The Possibility of Using Genotoxicity, Oxidative Stress and Inflammation Blood Biomarkers to Predict the Occurrence of Late Cutaneous Side Effects after Radiotherapy.

Despite the progresses performed in the field of radiotherapy, toxicity to the healthy tissues remains a major limiting factor. The aim of this work was to highlight blood biomarkers whose variations could predict the occurrence of late cutaneous side effects. Two groups of nine patients treated for Merkel Cell Carcinoma (MCC) were established according to the grade of late skin toxicity after adjuvant irradiation for MCC: grade 0, 1 or 2 and grade 3 or 4 of RTOG (Radiation Therapy Oncology Group)/EORTC (European Organization for Research and Treatment of Cancer). To try to discriminate these 2 groups, biomarkers of interest were measured on the different blood compartments after ex vivo irradiation. In lymphocytes, cell cycle, apoptosis and genotoxicity were studied. Oxidative stress was evaluated by the determination of the erythrocyte antioxidant capacity (superoxide dismutase, catalase, glutathione peroxidase, reduced and oxidized glutathione) as well as degradation products (protein carbonylation, lipid peroxidation). Inflammation was assessed in the plasma by the measurement of 14 cytokines. The most radiosensitive patients presented a decrease in apoptosis, micronucleus frequency, antioxidant enzyme activities, glutathione and carbonyls; and an increase in TNF-a (Tumor Necrosis Factor a), IL-8 (Interleukin 8) and TGF-ß1 (Transforming Growth Factor ß1) levels. These findings have to be confirmed on a higher number of patients and before radiotherapy and could allow to predict the occurrence of late skin side effects after radiotherapy.

Stereotactic ablative radiotherapy and systemic treatments for extracerebral oligometastases, oligorecurrence, oligopersistence and oligoprogression from lung cancer.

BACKGROUND: Stereotactic irradiation (SBRT) is a standard of care for inoperable stage I lung cancer and brain oligometastases from lung cancer but is controversial for extracranial oligometastases. We assessed outcomes of lung cancer patients with extracranial metastases in oligometastatic, oligorecurrent, oligopersistent and oligoprogressive settings ("oligometastatic spectrum") under strategies using SBRT +/- systemic treatments. METHODS: A retrospective multicentric study of consecutive lung cancer adult patients with 1-5 extracranial metastases treated with SBRT was conducted. RESULTS: Of 91 patients (99 metastases, median age 63, 64.8% adenocarcinomas, 19.8% molecular alterations), 11% had oligometastases, 49.5% oligorecurrence, 19.8% oligopersistence and 19.8% oligoprogression. Of 36% of patients under systemic treatments at initiation of SBRT, systemic treatment interruption was performed in 58% of them. With median follow up of 15.3 months, crude local control at irradiated metastases was 91%, while median distant progression-free survival (dPFS) and overall survival were 6.3 and 28.4 months (2-year survival 54%). Initial nodal stage and oligometastatic spectrum were prognostic factors for dPFS; age, initial primary stage and oligometastatic spectrum were prognostic factors for survival on multivariate analysis. Patients with oncogene-addicted tumors more frequently had oligoprogressive disease. Repeat ablative irradiations were preformed in 80% of patients who had oligorelapses. Worst acute toxicities consisted of 5.5% and one late toxic death occurred. CONCLUSION: The oligometastatic spectrum is a strong prognosticator in patients undergoing SBRT for extracranial metastases. Median survival was over two years but dPFS was about 6 months. Continuation of systemic therapy in oligoprogressive patients should be investigated.

Impact of suboptimal tandem implantation on local control and complications in intracavitary brachytherapy for cervix cancer.

PURPOSE: Correct tandem implantation for cervix cancer intracavitary brachytherapy may be challenging. We investigated whether suboptimal implantation can be related to patient and disease characteristics and may result in subsequent underutilization of brachytherapy in cervical cancer. METHODS AND MATERIALS: Consecutive cervix cancer patients referred for intracavitary brachytherapy after external beam radiation therapy performed in several general hospitals from 2013 to 2017 were included. RESULTS: In 172 patients having 301 procedures, 95 implantations were suboptimal (15% inadequate tandem insertions, 10% subserosal insertion, and 6% uterine perforation on postimplant CT scan). Risk factors were age, myometrium invasion, and uterine retroversion. Median followup was 21 months. Three-year local control and survival rates were 72% and 85%, respectively. Forty-seven patients (27%) failed to receive brachytherapy. Failure to perform brachytherapy was associated with poorer local control (OR = 0.34 [0.17-0.67], p = 0.001). By contrast, suboptimal implantation did not increase local failure or toxicity rates in patients undergoing brachytherapy. No peritoneal carcinomatosis occurred after uterine perforation in our cohort. CONCLUSIONS: Suboptimal implantation was frequent. In the absence of image guidance during implantation, conversion to other treatment modalities (including external beam radiation therapy) due to insertion difficulties resulted in worse local control. With optimization, however, suboptimal brachytherapy implantation did not result in suboptimal dose coverage or poorer local control. Failure to perform a brachytherapy boost correlates with increased local failure risk in patients with cervix cancer, whereas tandem malposition does not. Real-time intraoperative ultrasound guidance may be useful to reduce uterine perforation rates and thus increase brachytherapy use.

Radiosurgery or hypofractionated stereotactic radiotherapy for brain metastases from radioresistant primaries (melanoma and renal cancer).

BACKGROUND: Until 50% of patients with renal cancer or melanoma, develop brain metastases during the course of their disease. Stereotactic radiotherapy has become a standard of care for patients with a limited number of brain metastases. Given the radioresistant nature of melanoma and renal cancer, optimization of the fractionation of stereotactic radiotherapy is needed. The purpose of this retrospective study was to elucidate if hypofractionated stereotactic radiotherapy (HFSRT) impacts local control of brain metastases from radioresistant tumors such as melanoma and renal cancer, in comparison with radiosurgery (SRS). METHODS: Between 2012 and 2016, 193 metastases, smaller than 3 cm, from patients suffering from radioresistant primaries (melanoma and renal cancer) were treated with HFSRT or SRS. The primary outcome was local progression free survival (LPFS) at 6, 12 and 18 months. Overall survival (OS) and cerebral progression free survival (CPFS) were secondary outcomes, and were evaluated per patient. Objective response rate and radionecrosis incidence were also reported. The statistical analysis included a supplementary propensity score analysis to deal with bias induced by non-randomized data. RESULTS: After a median follow-up of 7.4 months, LPFS rates at 6, 12 and 18 months for the whole population were 83, 74 and 70%, respectively. With respect to fractionation, LPFS rates at 6, 12 and 18 months were 89, 79 and 73% for the SRS group and 80, 72 and 68% for the HFSRT group. The fractionation schedule was not statistically associated with LPFS (HR = 1.39, CI95% [0.65-2.96], p = 0.38). Time from planning MRI to first irradiation session longer than 14 days was associated with a poorer local control rate. Over this time, LPFS at 12 months was reduced from 86 to 70% (p = 0.009). Radionecrosis occurred in 7.1% for HFSRT treated metastases to 9.6% to SRS treated metastases, without any difference according to fractionation (p = 0.55). The median OS was 9.6 months. Six, 12 and 18 months CPFS rates were 54, 24 and 17%, respectively. CONCLUSION: Fractionation does not decrease LPFS. Even for small radioresistant brain metastases (< 3 cm), HFSRT, with 3 or 6 fractions, leads to an excellent local control rate of 72% at 1 year with a rate of 7.1% of radionecrosis. HFSRT is a safe and efficient alternative treatment to SRS.

Study of commercial detector responses in non-equilibrium small photon fields of a 1000MU/min CyberKnife system.

PURPOSE: The purpose of this study was to analyze the detector responses in non-equilibrium small photon fields. METHODS: Five detectors (PTW 31014 ionization chamber, PTW 60016, PTW 60017 and Sun Nuclear EDGE diodes and PTW 60003 diamond detector) and one passive dosimeter (Harshaw micro-LiF) as well as a 1000MU/min CyberKnife were modeled with the PENELOPE Monte Carlo code. Field factors, [Formula: see text] were calculated and perturbations due to volume averaging effect, active material effect and coating effect were quantified for the five detectors and passive dosimeter. RESULTS: The PTW 31014 ionization chamber under-response is mainly due to the fluence perturbation caused by the presence of air as detecting material. Regarding diodes, the high density materials used in their active volume and in their coating is responsible for their over-response. Regarding the PTW 60003 diamond, its under-response for the 5mm field size is due to a large volume averaging effect whereas for largest field sizes a nearly perfect compensation between the volume averaging effect and the material effect due to the diamond density occurs. Despite its small size, a volume averaging effect was observed for the micro-LiF for the 5mm field size. CONCLUSION: Perturbations due to volume averaging effect, active material effect and coating effect were investigated and quantified for five active detectors. Since these perturbations can cause opposite effects, wrong conclusions may be drawn regarding the radiological water-equivalence of detectors. Thus, we recommend performing such a study for each novel detector available on the market.