[Spatially fractionated radiotherapy : introduction into clinical practice]. / Radiothérapie fractionnée dans l'espace : introduction en pratique clinique.

Spatially fractionated radiotherapy is a new concept involving partial irradiation of tumor volumes. Different techniques are described: mini-beam and micro-beam radiotherapy (pre-clinical) and LATTICE radiotherapy (L-RT) (clinical). Although L-RT is emergent in clinical practice and its evidence is still limited, it has still revealed excellent outcomes. At least three clinical situations can be discussed: definitive palliative radiotherapy, dose escalation (boost) or salvage radiotherapy. The interaction between L-RT and the immune system is still under investigation. Preclinical observations have already demonstrated a strong interaction, with tumor response dependent on immune system stimulation and the generation of an abscopal effect.

La radiothérapie fractionnée dans l'espace est un nouveau concept consistant en une irradiation partielle des volumes tumoraux. Plusieurs techniques sont ainsi décrites : les radiothérapies mini-beam et micro-beam (pré-clinique) et la radiothérapie LATTICE (L-RT) (clinique). Bien que la L-RT soit relativement nouvelle dans la pratique clinique et que les preuves quant à son utilisation soient encore limitées, elle montre des résultats prometteurs. Au moins trois situations cliniques peuvent être examinées en détail : la radiothérapie palliative définitive, l'escalade de dose (boost) ou encore la radiothérapie de sauvetage. L'interaction entre la L-RT et le système immunitaire est encore en cours d'investigation, mais des observations précliniques ont déjà démontré une interaction forte, avec notamment la dépendance de la réponse tumorale à la stimulation du système immunitaire et la génération d'un effet abscopal.

Stereotactic Gamma Knife Radiosurgery for Extracranial Arteriovenous Malformations.

INTRODUCTION: Head and neck extracranial arteriovenous malformations (AVMs) are rare pathological conditions which pose diagnostic and reconstruction challenges. Stereotactic radiosurgery (SRS) is nowadays an established treatment method for brain AVMs, with high obliteration and low complication rates. Here we describe the first report of head extracranial AVMs successfully treated by Gamma Knife (GK) as a retrospective historical cohort. METHODS: Over a 9-year period, 2 cases of extracranial AVMs were treated by GK Perfexion (Elekta Instruments AB, Stockholm, Sweden) at a single institution. A stereotactic frame and multimodal imaging, including digital subtraction angiography (DSA), were used. The prescribed dose was 24 Gy at the 50% isodose line. RESULTS: The first case was of a patient with pulsating tinnitus and left superficial parotido-condylian AVM. Embolization achieved partial obliteration. Tinnitus disappeared during the following 6 months after GK. The second case was a patient with repetitive gingival hemorrhages and right superior maxillary AVM, fed by the right internal maxillary and facial arteries. Embolization achieved partial obliteration with recurrence of symptoms. GK was further performed. DSA confirmed complete obliteration in both patients. CONCLUSIONS: Single-fraction GK radiosurgery appears to be safe and effective for extracranial AVMs. We recommend prescribing doses that are comparable to the ones used for brain AVMs (i.e., 24 Gy). A stereotactic frame is an important tool to ensure higher accuracy in the context of these particular locations. However, in selected cases, a mask could be applied either for single fraction purposes (if in a non-mobile location) or for hypofractionation, in case of larger volumes. These findings should be validated in larger cohorts, inclusively in terms of dose prescription.

Gamma Knife radiosurgery for intravestibular and intracochlear schwannomas.

BACKGROUND: Schwannomas of the VIIIth cranial nerve are benign tumours, with vast majority occurring in vestibular division. Rarely, they can also arise from distal branches of cochlear, superior or inferior vestibular. We review our experience with Gamma Knife radiosurgery (GKR), as first intention treatment for intracochlear (ICS) and intravestibular (IVS) schwannomas. METHODS: A total number of five patients were analysed, treated over 8 years, between June 2010 and September 2018, with Leksell Gamma Knife Perfexion or Icon (Elekta Instruments, AB, Sweden). The marginal dose prescribed was 12 Gy at a mean prescription isodose line of 61.4% (range 50-70). Clinical evaluation included auditory and facial function. RESULTS: The mean age was 49.9 (range 34-63). The mean follow-up period was 52.8 months (range 12-84). The mean target volume (TV) was 0.087 ml (range 0.014-0.281). The mean maximal dose received by the cochlea was 11.2 Gy (range 2.6-20.3). The mean marginal dose received by the vestibule (e.g. utricula) was 14.2 Gy (range 3.8-17.5). No patient experienced an acute or subacute clinical adverse radiation effect after GKR. Four cases had overall symptom stability. In one patient (1/5), the vertigo, which was the main clinical complain, disappeared 1 year after GKR. However, it reappeared 3 years later, with same pretherapeutic characteristics and is currently fluctuating. One patient experienced hearing decrease after GKR, during the first 12 months. This case received 11.2 Gy to the cochlea. Follow-up MRI course showed a decrease in size in four patients, and stability in one. CONCLUSIONS: Gamma Knife radiosurgery is a valuable first intention treatment for ICS or IVS, in selected cases. Special attention should be paid for the dose delivered to the cochlea and the vestibular apparatus. Acute and subacute clinical effects are exceptional, while tumour control was achieved in all cases in our small series.

Lausanne checklist for safe stereotactic radiosurgery.

INTRODUCTION: Stereotactic radiosurgery (SRS) is increasingly used as a minimally invasive alternative in many neurosurgical conditions, including benign and malignant tumors, vascular malformations, and functional procedures. As for any surgical procedure, strict safety guidelines and checklists are necessary to avoid errors and the inherent unnecessary complications. With regard to the former, other groups have already reported human and/or technical errors. We describe our safety checklist for Gamma Knife radiosurgical procedures. METHODS: We describe our checklist protocol after an experience gained over 1500 radiosurgical procedures, using Gamma Knife radiosurgery, performed over a period of 8 years, while employing the same list of items. Minor implementation has been performed over time to address some safety issues that could be improved. RESULTS: Two types of checklist are displayed. One is related to the indications when a specific tissue volume is irradiated, including tumors or vascular disorders. The second corresponds to functional disorders, such as when the dose is prescribed to one specific point. Using these checklists, no human error had been reported during the past 8 years of practice in our institution. CONCLUSION: The use of a safety checklist for SRS procedures promotes a zero-tolerance attitude for errors. This can lower the complications and is of major help in promoting multidisciplinary cooperation. We highly recommend the use of such tool, especially in the context of the increased use of SRS in the neurosurgical field.

Impact of the Mean Cochlear Biologically Effective Dose on Hearing Preservation After Stereotactic Radiosurgery for Vestibular Schwannoma: A Retrospective Longitudinal Analysis.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) is a useful alternative for small- to medium-sized vestibular schwannoma. To evaluate whether biologically effective dose (BED Gy2.47 ), calculated for mean (BED Gy2.47 mean) and maximal (BED Gy2.47 max) cochlear dose, is relevant for hearing preservation. METHODS: This is a retrospective longitudinal single-center study. Were analyzed 213 patients with useful baseline hearing. Risk of hearing decline was assessed for Gardner-Robertson classes and pure tone average (PTA) loss. The mean follow-up period was 39 months (median 36, 6-84). RESULTS: Hearing decline (Gardner-Robertson class) 3 years after SRS was associated with higher cochlear BED Gy2.47 mean (odds ratio [OR] 1.39, P = .009). Moreover, BED Gy2.47 mean was more relevant as compared with BED Gy2.47 max (OR 1.13, P = .04). Risk of PTA loss (continuous outcome, follow-up minus baseline) was significantly corelated with BED Gy2.47 mean at 24 (beta coefficient 1.55, P = .002) and 36 (beta coefficient 2.01, P = .004) months after SRS. Risk of PTA loss (>20 dB vs ≤) was associated with higher BED Gy2.47 mean at 6 (OR 1.36, P = .002), 12 (OR 1.36, P = .007), and 36 (OR 1.37, P = .02) months. Risk of hearing decline at 36 months for the BED Gy2.47 mean of 7-8, 10, and 12 Gy 2.47 was 28%, 57%, and 85%, respectively. CONCLUSION: Cochlear BED Gy2.47 mean is relevant for hearing decline after SRS and more relevant as compared with BED Gy2.47 max. Three years after SRS, this was sustained for all hearing decline evaluation modalities. Our data suggest the BED Gy2.47 mean cut-off of ≤8 Gy 2.47 for better hearing preservation rates .

Salvage LATTICE radiotherapy for a growing tumour despite conventional radio chemotherapy treatment of lung cancer.

A 40-year-old patient with cT4cN1M0 squamous cell lung cancer of the upper right lobe received preoperative induction chemotherapy. Systemic induction treatment failed to reverse tumour growth with the addition of conventional radiotherapy (RT). A salvage lattice RT boost of 12 Gy was administered immediately to increase the dose to the tumour. Conventional RT was resumed at the planned dose of 60 Gy. The tumour shrank rapidly, and the patient was surged. The postoperative pathology remained ypT0ypN0 status.

The Relevance of Biologically Effective Dose for Hearing Preservation After Stereotactic Radiosurgery for Vestibular Schwannomas: A Retrospective Longitudinal Study.

BACKGROUND: Stereotactic radiosurgery has become a common treatment approach for small-to-medium size vestibular schwannomas. OBJECTIVE: To evaluate relationship between time (beam-on and treatment) and risk of hearing decline after stereotactic radiosurgery for vestibular schwannomas in patients with Gardner-Robertson (GR) baseline classes I and II. METHODS: This retrospective longitudinal single-center study included 213 patients with GR I and II treated between June 2010 and December 2019. Risk of passing from GR classes I and II (coded 0) to other classes III, IV, and V (coded 1) and the increase in pure tone average (continuous outcome) were evaluated using a mixed-effect regression model. Biologically effective dose (BED) was further assessed for an alpha/beta ratio of 2.47 (Gy 2.47 ). RESULTS: Binary outcome analysis revealed sex, dose rate, integral dose, time [beam-on time odds ratio 1.03, P = .03, 95% CI 1.00-1.06; treatment time ( P = .02) and BED ( P = .001) as relevant. Fitted multivariable model included the sex, dose rate, and BED. Pure tone average analysis revealed age, integral dose received by tumor, isocenter number, time (beam-on time odds ratio 0.20, P = .001, 95% CI 0.083-0.33) and BED ( P = .005) as relevant. CONCLUSION: Our analysis showed that risk of hearing decline was associated with male sex, higher radiation dose rate (cutoff 2.5 Gy/minute), higher integral dose received by the tumor, higher beam-on time ≥20 minutes, and lower BED. A BED between 55 and 61 was considered as optimal for hearing preservation.

The role of single fraction Gamma Knife radiosurgery for intraventricular central neurocytomas and the utility of F-18 fluroethyltyrosine: two case reports.

BACKGROUND: Primary treatment of central neurocytomas is surgical resection. Gamma Knife surgery is considered a valuable therapeutic option in case of residual (after subtotal resection) or recurrent central neurocytomas. Here, we focused on the role of F-18 fluroethyltyrosine as a marker to document tumor progression after initial resection, in the context of an atypical central neurocytoma. We also describe MIB-1's role in evaluating therapeutic decision-making. CASE PRESENTATION: Two patients with central neurocytomas were treated by Gamma Knife surgery in our center. The first case (31-year-old Caucasian male) had atypical central neurocytoma. Four and a half years after surgical resection, magnetic resonance imaging and F-18 fluroethyltyrosine documented clear progression of residual central neurocytoma, further treated by Gamma Knife surgery (18 Gy at 50%, target volume 1.4 cc, and prescription isodose volume 1.8 cc). The initial post-Gamma Knife surgery clinical course was uneventful, with progressive volumetric reduction of residual tumor up to 4.5 years, when out-of-field recurrence was suspected and confirmed by local F-18 fluroethyltyrosine hyperactivity. Second single-fraction Gamma Knife surgery was performed (18 Gy at 50%, target volume 0.49 cc, prescription isodose volume 0.72 cc). The second (32-year-old Caucasian female) had previous subtotal resection and typical central neurocytoma. Seven years later, she had residual tumor progression. Single-fraction Gamma Knife surgery was performed (16 Gy at 50% isodose line, target volume 1.7 cc, and prescription isodose volume 2.5 cc). Last follow-up showed tumor volume reduction. Follow-up magnetic resonance imaging showed important volumetric reduction of both treated lesions. CONCLUSIONS: In atypical central neurocytomas, F-18 fluroethyltyrosine could be used as postoperative examination to detect small tumor remnants, follow-up evaluation following the Gamma Knife surgery or, in select cases, following surgical resection. The role of MIB-1 is important in therapeutic decision-making, as tumors with MIB-1 exceeding 2% are characterized by more aggressive clinical course. Single-fraction Gamma Knife surgery remains a valuable therapeutic option for postoperative residual atypical central neurocytomas and central neurocytoma recurrences.

Percussion assisted radiation therapy in Hodgkin lymphoma allows a marked reduction in heart dose.

BACKGROUND AND PURPOSE: Early-stage Hodgkin lymphoma (HL) is a highly curable disease but the treatment can induce late complications many years later. Irradiation of the healthy heart is inevitable during radiation treatment of mediastinal sites. We developed a novel method to induce a prolonged apnea-like state that can help decrease the dose to organs at risk during radiation therapy. We present the results of the first 8 HL patients treated routinely with percussion assisted radiation therapy (PART) in our clinic. MATERIAL AND METHODS: We used a newly developed high-frequency non-invasive ventilation system to suppress respiratory motion for prolonged periods and push the heart away from the treated volume. RESULTS: All 8 patients were able to rapidly learn the technique and had an advantage to be treated by PART. We lowered the mean heart dose by an average of 3 Gy with similar target coverage compared to a classical free breathing treatment plan. They were all treated for 15 radiotherapy sessions by PART without any notable side effects. CONCLUSIONS: Percussion assisted radiation therapy can be used routinely to reduce the dose to the heart in Hodgkin lymphoma.

Treatment of a first patient with FLASH-radiotherapy.

BACKGROUND: When compared to conventional radiotherapy (RT) in pre-clinical studies, FLASH-RT was shown to reproducibly spare normal tissues, while preserving the anti-tumor activity. This marked increase of the differential effect between normal tissues and tumors prompted its clinical translation. In this context, we present here the treatment of a first patient with FLASH-RT. MATERIAL & METHODS: A 75-year-old patient presented with a multiresistant CD30+ T-cell cutaneous lymphoma disseminated throughout the whole skin surface. Localized skin RT has been previously used over 110 times for various ulcerative and/or painful cutaneous lesions progressing despite systemic treatments. However, the tolerance of these RT was generally poor, and it was hypothesized that FLASH-RT could offer an equivalent tumor control probability, while being less toxic for the skin. This treatment was given to a 3.5-cm diameter skin tumor with a 5.6-MeV linac specifically designed for FLASH-RT. The prescribed dose to the PTV was 15 Gy, in 90 ms. Redundant dosimetric measurements were performed with GafChromic films and alanine, to check the consistency between the prescribed and the delivered doses. RESULTS: At 3 weeks, i.e. at the peak of the reactions, a grade 1 epithelitis (CTCAE v 5.0) along with a transient grade 1 oedema (CTCAE v5.0) in soft tissues surrounding the tumor were observed. Clinical examination was consistent with the optical coherence tomography showing no decrease of the thickness of the epidermis and no disruption at the basal membrane with limited increase of the vascularization. In parallel, the tumor response was rapid, complete, and durable with a short follow-up of 5 months. These observations, both on normal skin and on the tumor, were promising and prompt to further clinical evaluation of FLASH-RT. CONCLUSION: This first FLASH-RT treatment was feasible and safe with a favorable outcome both on normal skin and the tumor.

The Advantage of FLASH Radiotherapy Confirmed in Mini-pig and Cat-cancer Patients.

PURPOSE: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. EXPERIMENTAL DESIGN: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called "FLASH-RT" and irradiation delivered at a conventional dose rate called "Conv-RT." A clinical, phase I, single-dose escalation trial (25-41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. RESULTS: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%. CONCLUSIONS: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients.See related commentary by Harrington, p. 3.

X-rays can trigger the FLASH effect: Ultra-high dose-rate synchrotron light source prevents normal brain injury after whole brain irradiation in mice.

This study is the first proof of concept that the FLASH effect can be triggered by X-rays. Our results show that a 10 Gy whole-brain irradiation delivered at ultra-high dose-rate with synchrotron generated X-rays does not induce memory deficit; it reduces hippocampal cell-division impairment and induces less reactive astrogliosis.

Commissioning of the Leksell Gamma Knife® Icon™.

PURPOSE: The Leksell Gamma Knife (LGK) Icon has been recently introduced to provide Gamma Knife technology with frameless stereotactic treatments which use an additional cone-beam CT (CBCT) imaging system and a motion tracking system (IFMM, Intra-Fraction Motion Management). The system was commissioned for the treatment unit itself as well as the imaging system. METHODS: The LGK Icon was calibrated using an A1SL ionization chamber. EBT3 radiochromic films were employed to independently check the machine calibration, to measure the relative output factors (ROFs) and to collect dose distributions. Coincidence between CBCT isocenter and radiological focus was evaluated by means of EBT3 films. CBCT image quality was investigated in terms of spatial resolution, contrast-to-noise ratio (CNR), and uniformity for the two presets available (low dose and high dose). Computed Tomography Dose Index (CTDI) was also measured for both presets. RESULTS: The absolute dose rate of the LGK Icon was 3.86 ± 0.09 Gy/min. This result was confirmed by EBT3 readings. ROF were found to be 0.887 ± 0.035 and 0.797 ± 0.032 for the 8 mm and 4 mm collimators, respectively, which are within 2% of the Monte Carlo-derived ROF values. Excellent agreement was found between calculated and measured dose distribution with the gamma pass rate >95% of points for the nine dose distributions analyzed with 3%/1 mm criteria. CBCT isocenter was found to be within 0.2 mm with respect to radiological focus. Image quality parameters were found to be well within the manufacturer's specifications with the high-dose preset being superior in terms of CNR and uniformity. CTDI values were 2.41 mGy and 6.32 mGy, i.e. -3.6% and 0.3% different from the nominal values for the low-dose and high-dose presets, respectively. CONCLUSIONS: The LGK Icon was successfully commissioned for clinical use. The use of the EBT3 to characterize the treatment unit was demonstrated to be feasible. The CBCT imaging system operates well within the manufacturer's specifications and provides good geometrical accuracy.