Incidence and evolution of imaging changes on cone-beam CT during and after radical radiotherapy for non-small cell lung cancer.

BACKGROUND AND PURPOSE: Cone beam CT (CBCT) is used to improve accuracy of radical radiotherapy by adjusting treatment to the observed imaging changes. To ensure appropriate adjustment, image interpretation should precede any changes to treatment delivery. This study provides the methodology for image interpretation and the frequency and evolution of the changes in patients undergoing radical radiotherapy for localised and locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From December 2012 to December 2014, 250 patients with localised and locally advanced NSCLC had 2462 chest CBCT scans during the course of fractionated radical radiotherapy (RT) (3-5 daily CBCTs in the first week followed by at least weekly imaging, mean 9.5 per patient, range 1-21). All CBCT images were reviewed describing changes and their evolution using diagnostic imaging definitions and validated by an independent chest radiologist. RESULTS: During radical RT for NSCLC 328 imaging changes were identified on CBCT in 180 (72%) patients; 104 (32%) had reduction and 41 (13%) increase in tumour size; 48 (15%) had changes in consolidations contiguous to the primary lesion, 26 (8%) non-contiguous consolidations, 43 (13%) changes in tumour cavitation, 36 (11%) pleural effusion and 30 (9%) changes in atelectasis. In 105 patients imaging changes were noted in continuity with the treated tumour of which only 41 (39%) represented tumour enlargement; others included new or enlarging adjacent consolidation (34%), and new or enlarging atelectasis (19%). The changes evolved during treatment. CONCLUSION: Imaging changes on CBCT include real and apparent changes in tumour size and parenchymal changes which evolve during treatment. Correct image interpretation, particularly when occurring adjacent to the tumour, is essential prior to adjustment to treatment delivery.

The Predictive Value of Insulin-Like Growth Factor 1 in Irradiation-Dependent Growth Hormone Deficiency in Childhood Cancer Survivors.

BACKGROUND: The literature contains conflicting reports on the value of low insulin-like growth factor 1 (IGF-1) levels in predicting radiation-induced growth hormone (GH) deficiency (GHD) in childhood cancer survivors (CCS). These reports often involve small samples of patients who have received irradiation or mixed cohorts including non-irradiated subjects. OBJECTIVE: We undertook an analysis of the predictive value of low IGF-1 in CCS at risk for GHD after cranial radiotherapy involving the hypothalamic-pituitary (HP) area in a large single-centre cohort. METHODS: We performed a retrospective analysis on 158 CCS diagnosed with GHD between January 1, 2003 and October 31, 2017 and identified 117 patients who received radiation for tumours not direct ly involving the HP area. RESULTS: In this cohort, IGF-1 levels <-2 standard deviation scores (SDS) had a sensitivity of 31.9% for GHD; however, they were statistically more frequent (p = 0.0023) and had a higher sensitivity (45.6%) among patients with severe GHD. At final height reassessment, IGF-1 <-2 SDS had a sensitivity of 35.0% for GHD, but a positive predictive value of 100%. Finally, pretreatment IGF-1 values showed no correlation with the number of impaired pituitary hormonal axes in patients with multiple pituitary deficiencies. CONCLUSIONS: IGF-1 levels <-2 SDS showed a low sensitivity at predicting radiation-induced GHD both in childhood and in adulthood, but a high positive predictive value for GH status at final height reassessment.

Stereotactic radiotherapy and radiosurgery for non-functioning and secreting pituitary adenomas.

Radiotherapy (RT) is frequently employed in patients with residual or recurrent pituitary adenoma with excellent rates of tumor control and remission of hormonal hypersecretion. Advances in RT have improved with the use of stereotactic techniques either as fractionated stereotactic radiotherapy (FSRT) or stereotactic radiosurgery (SRS), all aiming to improve the dose distribution to the tumor while reducing the amount of normal brain receiving significant doses of radiation. We provide an overview of the recent published literature on the long-term efficacy and adverse effects of stereotactic irradiation in nonfunctioning and secreting pituitary adenomas. Both techniques are associated with excellent clinical outcomes; however, advantages and drawbacks of each of these techniques in terms of local control, hormonal excess normalization, and radiation-induced toxicity remain a matter of debate. In clinical practice, single-fraction SRS may represent a convenient approach to patients with small and medium-sized pituitary adenoma away at least 2 mm from the optic chiasm, whereas FSRT is preferred over SRS for lesions >2.5-3 cm in size and/or involving the anterior optic pathway.

Repeated stereotactic radiosurgery for patients with progressive brain metastases.

In the present study we have evaluated the efficacy and toxicity of repeated stereotactic radiosurgery (SRS) in patients with recurrent/progressive brain metastases. Between March 2006 and October 2014, 43 patients (21 men and 22 women) with 47 lesions received a second course of SRS given in three daily fractions of 7-8 Gy. With a follow-up study of 19 months, the 1- and 2-year survival rates from repeated SRS were 37 and 20%, respectively, and the 1- and 2-year local control rates were 70 and 60%, respectively. Actuarial local control was significantly better for breast and lung metastases as compared with melanoma metastases; specifically, 1-year local control rates were 38% for melanoma, 78% for breast carcinoma and 73% for non-small cell lung cancer (NSCLC) metastases (p = 0.01). The cause of death was progressive systemic disease in 25 patients and progressive brain disease in 11 patients. Stable extracranial disease (p = 0.01) and Karnofsky performance status (KPS; p = 0.03) were predictive of longer survival. Radiologic changes suggestive of brain radionecrosis were observed in 9 (19%) out of 47 lesions, with an actuarial risk of 34% at 12 months. Neurological deficits (RTOG Grade 2 or 3) associated with brain necrosis occurred in 14% of patients. In conclusion, a second course of SRS given in three daily fractions is a feasible treatment for selected patients with recurrent/progressive brain metastases. Further studies are needed to explore the efficacy and safety of different dose-fractionation schedules, especially in patients with melanoma or large metastases.

Fractionated stereotactic radiosurgery for patients with skull base metastases from systemic cancer involving the anterior visual pathway.

BACKGROUND: To analyze the tumor control, survival outcomes, and toxicity after stereotactic radiosurgery (SRS) for skull base metastases from systemic cancer involving the anterior visual pathway. PATIENTS AND METHODS: We have analyzed 34 patients (23 females and 11 males, median age 59 years) who underwent multi-fraction SRS for a skull base metastasis compressing or in close proximity of optic nerves and chiasm. All metastases were treated with frameless LINAC-based multi-fraction SRS in 5 daily fractions of 5 Gy each. Local control, distant failure, and overall survival were estimated using the Kaplan-Meier method calculated from the time of SRS. Prognostic variables were assessed using log-rank and Cox regression analyses. RESULTS: At a median follow-up of 13 months (range, 2-36.5 months), twenty-five patients had died and 9 were alive. The 1-year and 2-year local control rates were 89% and 72%, and respective actuarial survival rates were 63% and 30%. Four patients recurred with a median time to progression of 12 months (range, 6-27 months), and 17 patients had new brain metastases at distant brain sites. The 1-year and 2-year distant failure rates were 50% and 77%, respectively. On multivariate analysis, a Karnofsky performance status (KPS) >70 and the absence of extracranial metastases were prognostic factors associated with lower distant failure rates and longer survival. After multi-fraction SRS, 15 (51%) out of 29 patients had a clinical improvement of their preexisting cranial deficits. No patients developed radiation-induced optic neuropathy during the follow-up. CONCLUSIONS: Multi-fraction SRS (5 x 5 Gy) is a safe treatment option associated with good local control and improved cranial nerve symptoms for patients with a skull base metastasis involving the anterior visual pathway.

Fractionated stereotactic radiosurgery for patients with brain metastases.

Stereotactic radiosurgery (SRS) delivered in 2-5 fractions (multi-fraction SRS) has been employed in patients with brain metastases as an alternative to single-fraction SRS with the aim to reduce late radiation-induced toxicity while maintaining high local control rate. In the present study we have evaluated the efficacy and toxicity of multi-fraction SRS in patients with 1-3 brain metastases. Between March 2006 and October 2012, 135 patients (63 men and 72 women) with 171 brain metastases have been treated with multi-fraction SRS (3 × 9 Gy or 3 × 12 Gy). At a median follow-up of 11.4 months, 16 lesions recurred locally. The 1- and 2-year local control rates were 88 and 72 %, respectively. The 1- and 2-year survival rates were 57 and 25 %, and respective distant failure rates were 52 and 73 %. Seventy-eight percent of patients succumbed to their extracranial disease and 22 % died of progressive intracranial disease. Multivariate analysis showed that melanoma histology was predictive of local failure (p = 0.02; HR 6.1, 95 % CI 1.5-24). Specifically, the 1-year local control rates were 68 % for melanoma, 92 % for breast carcinoma, and 88 % for NSCLC, respectively. Stable extracranial disease (p = 0.004) and Karnofsky performance status (p = 0.01) were predictive of longer survival. Radiologic changes suggestive of radionecrosis occurred in 12 (7 %) out of 171 lesions, with an actuarial risk of 9 % at 1 year and 17 % at 2 years, respectively. In conclusion, multi-fraction SRS appears to be an effective and safe treatment modality for brain metastases. It may represent an alternative to single-dose SRS for patients with large lesions or lesions located near critical structures.

Multidose stereotactic radiosurgery (9 Gy × 3) of the postoperative resection cavity for treatment of large brain metastases.

PURPOSE: To evaluate the clinical outcomes with linear accelerator-based multidose stereotactic radiosurgery (SRS) to large postoperative resection cavities in patients with large brain metastases. METHODS AND MATERIALS: Between March 2005 to May 2012, 101 patients with a single brain metastasis were treated with surgery and multidose SRS (9 Gy × 3) for large resection cavities (>3 cm). The target volume was the resection cavity with the inclusion of a 2-mm margin. The median cavity volume was 17.5 cm(3) (range, 12.6-35.7 cm(3)). The primary endpoint was local control. Secondary endpoints were survival and distant failure rates, cause of death, performance measurements, and toxicity of treatment. RESULTS: With a median follow-up of 16 months (range, 6-44 months), the 1-year and 2-year actuarial survival rates were 69% and 34%, respectively. The 1-year and 2-year local control rates were 93% and 84%, with respective incidences of new distant brain metastases of 50% and 66%. Local control was similar for radiosensitive (non-small cell lung cancer and breast cancer) and radioresistant (melanoma and renal cell cancer) brain metastases. On multivariate Cox analysis stable extracranial disease, breast cancer histology, and Karnofsky performance status >70 were associated with significant survival benefit. Brain radionecrosis occurred in 9 patients (9%), being symptomatic in 5 patients (5%). CONCLUSIONS: Adjuvant multidose SRS to resection cavity represents an effective treatment option that achieves excellent local control and defers the use of whole-brain radiation therapy in selected patients with large brain metastases.

Stereotactic radiosurgery in elderly patients with brain metastases.

Stereotactic radiosurgery (SRS) has been increasingly employed as an alternative to whole brain radiation therapy in patients with brain metastases, with the aim to reduce its potential toxicity. We have evaluated clinical outcomes of SRS as initial treatment for brain metastases in patients 70 years and older. Between November 2007 and October 2011, 102 patients of 70 years and older with 1-4 metastases were treated with SRS. The primary end point of the study was overall survival. Secondary end points were local control and distant failure rates, cause of death, performance measurements, and toxicity of treatment. At a median follow-up of 11.0 months (range 1-48 months), median survival and median time to distant failure were 13.2 and 10 months, respectively. The 1- and 2-year survival rates were 63 and 28 %, and respective distant failure rates were 54 and 78 %. Forty-five patients succumbed to their extracranial disease and 14 patients died of progressive intracranial disease. Nine patients recurred locally after SRS. The 1- and 2-year local control rates were 90 and 84 %, respectively. Evaluation of neurocognitive function using the Mini-Mental State Examination (MMSE) showed no significant neurocognitive decline after SRS. MMSE score improved in 15 % of patients, worsened in 12 % of patients, and remained stable in the others. Severe neurological complications were reported in 7 (7 %) patients, requiring surgery or medical treatment. Initial treatment with SRS with close monitoring may represent a relatively safe treatment strategy associated with survival benefit, with outcomes similar to those reported in historical series of SRS for younger patients.

Comparison of setup accuracy and intrafraction motion using stereotactic frame versus 3-point thermoplastic mask-based immobilization for fractionated cranial image guided radiation therapy.

PURPOSE: Prospectively compare patient setup accuracy and intrafraction motion of a standard 3-point thermoplastic mask with the Gill-Thomas-Cosman relocatable stereotactic frame, during fractionated cranial radiation therapy using the ExacTrac system (Brainlab AG Feldkirchen, Germany) for daily online correction. METHODS AND MATERIALS: The number of fractions with all postcorrection and post-treatment errors <2 mm was assessed in 21 patients undergoing fractionated stereotactic radiation therapy (13 frame setup, 8 mask setup) using daily online correction. Achievable patient setup accuracy and total intrafraction motion were evaluated. The relative contributions of movement during floor rotation and patient movement to intrafraction motion were calculated. RESULTS: With daily online correction, patient setup margins can be reduced from 1, 5, and 4 mm in the lateral, longitudinal, and vertical axes for mask setup and from 1-2, 2, and 1 mm, respectively, for frame setup to <1 mm isotropically for either immobilization system. Intrafraction movement was small for frame setup (mean [SD], -0.3 [0.3], -1.1[0.4], and -0.2 [0.6] in lateral, longitudinal and vertical axes, respectively; maximum, -2.7 mm [longitudinal axis]), and mask-setup (mean [SD], -0.4 [0.5], -0.8 [0.7], and 0.0 [0.3], respectively; maximum, -2.0 mm [longitudinal axis]) and is mainly due to floor rotation. Postcorrection and post-treatment errors were all <2 mm in 95% and 99% of fractions in the mask and frame, respectively, meeting the criteria for a 3-mm clinical target volume-planning target volume margin for either immobilization method. CONCLUSIONS: Daily online correction can compensate for less precise immobilization and permits stereotactic margins to be used for standard thermoplastic masks without the need for specialized mask systems.

Frameless linac-based stereotactic radiosurgery (SRS) for brain metastases: analysis of patient repositioning using a mask fixation system and clinical outcomes.

PURPOSE: To assess the accuracy of patient repositioning and clinical outcomes of frameless stereotactic radiosurgery (SRS) for brain metastases using a stereotactic mask fixation system. PATIENTS AND METHODS: One hundred two patients treated consecutively with frameless SRS as primary treatment at University of Rome Sapienza Sant'Andrea Hospital between October 2008 and April 2010 and followed prospectively were involved in the study. A commercial stereotactic mask fixation system (BrainLab) was used for patient immobilization. A computerized tomography (CT) scan obtained immediately before SRS was used to evaluate the accuracy of patient repositioning in the mask by comparing the isocenter position to the isocenter position established in the planning CT. Deviations of isocenter coordinates in each direction and 3D displacement were calculated. Overall survival, brain control, and local control were estimated using the Kaplan-Meier method calculated from the time of SRS. RESULTS: The mean measured isocenter displacements were 0.12 mm (SD 0.35 mm) in the lateral direction, 0.2 mm (SD 0.4 mm) in the anteroposterior, and 0.4 mm (SD 0.6 mm) in craniocaudal direction. The maximum displacement of 2.1 mm was seen in craniocaudal direction. The mean 3D displacement was 0.5 mm (SD 0.7 mm), being maximum 2.9 mm. The median survival was 15.5 months, and 1-year and 2-year survival rates were 58% and 24%, respectively. Nine patients recurred locally after SRS, with 1-year and 2-year local control rates of 91% and 82%, respectively. Stable extracranial disease (P = 0.001) and KPS > 70 (P = 0.01) were independent predictors of survival. CONCLUSIONS: Frameless SRS is an effective treatment in the management of patients with brain metastases. The presented non-invasive mask-based fixation stereotactic system is associated with a high degree of patient repositioning accuracy; however, a careful evaluation is essential since occasional errors up to 3 mm may occur.

Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis.

PURPOSE: to investigate the factors affecting survival and toxicity in patients treated with stereotactic radiosurgery (SRS), with special attention to volumes of brain receiving a specific dose (V10 - V16 Gy) as predictors for brain radionecrosis. PATIENTS AND METHODS: Two hundred six consecutive patients with 310 cerebral metastases less than 3.5 cm were treated with SRS as primary treatment and followed prospectively at University of Rome La Sapienza Sant'Andrea Hospital. Overall survival, brain control, and local control were estimated using the Kaplan-Meier method calculated from the time of SRS. Univariate and multivariate analysis using a Cox proportional hazards regression model were performed to determine the predictive value of prognostic factors for treatment outcome and SRS-related complications. RESULTS: Median overall survival and brain control were 14.1 months and 10 months, respectively. The 1-year and 2-year survival rates were 58% and 24%, and respective brain control were 43% and 22%. Sixteen patients recurred locally after SRS, with 1-year and 2-year local control rates of 92% and 84%, respectively. On multivariate analysis, stable extracranial disease and KPS >70 were associated with the most significant survival benefit. Neurological complications were recorded in 27 (13%) patients. Severe neurological complications (RTOG Grade 3 and 4) occurred in 5.8% of patients. Brain radionecrosis occurred in 24% of treated lesions, being symptomatic in 10% and asymptomatic in 14%. On multivariate analysis, V10 through V16 Gy were independent risk factors for radionecrosis, with V10 Gy and V12 Gy being the most predictive (p = 0.0001). For V10 Gy >12.6 cm3 and V12 Gy >10.9 cm3 the risk of radionecrosis was 47%. CONCLUSIONS: SRS alone represents a feasible option as initial treatment for patients with brain metastases, however a significant subset of patients may develop neurological complications. Lesions with V12 Gy >8.5 cm3 carries a risk of radionecrosis >10% and should be considered for hypofractionated stereotactic radiotherapy especially when located in/near eloquent areas.

Fractionated stereotactic conformal radiotherapy for large benign skull base meningiomas.

PURPOSE: To assess the safety and efficacy of fractionated stereotactic radiotherapy (FSRT) for large skull base meningiomas. METHODS AND MATERIALS: Fifty-two patients with large skull base meningiomas aged 34-74 years (median age 56 years) were treated with FSRT between June 2004 and August 2009. All patients received FSRT for residual or progressive meningiomas more than 4 centimeters in greatest dimension. The median GTV was 35.4 cm3 (range 24.1-94.9 cm3), and the median PTV was 47.6 cm3 (range 33.5-142.7 cm3). Treatment volumes were achieved with 5-8 noncoplanar beams shaped using a micromultileaf collimator (MLC). Treatment was delivered in 30 daily fractions over 6 weeks to a total dose of 50 Gy using 6 MV photons. Outcome was assessed prospectively. RESULTS: At a median follow-up of 42 months (range 9-72 months) the 3-year and 5-year progression-free survival (PFS) rates were 96% and 93%, respectively, and survival was 100%. Three patients required further debulking surgery for progressive disease. Hypopituitarism was the most commonly reported late complication, with a new hormone pituitary deficit occurring in 10 (19%) of patients. Clinically significant late neurological toxicity was observed in 3 (5.5%) patients consisting of worsening of pre-existing cranial deficits. CONCLUSION: FSRT as a high-precision technique of localized RT is suitable for the treatment of large skull base meningiomas. The local control is comparable to that reported following conventional external beam RT. Longer follow-up is required to assess long term efficacy and toxicity, particularly in terms of potential reduction of treatment-related late toxicity.

Fractionated stereotactic radiotherapy for skull base tumors: analysis of treatment accuracy using a stereotactic mask fixation system.

BACKGROUND: To assess the accuracy of fractionated stereotactic radiotherapy (FSRT) using a stereotactic mask fixation system. PATIENTS AND METHODS: Sixteen patients treated with FSRT were involved in the study. A commercial stereotactic mask fixation system (BrainLAB AG) was used for patient immobilization. Serial CT scans obtained before and during FSRT were used to assess the accuracy of patient immobilization by comparing the isocenter position. Daily portal imaging were acquired to establish day to day patient position variation. Displacement errors along the different directions were calculated as combination of systematic and random errors. RESULTS: The mean isocenter displacements based on localization and verification CT imaging were 0.1 mm (SD 0.3 mm) in the lateral direction, 0.1 mm (SD 0.4 mm) in the anteroposterior, and 0.3 mm (SD 0.4 mm) in craniocaudal direction. The mean 3D displacement was 0.5 mm (SD 0.4 mm), being maximum 1.4 mm. No significant differences were found during the treatment (P=0.4). The overall isocenter displacement as calculated by 456 anterior and lateral portal images were 0.3 mm (SD 0.9 mm) in the mediolateral direction, -0.2 mm (SD 1 mm) in the anteroposterior direction, and 0.2 mm (SD 1.1 mm) in the craniocaudal direction. The largest displacement of 2.7 mm was seen in the cranio-caudal direction, with 95% of displacements<2 mm in any direction. CONCLUSIONS: The results indicate that the setup error of the presented mask system evaluated by CT verification scans and portal imaging are minimal. Reproducibility of the isocenter position is in the best range of positioning reproducibility reported for other stereotactic systems.