Treatment Of Intracranial Metastases Research Articles

Survival outcomes and predicting intracranial metastasis in stage III non-small cell lung cancer treated with definitive chemoradiation: Real-world data from a tertiary cancer center

Purpose/ObjectiveAround 30% of patients with non-small cell lung cancers (NSCLC) are diagnosed with stage III disease at presentation, of which about 50% are treated with definitive chemoradiation (CRT). Around 65–80% of patients will eventually develop intracranial metastases (IM), though associated risk factors are not clearly described. We report survival outcomes and risk factors for development of IM in a cohort of patients with stage III NSCLC treated with CRT at a tertiary cancer center. Materials/MethodsWe identified 195 patients with stage III NSCLC treated with CRT from January 2010 to May 2021. Multivariable logistic regression was used to generate odds ratios for covariates associated with development of IM. Kaplan-Meier analysis with the Log Rank test was used for unadjusted time-to-event analyses. P-value for statistical significance was set at < 0.05 with a two-sided test. ResultsOut of 195 patients, 108 (55.4%) had stage IIIA disease and 103 (52.8%) had adenocarcinoma histology. The median age and follow-up (in months) was 67 (IQR 60–74) and 21 (IQR 12–43), respectively. The dose of radiation was 60 Gy in 30 fractions for148 patients (75.9%). Of the 77 patients who received treatment since immunotherapy was available and standard at our cancer center, 45 (58.4%) received at least one cycle. During follow-up, 84 patients (43.1%) developed any metastasis, and 33 (16.9%) developed IM (either alone or with extracranial metastasis). 150 patients (76.9%) experienced a treatment delay (interval between diagnosis and treatment > 4 weeks). Factors associated with developing any metastasis included higher overall stage at diagnosis (p = 0.013) and higher prescribed dose (p = 0.022). Factors associated with developing IM included higher ratio of involved over sampled lymph nodes (p = 0.001) and receipt of pre-CRT systemic or radiotherapy for any reason (p = 0.034). On multivariate logistical regression, treatment delay (OR 3.9, p = 0.036) and overall stage at diagnosis (IIIA vs. IIIB/IIIC) (OR 2.8, p = 0.02) predicted development of IM. These findings were sustained on sensitivity analysis using different delay intervals. Median OS was not reached for the overall cohort, and was 43.1 months for patients with IM and 40.3 months in those with extracranial-only metastasis (p = 0.968). In patients with any metastasis, median OS was longer (p = 0.003) for those who experienced a treatment delay (48.4 months) compared to those that did not (12.2 months), likely due to expedited diagnosis and treatment in patients with a higher symptom burden secondary to more advanced disease. ConclusionsIn patients with stage III NSCLC treated with definitive CRT, the risk of IM appears to increase with overall stage at diagnosis and, importantly, may be associated with experiencing a treatment delay (> 4 weeks). Metastatic disease of any kind remains the primary life-limiting prognostic factor in these patients with advanced lung cancer. In patients with metastatic disease, treatment delay was associated with better survival. Patients who experience a treatment delay and those initially diagnosed at a more advanced overall stage may warrant more frequent surveillance for early diagnosis and treatment of IM. Healthcare system stakeholders should strive to mitigate treatment delay in patients with locally NSCLC to reduce the risk of IM. Further research is needed to better understand factors associated with survival, treatment delay, and the development of IM after CRT in the immunotherapy era.

Clinical Outcomes of Stereotactic Radiosurgery-Related Radiation Necrosis in Patients with Intracranial Metastasis from Melanoma.

Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population. Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation. Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients. Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted.

РАЗРАБОТКА И АПРОБАЦИЯ МЕТОДА АДАПТИВНОЙ РАДИОХИРУРГИИ У ПАЦИЕНТОВ С МЕТАСТАТИЧЕСКИМ ПОРАЖЕНИЕМ ГОЛОВНОГО МОЗГА

Background. Intracranial metastases are detected in more than 20% of patients with advanced cancer; they dramatically worsen the prognosis for life and are one of the most common causes of death. Surgical resection and whole brain radiotherapy have been considered the standard treatments for cerebral metastases for many decades. Stereotactic radiosurgery (SRS) is increasingly used in the treatment of intracranial metastases. However, the treatment of large metastases by single-fraction SRS is problematic, since the administration of a dose that provides a sufficient level of local control is associated with a high risk of severe post-radiation complications. Purpose. To develop modes of fractionation for the use of SRS in irresectable patients with metastatic brain lesions and approbate the method of adaptive stereotactic radiosurgery (ASRS). Material and methods. The study included 39 patients with metastatic brain lesions, who in 2018-2021 underwent a two-fraction or three-fraction ASRS according to the developed method using the gamma-therapeutic complex "Gamma Knife Perfexion" (Elekta, Sweden). The average volume of metastases at the time of the first session was 11.9 cm3. Results. The median overall survival in the general cohort was 13.0 months, 1-year survival rate was 75.0%. When assessing local control, the absence of progression 6 months after irradiation was found in 33 out of 39 patients (84.6%). Conclusions. Analysis of literature data and our own preliminary experience demonstrate the relevance of the development and implementation of the ASRS method in the treatment of irresectable patients with metastatic brain lesions.

Innovations in radiotherapy and advances in immunotherapy for the treatment of brain metastases.

Radiotherapy for brain metastases has evolved tremendously over the past four decades, allowing for improved intracranial control of disease with reduced neurotoxicity. The main technological advance was provided by volumetric modulated arc therapy (VMAT), a computer-controlled delivery method that has opened the door for single-isocenter multi-metastases stereotactic radiosurgery (SRS) and hippocampal avoidance whole brain radiation therapy (HA-WBRT). Other notable advances have occurred in the combination of immune checkpoint inhibitors (ICI) and radiosurgery. When these two modalities are combined in the proper sequence (within 30days from each other), it provides promising results in the treatment of intracranial metastases from melanoma. There is emerging evidence of a synergistic interaction between ICI and SRS, providing better intracranial tumor control and lengthening the survival of patients afflicted by this common complication of cancer.

Melanoma brain metastases: is it time to eliminate radiotherapy?

Immunotherapy has demonstrated efficacy in treatment of intracranial metastasis from melanoma, calling into question the role of intracranial radiotherapy (RT). Herein, we assessed the utilization patterns of intracranial RT in patients with melanoma brain metastasis and compared outcomes in patients treated with immunotherapy alone versus immunotherapy in addition to intracranial RT. We queried the National Cancer Database (NCDB) for patients with melanoma brain metastases treated with immunotherapy and intracranial RT or immunotherapy alone. Multivariable logistic regression identified variables associated with increased likelihood of receiving immunotherapy alone. Multivariable Cox regression was used to identify co-variates predictive of overall survival (OS). Propensity matching was used to account for indication bias. We identified 528 and 142 patients that were treated with combination therapy and immunotherapy alone, respectively. Patients with lower comorbidity score were more likely to receive immunotherapy alone. Extracranial disease and treatment at a non-academic center were associated with worse OS. Median OS for all patients was 11.0months. Treatment with stereotactic radiosurgery (SRS) in addition to immunotherapy was superior to immunotherapy alone, median OS of 19.0 versus 11.5months (p = 0.006). Whole brain radiation therapy (WBRT) in combination with immunotherapy performed worse than immunotherapy alone, median OS of 7.7 versus 11.5months (p = 0.0255). For melanoma patients requiring WBRT, immunotherapy alone may be reasonable in asymptomatic patients. For those eligible for SRS, combination therapy may provide better outcomes. Results of ongoing prospective studies will help provide guidance regarding the use of radioimmunotherapy in this population.

Long-term Survivors After Treatment of Intracranial Metastases With Radiosurgery

Long-term Survivors After Treatment of Intracranial Metastases With Radiosurgery

Single fraction radiosurgery using RapidArc® for the treatment of intracranial metastases

Single fraction radiosurgery using RapidArc® for the treatment of intracranial metastases

Translating SBRT From Academic to Community Practice

Purpose/Objective(s): Similar to stereotactic radiosurgery (SRS) used for decades in treatment of intra-cranial metastasis, stereotactic body radiation therapy (SBRT) is becoming an established, efficient, and effective means in achieving high rates of local tumor control. The institution is one of the largest cancer care delivery systems in the United States, In 2008 and 2009, it expanded its radiosurgical practice to two of its large communitybased practices. Materials/Methods: We adapted the practice of SRS and SBRT utilizing LINAC-based radiosurgical techniques that include cone-based, 3D conformal, IMRT/IMRS, VMAT, and gated-VMAT techniques employing the clinical and research foundation established at our academic hub. With centralized training, clinical guidance, and routine oversight, the two clinical programs were established separately. Centralized treatment planning and review was essential in establishing treatment guidelines. Results: Two hundred thirty patients treated from May 2008 and Dec 2011 were analyzed, most with metastatic or recurrent neoplasms. Separate data bases were established to document and summarize: (1) various treatment sites, (2) dose-fractionation schemes, (3) response, (4) toxicity, (5) survival, (6) demographics, and several other endpoints. A collaborative effort was established to combine the databases. An additional and more in depth analysis of patients with oligometastases, lung cancer, and the special population of the elderly were performed and will be summarized in separate manuscripts. The well-described efficacy and toxicity profiles have been replicated in this setting as well as achieving a high rate of local control, palliation and, in some settings, improved survival. Acute side effects are relatively minor and significantly less compared to standard fractionated radiation therapy. Conclusions: Utilizing a team-based approach and following standardized guidelines for dose-fractionation and normal tissue protection, SBRT can become a standard part of practice of an experienced comprehensive community-based cancer center. Special attention to appropriate imaging, target delineation, patient immobilization, quality assurance and patient safety may allow this modality to become the next major improvement in treatment options demonstrating better disease control and less toxicity for many situations. Our analysis validates previous observations of a potential cost savings for our healthcare system, greater access to treatment secondary to increased patient convenience, fewer treatments, and increased quality of life for patients. Author Disclosure: R.B. Wynn: None. A. Mihai: None. P. Thiron: None. J. Westrup: None. M. Krebs: None. J. Armstrong: None. L.A. Rock: None. G. Fagan: None. R. Bhatnagar: None. D.E. Heron: None.

Comparison of fractionated and single session radiosurgery for radiation resistant brain metastases.

2091 Background: Melanoma and renal cell carcinoma are commonly called radiation resistant tumors due to the decreased response rate to traditional radiation (1.8-2 Gy /Fraction). Large brain metastases from radioresistant primaries are clinical challenges. This study examines the impact of fractionation on the treatment of intracranial metastases from radiation resistant tumors. Methods: Patients with a primary diagnosis of melanoma or renal cell carcinoma and intracranial metastases who completed treatment at The University of North Carolina with frameless robotic radiosurgery between 2007-2011 were retrospectively analyzed. Patients were treated with either single or 3-5 fractions depending on volume. The study’s primary endpoints were overall survival (OS) and local control (LC), and its secondary endpoint was patient steroid requirements. Outcomes data and pre-treatment variables were analyzed for significance using appropriate non-parametric tests. Results: 25 patients were included in the single fraction arm and 13 patients in the multi-fraction arm, and both had equivalent pre-treatment characteristics with the exception of tumor volume which was larger in the multi-fraction arm (p=0.01). At a median follow-up of 4.7 months (range, 1.8-11.6), the median OS for all patients was 6.2 months. One year survival was 35.1% and 5 patients (13%) had local failures at a median time to local failure of 5.5 months. Patients in the multi-fraction arm failed at a higher rate (10.5%) than patients in the single fraction arm (2.6%) (p=0.04), but there was no difference in OS (p=0.34). There was no difference between pre-treatment and post-treatment steroid requirements between the two arms (p=0.351). Conclusions: Fractionation is intended to facilitate radiosurgery in large tumors by limiting high doses of radiation to a large portion of normal brain. In our study of radioresistant intracranial metastases, large tumors receiving multi-fraction radiosurgery had decreased local control with no difference in toxicity or OS. These results suggest a need for either dose escalation, or combination therapy designed to reduce tumor size (resection or aspiration) in order to facilitate single fraction treatment.

Frameless Stereotactic Radiosurgery for Treatment of Intracranial Metastases

Frameless Stereotactic Radiosurgery for Treatment of Intracranial Metastases

TH-D-AUD C-08: Closed-Loop Guidance of Laser Induced Thermal Therapy Using MRI

Purpose: A closed‐loop MR‐guided laser induced thermal therapy (LITT) system has been developed and validated in large animals, obtained 510(k) clearance and undergone initial safety studies in humans. In this work we outline the capabilities and potential applications of the system, recent advances and current challenges in MR temperatureimaging for guidance of these procedures, initial results in human subjects and current work in integrating the system with an interventional MR suite. Method and Materials: All imaging has been performed on 1.5T MRI scanners. Temperature was measured in real‐time using MR thermography based on the proton resonance frequency shift and used to control a high‐power 980‐nm diode actively‐cooled laser for interstitial LITT. An MR compatible targeting template, similar to that used for brachytherapy delivery, was developed and used to investigate the feasibility of performing MR‐guided LITT in prostate using a canine model. Treatments in spine used a canine sarcoma model. Intracranial treatment in a canine model were performed to test the safety of the equipment and evaluate the lesions over time prior to commencing treatment of intracranial metastasis in patients. MR‐guided LITT using MRTI feedback was also performed in patients with liver metastases. The system was integrated into a multi‐modality interventional suite featuring a large bore 1.5T magnet and floor mounted fluoroscopy unit for image guided procedures. Results: Actively‐cooled laser applicators facilitate much more rapid therapy delivery than previous laser technology allowing 2‐cm treatments to be completed in <90 seconds in many cases. MR temperatureimaging provided valuable feedback during therapy allowing a more aggressive therapy delivery. Procedures were well tolerated in both animal and human subjects. Conclusion: MRI‐guided LITT is feasible and safe. MR temperatureimaging provides a means to either qualitatively monitor the therapy or apply quantitative dosimetry which can accurately predict the region of ablation.

Physics and Imaging for Targeting of Oligometastases

Oligometastases refer to metastases that are limited in number and location and are amenable to regional treatment. The majority of these metastases appear in the brain, lung, liver, and bone. Although the focus of interest in the past within radiation oncology has been on the treatment of intracranial metastases, there has been growing interest in extracranial sites such as the liver and lung. This is largely because of the rapid development of targeting techniques for oligometastases such as intensity-modulated and image-guided radiation therapy, which has made it possible to deliver single or a few fractions of high-dose radiation treatments, highly conformal to the target. The clinical decision to use radiation to treat oligometastases is based on both radiobiological and physics considerations. The radiobiological considerations involve improvement of treatment schema for time, dose, and volume. Areas of interests are hypofractionation, tumor and normal tissue tolerance, and hypoxia. The physics considerations for oligometastases treatment are focused mainly on ensuring treatment accuracy and precision. This article discusses the physics and imaging aspects involved in each step of the radiation treatment process for oligometastases, including target definition, treatment simulation, treatment planning, pretreatment target localization, radiation delivery, treatment verification, and treatment evaluation.

Stereotactic radiotherapy for patients who initially presented with brain metastases from non-small cell carcinoma

The purpose of this study was retrospectively to evaluate the effectiveness of fractionated stereotactic radiotherapy (FSRT) for patients who presented with intracranial metastases as the initial symptom of lung carcinoma. Fifteen patients with three or fewer brain metastases from lung carcinoma underwent FSRT receiving 42 Gy in 7 fractions or 40 Gy in 4 fractions from April 1999 to October 2002. Patients who developed new lesions were retreated with FSRT or whole brain radiotherapy (WBRT). Tumor control was obtained in 14 patients during a median period of 21.0 months (ranging from 11 to 34 months) with salvage radiotherapy whenever required. None died from brain metastasis. The median survival time was 7.0±3.0 months and 21.0±1.0 months for patients with or without extracranial metastases, respectively (p<0.01). Those who received treatment for the primary and mediastinal lymph nodes (22.0±1.4 months) survived longer than those who did not (8.0±2.5 months) (p<0.001). Overall high local control and high survival rates for the patients suggest that FSRT appears effective and safe in the treatment of patients who present with intracranial metastases as the initial symptom of lung carcinoma. After treatment of intracranial metastases, further therapy for the primary appears to improve survival rates.

Stereotactic Radiosurgery Versus Microsurgical Resection for the Initial Treatment of Metastatic Cancer to the Brain

The use of Stereotactic radiosurgery for the treatment of intracranial metastases from systemic cancer has grown considerably in the last few years. Review of the literature, however, reveals a paucity of well-controlled studies to substantiate this expansion. We conducted this study to address the issue of survival after treatment with either stereotactic radiosurgery or surgical resection. Whole brain radiation was instituted in both treatment arms. This was a retrospective, case-controlled study comparing patients whose only treatment for intracranial disease was either stereotactic radio-surgery or a single surgical resection. Controlling for age, histology, whole brain radiation, tumor size, number of intracranial lesions, and pre-procedural Karnofsky performance scores, we believe this study to be the most rigorous analysis to date. Patients in the radiosurgery group survived longer (median survival = 12.5 months) than those in the surgically resected group (median survival = 8 months). Statistical analysis of these curves did not show a significant difference. Considering only length of patient survival, there is no statistical difference between stereotactic radiosurgery and microsurgical resection for the treatment of new brain metastases from systemic cancer. This conclusion is based on strict criteria as outlined in the text. A larger, prospective, randomized investigation is needed to more definitively address the issue.

Intracranial metastases from melanoma. Clinical features and treatment by accelerated fractionation.

One hundred ninety-four patients with intracranial metastatic melanoma were treated at the M. D. Anderson Hospital between January 1972 and September 1977, using seven different accelerated irradiation regimens. The total tumor dose varied from 3000 to 4800 rad, and the overall treatment time from 1 to 2 weeks. In these patients, whose disease had progressed to brain metastases, freedom from such metastases had decreased logarithmically with time from initial presentation. This suggests a random distribution of progression rates with a mean time of 2.5 years between diagnosis and development of intracranial metastases. Overall, there was no significant improvement in the results from accelerated fractionation in the treatment of intracranial metastases. The result of treatment did not depend on the site of the primary, the number of intracranial metastases, the total dose, or the dose per fraction. There were, however, two subgroups not mutually exclusive, that benefited significantly from the accelerated fractionation: patients having had a complete resection of brain metastases, and those having no detectable extracranial metastases at the time of their treatment for intracranial metastases.

Treatment of Intracranial Metastases

Treatment of Intracranial Metastases