Volume 54 (2020): Edizione 4 (December 2020)

Vulvar cancer accounts for 3–5% of malignant diseases of the female genital tract. The Slovenian incidence rate is 5.5/100,000, which means 57 new cases per year. The most common histological type (90%) is squamous cell carcinoma. Based on etiology, it can be classified into the first type which correlates with human papillomavirus (HPV) infection and the second type which is not associated with HPV. The most common and long-lasting symptom of vulvar cancer is pruritus. The preferred diagnostic procedure to confirm the diagnosis is a punch or incision biopsy. Surgery in combination with radiotherapy is the standard treatment for vulvar cancer. Sentinel lymph node biopsy with lymphoscintigraphy is now a standard part of surgical treatment. Chemotherapy is a palliative treatment option.

Vulvar cancer is a rare disease. Because of the pathogenesis, surgery and radiotherapy are the main treatment modalities. The sentinel node biopsy (SNB) represents a contemporary approach to the vulvar cancer treatment and significantly reduces morbidity. Improvements in treatment of vulvar cancer contributed to the decrease of mortality among Slovenian women.

Head and neck squamous cell carcinoma (HNSCC) presents as locally advanced disease in a majority of patients and is prone to relapse despite aggressive treatment. Since immune checkpoint inhibitors (ICI) have shown clinically significant efficacy in patients with recurrent/metastatic HNSCC (R/M HNSCC), a plethora of trials are investigating their role in earlier stages of disease. At the same time, preclinical data showed the synergistic role of concurrently administered radiotherapy and ICIs (immunoradiotherapy) and explained several mechanisms behind it. Therefore, this approach is prospectively tested in a neoadjuvant, definitive, or adjuvant setting in non-R/M HNSCC patients. Due to the intricate relationship between host, immunotherapy, chemotherapy, and radiotherapy, each of these approaches has its advantages and disadvantages. In this narrative review we present the biological background of immunoradiotherapy, as well as a rationale for, and possible flaws of, each treatment approach, and provide readers with a critical summary of completed and ongoing trials.

While immunotherapy with ICIs has already become a standard part of treatment in patients with R/M HNSCC, its efficacy in a non-R/M HNSCC setting is still the subject of extensive clinical testing. Irradiation can overcome some of the cancer’s immune evasive manoeuvres and can lead to a synergistic effect with ICIs, with possible additional benefits of concurrent platinum-based chemotherapy. However, the efficacy of this combination is not robust and details in trial design and treatment delivery seem to be of unprecedented importance.

Specific correlations among diffusion tensor imaging (DTI)-derived metrics and magnetic resonance spectroscopy (MRS) metabolite ratios in brains with glioblastoma are still not completely understood.

We made retrospective cohort study. MRS ratios (choline-to-N-acetyl aspartate [Cho/NAA], lipids and lactate to creatine [LL/Cr], and myo-inositol/creatine [mI/Cr]) were correlated with eleven DTI biomarkers: mean diffusivity (MD), fractional anisotropy (FA), pure isotropic diffusion (p), pure anisotropic diffusion (q), the total magnitude of the diffusion tensor (L), linear tensor (Cl), planar tensor (Cp), spherical tensor (Cs), relative anisotropy (RA), axial diffusivity (AD) and radial diffusivity (RD) at the same regions: enhanced rim, peritumoral oedema and normal-appearing white matter. Correlational analyses of 546 MRS and DTI measurements used Spearman coefficient.

At the enhancing rim we found four significant correlations: FA ⇔ LL/Cr, Rs = -.364, p = .034; Cp ⇔ LL/Cr, Rs = .362, p = .035; q ⇔ LL/Cr, Rs = -.349, p = .035; RA ⇔ LL/Cr, Rs = -.357, p = .038. Another ten pairs of significant correlations were found in the peritumoral edema: AD ⇔ LL/Cr, AD ⇔ mI/Cr, MD ⇔ LL/Cr, MD ⇔ mI/Cr, p ⇔ LL/Cr, p ⇔ mI/ Cr, RD ⇔ mI/Cr, RD ⇔ mI/Cr, L ⇔ LL/Cr, L ⇔ mI/Cr.

DTI and MRS biomarkers answer different questions; peritumoral oedema represents the biggest challenge with at least ten significant correlations between DTI and MRS that need additional studies. The fact that DTI and MRS measures are not specific of one histologic type of tumour broadens their application to a wider variety of intracranial pathologies.

Adrenal vein sampling (AVS) is essential for diagnostics of primary aldosteronism, distinguishing unilateral from bilateral disease and determining treatment options. We reviewed the performance of AVS for primary aldosteronism at our center during first 15 years, comparing the initial period to the period after the introduction of a dedicated radiologist. Additionally, AVS outcomes were checked against CT findings and the proportion of operated patients with proven unilateral disease was estimated.

A retrospective cross-sectional study conducted at the national endocrine referral center included all patients with primary aldosteronism who underwent AVS after its introduction in 2004 until the end of 2018. AVS was performed sequentially during Synacthen infusion. When the ratio of cortisol concentrations from adrenal vein and inferior vena cava was at least 5, AVS was considered successful.

Data from 235 patients were examined (168 men; age 32–73, median 56 years; BMI 18–48, median 30.4 kg/ m²). Average number of annual AVS procedures increased from 7 in the 2004–2011 period to 29 in the 2012–2018 period (p < 0.001). AVS had to be repeated in 10% of procedures; it was successful in 77% of procedures and 86% of patients. The proportion of patients with successful AVS (92% in 2012–2018 vs. 66% in 2004–2011, p < 0.001) and of successful AVS procedures (82% vs. 61%, p < 0.001) was statistically significantly higher in the recent period.

Number of AVS procedures and success rate at our center increased over time. Introduction of a dedicated radiologist and technical advance expanded and improved the AVS practice.

To assess different types of adnexal masses as identified by 3T MRI and to discuss the added value of diffusion techniques compared with conventional sequences.

174 women age between 13 and 87 underwent an MRI examination of the pelvis for a period of three years. Patients were examined in two radiology departments – 135 of them on 3 Tesla MRI Siemens Verio and 39 on 3 Tesla MRI Philips Ingenia. At least one adnexal mass was diagnosed in 98 patients and they are subject to this study. Some of them were reviewed retrospectively. Data from patients’ history, physical examination and laboratory tests were reviewed as well.

124 ovarian masses in 98 females’ group of average age 47.2 years were detected. Following the MRI criteria, 59.2% of the cases were considered benign, 30.6% malignant and 10.2% borderline. Out of all masses 58.1% were classified as cystic, 12.9% as solid and 29% as mixed. Оf histologically proven tumors 74.4% were benign and 25.6% were malignant. All of the malignant tumors had restricted diffusion. 64 out of all patients underwent contrast enhancement. (34 there were a subject of contraindications). 39 (61%) of the masses showed contrast enhancement.

Classifying adnexal masses is essential for the preoperative management of the patients. 3T MRI protocols, in particular diffusion techniques, increase significantly the accuracy of the diagnostic assessment.

Asbestos exposure is associated with the development of pleural plaques as well as malignant mesothelioma (MM). Asbestos fibres activate macrophages, leading to the release of inflammatory mediators including interleukin 1 beta (IL-1β). The expression of IL-1β may be influenced by genetic variability of IL1B gene or regulatory microRNAs (miRNAs). This study investigated the effect of polymorphisms in IL1B and MIR146A genes on the risk of developing pleural plaques and MM.

In total, 394 patients with pleural plaques, 277 patients with MM, and 175 healthy control subjects were genotyped for IL1B and MIR146A polymorphisms. Logistic regression was used in statistical analysis.

We found no association between MIR146A and IL1B genotypes, and the risk of pleural plaques. MIR146A rs2910164 was significantly associated with a decreased risk of MM (OR = 0.31, 95% CI = 0.13–0.73, p = 0.008). Carriers of two polymorphic alleles had a lower risk of developing MM, even after adjustment for gender and age (OR = 0.34, 95% CI = 0.14–0.85, p = 0.020). Among patients with known asbestos exposure, carriers of at least one polymorphic IL1B rs1143623 allele also had a lower risk of MM in multivariable analysis (OR = 0.50, 95% CI = 0.28–0.92, p = 0.025). The interaction between IL1B rs1143623 and IL1B rs1071676 was significantly associated with an increased risk of MM (p = 0.050).

Our findings suggest that genetic variability of inflammatory mediator IL-1β could contribute to the risk of developing MM, but not pleural plaques.

The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were analyzed in various carcinomas and their potential prognostic significance was determined. The objective of present study was to determine the correlation between these parameters and the survival of patients with small cell lung cancer (SCLC), since very few studies have been published on this type of carcinoma.

One hundred and forty patients diagnosed with SCLC at University Hospital Center Zagreb, between 2012 and 2016 were retrospectively analyzed. Extensive-stage disease (ED) was verified in 80 patients and limited-stage disease (LD) in 60 patients. We analyzed the potential prognostic significance of various laboratory parameters, including NLR, PLR, and LMR, measured before the start of treatment.

Disease extension, response to therapy, chest irradiation and prophylactic cranial irradiation (PCI), as well as hemoglobin, monocyte count, C-reactive protein (CRP), and lactate dehydrogenase (LDH) showed a prognostic significance in all patients. When we analyzed the patients separately, depending on the disease extension, we found that only skin metastases as well as LDH and NLR values, regardless of the cut-off value, had a prognostic significance in ED. Meanwhile, the ECOG performance status, chest irradiation, PCI, and hemoglobin and creatinine values had a prognostic significance in LD.

NLR calculated before the start of the treatment had a prognostic significance for ED, while PLR and LMR had no prognostic significance in any of the analyzed groups of patients.

The aim of this project was to collect real-world evidence and describe treatment patterns for stage III non-small cell lung cancer in Central and Eastern Europe. Based on real-world evidence, an expert opinion was developed, and the unmet needs and quality indicators were identified.

A systematic literature search and a multidisciplinary expert panel of 10 physicians from 7 countries used a modified Delphi process to identify quality indicators and unmet needs in patients with stage III non-small cell lung cancer. The profound questionnaire was used to characterize treatment patterns used for stage III non-small cell lung cancer, and a systematic review identified patterns in Central and Eastern Europe. The first questionnaire was completed by a group of medical oncologists, radiation oncologists and pneumologists. The panel of experts attended an in-person meeting to review the results of the questionnaire and to process a second round Delphi. An additional survey was then compiled and completed by the panel.

A complete consensus was reached by the panel of experts on a set of evidence-based clinical recommendations. The experience-based questionnaire generated a highly variable map of treatment patterns within the region. A list of unmet needs and barriers to quality care were developed with near-unanimous consent of the panel of experts.

The current landscape of diagnostic and therapeutic approaches in Central and Eastern European countries is highly variable. We identified several significant barriers, mainly related to the availability of diagnostic and imaging methods and low rates of chemoradiotherapy with curative intention as initial treatment for unresectable stage III NSCLC.

Survival of children with cancer in Eastern and Central Europe is 10–20% lower than in high income European countries. We evaluated outcome of children and adolescents with rhabdomyosarcoma (RMS) in Slovenia, Croatia, Slovakia and in Romania.

We retrospectively analysed event-free survival (EFS) and overall survival (OS) for all patients treated in Slovenia and Croatia. Slovakia included patients from two centers, representing half of expected cases. Romania included patients from single institution, representing only 10% of expected patients. Joint database for analysis was established.

One hundred seventy-eight children and adolescent with RMS diagnosed from January 2000 to December 2015 were included. Mean patient age at diagnosis was 7.7 years, one third was older than 10 years. Twenty-five percent had alveolar histology and 72% unfavorable location. Higher than expected proportion of patients had nodal involvement (24%) or metastatic disease (27%). All patients received systemic chemotherapy, 57% had radiotherapy and 63% surgery as local control. Kaplan- Meier estimates for 5-year EFS and OS were 50.7% and 59.6%, respectively. Five-year OS for patients with localised disease was 72% compared to 24% for metastatic disease.

Children with RMS treated in Eastern and Central Europe have inferior outcome compared to their counterparts treated in high income European countries. Active participation of low health expenditures average rates (LHEAR) countries in international clinical trials may improve outcome of paediatric oncology patients.

Few studies reported early results on efficacy, toxicity of combined modality treatment for locally advanced rectal cancer (LARC) by adding bevacizumab to preoperative chemoradiotherapy, but long-term data on survival, and late complications are lacking. Further, none of the studies reported on the assessment of quality of life (QOL).

After more than 5 years of follow-up, we updated the results of our previous phase II trial in 61 patients with LARC treated with neoadjuvant capecitabine, radiotherapy and bevacizumab (CRAB study) before surgery and adjuvant chemotherapy. Secondary endpoints of updated analysis were local control (LC), disease free (DFS) and overall survival (OS), late toxicity and longitudinal health related QOL (before starting the treatment and one year after the treatment) with questionnaire EORTC QLQ-C30 and EORTC QLQ-CR38.

Median follow-up was 67 months. During the follow-up period, 16 patients (26.7%) died. The 5-year OS, DFS and LC rate were 72.2%, 70% and 92.4%. Patients with pathological positive nodes or pathological T3–4 tumors had significantly worse survival than patients with pathological negative nodes or T0–2 tumors. Nine patients (14.8%) developed grade ³3 late complications of combined modality treatment, first event 12 months and last 87 months after operation (median time 48 months). Based on EORTC QLQ-C30 scores one year after treatment there were no significant changes in global QOL and three symptoms (pain, insomnia and diarrhea), but physical and social functioning significantly decreased. Based on QLQ-CR38 scores body image scores significantly increase, problems with weight loss significantly decrease, but sexual dysfunction in men and chemotherapy side effects significantly increase.

Patients with LARC and high risk factors, such as positive pathological lymph nodes and high pathological T stage, deserve more aggressive treatment in the light of improving long-term survival results. Patients after multimodality treatment should be given greater attention to the regulation of individual aspects of quality of life and the occurrence of late side effects.

The aim of the study was to quantify planned doses to the heart and specific cardiac substructures in free-breathing adjuvant three-dimensional radiation therapy (3D-CRT) and tangential intensity modulated radiotherapy (t-IMRT) for left-sided node-negative breast cancer, and to assess the differences in planned doses to organs at risk according to patients’ individual anatomy, including breast volume.

In the study, the whole heart and cardiac substructures were delineated for 60 patients using cardiac atlas. For each patient, 3D-CRT and t-IMRT plans were generated. The prescribed dose was 42.72 Gy in 16 fractions. Patients were divided into groups with small, medium, and large clinical target volume (CTV). Calculated dose distributions were compared amongst the two techniques and the three different groups of CTV.

Mean absorbed dose to the whole heart (MWHD) (1.9 vs. 2.1 Gy, P < 0.005), left anterior descending coronary artery mean dose (8.2 vs. 8.4 Gy, P < 0.005) and left ventricle (LV) mean dose (3.0 vs. 3.2, P < 0.005) were all significantly lower with 3D-CRT technique compared to t-IMRT. Apical (8.5 vs. 9.0, P < 0.005) and anterior LV walls (5.0 vs. 5.4 Gy, P < 0.005) received the highest mean dose (D_mean). MWHD and LV-D_mean increased with increasing CTV size regardless of the technique. Low MWHD values (< 2.5 Gy) were achieved in 44 (73.3%) and 41 (68.3%) patients for 3D-CRT and t-IMRT techniques, correspondingly.

Our study confirms a considerable range of the planned doses within the heart for adjuvant 3D-CRT or t-IMRT in node-negative breast cancer. We observed differences in heart dosimetric metrics between the three groups of CTV size, regardless of the radiotherapy planning technique.

Stereotactic ablative radiotherapy (SABR) is effective for thoracic cancer and metastases; however, adverse effects are greater for central tumors. We evaluated factors affecting outcomes and toxicities after SABR for patients with primary lung and oligometastatic tumors.

We retrospectively identified consecutive patients with centrally located lung tumors that were treated at our hospital from 2009-2016. The effects of patient, disease, and treatment-related parameters on local control (LC), overall survival (OS), and toxicity-free survival (TFS) were evaluated with multivariate analyses.

Among 65 consecutive patients identified with 70 centrally located tumors, 20 tumors (28%) were reirradiated. Median (range) total dose for all tumors was 55 (30–60) Gy in 5 (3–10) fractions. Radiographic complete response was obtained in 43 lesions (61%). None of the analyzed factors were correlated with complete response. After a median follow-up of 57 (95% CI, 48–65) months, 10 tumors (14%) relapsed and 37 patients (57%) died; the actuarial 2- and 5-year OS rates were 52% and 28%, respectively. Median OS was significantly lower in patients with grade 3 or higher toxicity vs. lower toxicity (5 vs. 39 months; P < 0.001). Among 17 severe toxicities, 5 were grade 5, and 3 of them were reirradiated to the same field. Grade 3 to 5 TFS was lower with vs. without reirradiation (2-year TFS, 63% vs. 96%; P = 0.02).

Our study showed that modern SABR is effective for central lung tumors, and toxicities are acceptable. SABR for reirradiated central lung lesions and possibly for lesions abutting the tracheobronchial tree may result in higher risk of serious toxicities.

The aim of our study was to evaluate the quality of surgery of Slovenian breast cancer screening program (DORA) using the requested EU standards. Furthermore, we investigated whether regular quality control over the 3-year period improved the quality of surgical management.

Patients who required surgical management within DORA between January 1st, 2016 and December 31st, 2018 were included in the retrospective study. Quality indicators (QIs) were adjusted mainly according to European Society of Breast Cancer Specialists (EUSOMA) and European Breast Cancer Network (EBCN) recommendations. Five QIs for therapeutic and two for diagnostic surgeries were selected. Additionally, variability in achieving the requested QIs among surgeons was analysed.

Between 2016 and 2018, 14 surgeons performed 1421 breast procedures in 1398 women. There were 1197 therapeutical (for proven breast cancer) and 224 diagnostic surgical interventions respectively. Overall, the minimal standard was met in two QIs for therapeutic and none for diagnostic procedures. A statistically significant improvement in three QIs for therapeutic and in one QI for diagnostic procedures was observed however, indicating that regular quality control improves the quality of surgery. A high variability in achieving the requested QIs was observed among surgeons, which remained high throughout the study period.

Adherence to all selected surgical QIs in patients from screening program is difficult to achieve, especially to those specifically defined for screen-detected lesions. Regular quality control may improve results over time. Reducing the number of surgeons dedicated to breast pathology may reduce variability of management inside the institution.

Advanced, Monte Carlo (MC) based dose calculation algorithms, determine absorbed dose as dose to medium-in-medium (D_m,m) or dose to water-in-medium (D_w,m). Some earlier studies identified the differences in the absorbed doses related to the calculation mode, especially in the bone density equivalent (BDE) media. Since the calculation algorithms built in the treatment planning systems (TPS) should be dosimetrically verified before their use, we analyzed dose differences between two calculation modes for the Elekta Monaco TPS. We compared them with experimentally determined values, aiming to define a supplement to the existing TPS verification methodology.

In our study, we used a 6 MV photon beam from a linear accelerator. To evaluate the accuracy of the TPS calculation approaches, measurements with a Farmer type chamber in a semi-anthropomorphic phantom were compared to those obtained by two calculation options. The comparison was made for three parts of the phantom having different densities, with a focus on the BDE part.

Measured and calculated doses were in agreement for water and lung equivalent density materials, regardless of the calculation mode. However, in the BDE part of the phantom, mean dose differences between the calculation options ranged from 5.7 to 8.3%, depending on the method used. In the BDE part of the phantom, neither of the two calculation options were consistent with experimentally determined absorbed doses.

Based on our findings, we proposed a supplement to the current methodology for the verification of commercial MC based TPS by performing additional measurements in BDE material.

The purpose of the study was to compare the results of gamma value based film analysis according to the used type of self-developer film and software product.

The films were irradiated with different treatment techniques such as 3D conformal and intensity modulated radiotherapy with static and rotational delivery. Stereotactic plans with conformal and intensity modulated arc techniques, using coplanar and non-coplanar beam setup were also evaluated. The data of irradiated film were compared with the planned planar dose distribution exported from the treatment planning system. Three film analysis software programs were evaluated: PTW Mephysto (PTW), FilmQA Pro (FQP) and radiohromic.com(RC). Both EBT2 and EBT3 types of films were examined. The comparisons of dose distributions were performed with gamma analysis using 10% cut-off level.

The results of the gamma analysis for larger fields were between 78.3% and 98.3%, 75.7% and 100%, 80.2% and 98.8% with PTW, FQP and RC, respectively. The results of evaluation in case of stereotactic measurements were 76.8%–99.2% for PTW, 95.7%–100% for FQP and 91.2%–99.9% for RC.

All the three software programs are suitable for calibrating and evaluating films, performing gamma analysis, and can be used for patient specific quality assurance measurements. There is no direct connection between gamma passing rate and absolute accuracy or software quality, it is just a feature of the software. The interpretation of own results has to be defined on an institutional level according to given workflow and preliminary results.