Global post­marketing safety surveillance of Tumor Treating Fields (TTFields) therapy in over 25,000 patients with CNS malignancies treated between 2011-2022.

BACKGROUND: Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes. TTFields therapy is approved for recurrent glioblastoma (rGBM), and newly-diagnosed (nd) GBM (with concomitant temozolomide for ndGBM; US), and for grade IV glioma (EU). We present an updated global, post-marketing surveillance safety analysis of patients with CNS malignancies treated with TTFields therapy. METHODS: Safety data were collected from routine post-marketing activities for patients in North America, Europe, Israel, and Japan (October 2011-October 2022). Adverse events (AEs) were stratified by age, sex, and diagnosis. RESULTS: Overall, 25,898 patients were included (diagnoses: ndGBM [68%], rGBM [26%], anaplastic astrocytoma/oligodendroglioma [4%], other CNS malignancies [2%]). Median (range) age was 59 (3-103) years; 66% patients were male. Most (69%) patients were 18-65 years; 0.4% were < 18 years; 30% were > 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%) patients, respectively. Most common treatment-related AEs were beneath-array skin reactions (43%), electric sensation (tingling; 14%), and heat sensation (warmth; 12%). Treatment-related skin reactions were comparable in pediatric (39%), adult (42%), and elderly (45%) groups, and in males (41%) and females (46%); and similar across diagnostic subgroups (ndGBM, 46%; rGBM, 34%; anaplastic astrocytoma/oligodendroglioma, 42%; other, 40%). No TTFields-related systemic AEs were reported. CONCLUSIONS: This long-term, real-world analysis of > 25,000 patients demonstrated good tolerability of TTFields in patients with CNS malignancies. Most therapy-related AEs were manageable localized, non-serious skin events. The TTFields therapy safety profile remained consistent across subgroups (age, sex, and diagnosis), indicative of its broad applicability.

Association of partial T2-FLAIR mismatch sign and isocitrate dehydrogenase mutation in WHO grade 4 gliomas: results from the ReSPOND consortium.

PURPOSE: While the T2-FLAIR mismatch sign is highly specific for isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted astrocytomas among lower-grade gliomas, its utility in WHO grade 4 gliomas is not well-studied. We derived the partial T2-FLAIR mismatch sign as an imaging biomarker for IDH mutation in WHO grade 4 gliomas. METHODS: Preoperative MRI scans of adult WHO grade 4 glioma patients (n = 2165) from the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium were analyzed. Diagnostic performance of the partial T2-FLAIR mismatch sign was evaluated. Subset analyses were performed to assess associations of imaging markers with overall survival (OS). RESULTS: One hundred twenty-one (5.6%) of 2165 grade 4 gliomas were IDH-mutant. Partial T2-FLAIR mismatch was present in 40 (1.8%) cases, 32 of which were IDH-mutant, yielding 26.4% sensitivity, 99.6% specificity, 80.0% positive predictive value, and 95.8% negative predictive value. Multivariate logistic regression demonstrated IDH mutation was significantly associated with partial T2-FLAIR mismatch (odds ratio [OR] 5.715, 95% CI [1.896, 17.221], p = 0.002), younger age (OR 0.911 [0.895, 0.927], p < 0.001), tumor centered in frontal lobe (OR 3.842, [2.361, 6.251], p < 0.001), absence of multicentricity (OR 0.173, [0.049, 0.612], p = 0.007), and presence of cystic (OR 6.596, [3.023, 14.391], p < 0.001) or non-enhancing solid components (OR 6.069, [3.371, 10.928], p < 0.001). Multivariate Cox analysis demonstrated cystic components (p = 0.024) and non-enhancing solid components (p = 0.003) were associated with longer OS, while older age (p < 0.001), frontal lobe center (p = 0.008), multifocality (p < 0.001), and multicentricity (p < 0.001) were associated with shorter OS. CONCLUSION: Partial T2-FLAIR mismatch sign is highly specific for IDH mutation in WHO grade 4 gliomas.

Radiomic signatures of meningiomas using the Ki-67 proliferation index as a prognostic marker of clinical outcomes.

OBJECTIVE: The clinical behavior of meningiomas is not entirely captured by its designated WHO grade, therefore other factors must be elucidated that portend increased tumor aggressiveness and associated risk of recurrence. In this study, the authors identify multiparametric MRI radiomic signatures of meningiomas using Ki-67 as a prognostic marker of clinical outcomes independent of WHO grade. METHODS: A retrospective analysis was conducted of all resected meningiomas between 2012 and 2018. Preoperative MR images were used for high-throughput radiomic feature extraction and subsequently used to develop a machine learning algorithm to stratify meningiomas based on Ki-67 indices < 5% and ≥ 5%, independent of WHO grade. Progression-free survival (PFS) was assessed based on machine learning prediction of Ki-67 strata and compared with outcomes based on histopathological Ki-67. RESULTS: Three hundred forty-three meningiomas were included: 291 with WHO grade I, 43 with grade II, and 9 with grade III. The overall rate of recurrence was 19.8% (15.1% in grade I, 44.2% in grade II, and 77.8% in grade III) over a median follow-up of 28.5 months. Grade II and III tumors had higher Ki-67 indices than grade I tumors, albeit tumor and peritumoral edema volumes had considerable variation independent of meningioma WHO grade. Forty-six high-performing radiomic features (1 morphological, 7 intensity-based, and 38 textural) were identified and used to build a support vector machine model to stratify tumors based on a Ki-67 cutoff of 5%, with resultant areas under the curve of 0.83 (95% CI 0.78-0.89) and 0.84 (95% CI 0.75-0.94) achieved for the discovery (n = 257) and validation (n = 86) data sets, respectively. Comparison of histopathological Ki-67 versus machine learning-predicted Ki-67 showed excellent performance (overall accuracy > 80%), with classification of grade I meningiomas exhibiting the greatest accuracy. Prediction of Ki-67 by machine learning classifier revealed shorter PFS for meningiomas with Ki-67 indices ≥ 5% compared with tumors with Ki-67 < 5% (p < 0.0001, log-rank test), which corroborates divergent patient outcomes observed using histopathological Ki-67. CONCLUSIONS: The Ki-67 proliferation index may serve as a surrogate marker of increased meningioma aggressiveness independent of WHO grade. Machine learning using radiomic feature analysis may be used for the preoperative prediction of meningioma Ki-67, which provides enhanced analytical insights to help improve diagnostic classification and guide patient-specific treatment strategies.

Definitive radiotherapy for meningeal brainstem melanocytoma: a case report.

Meningeal melanocytomas are rare, benign tumours of the central nervous system arising from the melanocytes of the leptomeninges. First-line treatment consists of either gross or subtotal resection with or without radiotherapy. However, given the sensitive locations of these tumours, alternative treatment options such as definitive radiotherapy may be warranted in patients deemed high-risk or without accessible tumours. A 67-year-old male presenting with spastic gait, frequent falls, and vertical gaze palsy was diagnosed with a 2.4 cm primary meningeal melanocytoma arising from the interpeduncular fossa. Given the critical tumour position within the brainstem, definitive radiotherapy was recommended. He received fractionated stereotactic radiotherapy (FSRT) to a total dose of 54 Gy in 27 fractions, resulting in a gradual improvement in gait and ocular range of motion. Follow-up imaging over the next three years revealed largely stable disease and an increase in edema with mild upper extremity weakness that improved with steroids. He was followed for three years and expired four years after treatment due to pneumonia. For patients unable to receive surgical resection, definitive RT may provide local control with minimal morbidity.

The safety profile of Tumor Treating Fields (TTFields) therapy in glioblastoma patients with ventriculoperitoneal shunts.

INTRODUCTION: Tumor Treating Fields (TTFields, 200 kHz) therapy is a noninvasive, locoregional cancer treatment approved for use in newly diagnosed glioblastoma (GBM), recurrent GBM, and malignant pleural mesothelioma. GBM patients with hydrocephalus may require implantation of a ventriculoperitoneal (VP) shunt, however, the current TTFields therapy label does not include the use of VP shunts in GBM patients due to insufficient safety data. This analysis evaluates the safety of TTFields therapy use in this population. METHODS: Unsolicited post-marketing global surveillance data from patients with GBM and a VP shunt (programmable/non-programmable) who received TTFields therapy between November 2012-April 2021 were retrospectively analyzed. Adverse events (AEs) were assessed using the Medical Dictionary for Regulatory Activities version 24.0. RESULTS: Overall, 156 patients with VP shunts were identified and included in this analysis. In total, 77% reported ≥ 1 AE; the most common TTFields therapy-related AEs were non-serious and localized, beneath-array skin AEs (43%). The incidence and categories of AEs were comparable between patients with or without VP shunts. Six patients with VP shunts experienced seven serious TTFields therapy-related AEs: skin erosion at the shunt site (n = 3); wound dehiscence at the shunt site (n = 2) and at the resection scar (n = 2). No shunt malfunctions were deemed related to TTFields therapy. CONCLUSIONS: In the real-world setting, TTFields therapy in GBM patients with VP shunts demonstrated good tolerability and a favorable safety profile. There was no evidence that TTFields therapy disrupted VP shunt effectiveness. These results suggest TTFields therapy may be safely used in patients with VP shunts.

Concurrent chemoradiation and Tumor Treating Fields (TTFields, 200 kHz) for patients with newly diagnosed glioblastoma: patterns of progression in a single institution pilot study.

Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We conducted a pilot clinical trial of concurrent chemoradiation with TTFields and report pattern of progression. MATERIALS AND METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from the primary enhancing lesion. RESULTS: Thirty patients were enrolled on the trial. Twenty were male with median age 58 years (19-77 years). Median KPS was 90 (70-100). Median follow-up was 15.2 months (1.7-23.6 months). Ten (33.3%) patients had a methylated promoter status. Twenty-seven patients (90%) had progression, with median PFS of 9.3 months (range 8.5 to 11.6 months). Six patients presented with distant recurrence, with median distance from primary lesion of 5.05 cm (2.26-6.95 cm). One infratentorial progression was noted. CONCLUSIONS: We observed improved local control using concurrent chemoradiation with TTFields for patients with newly diagnosed when compared to historical controls. Further data are needed to validate this finding. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03477110.

Disease characteristics, prognosis, and response to therapy in patients with large-cell transformed mycosis fungoides: A single-center retrospective study.

BACKGROUND: Mycosis fungoides with large-cell transformation (MF-LCT) is associated with an aggressive clinical course, yet data comparing treatment outcomes in MF-LCT are sparse. OBJECTIVE: To compare treatment outcomes and to determine disease prevalence and characteristics associated with survival in MF-LCT. METHODS: A retrospective review was conducted of mycosis fungoides patients from 2012 to 2020 treated at Thomas Jefferson University. Patients with histopathologic diagnosis of MF-LCT were included. Treatment outcomes were assessed by mean changes in the modified Severity Weighted Assessment Tool (mSWAT) and stage. RESULTS: Of 171 patients with mycosis fungoides, 23 (13.4%) had histologic diagnosis of MF-LCT. The overall 5-year survival rate for MF-LCT was 74% and was not significantly associated with sex, age, or initial stage at the time of MF-LCT diagnosis. Brentuximab vedotin showed the greatest mean decrease in mSWAT (-20.53) and stage progression (change in Δ stage: -0.4) in MF-LCT compared to oral bexarotene (ΔmSWAT: +4.51; Δstage: +0.27), skin-directed therapy (ΔmSWAT: -5.93; Δstage: -0.08), and chemotherapy (ΔmSWAT: +4.97; Δstage: +0.85). LIMITATIONS: Single-center retrospective design, and patients often on multiple treatment modalities. CONCLUSIONS: We report superior treatment outcomes for brentuximab vedotin compared to oral bexarotene, skin-directed therapy, and chemotherapy in MF-LCT in both early and advanced disease.

Chronoradiobiology of Breast Cancer: The Time Is Now to Link Circadian Rhythm and Radiation Biology.

Circadian disruption has been linked to cancer development, progression, and radiation response. Clinical evidence to date shows that circadian genetic variation and time of treatment affect radiation response and toxicity for women with breast cancer. At the molecular level, there is interplay between circadian clock regulators such as PER1, which mediates ATM and p53-mediated cell cycle gating and apoptosis. These molecular alterations may govern aggressive cancer phenotypes, outcomes, and radiation response. Exploiting the various circadian clock mechanisms may enhance the therapeutic index of radiation by decreasing toxicity, increasing disease control, and improving outcomes. We will review the body's natural circadian rhythms and clock gene-regulation while exploring preclinical and clinical evidence that implicates chronobiological disruptions in the etiology of breast cancer. We will discuss radiobiological principles and the circadian regulation of DNA damage responses. Lastly, we will present potential rational therapeutic approaches that target circadian pathways to improve outcomes in breast cancer. Understanding the implications of optimal timing in cancer treatment and exploring ways to entrain circadian biology with light, diet, and chronobiological agents like melatonin may provide an avenue for enhancing the therapeutic index of radiotherapy.

Safety and efficacy of Hypofractionated stereotactic radiosurgery for high-grade Gliomas at first recurrence: a single-center experience.

BACKGROUND: The optimal treatment for recurrent high-grade gliomas (rHGGs) remains uncertain. This study aimed to investigate the efficacy and safety of hypofractionated stereotactic radiosurgery (HSRS) as a first-line salvage treatment for in-field recurrence of high-grade gliomas. METHODS: Between January 2016 and October 2019, 70 patients with rHGG who underwent HSRS were retrospectively analysed. The primary endpoint was overall survival (OS), and secondary endpoints included both progression-free survival (PFS) and adverse events, which were assessed according to Common Toxicity Criteria Adverse Events (CTCAE) version 5. The prognostic value of key clinical features (age, performance status, planning target volume, dose, use of bevacizumab) was evaluated. RESULTS: A total of 70 patients were included in the study. Forty patients were male and 30 were female. Forty-nine had an initial diagnosis of glioblastoma (GBM), and the rest (21) were confirmed to be WHO grade 3 gliomas. The median planning target volume (PTV) was 16.68 cm3 (0.81-121.96 cm3). The median prescribed dose was 24 Gy (12-30 Gy) in 4 fractions (2-6 fractions). The median baseline of Karnofsky Performance Status (KPS) was 70 (40-90). With a median follow-up of 12.1 months, the median overall survival after salvage treatment was 17.6 months (19.5 and 14.6 months for grade 3 and 4 gliomas, respectively; p = .039). No grade 3 or higher toxicities was recorded. Multivariate analysis showed that concurrent bevacizumab with radiosurgery and KPS > 70 were favourable prognostic factors for grade 4 patients with HGG. CONCLUSIONS: Salvage HSRS showed a favourable outcome and acceptable toxicity for rHGG. A prospective phase II study (NCT04197492) is ongoing to further investigate the value of hypofractionated stereotactic radiosurgery (HSRS) in rHGG.

Resected WHO grade I meningioma and predictors of local control.

INTRODUCTION: Despite optimal surgical resection, meningiomas may recur, with increasing grade and the degree of resection being predictive of risk. We hypothesize that an increasing Ki67 correlates with a higher risk of recurrence of resected WHO grade I meningiomas. METHODS: The study population consisted of patients with resected WHO grade 1 meningiomas in locations outside of the base of skull. Digitally scanned slides stained for Ki67 were analyzed using automatic image analysis software in a standardized fashion. RESULTS: Recurrence was observed in 53 (17.7%) of cases with a median follow up time of 25.8 months. Ki67 ranged from 0 to 30%. Median Ki67 was 5.1% for patients with recurrence and 3.5% for patients without recurrence. In unadjusted analyses, high Ki-67 (≥ 5 vs. < 5) vs. ≥ 5) was associated with over a twofold increased risk of recurrence (13.1% vs. 27% respectively; HR 2.1731; 95% CI [1.2534, 3.764]; p = 0.006). After Adjusting for patient or tumor characteristics, elevated Ki-67 remained significantly correlated with recurrence. Grade 4 Simpson resection was noted in 71 (23.7%) of patients and it was associated with a significantly increased risk of recurrence (HR 2.56; 95% CI [1.41, 4.6364]; p = 0.002). CONCLUSIONS: WHO grade 1 meningiomas exhibit a significant rate of recurrence following resection. While Ki-67 is not part of the WHO grading criteria of meningiomas, a value greater than 5% is an independent predictor for increased risk of local recurrence following surgical resection.

Response to topical corticosteroid monotherapy in mycosis fungoides.

BACKGROUND: Topical corticosteroids alone or in combination with other therapies are widely used to treat mycosis fungoides (MF), but data on response rates to their use as monotherapy in MF are limited. OBJECTIVE: To evaluate the efficacy of topical corticosteroid monotherapy in MF; compare sex, age, stage distributions, and histopathologic features between responders and nonresponders. METHODS: A retrospective cross-sectional review of patients with MF from 2013 to 2019 treated at Thomas Jefferson University was conducted. Patients with biopsy-proven MF, all stages, who received topical corticosteroid monotherapy were included. Response rates were determined by percent change in body surface area (BSA) involvement and modified Severity-Weighted Assessment Tool (mSWAT). RESULTS: Of the 163 patients with MF in our database, 23% (37/163) initially received topical steroid monotherapy. Of these, 73% (27/37) improved, with an average 65% decrease in BSA (67% in mSWAT); 27% (10/37) did not respond/progressed, with an average 51.6% increase in BSA (57% in mSWAT); and 33% (12/37) had a complete response (BSA, 0%) with prolonged topical steroid use. Early-stage MF and female sex were more represented in responders. LIMITATIONS: Single-center retrospective design. CONCLUSIONS: Topical steroid monotherapy in early-stage MF can produce measurable improvements in BSA and mSWAT scores and achieve complete remission in a limited subset of patients.

Ursolic acid reduces Adriamycin resistance of human ovarian cancer cells through promoting the HuR translocation from cytoplasm to nucleus.

Ursolic acid (UA) has been shown to suppress various tumor progression, however, its roles in Adriamycin resistance of human ovarian cancer (OC) cells are still unclear. This work aims to investigate the effects of UA on the Adriamycin resistance of human OC cells. Here, we constructed Adriamycin-resistant OC SKOV3-Adr cells and found that UA attenuated Adriamycin resistance in SKOV3-Adr cells. Additionally, UA enhanced Adriamycin sensitivity in the parental SKOV3 and another OC cell line A2780 cells. Mechanistic studies showed that HuR mRNA level was similar between SKOV3 and SKOV3-Adr cells, but the cytoplasmic expression of HuR protein was increased in SKOV3-Adr cells compared with that in SKOV3 cells, and subsequently enhancing the mRNA stability of multidrug resistance gene 1 (MDR1). Moreover, UA had no effects on HuR expression, but promoted the cytoplasm-nucleus translocation of HuR protein, decreased MDR1 mRNA stability and thus reduced MDR1 expression. Furthermore, overexpression of MDR1 rescued the effects of UA on Adriamycin resistance and sensitivity. This work reveals a novel HuR/MDR1 axis responsible for UA-mediated attenuation on Adriamycin resistance in OC cells.

Exenteration and Adjuvant Radiotherapy for Primary Carcinosarcoma of the Anterior Orbit: A Case Report.

Carcinosarcoma is a malignant mixed tumor composed of epithelial and mesenchymal components which arises in a variety of tissues, including, in rare cases, the orbit. A 75-year-old male with a history of basal cell carcinoma of the left medial canthus, previously treated with surgical resection and adjuvant radiation therapy, presented with a recurrent 3 cm nodule of the left medial canthus. He underwent surgical resection of the left superior and inferior eyelid with pathology revealing invasive squamous cell carcinoma of upper and lower eyelids with deep orbital tissue involvement and undifferentiated pleomorphic sarcoma involving the dermis and periosteum, consistent with carcinosarcoma. Orbital exenteration was subsequently performed. He successfully underwent adjuvant stereotactic body radiation therapy 30 Gy in 5 fractions with no significant side effects. Follow-up MRI revealed posttreatment changes without evidence of recurrent disease.

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of emerging developments in the management of newly diagnosed glioblastoma.

TARGET POPULATION: These recommendations apply to adult patients with newly diagnosed or suspected glioblastoma. IMAGING: Question What imaging modalities are in development that may be able to provide improvements in diagnosis, and therapeutic guidance for individuals with newly diagnosed glioblastoma? RECOMMENDATION: Level III: It is suggested that techniques utilizing magnetic resonance imaging for diffusion weighted imaging, and to measure cerebral blood and magnetic spectroscopic resonance imaging of N-acetyl aspartate, choline and the choline to N-acetyl aspartate index to assist in diagnosis and treatment planning in patients with newly diagnosed or suspected glioblastoma. SURGERY: Question What new surgical techniques can be used to provide improved tumor definition and resectability to yield better tumor control and prognosis for individuals with newly diagnosed glioblastoma? RECOMMENDATIONS: Level II: The use of 5-aminolevulinic acid is recommended to improve extent of tumor resection in patients with newly diagnosed glioblastoma. Level II: The use of 5-aminolevulinic acid is recommended to improve median survival and 2 year survival in newly diagnosed glioblastoma patients with clinical characteristics suggesting poor prognosis. Level III: It is suggested that, when available, patients be enrolled in properly designed clinical trials assessing the value of diffusion tensor imaging in improving the safety of patients with newly diagnosed glioblastoma undergoing surgery. NEUROPATHOLOGY: Question What new pathology techniques and measurement of biomarkers in tumor tissue can be used to provide improved diagnostic ability, and determination of therapeutic responsiveness and prognosis for patients with newly diagnosed glioblastomas? RECOMMENDATIONS: Level II: Assessment of tumor MGMT promoter methylation status is recommended as a significant predictor of a longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma. Level II: Measurement of tumor expression of neuron-glia-2, neurofilament protein, glutamine synthetase and phosphorylated STAT3 is recommended as a predictor of overall survival in patients with newly diagnosed with glioblastoma. Level III: Assessment of tumor IDH1 mutation status is suggested as a predictor of longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma. Level III: Evaluation of tumor expression of Phosphorylated Mitogen-Activated Protein Kinase protein, EGFR protein, and Insulin-like Growth Factor-Binding Protein-3 is suggested as a predictor of overall survival in patients with newly diagnosed with glioblastoma. RADIATION: Question What radiation therapy techniques are in development that may be used to provide improved tumor control and prognosis for individuals with newly diagnosed glioblastomas? RECOMMENDATIONS: Level III: It is suggested that patients with newly diagnosed glioblastoma undergo pretreatment radio-labeled amino acid tracer positron emission tomography to assess areas at risk for tumor recurrence to assist in radiation treatment planning. Level III: It is suggested that, when available, patients be with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of radiation dose escalation, altered fractionation, or new radiation delivery techniques. CHEMOTHERAPY: Question What emerging chemotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas? RECOMMENDATION: Level III: As no emerging chemotherapeutic agents or techniques were identified in this review that improved tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of chemotherapy. MOLECULAR AND TARGETED THERAPY: Question What new targeted therapy agents are available to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas? RECOMMENDATION: Level III: As no new molecular and targeted therapies have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of molecular and targeted therapies IMMUNOTHERAPY: Question What emerging immunotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas? RECOMMENDATION: Level III: As no immunotherapeutic agents have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of immunologically-based therapies. NOVEL THERAPIES: Question What novel therapies or techniques are in development to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas? RECOMMENDATIONS: Level II: The use of tumor-treating fields is recommended for patients with newly diagnosed glioblastoma who have undergone surgical debulking and completed concurrent chemoradiation without progression of disease at the time of tumor-treating field therapy initiation. Level II: It is suggested that, when available, enrollment in properly designed studies of vector containing herpes simplex thymidine kinase gene and prodrug therapies be considered in patients with newly diagnosed glioblastoma.

Outcomes after stereotactic radiosurgery for CNS lymphoma.

BACKGROUND: The standard of care for CNS lymphoma typically includes high dose methotrexate followed by whole brain radiation therapy, but there is an increased risk of neurotoxicity with this regimen. In our institution, we offered stereotactic radiosurgery (SRS) for disease refractory to HD-MTX in a subset of patients. A search of the literature on this modality for CNS lymphoma was also conducted. METHODS: Medical records of six patients who received partial brain radiation therapy for persistent CNS lymphoma were reviewed. SRS was given via 1-3 fractions to doses of 21 or 24 Gy. PubMed, SCOPUS, and Cochrane Library databases were systematically searched for articles reporting on outcomes for CNS lymphoma treated with SRS. RESULTS: Six patients (eleven lesions) were treated with SRS for CNS lymphomas. Median follow up was 15.6 months (range 3.3-37.8). Median RT dose per lesion was 21 Gy and median time to progression was 12.7 months. Median overall survival was not reached. Four patients had distant intracranial failure with two developing local recurrence. The search strategy yielded 16 studies of which only one was prospective and included a control group. 183 out of 256 evaluated lesions (69%) responded completely to treatment and 13 of 204 patients (6%) recurred within the treatment area at last follow-up. Overall, the treatment was well tolerated. CONCLUSION: SRS may provide favorable local control in patients with refractory CNS lymphomas. A prospective trial is warranted to validate the efficacy of such an approach.

Global post-marketing safety surveillance of Tumor Treating Fields (TTFields) in patients with high-grade glioma in clinical practice.

INTRODUCTION: Tumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields (200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting. METHODS: Unsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011-February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA [Europe, Middle East, Africa], Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age (< 18 [pediatric], 18-64 [adults], ≥ 65 [elderly]; years of age). RESULTS: Of 11,029 patients, 53% were diagnosed with ndGBM and 39% were diagnosed with rGBM at any line of disease recurrence. Most were adults (73%), 26% were elderly, and the male-to-female ratio was ~ 2:1 (close to published ratios of typical GBM populations). The most commonly reported TTFields-related AE was array-associated skin reaction, occurring in patients with ndGBM (38%), rGBM (29%), anaplastic astrocytoma/oligodendroglioma (38%), and other brain tumors (31%); as well as 37% of pediatric, 34% of adult, and 36% of elderly patients. Most skin AEs were mild/moderate and manageable. Other TTFields-related AEs in patients with ndGBM/rGBM included under-array heat sensation (warmth; 11%, 10%, respectively) and electric sensation (tingling; 11%, 9%, respectively), and headache (7%, 6%, respectively). CONCLUSIONS: This TTFields safety surveillance analysis in > 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients.

Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma.

INTRODUCTION: Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our initial experience evaluating toxicity and tolerability of scalp-sparing radiation with concurrent TTFields. METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed glioblastoma were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent temozolomide (75 mg/m2 daily), and TTFields. Maintenance therapy included standard temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma. RESULTS: We report the first ten patients on the trial. Eight were male, and two were female, with median age 61 years (range 49 to 73 years). Median KPS was 90 (range 70-90). Median follow-up was 7.9 months (2.8 to 17.9 months). Nine (90%) patients with unmethylated MGMT promotor, and one with methylated. Median time from surgery to radiation was 33 days (28 to 49 days). All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. Scalp dose constraints were achieved for all patients, with mean dose having a median value of 7.7 Gy (range 4.9 to 13.2 Gy), D20cc median 22.6 Gy (17.7 to 36.8 Gy), and D30cc median 19.8 Gy (14.8 to 33.4 Gy). Average daily use during concurrent phase had median value of 83.5% and 77% for maintenance. There was no related ≥ Grade 3 toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in 80% of patients, however, these were limited to Grade 1 or 2 events which resolved spontaneously or responded to topical medications. Eight patients (80%) had progression, with median PFS of 6.9 months (range 2.8 to 9.6 months). CONCLUSIONS: Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trial is warranted to define therapeutic advantages of concurrent TTFields with chemoradiation. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03477110.

A prospective cohort study of condensed low-dose total skin electron beam therapy for mycosis fungoides: Reduction of disease burden and improvement in quality of life.

BACKGROUND: Low-dose total skin electron beam therapy (TSEBT) for mycosis fungoides is popular because of reduced toxicity with effective palliation. We condensed TSEBT, reducing visits by half and overall treatment length by one third. OBJECTIVE: To determine the efficacy and safety of a novel condensed low-dose TSEBT for mycosis fungoides. METHODS: We conducted a cohort study (2014-2018) with a median follow-up of 22.8 months. We delivered 12 Gy per 6 fractions with the modified Stanford technique, 3 fractions per week, with boosts to shadowed sites at risk between treatments, completing in 2 weeks. Primary outcomes included clinical response, duration of and time to response, and toxicity. Secondary outcomes included patient-reported quality of life (pain, pruritus, and Dermatology Life Quality Index) and physician-scored disease burden (body surface area involvement and Modified Skin Weighted Assessment Tool). RESULTS: Of 25 patients, stage IB was most common at the time of TSEBT (36%). The overall response rate was 88%. Most common was a near complete response (36%), and complete response was achieved in 6 (24%) patients. The median duration of response was 17.5 months (3.5-44.2), and the median time to response was 2 months (range, 0.9-4.1). No patients had toxicity of grade 3 or greater. QOL and disease burden showed significant benefit after TSEBT (P < .001). LIMITATIONS: Cohort study with limited sample size. CONCLUSIONS: Condensed, low-dose TSEBT has favorable outcomes and toxicity with logistical convenience.

Feasibility of removable balloon implant for simultaneous magnetic nanoparticle heating and HDR brachytherapy of brain tumor resection cavities.

AIM: Hyperthermia (HT) has been shown to improve clinical response to radiation therapy (RT) for cancer. Synergism is dramatically enhanced if HT and RT are combined simultaneously, but appropriate technology to apply treatments together does not exist. This study investigates the feasibility of delivering HT with RT to a 5-10mm annular rim of at-risk tissue around a tumor resection cavity using a temporary thermobrachytherapy (TBT) balloon implant. METHODS: A balloon catheter was designed to deliver radiation from High Dose Rate (HDR) brachytherapy concurrent with HT delivered by filling the balloon with magnetic nanoparticles (MNP) and immersing it in a radiofrequency magnetic field. Temperature distributions in brain around the TBT balloon were simulated with temperature dependent brain blood perfusion using numerical modeling. A magnetic induction system was constructed and used to produce rapid heating (>0.2°C/s) of MNP-filled balloons in brain tissue-equivalent phantoms by absorbing 0.5 W/ml from a 5.7 kA/m field at 133 kHz. RESULTS: Simulated treatment plans demonstrate the ability to heat at-risk tissue around a brain tumor resection cavity between 40-48°C for 2-5cm diameter balloons. Experimental thermal dosimetry verifies the expected rapid and spherically symmetric heating of brain phantom around the MNP-filled balloon at a magnetic field strength that has proven safe in previous clinical studies. CONCLUSIONS: These preclinical results demonstrate the feasibility of using a TBT balloon to deliver heat simultaneously with HDR brachytherapy to tumor bed around a brain tumor resection cavity, with significantly improved uniformity of heating over previous multi-catheter interstitial approaches. Considered along with results of previous clinical thermobrachytherapy trials, this new capability is expected to improve both survival and quality of life in patients with glioblastoma multiforme.

Prognostic nomogram for bladder cancer with brain metastases: a National Cancer Database analysis.

BACKGROUND: This study aimed to establish and validate a nomogram for predicting brain metastasis in patients with bladder cancer (BCa) and assess various treatment modalities using a primary cohort comprising 234 patients with clinicopathologically-confirmed BCa from 2004 to 2015 in the National Cancer Database. METHODS: Machine learning method and Cox model were used for nomogram construction. For BCa patients with brain metastasis, surgery of the primary site, chemotherapy, radiation therapy, palliative care, brain confinement of metastatic sites, and the Charlson/Deyo Score were predictive features identified for building the nomogram. RESULTS: For the original 169 patients considered in the model, the areas under the receiver operating characteristic curve (AUC) were 0.823 (95% CI 0.758-0.889, P < 0.001) and 0.854 (95% CI 0.785-0.924, P < 0.001) for 0.5- and 1-year overall survival respectively. In the validation cohort, the nomogram displayed similar AUCs of 0.838 (95% CI 0.738-0.937, P < 0.001) and 0.809 (95% CI 0.680-0.939, P < 0.001), respectively. The high and low risk groups had median survivals of 1.91 and 5.09 months for the training cohort and 1.68 and 8.05 months for the validation set, respectively (both P < 0.0001). CONCLUSIONS: Our prognostic nomogram provides a useful tool for overall survival prediction as well as assessing the risk and optimal treatment for BCa patients with brain metastasis.