Acute toxicities and cumulative dose to the brain of repeated sessions of stereotactic radiotherapy (SRT) for brain metastases: a retrospective study of 184 patients.

BACKGROUND: Stereotactic radiation therapy (SRT) is a focal treatment for brain metastases (BMs); thus, 20 to 40% of patients will require salvage treatment after an initial SRT session, either because of local or distant failure. SRT is not exempt from acute toxicity, and the acute toxicities of repeated SRT are not well known. The objective of this study was to analyze the acute toxicities of repeated courses of SRT and to determine whether repeated SRT could lead to cumulative brain doses equivalent to those of whole-brain radiotherapy (WBRT). MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs via two to six SRT sessions for local or distant BM recurrence without previous or intercurrent WBRT were retrospectively reviewed. Patients were seen via consultations during SRT, and the delivered dose, the use of corticosteroid therapy and neurological symptoms were recorded and rated according to the CTCAEv4. The dosimetric characteristics of 79% of BMs were collected, and summation plans of 76.6% of BMs were created. RESULTS: 36% of patients developed acute toxicity during at least one session. No grade three or four toxicity was registered, and grade one or two cephalalgy was the most frequently reported symptom. There was no significant difference in the occurrence of acute toxicity between consecutive SRT sessions. In the multivariate analysis, acute toxicity was associated with the use of corticosteroid therapy before irradiation (OR = 2.6; p = 0.01), BMV grade (high vs. low grade OR = 5.17; p = 0.02), and number of SRT sessions (3 SRT vs. 2 SRT: OR = 2.64; p = 0.01). The median volume equivalent to the WBRT dose (VWBRT) was 47.9 ml. In the multivariate analysis, the VWBRT was significantly associated with the total GTV (p < 0.001) and number of BMs (p < 0.001). Even for patients treated for more than ten cumulated BMs, the median BED to the brain was very low compared to the dose delivered during WBRT. CONCLUSION: Repeated SRT for local or distant recurrent BM is well tolerated, without grade three or four toxicity, and does not cause more acute neurological toxicity with repeated SRT sessions. Moreover, even for patients treated for more than ten BMs, the VWBRT is low.

Changes in the characteristics of patients treated for brain metastases with repeat stereotactic radiotherapy (SRT): a retrospective study of 184 patients.

PURPOSE: Brain metastases (BMs) are the leading cause of intracranial malignant neoplasms in adults. WHO, Karnofsky performance status (KPS), age, number of BMs, extracerebral progression (ECP), recursive partitioning analysis (RPA), diagnosis-specific graded prognostic assessment (Ds-GPA) are validated prognostic tools to help clinicians decide on treatment. No consensus exists for repeat stereotactic radiotherapy (SRT) for BMs. The aim of this study was to review the changes in patient characteristics treated with repeated SRTs. METHODS AND MATERIALS: The data of patients treated between 2010 and 2020 with at least two courses of SRT without previous whole brain radiotherapy (WBRT) were reviewed. Age, WHO, KPS, ECP, type of systemic treatment, number of BMs were recorded. RPA, Ds-GPA and brain metastasis velocity (BMV) were calculated. RESULTS: 184 patients were treated for 915 BMs and received two to six SRTs for local or distant brain recurrence. The median number of BMs treated per SRT was 1 (range: 1-6), for a median of 4 BMs treated during all sessions (range: 2-19). WHO, Ds-GPA and RPA were stable between each session of SRT, whereas KPS was significantly better in SRT1 than in the following SRT. The number of BMs was not significantly different between each SRT, but there was a tendency for more BM at SRT1 (p = 0.06). At SRT1, patients had largest BM and undergo more surgery than during the following SRT (p < 0.001). 6.5%, 37.5% and 56% of patients were classified as high, intermediate, and low BMV, respectively, at the last SRT session. There was almost perfect concordance between the BMV-grade calculated at the last SRT session and at SRT2 (r = 0.89; p < 0.001). CONCLUSION: Repeated SRT doesn't lead to a marked alteration in the general condition, KPS was maintained at over 70% for more than 95% of patients during all SRTs. Long survival can be expected, especially in low-grade BMV patients. WBRT shouldn't be aborted, especially for patients developing more than twelve BMs annually.

Radionecrosis after repeated courses of radiotherapy under stereotactic conditions for brain metastases: Analysis of clinical and dosimetric data from a retrospective cohort of 184 patients.

PURPOSE: Between 10 and 40% of patients with cancer will develop one or more brain metastases (BMs). Stereotactic radiotherapy (SRT) is part of the therapeutic arsenal for the treatment of de novo or recurrent BM. Its main interest is to delay whole brain radiation therapy (WBRT), which may cause cognitive toxicity. However, SRT is not exempt from long-term toxicity, and the most widely known SRT is radionecrosis (RN). The objective of this study was to analyze the occurrence of RN per BM and per patient. MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs by two to six SRT sessions for local or distant brain recurrence without previous or intercurrent WBRT were retrospectively reviewed. RN was examined on trimestral follow-up MRI and potentially confirmed by surgery or nuclear medicine. For each BM and SRT session plan, summation V12Gy, V14Gy, V21Gy and V23Gy isodoses were collected. Volumes of intersections were created between the 12Gy isodose at the first SRT and the 18Gy isodose of the following SRT (V18-12Gy). RESULTS: At the end of follow-up, 23.0% of patients presented RN, and 6.3% of BM presented RN. Median follow-up of BM was 13.3 months (95%CI 18.3-20.8). The median interval between BM irradiation and RN was 8.7 months (95% CI 9.2-14.7). Six-, 12- and 24-month RN-free survival rates per BM were 75%, 54% and 29%, respectively. The median RN-free survival per patient was 15.3 months (95% CI 13.6-18.1). In multivariate analysis, the occurrence of RN per BM was statistically associated with local reirradiation (P<0.001) and the number of SRTs (P<0.001). In univariate analysis, the occurrence of RN per patient was statistically associated with the sum of all V18-12Gy (P=0.02). No statistical association was found in multivariate analysis. A sum of all V18-12Gy of less than 1.5ml was associated with a 14.6% risk of RN, compared with 35.6% when the sum of all V18-12Gy was superior to 1.5ml. The sum of all V18-12Gy larger than 1.5ml was associated with a 74% specificity and 53% sensitivity of RN (P<0.001). CONCLUSION: Based on these results, a small number of BMs show RN during repeated SRT for local or distant recurrent BMs. Local reirradiation was the most predictive factor of brain RN. A V18-12Gy larger than 7.6ml in the case of local reirradiation or larger than 1.5ml in proximity reirradiation were prognostic factors of RN. The more BM patients need radiation therapy, and the longer they survive after irradiation, the higher their individual risk of developing RN.

Detecting anomalies in a deliberately biased tomotherapy plan: Comparison of two patient-specific quality assurance processes involving ArcCHECK® and Gafchromic® EBT3 films.

PURPOSE: This work proposes a comparative evaluation of two of our patient-specific quality assurance processes involving ArcCHECK® (Sun Nuclear) and Gafchromic® EBT3 films (Ashland) in order to determine which detector is able to most effectively detect an anomaly in a deliberately biased tomotherapy plan. MATERIAL AND METHODS: A complex clinical head and neck tomotherapy plan was deliberately biased by introducing six errors: multileaf collimator leaf positional errors by leaving one and two central leafs closed during the whole treatment, initial radiation angle errors (+0.5° and +1.0°) and multileaf collimator leafs opening time errors (+0.5% and +1.0%). For each error-induced plan, comparison of ArcCHECK® with Gafchromic® EBT3 films (20.3×25.4cm2) was performed through two methods: a dose matrices subtraction study and a gamma index analysis. RESULTS: The dose matrices subtraction study shows that our ArcCHECK® processing is able to detect all the six induced errors contrary to the one using films, which are only able to detect the two biases involving multileaf collimator leaf positional errors. The gamma index analysis confirms the previous method, since it shows all six errors induced in the reference plan seem to be widely detected with ArcCHECK® with the more restrictive 1%/1mm gamma criterion, whereas films may only be able to detect biases in relation to multileaf collimator leaf positional errors. It also shows the common 3%/3mm gamma criterion does not allow deciding between both detectors in the detection of the six induced biases. CONCLUSION: Both comparative methods showed ArcCHECK® processing is more suitable to detect the six errors introduced in the reference treatment plan.

[Risk of radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases]. / Risque de radionécrose après radiothérapie hypofractionnée en conditions stéréotaxiques du lit opératoire de métastases cérébrales.

PURPOSE: To investigate the factors that potentially lead to brain radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases. METHODS AND MATERIALS: A retrospective analysis conducted in two French centres, was performed in patients treated with trifractionated stereotactic radiotherapy (3×7.7Gy prescribed to the 70% isodose line) for resected brain metastases. Patients with previous whole-brain irradiation were excluded of the analysis. Radionecrosis was diagnosed according to a combination of criteria including clinical, serial imaging or, in some cases, histology. Univariate and multivariate analyses were performed to determine the predictive factors of radionecrosis including clinical and dosimetric variables such as volume of brain receiving a specific dose (V8Gy-V22Gy). RESULTS: One hundred eighty-one patients, with a total of 189 cavities were treated between March 2008 and February 2015. Thirty-five patients (18.5%) developed radionecrosis after a median follow-up of 15 months (range: 3-38 months) after hypofractionated stereotactic radiotherapy. One third of patients with radionecrosis were symptomatic. Multivariate analysis showed that infra-tentorial location was predictive of radionecrosis (hazard ratio [HR]: 2.97; 95% confidence interval [95% CI]: 1.47-6.01; P=0.0025). None V8Gy-V22Gy was associated with appearance of radionecrosis, even if V14Gy trended toward significance (P=0.059). CONCLUSION: Analysis of patients and treatment variables revealed that infratentorial location of brain metastases was predictive for radionecrosis after hypofractionated stereotactic radiotherapy for postoperative resection cavities.

[Pediatric medulloblastoma: Retrospective series of 52 patients]. / Médulloblastomes de l'enfant: étude rétrospective portant sur 52 patients.

PURPOSE: Retrospective analysis of the results of 52 children irradiated for a medulloblastoma. PATIENTS AND METHODS: Between 1974 and 2012, 52 children with an average age of 6 years and a half (11 months-17 years and a half) were treated with surgery then with radiotherapy at the Comprehensive Cancer Centre of Strasbourg (France). For 44 children, the treatment consisted of a chemotherapy. RESULTS: After a mean follow-up of 106.6 months (7-446 months), 13 relapses and 24 deaths were observed. Overall survival at 5 years and 10 years were 62% and 57%, respectively. Disease-free survival at 5 years and 10 years were 80% and 63%, respectively. Univariate analysis found the following adverse prognostic factors: the existence of a postoperative residue, the positivity of the cerebrospinal fluid, the metastatic status and medulloblastoma of high-risk. Positivity of the cerebrospinal fluid remains a negative factor in multivariate analysis. CONCLUSION: These results confirm the survival rate obtained by a conventional approach (surgery then irradiation). Insufficiency of results and rarity of medulloblastoma require the establishment of international protocols.

[Adult medulloblastoma: Retrospective series of 21 patients]. / Médulloblastomes de l'adulte: étude rétrospective portant sur 21 patients.

PURPOSE: Retrospective analysis of the results of 21 adults treated for medulloblastoma. PATIENTS AND METHODS: Between 1978 and 2011, 21 adults with an average age of 31 years (18.3-50) were treated with surgery then with radiotherapy (n=20) at the Comprehensive Cancer Center of Strasbourg. For some (n=12), treatment consisted of chemotherapy. RESULTS: After a mean follow-up of 122 months (19-423), six relapses and seven deaths were observed. Overall survival at 5 years and 10 years was 89.4 ± 7.1% for both. Disease-free survival at 5 years and 10 years was 79.6 ± 9.2% and 85.7 ± 7.6% and 60.6 ± 17.7%, respectively. CONCLUSION: The rarity of medulloblastoma, especially in adults and these results confirm the necessity of international protocols.

Mitochondrial targeting by use of lipid nanocapsules loaded with SV30, an analogue of the small-molecule Bcl-2 inhibitor HA14-1.

Taking advantage from the development of SV30, a new analogue of the pro-apoptotic molecule HA14-1, the aim of this study was to functionally evaluate SV30 and to develop safe nanocarriers for its administration. By using an inversion phase process, 57nm organic solvent-free lipid nanocapsules loaded with SV30 (SV30-LNCs) were formulated. Biological performance of SV30 and SV30-LNCs were evaluated on F98 cells that express Bax and Bcl-2, through survival assays, HPLC, flow cytometry, confocal microscopy and spectral imaging. We observed that SV30 alone or in combination with paclitaxel, etoposide or beam radiation could trigger cell death in a similar fashion to HA14-1. Although partially blocked by Z-VAD-fmk, this effect was coincident to caspase-3 activation. Hence, we established that SV30-LNCs improved SV30 biological activity together with a potentiation of the mitochondrial membrane potential decrease. Interestingly, flow cytometry and confocal analysis indicated that SV30 itself conferred to LNCs improved mitochondrial targeting skills that may present a great interest toward the development of mitochondria targeted nanomedicines.

Local implantation of doxorubicin drug eluting beads in rat glioma.

We evaluated the safety and the efficacy of doxorubicin drug eluting beads "CM-BC1" when used locally in a 9L glioma model. Twenty microlitres of 1mg/ml CM-BC1 (4µg/rat), 10mg/ml CM-BC1 (40µg/rat) or unloaded beads were injected into the brain of 27 rats which was analyzed on day 8, month 3 or month 6. Then, after tumor implantation, rats were treated locally: (1) control group; (2) a group receiving 20µl of unloaded beads, (3) a group "3×6Gy whole-brain irradiation" (WBI), (4) a group receiving 20µl of 1mg/ml CM-BC1 and (5) a group receiving 20µl of 1mg/ml CM-BC1 followed by a WBI. Both the unloaded beads and the lower dose of 1mg/ml CM-BC1 were well tolerated with no early deaths in opposite to 10mg/ml CM-BC1. Medians of survival for the "1mg/ml CM-BC1" group and the combination group are respectively 28.9 and 64.4 days. These results were significant compared to the "unloaded beads" group. The rat's survival was not significantly improved in comparison with the radiotherapy group. This preliminary evidence suggests that 1mg/ml CM-BC1 could be interesting for recurrent high-grade gliomas. Further work is necessary to improve this seducing tool.

New thermoluminescent dosimeters (TLD): optimization and characterization of TLD threads sterilizable by autoclave.

To improve the performance of mono-extruded TLD threads as a dosimetric thermoluminescent tool (French Patent 9903729), a new process was developed by co-extrusion methodology leading to threads of 600 microm diameter with a 50 microm homogeneous polypropylene sheath. In this optimization work, study of parameters such as LiF:Mg,Cu,P powder granulometry, load rate and proportion of components led to an increased sensitivity of around 40%. Moreover, the co-extrusion technique allowed the threads to be sterilized by humid steam (134 degrees C/18 min) without significant variation of the linearity response between 0 and 30 Gy after gamma irradiation (60Co).