Trends in opioid utilization in Hungary, 2006-2020: A nationwide retrospective study with multiple metrics.

BACKGROUND: Opioid use is well documented in several countries: some countries struggle with overuse, whereas others have almost no access to opioids. For Europe, limited data are available. This study analysed Hungarian opioid utilization in ambulatory care between 2006 and 2020. METHODS: We obtained national drug utilization data on reimbursed opioid analgesics (ATC code: N02A) from a national health insurance database for a 15-year period. We investigated utilization trends, using three volume-based metrics [defined daily dose per 1000 inhabitants per day (DID), oral morphine equivalent per 1000 inhabitants per day, packages dispensed per 1000 inhabitants per year]. We stratified data based on administration routes, analgesic potency and reimbursement categories. RESULTS: Total opioid utilization increased during the study period according to all three metrics (74% in DID) and reached 5.31 DID by 2020. Upward trends were driven by an increase both in weak and strong opioid use (79% vs. 53%). The most commonly used opioids were fentanyl (in the strong category; 0.76 DID in 2020) and tramadol (in the weak category; 2.62 DID in 2020). Overall, tramadol was also the most commonly used opioid throughout the study period. Oral administration of opioid medications was dominant. Based on reimbursement categories, musculoskeletal pain was becoming a more frequent indication for opioid use (1552% increase in DID), while opioid use for cancer pain declined significantly during the study period (-33% in DID). CONCLUSIONS: Our low utilization numbers might indicate underuse of opioid analgesia, especially for cancer pain. SIGNIFICANCE: This study was one of the recent opioid utilization studies using three volume-based metrics, covering a long time period. To our knowledge, this was also the first national, population level study describing opioid utilization in Hungary. National opioid utilization data suggested not an overuse but rather an underuse of opioid analgesics in a developed, Central European country.

Clinical benefit of fulvestrant monotherapy in the multimodal treatment of hormone receptor and HER2 positive advanced breast cancer: a case series.

Fulvestrant is a pure estrogen receptor (ER) antagonist approved for the treatment of metastatic ER positive breast cancer in postmenopausal women with disease progression following antiestrogen therapy. The clinical results of fulvestrant demonstrated encouraging activity in tumors in spite of HER2 positivity, but data about its use after progression on anti-HER2 agents are limited. Partial responses and durations of response of 12, 25, and 38 months in three cases with multiple metastases of ER positive and HER2 positive breast cancer were observed; all patients had been treated with 1-4 regimens of an anti-HER2 agent in combination with chemotherapy or an aromatase inhibitor before the initiation of fulvestrant. Fulvestrant is a valuable option with limited toxicity and durable response in metastatic HER2 and ER positive breast cancer after progression on anti-HER2 agents as well. Therapeutic benefit even in extensive skin metastases and (irradiated) brain metastases may be expected. Further investigations are warranted to establish where it fits into the multimodal management of ER and HER positive breast cancer.

[Role of 18FDG-PET/CT in the management and gross tumor volume definition for radiotherapy of head and neck cancer; single institution experiences based on long-term follow-up]. / 18FDG-PET/CT szerepe fej-nyak daganatok kezelésében és a sugárterápiás tumortérfogat meghatározásában - Az SZTE Onkoterápiás Klinika eredményeinek értékelése.

The purpose of our work is evaluation of the impact of 18FDG-PET/CT on the complex management of locoregionally advanced (T3-4N1-3) head and neck squamous cell cancer (LAHNSC), and on the target definition for 3D conformal (3DCRT) and intensity-modulated radiotherapy (IMRT). 18FDG-PET/CT were performed on 185 patients with LAHNSC prior to radiotherapy/chemoradiation in the treatment position between 2006 and 2011. Prior to it 91 patients received induction chemotherapy (in 20 cases of these, baseline PET/CT was also available). The independently delineated CT-based gross tumor volume (GTVct) and PET/CT based ones (GTVpet) were compared. Impact of PET/CT on the treatment strategy, on tumor response evaluation to ICT, on GTV definition furthermore on overall and disease-specific survival (OS, DSS) was analysed. PET/CT revealed 10 head and neck, 2 lung cancers for 15 patients with carcinoma of unknown primary (CUP) while 3 remained unknown. Second tumors were detected in 8 (4.4%), distant metastasis in 15 (8.2%) cases. The difference between GTVct and GTVpet was significant (p=0.001). In 16 patients (14%) the GTVpet were larger than GTVct due to multifocal manifestations in the laryngo-pharyngeal regions (4 cases) or lymph node metastases (12 cases). In the majority of the cases (82 pts, 72%) PET/CT-based conturing resulted in remarkable decrease in the volume (15-20%: 4 cases, 20-50%: 46 cases, >50%: 32 cases). On the basis of the initial and post-ICT PET/CT comparison in 15/20 patients more than 50% volume reduction and in 6/20 cases complete response were achieved. After an average of 6.4 years of follow-up the OS (median: 18.3±2.6 months) and DSS (median: 25.0±4.0 months) exhibited close correlation (p=0.0001) to the GTVpet. In cases with GTVpet <10 cm3 prior to RT, DSS did not reach the median, the mean is 82.1±6.1 months, while in cases with GTVpet 10-40 cm3 the median of the DSS was 28.8±4.9 months (HR = 3.57; 95% CI: 1.5-8.3), and in those with GTVpet >40 cm3 the median DSS was 8.4±0.96 months (HR= 11.48; 95% CI: 5.3-24.9). Our results suggest that 18FDG-PET/CT plays an important role for patient with LAHNSC, by modifying the treatment concept and improving the target definition for selective RT modalities. Volumetric PET/CT-based assessment of the tumor response after ICT gives valuable contribution to further therapy planning.

Radiation dose to the nodal regions during prone versus supine breast irradiation.

BACKGROUND: Prone positioning for breast radiotherapy is preferable when the aim is a reduction of the dose to the ipsilateral lung or the heart in certain left-sided cases. MATERIALS AND METHODS: In 100 breast cancer cases awaiting postoperative whole-breast radiotherapy, conformal radiotherapy plans were prospectively generated in both prone and supine positions. The axillary nodal region (levels I-III) and internal mammary (IM) lymph-node region in the upper three intercostal spaces were retrospectively contoured. The mean doses to the nodal regions and the volume receiving 25 Gy (V25Gy), V45Gy, and V47.5Gy were compared between the two treatment positions. RESULTS: In most cases, the doses to axillary levels I-III and the IM lymph nodes were inadequate, regardless of the treatment position. The nodal doses were significantly lower in the prone than in the supine position. The radiation doses to levels II-III and IM nodes were especially low. The V45Gy and V47.5Gy of the level I axillary lymph nodes were 54.6% and 40.2%, respectively, in the supine, and 3.0% and 1.7%, respectively, in the prone position. In the supine position, only 17 patients (17%) received a mean dose of 45 Gy to the axillary level I nodes. CONCLUSION: The radiation dose to the axillary and IM lymph nodes during breast radiotherapy is therapeutically insufficient in most cases, and is significantly lower in the prone position than in the supine position.

Tumour topoisomerase II alpha protein expression and outcome after adjuvant dose-dense anthracycline-based chemotherapy.

There is a need for the selection of those breast cancers where benefit may be attained from the addition of an anthracycline to the adjuvant chemotherapy. The expression of topoisomerase II alpha (TOP2A) protein in 3 cohorts of breast cancers treated with adjuvant dose-dense anthracycline-based chemotherapy was determined retrospectively. The TOP2A status was analysed in relation with the other standard tumour features and the outcome. TOP2A IHC results were assessable in 106 patients: with a cut-off value of 15%, 48% of the tumours were classified as TOP2A-positive. The expression of TOP2A correlated with that of Ki67 (R = 0.532, p < 0.001) and a high grade (p = 0.04), but did not correlate with the proportion of ER- or PR-positive cells in the tumour. More tumors were TOP2A-negative among the ER- or PR-positive cancers than among the ER/PR-negative cancers (p = 0.021 and p = 0.002, respectively). After a median follow-up time of 64.5 months, 31 relapses (23.5%) and 23 deaths (17.4%) had occurred in 131 patients. The overall survival was longer in the TOP2A-positive cases than in the TOP2A-negative cases. The recurrence-free survival and the overall survival were significantly more favourable in the ER/PR-negative and TOP2A-positive tumours than in other subgroups. In a Cox proportional hazards model, the grade and TOP2A remained significant determinants in the ER/PR-negative subgroup. TOP2A positivity and grade 3 indicated a decrease in the risk of death with HR = 0.211 (95% CI: 0.042-1.05, p = 0.056) and HR = 0.216 (95% CI: 0.047-0.990, p = 0.048), respectively. A higher sensitivity to anthracycline-containing regimens is suggested in ER/PR-negative and TOP2A-positive cancers.

[Approaches to individual radiotherapy in breast cancer: individual risk estimation and individualized techniques]. / Törekvés a sugárterápia individualizálására emlorákban: egyéni rizikóbecslés és egyénileg alkalmazott technikák.

INTRODUCTION: Radiotherapy comprises an integral part of the curative therapy of breast cancer by improving the locoregional control and survival when given on an individualized basis. Conformal radiotherapy and three-dimensional radiation treatment planning enhance the safety of radiotherapy by adjusting the irradiated volume to the shape of the target volume, and providing control of the radiation dose to the organs at risk (OARs). PATIENTS AND METHODS: The methods introduced at the authors' institute in 2002 are demonstrated. The breast/chest wall and lymph node areas were irradiated provided that there was a minimum risk of local or locoregional relapse of 10%. CT-based 3D radiotherapy treatment planning and individual patient-positioning were applied, with thermoplastic mask-fixation in the second part of the study. The dose constraints of the OARs were given in accordance with the literature recommendations. In the first group of patients, individually shaped blocks, in the second group, multileaf collimator, and in the third group, with the aim of a more homogenous dose-distribution in the target volume, intensity-modulated beams were applied. RESULTS: During the study, 737 breast cancer patients received conformal radiotherapy based on individual risk estimation. In 372 cases only local, while in 365 cases locoregional radiotherapy was delivered. The dose-homogeneity in the target volume was significantly improved in the second period of the study, when segments were superposed on the radiotherapy fields. The proportions of the target volumes irradiated with +/-10% of the planned dose in the breast/chest wall, axillary and supraclavicular lymph nodes and internal mammary lymph nodes varied between 90.5-94.2%, 84.1-93.8% and 86.7-91.6%, respectively, depending on the radiation technique used. The parameters indicating the dose to the ipsilateral lung or to the heart were significantly higher when locoregional radiotherapy was applied compared to that in case of local radiotherapy. Radiation dose to the ipsilateral lung and the heart was significantly reduced in the second part of the study when locoregional, but not when local radiotherapy was delivered. The introduction of individual immobilization by means of thermoplastic mask-fixation resulted in a relevant decrease in the uncertainty due to breathing motion and daily positioning errors, and also in a significant reduction of the dose to the contralateral breast. CONCLUSIONS: Adjuvant radiotherapy should be based on individual risk-benefit features. The need of the introduction of special techniques may be decided after the dose-volume analysis of the conformal radiotherapy plan based on 3D radiation treatment planning.

The risk of early and late lung sequelae after conformal radiotherapy in breast cancer patients.

PURPOSE: To study the risks of early and late radiogenic lung damage in breast cancer patients after conformal radiotherapy. METHODS AND MATERIALS: Radiogenic lung sequelae were assessed prospectively in 119 patients by means of clinical signs, radiologic abnormalities, and the mean density change (MDC) of the irradiated lung on CT. RESULTS: Significant positive associations were detected between the development of lung abnormalities 3 months or 1 year after the radiotherapy and the age of the patient, the ipsilateral mean lung dose (MLD), the radiation dose to 25% of the ipsilateral lung (D(25%)) and the volume of the ipsilateral lung receiving 20 Gy (V(20 Gy)). The irradiation of the axillary and supraclavicular lymph nodes favored the development of pneumonitis but not that of fibrosis. No relation was found between the preradiotherapy plasma TGF-beta level and the presence of radiogenic lung damage. At both time points, MDC was strongly related to age. Significant positive associations were demonstrated between the risks of pneumonitis or fibrosis and the age of the patient, MLD, D(25%), and V(20 Gy). A synergistic effect of MLD, D(25%), and V(20 Gy) with age in patients older than 59 years is suggested. CONCLUSION: Our analyses indicate that the risks of early and late radiogenic lung sequelae are strongly related to the age of the patient, the volume of the irradiated lung, and the dose to it.