Treatment for paraganglioma with stereotactic radiotherapy.

BACKGROUND: Paragangliomas (PG) are rare neoplasms of neuroendocrine origin that tend to be highly vascularized, slow-growing, and usually sporadic. To date, common treatment options are surgical resection (SR), with or without radiation therapy (RT), and a watch-and-wait approach. AIM: To evaluate the local control and effectiveness of exclusive fractionated stereotactic RT (FSRT) treatment in unresectable PG (uPG). METHODS: We retrospectively evaluated patients with uPG (medically inoperable or refused SR) treated with FSRT with a Cyberknife System (Accuray Incorporated, Sunnyvale, California). Toxicity and initial efficacy were evaluated. RESULTS: From May 2009 to January 2023, 6 patients with a median age of 68 (range 20-84) were treated with FSRT. The median delivered dose was 21 Gy (range 20-30 Gy) at a median isodose line of 75.5% (range 70%-76%) in 4 fractions (range 3-5 fractions). The median volume was 13.6 mL (range 12.4-65.24 mL). The median cumulative biological effective dose and equivalent dose in 2-Gy fractions were 70 Gy and 37.10 Gy respectively. Site of origin involved were the timpa-nojugular glomus (4/6), temporal bone, and cervical spine. In 1 of the 6 patients, the follow-up was insufficient; 5 of 6 patients showed a 5-year overall survival and 5-year progression-free survival of 100%. We observed negligible toxicities during and after RT. The majority of patients showed stable symptoms during follow-up. Only 1 patient developed spine metastases. CONCLUSION: Our preliminary results on this small cohort of patients suggest that FSRT could be an effective and safe alternative to SR.

Reirradiation of metastases of the central nervous system: part 1-brain metastasis.

Because of improved survival of cancer patients, more patients irradiated for brain metastases develop intracerebral recurrences requiring subsequent courses of radiotherapy. Five studies focused on reirradiation with whole-brain radiation therapy (WBRT) after initial WBRT for brain metastases. Following the second WBRT course, improvement of clinical symptoms was found in 31-68% of patients. Rates of neurotoxicity, such as encephalopathy or cognitive decline, were reported in two studies (1.4% and 32%). In another study, severe or unexpected adverse events were not observed. Survival following the second WBRT course was generally poor, with median survival times of 2.9-4.1 months. The survival prognosis of patients receiving two courses of WBRT can be estimated by a scoring tool considering five prognostic factors. Three studies investigated reirradiation with single-fraction stereotactic radiosurgery (SF-SRS) following primary WBRT. One-year local control rates were 74-91%, and median survival times ranged between 7.8 and 14 months. Rates of radiation necrosis (RN) after reirradiation were 0-6%. Seven studies were considered that investigated re-treatment with SF-SRS or fractionated stereotactic radiation therapy (FSRT) following initial SF-SRS or FSRT. One-year local control rates were 60-88%, and the median survival times ranged between 8.3 and 25 months. During follow-up after reirradiation, rates of overall (asymptomatic or symptomatic) RN ranged between 12.5% and 30.4%. Symptomatic RN occurred in 4.3% to 23.9% of cases (patients or lesions). The risk of RN associated with symptoms and/or requiring surgery or corticosteroids appears lower after reirradiation with FSRT when compared to SF-SRS. Other potential risk factors of RN include the volume of overlap of normal tissue receiving 12 Gy at the first course and 18 Gy at the second course of SF-SRS, maximum doses ≥40 Gy of the first or the second SF-SRS courses, V12 Gy >9 cm3 of the second course, initial treatment with SF-SRS, volume of normal brain receiving 5 Gy during reirradiation with FSRT, and systemic treatment. Cumulative EQD2 ≤100-120 Gy2 to brain, <100 Gy2 to brainstem, and <75 Gy2 to chiasm and optic nerves may be considered safe. Since most studies were retrospective in nature, prospective trials are required to better define safety and efficacy of reirradiation for recurrent or progressive brain metastases.

Successful treatment of medically and surgically refractory lymphocytic hypophysitis with fractionated stereotactic radiotherapy: a single-center experience and systematic literature review.

PURPOSE: To explore the potential role of focused radiotherapy in managing the lymphocytic hypophysitis (LH) refractory to medical therapy and surgery. METHOD: A systematic literature review was conducted following PRISMA guidelines to identify the studies on radiation treatment for hypophysitis, along with the experience in our institution. RESULTS: The study included eight patients, three from our institution and five from existing literature. The age at presentation ranged from 37 to 75 years old, with a median age of 58. The presenting symptoms involved headache in seven patients and diplopia in two patients. Pre-radiation visual field defects were noticed in four patients. All patients exhibited variable degrees of hypopituitarism before radiation, with oral corticosteroids being the initial medical treatment. Immunosuppressive therapy was attempted in two patients prior to radiation. Seven patients had a history of transsphenoidal surgery with a histologically confirmed LH. Three patients underwent stereotactic radiosurgery (SRS), while the remaining received FSRT, with a mean irradiation volume of 2.2 cm3. A single-session total dose of 12 -15 Gy was administered in the SRS group. In the FSRT group, doses ranged from 24 to 30 Gy with a median dose of 25 Gy, delivered in 2 Gy fractions. Four patients achieved a resolution of visual field defects, while another two patients demonstrated improvement in their associated focal neurologic deficits. No change in pre-existing endocrine status was shown after radiation, except in one patient. Clinical response was achieved in seven patients after a single course of radiation, while one patient required the second course. Six patients remained stable on low-dose glucocorticoid during at least a 12-month follow-up period, and one discontinued it entirely without experiencing relapse. Three patients demonstrated a complete radiologic response, while the remaining showed a partial radiologic response. CONCLUSIONS: Focused radiation, including FSRT, can play a role in symptomatic relief, effective mass shrinkage, and minimizing radiation exposure to critical surrounding structures in patients with refractory LH. However, further research efforts are necessary to better clarify its effects and optimal dose planning.

Growth speed of large brain metastases between diagnostic and radiosurgical planning MRI and predictors of rapid tumor growth.

PURPOSE: We aimed to assess volumetric changes of large brain metastases (≥ 2 cm) between their diagnosis and planning for treatment with fractionated stereotactic radiation surgery (fSRS). Predictors of rapid tumor growth were also analyzed. MATERIALS AND METHODS: One hundred nine patients harboring 126 large brain metastases were retrospectively evaluated. Tumor characteristics were evaluated on diagnostic magnetic resonance imaging (dMRI) and MRI performed when planning fSRS (pMRI). Average tumor growth rate and percentage growth rate were calculated. Predictors of rapid growth (percentage growth rate > 5%) were determined using multivariate logistic regression. RESULTS: Both tumor diameter and volume were significantly larger on pMRI than on dMRI (P < 0.001). Median tumor percentage growth rate was 2.6% (range, - 10.8-43.3%). Eighty-eight tumors (70%) were slow-growing (percentage growth rate < 5%) and 38 (30%) grew rapidly (percentage growth rate ≥ 5%). Major peritumoral edema and no steroids were predictors of rapid tumor growth. CONCLUSION: Large brain metastases can grow considerably between the time of diagnosis and the time of fSRS treatment planning. We recommend the time between dMRI and fSRS treatment initiation be as short as possible.

Whole Brain Irradiation or Stereotactic RadioSurgery for five or more brain metastases (WHOBI-STER): A prospective comparative study of neurocognitive outcomes, level of autonomy in daily activities and quality of life.

AIMS: To evaluate neurocognitive performance, daily activity and quality of life (QoL), other than usual oncologic outcomes, among patients with brain metastasis ≥5 (MBM) from solid tumors treated with Stereotactic Brain Irradiation (SBI) or Whole Brain Irradiation (WBI). METHODS: This multicentric randomized controlled trial will involve the enrollment of 100 patients (50 for each arm) with MBM ≥ 5, age ≥ 18 years, Karnofsky Performance Status (KPS) ≥ 70, life expectancy > 3 months, known primary tumor, with controlled or controllable extracranial disease, baseline Montreal Cognitive Assessment (MoCA) score ≥ 20/30, Barthel Activities of Daily Living score ≥ 90/100, to be submitted to SBI by LINAC with monoisocentric technique and non-coplanar arcs (experimental arm) or to WBI (control arm). The primary endpoints are neurocognitive performance, QoL and autonomy in daily-life activities variations, the first one assessed by MoCa Score and Hopkins Verbal Learning Test-Revised, the second one through the EORTC QLQ-C15-PAL and QLQ-BN-20 questionnaires, the third one through the Barthel Index, respectively. The secondary endpoints are time to intracranial failure, overall survival, retreatment rate, acute and late toxicities, changing of KPS. It will be considered significant a statistical difference of at least 30% between the two arms (statistical power of 80% with a significance level of 95%). DISCUSSION: Several studies debate what is the decisive factor accountable for the development of neurocognitive decay among patients undergoing brain irradiation for MBM: radiation effect on clinically healthy brain tissue or intracranial tumor burden? The answer to this question may come from the recent technological advancement that allows, in a context of a significant time saving, improved patient comfort and minimizing radiation dose to off-target brain, a selective treatment of MBM simultaneously, otherwise attackable only by WBI. The achievement of a local control rate comparable to that obtained with WBI remains the fundamental prerequisite. TRIAL REGISTRATION: NCT number: NCT04891471.

Cavernous sinus meningioma.

Cavernous sinus meningioma (CSM) presents a management challenge to present-day neurosurgeons. Lack of adequate understanding of the natural history of these lesions, the early involvement of vital neurovascular structures, the absence of clear tissue planes with normal surrounding structures, and a high rate of aggressive surgery-related morbidity each pose management dilemmas for neurosurgeons. Over the past few decades, the enthusiasm of the neurosurgical community has shifted from aggressive microsurgical resection to maximal safe resection and institution of adjuvant radiotherapy, if necessary. This paradigm shift has ensured better functional outcome in treated patients. This chapter has been designed to discuss the current treatment algorithm and the importance of multimodality management for optimal outcome in patients with CSM. The technical aspects of this approach to management are presented, and the various treatment options are compared.

Neoadjuvant stereotactic radiosurgery for intracerebral metastases of solid tumors (NepoMUC): a phase I dose escalation trial.

BACKGROUND: More than 25% of patients with solid cancers develop intracerebral metastases. Aside of surgery, radiation therapy (RT) is a mainstay in the treatment of intracerebral metastases. Postoperative fractionated stereotactic RT (FSRT) to the resection cavity of intracerebral metastases is a treatment of choice to reduce the risk of local recurrence. However, FSRT has to be delayed until a sufficient wound healing is attained; hence systemic therapy might be postponed. Neoadjuvant stereotactic radiosurgery (SRS) might offer advantages over adjuvant FSRT in terms of better target delineation and an earlier start of systemic chemotherapy. Here, we conducted a study to find the maximum tolerated dose (MTD) of neoadjuvant SRS for intracerebral metastases. METHODS: This is a single-center, phase I dose escalation study on neoadjuvant SRS for intracerebral metastases that will be conducted at the Klinikum rechts der Isar Hospital, Technical University of Munich. The rule-based traditional 3 + 3 design for this trial with 3 dose levels and 4 different cohorts depending on lesion size will be applied. The primary endpoint is the MTD for which no dose-limiting toxicities (DLT) occur. The adverse events of each participant will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 continuously during the study until the first follow-up visit (4-6 weeks after surgery). Secondary endpoints include local control rate, survival, immunological tumor characteristics, quality of life (QoL), CTCAE grade of late clinical, neurological, and neurocognitive toxicities. In addition to the intracerebral metastasis which is treated with neoadjuvant SRS and resection up to four additional intracerebral metastases can be treated with definitive SRS. Depending on the occurrence of DLT up to 72 patients will be enrolled. The recruitment phase will last for 24 months. DISCUSSION: Neoadjuvant SRS for intracerebral metastases offers potential advantages over postoperative SRS to the resection cavity, such as better target volume definition with subsequent higher efficiency of eliminating tumor cells, and lower damage to surrounding healthy tissue, and much-needed systemic chemotherapy could be initiated more rapidly. Trial registration The local ethical review committee of Technical University of Munich (199/18S) approved this study on September 05, 2018. This trial was registered on German Clinical Trials Register (DRKS00016613; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016613) on January 29, 2019.

Post-Craniopharyngioma and Cranial Nerve-VI Palsy Update on a MS Patient with Major Depression and Concurrent Neuroimmune Conditions.

We report the case of a male multiple sclerosis (MS) patient with type 2 diabetes (T2D), asthma, major depression (MD or major depressive disorder, MDD), and other chronic conditions, after his recent difficulties with craniopharyngioma and cranial nerve-VI (CN6) palsy. In addition, we show magnetic resonance image and spectroscopy (MRI, MRS), Humphrey's Visual Field (HVF), and retinal nerve fiber layer thickness (RNFLT) findings to explain the changes in the patient's health, and discuss the methods that helped/help him sustain productivity and euthymia despite long-standing problems and new CNS changes.

Impact of 68Ga-DOTATOC PET/MRI on robotic radiosurgery treatment planning in meningioma patients: first experiences in a single institution.

OBJECTIVEFor stereotactic radiosurgery (SRS) planning, precise contouring of tumor boundaries and organs at risk is of utmost importance. Correct interpretation of standard neuroimaging (i.e., CT and MRI) can be challenging after previous surgeries or in cases of skull base lesions with complex shapes. The aim of this study was to evaluate the impact of 68Ga-DOTATOC PET/MRI on treatment planning for image-guided SRS by CyberKnife.METHODSThe authors retrospectively identified 11 meningioma treatments in 10 patients who received a 68Ga-DOTATOC PET/MRI prior to SRS. The planning target volume (PTV) used for the patients' treatment was defined as the reference standard. This was contoured by a treating radiosurgeon (RS0) using fused planning CT and PET/MRI data sets. The same tumors were then contoured by another experienced radiosurgeon (RS1) and by a less-experienced radiosurgeon (RS2), both blinded to PET data sets. A comparison of target volumes with focus on volume-based metrics and distance to critical structures was performed. RS1 and RS2 also filled in a questionnaire analyzing the confidence level and the subjective need for the implementation of PET data sets for contouring.RESULTSAnalysis showed a subjective personal preference for PET/MRI in all cases for both radiosurgeons, particularly in proximity to critical structures. The analysis of the planning volumes per physician showed significantly smaller RS2-PTV in comparison to RS1-PTV and to RS0-PTV, whereas the median volumes were comparable between RS1-PTV and RS2-PTV (median: RS0: 4.3 cm3 [IQR 3.4-6.5 cm3] and RS1: 4.5 cm3 [IQR 2.7-6 cm3] vs RS2: 2.6 cm3 [IQR 2-5 cm3]; p = 0.003). This was also reflected in the best spatial congruency between the 2 experienced physicians (RS0 and RS1). The percentage of the left-out volume contoured by RS1 and RS2 compared to RS0 with PET/MRI demonstrated a relevant left-out-volume portion in both cases with greater extent for the less-experienced radiosurgeon (RS2) (RS1: 19.1% [IQR 8.5%-22%] vs RS2: 40.2% [IQR 34.2%-53%]). No significant differences were detected regarding investigated critical structures.CONCLUSIONSThis study demonstrated a relevant impact of PET/MRI on target volume delineation of meningiomas. The extent was highly dependent on the experience of the treating physician. This preliminary study supports the relevance of 68Ga-DOTATOC PET/MRI as a tool for radiosurgical treatment planning of meningiomas.

Increasing time to postoperative stereotactic radiation therapy for patients with resected brain metastases: investigating clinical outcomes and identifying predictors associated with time to initiation.

We sought to determine the impact of time to initiation (TTI) of post-operative radiosurgery on clinical outcomes for patients with resected brain metastases and to identify predictors associated with TTI. All patients with resected brain metastases treated with postoperative SRS or fractionated stereotactic radiation therapy (fSRT) from 2012 to 2016 at a single institution were reviewed. TTI was defined as the interval from resection to first day of radiosurgery. Receiver operating characteristic (ROC) curves were used to identify an optimal threshold for TTI with respect to local failure (LF). Survival outcomes were estimated using the Kaplan-Meier method and analyzed using the log-rank test and Cox proportional hazards models. Logistic regression models were used to identify factors associated with ROC-determined TTI covariates. A total of 79 resected lesions from 73 patients were evaluated. An ROC curve of LF and TTI identified an optimal threshold for TTI of 30.5 days, with an area under the curve of 0.637. TTI > 30 days was associated with an increased hazard of LF (HR 4.525, CI 1.239-16.527) but was not significantly associated with survival (HR 1.002, CI 0.547-1.823) or distant brain failure (DBF, HR 1.943, CI 0.989-3.816). Fifteen patients (20.5%) required post-operative inpatient rehabilitation. Post-operative rehabilitation was associated with TTI > 30 days (OR 1.48, CI 1.142-1.922). In our study of resected brain metastases, longer time to initiation of post-operative radiosurgery was associated with increased local failure. Ideally, post-op SRS should be initiated within 30 days of resection if feasible.

Clinical evaluation of stereotactic radiation therapy for recurrent or second primary mediastinal lymph node metastases originating from non-small cell lung cancer.

AIMS: To evaluate the safety and efficacy of stereotactic radiotherapy (SRT, both stereotactic body RT [SBRT] and fractionated stereotactic RT [FSRT]) in the treatment of patients with recurrent or second primary mediastinal lymph node metastases (R/SP-MLNMs) originating from non-small cell lung cancer (NSCLC). METHODS: Between 10/2006 and 7/2013, patients with R/SP-MLNMs originating from NSCLC were enrolled and treated with SRT at our hospital; their data was stored in prospectively-collected database. The enrolled patients were divided into Group A (without prior RT) and Group B (with prior RT). The primary end-point was overall survival (OS). The secondary end-points were the MLNM local control (LC), the time to symptom alleviation, and toxicity using the Common Terminology Criteria for Adverse Events (CTCAE v4.0). RESULTS: Thirty-three patients were treated (16 in Group A with 19 R/SP-MLNMs and 17 in Group B with 17 R/SP-MLNMs). For the entire cohort, the median OS was 25.5 months with a median follow-up of 20.9 months (range, 3.2-82). The 1-year and 3-year actuarial LC rates were 100% and 86%, respectively. Symptom alleviation was observed in 52% of patients, after a median of 6 days (range, 3-18). CTCAE v4.0 ≥ Grade 3 toxicities occurred in 5 patients (15%; all in Group B); among them, Grade 5 in 2 patients. CONCLUSIONS: We recommend exercising extreme caution in using SRT for R/SP-MLNMs in patients who received prior RT (particularly to LN station 7). For patients without previous RT, SRT appears to be safe and efficacious treatment modality; prospective studies are warranted.

Fractionated Stereotactic Radiation Therapy for Intracranial Benign Tumor: Preliminary Results of Clinical Application / 대한방사선종양학회지

PURPOSE: With the development of stereotactic immobilization systems capable of reliable serial repositioning, fractionated stereotactic radiation therapy (FSRT) offers the potential for an improved treatment outcome by excellent dose delivery, and dose distribution characteristics with the favorable radiobiological properties of fractionated irradiation. We describe our initial experience using FSRT for the treatment of intracranial benign tumor. MATERIALS AND METHODS: Between August 1995 and December 1996, 15 patients (7 males and 8 females aged 6-70 years) were treated with FSRT. The patients had the following diagnosis : pituitary adenoma (10) including one patient who previously had received radiotherapy, craniopharyngioma (2), acoustic neurinoma (1), meningioma (2). Using the Gill-Thomas-Cosman relocatable head frame and multiple non-coplanar therapy, the daily dose of 2Gy was irradiated at 90% to 100% isodose surface of the isocenter. The collimator sizes ranged from 26mm to 70mm. RESULTS: In all patients except one follow-up lost, disease was well- controlled. Acute complication was negligible and no patient experienced cranial nerve neuropathies and radiation necrosis. In overall patient setup with scalp measurements, reproducibility was found to have mean of 1.1+/-0.6mm from the baseline reading. CONCLUSION: Relocatable stereotactic system for FSRT is highly reproducible and comfortable. Although the follow-up period was relatively short, FSRT is considered to be a safe and effective radiation technique as the treatment of intracranial tumor. But the fractionation schedule (fraction size, overall treatment time and total dose) still remains to be solved by further clinical trials.

Fractionated Stereotactic Radiation Therapy for Intracranial Malignant Tumor: Preliminary Results of Clinical Application / 대한암학회지

PURPOSE: Fractionated stereotactic radiation therapy(FSRT) is a new modality that combines the accurate focal dose delivery of stereotactic radiosurgery with the biological advantages of conventional radiotherapy. We report our early experience using FSRT for intracranial malignant tumor. MATERIALS AND METHODS: Between October 1995 and December 1996, 16 patients(9 males and 7 females aged between 10~64 years) with central nerve system malignancy were treated using FSRT. Sixteen patients had the following diagnosis: 6 high-grade gliomas, 1 pineoblastoma, 4 germinomas, 2 medulloblastomas, and 3 solitary brain metastases. Using the Gill-Thomas-Cosman relocatable head frame and multiple non-coplanar therapy, the daily dose of 2 Gy(3 Gy in metastasis) was irradiated at 85~100% isodose surface. RESULTS: Although the follow-up period is relatively short(range; 2~18 months), post- treatment clinical courses in 16 patients have been consistent with changes similar to those found after conventional radiation therapy. No significant adverse effects were observed in our neurological and radiological studies. Four out of 5 patients with high grade glioma died from progressive disease, surviving from 7 to 17 months(median 14 months), but patients with pineoblastoma, germinoma and medulloblastoma showed no evidence of recurrence. All patients with metastasis obtained a neurologic response, but two among them died with extracranial progression and one die from multiple intracranial metastasis.In overall patient setup with scalp measurements, reproducibility was found to have mean of 1.1+/-0.6 mm from the baseline reading. CONCLUSION: FSRT and relocatable stereotactic head frames were well tolerated with minimal transient acute side effects. Subacute or late complications were not observed, because the follow-up period was short. We expect that FSRT might be a good indication for; recurrent disease with previous radiation therapy history, tumors of relatively large volume, lesions adjacent to radiosensitive organs, and as a boost, following conventional radiation therapy.

Excellent Local Tumor Response after Fractionated Stereotactic Radiation Therapy for Locally Recurrent Nasopharynx Cancer / 대한치료방사선과학회지

PURPOSE: This study is to report experience with Fractionated Stereotactic Radiation Therapy (FSRT) for locally recurrent nasopharynx cancer after curative conventional radiation therapy. MATERIALS AND METHODS: Three patients with locally recurrent and symptomatic nasopharynx cancer were given FSRT as reirradiation method between the period of September of 1995 and August of 1996. For two patients, application of FSRT is their third radiation therapy directed to the nasopharynx. Two patients were given low dose chemotherapy as radiation sensitizer concurrently with FSRT. Authors used 3-dimensional coordinate system by individually made, relocatable Gill-Thomas-Cosman (GTC) stereotactic frame and multiple non-coplanar arc therapy dose planning was done using XKnife-3. Total of 45 Gy/18 fractions or 50 Gy/20 fractions were given. RESULTS: Authors observed satisfactory symptomatic improvement and remarkable objective tumor size decrease by follow-up MR images taken 1 month post-FSRT in all three patients, while no neurologic side effect attributable to reirradiation was noticed. Two died at 7 and 9 months with loco-regional and distant seeding outside FSRT field, while one patient is living for 4 month. CONCLUSION: Authors experienced satisfactory therapeutic effectiveness and safety of FSRT as reirradiation method for locally recurrent nasopharynx cancer. Development of more effective systemic chemotherapeutic regimen is desired for distant metastasis.