Justyna Chalubinska-Fendler

Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer

BackgroundRisk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities—such as radiation pneumonitis—during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors.MethodsWe performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines.ResultsmiRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation.ConclusionsmiR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity.

Does obesity hinder radiotherapy in endometrial cancer patients? The implementation of new techniques in adjuvant radiotherapy – focus on obese patients

The increasing incidence of obesity in Poland and its relation to endometrioid endometrial cancer (EEC) is resulting in the increasing necessity of treating obese women. Treatment of an overweight patient with EEC may impede not only the surgical procedures but also radiotherapy, especially external beam radiotherapy (EBRT). The problems arise both during treatment planning and when delivering each fraction due to the difficulty of positioning such a patient – it implies the danger of underdosing targets and overdosing organs at risk. Willingness to use dynamic techniques in radiation oncology has increased for patients with EEC, even those who are obese. During EBRT careful daily verification is necessary for both safety and treatment accuracy. The most accurate method of verification is cone beam computed tomography (CBCT) with soft tissue assessment, although it is time consuming and often requires a radiation oncologist. In order to improve the quality of such treatment, the authors present the practical aspects of planning and treatment itself by means of dynamic techniques in EBRT. The authors indicate the advantages and disadvantages of different types of on-board imaging (OBI) verification images. Considering the scanty amount of literature in this field, it is necessary to conduct further research in order to highlight proper planning and treatment of obese endometrial cancer patients. The review of the literature shows that all centres that wish to use EBRT for gynaecological tumours should develop their own protocols on qualification, planning the treatment and methods of verifying the patients’ positioning.

Preoperative radiotherapy and local excision of rectal cancer: Long-term results of a randomised study

BACKGROUND AND PURPOSE It is uncertain whether local control is acceptable after preoperative radiotherapy and local excision (LE). An optimal preoperative dose/fractionation schedule has not yet been established. MATERIAL AND METHODS In a phase III study, patients with cT1-2N0M0 or borderline cT2/T3N0M0 < 4 cm rectal adenocarcinomas were randomised to receive either 5 × 5 Gy plus 1 × 4 Gy boost or chemoradiation: 50.4 Gy in 28 fractions plus 3 × 1.8 Gy boost and 5-fluorouracil with leucovorin bolus. LE was performed 6-8 weeks later. Patients with ypT0-1R0 disease were observed. Completion total mesorectal excision (CTME) was recommended for poor responders, i.e. ypT1R1/ypT2-3. RESULTS Of 61 randomised patients, 10 were excluded leaving 51 for analysis; 29 in the short-course group and 22 in the chemoradiation group. YpT0-1R0 was observed in 66% of patients in the short-course group and in 86% in the chemoradiation group, p = 0.11. CTME was performed only in 46% of patients with ypT1R1/ypT2-3. The median follow-up was 8.7 years. Local recurrence incidences and overall survival at 10 years were respectively for the short-course group vs. the chemoradiation group 35% vs. 5%, p = 0.036 and 47% vs. 86%, p = 0.009. In total, local recurrence at 10 years was 79% for ypT1R1/T2-3 without CTME. CONCLUSIONS This trial suggests that in the LE setting, both local recurrence and survival are worse after short-course radiotherapy than after chemoradiation. Because of the risk of bias, a confirmatory study is desirable. Lack of CTME is associated with an unacceptably high local recurrence rate.

Expression of Vascular Endothelial Growth Factor (VEGF) and its Correlation with Clinical Symptoms and Endoscopic Findings in Patients with Chronic Radiation Proctitis

The aim of this study was to assess the expression of vascular endothelial growth factor (VEGF) as a key proangiogenic factor and determine whether there is any correlation between its expression and clinical symptoms or endoscopic changes in patients with chronic radiation proctitis (ChRP).

Determinants of quality of life in patients with breast cancer undergoing external beam radiotherapy.

Quality of life (QoL) of patients with breast cancer is not dependent only on the presence of the disease, as there is such a multitude of social and clinical factors [1, 2]. However, data on the determinants of QoL in Polish breast cancer patients during the course of radiotherapy are scarce and based on custom-made questionnaires [3], rather than the EORTC QLQ-C30 or QLQ-BR23, which are the tools of choice for such patients [4, 5]. We evaluated breast cancer patients undergoing radiotherapy for treatment-related determinants of QoL and compared them with the intensity of depressive symptoms. A total of 98 women with breast cancer during the standard course of external beam radiotherapy agreed to complete the validated Polish versions 3.0 of EORTC QLQ-C30, QLQ-BR23 (all global, functional and symptom scales) and – at the same time point – the Beck Depression Inventory (BDI) to evaluate the intensity of depressive symptoms. A control group of 127 healthy women referred to the mammography department for screening purposes was evaluated using the BDI. Median age of the study group was 54 (25–75%: 46.7–60.5) years. Breast conserving therapy (BCT) had been performed in 50% of patients. In the breast cancer group, 65% of subjects had undergone some form of chemotherapy and 51% were undergoing hormone therapy. Cronbachs α values for QLQ-C30, QLQ-BR23 and BDI were 0.91, 0.81 and 0.83 respectively, confirming adequate test performance. Median total radiation dose given to the patients was 34 Gy (25–75%: 18–42 Gy), and only affected intensity of nausea/vomiting and constipation subscales (R = 0.25, p = 0.04; R = 0.27, p = 0.03 respectively) of the QLQ-C30 functional scales. No statistically significant correlations were found between the total dose and QLQ-BR23 scales, but the early reactions (RTOG staged ≥ 2 [6]) significantly worsened arm symptom subscale score assessment in QLQ-BR23. Hormonal therapy was not significantly correlated with any of those three questionnaires’ subscores. Previously received chemotherapy impacted neither QLQ-C30 nor BDI results, but it was associated with body image (BRBI) and systemic therapy side effect scores (BRST) (p = 0.02 and p = 0.005). Type of surgical intervention before radiotherapy impacted the field of global health status, resulting in better overall QoL in patients who had undergone BCT (58% (25–75%: 50–67) vs. 50% (25–75%: 42–58); p = 0.0405). BCT was also associated with lower reported intensity of breast symptoms (p = 0.0338) and better perception of future perspectives (BRFU; p = 0.0328). The level of depressive symptoms measured in controls was significantly lower than in cancer patients (median 5 (25–75%: 1–10) vs. 12 (25–75%: 6–17) points; p < 0.0001). BDI scores were correlated negatively and significantly with all functional scales of QLQ-C30 (Spearmans correlation coefficients ranging from –0.36 to –0.46, all p < 0.05) and QLQ-BR23 subscales: BRBI and BRFU (R = –0.47 and –0.51; p < 0.05). In conclusion, radiotherapy itself has a minor influence on QoL of breast cancer patients, although organ-specific complications may significantly impair physical functioning. Other forms of oncological treatment, such as the type of surgical procedure performed, have a much more profound impact on all fields of QoL. Intensity of depressive symptoms is an important determinant of QoL in cancer patients which mandates routine psychological evaluation.

Central nervous system metastases from epithelial ovarian cancer

The aim of the study was to assess the clinical features and prognosis in patients with epithelial ovarian cancer (EOC) metastasised to the central nervous system (CNS). A total of 15 patients were studied retrospectively. Clinical and pathological data and follow-up were analysed. It was found that at the diagnosis of primary EOC, the patients were 41–69 years old (56.6 ± 8.3). The interval from diagnosis of primary EOC until the relapse was 2–39 months (19.1 ± 10.5). Palliative radiotherapy was the treatment of the CNS relapse in 13 patients (86.7%). The follow-up after CNS relapse varied 0.5–15 months (4.7 ± 4.2). At the time of retrospective analysis, none of the patients were still alive. Multifocality of the CNS metastases, the presence of synchronous extracranial metastases and locations in the brain were not associated with survival. It was concluded that the development of the CNS metastases seems to be not uncommon in patients with advanced ovarian cancer. Despite oncological treatment, they are indicators of poor prognosis, and most of the patients do not survive beyond the first year of follow-up.

Potential of serum microRNAs as biomarkers of radiation injury and tools for individualization of radiotherapy

Abstract Due to tremendous technological advances, radiation oncologists are now capable of personalized treatment plans and deliver the dose in a highly precise manner. However, a crucial challenge is how to escalate radiation doses to cancer cells while reducing damage to surrounding healthy tissues. This determines the probability of achieving therapeutic success whilst safeguarding patients from complications. The current dose constraints rely on observational data. Therefore, incidental toxicity observed in a minority of patients limits the admissible dose thresholds for the whole population, theoretically narrowing down the curative potential of radiotherapy. Future tools for measurements of individuals radiosensitivity before and during treatment would allow proper treatment personalization. Variation in tissue tolerance is at least partially genetically‐determined and recent progress in the field of molecular biology raises the possibility that novel assays will allow to predict the response to ionizing radiation. Recently, microRNAs have garnered interest as stable biomarkers of tumor radiation response and normal‐tissue toxicity. Preclinical studies in mice and nonhuman primates have shown that serum circulating microRNAs can be used to accurately distinguish pre‐ and postirradiation states and predict the biological impact of high‐dose irradiation. First reports from human studies are also encouraging, however biology‐driven precision radiation oncology, which tailors treatment to individual patients needs, still remains to be translated into clinical studies. In this review, we summarize current knowledge about the potential of serum microRNAs as biodosimeters and biomarkers for radiation injury to lung and hematopoietic cells.

Variation in treatment and survival of older patients with non-metastatic breast cancer in five European countries: a population-based cohort study from the EURECCA Breast Cancer Group

BackgroundOlder patients are poorly represented in breast cancer research and guidelines do not provide evidence based recommendations for this specific group. We compared treatment strategies and survival outcomes between European countries and assessed whether variance in treatment patterns may be associated with variation in survival.MethodsPopulation-based study including patients aged ≥ 70 with non-metastatic BC from cancer registries from the Netherlands, Belgium, Ireland, England and Greater Poland. Proportions of local and systemic treatments, five-year relative survival and relative excess risks (RER) between countries were calculated.ResultsIn total, 236,015 patients were included. The proportion of stage I BC receiving endocrine therapy ranged from 19.6% (Netherlands) to 84.6% (Belgium). The proportion of stage III BC receiving no breast surgery varied between 22.0% (Belgium) and 50.8% (Ireland). For stage I BC, relative survival was lower in England compared with Belgium (RER 2.96, 95%CI 1.30–6.72, P < .001). For stage III BC, England, Ireland and Greater Poland showed significantly worse relative survival compared with Belgium.ConclusionsThere is substantial variation in treatment strategies and survival outcomes in elderly with BC in Europe. For early-stage BC, we observed large variation in endocrine therapy but no variation in relative survival, suggesting potential overtreatment. For advanced BC, we observed higher survival in countries with lower proportions of omission of surgery, suggesting potential undertreatment.

Successful combination treatment of a bifocal secretory germinoma with brain stem compression in a 17-year-old girl

A 17-year-old girl, evaluated since 2007 for endocrinological disorders due to secondary amenorrhea and weight loss, was referred to the neurosurgery department in May 2011 due to symptoms of rapidly increasing intracranial pressure. Computed tomography revealed a bifocal, irregular, non-homogeneous tumour localised in pineal and suprasellar regions (Figures 1 A, B). Immediate septostomy, ventriculo-peritoneal valve implantation and suprasellar tumour biopsy were performed. Histopathological examination confirmed the tumour to be a secretory type germinoma (β-HCG = 0.696 mIU/ml; AFP = 79.89 µg/ml in serum). After surgical biopsy (Figure 1 C) the chemotherapy was introduced according to the GCT SIOP96 protocol – which is the standard protocol for children in Poland with this diagnosis. The control magnetic resonance imaging (MRI) confirmed total regression of the suprasellar tumour and a residual pineal mass (Figure 1 D). At the end of July 2011 the patient was transferred to the Radiotherapy Department for treatment planning. Radiation therapy was initiated using both static and dynamic fields, including 3 target volumes (Figure 1 E): brain ventricles (blue) irradiated up to 30.6 Gy, PTV2 (cyan) – both tumour loci – up to 45.0 Gy with dose escalation on the pineal tumour residue up to 52.2 Gy (turquoise). Currently the patient is in 3.5-year follow-up (Figure 1 F) in a good clinical condition, presenting only minor left-sided convergent strabismus, slight deafness for high frequency sounds and requires hormonal supplementation. The last MRI revealed only a residual mass in the pineal region 10 × 7 × 12 mm and a “flat” pituitary gland as deviations from the normal condition. Figure 1 A, B – Transverse and sagittal computed tomography scans before initiation of treatment of pineal (38 × 30 × 30 mm) and suprasellar regions (25 × 20 × 20 mm), C – MRI scan after the surgical procedure, ... Intracranial germ cell tumours (GCTs) account for 1–2% of all primary paediatric central nervous system (CNS) tumours and have a peak incidence at between 10 and 14 years with a male-female ratio of 2 : 1 [1]. Although multiple loci at presentation are associated with poorer prognosis [2], in this relatively unusual case, despite dramatic onset of symptoms, the treatment has proven successful thus far. Up to 20% of intracranial GCTs are multifocal, and they usually involve the suprasellar and pineal gland region. This is typically observed in adolescent males rather than females. Pineal GCTs induce acute symptoms of intracranial pressure which may be manifested by the classic triad of chronic symptoms: diabetes insipidus, visual deficits and precocious or delayed sexual maturity [3]. Evaluation must include MRI of the brain and serum marker levels (AFP, β-HCG) should be obtained. Biopsy sampling is recommended in all cases nowadays. Surgical treatment of intracranial GCTs remains controversial. Limited volume radiation therapy (whole ventricle followed by boost for residual tumour) is an important part of treatment preceded by chemotherapy according to currently used protocols. Endocrinopathies are a common complication of treating brain GCTs [4]. If pituitary gland insufficiency persists, it may however be easily corrected by hormonal treatment. The potential late sequelae due to chemotherapy and radiotherapy do not generally impair future mental and social development in adolescents, which gives a chance for a good quality of life in the future for these patients [5]. However, in younger patients, persistent neurological deficiencies resulting from surgical and radiotherapeutic complications may be a serious issue [4, 5].

Availability and outcomes of radiotherapy in Central Poland during the 2005-2012 period - an observational study

BackgroundUsing a cross-database integrative approach, we performed an epidemiological analysis in a representative region of central Poland to evaluate the availability of radiotherapy (RTx) and overall survival of adult patients undergoing RTx for cancer.MethodsEpidemiological data on cancer incidence in the 2005–2012 period were obtained from the Nationwide Cancer Registry. Using data from the Ministry of Internal Affairs, we collected survival information of all patients treated in the only centre providing RTx for a region inhabited by approximately 2.6 million people.ResultsAfter filtering out individuals on the basis of exclusion criteria, the final dataset covered 17,736 patients. Availability of RTx increased marginally, from 23.5% (2005) to 24.4% (2011, R = 0.39, p = 0.38), with the highest values noted in patients with cervical (78.5%), prostate (70.6%) and breast cancer (62.7%). However, due to the decreasing population of the region, we noted increasing disparity in the likelihood of receiving RTx depending on the patient’s area of residence, with rural areas becoming progressively more neglected. The best prognosis was noted among patients with breast or prostate cancer with 5-year OS rates reaching 81.2% and 83.3%, respectively. Multivariate analysis controlling for type of diagnosis and patient age showed a time-dependent improvement in outcomes (HR(95% CI): 0.96(0.94-0.98); p < 0.0001).ConclusionsAvailability of RTx in Poland is still below that reported by developed European centres. Survival of patients undergoing radical RTx has gradually improved, although it is still below that of leading RTx departments, potentially due to delayed diagnosis or organisational barriers, necessitating further investigations.