Dose-response relationship between volume base dose and tumor local control in definitive radiotherapy for vaginal cancer.

OBJECTIVE: This study aimed to establish the dose-response relationship between volume base dose and tumor local control for vaginal cancer, including primary vaginal cancer and recurrent gynecologic malignancies in the vagina. MATERIALS AND METHODS: We identified studies that reported volume base dose and local control by searching the PubMed, the Web of Science, and the Cochrane Library Database through August 12, 2023. The regression analyses were performed using probit model between volume based dose versus clinical outcomes. Subgroup analyses were performed according to stratification: publication year, country, inclusion time of patients, patients with prior radiotherapy, age, primaries or recurrent, tumor size, concurrent chemoradiotherapy proportion, dose rate, image modality for planning, and interstitial proportion. RESULTS: A total of 879 patients with vaginal cancer were identified from 18 studies. Among them, 293 cases were primary vaginal cancer, 573 cases were recurrent cancer in the vagina, and 13 cases were unknown. The probit model showed a significant relationship between the HR-CTV (or CTV) D90 versus the 2-year and 3-year local control, P values were 0.013 and 0.014, respectively. The D90 corresponding to probabilities of 90% 2-year local control were 79.0 GyEQD2,10 (95% CI: 75.3-96.6 GyEQD2,10). CONCLUSIONS: A significant dependence of 2-year or 3-year local control on HR-CTV (or CTV) D90 was found. Our research findings encourage further validation of the dose-response relationship of radical radiotherapy for vaginal cancer through protocol based multicenter clinical trials.

The role of spine stereotactic radiosurgery for patients with breast cancer metastases.

PURPOSE: Breast cancer that metastasizes to the spine is associated with low quality of life and poor survival. Radiosurgery has an increasing role in this patient population. This single-institution (2003-2023) study analyzes clinical outcomes and prognostic factors for patients who underwent spinal stereotactic radiosurgery (SSRS) for metastatic breast cancer. METHODS: Ninety patients (155 unique breast cancer spinal metastases) were treated with SSRS. The median age was 57 years (range: 35-88), and the median KPS was 80 (range: 40-100). Forty-two (27%) lesions were managed surgically prior to radiosurgery. At SSRS, 75 (48%) lesions impinged or compressed the spinal cord per the epidural spinal cord scale (ESCC). Seventy-nine (51%) lesions were categorized as potentially unstable or unstable by the Spinal Instability Neoplastic Score (SINS). RESULTS: The median follow-up was 15 months (range: 1-183). The median single-session tumor volume was 25.4 cc (range: 2-197), and the median single-fraction prescription dose was 17 Gy (range: 12-25). Seven (5%) lesions locally progressed. The 1-, 2-, and 5-year local control rates were 98%, 97%, and 92%, respectively. The median overall survival (OS) for the cohort was 32 months (range: 2-183). The 1-, 2-, and 5-year OS rates were 72%, 53%, and 30%, respectively. On univariate analysis, KPS ≥ 80 (p = 0.009, HR: 0.51, 95% CI: 0.31-0.84) was associated with improved OS. Patient-reported pain improved (68%), remained stable (29%), or worsened (3%) following radiosurgery. Fifteen (10%) radiation-induced toxicities were reported. CONCLUSIONS: Spinal radiosurgery is a safe and highly effective long-term treatment modality for metastases to the spine that originate from breast cancer.

Repeat stereotactic radiosurgery for progressive vestibular schwannomas after primary gamma knife radiosurgery.

PURPOSE: Limited data provides guidance on the management of vestibular schwannomas (VSs) that have progressed despite primary Gamma Knife radiosurgery (GKRS). The present article reports our long-term experience after repeat GKRS for VS with sustained progression after solely primary GKRS management. METHODS: A retrospective review of 1997 patients managed between 1987 and 2023 was conducted. Eighteen patients had sustained tumor progression after primary GKRS and underwent repeat GKRS. The median repeat GKRS margin dose was 11 Gy (IQR: 11-12), the median tumor volume was 2.0 cc (IQR: 1.3-6.3), and the median cochlear dose in patients with preserved hearing was 3.9 Gy (IQR: 3-4.1). The median time between initial and repeat GKRS was 65 months (IQR: 38-118). RESULTS: The median follow-up was 70 months (IQR: 23-101). After repeat GKRS, two patients had further tumor progression at 4 and 21 months and required partial resection of their tumors. The 10-year actuarial tumor control rate after repeat GKRS was 88%. Facial nerve function was preserved in 13 patients who had House-Brackmann grade 1 or 2 function at the time of repeat GKRS. Two patients with serviceable hearing preservation (Gardner-Robertson grade 1 or 2) at repeat GKRS retained that function afterwards. In patients with tinnitus, vestibular dysfunction, and trigeminal neuropathy, symptoms remained stable or improved for 16/16 patients, 12/15 patients, and 10/12 patients, respectively. One patient developed facial twitching in the absence of tumor growth 21 months after repeat GKRS. CONCLUSIONS: Repeat GKRS effectively controlled tumor growth and preserved cranial nerve outcomes in most patients whose VS had sustained progression after initial primary radiosurgery.

Comparative effectiveness of frame-based and mask-based Gamma Knife stereotactic radiosurgery in brain metastases: A 509 patient meta-analysis.

PURPOSE: Stereotactic Radiosurgery (SRS) is the primary treatment for patients with limited numbers of small brain metastases. Head fixation is usually performed with framed-based (FB) fixation; however, mask-based (MB) fixation has emerged as a less invasive alternative. A comparative meta-analysis between both approaches has not been performed. METHODS: Databases were searched until August 28th, 2023, to identify studies comparing MB and FB SRS in the treatment of brain metastases. Our outcomes of interest included local tumor control (LTC), radiation necrosis (RN), mortality, and treatment time (TT). Mean difference (MD), risk ratio (RR), and hazard ratio (HR) were used for statistical comparisons. RESULTS: From 295 articles initially identified, six studies (1 clinical trial) involving 509 patients were included. LTC revealed comparable RR at 6-months (RR = 0.95[95%CI = 0.89-1.01], p = 0.12) and a marginal benefit in FB SRS at 1-year (RR = 0.87[95%CI = 0.78-0.96], p = 0.005). However, in oligometastases exclusively treated with single-fraction SRS, LTC was similar among groups (RR = 0.92 [95%CI = 0.89-1.0], p = 0.30). Similarly, in patients with oligometastases treated with single-fraction SRS, RN (HR = 1.69; 95%CI = 0.72-3.97, p = 0.22), TT (MD = -29.64; 95%CI = -80.38-21.10, p = 0.25), and mortality were similar among groups (RR = 0.62; 95%CI = 0.22-1.76, p = 0.37). CONCLUSION: Our findings suggest that FB and MB SRS, particularly oligometastases treated with single-fraction, are comparable in terms of LTC, RN, TT, and mortality. Further research is essential to draw definitive conclusions.

Oscillations in a Spatial Oncolytic Virus Model.

Virotherapy treatment is a new and promising target therapy that selectively attacks cancer cells without harming normal cells. Mathematical models of oncolytic viruses have shown predator-prey like oscillatory patterns as result of an underlying Hopf bifurcation. In a spatial context, these oscillations can lead to different spatio-temporal phenomena such as hollow-ring patterns, target patterns, and dispersed patterns. In this paper we continue the systematic analysis of these spatial oscillations and discuss their relevance in the clinical context. We consider a bifurcation analysis of a spatially explicit reaction-diffusion model to find the above mentioned spatio-temporal virus infection patterns. The desired pattern for tumor eradication is the hollow ring pattern and we find exact conditions for its occurrence. Moreover, we derive the minimal speed of travelling invasion waves for the cancer and for the oncolytic virus. Our numerical simulations in 2-D reveal complex spatial interactions of the virus infection and a new phenomenon of a periodic peak splitting. An effect that we cannot explain with our current methods.

Theoretical evaluation of the impact of diverse treatment conditions by calculation of the tumor control probability (TCP) of simulated cervical cancer Hyperthermia-Radiotherapy (HT-RT) treatments in-silico.

INTRODUCTION: Hyperthermia (HT) induces various cellular biological processes, such as repair impairment and direct HT cell killing. In this context, in-silico biophysical models that translate deviations in the treatment conditions into clinical outcome variations may be used to study the extent of such processes and their influence on combined hyperthermia plus radiotherapy (HT + RT) treatments under varying conditions. METHODS: An extended linear-quadratic model calibrated for SiHa and HeLa cell lines (cervical cancer) was used to theoretically study the impact of varying HT treatment conditions on radiosensitization and direct HT cell killing effect. Simulated patients were generated to compute the Tumor Control Probability (TCP) under different HT conditions (number of HT sessions, temperature and time interval), which were randomly selected within margins based on reported patient data. RESULTS: Under the studied conditions, model-based simulations suggested a treatment improvement with a total CEM43 thermal dose of approximately 10 min. Additionally, for a given thermal dose, TCP increased with the number of HT sessions. Furthermore, in the simulations, we showed that the TCP dependence on the temperature/time interval is more correlated with the mean value than with the minimum/maximum value and that comparing the treatment outcome with the mean temperature can be an excellent strategy for studying the time interval effect. CONCLUSION: The use of thermoradiobiological models allows us to theoretically study the impact of varying thermal conditions on HT + RT treatment outcomes. This approach can be used to optimize HT treatments, design clinical trials, and interpret patient data.

Impact of prostate position-based image-guidance in intensity-modulated radiation therapy for localized prostate cancer.

BACKGROUND/PURPOSE: The long-term clinical impact of prostate position-based image-guided radiotherapy (IGRT) for localized prostate cancer remains unclear. MATERIALS AND METHODS: We retrospectively compared clinical outcomes following intensity-modulated radiation therapy (IMRT) with cone-beam computed tomography-based prostate position-based IGRT (P-IGRT) or without P-IGRT (non-P-IGRT). From June 2011, we applied P-IGRT in IMRT for intermediate-risk (IR) prostate cancer (PCa) (D'Amico risk classification) (76 Gy in 38 fractions, with smaller margins). Clinical outcomes of patients who received P-IGRT between June 2011 and June 2019 were retrospectively compared with those of patients with IR PCa who received IMRT without P-IGRT between October 2002 and May 2011 in our institution (74 Gy in 37 fractions). RESULTS: A total of 222 consecutive patients were analyzed: 114 in the P-IGRT cohort and 108 in the non-P-IGRT cohort. The median follow-up period after IMRT was 7.1 years for the P-IGRT cohort and 10.8 years for the non-P-IGRT cohort. The biochemical failure-free rate was significantly better in the P-IGRT cohort (94.9% for the P-IGRT cohort vs 82.7% for the non-P-IGRT cohort at 10 years, p = 0.041). The rate of rectal bleeding which needs intervention including the use of suppositories was significantly lower in the P-IGRT cohort (p < 0.001). CONCLUSIONS: The use of P-IGRT with higher doses and smaller margins was correlated with significantly better biochemical control, and a lower incidence of rectal bleeding in IMRT for intermediate-risk prostate cancer. The enhanced accuracy using P-IGRT has the potential to independently improve disease control and reduce late rectal bleeding.

Surgical and radiosurgical outcomes for Koos grade 3 vestibular schwannomas.

This study aimed to reveal the preferred initial treatment for Koos grade 3 vestibular schwannomas (VS). We performed a two-institutional retrospective study on 21 patients with Koos grade 3 VS undergoing resection at Yokohama Medical Center and 37 patients undergoing radiosurgery at Yokohama Rosai Hospital from 2010 to 2021. Tumor control, complications, and functional preservation were compared. The median pre-treatment volume and follow-up duration were 2845 mm3 and 57.0 months, respectively, in the resection group and 2127 mm3 and 81.7 months, respectively, in the radiosurgery group. In the resection group, 16 (76.2%) underwent gross total resection, and three patients (14.3%) experienced regrowth; however, no one required additional treatment. In the radiosurgery group, the tumor control rate was 86.5%, and three cases (8.1%) required surgical resection because of symptomatic brainstem compression. Kaplan-Meier analyses revealed that tumors with delayed continuous enlargement and large thin-walled cysts were significantly associated with poor prognostic factors (p = 0.0027, p < 0.001). The pre-radiosurgery growth rate was also associated with the volume increase (p = 0.013). Two cases (9.5%) required additional operation due to complications such as post-operative hematoma and cerebrospinal fluid leaks in the resection group, whereas temporary cranial neuropathies were observed in the radiosurgery group. Two patients (9.5%) had poor facial nerve function (House-Brackmann grading grade 3) in the resection group, while no one developed facial paresis in the radiosurgery group. Trigeminal neuropathy improved only in the resection group.Radiosurgery can be considered for the treatment of Koos grade 3 VS for functional preservation. However, resection may also be considered for patients with severe trigeminal neuropathy or a high risk of volume increments, such as large thin-walled cysts and rapid pre-treatment growth.

Upfront stereotactic radiosurgery versus adjuvant radiosurgery for parasagittal and parafalcine meningiomas: a systematic review and meta-analysis.

Parafalcine and parasagittal (PFPS) are common locations for meningiomas. Surgical resection for these tumors, the first-line treatment, poses challenges due to their proximity to critical structures. This systematic review investigates the use of stereotactic radiosurgery (SRS) as a treatment for PFPS meningiomas, aiming to elucidate its safety and efficacy. The review adhered to PRISMA guidelines. Searches were conducted on MEDLINE, Embase, and Cochrane. Inclusion criteria involved studies on SRS for PFPS meningiomas, reporting procedure outcomes and complications. Tumors were presumed or confirmed to be WHO grade 1. Data was systematically extracted. Meta-analysis was performed where applicable. The review included data from eight studies, 821 patients with 878 lesions. Tumor control was achieved in greater than 80% of cases. Adverse radiation effects were reported in 7.3% of them. Recurrence and further surgical approach were observed in 17.1% and 9.2% of cases, respectively. Symptom improvement was noted in 33.2% of patients. Edema occurred in approximately 25.1% of patients. A subgroup of 283 patients had upfront SRS, achieving tumor control in approximately 97% of such cases. SRS is a safe and effective treatment for PFPS meningiomas, both as an adjuvant therapy and as an upfront treatment for often smaller tumors. Post-SRS edema can typically be managed medically and usually does not require further surgical intervention. Further studies should provide more specific data on PFPS meningiomas. The use of single and hypofractionated SRS for larger volume PFPS meningiomas should be more explored to better define the risks and benefits.

Magnetic resonance-guided focused ultrasound versus percutaneous thermal ablation in local control of bone oligometastases: a systematic review and meta-analysis.

BACKGROUND: The percutaneous thermal ablation techniques (pTA) are radiofrequency ablation, cryoablation, and microwave ablation, suitable for the treatment of bone oligometastases. Magnetic resonance-guided focused ultrasound (MRgFUS) is a noninvasive ablation technique. OBJECTIVES: To compare the effectiveness and safety of MRgFUS and pTA for treating bone oligometastases and their complications. METHODS: Studies were selected with a PICO/PRISMA protocol: pTA or MRgFUS in patients with bone oligometastases; non-exclusive curative treatment. Exclusion criteria were: primary bone tumor; concurrent radiation therapy; palliative therapy; and absence of imaging at follow-up. PubMed, BioMed Central, and Scopus were searched. The modified Newcastle-Ottawa Scale assessed articles quality. For each treatment (pTA and MRgFUS), we conducted two separate random-effects meta-analyses to estimate the pooled effectiveness and safety. The effectiveness was assessed by combining the proportions of treated lesions achieving local tumor control (LTC); the safety by combining the complications rates of treated patients. Meta-regression analyses were performed to identify any outcome predictor. RESULTS: A total of 24 articles were included. Pooled LTC rate for MRgFUS was 84% (N = 7, 95% CI 66-97%, I2 = 74.7%) compared to 65% of pTA (N = 17, 95% CI 51-78%, I2 = 89.3%). Pooled complications rate was similar, respectively, 13% (95% CI 1-32%, I2 = 81.0%) for MRgFUS and 12% (95% CI 8-18%, I2 = 39.9%) for pTA, but major complications were recorded with pTA only. The meta-regression analyses, including technique type, study design, tumor, and follow-up, found no significant predictors. DISCUSSION: The effectiveness and safety of the two techniques were found comparable, even though MRgFUS is a noninvasive treatment that did not cause any major complication. Limited data availability on MRgFUS and the lack of direct comparisons with pTA may affect these findings. CONCLUSIONS: MRgFUS can be a valid, safe, and noninvasive treatment for bone oligometastases. Direct comparison studies are needed to confirm its promising benefits.

Targeting the Tumor Vascular Supply to Enhance Radiation Therapy Administered in Single or Clinically Relevant Fractionated Schedules.

This pre-clinical study was designed to demonstrate how vascular disrupting agents (VDAs) should be administered, either alone or when combined with radiation in clinically relevant fractionated radiation schedules, for the optimal anti-tumor effect. CDF1 mice, implanted in the right rear foot with a 200 mm3 murine C3H mammary carcinoma, were injected with various doses of the most potent VDA drug, combretastatin A-1 phosphate (CA1P), under different schedules. Tumors were also locally irradiated with single-dose, or stereotactic (3 × 5-20 Gy) or conventional (30 × 2 Gy) fractionation schedules. Tumor growth and control were the endpoints used. Untreated tumors had a tumor growth time (TGT5; time to grow to 5 times the original treatment volume) of around 6 days. This increased with increasing drug doses (5-100 mg/kg). However, with single-drug treatments, the maximum TGT5 was only 10 days, yet this increased to 19 days when injecting the drug on a weekly basis or as three treatments in one week. CA1P enhanced radiation response regardless of the schedule or interval between the VDA and radiation. There was a dose-dependent increase in radiation response when the combined with a single, stereotactic, or conventional fractionated irradiation, but these enhancements plateaued at around a drug dose of 25 mg/kg. This pre-clinical study demonstrated how VDAs should be combined with clinically applicable fractionated radiation schedules for the optimal anti-tumor effect, thus suggesting the necessary pre-clinical testing required to ultimately establish VDAs in clinical practice.

Safety and efficacy of helical tomotherapy following lung-sparing surgery in locally advanced malignant pleural mesothelioma.

PURPOSE: To assess the value of radiation therapy (RT) with helical tomotherapy (HT) in the management of locally advanced malignant pleural mesothelioma (MPM) receiving no or lung-sparing surgery. METHODS: Consecutive MPM cases not undergoing extrapleural pneumonectomy and receiving intensity-modulated (IM) HT were retrospectively evaluated for local control, distant control, progression-free survival (PFS), and overall survival (OS). Impact of age, systemic treatment, RT dose, and recurrence patterns was analyzed by univariate and multivariate analysis. As a secondary endpoint, reported toxicity was assessed. RESULTS: A total of 34 localized MPM cases undergoing IMHT were identified, of which follow-up data were available for 31 patients. Grade 3 side effects were experienced by 26.7% of patients and there were no grade 4 or 5 events observed. Median PFS was 19 months. Median OS was 20 months and the rates for 1­ and 2­year OS were 86.2 and 41.4%, respectively. OS was significantly superior for patients receiving adjuvant chemotherapy (p = 0.008). CONCLUSION: IMHT of locally advanced MPM after lung-sparing surgery is safe and feasible, resulting in satisfactory local control and survival. Adjuvant chemotherapy significantly improves OS. Randomized clinical trials incorporating modern RT techniques as a component of trimodal treatment are warranted to establish an evidence-based standard of care pattern for locally advanced MPM.

Let's make size not matter: tumor control and toxicity outcomes of hypofractionated Gamma Knife radiosurgery for large brain metastases.

PURPOSE: Management of patients with large brain metastases poses a clinical challenge, with poor local control and high risk of adverse radiation events when treated with single-fraction stereotactic radiosurgery (SF-SRS). Hypofractionated SRS (HF-SRS) may be considered, but clinical data remains limited, particularly with Gamma Knife (GK) radiosurgery. We report our experience with GK to deliver mask-based HF-SRS to brain metastases greater than 10 cc in volume and present our control and toxicity outcomes. METHODS: Patients who received hypofractionated GK radiosurgery (HF-GKRS) for the treatment of brain metastases greater than 10 cc between January 2017 and June 2022 were retrospectively identified. Local failure (LF) and adverse radiation events of CTCAE grade 2 or higher (ARE) were identified. Clinical, treatment, and radiological information was collected to identify parameters associated with clinical outcomes. RESULTS: Ninety lesions (in 78 patients) greater than 10 cc were identified. The median gross tumor volume was 16.0 cc (range 10.1-56.0 cc). Prior surgical resection was performed on 49 lesions (54.4%). Six- and 12-month LF rates were 7.3% and 17.6%; comparable ARE rates were 1.9% and 6.5%. In multivariate analysis, tumor volume larger than 33.5 cc (p = 0.029) and radioresistant histology (p = 0.047) were associated with increased risk of LF (p = 0.018). Target volume was not associated with increased risk of ARE (p = 0.511). CONCLUSIONS: We present our institutional experience treating large brain metastases using mask-based HF-GKRS, representing one of the largest studies implementing this platform and technique. Our LF and ARE compare favorably with the literature, suggesting that target volumes less than 33.5 cc demonstrate excellent control rates with low ARE. Further investigation is needed to optimize treatment technique for larger tumors.

Outcome assessment of intraoperative radiotherapy for brain metastases: results of a prospective observational study with comparative matched-pair analysis.

PURPOSE: Intraoperative radiation therapy (IORT) is an emerging alternative to adjuvant stereotactic external beam radiation therapy (EBRT) following resection of brain metastases (BM). Advantages of IORT include an instant prevention of tumor regrowth, optimized dose-sparing of adjacent healthy brain tissue and immediate completion of BM treatment, allowing an earlier admission to subsequent systemic treatments. However, prospective outcome data are limited. We sought to assess long-term outcome of IORT in comparison to EBRT. METHODS: A total of 35 consecutive patients, prospectively recruited within a study registry, who received IORT following BM resection at a single neuro-oncological center were evaluated for radiation necrosis (RN) incidence rates, local control rates (LCR), distant brain progression (DBP) and overall survival (OS) as long-term outcome parameters. The 1 year-estimated OS and survival rates were compared in a balanced comparative matched-pair analysis to those of our institutional database, encompassing 388 consecutive patients who underwent adjuvant EBRT after BM resection. RESULTS: The median IORT dose was 30 Gy prescribed to the applicator surface. A 2.9% RN rate was observed. The estimated 1 year-LCR was 97.1% and the 1 year-DBP-free survival 73.5%. Median time to DBP was 6.4 (range 1.7-24) months in the subgroup of patients experiencing intracerebral progression. The median OS was 17.5 (0.5-not reached) months with a 1 year-survival rate of 61.3%, which did not not significantly differ from the comparative cohort (p = 0.55 and p = 0.82, respectively). CONCLUSION: IORT is a safe and effective fast-track approach following BM resection, with comparable long-term outcomes as adjuvant EBRT.

Natural history of lung squamous cell brain metastases in patients treated with radiosurgery: a thirty-year experience at a tertiary medical center.

PURPOSE: In this study we report our 30-year experience in stereotactic radiosurgery (SRS) treatment of lung squamous cell carcinoma (LUSC) brain metastases (BMs). It will serve to provide detailed longitudinal outcomes and predictors of efficacy in treating LUSC-BMs with SRS. METHOD: We retrospectively reviewed 51 patients and 109 tumors treated with SRS at our center between 1993 and 2022. Patient demographics, PDL1 genotype, immunotherapy use and mortality cause were recorded. Radiological and clinical outcomes were followed at 1-3-month intervals post-SRS. Cox-regression analysis and Kaplan-Meier survival curves were performed in statistical analysis. RESULTS: We included 37 male and 14 female patients (median age 62.7 years at BM diagnosis). Median overall survival (OS) time was 6.9 months, 6-month OS rate was 62.1%, and Karnofsky performance scale (KPS) was the only independent predictor. Median time for local control maintenance was 7.6 months, 6-month local control rate was 69.1%, with TKI as the only independent predictor. Median time to distant failure was 5.13 months, 6-month distant failure rate was 51.1%, and factors with significant impact included gender (p = 0.002), presence of extracranial metastases (p < 0.001), use of immunotherapy(p < 0.001), PDL1 genotype (p = 0.034), and total intracranial metastases number (p = 0.008). However, no definitive benefits of immunotherapy were identified in patients with higher PDL1 mutational tumors. CONCLUSION: In this study we defined the natural history of disease progression and outcomes in SRS-treated LUSC-BM patients. We also identified predictors of OS and tumor control among these patients. The findings of this study will serve as a guide when counseling these patients for SRS.

The risk of radiation-induced neurocognitive impairment and the impact of sparing the hippocampus during pediatric proton cranial irradiation.

BACKGROUND AND PURPOSE: Hippocampus is a central component for neurocognitive function and memory. We investigated the predicted risk of neurocognitive impairment of craniospinal irradiation (CSI) and the deliverability and effects of hippocampal sparing. The risk estimates were derived from published NTCP models. Specifically, we leveraged the estimated benefit of reduced neurocognitive impairment with the risk of reduced tumor control. MATERIAL AND METHODS: For this dose planning study, a total of 504 hippocampal sparing intensity modulated proton therapy (HS-IMPT) plans were generated for 24 pediatric patients whom had previously received CSI. Plans were evaluated with respect to target coverage and homogeneity index to target volumes, maximum and mean dose to OARs. Paired t-tests were used to compare hippocampal mean doses and normal tissue complication probability estimates. RESULTS: The median mean dose to the hippocampus could be reduced from 31.3 GyRBE to 7.3 GyRBE (p < .001), though 20% of these plans were not considered clinically acceptable as they failed one or more acceptance criterion. Reducing the median mean hippocampus dose to 10.6 GyRBE was possible with all plans considered as clinically acceptable treatment plans. By sparing the hippocampus to the lowest dose level, the risk estimation of neurocognitive impairment could be reduced from 89.6%, 62.1% and 51.1% to 41.0% (p < .001), 20.1% (p < .001) and 29.9% (p < .001) for task efficiency, organization and memory, respectively. Estimated tumor control probability was not adversely affected by HS-IMPT, ranging from 78.5 to 80.5% for all plans. CONCLUSIONS: We present estimates of potential clinical benefit in terms of neurocognitive impairment and demonstrate the possibility of considerably reducing neurocognitive adverse effects, minimally compromising target coverage locally using HS-IMPT.

Blockade of ß-Adrenergic Receptors by Nebivolol Enables Tumor Control Potential for Uveal Melanoma in 3D Tumor Spheroids and 2D Cultures.

Uveal melanoma (UM) is the most common primary cancer of the eye in adults. A new systemic therapy is needed to reduce the high metastasis and mortality rate. As ß-blockers are known to have anti-tumor effects on various cancer entities, this study focuses on investigating the effect of ß1-selective blockers atenolol, celiprolol, bisoprolol, metoprolol, esmolol, betaxolol, and in particular, nebivolol on UM. The study was performed on 3D tumor spheroids as well as 2D cell cultures, testing tumor viability, morphological changes, long-term survival, and apoptosis. Flow cytometry revealed the presence of all three ß-adrenoceptors with a dominance of ß2-receptors on cell surfaces. Among the blockers tested, solely nebivolol concentration-dependently decreased viability and altered 3D tumor spheroid structure. Nebivolol blocked the repopulation of cells spreading from 3D tumor spheroids, indicating a tumor control potential at a concentration of ≥20 µM. Mechanistically, nebivolol induced ATP depletion and caspase-3/7 activity, indicating that mitochondria-dependent signaling is involved. D-nebivolol or nebivolol combined with the ß2-antagonist ICI 118.551 displayed the highest anti-tumor effects, suggesting a contribution of both ß1- and ß2-receptors. Thus, the present study reveals the tumor control potential of nebivolol in UM, which may offer a perspective for co-adjuvant therapy to reduce recurrence or metastasis.

EGFR mutant status and tyrosine-kinase inhibitors affect the GKRS outcomes for NSCLC brain metastases.

OBJECTIVE: Tyrosine kinase inhibitors (TKIs) is the first-line treatment for EGFR-positive non-small cell lung cancer (NSCLC); however, its applicability to patients with wild-type NSCLC remains an issue of contention. This study compared the effects of gamma knife radiosurgery (GKRS) alone versus combining GKRS and TKIs in treating two genetic forms of NSCLC. METHODS: This retrospective study examined 479 NSCLC patients with 1982 brain metastases who underwent GKRS and for whom imaging follow-up data or death records were available. All our patients were consecutive. All gene mutations were confirmed by lung biopsy. The three main endpoints in this study were overall survival (OS), local intracranial tumor control (LC), and distal intracranial tumor control (DC). RESULTS: There were 296 NSCLC patients with EGFR positive: TKI treatment (n = 262) and without TKI treatment (n = 34). GKRS + TKIs was more effective than GKRS alone in terms of OS (HR 0.53, p = 0.085) and DC (HR 0.51, p < 0.001). There were 150 NSCLC patients with wild-type EGFR: TKI treatment (n = 50) and without TKI treatment (n = 100). GKRS + TKIs was less effective than GKRS alone in terms of OS (HR 1.82, p = 0.049) and DC (HR: 1.40, p = 0.011). We observed no difference in terms of LC in both genetic groups. CONCLUSIONS: Combining GKRS with TKIs proved effective in EGFR positive NSCLC patients; however, we do not observe the similar results when combining GKRS with TKIs for patients with wild-type NSCLC.

Long-term results of upfront, single-session Gamma Knife radiosurgery for large cystic vestibular schwannomas.

Anecdotally, cystic vestibular schwannomas (cVSs) are regarded to have unpredictable biologic activity with poorer clinical results, and most studies showed a less favorable prognosis following surgery. While stereotactic radiosurgery (SRS) is a well-established therapeutic option for small- to medium-sized VSs, cVSs are often larger, thus making upfront SRS more complicated. The purpose of this retrospective study was to assess the efficacy and safety of upfront SRS for large cVSs. The authors reviewed the data of 54 patients who received upfront, single-session Gamma Knife radiosurgery (GKRS) with a diagnosis of large cVS (> 4 cm3). Patients with neurofibromatosis type 2, multiple VSs, or recurrent VSs and < 24 months of clinical and neuroimaging follow-up were excluded. Hearing loss (48.1%) was the primary presenting symptom. The majority of cVSs were Koos grade IV (66.7%), and the most prevalent cyst pattern was "mixed pattern of small and big cysts" (46.3%). The median time between diagnosis and GKRS was 12 months (range, 1-147 months). At GKRS, the median cVS volume was 6.95 cm3 (range, 4.1-22 cm3). The median marginal dose was 12 Gy (range, 10-12 Gy). The mean radiological and clinical follow-up periods were 62.2 ± 34.04 months (range, 24-169 months) and 94.9 ± 45.41 months (range, 24-175 months), respectively. At 2, 6, and 12 years, the tumor control rates were 100%, 95.7%, and 85.0%, respectively. Tumor shrinkage occurred in 92.6% of patients (n = 50), tumor volume remained stable in 5.6% of patients (n = 3), and tumor growth occurred in 1.9% of patients (n = 1). At a median follow-up of 53.5 months, the pre-GKRS tumor volume significantly decreased to 2.35 cm3 (p < 0.001). While Koos grade 3 patients had a greater possibility of attaining higher volume reduction, "multiple small thick-walled cyst pattern" and smaller tumor volumes decreased the likelihood of achieving higher volume reduction. Serviceable hearing (Gardner-Robertson Scale I-II) was present in 16.7% of patients prior to GKRS and it was preserved in all of these patients following GKRS. After GKRS, 1.9% of patients (n = 1) had new-onset trigeminal neuralgia. There was no new-onset facial palsy, hemifacial spasm, or hydrocephalus. Contrary to what was believed, our findings suggest that upfront GKRS seems to be a safe and effective treatment option for large cVSs.

Is salvage surgery for large vestibular schwannomas after failed gamma knife radiosurgery more challenging?

In order to verify whether a previous gamma knife surgery (GKS) treatment could influence the oncological and functional outcome in large vestibular schwannoma (VS) surgery, we have compared group of patients operated on for large VS after failed GKS to a group of genuine VS that underwent the same functional nerve-sparing resection technique regimen in the same period. Single center retrospective cohort study of 23 consecutive GKS failure and 170 genuine VS patients operated on between April 2003 and March 2019. After resection, patients were allocated to a Wait-&-rescan or an upfront GKS policy. At last follow-up examination, the facial nerve function was good (House-Brackmann grades I or II) in 95% of the GKS failure and 84% of the genuine VS patients (p = .25). The median volume of tumor residue was .56 cc in the GKS failure group and .62 cc in the genuine VS group (p = .70). Tumor control was achieved in 91% and 83% of cases with a mean follow-up of 74 and 63 months in the GKS failure and the genuine VS populations, respectively. The 1-, 5-, and 7-year progression-free survival were 100%, 95%, and 85% respectively in the GKS failure group and 97%, 80%, and 81% in the genuine VS group (p = .27). Despite significant modifications of the microsurgical environment associated to salvage surgery after GKS failure, a functional nerve-sparing resection is an effective strategy to optimize the results on facial nerve function, with similar long-term tumor control to those observed in the genuine VS population.