Course Of Whole-brain Radiotherapy Research Articles

RADT-16. A RETROSPECTIVE COMPARISON OF OUTCOMES AFTER WHOLE BRAIN RADIOTHERAPY AND RAPID SIMPLE (RAPPLE) TARGETED THERAPY FOR BRAIN METASTASES IN MATCHED COHORTS OF PATIENTS WITH POOR PROGNOSIS

Abstract BACKGROUND For patients whose poor prognosis does not warrant stereotactic radiosurgery, we use the RAPPLE radiotherapy technique to treat multiple brain metastases. RAPPLE uses single-isocenter, coplanar volumetric modulated arc therapy and a non-stereotactic head-shell with IntegraBite™. Brain metastasis are contoured in a single gross tumour volume and expanded by 3 mm to create a planning target volume, covered by 95-110% of 20 Gy in 5 fractions. Our study compares clinical outcomes after RAPPLE and whole brain radiotherapy (WBRT). METHODS From January 2017 to December 2021, we identified patients receiving a first course of RAPPLE and matched patients receiving a first course of WBRT. Cox regression was used to analyze overall survival and Fine-Gray analysis was used to analyze intracranial progression. For each cohort, we compared patient-reported fatigue before and 2-6 weeks after radiotherapy. RESULTS Each cohort had 137 patients whose median Karnofsky Performance Score was 70. The diagnoses were lung cancer (72%) and other cancers (28%). The median survival was 4.1 months for RAPPLE and 4.2 months for WBRT (log-rank p = 0.8). On multivariable analysis of survival, the radiotherapy technique was not predictive (HR = 0.96, 95%CI: 0.73-1.25, p = 0.7). On multivariable analysis, intracranial progression was more likely after RAPPLE (HR = 1.6, 95%CI: 1.1 – 2.3, p = 0.02). The 18-month risk of intracranial progression was 0.49 for RAPPLE and 0.37 for WBRT (p = 0.04). After RAPPLE, 17% of patients required more focal RT and 4% required salvage WBRT, while after WBRT, 3% required focal RT and 4% required repeat WBRT. After RAPPLE, mean patient-reported fatigue remained stable from baseline to first follow-up (2.18 vs. 2.27, p = 0.9), but after WBRT it worsened (1.95 vs. 2.63, p = 0.002). CONCLUSIONS Ninety-six percent of patients treated with RAPPLE avoided WBRT. Patients reported worse fatigue after WBRT.

RAPid SimPLE (RAPPLE) Targeted Radiation Treatment vs. Whole Brain Radiotherapy: A Retrospective Study of Matched Patients with Brain Metastases and Poor Prognosis

Patients with brain metastases and poor prognosis are often treated with whole brain radiotherapy (WBRT) which can cause a variety of side effects. Our institution devised a new brain-sparing radiotherapy technique to treat multiple brain metastasis for patients whose poor prognosis does not warrant SRS. This study compares the oncologic outcomes of matched patients treated with RAPPLE and WBRT. RAPPLE uses single-isocenter, coplanar volumetric modulated arc therapy and a non-stereotactic head-shell with IntegraBite™. Brain metastasis were contoured in a single gross tumor volume and expanded by 3 mm to create a planning target volume, of which 99.5% was covered with 95-110% of 20 Gy in 5 fractions. Patients treated with a first course of RAPPLE from January 2017 to December 2021 were identified in an institutional database. Using age, cancer diagnosis, and treatment date, we identified a matched cohort of patients receiving a first course of WBRT with 20 Gy in 5 fractions. Overall survival (OS) was calculated using the Kaplan-Meier method, and intracranial progression was calculated using cumulative incidence with a competing risk of death. Log-rank, Cox regression and Fine-Gray analyses were used for comparisons. Paired t-tests were used to compare patient-reported fatigue measured using 5-level Likert scales before and 2-6 weeks after radiotherapy. The RAPPLE and WBRT cohorts each had 137 patients. The matched median age was 69 years. Primary diagnoses were lung cancer (72%) and other cancers (28%). The minimum, median, and maximum numbers of metastases treated with RAPPLE were 1, 3, and 18, respectively. The median Karnofsky Performance Score (KPS) was 70 in both cohorts. The median survival was 4.1 months for RAPPLE and 4.2 months for WBRT, and the 18-month OS was 11% for RAPPLE and 12% for WBRT (log-rank p = 0.8). On multivariable analysis, KPS, diagnosis, extracranial disease, and use of systemic therapy before and after RT were predictive of OS, but use of RAPPLE vs. WBRT was not (HR = 0.97, 95% CI: 0.75-1.25, p = 0.8). The 18-month cumulative incidence of intracranial progression was 0.49 for RAPPLE and 0.37 for WBRT (p = 0.04). After RAPPLE, 17% required more focal RT and 4% required salvage WBRT, while after WBRT, 3% required focal RT and 4% required repeat WBRT. After RAPPLE, mean patient-reported fatigue remained stable from baseline to first follow-up (2.18 vs. 2.27, p = 0.9), but, after WBRT, it worsened from baseline to first follow-up (1.95 vs. 2.63, p = 0.002). As expected, after RAPPLE, more targeted radiotherapy was required for intracranial progression, but there was no difference in OS between the RAPPLE and WBRT cohorts. Patients reported significantly worse fatigue after WBRT. Almost all patients (96%) treated with RAPPLE avoided WBRT.

SURVIVAL OUTCOMES AFTER WHOLE BRAIN RADIOTHERAPY

Abstract AIMS Cerebral metastases from extra-cranial primary cancer carries a poor prognosis. For patients in whom surgical resection or SRS are not suitable, local control rates are poor. There is considerable debate surrounding the value of whole brain radiotherapy in this patient cohort in terms of local control, survival and functional status. We aimed to measure survival in patients receiving whole brain radiotherapy at the Norfolk and Norwich University Hospital. METHOD All patients who completed a course of whole brain radiotherapy at our centre between April 2018 and December 2022 were retrospectively analysed. Patients who were receiving prophylactic cranial irradiation of small cell lung cancer were excluded. Baseline demographics, oncologist declared ECOG performance status at referral for treatment, radiotherapy dose and survival were recorded. RESULTS 88 patients received WBRT during this period. The median follow-up interval was 85 days. 12 patients received 30 Gy in 10 fractions, 59 received 20 Gy in 5 fractions and 17 received 12 Gy in 2 fractions. The median overall survival following completion of radiotherapy was 85 days. At 6 weeks after radiotherapy, 23.9% of patients had died. Univariate analysis with Cox proportional hazards model did not demonstrate a significant hazard ratio for age (<65 or ≥65), ECOG performance status or radiotherapy dose. CONCLUSIONS Survival following whole brain radiotherapy remains poor. In particular, almost a quarter of patients are not alive 6 weeks after treatment. This is particularly pertinent given the anticipated trajectory of acute toxicities from treatment.

Optimizing Whole Brain Radiation Therapy Dose and Fractionation: Results From a Prospective Phase 3 Trial (NCCTG N107C [Alliance]/CEC.3)

Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher's exact tests. Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P = .01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P = .66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P = .14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P = .09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P = .18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade ≥3 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P = .03). This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care.

Dosimetric Outcomes for Patients Undergoing Stereotactic Radiosurgery for Treatment of Ten or More Brain Metastases

Radiotherapy plays an important role in the treatment of brain metastases (BM). The standard radiation modality for patients undergoing radiotherapy for high burden of disease (often 10+ lesions) is whole brain radiotherapy (WBRT) as opposed to stereotactic radiosurgery (SRS). However, SRS confers several advantages relative to WBRT, including significantly lower incidence and magnitude of neurocognitive decline, minimal hair loss, and completion in only one day as opposed to the 1-2 weeks needed for WBRT. The decision to offer WBRT rather than SRS is driven by the belief that the entire brain may be seeded with micrometastatic disease in patients with many BM; therefore, irradiating the entire brain may theoretically confer a survival advantage. However, data increasingly suggest that the number of BM is not a clinically meaningful prognostic indicator and has led more radiation oncologists to offer SRS as an initial treatment for patients with many BM. However, the dosimetric consequences of SRS for ten or more lesions are not well established. There is concern that irradiating many BM with SRS may increase the risk of toxicity and begin to approximate the dose from a course of WBRT. To evaluate this concern more thoroughly, we retrospectively assessed cumulative radiation doses to the brain in patients who underwent SRS for ten or more lesions at a single institution. We hypothesized that the mean dose for patients treated with GK SRS for ten or more lesions would remain low and not approximate the dosing of WBRT. We retrospectively evaluated the Leksell GammaPlan (Elekta, Stockholm, Sweden) data of 32 patients who received GK SRS for ten or more BM in one session at a single institution between June 2000 and September 2018. We imported Leksell GammaPlan patient data, a commercially available deformable registration algorithm and then utilized the software to contour the whole brain. We then accumulated the doses from all treated lesions and exported corresponding dose-volume histogram data from the contoured whole brain. From these data, we determined the primary endpoint of mean dose delivered to the whole brain. The cohort of 32 patients had a median number of 13 treated lesions (range 10 to 26 lesions). Median dose to each lesion was 2000 cGy (range 900 to 2000 cGy). We determined the mean dose to the whole brain to be 310 ± 190 cGy (range 60 to 730 cGy). The number of treated lesions correlated proportionally with the mean dose to the whole brain. Given the advantages of SRS over WBRT, coupled with data increasingly suggesting that the number of BM is not a key determinant of survival, more patients are being offered upfront SRS rather than WBRT. The data from this dosimetric analysis suggest that the mean dose to the whole brain in patients treated with GK SRS for 10 or more BM remains low and does not approximate WBRT dosing.

Optimizing Whole Brain Radiotherapy Dose and Fractionation: Results from a Prospective Phase III Trial (NCCTG N107C (Alliance)/CEC.3)

Whole brain radiotherapy (WBRT) remains a commonly employed cancer treatment today, although controversy exists regarding the optimal dose and fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. We sought to utilize the results of N107C/CEC.3, a prospective clinical trial for patients with brain metastases, to evaluate the impact of WBRT dose and fractionation on tumor control, overall survival (OS), and toxicity. N107C/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the fractionation schedule that would be used for all patients treated at that site (either 30 Gy in 10 fractions (fx), or 37.5 Gy in 15 fx). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher’s exact tests, where appropriate. Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fx (53%), and 43 were treated with 37.5 Gy in 15 fx (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology more frequent with protracted WBRT, 74% vs. 47%, p=0.01), and 93% of patients completed the full course of WBRT. Protracted WBRT dose/fx did not impact time to cognitive failure (hazard ratio, HR=0.91, p=0.64), surgical bed control (HR=0.52, p=0.14), intracranial tumor control (HR=0.56, p=0.09), or OS (HR=0.73, p=0.18). Although there were no reports of radionecrosis, there is a statistically significant increase in the risk of at least one grade 3 or higher adverse event with 37.5 Gy/15 fx vs. 30 Gy/10 fx (54% vs. 31%, respectively, p=0.03). This unplanned analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with lengthened courses. For patients with brain metastases where WBRT is recommended, a short course hypofractionated regimen remains the current standard of care. Support: U10CA180821, U10CA180882; U10CA180863; U10CA180868; NCT01372774; Alliance NCORP grant UG1CA189823.

Integrating Neuropsychological Outcomes into Clinical Studies for Treating Secondary or Primary Intracranial Malignancies in the Era of Modern Radiation Therapy

In managing patients with brain metastasis in the disciplines of neuro-oncology, neurosurgery, and radiation oncology, intracranial control and care. Of note, the controversies and problems associated with delayed radiation-related cognitive dysfunction cannot be ignored, particularly in patients who have undergone whole-brain radiation therapy (WBRT). Concerning neurocognitive consequences related to cranial irradiation, previous studies have shown that impaired hippocampal neurogenesis may be responsible for such cognitive impacts resulting from the delivery of WBRT. Therefore, it has been hypothesized that conformal hippocampal sparing during the course of WBRT (HS-WBRT) would contribute to meaningful preservation with regard to neurocognitive functions (NCFs).

Radiosurgery for brainstem metastases with and without whole brain radiotherapy: clinical series and literature review

ObjectiveThe objective of this study was to investigate outcomes for patients with brainstem metastases treated with stereotactic radiosurgery (SRS).MethodsPatients with brainstem metastases treated with SRS between April 2006 and June 2012 were identified from a prospective database. Patient and treatment-related factors were recorded. Kaplan-Meier analysis was used to calculate survival and freedom from local and distant brain progression. Univariate and multivariate Cox regression was used to identify factors important for overall survival.ResultsIn total, 44 patients received SRS for 48 brainstem metastases of whom 33 (75 %) also received whole brain radiotherapy (WBRT): 23 patients (52 %) WBRT prior to SRS, 6 (13.6 %) WBRT concurrently with SRS and 4 (9.0 %) WBRT after SRS. Eight patients received a second course of WBRT at further progression. Median target volume was 1.33 cc (range 0.04–12.17) and median prescribed marginal dose was 15 Gy (range 10–22). There were four cases of local failure, and 6-month and 1-year freedom from local failure was 84.6 and 76.9 %, respectively. Median overall survival (OS) was 5.4 months. There were four cases of radionecrosis, 2 (4.8 %) of which were symptomatic. The absence of external beam brain radiotherapy (predominantly WBRT) showed a trend towards improved OS on univariate analysis. Neither local nor distant brain failure significantly impacted OS.ConclusionThis retrospective series of patients treated with SRS for brainstem metastases, largely in combination with at least one course of WBRT, demonstrates that this approach is safe and results in good local control. In this cohort, no variables significantly impacted OS, including intracranial control.

Management of leptomeningeal metastases: Prognostic factors and associated outcomes

Limited data are currently available to direct treatment recommendations in the management of leptomeningeal metastases (LM). Here we review treatment modalities clinicians should understand in order to manage patients with LM. We first describe our institution’s experience with the treatment of LM and use this dataset to frame the discussion of LM management. Between 1999 and 2014, 1361 patients with central nervous system metastases were reviewed, 124 (9.1%) had radiographic evidence of LM, and these patients form the cohort for this analysis. Mean age at diagnosis of LM was 52years. Median survival for the entire cohort was 2.3months. The most common primary malignancies were non-small cell lung cancer (25.8%), breast cancer (17.7%), small cell lung cancer (16.9%) and melanoma (8.9%). Univariate analyses demonstrated that greater Karnofsky Performance Status (KPS) (p=0.001) and administration of systemic chemotherapy (p<0.001) resulted in improved median survival. Multivariate Cox analyses revealed that receipt of chemotherapy and a complete course of whole brain radiotherapy (WBRT) (median dose 30Gy in 10 fractions, range 24–40Gy) were predictive of longer survival, (p=0.013 and 0.019, respectively). These data suggest that there is a group of patients with good KPS who may experience significantly longer median survival than expected. Multivariate analysis from this single institution retrospective study demonstrated a benefit for WBRT and chemotherapy in individuals with good KPS. These findings provide contemporary data from a large cohort of LM patients, which may be utilized to guide treatment recommendations, assist in patient counseling and direct future investigations into optimization of treatment regimens.

Outcomes of reirradiation in the treatment of patients with multiple brain metastases of solid tumors: a retrospective analysis.

Patients with multiple brain metastases are often treated with whole brain radiation therapy (WBRT). Second course of WBRT is an important treatment option for patients with clinical or radiological intracranial disease progression. This study examines the outcomes in patients with multiple brain metastases who underwent reirradiation. We examined the medical records of 34 patients with multiple brain metastases who were treated WBRT. The median dose for the first course of WBRT was 30 Gy (range, 25-30 Gy) and for the second course 25 Gy (range, 20-30 Gy). Statistical analyses were performed with using Cox regression analyses, log-rank test and Kaplan-Meier method. The median Karnofsky performance status (KPS) was 80 (range, 50-100) before reirradiation. Patients with KPS of >70 had a median survival of 11.4 months, compared to 2.2 months with KPS of ≤70 (P=0.012) and patients who have severe symptoms at the time of reirradiation with median survival 2.2 months while those with mild symptoms had a median of 4.8 months survival (P=0.08). The median overall survival for all patients after diagnosis of metastases was 24.7 months, after the re-irradiation WBRT (re-WBRT) it was 5.3 months (95% CI, 4.08-6.62) and from the diagnosis of primary tumor was 27.1 months (95% CI, 17.75-37.04). In select patients who have good performance status and who do not have severe symptoms might benefit from re-WBRT and re-WBRT seems to be associated with minimal toxicity in patients treated with lower palliation doses.

Relationship Between Subventricular Zone Dose and Survival in Patients With Glioblastoma Multiforme Treated With Surgery Followed Radiation Chemotherapy

Purpose/Objective(s): Whole brain radiation therapy (WBRT) is the treatment of choice for patients with brain metastases. However, neurocognitive functions (NCF) decline due to impaired hippocampal neurogenesis might occur after WBRT. It is hypothesized that conformal hippocampal sparing during the course of WBRT (HS-WBRT) might provide meaningful NCF preservation. Our study aims to demonstrate the impact of delivering HA-WBRT on NCF changes in patients receiving therapeutic or prophylactic WBRT. Additionally, we attempt to investigate the correlations between hippocampal dosimetric parameters and the above NCF changes or declines Materials/Methods: Forty prospectively enrolled patients were referred for WBRT for PCI or treating oligometastatic brain disease. Before the initiation of HA-WBRT course, all participants must receive baseline neurocognitive assessment, including memory, executive functions and psychomotor speed. The primary endpoint is delayed recall, as determined by the change/decline in either verbal memory (WMS IIIe Word List Learning) or non-verbal memory (WMS IIIVisual Reproduction) from baseline assessment to 4 months after the start of HA-WBRT. Hippocampal dosimetric parameters include mean dose received by the hippocampus, the dose delivered to 100% (D100%) of the hippocampus, and V40. Results: Only 3 patients belonged to the clinical setting of PCI; the remaining 37 patients had oligometastatic brain disease, in which the majority metastasized from primary lung cancer. Regarding neurocognitive outcomes, no statistically significant differences were found between various NCF scores obtained at baseline and at post-radiation therapy intervals, in terms of immediate verbal memory and non-verbal memory, except for delayed recall memory on Word List (F Z5.727, p Z0.048). According to the Spearman correlation coefficients, all dosimetric parameters we are interested in fail to be significantly correlated with NCF decline/change after HS-WBRT in the current report. Conclusion: Functional preservation by hippocampal sparing during the course ofWBRTcould largely be achieved in this preliminary study.Our study further suggests that HA-WBRT should be a feasible technique preserving important neurocognitive functions while maintaining intracranial control. Author Disclosure: P. Tsai: None. T. Wu: None. C. Yang: None. C. Tseng: None. P. Pai: None. D. Tsan: None. S. Lin: None.

Evaluating the Impact of Hippocampal Sparing During Whole-Brain Radiation Therapy on Neurocognitive Functions and the Correlations With Hippocampal Dosimetry: A Preliminary Report of a Prospective Observational Study

Purpose/Objective(s): Whole brain radiation therapy (WBRT) is the treatment of choice for patients with brain metastases. However, neurocognitive functions (NCF) decline due to impaired hippocampal neurogenesis might occur after WBRT. It is hypothesized that conformal hippocampal sparing during the course of WBRT (HS-WBRT) might provide meaningful NCF preservation. Our study aims to demonstrate the impact of delivering HA-WBRT on NCF changes in patients receiving therapeutic or prophylactic WBRT. Additionally, we attempt to investigate the correlations between hippocampal dosimetric parameters and the above NCF changes or declines Materials/Methods: Forty prospectively enrolled patients were referred for WBRT for PCI or treating oligometastatic brain disease. Before the initiation of HA-WBRT course, all participants must receive baseline neurocognitive assessment, including memory, executive functions and psychomotor speed. The primary endpoint is delayed recall, as determined by the change/decline in either verbal memory (WMS IIIe Word List Learning) or non-verbal memory (WMS III- Visual Reproduction) from baseline assessment to 4 months after the start of HA-WBRT. Hippocampal dosimetric parameters include mean dose received by the hippocampus, the dose delivered to 100% (D100%) of the hippocampus, and V40. Results: Only 3 patients belonged to the clinical setting of PCI; the remaining 37 patients had oligometastatic brain disease, in which the majority metastasized from primary lung cancer. Regarding neurocognitive outcomes, no statistically significant differences were found between various NCF scores obtained at baseline and at post-radiation therapy intervals, in terms of immediate verbal memory and non-verbal memory, except for delayed recall memory on Word List (F Z5.727, p Z0.048). According to the Spearman correlation coefficients, all dosimetric parameters we are interested in fail to be significantly correlated with NCF decline/change after HS-WBRT in the current report. Conclusion: Functional preservation by hippocampal sparing during the courseofWBRTcouldlargelybeachievedinthispreliminarystudy.Ourstudy further suggests that HA-WBRT should be a feasible technique preserving important neurocognitive functions while maintaining intracranial control. Author Disclosure: P. Tsai: None. T. Wu: None. C. Yang: None. C. Tseng: None. P. Pai: None. D. Tsan: None. S. Lin: None.

Repeat Whole Brain Radiation Therapy with a Simultaneous Infield Boost: A Novel Technique for Reirradiation

The treatment of patients who experience intracranial progression after whole brain radiation therapy (WBRT) is a clinical challenge. Novel radiation therapy delivery technologies are being applied with the objective of improving tumor and symptom control in these patients. The purpose of this study is to describe the clinical outcomes of the application of a novel technology to deliver repeat WBRT with volume modulated arc therapy (VMAT) and a simultaneous infield boost (WB-SIB) to gross disease. A total of 16 patients were initially treated with WBRT between 2000 and 2008 and then experienced intracranial progression, were treated using repeat WB-SIB, and were analyzed. The median dose for the first course of WBRT was 35 Gy (range: 30–50.4 Gy). Median time between the initial course of WBRT and repeat WB-SIB was 11.3 months. The median dose at reirradiation was 20 Gy to the whole brain with a median boost dose of 30 Gy to gross disease. A total of 2 patients demonstrated radiographic disease progression after treatment. The median overall survival (OS) time from initial diagnosis of brain metastases was 18.9 months (range: 7.1–66.6 (95% CI: 0.8–36.9)). The median OS time after initiation of reirradiation for all patients was 2.7 months (range: 0.46–14.46 (95% CI: 1.3–8.7)). Only 3 patients experienced CTCAE grade 3 fatigue. No other patients experienced any ≥ CTCAE grade 3 toxicity. This analysis reports the result of a novel RT delivery technique for the treatment of patients with recurrent brain metastases. Side effects were manageable and comparable to other conventional repeat WBRT series. Repeat WB-SIB using the VMAT RT delivery technology is feasible and appears to have acceptable short-term acute toxicity. These results may provide a foundation for further exploration of the WB-SIB technique for repeat WBRT in future prospective clinical trials.

Whole brain reirradiation and concurrent temozolomide in patients with brain metastases

A second course of whole brain radiation therapy (WBRT) has been employed in selected patients with progressive brain metastases providing favorable symptomatic palliation with acceptable toxicity, although its efficacy and safety remain matter of debate. In the present study we have evaluated the outcomes in patients with progressive intracranial disease treated with WBRT reirradiation and concurrent temozolomide between October 2010 and May 2013. Data were obtained from a prospectively maintained database including patients with brain tumors treated with radiotherapy at Sant'Andrea Hospital. We identified 27 patients (10 males and 17 females) with a median age of 54 years who received WBRT reirradiation at a dose of 25 Gy in ten fractions plus concomitant daily temozolomide administered orally at a dose of 75 mg/m(2). At the time of repeat WBRT all patients had a KPS ≥ 60. The primary disease sites were lung (n = 18) and breast (n = 9). The median overall survival after the second course of WBRT was 6.2 months and the median time to progression was 5.5 months. Eight patients experienced complete resolution of symptoms, 9 patients had a significant improvement, and 6 patients had no change in their neurologic function. Four patients had further deterioration after reirradiation. Overall, 85 % of patients improved or maintained their neurologic status. No severe acute toxicity during or after the second course of WBRT reirradiation was observed. On multivariate analysis with the Cox proportional hazards model, stable or absent extracranial metastases (p = 0.005) and response to treatment (p = 0.01) were independent favorable prognostic factors for survival. The median and 12-month survival rates were 12 months and 50 % in patients with stable or absent extracranial disease and 4.6 months and 7 % in those with progressive extracranial disease (p = 0.001). In conclusion, in the respect to the small number of treated patients, repeat WBRT plus concomitant temozolomide may be a treatment option in selected patients with multiple brain metastases to improve or maintain neurological conditions and quality of life with acceptable toxicity. The favorable effects of concomitant temozolomide on survival remain unclear.

The benefit of whole brain reirradiation in patients with multiple brain metastases

BackgroundTo assess the outcomes, symptom palliation and survival rates in patients who received repeat whole brain radiotherapy (WBRT).MethodsTwenty-eight patients who had progression of brain metastasis received a second course of WBRT. Univariate log-rank testing and multivariate Cox regression analysis were used to determine the factors for death among several variables (cumulative BED [BEDcumulative], primary tumor site, Karnofsky performance scale [KPS], previous SRS, number of metastases and absence of extracranial metastases). Correlations between variables and treatment response were evaluated with the Chi-squared test.ResultsThe median KPS was 60 (range 50 to 100) at the initiation of reirradiation. The median time interval between the two courses of WBRT was 9.5 months (range 3–27 months). The median doses of the first course and the second course of WBRT were 30 Gy (range 20 to 30 Gy) and 25 Gy (range 20 to 30 Gy), respectively. The mean BEDcumulative was 129.5 Gy (range 110 to 150 Gy). Severe or unexpected toxicity was not observed. Symptomatic response was detected in 39% of the patients. The median overall survival following reirradiation was 3 months (range 1 to 12 months, 95% CI 1.82-4.118). Survival was significantly better in responders (median 10 months, 95% CI 3.56-16.43) compared with non-responders (median 2 months, 95% CI 1.3-2.64) (p = 0.000). In multivariate analysis, patients that had lung cancer (p = 0.01), initial KPS ≥60 (p = 0.03) or longer intervals to reirradiation (p = 0.01) had significantly better survival rates.ConclusionsA careful second course of whole brain irradiation might provide a symptomatic and survival benefit in patients with good performance status and longer cranial progression-free intervals.

PP134: Case report of palliative radiotherapy for anaplastic carcinoma of ectopic thyroid tissue

Purpose Ectopic thyroid tissue is found in 7% of the adult population. The most common site of growth is along the course of thyroglossal duct or around the two lobes of the gland. Other sites of possible growth are the larynx, trachea, esophagus, mediastinum, pericardium or the diaphragm. Most reports deal with papillary carcinoma of ectopic thyroid tissue. The first report of anaplastic carcinoma of ectopic thyroid tissue was in 1981 and concerned a tumor growing at a thyroglossal duct remnant. Materials and methods We present the case of a 70 year old man with a preexisting lesion of the right submandibular triangle with a progressive increase in size the last 6 months. The imaging studies revealed a tumor in close proximity to the salivary gland and few enlarged lymph nodes. The lesion was characterized as a mixed salivary gland tumor. After surgical excision the histologic report revealed a malignant tumor with necrosis, fibrosis and immunohistochemical characteristics of an anaplastic carcinoma of ectopic thyroid tissue. After 3 cycles of chemotherapy (CDDP/Paclitaxel) the patient had local tumor progression and was referred for radiation therapy. The patient was offered a short course of palliative radiotherapy due to metastatic lung lesions. He was treated with hypofractionated radiation therapy to a total dose of 39 Gy in 13 fractions. Results At the end of radiotherapy course the patient had a remarkable clinical and radiological response with a significant decrease of preexisting dyspnea. However, one month later the patient was diagnosed with multiple brain metastasis and was offered a short course of whole brain radiotherapy. Conclusion Short-course palliative radiotherapy is effective in controlling obstructive symptoms of patients with anaplastic thyroid carcinoma.

123IN - The Biological Rationale and Potential Role of Radiation Dose Escalation in Patients with Brain Metastases

ABSTRACT The majority of patients with BM from solid tumors have a prognosis of only a few months based on extracranial tumor activity and performance status. The standard of care for these patients consists of palliative treatment with steroids, and, if appropriate, a short course of whole brain radiotherapy (WBRT). Several prognostic classification systems such as the RPA classification [Gaspar 1997] or the DS-GPA [Sperduto 2008] enable identifying a subset of patients that may have long-term survival, provided that the BM are treated aggressively. Although neurosurgery is the traditional treatment for single BM at an accessible location, radiosurgery (RS) has been established as a non-invasive alternative. RS involves high-precision delivery of a single fraction of approximately 20 Gy directed to the lesion, resulting in local control rates of 60-90%, dependent on the size and aspect (poorer control for necrotic lesions). The survival benefit of RS has only been confirmed for a single BM in a randomized study [Andrews 2004], but improved functional autonomy was observed in all groups with 1-3 BM. The question whether WBRT should be added to RS has been a long-standing unresolved issue with proponents highlighting the better intracranial control, and opponents pointing out the neurocognitive toxicity of WBRT and available salvage options. As the risk of developing new BM following RS alone is not only dependent on extracranial tumor activity (reseeding) but also on the number of initially treated BM (misdiagnosis of occult BM), a more differentiated approach may be better suited. A well selected patient group with multiple BM in good performance status and absent progressive extracranial disease may be candidates for recently developed advanced radiation planning and delivery. Techniques such as volumetric intensity-modulated arc therapy (VMAT, RapidArc) or Tomotherapy have enabled fast and accurate delivery of fractionated stereotactic integrated boosts to multiple BM in combination with WBRT. The integrated approach of this technique allows steep dose gradients outside the BM, thereby minimizing toxicity. Early experiences with this technique have reported relatively high intracranial control rates. Disclosure F.J. Lagerwaard: The Department of Radiation Oncology has research agreements with Varian medical systems and BrainLAB AG. The author has received honoraria for presentations from Varian medical systems and BrainLAB AG

Does overall treatment time impact on survival after whole-brain radiotherapy for brain metastases?

PURPOSE To evaluate whether reduced overall treatment time (OTT), i.e., administration of more than 5 fractions per week, or uncompensated treatment interruption resulting in increased OTT influences survival of patients treated with whole-brain radiotherapy (WBRT) for brain metastases. METHODS Retrospective multi-institutional intention-to-treat study including 233 patients treated with primary WBRT (prescribed dose 10 fractions of 3 Gy; no previous SRS or surgery) administered over 10-38 days. Four groups were studied: OTT 10-11 vs. 12 days, 13-15 or >15 days. RESULTS Fourteen patients (6%) failed to complete WBRT and received 3-9 fractions (median 7). Their median survival was 0.5 months as compared to 3 months in patients who completed WBRT. No significant impact of OTT on survival was found. Median survival was 1.5, 2.9, 3.0 and 3.1 months in the four groups mentioned above. CONCLUSIONS Compensation for unintended treatment interruption is generally recommended but might not always be feasible. Depending on histological tumour type or expected repopulation, prognostic factors and neurological status, it might be acceptable to complete an interrupted course of WBRT without compensation in selected patients. While survival might be largely independent from OTT, it should also be evaluated whether this parameter has any impact on quality of life and duration of palliation.

Outcomes After Whole Brain Reirradiation in Patients With Brain Metastases

Patients with brain metastases are often treated with whole brain radiation therapy (WBRT) for purposes of palliation. The treatment of those who experience subsequent intracranial disease progression can include a second course of WBRT, although there is controversy surrounding its safety and efficacy. This study examines the outcomes in patients at Massachusetts General Hospital who underwent reirradiation. We examined the medical records of 17 patients at Massachusetts General Hospital with brain metastases who were initially treated with WBRT between 2002 and 2008 and were subsequently retreated with a second course of WBRT. The median dose for the first course of WBRT was 35 Gy (range, 28-40 Gy), with a fraction size of 2 to 3 Gy (median, 2.5 Gy). The median dose at reirradiation was 21.6 Gy (range, 14-30 Gy), with a fraction size of 1.5 to 2 Gy (median, 1.8 Gy). The second course of WBRT was administered upon radiographic disease progression in all patients. Of 10 patients with complete follow-up data, 8 patients experienced complete or partial symptom resolution, and 2 did not show clinical improvement. The time to radiographic progression was 5.2 months. The median overall survival for all patients after diagnosis of metastases was 24.7 months. The median survival time after initiation of reirradiation was 5.2 months (95% CI, 1.3-8.7). In 6 patients with stable extracranial disease, the median survival time after retreatment was 19.8 months (95% CI, 2.7-∞), compared with 2.5 months (95% CI, 0.8-5.5) for those with extracranial disease progression (p = 0.05). Acute adverse reactions occurred in 70.5% of patients but were mild to moderate in severity. In select patients and especially those with stable extracranial disease, reirradiation may be an appropriate and effective intervention to provide symptomatic relief and slow intracranial disease progression. Side effects were minimal and did not cause substantial changes in quality of life.

Novel insights into the management of brain metastases

This review provides available clinical evidence regarding current therapies, discusses ongoing controversies, and introduces investigational approaches in the management of brain metastases. Novel approaches to estimating prognosis of patients with brain metastases highlight the importance of tailoring treatment to each particular patient. In the setting of unfavorable prognosis, either hospice care, symptom management, or short-course whole-brain radiotherapy (WBRT) is a critical component of palliation. In the setting of favorable or intermediate prognosis, treatment options can include a slightly more prolonged course of WBRT, surgery, stereotactic radiosurgery, systemic therapy, or a combination. Selection of the appropriate treatment is influenced by the number of brain metastases, overall patient performance status and residual life expectancy, as well as an understanding of the benefits and toxicities of each modality. Recent clinical studies have shed novel insight on the temporal sequence of memory changes following WBRT. Innovative approaches to mitigating these radiation-induced memory effects are currently being investigated. Evidence-based management of brain metastases represents an evolving field of active clinical research. Ongoing and future investigations focus on the preservation of cognition and quality of life, in addition to conventional outcomes such as intracranial tumor control and survival.