Dose-fractionation studies of a Plasmodium phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria.

UCT594 is a 2-aminopyrazine carboxylic acid Plasmodium phosphatidylinositol 4-kinase inhibitor with potent asexual blood-stage activity, the potential for interrupting transmission, as well as liver-stage activities. Herein, we investigated pharmacokinetic/pharmacodynamic (PK/PD) relationships relative to blood-stage activity toward predicting the human dose. Dose-fractionation studies were conducted in the Plasmodium falciparum NSG mouse model to determine the PK/PD indices of UCT594, using the in vivo minimum parasiticidal concentration as a threshold. UCT594 demonstrated concentration-dependent killing in the P. falciparum-infected NSG mouse model. Using this data and the preclinical pharmacokinetic data led to a low predicted human dose of <50 mg. This makes UCT594 an attractive potential antimalarial drug.

Overview of Radiation Therapy in the Management of Localized and Metastatic Prostate Cancer.

PURPOSE OF REVIEW: The goal is to describe the evolution of radiation therapy (RT) utilization in the management of localized and metastatic prostate cancer. RECENT FINDINGS: Long term data for a variety of hypofractionated definitive RT dose-fractionation schemes has matured, allowing patients and providers many standard-of-care options to choose from. Post-prostatectomy, adjuvant RT has largely been replaced by an early salvage approach. Multiparametric MRI and PSMA PET have enabled increasingly targeted RT delivery to the prostate and oligometastatic tumors. Areas of active investigation include determining the value of proton beam therapy and perirectal spacers, and optimally incorporate genomic tumor profiling and next generation hormonal therapies with RT in the curative setting. The use of radiation therapy to treat prostate cancer is rapidly evolving. In the coming years, there will be continued improvements in a variety of areas to enhance the value of RT in multidisciplinary prostate cancer management.

Integrating Pharmacokinetic-Pharmacodynamic Modeling and Physiologically Based Pharmacokinetic Modeling to Optimize Human Dose Predictions for Plasmodium falciparum Malaria: a Chloroquine Case Study.

The translation of a preclinical antimalarial drug development candidate to the clinical phases should be supported by rational human dose selection. A model-informed strategy based on preclinical data, which incorporates pharmacokinetic-pharmacodynamic (PK-PD) properties with physiologically based pharmacokinetic (PBPK) modeling, is proposed to optimally predict an efficacious human dose and dosage regimen for the treatment of Plasmodium falciparum malaria. The viability of this approach was explored using chloroquine, which has an extensive clinical history for malaria treatment. First, the PK-PD parameters and the PK-PD driver of efficacy for chloroquine were determined through a dose fractionation study in the P. falciparum-infected humanized mouse model. A PBPK model for chloroquine was then developed for predicting the drug's PK profiles in a human population, from which the human PK parameters were determined. Lastly, the PK-PD parameters estimated in the P. falciparum-infected mouse model and the human PK parameters derived from the PBPK model were integrated to simulate the human dose-response relationships against P. falciparum, which subsequently allowed the determination of an optimized treatment. The predicted efficacious human dose and dosage regimen for chloroquine were comparable to those recommended clinically for the treatment of uncomplicated, drug-sensitive malaria, which provided supportive evidence for the proposed model-based approach to antimalarial human dose predictions.

Immunogenicity, efficacy, and safety of SARS-CoV-2 vaccine dose fractionation: a systematic review and meta-analysis.

BACKGROUND: Dose fractionation of a coronavirus disease 2019 (COVID-19) vaccine could effectively accelerate global vaccine coverage, while supporting evidence of efficacy, immunogenicity, and safety are unavailable, especially with emerging variants. METHODS: We systematically reviewed clinical trials that reported dose-finding results and estimated the dose-response relationship of neutralizing antibodies (nAbs) of COVID-19 vaccines using a generalized additive model. We predicted the vaccine efficacy against both ancestral and variants, using previously reported correlates of protection and cross-reactivity. We also reviewed and compared seroconversion to nAbs, T cell responses, and safety profiles between fractional and standard dose groups. RESULTS: We found that dose fractionation of mRNA and protein subunit vaccines could induce SARS-CoV-2-specific nAbs and T cells that confer a reasonable level of protection (i.e., vaccine efficacy > 50%) against ancestral strains and variants up to Omicron. Safety profiles of fractional doses were non-inferior to the standard dose. CONCLUSIONS: Dose fractionation of mRNA and protein subunit vaccines may be safe and effective, which would also vary depending on the characteristics of emerging variants and updated vaccine formulations.

Acute skin toxicity of conventional fractionated versus hypofractionated radiotherapy in breast cancer patients receiving regional node irradiation: the real-life prospective multicenter HYPOBREAST cohort.

BACKGROUND: Large-scale trials have shown that hypofractionated adjuvant breast radiotherapy was as effective in terms of survival and local control as conventional fractionated radiotherapy, and acute toxicity was reduced with hypofractionated radiotherapy. However, there is a lack of data about the toxicity of breast with regional nodal irradiation (RNI). The aim of this study was to assess the effect of fractionation on radiation-related acute skin toxicity in patients receiving RNI in addition to whole-breast or chest wall irradiation, using real-life data. METHODS: We conducted a prospective, multicenter cohort study with systematic computerized data collection integrated into Mosaiq®. Three comprehensive cancer centers used a standardized form to prospectively collect patient characteristics, treatment characteristics and toxicity. RESULTS: Between November 2016 and January 2022, 1727 patients were assessed; 1419 (82.2%) and 308 (17.8%) patients respectively received conventional fractionated and hypofractionated radiation therapy. Overall, the incidence of acute grade 2 or higher dermatitis was 28.4% (490 patients). Incidence was lower with hypofractionated than with conventional fractioned radiation therapy (odds ratio (OR) 0.34 [0.29;0.41]). Two prognostic factors were found to increase the risk of acute dermatitis, namely 3D (vs IMRT) and breast irradiation (vs chest wall). CONCLUSION: Using real-life data from unselected patients with regional nodal irradiation, our findings confirm the decreased risk of dermatitis previously reported with hypofractionated radiation therapy in clinical trials. Expansion of systematic data collection systems to include additional centers as well as dosimetric data is warranted to further evaluate the short- and long-term effects of fractionation in real life.

The implications from the interplay of neoadjuvant chemoradiotherapy and the immune microenvironment in rectal cancer.

Neoadjuvant chemoradiotherapy (nCRT) is recommended for the treatment of locally advanced rectal cancer. Even though the combination of nCRT and immune checkpoint inhibitors (ICIs) has received much attention, the specific combination modes and dose fractions in radiotherapy (RT) are still indistinct. This review focuses on the immunological mechanism involved in nCRT, the clinical efficacy, the immunological effect of different combined strategies, concurrent or sequential nCRT plus ICIs, long-course RT and short-course RT. This review discusses the impact of nCRT on tumor immunity and summarizes the availability of different dose fractions in RT and distinct combined strategies, aiming at providing clues for optimal neoadjuvant therapy options that maximize efficacy and minimize side effects.

Radiotherapy (RT) and/or chemotherapy before surgery is the most common therapeutic strategy for patients with rectal cancer. This review summarizes the changes in tumor immunity, including immune cells and immune components, after receiving RT and chemotherapy. The authors looked for clues to the proper strategy of combined RT, chemotherapy and other novel agents to magnify antitumor immunity based on these changes. In addition, it emphasizes the RT regimens implicated in distinct immune alterations, which might help improve the efficacy of RT in clinical applications.

Hypofractionated volumetric-modulated arc therapy for breast cancer: A propensity-score-weighted comparison of radiation-related toxicity.

We assessed the clinical benefit of combining volumetric-modulated arc therapy (VMAT) and hypofractionated radiotherapy (HF-RT) considering the incidence of radiation-related toxicities. After a retrospective review for breast cancer patients treated with adjuvant RT between 2005 and 2017, a total of 4209 patients treated with three-dimensional conventional fractionation (CF-3D, 50.4 Gy/28 fractions) and 1540 patients treated with HF-RT (768 received HF-3D; 772, HF-VMAT; 40 Gy/15 fractions) were included. A total of 2229 patients (38.8%) received regional node irradiation (RNI): 1642 (39.0%), 167 (21.7%) and 420 (54.4%) received RNI via CF-3D, HF-3D and HF-VMAT, respectively. Acute/subacute and late toxicities were evaluated. Propensity scores were calculated via logistic regression. Grade 2+ acute/subacute toxicities was the highest in CF-3D group (15.0%, 2.6% and 1.6% in CF-3D, HF-3D and HF-VMAT, respectively; P < .001). HF-VMAT reduced Grade 2+ acute/subacute toxicities significantly compared to CF-3D (odds ratio [OR] 0.11, P < .001) and HF-3D (OR 0.45, P = .010). The 3-year cumulative rate of late toxicities was 18.0% (20.1%, 10.9% and 13.4% in CF-3D, HF-3D and HF-VMAT, respectively; P < .001). On sensitivity analysis, the benefit of HF-VMAT was high in the RNI group. Acute and late toxicities were fewer after HF-VMAT than after HF-3D or CF-3D, especially in women who underwent RNI.

Dose Fractionation of Moxifloxacin for Treatment of Tuberculosis: Impact of Dosing Interval and Elimination Half-Life on Microbial Kill and Resistance Suppression.

The repurposed agent moxifloxacin has become an important addition to the physician's armamentarium for the therapy of Mycobacterium tuberculosis When a drug is administered, we need to have metrics for success. As for most antimicrobial chemotherapy, we contend that for Mycobacterium tuberculosis therapy, these metrics should be a decline in the susceptible bacterial burden and the suppression of amplification of less-susceptible populations. To achieve optimal outcomes relative to these metrics, a dose and schedule of administration need to be chosen. For large populations of patients, there are true between-patient differences in important pharmacokinetic parameters. These distributions of parameter values may have an impact on these metrics, depending on what measure of drug exposure drives the metrics. To optimize dose and schedule choice of moxifloxacin, we performed a dose fractionation experiment in the hollow fiber infection model. We examined 12-, 24-, and 48-h dosing intervals with doses of 200, 400, and 800 mg for each interval, respectively. Within each interval, we had an arm where half-lives of 12, 8, and 4 h were simulated. We attempted to keep the average concentration (Cavg) or area under the concentration-time curve (AUC) constant across arms. We found that susceptible bacterial load decline was linked to Cavg, as we had indicated previously. Resistance suppression, a nonmonotonic function, had minimum concentration (Cmin) as the linked index. The 48-h interval with the 4-h half-life had the largest less-susceptible population. Balancing bacterial kill, resistance suppression, toxicity (linked to peak concentration [Cpeak]), and adherence, we conclude that the dose of 400 mg daily is optimal for moxifloxacin.

Retrospective fractional dose reduction in Tc-99m cardiac perfusion SPECT/CT patients: A human and model observer study.

BACKGROUND: In the ongoing efforts to reduce cardiac perfusion dose (injected radioactivity) for conventional SPECT/CT systems, we performed a human observer study to confirm our clinical model observer findings that iterative reconstruction employing OSEM (ordered-subset expectation-maximization) at 25% of the full dose (quarter-dose) has a similar performance for detection of hybrid cardiac perfusion defects as FBP at full dose. METHODS: One hundred and sixty-six patients, who underwent routine rest-stress Tc-99m sestamibi cardiac perfusion SPECT/CT imaging and clinically read as normally perfused, were included in the study. Ground truth was established by the normal read and the insertion of hybrid defects. In addition to the reconstruction of the 25% of full-dose data using OSEM with attenuation (AC), scatter (SC), and spatial resolution correction (RC), FBP and OSEM (with AC, SC, and RC) both at full dose (100%) were done. Both human observer and clinical model observer confidence scores were obtained to generate receiver operating characteristics (ROC) curves in a task-based image quality assessment. RESULTS: Average human observer AUC (area under the ROC curve) values of 0.725, 0.876, and 0.890 were obtained for FBP at full dose, OSEM at 25% of full dose, and OSEM at full dose, respectively. Both OSEM strategies were significantly better than FBP with P values of 0.003 and 0.01 respectively, while no significant difference was recorded between OSEM methods (P = 0.48). The clinical model observer results were 0.791, 0.822, and 0.879, respectively, for the same patient cases and processing strategies used in the human observer study. CONCLUSIONS: Cardiac perfusion SPECT/CT using OSEM reconstruction at 25% of full dose has AUCs larger than FBP and closer to those of full-dose OSEM when read by human observers, potentially replacing the higher dose studies during clinical reading.

A retrospective analysis on safety and effectiveness of hypofractioned post-mastectomy radiotherapy.

The data supporting hypofractionated post-mastectomy radiotherapy is limited. The purpose of this study is to present the experience from Tarnów of hypofractionated PMRT over 20 fractions with respect to toxicity and effectiveness. We delivered post-mastectomy radiotherapy at the dose of 45 Gy in 20 fractions to the chest wall and the draining regional lymph nodes. The primary outcome of interest was to ensure that the rate of grade 3 or greater toxicity from the hypofractionation, at any time point, was non-inferior to standard post-mastectomy radiotherapy. We conducted a retrospective analysis of 211 women with stages I-IV breast cancer. After a median follow-up of 30 months, there were four reported grade 3 toxicities, with grade 3 lymphedema being the most frequent (1.5%). There were 134 reported grade 2 toxicities, with grade 2 fatigue being the most frequent (18%). There were six instances of isolated locoregional (6 of 211; 2.8%). Three-year estimated local recurrence-free survival was 96.4% (95% CI 0.921-0.984). The 3-year estimated distant recurrence-free survival was 77.8% (95% CI 0.699-0.838). To our knowledge, the results presented here are the largest single institution experience of hypofractionated post-mastectomy radiotherapy published in the literature to date. Our fractionation scheme, 45 Gy in 20 fractions, seems to be safe and effective with low toxicity.

A single-institutional experience with low dose stereotactic body radiation therapy for liver metastases.

AIM: This study reports a single-institutional experience treating liver metastases with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: 107 patients with 169 lesions were assessed to determine factors predictive for local control, radiographic response, and overall survival (OS). Machine learning techniques, univariate analysis, and the Kaplan-Meier method were utilized. RESULTS: Patients were treated with a relatively low median dose of 30 Gy in 3 fractions. Fractions were generally delivered once weekly. Median biologically effective dose (BED) was 60 Gy, and the median gross tumor volume (GTV) was 12.16 cc. Median follow-up was 7.36 months. 1-year local control was 75% via the Kaplan-Meier method. On follow-up imaging, 43%, 40%, and 17% of lesions were decreased, stable, and increased in size, respectively. 1-year OS was 46% and varied by primary tumor, with median OS of 34.3, 25.1, 12.5, and 4.6 months for ovarian, breast, colorectal, and lung primary tumors, respectively. Breast and ovarian primary patients had better OS (p < 0.0001), and lung primary patients had worse OS (p = 0.032). Higher BED values, the number of hepatic lesions, and larger GTV were not predictive of local control, radiographic response, or OS. 21% of patients suffered from treatment toxicity, but no grade ≥3 toxicity was reported. CONCLUSION: Relatively low-dose SBRT for liver metastases demonstrated efficacy and minimal toxicity, even for patients with large tumors or multiple lesions. This approach may be useful for patients in whom higher-dose therapy is contraindicated or associated with high risk for toxicity. OS depends largely on the primary tumor.

Feasibility of radiotherapy in nonagenarian patients: a retrospective study.

PURPOSE: Specific information about radiation therapy in nonagenarians is limited. In order to shed more light on the feasibility of radiotherapy in this challenging subgroup, a retrospective study was performed. METHODS: The data of 93 consecutive patients receiving irradiation treatment at the Department of Radiation Oncology, Ordensklinikum Linz Barmherzige Schwestern between June 2005 and December 2016 were analyzed. Patient- and treatment-related factors were extracted from the patient records. Overall survival (OS) was defined as time from irradiation to death or last follow-up. The survival rates were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: The study population of 93 patients was between 90 and 99 years old (median 91 years). It included 59 women (63%) and 34 men (37%). Of these, 38 (41%) received definitive radiotherapy, 14 (15%) received neoadjuvant or adjuvant radiotherapy, whereas a palliative regimen was prescribed in 44% of the cases (n = 41). In all, 79 patients (85%) were able to complete their prescribed course of radiotherapy. While 16 (17%) patients reported grade 2 toxicities or higher, 4 had ≥grade 3 side effects (4%). The median survival was significantly higher in patients treated with adjuvant, neoadjuvant or definitive radiotherapy (13.8 months) compared to patients treated with palliative radiotherapy (3.6 months; p < 0.001). CONCLUSION: Even in patients managed without preradiotherapy comprehensive geriatric assessment, carefully planned fractionated radiotherapy was feasible and resulted in acceptable rates of acute toxicities.

Image processing techniques for high-resolution structure determination from badly ordered 2D crystals.

2D electron crystallography can be used to study small membrane proteins in their native environment. Obtaining highly ordered 2D crystals is difficult and time-consuming. However, 2D crystals diffracting to only 10-12 Šcan be prepared relatively conveniently in most cases. We have developed image-processing algorithms allowing to generate a high resolution 3D structure from cryo-electron crystallography images of badly ordered crystals. These include movie-mode unbending, refinement over sub-tiles of the images in order to locally refine the sample tilt geometry, implementation of different CTF correction schemes, and an iterative method to apply known constraints in the real and reciprocal space to approximate amplitudes and phases in the so-called missing cone regions. These algorithms applied to a dataset of the potassium channel MloK1 show significant resolution improvements to better than 5 Å.

Early versus late prophylactic cranial irradiation in patients with extensive small cell lung cancer.

OBJECTIVE: Previous studies demonstrated that prophylactic cranial irradiation (PCI) significantly reduced the incidence of brain metastases in patients with extensive disease small cell lung cancer (ED-SCLC). However, the appropriate timing for PCI in treating ED-SCLC is still unclear. This study aimed to compare the effect and safety of early versus late PCI. METHODS: Between November 2011 and July 2016, 103 patients with ED-SCLC were reviewed, receiving appropriate imaging tests to exclude brain metastases prior to cranial irradiation. Of these 103 patients, early PCI was performed in 47 patients and the other 56 patients received late PCI. The primary endpoint was the incidence of brain metastases. The progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were also assessed. RESULTS: Early PCI significantly lowered the risk of brain metastases, as compared to late PCI (p = 0.024). Additionally, multivariate analyses demonstrated that early PCI was a favorable independent predictor of the incidence of brain metastases. The PFS and OS of patients in the early and late PCI groups were comparable (PFS: 8.4 months vs. 7.5 months, p = 0.234; OS: 16.1 months vs. 15.2 months, p = 0.753). The AEs were generally acceptable in both groups. CONCLUSION: To reduce the incidence of brain metastases, early PCI is more effective than late PCI for ED-SCLC patients.

Robust image alignment for cryogenic transmission electron microscopy.

Cryo-electron microscopy recently experienced great improvements in structure resolution due to direct electron detectors with improved contrast and fast read-out leading to single electron counting. High frames rates enabled dose fractionation, where a long exposure is broken into a movie, permitting specimen drift to be registered and corrected. The typical approach for image registration, with high shot noise and low contrast, is multi-reference (MR) cross-correlation. Here we present the software package Zorro, which provides robust drift correction for dose fractionation by use of an intensity-normalized cross-correlation and logistic noise model to weight each cross-correlation in the MR model and filter each cross-correlation optimally. Frames are reliably registered by Zorro with low dose and defocus. Methods to evaluate performance are presented, by use of independently-evaluated even- and odd-frame stacks by trajectory comparison and Fourier ring correlation. Alignment of tiled sub-frames is also introduced, and demonstrated on an example dataset. Zorro source code is available at github.com/CINA/zorro.

High-dose-rate brachytherapy as salvage modality for locally recurrent prostate cancer after definitive radiotherapy : A systematic review.

PURPOSE: To review the current status of interstitial high-dose-rate brachytherapy as a salvage modality (sHDR BRT) for locally recurrent prostate cancer after definitive radiotherapy (RT). MATERIALS AND METHODS: A literature search was performed in PubMed using "high-dose-rate, brachytherapy, prostate cancer, salvage" as search terms. In all, 51 search results published between 2000 and 2016 were identified. Data tables were generated and summary descriptions created. The main outcome parameters used were biochemical control (BC) and toxicity scores. RESULTS: Eleven publications reported clinical outcome and toxicity with follow-up ranging from 4-191 months. A variety of dose and fractionation schedules were described, including 19.0 Gy in 2 fractions up to 42.0 Gy in 6 fractions. The 5­year BC ranged from 18-77%. Late grade 3 genitourinary and gastrointestinal toxicity was 0-32% and 0-5.1%, respectively. CONCLUSIONS: sHDR BRT appears as safe and effective salvage modality for the reirradiation of locally recurrent prostate cancer after definitive RT.

BioXmark for high-precision radiotherapy in an orthotopic pancreatic tumor mouse model : Experiences with a liquid fiducial marker.

BACKGROUND AND PURPOSE: High-precision radiotherapy (RT) requires precise positioning, particularly with high single doses. Fiducial markers in combination with onboard imaging are excellent tools to support this. The purpose of this study is to establish a pancreatic cancer mouse model for high-precision image-guided RT (IGRT) using the liquid fiducial marker BioXmark (Nanovi, Kongens Lyngby, Denmark). METHODS: In an animal-based cancer model, different volumes of BioXmark (10-50 µl), application forms, and imaging modalities-cone-beam computer tomography (CBCT) incorporated in either the Small Animal Radiation Research Platform (SARRP) or the small-animal micro-CT Scanner (SkyScan; Bruker, Brussels, Belgium)-as well as subsequent RT with the SARRP system were analyzed to derive recommendations for BioXmark. RESULTS: Even small volumes (10 µl) of BioXmark could be detected by CBCT (SARRP and Skyscan). Larger volumes (50 µl) led to hardening artefacts. The position of BioXmark was monitored at least weekly by CBCT and was stable over 4 months. BioXmark was shown to be well tolerated; no changes in physical condition or toxic side effects were observed in comparison to control mice. BioXmark enabled an exact fusion with the original treatment plan with less hardening artefacts, and minimized the application of contrast agent for fractionated RT. CONCLUSION: An orthotopic pancreatic tumor mouse model was established for high-precision IGRT using a fiducial marker. BioXmark was successfully tested and provides the perfect basis for improved imaging in high-precision RT. BioXmark enables a unique application method and optimal targeted precision in fractionated RT. Therefore, preclinical trials evaluating novel fractionation regimens and/or combination treatment with high-end RT can be performed.

Propensity score matching analysis of a phase II study on simultaneous modulated accelerated radiation therapy using helical tomotherapy for nasopharyngeal carcinomas.

BACKGROUND: Using propensity score matching method (PSM) to evaluate the feasibility and clinical outcomes of simultaneous modulated accelerated radiation therapy (SMART) using helical tomotherapy (HT) in patients with nasopharyngeal carcinoma (NPC). METHODS: Between August 2007 and January 2016, 381 newly diagnosed NPC patients using HT were enrolled in pre-PSM cohort, including 161 cases in a prospective phase II study (P67.5 study, with a prescription dose of 67.5Gy in 30 fractions to the primary tumour and positive lymph nodes) and 220 cases in a retrospective study (P70 study, with a prescription dose of 70Gy in 33 fractions to the primary tumour and positive lymph nodes). Acute and late toxicities were assessed according to the established RTOG/EORTC criteria and Common Terminology Criteria for Adverse Events (CTCAE) V 3.0. Survival rate were assessed with Kaplan-Meier method, log-rank test and Cox regression. RESULTS: After matching, 148 sub-pairs of 296 patients were generated in post-PSM cohort. The incidence of grade 3-4 leukopenia, thrombocytopenia and anemia in the P67.5 group was significantly higher than in the P70 study, but no significant different was found in other acute toxicities or late toxicities between the two groups. The median follow-up was 33 months in the P67.5 and P70 group, ranging 12-54 months and 6-58 months, respectively. No significant differences in 3-year local-regional recurrence free survival (LRRFS), distant metastasis-free survival (DMFS), disease free survival (DFS) and overall survival (OS) were observed between the 2 groups. Univariate analysis showed that age, T stage, clinical stage were the main factors effecting survival. Cox proportional hazards model showed that 67.5Gy/30F pattern seemed superior in 3-year OS (HR = 0.476, 95% CI: 0.236-0.957). CONCLUSIONS: Through increasing fraction dose and shortening treatment time, the P67.5 study achieved excellent short-term outcomes and potential clinical benefits, with acceptable acute and late toxicities. TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Registry on 5 July 2014 with a registration code of ChiCTRONC-14,004,895.

Radiosurgical decompression for benign perioptic tumors causing compressive cranial neuropathies: a feasible alternative to microsurgery?

Several studies have reported the efficacy and safety of hypofractionated stereotactic radiosurgery (hSRS) in the treatment of benign perioptic tumors. This study went further and evaluated the feasibility of hSRS in the treatment of those causing compressive cranial neuropathies (CCNs) among perioptic tumors with special consideration of functional improvement. Twenty-six patients with CCNs (CN II = 19; CN III/IV/VI = 9; CN V = 3) caused by perioptic tumors underwent hSRS between 2011 and 2015. hSRS was delivered in five fractions with a median marginal dose of 27.8 Gy (≈14 Gy in a single fraction, assuming an α/ß of three) to a tumor volume of 8.2 ± 8.3 cm3. All tumors except one shrank after treatment, with a mean volume decrease of 35 % (range 4-84 %) during the mean follow-up period of 20 months. In 19 patients (38 eyes) with compressive optic neuropathy, vision improved in 55.3 % of eyes (n = 21), was unchanged in 36.8 % (n = 14), and worsened in 7.9 % (n = 3) (2.6 % after excluding two eyes deteriorated due to transient tumor swelling). A higher conformity index (p = 0.034) and volume of the optic apparatus receiving >23.0 Gy (p = 0.019) were associated with greater tumor shrinkage. A greater decrease in tumor volume (p = 0.035) was associated with a better improvement in vision. Ophthalmoplegia and facial hypesthesia improved in six of nine (66.7 %) and three of three (100 %) patients, respectively. There was no newly developed neurological deficit. Decompressive SRS for benign perioptic tumors causing CCN is feasible using hypofractionation, representing a useful alternative to microsurgical resection.

Prophylactic cranial irradiation could improve overall survival in patients with extensive small cell lung cancer : A retrospective study.

OBJECTIVE: To evaluate the effect of prophylactic cranial irradiation (PCI) on overall survival (OS) in patients with extensive small cell lung cancer (ESCLC). METHODS: Between April 2005 and May 2014, 204 patients with ESCLC who had any response (according to RECIST 1.1) to initial chemotherapy were reviewed. All patients had undergone appropriate imaging tests to exclude brain metastases before initial chemotherapy. PCI was performed on 45 patients (22.1 %) and the remaining patients (77.9 %) received no such treatment (control group). Primary endpoint was OS. The incidence of brain metastases, brain metastases-free survival (BMFS), and adverse effects were also evaluated. RESULTS: Survival data of the 204 patients were analyzed statistically. PCI significantly prolonged median OS from 12.6 to 16.5 months as compared to the control group (hazard ratio, HR, 0.63; 95 % confidence interval, CI, 0.41 to 0.96; p = 0.033). PCI significantly lowered the risk of brain metastases (HR 0.48; 95 % CI 0.30 to 0.76; p = 0.001). The 1­year incidence of brain metastases was 17.1 and 55.9 % in the PCI and control group, respectively. PCI significantly correlated with the increased median BMFS (p = 0.002). Additionally, multivariate analyses demonstrated that PCI was a favorable independent predictor of OS, BMFS, and the incidence of brain metastases. Acute and chronic adverse effects were generally low grade and well tolerated in patients receiving PCI. CONCLUSION: PCI after any response to initial chemotherapy significantly improved OS of ESCLC patients analyzed in this study.