Dose coverage impacts local control in ultra-central lung oligometastases treated with stereotactic radiotherapy.

INTRODUCTION: The use of Stereotactic Body Radiotherapy (SBRT) is controversial in Ultra-Central lung tumors, a subset of central lung tumors characterized by proximity to critical mediastinal structures. This is of interest in oligometastatic (≤3 metastases) patients, who can yield survival benefit from local treatments. The aim of our study is to assess the determinants of efficacy and toxicity in this setting. MATERIALS AND METHODS: Clinical and dosimetric parameters were reviewed in a cohort of oligometastatic patients treated with SBRT for ultra-central tumors. Local control rate (LC) and toxicity were assessed. Statistical Analysis was carried out to assess the impact of those predictors on local recurrence and adverse events. RESULTS: One-hundred-nine consecutive patients were included. A median Biologic Effective Dose (BED) of 105 (75-132) Gy10 was prescribed. At a median follow-up of 17 (range 3-78) months, 2-year LC was 87%. Improved LC was correlated to Planning Treatment Volume (PTV) covered by 95% of the prescription dose (V95% PTV) > 85% (HR 0.15, 95%CI 0.05-0.49, p = 0.0017) and to Gross Tumor Volume (GTV) < 90 cm3 (HR 0.2, 95%CI 0.07-0.56, p = 0.0021). Overall and grade ≥ 3 toxicity incidence was 20% and 5%, respectively. Patients experiencing acute and late toxicities received significantly higher dose to 1 cm3 (D1cm3) of esophagus and lung volume receiving ≥5 Gy (V5Gy) (p = 0.016 and p = 0.013), and higher dose to 0.1 cm3 (D0.1cm3) of heart (p = 0.036), respectively. CONCLUSION: V95% PTV > 85% and GTV < 90 cm3 are independent predictors of LC. Dose to esophagus, lung and heart should be carefully assessed to minimize treatment-related toxicities.

Soft tissue sarcomas: new opportunity of treatment with PARP inhibitors?

BACKGROUND: Poly(ADP-ribose) polymerases (PARP) are a large family of enzymes involved in several cellular processes, including DNA single-strand break repair via the base-excision repair pathway. PARP inhibitors exert antitumor activity by both catalytic PARP inhibition and PARP-DNA trapping, moreover PARP inhibition represents a potential synthetic lethal approach against cancers with specific DNA-repair defects. Soft tissue sarcoma (STSs) are a heterogeneous group of mesenchymal tumors with locally destructive growth, high risk of recurrence and distant metastasis. OBJECTIVES: The purpuse of this review is to provide an overview of the main preclinical and clinical data on use of PARPi in STSs and of effect and safety of combination of PARPi with irradiation. RESULTS: Due to numerous genomic alterations in STSs, the DNA damage response pathway can offer an interesting target for biologic therapy. Preclinical and clinical studies showed promising results, with the most robust evidences of PARPi efficacy obtained on Ewing sarcoma bearing EWS-FLI1 or EWS-ERG genomic fusions. The activity of PARP inhibitors resulted potentiated by chemotherapy and radiation. Although mechanisms of synergisms are not completely known, combination of radiation therapy and PARP inhibitors exerts antitumor effect by accumulation of unrepaired DNA damage, arrest in G2/M, activity both on oxic and hypoxic cells, reoxygenation by effect on vessels and promotion of senescence. Early trials have shown a good tolerance profile. CONCLUSIONS: The use of PARP inhibitors in advanced stage STSs, alone or combined in multimodal treatments, is of great interest and warrants further investigations.

hERG1 channel expression associates with molecular subtypes and prognosis in breast cancer.

BACKGROUND: Breast cancer (BC) is the most frequent malignancy among females worldwide. Despite several efforts and improvements in early diagnosis and treatment, there are still tumors characterized by an aggressive behavior due to unfavorable biology, thus quite difficult to treat. In this view, searching for novel potential biomarkers is mandatory. Among them, in the recent years data have been gathered addressing ion channel as important players in oncology. METHODS: A retrospective pilot study was performed on 40 BC samples by means of immunohistochemistry in order to evaluate hERG1 potassium channels expression in BC. RESULTS: We provide evidence that hERG1 is expressed in all the BC samples analyzed. hERG1 expression was significantly associated with molecular subtype with the highest expression in Luminal A and the lowest in basal-like tumors (p = 0.001), tumor grading (the highest hERG1 expression in well-moderate differentiated tumors, p = 0.020), estrogen receptors (high hERG1 expression in ER-positive samples, p = 0.008) and Ki67 proliferative index (high hERG1 scoring in samples with low proliferative index, p = 0.038). Also, a p value close to significance was noticed for the association between hERG1 and HER2 expression (p = 0.079). At the survival analysis, patients with high hERG1 expression turned out to have a longer progression-free survival, although statistical significance was not reached (p = 0.195). The same trend was observed analyzing local relapse free-survival (LRFS) and metastases-free survival (MFS): patients with higher hERG1 scoring had longer LRFS and MFS (p = 0.124 and p = 0.071, respectively). CONCLUSIONS: The results of this pilot study provide the first evidence that the hERG1 protein is expressed in primary BC, and its expression associates with molecular subtype. hERG1 apparently behaves as a protective factor, since it contributes to identify a subset of patients with better outcome. Overall, these data suggest that hERG1 might be an additional tool for the management of BC, nevertheless further investigations are warranted to better clarify hERG1 role and clinical usefulness in BC.

Micronuclei and chromosome aberrations in subjects occupationally exposed to antineoplastic drugs: a multicentric approach.

OBJECTIVES: Recently published works showed that occupational exposure to antineoplastic drugs (ANPD) is still frequent in hospital settings, despite significant safety policy improvements. The aim of this study was to assess the current level of occupational exposure to ANPD and any potentially associated cytogenetic damages in hospital nurses routinely handling ANPD. METHODS: Occupationally ANPD-exposed (n = 71) and ANPD-unexposed (n = 77; control) nurses were recruited on a voluntary basis from five hospitals in Northern and Central Italy. Evaluation of surface contamination and dermal exposure to ANPD was assessed by determining cyclophosphamide (CP) on selected surfaces (wipes) and on exposed nurses' clothes (pads). The concentration of unmetabolized CP­as a biomarker of internal dose­was measured in end-shift urine samples. Biomonitoring of genotoxic effects (i.e., biological effect monitoring) was conducted by analyzing micronuclei (MN) and chromosome aberrations (CA) in peripheral blood lymphocytes. Genetic polymorphisms for enzymes involved in metabolic detoxification (i.e., glutathione S-transferases) were analyzed as well. RESULTS: We observed a significant increase in MN frequency (5.30 ± 2.99 and 3.29 ± 1.97; mean values ± standard deviation; p < 0.0001) in exposed nurses versus controls, as well as in CA detection (3.30 ± 2.05 and 1.84 ± 1.67; p < 0.0001), exposed subjects versus controls. Our results provide evidence that, despite safety controlled conditions, ANPD handling still represents a considerable genotoxic risk for occupationally exposed personnel. CONCLUSIONS: Because both MN and CA have been described as being predictive of group-increased cancer risk, our findings point to a need for improving specific safety procedures in handling and administering ANPD.

Primary DNA damage in welders occupationally exposed to extremely-low-frequency magnetic fields (ELF-MF).

BACKGROUND: Electric arc welding is known to involve considerable exposure to extremely-low-frequency magnetic fields (ELF-MF; 50 Hz). The aim of the present study was to evaluate individual exposure to ELF-MF during arc welding and to assess the eventually associated genotoxic hazard by evaluating primary DNA damage. METHODS: The study group comprised 21 electric arc welders (exposed) and 21 non-exposed control subjects (healthy blood donors). Occupational exposure to ELF-MF was measured using personal dosimeters worn during one complete work-shift (7 am to 5 pm). The extent of primary DNA damage was measured in peripheral blood leukocytes with the standard procedure of the alkaline comet assay. RESULTS: Tail length showed to have similar values in welders and controls. Whereas, the data showed a significant decrease for tail intensity (p = 0.01) and tail moment (p = 0.02) counts in exposed subjects compared to controls. CONCLUSIONS: The different results of our present study and published investigations from other research groups reporting positive results in the comet assay might be a result of different chromium and/or nickel (or other metals) exposure levels, which lead to DNA-protein cross-links at lower concentrations and DNA single-strand breakages at higher concentrations. Since these results are derived from a small-scale pilot study, a larger scale study should be undertaken.

Investigation of the cytotoxic, genotoxic, and apoptosis-inducing effects of estragole isolated from fennel (Foeniculum vulgare).

The present study was undertaken to evaluate, in the HepG2 human hepatoma cell line, the in vitro cytotoxic, genotoxic, and apoptotic activities of estragole (1), contained in the essential oil of Foeniculum vulgare (fennel) and suspected to induce hepatic tumors in susceptible strains of mice. Toward this end, an MTT cytotoxicity assay, a trypan blue dye exclusion test, a double-staining (acridine orange and DAPI) fluorescence viability assay, a single-cell microgel-electrophoresis (comet) assay, a mitochondrial membrane potential (Δψm) assay, and a DNA fragmentation analysis were conducted. In terms of potential genotoxic effects, the comet assay indicated that estragole (1) was not able to induce DNA damage nor apoptosis under the experimental conditions used.

Predictive Factors for Long-Term Disease Control in Systemic Treatment-Naïve Oligorecurrent Renal Cell Carcinoma Treated with Up-Front Stereotactic Ablative Radiotherapy (SABR).

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is emerging as a potential local treatment option for oligometastatic RCC. This study aims to evaluate the efficacy of SABR in patients with oligorecurrent RCC. METHODS: A total of 50 patients with histologically confirmed RCC underwent SABR for oligorecurrence between 2006 and 2022. Eligible patients had up to five extracranial metastases and were systemic treatment-naïve at the time of irradiation. The primary endpoints of the analysis were overall survival (OS), local control (LC), distant metastasis-free survival (DMFS), and time to systemic therapy initiation. RESULTS: The median OS was not reached, with 1- and 3-year OS rates of 93.8% and 77.5%, respectively. LC rates at one and three years were 95.8% and 86.5%, respectively. The median time to systemic therapy initiation was 63.8 months, and the median DMFS was 17.9 months, with one- and three-year rates of 63.4% and 36.6%, respectively. Multiple metastases were a negative predictive factor for DMFS (HR 2.39, p = 0.023), whereas lung metastases were associated with a more favorable outcome (HR 0.38, p = 0.011). CONCLUSIONS: SABR offers a valuable treatment option for oligometastatic RCC, demonstrating significant potential for achieving long-term disease control and delaying the need for systemic therapy.

STRILL: Phase I Trial Evaluating Stereotactic Body Radiotherapy (SBRT) Dose Escalation for Re-Irradiation of Inoperable Peripheral Lung Lesions.

Few data are available on the role of SBRT re-irradiation for isolated recurrences. We designed a prospective phase I study to evaluate the maximum tolerated dose (MTD) of SBRT for thoracic re-irradiation, for peripheral lung lesions. RT was delivered with a dose escalation design from 30 Gy in five fractions up to 50 Gy in five fractions. The primary end point was the definition of the maximum tolerated dose (MTD) of SBRT for thoracic re-irradiation. The dose-limiting toxicity was pneumonia ≥G3. Fifteen patients were enrolled. No cases of pneumonia ≥G3 occurred in any of our cohorts. Only one patient developed pneumonia G1 during treatment. Three patients developed acute toxicities that included dyspnea G1, cardiac failure G3, and chest wall pain. One patient developed G3 late toxicity with acute coronary syndrome. After a median follow-up of 21 months (range 3.6-29.1 months), six patients (40%) had a local relapse. Distant relapse occurred in five patients (33.3%). At the last follow-up, six patients died, all but two due to progressive disease. SBRT dose escalation for thoracic re-irradiation is an effective and well-tolerated option for patients with inoperable lung lesions after a first thoracic RT with acceptable acute and late toxicities.

Multicentre study for the evaluation of mutagenic/carcinogenic risk in nurses exposed to antineoplastic drugs: assessment of DNA damage.

OBJECTIVES: People who handle antineoplastic drugs, many of which classified as human carcinogens by International Agency for Research on Cancer, are exposed to low doses in comparison with patients; however, the long duration of exposure could lead to health effects. The aim of this work was to evaluate DNA damage in white blood cells from 63 nurses who handle antineoplastic drugs in five Italian hospitals and 74 control participants, using different versions of the Comet assay. METHODS: Primary DNA damage was assessed by using the alkaline version of the assay on leucocytes, whereas to detect DNA oxidative damage and cryptic lesions specifically, the Comet/ENDO III assay and the Comet/araC assay were performed on leucocytes and lymphocytes, respectively. RESULTS: In the present study, no significant DNA damage was correlated with the work shift. The exposed population did not differ significantly from the reference group with respect to DNA primary and oxidative damage in leucocytes. Strikingly, in isolated lymphocytes treated with araC, lower data dispersion as well as a significantly lower mean value for the percentage of DNA in the comet tail was observed in exposed participants as compared with the control group (p<0.05), suggesting a potential chronic exposure to crosslinking antineoplastic drugs. CONCLUSIONS: Although stringent rules were adopted at national and international levels to prevent occupational exposure to antineoplastic drugs, data reported in this study support the idea that a more efficient survey on long-lasting exposures at very low concentrations is needed.

[Evaluation of genotoxic effects in subjects occupationally exposed to antineoplastic drugs]. / Valutazione di effetti genotossici in soggetti con esposizione occupazionale a chemioterapici antiblastici.

The present molecular epidemiology study was carried out to evaluate the genotoxic effects of occupational exposure to antineoplastic drugs (ANP). The study was conducted in 52 hospital workers involved in the preparation, handling or administration of ANP in a hospital in Perugia (central Italy) and in 52 non-exposed control subjects matched for age, gender and smoking habits to the exposed subjects. Both comet assay and the micronucleus test were used to evaluate genome damage in peripheral blood lymphocytes in study subjects. The extent of primary DNA damage, as evaluated by the comet assay, was significantly increased in exposed personnel with respect to matched controls. On the other hand, no significant differences in micronuclei frequency was observed between the two groups. Multivariate linear regression analysis showed an association between years of occupational exposure over 10 years and higher extent of primary DNA damage in the exposed group. The results of this study confirm that handling ANP without appropriate precautions carries a genotoxic risk for exposed healthcare workers. These results address the need for regular biological effect monitoring of staff occupationally-exposed to ANP.

Radiotherapy of orbital metastases: a systematic review of management and treatment outcomes on behalf of palliative care study group of Italian association of radiotherapy and clinical oncology (AIRO).

OBJECTIVES: We search the current literature on data regarding the role of RT in OM treatment, focusing on the improvement of symptoms and patient quality of life. METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. RESULTS: From 340 citations, 60 papers were finally selected: 45 case reports and 15 case series. The case reports accounted for 47 patients. In 37/39 cases (95%), EBRT was done. Patients were mainly treated with 3DCRT, IMRT, and with SBRT. The most used RT regimens were 30 Gy in 10 fractions (23%) and 20-25 Gy in 5 fx (13%). No sever toxicity was reported. A median LC of 11 months (range 1-54 months) and a median OS of 12 months (range 1-54 months) were registered. Among the case series, a total of 457 patients were examined, 227 of whom underwent RT. The main used techniques were 3DCRT, CK, GK, SBRT, and BRT. RT doses could vary from 30 Gy/10 fractions to 60 Gy/30 fractions, 50 Gy/5 fractions, or 16.5-21 Gy in single fraction. No toxicity above G2 was reported. ORR could vary between 75 and 100%. Only two study provided information on response duration: a mean LC time of 22.8 months and a mean time to local progression of 5 months (range: 3-7). Regarding OS, the data were heterogeneous, ranging between 1 and 54 months. CONCLUSIONS: RT for OM seems to be a safe and feasible option. More information on the RT ideal techniques and dose are still needed. ADVANCES IN KNOWLEDGE: This paper tried to sum up the few and fragmented data on the use of radiotherapy for orbital metastases: the possible option ranged from 3D- and 2D-CRT to SBRT, CK, and GK, with different possible fractionations (30Gy in 10 fractions, 60 Gy/30 fractions, 20-50 Gy/5 fractions, or 16.5-21 Gy in single fraction). Regardless of the chosen approach, almost all treated patients experienced a benefit after RT in terms of OM-related symptom intensity reduction and a good acute and late toxicity profile.

Stereotactic radiation therapy for oligometastatic esophagogastric adenocarcinoma: outcome and prognostic factors.

OBJECTIVE: The aim of this study was to evaluate clinical results and prognostic factors in a cohort of patient with oligometastatic esophagogastric adenocarcinoma treated with stereotactic radiation therapy (SRT). METHODS: This retrospective study included patients affected by 1-3 metastases treated with SRT from 2013 to 2021. Local control (LC), overall survival (OS), progression-free survival (PFS), time to polymetastatic dissemination (TTPD) and time to systemic therapy change/initiation (TTS) were evaluated. RESULTS: Between 2013 and 2021, 55 patients were treated with SRT on 80 oligometastatic sites. Median follow-up was 20 months. Nine patients had local progression. 1 and 3 years LC was respectively 92 and 78%. 41 patients experienced further distant disease progression, median PFS was 9.6 months, 1 and 3 years PFS was respectively 40 and 15%. 34 patients died, median OS was 26.6 months, 1 and 3 years OS was respectively 78 and 40%. During follow-up, 24 patients changed or initiated a new systemic therapy; median TTS time was 9 months. 27 patients experienced poliprogression, 44% after 1 year and 52% after 3 years. Median TTPD was 8 months. The best local response (LR), tyming of metastases and PS were related with prolonged PFS on multivariate analysis. LR was correlated with OS at multivariate analysis. CONCLUSION: SRT represents a valid treatment for oligometastatic esophagogastric adenocarcinoma. CR correlated with PFS and OS, while metachronous metastasis and a good PS correlated with a better PFS. ADVANCES IN KNOWLEDGE: In selected gastroesopagheal oligometastatic patients, SRT can prolong OS Local response to SRT, metachronous timing of metastases and better PS improve PFS.Local response correlates with OS.

Reirradiation on spine metastases: an Italian survey on behalf of palliative care and reirradiation study groups of Italian association of radiotherapy and clinical oncology (AIRO).

AIM: This survey derived from the collaboration between the Palliative Care and Reirradiation Study Groups of the Italian Association of Radiotherapy and Clinical Oncology (AIRO). Its aim was to obtain a real "snapshot" on the treatments of spinal metastases, focusing on reirradiation, among radiation oncologists in Italy. METHODS: The survey was elaborated on SurveyMonkey's online interface and was sent via e-mail to all Radiation Oncologists of AIRO that were invited to anonymously fill in the electronic form within 60 days. The questionnaire was prepared by the AIRO "Palliative care" and "Reirradiation" Study Groups and it consisted of 36 questions, 19 single-choice questions, 10 multiple-choice questions and 6 open questions. The data were analyzed and represented with tables and graphs. RESULTS: The survey shows that palliative radiotherapy remains a field of interest for most ROs in the Italian centers. 3D Conventional Radiation Therapy (3DCRT) alone or in combination with other techniques is the primary choice for patients with a life expectancy of less than 6 months. For patients with a life expectancy of more than six months, there is an increased use of new technologies, such as Volumetric Modulated Arc Therapy (VMAT). Factors considered for retreatment are time between first and second treatment, dose delivered to spine metastasis and spinal cord in the first treatment, vertebral stability, symptoms, and/or performance status. The most feared complication are myelopathy followed by vertebral fracture and local recurrence. This explain an increasing focus on patient selection and the use of high technology in the treatment of metastatic patients. CONCLUSION: Stereotactic body radiotherapy (SBRT) and image-guided radiotherapy allow the administration of ablative RT doses while sparing the constraints of healthy tissue in spinal metastases. However, there is still an unclear and heterogeneous reality in the reirradiation of spinal metastases. A national registry with the aim of clarifying the most controversial aspects of vertebral metastasis retreatments will enable better management of these patients and design more targeted study designs.

Prognostic Score in Radiotherapy Practice for Palliative Treatments (PROPHET) Study for Bone Metastases: An Investigation Into the Clinical Effect on Treatment Prescription.

Purpose: Bone metastases frequently occur during malignant disease. Palliative radiation therapy (PRT) is a crucial part of palliative care because it can relieve pain and improve patients' quality of life. Often, a clinician's survival estimation is too optimistic. Prognostic scores (PSs) can help clinicians tailor PRT indications to avoid over- or undertreatment. Although the PS is supposed to aid radiation oncologists (ROs) in palliative-care scenarios, it is unclear what type of support, and to what extent, could impact daily clinical practice. Methods and Materials: A national-based investigation of the prescriptive decisions on simulated clinical cases was performed in Italy. Nine clinical cases from real-world clinical practice were selected for this study. Each case description contained complete information regarding the parameters defining the prognosis class according to the PS (in particular, the Mizumoto Prognostic Score, a validated PS available in literature and already applied in some clinical trials). Each case description contained complete information regarding the parameters defining the prognosis class according to the PS. ROs were interviewed through questionnaires, each comprising the same 3 questions per clinical case, asking (1) the prescription after detailing the clinical case features but not the PS prognostic class definition; (2) whether the RO wanted to change the prescription once the PS prognostic class definition was revealed; and (3) in case of a change of the prescription, a new prescriptive option. Three RO categories were defined: dedicated to PRT (RO-d), nondedicated to PRT (RO-nd), and resident in training (IT). Interviewed ROs were distributed among different regions of the country. Results: Conversion rates, agreements, and prescription trends were investigated. The PS determined a statistically significant 11.12% of prescription conversion among ROs. The conversion was higher for the residents and significantly higher for worse prognostic scenario subgroups, respectively. The PS improved prescriptive agreement among ROs (particularly for worse-prognostic-scenario subgroups). Moreover, PS significantly increased standard prescriptive approaches (particularly for worse-clinical-case presentations). Conclusions: To the best of our knowledge, the PROPHET study is the first to directly evaluate the potential clinical consequences of the regular application of any PS. According to the Prophet study, a prognostic score should be integrated into the clinical practice of palliative radiation therapy for bone metastasis and training programs in radiation oncology.

Locally Advanced Non-Small Cell Lung Cancer: Clinical Outcome, Toxicity and Predictive Factors in Patients Treated with Hypofractionated Sequential or Exclusive Radiotherapy.

BACKGROUND: This study evaluated the outcome, toxicity and predictive factors in patients unfit for concurrent chemo-radiotherapy (CT-RT) treated with hypofractionated sequential CT-RT or exclusive radiotherapy (RT) for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: We included patients affected by LA-NSCLC (stage IIA-IVA) treated with a total dose of 50-60 Gy in 20 fractions. The primary outcomes were local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS). Univariate analysis was used to correlate outcomes with prognostic factors. RESULTS: Between 2011 and 2019, 210 patients were treated, 113 (53.8%) with sequential CT-RT and 97 (46.2%) with exclusive RT. After a median follow-up of 15.3 months, 74 patients (35.2%) had a local progression and 133 (63.3%) had a distant progression. The one-, two- and five-year LC were 73.6%, 55.3% and 47.9%, respectively. At the time of analysis, 167 patients (79.5%) died. The one-, two- and five-year OS were 64.7%, 36% and 20%, respectively. PTV volume correlated with PFS (p = 0.001) and LC (p = 0.005). Acute and late toxicity occurred in 82% and 26% of patients. CONCLUSIONS: Albeit with the known limitations of a retrospective and heterogeneous study, our work shows that hypofractionated sequential CT-RT or exclusive RT offer a good local control and toxicity profile and a promising survival rate in LA-NSCLC patients unfit for the concurrent CT-RT scheme.

Training and validation of a knowledge-based dose-volume histogram predictive model in the optimisation of intensity-modulated proton and volumetric modulated arc photon plans for pleural mesothelioma patients.

BACKGROUND: To investigate the performance of a narrow-scope knowledge-based RapidPlan (RP) model for optimisation of intensity-modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) plans applied to patients with pleural mesothelioma. Second, estimate the potential benefit of IMPT versus VMAT for this class of patients. METHODS: A cohort of 82 patients was retrospectively selected; 60 were used to "train" a dose-volume histogram predictive model; the remaining 22 provided independent validation. The performance of the RP models was benchmarked, comparing predicted versus achieved mean and near-to-maximum dose for all organs at risk (OARs) in the training set and by quantitative assessment of some dose-volume metrics in the comparison of the validation RP-based data versus the manually optimised training datasets. Treatment plans were designed for a prescription dose of 44 Gy in 22 fractions (proton doses account for a fixed relative biological effectiveness RBE = 1.1). RESULTS: Training and validation RP-based plans resulted dosimetrically similar for both VMAT and IMPT groups, and the clinical planning aims were met for all structures. The IMPT plans outperformed the VMAT ones for all OARs for the contra-lateral and the mean and low dose regions for the ipsilateral OARs. Concerning the prediction performance of the RP models, the linear regression for the near-to-maximum dose resulted in Dachieved = 1.03Dpredicted + 0.58 and Dachieved = 1.02Dpredicted + 1.46 for VMAT and IMPT, respectively. For the mean dose it resulted: Dachieved = 0.99Dpredicted + 0.34 and Dachieved = 1.05Dpredicted + 0.27 respectively. In both cases, the linear correlation between prediction and achievement is granted with an angular coefficient deviating from unity for less than 5%. Concerning the dosimetric comparison between manual plans in the training cohort and RP-based plans in the validation cohort, no clinical differences were observed for the target volumes in both the VMAT and IMPT groups. Similar consistency was observed for the dose-volume metrics analysed for the OAR. This proves the possibility of achieving the same quality of plans with manual procedures (the training set) or with automated RP-based methods (the validation set). CONCLUSION: Two models were trained and validated for VMAT and IMPT plans for pleural mesothelioma. The RP model performance resulted satisfactory as measured by the agreement between predicted and achieved (after full optimisation) dose-volume metrics. The IMPT plans outperformed the VMAT plans for all the OARs (with different intensities for contra- or ipsilateral structures). RP-based planning enabled the automation of part of the optimisation and the harmonisation of the dose-volume results between training and validation. The IMPT data showed a systematic significant dosimetric advantage over VMAT. In general, using an RP-based approach can simplify the optimisation workflow in these complex treatment indications without impacting the quality of plans.

Stereotactic Body Radiation Therapy for Lung and Liver Oligometastases from Breast Cancer: Toxicity Data of a Prospective Non-Randomized Phase II Trial.

AIMS: We report the mature toxicity data of a phase II non-randomized trial on the use of SBRT for lung and liver oligometastases. METHODS: Oligometastatic patients from breast cancer were treated with SBRT for up to five lung and/or liver lesions. Inclusion criteria were: age > 18 years, ECOG 0-2, diagnosis of breast cancer, less than five lung/liver lesions (with a maximum diameter <5 cm), metastatic disease confined to the lungs and liver or extrapulmonary or extrahepatic disease stable or responding to systemic therapy. Various dose-fractionation schedules were used. Then, a 4D-CT scan and FDG-CTPET were acquired for simulation and fused for target definition. RESULTS: From 2015 to 2021, 64 patients and a total of 90 lesions were irradiated. Treatment was well tolerated, with no G 3-4 toxicities. No grade ≥3 toxicities were registered and the coprimary endpoint of the study was met. Median follow-up was 19.4 months (range 2.6-73.1). CONCLUSIONS: The co-primary endpoint of this phase II trial was met, showing excellent tolerability of SBRT for lung and liver oligometastatic in breast cancer patients. Until efficacy data will mature with longer follow-up, SBRT should be regarded as an opportunity for oligometastatic breast cancer patients.

Assessment of primary, oxidative and excision repaired DNA damage in hospital personnel handling antineoplastic drugs.

The International Agency for Research on Cancer has classified several antineoplastic drugs in Group 1 (human carcinogens), among which chlorambucil, cyclophosphamide (CP) and tamoxifen, Group 2A (probable human carcinogens), among which cisplatin, etoposide, N-ethyl- and N-methyl-N-nitrosourea, and Group 2B (possible human carcinogens), among which bleomycins, merphalan and mitomycin C. The widespread use of these mutagenic/carcinogenic drugs in the treatment of cancer has led to anxiety about possible genotoxic hazards to medical personnel handling these drugs. The aim of the present study was to evaluate work environment contamination by antineoplastic drugs in a hospital in Central Italy and to assess the genotoxic risks associated with antineoplastic drug handling. The study group comprised 52 exposed subjects and 52 controls. Environmental contamination was assessed by taking wipe samples from different surfaces in preparation and administration rooms and nonwoven swabs were used as pads for the surrogate evaluation of dermal exposure, 5-fluorouracil and cytarabine were chosen as markers of exposure to antineoplastic drugs in the working environment. The actual exposure to antineoplastic drugs was evaluated by determining the urinary excretion of CP. The extent of primary, oxidative and excision repaired DNA damage was measured in peripheral blood leukocytes with the alkaline comet assay. To evaluate the role, if any, of genetic variants in the extent of genotoxic effects related to antineoplastic drug occupational exposure, the study subjects were genotyped for GSTM1, GSTT1, GSTP1 and TP53 polymorphisms. Primary DNA damage significantly increased in leukocytes of exposed nurses compared to controls. The use of personal protective equipment (i.e. gloves and/mask) was associated with a decrease in the extent of primary DNA damage.

A study protocol for the evaluation of occupational mutagenic/carcinogenic risks in subjects exposed to antineoplastic drugs: a multicentric project.

BACKGROUND: Some industrial hygiene studies have assessed occupational exposure to antineoplastic drugs; other epidemiological investigations have detected various toxicological effects in exposure groups labeled with the job title. In no research has the same population been studied both environmentally and epidemiologically. The protocol of the epidemiological study presented here uses an integrated environmental and biological monitoring approach. The aim is to assess in hospital nurses preparing and/or administering therapy to cancer patients the current level of occupational exposure to antineoplastic drugs, DNA and chromosome damage as cancer predictive effects, and the association between the two. METHODS/DESIGN: About 80 healthy non-smoking female nurses, who job it is to prepare or handle antineoplastic drugs, and a reference group of about 80 healthy non-smoking female nurses not occupationally exposed to chemicals will be examined simultaneously in a cross-sectional study. All the workers will be recruited from five hospitals in northern and central Italy after their informed consent has been obtained.Evaluation of surface contamination and dermal exposure to antineoplastic drugs will be assessed by determining cyclophosphamide on selected surfaces (wipes) and on the exposed nurses' clothes (pads). The concentration of unmetabolized cyclophosphamide as a biomarker of internal dose will be measured in end-shift urine samples from exposed nurses. Biomarkers of effect and susceptibility will be assessed in exposed and unexposed nurses: urinary concentration of 8-hydroxy-2-deoxyguanosine; DNA damage detected using the single-cell microgel electrophoresis (comet) assay in peripheral white blood cells; micronuclei and chromosome aberrations in peripheral blood lymphocytes. Genetic polymorphisms for enzymes involved in metabolic detoxification (i.e. glutathione S-transferases) will also be analysed.Using standardized questionnaires, occupational exposure will be determined in exposed nurses only, whereas potential confounders (medicine consumption, lifestyle habits, diet and other non-occupational exposures) will be assessed in both groups of hospital workers.Statistical analysis will be performed to ascertain the association between occupational exposure to antineoplastic drugs and biomarkers of DNA and chromosome damage, after taking into account the effects of individual genetic susceptibility, and the presence of confounding exposures. DISCUSSION: The findings of the study will be useful in updating prevention procedures for handling antineoplastic drugs.

Knowing When to Use Stereotactic Ablative Radiation Therapy in Oligometastatic Cancer.

Oligometastatic patients are a heterogeneous and yet not well-defined population. The actual definition identifies as oligometastatic, patients with 1-5 metastases in 1-3 different organs. However, only a proportion of these patients are "true" oligometastatic and therefore derive some kinds of benefit from local ablative approaches like stereotactic ablative radiation therapy (SABR). Since SABR is an easily accessible, effective and well-tolerated treatment, it is widely employed in the oligometastatic scenarios, without a particular focus on selection criteria. However, it should be crucial to identify predictive and prognostic features that could be clinically implemented. Therefore, we conducted this narrative review of the available literature to summarize all clinical, radiomic, genetic and epigenetic features found to be predictive of overall survival, progression-free survival or local control of oligometastatic patients treated with SABR.