Gy). Relative intensities of the signals relating to N-acetyl-aspartate (NAA), choline-based compounds, creatine and phosphocreatine (Cr), mio-Inositol, lactate, and lipids were obtained.The spectra of "normal brain" taken 9 months after pRT are significantly different from those obtained for control volunteers and from the spectra acquired before radiotherapy. The lactate and lipids signals are very strong; however, they are not correlated with absorbed dose. NAA/Cr ratios are significantly lower than before radiotherapy even for the low-dose regions. Differences increase with radiation dose: the NAA/Cr ratio is significantly lower for the regions of brain receiving a high dose of radiation than for the low-dose areas.Combined treatment of primary brain tumors (surgery + postoperative radiotherapy) causes alteration of brain metabolism, even in regions of the brain far from the postoperative tumor bed and receiving relatively low total doses of radiation. Single voxel MRS spectroscopy in vivo cannot help in delineating target volumes for secondary irradiation.

Purpose To study locoregional tumor control in postoperative radiotherapy (PRT) for head-and-neck cancer in relation to the position and duration of treatment gaps, duration of the interval surgery-radiotherapy, and to the other potentially prognostic variables. Methods and materials The retrospective study included 868 patients with cancer of the larynx, oral cavity, oropharynx, and hypopharynx treated in Gliwice between 1980 and 1997. Mean total radiation dose, dose per fraction, overall radiation treatment time (OTT), and the interval surgery-PRT were 62.8 Gy, 2.1 Gy, 45 days, and 63 days, respectively. No interruptions during PRT (except for weekend breaks) appeared in 30% of patients, whereas 19% had more than 5 days of gap. The actuarial locoregional recurrence-free survival (RFS) has been examined using multivariate Cox regression model, and the ultimate locoregional tumor control probability using a logistic model. Results Increased duration of treatment gaps, positive resection margins, pathologically proven metastases to the neck nodes, and extralaryngeal site of cancer were significantly related to a decrease in RFS. The duration of time interval surgery-PRT appeared, by contrast, only borderline significant for RFS. The relative risk of locoregional recurrence was approximately the same for the gaps in days 1–21 as for the “late” gaps (days >21), except in a subgroup of patients with positive clinical margins. The logistic analysis revealed a significant time-related displacement of the dose–response curves for PRT. The detriment from the protraction of OTT appeared to be larger than the benefit from the equivalent shortening of OTT. Conclusions Although the conclusions from this study must be regarded as only hypothesis-generating, we assume that a highly significant adverse influence of radiation treatment gaps on the rate of tumor control is consistent with rapid repopulation of cancer clonogenes during PRT. Lack of significant effect of the position of gaps on locoregional tumor control after radical surgery may suggest that a lag time for the onset of repopulation in PRT is short. A less likely explanation is that the total amount of regeneration during OTT is the same, regardless of the timing of the gap, even if all the repopulation occurred late. The magnitude of the detriment in tumor control from prolonged interval surgery-PRT indicates that repopulation of cancer cells between surgery and radiotherapy is not as fast as between the fractions of radiotherapy.

Purpose To report long-term results of randomized trial comparing 2 accelerated fractionations of definitive radiation therapy assessing the need to irradiate during weekend in patients with head and neck squamous cell carcinoma. Methods and Materials A total of 345 patients with SCC of the oral cavity, larynx, and oro- or hypo-pharynx, stage T2-4N0-1M0, were randomized to receive continuous accelerated irradiation (CAIR: once per day, 7 days per week) or concomitant accelerated boost (CB: once per day, 3 days per week, and twice per day, 2 days per week). Total dose ranged from 66.6-72 Gy, dose per fraction was 1.8 Gy, number of fractions ranged from 37-40 fractions, and overall treatment time ranged from 37-40 days. Results No differences for all trial end-points were noted. At 5 and 10 years, the actuarial rates of local-regional control were 63% and 60% for CAIR vs 65% and 60% for CB, and the corresponding overall survival were 40% and 25% vs 44% and 25%, respectively. Confluent mucositis was the main acute toxicity, with an incidence of 89% in CAIR and 86% in CB patients. The 5-year rate of grade 3-4 late radiation morbidity was 6% for both regimens. Conclusions Results of this trial indicate that the effects of accelerated fractionation can be achieve by delivering twice-per-day irradiation on weekday(s). This trial has also confirmed that an accelerated, 6-weeks schedule is a reasonable option for patients with intermediate-stage head-and-neck squamous cell carcinoma because of the associated high cure rate and minimal severe late toxicity.

Mass spectrometry-based analyses of the low-molecular-weight fraction of serum proteome allow identifying proteome profiles (signatures) that are potentially useful in detection and diagnostics of cancer. Here we compared serum proteome profiles of healthy donors and patients with three different types of cancer aiming to identify peptide signatures that were either common for all cancer samples or specific for cancer type. Blood samples were collected before start of the therapy from patients with head and neck squamous cell cancer, colorectal adenocarcinoma and non-small cell lung cancer, and from a corresponding group of healthy volunteers. Mass profiles of the serum proteome were recorded in the range between 2 and 13 kDa using MALDI-ToF spectrometry and 131 identified peptide ions were used for statistical analyses. Similar degrees of overall similarities were observed in all intra-group and inter-group analyses when general features of serum proteome profiles were compared between individual samples. However, classifiers built of selected spectral components allowed differentiation between healthy donors and three groups of cancer patients with 69-74% sensitivity and 82-84% specificity. There were two common peptide species (3766 and 5867 Da) with increased levels in all cancer samples. Several spectral components permitted differentiation between lung cancer samples and either head and neck cancer or colorectal cancer samples, but two latter types of samples could not be properly discriminated. Abundance of spectral components that putatively corresponded to fragments of serum amyloid A (11511 and 11667 Da) was highest in lung cancer samples, yet increased levels of these peptides appeared to generally associate with more advanced cancer cases. We concluded that certain components of serum peptide signatures are common for different cancer signatures and putatively reflect general response of organism to the disease, yet other components of such signatures are more specific and most likely correspond to clinical stage of the malignancy.

Purpose To evaluate severity of acute mucosal reactions (AMR) caused by conventional (CF) and accelerated fractionation (AF) regimens using a modified Dische system and to analyze differences in incidence and severity of AMR according to frequency and regularity of scoring. Methods and Materials Sixty-six consecutive patients (33 CF, 33 AF) with head and neck cancer irradiated with 5 fractions in 5 days per week (CF) or with 7 fractions in 7 days (AF) to a total dose of 70 Gy. A modified Dische system was used for daily quantitation of AMR during radiotherapy until complete healing. Results Confluent mucositis (CM) was noted in 79% of patients in the CF group and 85% in the AF group. In 24% of the CF group and 18% of the AF group the CM presented a wave-like pattern. In 55% of CF and 67% of AF a classic triphasic pattern was noted. In 12 patients acute reactions did not transgress the level of spotted mucositis. The present study clearly shows that quantitation of the incidence and severity of acute mucosal effects strongly depends on frequent and regular scoring. A significant difference in the incidence of CM between the CF and AF groups was noted, mainly in weeks 4–6 of irradiation. When once-weekly irregular instead of daily scoring was evaluated, the incidence of CM was underestimated by approximately 20–36%. Conclusions Acute mucosal reactions occur as a complex of morphologic and functional disorders with individual intensity, even among patients treated with the same fractionation regimen. In some cases they present a “wave-like” pattern during irradiation. Therefore, precise quantitation of acute effects requires regular and frequent scoring.

Purpose To investigate the prognostic value of hemoglobin (Hb) concentration in patients with laryngeal cancer treated with postoperative radiotherapy (pRT). Methods and Materials The records of 835 patients who underwent pRT between 1980 and 2003 were reviewed. Most patients (526 of 835 patients; 63%) were in advanced clinical stages (T3–T4) and 371 of 835 patients (44%) were node positive. Total laryngectomy had been performed in 676 of 835 patients (81%). Median Hb concentration before (Hb0) and after pRT (Hb1) was the same (13.3 g/dl). However, individual differences between Hb1 and Hb0 (dHb) varied within a broad range (−8.8; 5.0 g/dl). Univariate and multivariate analyses were performed to identify variables significantly associated with locoregional control (LRC), metastases-free survival, and overall survival. Results Patients with dHb greater than 0 had significantly improved 5-year LRC compared with those with dHb of 0 or less (80% vs. 72%, p = 0.01). Conversely, when categorized, neither Hb0 nor Hb1 had a significant influence on LRC. In multivariate analysis, dHb remained a prognostic factor for LRC ( p = 0.01) among the other variables, which included overall radiation treatment time and nodal status. None of the Hb-related variables significantly influenced metastases-free or overall survival. Conclusion Individual change in Hb concentration during the course of pRT (dHb) rather than Hb level before or after pRT appeared as an independent prognostic factor for LRC in this set of patients.

CelPrzedstawienie wyników łeczenia skojarzonego chorych na nowotwory jamy ustnej w ramach Zespołu Narządowego Nowotworów Głowy i Szyi w latach 1995 – 2000 w Instytucie Onkologii w Gliwicach.MaterialPodmiotem analizy jest grupa 102 chorych; 70 (69%) mężczyzn i 32 (31%) kobiet w średnim wieku 54 lat chorych na raka jamy ustnej leczonych za pomocą chirurgii i pooperacyjnej radioterapii. Najczęstsza lokalizacją guza pierwotnego była część ruchoma języka i dno jamy ustnej oraz wyrostek zębodołowy żuchwy odpowiednio 48 (47%) i 27 (26%) chorych, a rozpoznanie raka płaskonabłonkowego postawiono w 93 (92%) przypadkach. Zaawansowanie guza pierwotnego postawione na podstawie badania klinicznego oraz metod obrazowych ustalono w największym odsetku jako T2 oraz T3; odpowiednio 41 (40%) i 33 (34%) chorych. U 42 (41%) chorych nie stwierdzono przerzutowo zmienionych węzłów chłonnych, a w 31 (30%) przypadkach zanotowano pojedyncze (N1) przerzuty do węzłów chłonnych szyi. U 26 (25%) chorych wykonano zabieg miejscowy usunięcia guza z marginesem zdrowych tkanek, u pozostałych 76 (75%) zabieg blokowy obejmujące ognisko pierwotne jak i węzły chłonne. Mikroskopowa radykałność leczenia chirurgicznego została potwierdzona w 55 (54%) przypadków, a średnia szerokość ocenionych w preparatach pooperacyjnych marginesów wyniosła 3.8 mm, przy średnio 3 ocenionych marginesach. Wszyscy chorzy poddani zostali pooperacyjnej radioterapii, którą rozpoczynano 56 dni po zabiegu. W 87 (86%) przypadkach zastosowano konwencjonalne frakcjonowanie dawki, u pozostałych frakcjonowanie przyśpieszone, do średniej dawki całkowitej 66. 6 Gy. 101 (99%) chorych zakończyło leczenie zgodnie z planem. Średni całkowity czas leczenia skojarzonego wyniósł 100 dni, a mediana okresu obserwacji 5 lat.Wyniki5-letnie odsetki wyleczeń miejscowych, przeżyć bezobjawowych oraz ca łkowitych wyniosło odpowiednio: 87%, 72% oraz 70%. Ana łiza jednowariantowa wykazała, iż zaawansowanie guza pierwotnego (T4) związane było ze znamiennie niższym prawdopodobieństwem wyleczenia miejscowego, a niekonwencjonalne frakcjonowanie dawki z obniżeniem odsetka przeżyć bezobjawowych (p

HRZ3.51, 95% CI: 1.56-7.90, pZ0.001). Interrogation of The Cancer Genome Atlas database for HNSCC samples with both methylation and outcome data available (nZ305), revealed a similarly absent or low frequency of methylation events for the loci investigated. However, the presence of RUNX3 hypermethylation did not correlate with worse outcome for patients (HR Z 1.27; 95% CI: 0.56 2.88; pZ0.57 and HR Z 1.08; 95% CI: 0.65 1.82; p Z0.76, OTSCC and HNSCC, respectively). Conclusion: In OTSCC, we found little evidence of promoter hypermethylation of genes previously reported to be frequently methylated in HNSCC. Whilst OTSCC may have subsite-specific methylation for the loci examined, it is likely that previously reports have overestimated methylation events with the use of non-quantitative methodology. Author Disclosure: A.M. Lim: None. I.L.M. Candiloro: None. N. Wong: None. M. Collins: None. H. Do: None. C. Angel: None. J. Corry: None. D. Rischin: None. B. Solomon: None. A. Dobrovic: None.