Bevacizumab and re-irradiation for recurrent high grade gliomas: does sequence matter?

PURPOSE/OBJECTIVES: We report the outcomes of the largest cohort to date of patients receiving both bevacizumab (BEV) and fractionated stereotactic radiotherapy (FSRT) for progressive or recurrent high grade glioma (HGG). Furthermore, the sequence of these two treatment regimens was analyzed to determine an optimal treatment paradigm for recurrent HGG. MATERIALS/METHODS: After Institutional Review Board approval, patients with pathologically confirmed WHO grade III anaplastic astrocytoma (AA) or IV glioblastoma multiforme (GBM) glioma who subsequently underwent re-irradiation at recurrence with FSRT were retrospectively reviewed. Patients from this group who had received BEV were also identified. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were analyzed as study endpoints. Date of recurrence was defined as the date of radiographic evidence of progressive/recurrent disease. Kaplan-Meier curves were generated utilizing a log-rank test with a p-value ≤ 0.05 considered significant to compare treatment sequences in terms of survival outcomes. RESULTS: A total of 118 patients with recurrent/progressive HGG (GBM = 87, AA = 31) had received both BEV and FSRT. Patient characteristics were as follows: median KPS at recurrence was 80 (range 50-100); median age at recurrence was 57 years; median time to radiographic recurrence/progression was 10.8 months (mo) and 33.1% of patients had surgery for recurrence. The median time from the start of BEV to FSRT was 6.4 months and from FSRT to the start of BEV was 5.1 months. For the entire cohort, median overall survival (OS) was 26.7 months and median survival time (MST) from recurrence was 13.8 months (24.4 months and 11.9 months for GBM only). In patients that received BEV prior to FSRT (n = 50), median OS and MST from recurrence were 25.2 and 13.3 months respectively. In patients receiving FSRT first (n = 56), median OS and MST from recurrence were 28.8 months and 13.9 months, respectively. Sequencing of BEV and FSRT at recurrence was not significantly associated with OS (p = 0.08) or median survival from recurrence (p = 0.75). CONCLUSIONS: The combination of FSRT and BEV for recurrent/progressive HGG provides promising results in terms of overall survival and survival from recurrence. Combining these treatment modalities appears to improve upon the historic outcomes of either treatment alone. The outcomes data from this study support the ongoing RTOG trial exploring the combination of BEV and FSRT for recurrent HGG.

Immunotherapy Plus Stereotactic Radiosurgery: Building on the Promise of Precision Medicine for CNS Malignancies-PART 2: Existing Experience and Considerations for Future Trials.

The brain has long been considered an immunologically privileged site, and the role of immunotherapy in treating intracranial disease has only recently been revived-with preclinical evidence showing that the systemic immune system responds to immunotherapy for intracranial disease, and with clinical evidence demonstrating improved locoregional control and survival compared with historical outcomes when immune-directed therapies are combined with radiation. Pharmaceutical industry-supported multi-institutional drug efficacy studies routinely exclude patients with brain metastases, so current evidence for treatment of brain metastases using stereotactic radiosurgery combined with immunotherapy comes from single-institution studies. Many studies of combinations of immune checkpoint blockade (with anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed death 1 antibodies) with stereotactic radiosurgery have demonstrated promising improvements in intracranial control and survival. In addition to evaluating the optimal combination of these therapies, future studies will likely search for predictive biomarkers to better select patients whose disease is most appropriately managed with this combined-modality approach.

Immunotherapy Plus Stereotactic Radiosurgery: Building on the Promise of Precision Medicine for CNS Malignancies-PART 1: Principles of Combined Treatment.

The role of systemic therapy in the treatment of intracranial metastases has traditionally been limited by the blood-brain barrier, and radiation therapy-either with whole-brain treatment or stereotactic radiosurgery-has remained a primary treatment modality. Recent evidence has demonstrated that antigens released in the brain can inform the systemic immune system, and systemic antibodies can traverse into the brain. This has led to a renewed interest in investigating novel immunotherapy agents to treat both systemic and intracranial disease. Currently, several trials of immunotherapy, with or without sequential or concurrent radiation, have been performed in patients with brain metastases to evaluate the safety and efficacy of combined treatment. Combined use of stereotactic radiosurgery and checkpoint inhibitors appears safe and effective in the treatment of various brain metastases. Future studies will evaluate the optimal sequencing of radiosurgery and immunotherapy and assess the radiation doses and fractionations that will provide the best tumor response.

Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.

The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

Dietary Factors and Early-Onset Colorectal Cancer in the United States-an Ecologic Analysis.

BACKGROUND: Incidence of early-onset colorectal cancer (EOCRC; e.g., diagnosed before age 50) in the United States has increased substantially since the 1990s but the underlying reasons remain unclear. METHODS: We examined the ecologic associations between dietary factors and EOCRC incidence in adults aged 25-49 during 1977-2016 in the United States, using negative binomial regression models, accounting for age, period, and race. The models also incorporated an age-mean centering (AMC) approach to address potential confounding by age. We stratified the analysis by sex and computed incidence rate ratio (IRR) for each study factor. Study factor data (for 18 variables) came from repeated national surveys; EOCRC incidence data came from the Surveillance Epidemiology, and End Results Program. RESULTS: Results suggest that confounding by age on the association with EOCRC likely existed for certain study factors (e.g., calcium intake), and that AMC can alleviate the confounding. EOCRC incidence was positively associated with smoking [IRR (95% confidence interval (CI): 1.17 (1.10-1.24) for men; 1.15 (1.09-1.21) for women] and alcohol consumption [IRR (95% CI), 1.08 (1.04-1.12) for men; 1.08 (1.04-1.11) for women]. No strong associations were found for most other study factors (e.g., fiber and calcium). CONCLUSIONS: Alcohol consumption was positively associated with EOCRC and has increased among young adults since the 1980s, which may have contributed to the EOCRC incidence increases since the 1990s. The AMC approach may help alleviate age confounding in similar ecologic analyses. IMPACT: Increases in alcohol consumption may have contributed to the recent increases in colorectal cancer incidence among young adults. See related commentary by Ni et al., p. 164.

Piezo-Type Mechanosensitive Ion Channel Component 1 (Piezo1): A Promising Therapeutic Target and Its Modulators.

Piezo1 is a member of the mechanosensitive piezo ion channel family, which transduces various mechanical stimulations into electrochemical signals. Piezo1 is closely implicated in different physiological processes ranging from erythrocyte volume homeostasis to lymphatic vessel formation and bone homeostasis. Aberrant Piezo1 functions caused by gain-of-function or loss-of-function mutations are associated with various pathological conditions. Due to the significant contribution on the recognition of Piezo ion channels for sensing mechanical stress, Ardem Patapoutian received the 2021 Nobel Prize in Physiology or Medicine (jointly). Strategies of targeting and modulating Piezo1 have shown potential to produce significant therapeutic effects, thus validating Piezo1 as a promising drug target for diseases. In this Perspective, we review the cryo-EM structure, mechanogating mechanism, and physiological profiles of Piezo1, together with the latest advances in the development of its modulators. Limitations and challenges as well as future development of Piezo1 modulators are discussed as well.

Quality of Life Outcomes Following Organ-Sparing SBRT in Previously Irradiated Recurrent Head and Neck Cancer.

Purpose: To present a retrospective analysis of the efficacy, toxicity, and quality of life (QoL) of patients treated with OAR Extreme -sparing stereotactic body radiotherapy (SBRT) in previously-irradiated head and neck cancer. Materials/Methods: From 11/2012 to 7/2015, 60 patients with in-field recurrence of head and neck cancer underwent re-irradiation with SBRT. Retreatment sites included the aerodigestive tract (43%), lateral neck (22%), and skull base (35%). The median prior RT dose was 63.6 Gy with a median time from prior irradiation of 16.5 months. The median volume treated was 61.0 cc. Patients were treated with 40 Gy in the definitive setting or 35 Gy in the post-operative setting in five fractions. Dose constraints to the OAR Extreme were calculated with a BED calculator using an alpha/beta ratio of 3 to reduce the risk of late toxicities. QoL data was collected from patients at the time of consultation and at subsequent follow up appointments using the MD Anderson Dysphagia Inventory (MDADI) and Symptom Inventory (MDASI). Results: The 1- and 2- year rates of local, regional, and distant control and overall survival were 79/79, 74/70, 74/71, and 59/45%, respectively. Late grade 3 toxicities were seen in 3% in the group treated to the aerodigestive tract and 1% in the group treated to the skull base. No grade 4 or 5 toxicities were observed. Patients with skull base re-irradiation maintained a stable QoL score after radiation treatment, while patients treated to the aerodigestive tract demonstrated a slight impairment associated with worsening dysphagia, compared to their pretreatment baseline. All groups experienced an increase in xerostomia. Conclusions: OAR Extreme -sparing SBRT is able to achieve excellent tumor coverage while protecting the organs at highest risk of re-irradiation-related complications. The potential for lower toxicities and maintained QoL with this treatment makes it a promising option for salvage of recurrent head and neck cancer. SUMMARY: Local control and overall survival rates for recurrent head and neck cancer remain poor, despite the use of local therapy. In addition, re-irradiation with conventional radiation therapy confers a high rate of grade 3 and higher late toxicities. SBRT appears to improve the therapeutic ratio in this patient population, and treatment planning with a focus on sparing OAR Extreme may further decrease the rates of morbidity in these patients.

Clinical response to radium-223 dichloride in men with metastatic castrate-resistant prostate cancer.

PURPOSE/OBJECTIVE: Radium-223 prolongs survival and decreases symptomatic skeletal events in men with metastatic castrate-resistant prostate cancer and is indicated in patients with painful bone metastases. However, pain responses are rarely reported and often asked about by patients. Further, patients and their physicians are concerned about a lack of pain response portending a poor treatment response and may be inclined to change systemic therapies before completing 6 cycles. We evaluated the likelihood and time course of pain response, potential predictors of response, and its prognostic value in patients receiving radium-223. MATERIALS AND METHODS: We reviewed the charts of patients who received radium-223 in our department. All patients were planned for 6 cycles with a prescribed dose of 50-55 kBq/kg at each administration. Pain scores, subjective response to pain, analgesic use, treatment toxicities, and laboratory values were recorded at each visit. Symptomatic skeletal events and survival were also recorded. RESULTS: 48 patients received at least one cycle of radium-223 and 27 (56%) received all 6 planned cycles. Median survival from first treatment was 16.0 months (95% CI 8.9 to 19.2 months). 33% experienced at least one symptomatic skeletal event during or after treatment. 62.5% of men reported a decrease in pain from pre-treatment baseline. Of men with improved pain, 96% experienced an improvement before the third cycle. Pain relief was not associated with a decrease in ALK-P or PSA or improved survival. CONCLUSIONS: Approximately two-thirds of patients who undergo treatment with radium-223 will experience an improvement in pain and, if it occurs, it will most likely occur within the first two cycles. Patients should be counseled about this timeline and, if pain improvement isn't achieved, palliative radiation and oral analgesic readjustment should be considered. Pain response is not associated with survival and should not be used to evaluate the effectiveness of treatment.

Stereotactic radiosurgery of the brain: a review of common indications.

Over the past half-century since Lars Leksell first utilized radiation to address deep and difficult to treat lesions of the central nervous system (CNS), intracranial stereotactic radiosurgery (SRS) has become an increasingly valued tool in the hands of neurosurgeons and radiation oncologists. Following developments in medical imaging and radiation technology, radiosurgery has evolved from its first application in movement disorders to widespread use for a varied range of malignant and benign conditions. SRS remains a powerful, minimally invasive instrument that offers additional options for intervention to a diverse patient population. In this review, we will touch upon the common indications for SRS, including its use in brain metastases, malignant gliomas, meningiomas, arteriovenous malformations (AVMs), vestibular schwannomas, pituitary adenomas, and functional disorders, as well as consider the future possibilities of combining radiosurgery with immunotherapy.

Hippocampal-sparing and target volume coverage in treating 3 to 10 brain metastases: A comparison of Gamma Knife, single-isocenter VMAT, CyberKnife, and TomoTherapy stereotactic radiosurgery.

PURPOSE: Our purpose was to evaluate hippocampal doses and target volume coverage with and without hippocampal sparing when treating multiple brain metastases using various stereotactic radiosurgery (SRS) platforms. METHODS AND MATERIALS: We selected 10 consecutive patients with 14 separate treatments who had been treated in our department for 3 to 10 brain metastases and added hippocampal avoidance contours. All 14 treatments were planned with GammaPlan for Gamma Knife, Eclipse for single isocenter volumetric modulated arc therapy (VMAT), TomoTherapy Treatment Planning System (TPS) for TomoTherapy, and MultiPlan for CyberKnife. Initial planning was performed with the goal of planning target volume coverage of V100 ≥95% without hippocampal avoidance. If the maximum hippocampal point dose (Dmax) was <6.6 Gy in a single fraction and <40% of the hippocampi received ≤4.5 Gy, no second plan was performed. If either constraint was not met, replanning was performed with these constraints. RESULTS: There was a median of 6 metastases per plan, with an average total tumor volume of 7.32 mL per plan. The median hippocampal Dmax (in Gy) without sparing averaged 1.65, 9.81, 4.38, and 5.46, respectively (P < .0001). Of 14 plans, 3 Gamma Knife and CyberKnife plans required replanning, whereas 13 VMAT and 8 TomoTherapy plans required replanning. The hippocampal constraints were not achievable in 1 plan on any platform when the tumor was bordering the hippocampus. The mean volume of brain receiving 12 Gy (in mL), which has been associated with symptomatic radionecrosis, was 23.57 with Gamma Knife, 76.77 with VMAT, 40.86 with CyberKnife, and 104.06 with TomoTherapy (P = .01). The overall average conformity indices for all plans ranged from 0.36 to 0.52. CONCLUSIONS: Even with SRS, the hippocampi can receive a considerable dose; however, if the hippocampi are outlined as organs of risk, sparing these structures is feasible in nearly all situations with all 4 platforms, without detriment to target coverage, and should be considered in all patients undergoing SRS for multiple brain metastases. SUMMARY: Hippocampi play an important role in memory, and sparing of these structures in whole brain radiation can improve neurocognitive outcomes. The hippocampi are not routinely spared when using stereotactic radiosurgery. We evaluated the incidental dose to the hippocampi when treating multiple brain metastases and sought to examine if hippocampal sparing is feasible without detriment to target coverage. We found that hippocampal sparing is possible without affecting coverage or conformality in most cases across treatment platforms.

Chondrosarcoma of the hyoid bone: case report and review of current management options.

BACKGROUND: We describe a 53-year-old man who presented with a painless neck mass and underwent a resection that identified the tumor as a low-grade chondrosarcoma of the hyoid bone. We reviewed the literature for diagnosis and management options of this exceptionally rare diagnosis. METHODS: We conducted a search of the published medical literature before September 2012 in MEDLINE and PubMed using the terms "chondrosarcoma" and "hyoid." The search led to 19 case reports. We then searched for recent advances in diagnosis and treatment. RESULTS: Chondrosarcomas of the hyoid bone present as slow-growing, painless masses of the neck. CT and MRI are useful for imaging, but definitive diagnosis is made by biopsy. CONCLUSION: The preferred treatment is complete surgical removal, whereas radiation is used as adjuvant therapy. Positive surgical margin is a significant risk factor for recurrence. Long-term follow-up is recommended because of recurrences many years later.

Prostate implant dosimetric outcomes and migration patterns between bio-absorbable coated and uncoated brachytherapy seeds.

PURPOSE: To evaluate the lung and pelvic seed migration and intraprostatic dose variability for prostate seed implant (PSI) using bio-absorbable polymer "coated" seeds for intraoperative planning. METHODS AND MATERIALS: A total of 100 PSI patients were initially implanted with uncoated I-125 (STM 1251 or I125-SL, N = 85) or Pd-103 (mod 200, N = 15) seeds, and 105 PSI patients were implanted subsequently with coated seeds using inverse optimization with real-time planning. Implant technique, average number of needles, and dose objectives remained identical among the cohorts. RESULTS: Day 30 postimplant comparison of seed migration demonstrated a significant reduction in overall lung and pelvic seed migration from 25% (uncoated) to 4% (coated) (p < 0.0001). A measurable reduction in intraprostatic dose variability was observed in patients with the coated seeds when comparing 30 days dosimetry results for V100, V150, and D90 for prostate, and V110 for the rectum. A statistically significant reduction in the standard deviation from Day 0 to Day 30 for the above parameters for the prostate as well as for V110 of rectum was also observed. A significant improvement in implant quality at Day 30 was demonstrated using Radiation Therapy Oncology Group (RTOG) evaluation criteria range with the coated seeds cohort. CONCLUSIONS: PSI using coated seeds shows lower lung and pelvic seed migration compared with those using uncoated seeds and compares favorably to pelvic stranded seed migration reports. A higher concordance was observed with less dose variability in dosimetric parameters on Day 30 dosimetry compared with that on Day 0. Improvement in the implant quality was also observed using the RTOG criteria, suggesting reduced intraprostatic migration.