Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Background: Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Methods: This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Results: Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). Conclusions: The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

Ultra-High Dose-Rate, Pulsed (FLASH) Radiotherapy with Carbon Ions: Generation of Early, Transient, Highly Oxygenated Conditions in the Tumor Environment.

It is well known that molecular oxygen is a product of the radiolysis of water with high-linear energy transfer (LET) radiation, which is distinct from low-LET radiation wherein O2 radiolytic yield is negligible. Since O2 is a powerful radiosensitizer, this fact is of practical relevance in cancer therapy with energetic heavy ions, such as carbon ions. It has recently been discovered that large doses of ionizing radiation delivered to tumors at very high dose rates (i.e., in a few milliseconds) have remarkable benefits in sparing healthy tissue while preserving anti-tumor activity compared to radiotherapy delivered at conventional, lower dose rates. This new method is called "FLASH radiotherapy" and has been tested using low-LET radiation (i.e., electrons and photons) in various pre-clinical studies and recently in a human patient. Although the exact mechanism(s) underlying FLASH are still unclear, it has been suggested that radiation delivered at high dose rates spares normal tissue via oxygen depletion. In addition, heavy-ion radiation achieves tumor control with reduced normal tissue toxicity due to its favorable physical depth-dose profile and increased radiobiological effectiveness in the Bragg peak region. To date, however, biological research with energetic heavy ions delivered at ultra-high dose rates has not been performed and it is not known whether heavy ions are suitable for FLASH radiotherapy. Here we present the additive or even synergistic advantages of integrating the FLASH dose rates into carbon-ion therapy. These benefits result from the ability of heavy ions at high LET to generate an oxygenated microenvironment around their track due to the occurrence of multiple (mainly double) ionization of water. This oxygen is abundant immediately in the tumor region where the LET of the carbon ions is very high, near the end of the carbon-ion path (i.e., in the Bragg peak region). In contrast, in the "plateau" region of the depth-dose distribution of ions (i.e., in the normal tissue region), in which the LET is significantly lower, this generation of molecular oxygen is insignificant. Under FLASH irradiation, it is shown that this early generation of O2 extends evenly over the entire irradiated tumor volume, with concentrations estimated to be several orders of magnitude higher than the oxygen levels present in hypoxic tumor cells. Theoretically, these results indicate that FLASH radiotherapy using carbon ions would have a markedly improved therapeutic ratio with greater toxicity in the tumor due to the generation of oxygen at the spread-out Bragg peak.

An open-source software for monitoring intrafraction motion during external beam radiation therapy based on superimposition of contours of projected ROIs on cine-MV images.

PURPOSE: To present an open-source software (https://github.com/CHUSRadOncPhys/FluoMV) for monitoring intrafraction motion that is based on the visualization of superimposed contours of projected region-of-interests from DICOM RTSTRUCT files on cine-MV images acquired and displayed in real-time during radiation therapy delivery. Clinical use with prostate gold fiducial markers is presented. METHODS: Projections of regions of interest (ROI) in the reference frame of the electronic portal imaging device are computed offline for different gantry angles before the first treatment fraction. During treatment delivery, the contrast of portal images is automatically adjusted using a histogram equalization algorithm. The projections associated with the current gantry angle are then superimposed on the images in real time. This allows the therapist to evaluate if the imaged structures of interest remain within their respective contours during treatment delivery and to potentially interrupt the treatment if deemed necessary. The spatial accuracy of the method was evaluated by imaging a ball bearing phantom in a set-up where the position of the projected ROI is highly sensitive to gantry angle errors. The visibility of fiducial markers during one fraction of seven different volumetric modulated arc therapy (VMAT) prostate treatments is characterized. RESULTS: The geometric validation showed a negligible systematic error µ < 0.1 mm for the position of the projections. The random errors associated with the time accuracy of the gantry angle readout were characterized by standard deviations σ ≤ 0.6 mm. The VMAT clinical treatments showed that the fiducial markers were frequently visible, allowing for a meaningful clinical use. CONCLUSIONS: The results demonstrate that the method presented is sufficiently accurate to be used for intrafraction monitoring of patients. The fact that this method could be implemented on many modern linacs at little to no cost and with no additional dose delivered to the patients makes this solution very attractive for improving patient care and safety in radiation therapy.

Orbital metastasis secondary to merkel cell carcinoma: case report and literature review.

INTRODUCTION: Merkel cell carcinoma is an aggressive malignancy often associated with metastatic spread, but has never been reported to metastasize to the orbit. CASE: An 80 year old male with metastatic Merkel cell carcinoma presented with ptosis and extraocular movement abnormalities, and was found to have a lesion of the orbit consistent with metastatic spread. The lesion responded favorably to radiation therapy. COMMENT: Although the orbit is a frequent site of metastatic disease, this is the first reported case of presumed Merkel cell carcinoma metastasizing to the orbit.