Without Whole Brain Radiotherapy Research Articles

A single-center, retrospective analysis of relapse and progression patterns of primary central nervous system lymphoma: can whole brain radiotherapy be replaced?

To analyze recurrence and progression patterns of primary central nervous system lymphoma (PCNSL) in patients without whole brain radiotherapy (WBRT) and assess the value of WBRT in PCNSL treatment. This retrospective single-center study included 27 patients with PCNSL, who experienced recurrence/progression after achieving complete remission (CR), partial remission, or stable disease following initial treatments with chemotherapy but without WBRT. The patients were followed up regularly after the treatment for treatment efficacy assessment. By comparing the anatomical location of the lesions on magnetic resonance images (MRI) at the initial diagnosis and at recurrence/progression, we analyzed the patterns of relapse/progression in patients with different treatment responses and different initial status of the lesions. MRI data showed that in 16 (59.26%) of the 27 patients, recurrence/progression occurred in out-field area (outside the simulated clinical target volume [CTV]) but within the simulated WBRT target area in 16 (59.26%) patients, and within the CTV (in-field) in 11 (40.74%) patients. None of the patients had extracranial recurrence of the tumor. Of the 11 patients who achieved CR after the initial treatments, 9 (81.82%) had PCNSL recurrences in the out-field area but within WBRT target area; of the 13 patients with a single lesion at the initial treatment, 11 (84.62%) experienced PCNSL recurrence in the out-field area but within WBRT target area. Systemic therapy combined with WBRT still remains the standard treatment for PCNSL patients, especially those who achieve CR after treatment or have a single initial lesion. Future prospective studies with larger sample sizes are needed to further explore the role of low-dose WBRT in PCNSL treatment.

Primary Central Nervous System Lymphoma: Long-Term Treatment Outcomes and Cost-Analysis from a Retrospective Study of High-Dose Methotrexate Based Chemoimmunotherapy and Reduced Dose Radiation Therapy Approach.

Standard treatment of primary central nervous system lymphoma (PCNSL) in countries with limited resources remains conventional chemotherapy, with or without whole brain radiotherapy (WBRT). To evaluate the treatment outcomes, prognostic factors and costs in patients with PCNSL treated with high-dose Methotrexate, vincristine and procarbazine, plus Rituximab (MVP-R) followed by consolidation with reduced dose (rd) WBRT and Cytarabine chemotherapy. We conducted an institutional audit of the first line treatment of patients with PCNSL, who were treated with MVP-R regimen, WBRT, or both between September 2011 and January 2020. Long term neuro-cognitive toxicity was recorded on follow up. The 5-year overall survival (OS) was the primary end point. Of 54 patients, 42 were evaluable [median age: 54 years (19-73 years)]. The commonest subtype was activated B-cell subtype (90%). At presentation, multiple and deep brain lesions were reported in 38 and 73% patients, respectively. Combined chemoimmunotherapy was given to 41 patients and WBRT to 29 patients. 27 patients (65%) achieved a complete response, and 22 received rdWBRT. 7 patients with partial response received conventional dose WBRT. Among tested prognostic factors, response to treatment was the single most significant determinant. At a median follow-up of 58 months, the 5-year progression free survival was 42%, and 5-year OS was 60%. The median direct hospital costs incurred by most patients for investigations and treatment were $1976.45 and $12,078.49, respectively. MVP-R is a well-tolerated regimen with substantial long term outcomes. Among all prognostic factors, response to therapy is the most significant.

ML-02 Chemotherapy for patients with relapsed or refractory primary CNS lymphoma

BACKGROUNDS: Standard of care for patients with primary CNS lymphoma (PCNSL) has been high-dose methotrexate (HD-MTX)-based multiagent immunochemotherapy, particularly with R-MPV-A with or without whole-brain radiotherapy (WBRT), however, the optimal treatment for relapsed/refractory (r/r)PCNSL has not been established yet. Approval of a second-generation BTK inhibitor, tirabrutinib, for r/rPCNSL in Japan in March 2020, prompted us to evaluate retrospectively efficacy of R-MPV-A for r/rPCNSL to compare their activities. PATIENTS: Histologically proven PCNSL patients treated at relapse in our institution from April 2000 to November 2019 were analyzed. Outcomes were compared between those treated with RMPVA or other regimens. RESULTS: Among 148 PCNSL patients identified, 73 had at least one relapse, of whom 47 received salvage chemotherapy including 23 treated with RMPVA, 14 with HD-MTX monotherapy, and 11 with DeVIC (DEX, etoposide, ifosfamide, CDBCA). Median age/KPS were 69 yo (20–87)/ 80 (40–100), 27 patients had received prior WBRT. RMPVA was given at the first relapse in 11 patients, median number of RMPV cycles was 8 (1–4 cycles: 10; 8 cycles 13). CR/CRu were achieved in 19 (83%), response rate was 87%, while there were two PDs (9%). After median follow-up of 21.9 months, the median PFS after salvage RMPVA was 13.0 m (95%CI: 9.1–16.9), 1-year overall survival (OS) was 82%, median OS was 70.0 m (95%CI: 12.9–127.1), which were longer than those in 24 patients with salvage treatment other than RMPVA (mPFS 4.4 m, P=0.054; mOS 13.6 m, P=0.009). Median PFS and OS for HD-MTX monotherapy were 5.1m and 36.6 m, while those for DeVIC were 4.4 m and 9.1 m, respectively. Treatment was generally well-tolerated but there was one treatment-related death. CONCLUSIONS: Salvage RMPVA at relapses was active and associated with longer survival compared with other regimens, necessitating further development of salvage regimens incorporating tirabrutinib in the future studies.

Analysis of the drivers of cost of management when patients with brain metastases are treated with upfront radiosurgery

ObjectivesWe aimed to assess the driving factors for increased cost of brain metastasis management when using upfront stereotactic radiosurgery (SRS). Patient and Methods737 patients treated with upfront SRS without whole brain radiotherapy (WBRT). Patients were evaluated for use of craniotomy, length of hospital stay, need for rehabilitation or facility placement, and use of salvage SRS or salvage WBRT. Costs of care of these interventions were estimated based on 2013 Medicare reimbursements. Multiple linear regression was performed to determine factors that predicted for higher cost of treatment per month of life, as well as highest cumulative cost of care for brain metastasis. ResultsMean cost of brain metastasis management per patient was $42,658, and $4673 per month of life. Upfront SRS represented the greatest contributor of total cost of brain metastasis management over a lifetime (49%), followed by use of any salvage SRS (21%), use of initial surgery (14%), use of salvage surgery (10%), hospitalization (3%) and cost of salvage WBRT (3%). Multiple linear regression identified brain metastasis velocity (BMV) (p < 0.001), use of cavity-directed SRS (<0.001), and CNS symptoms at time of presentation (p = 0.005) as factors that increased costs of care per month of survival. Use of salvage WBRT decreased per month cost of care in patients requiring salvage (p < 0.001). ConclusionThe cost of upfront SRS is the greatest contributor to cost of brain metastasis management when using upfront SRS. Higher BMV, progressive systemic disease and presence of symptoms are associated with increased cost of care.

Survival and prognostic factors for patients with melanoma brain metastases in the era of modern systemic therapy

Historically, the prognosis of patients with melanoma brain metastases is poor, with median overall survival (OS) of 4-6months. Little is known of OS in the era of modern systemic therapies and local therapy with stereotactic radiosurgery (SRS) or surgery. Patients diagnosed with melanoma brain metastases at Melanoma Institute Australia from January 2011 to December 2014 were included. OS and prognostic factors were analysed using Cox regression and Kaplan-Meier survival analyses.355 patients were included. The median OS was 7.1 months (95% confidence interval [CI] 6.0-8.1). Median OS differed by treatment modality: systemic therapy and SRS and/or surgery 14.9months (95% CI 10.7-19.0), SRS and/or surgery with or without whole brain radiotherapy (WBRT) 6.4months (95% CI 5.4-7.5), systemic therapy 5.4months (95% CI 3.1-7.7), systemic therapy and WBRT 5.2months (95% CI 4.1-6.4), WBRT 4.4months (95% CI 2.4-6.3), and best supportive care 1.8months (95% CI 1.2-2.3). OS for patients with melanoma brain metastases appears improved in the modern era, particularly for patients who are candidates for systemic therapy with SRS and/or surgery.

The Risk of Radiation Necrosis Following Stereotactic Radiosurgery with Concurrent Systemic Therapies

To investigate late toxicity among patients with newly-diagnosed brain metastases undergoing stereotactic radiosurgery (SRS) with concurrent systemic therapies with or without whole-brain radiation therapy (WBRT). Patients with newly-diagnosed brain metastasis who underwent SRS and follow-up at a single tertiary-care institution from 1997-2015 were eligible for inclusion. The class of agent and timing of all systemic therapies were collected for each patient. The primary outcome was the cumulative incidence of radiographic radiation necrosis (RN). Multivariable competing risks regression was used to adjust for confounding. During the study period, 1,650 patients presented with 2,843 intracranial metastases. Among these, 445 patients (27%) were treated with SRS and concurrent systemic therapy. Concurrent systemic therapy was defined as an agent administered on the same day as SRS, or within five biological half-lives of the date of SRS. Radiographic RN developed following treatment of 222 (8%) lesions, 120 (54%) of which were symptomatic. The 12-month cumulative incidences of RN among lesions treated with and without concurrent therapies were 6.6% (95% CI = 4.8-8.3%) and 5.3% (95% CI = 4.3-6.3%), respectively (P = 0.14). Concurrent systemic therapy was associated with a significantly increased rate of RN among lesions treated with upfront SRS and WBRT (8.7% vs. 3.7%, P = 0.04). Concurrent cytokine (0.0% vs. 5.3%, P = 0.4), cytotoxic (2.7% vs. 5.3%, P = 0.07), and hormone therapies (6.5% vs. 5.3%, P = 0.2) were not associated with significantly greater 12-month cumulative incidences of RN. In contrast, concurrent targeted therapies significantly increased the 12-month cumulative incidence of RN (8.8% vs. 5.3%, P < 0.01). Among these therapies, significantly increased rates of RN were observed with the use of VEGFR tyrosine kinase inhibitors (TKIs) (14.3% vs. 6.6%, P = 0.04) among renal metastases and EGFR TKIs (15.6% vs. 6.0%, P = 0.04) among lung adenocarcinoma metastases. Most classes of systemic therapies may be safely delivered concurrently with SRS alone in the treatment of newly-diagnosed brain metastases. However, the rate of radiographic RN was significantly increased with the addition of concurrent systemic therapies to SRS and WBRT. Moreover, in pooled and subset analyses, VEGFR and EGFR TKIs were implicated as agents associated with an increased rate of RN.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies.

To investigate late toxicity among patients with newly-diagnosed brain metastases undergoing stereotactic radiosurgery (SRS) with concurrent systemic therapies with or without whole-brain radiation therapy (WBRT). Patients with newly-diagnosed brain metastasis who underwent SRS at a single tertiary-care institution from 1997 to 2015 were eligible for inclusion. The class and timing of all systemic therapies were collected for each patient. The primary outcome was the cumulative incidence of radiographic radiation necrosis (RN). Multivariable competing risks regression was used to adjust for confounding. During the study period, 1650 patients presented with 2843 intracranial metastases. Among these, 445 patients (27%) were treated with SRS and concurrent systemic therapy. Radiographic RN developed following treatment of 222 (8%) lesions, 120 (54%) of which were symptomatic. The 12-month cumulative incidences of RN among lesions treated with and without concurrent therapies were 6.6 and 5.3%, respectively (p = 0.14). Concurrent systemic therapy was associated with a significantly increased rate of RN among lesions treated with upfront SRS and WBRT (8.7 vs. 3.7%, p = 0.04). In particular, concurrent targeted therapies significantly increased the 12-month cumulative incidence of RN (8.8 vs. 5.3%, p < 0.01). Among these therapies, significantly increased rates of RN were observed with VEGFR tyrosine kinase inhibitors (TKIs) (14.3 vs. 6.6%, p = 0.04) and EGFR TKIs (15.6 vs. 6.0%, p = 0.04). Most classes of systemic therapies may be safely delivered concurrently with SRS in the management of newly-diagnosed brain metastases. However, the rate of radiographic RN is significantly increased with the addition of concurrent systemic therapies to SRS and WBRT.

Stereotactic radiosurgery alone for multiple brain metastases? A review of clinical and technical issues.

Over the past three decades several randomized trials have enabled evidence-based practice for patients presenting with limited brain metastases. These trials have focused on the role of surgery or stereotactic radiosurgery (SRS) with or without whole brain radiation therapy (WBRT). As a result, it is clear that local control should be optimized with surgery or SRS in patients with optimal prognostic factors presenting with up to 4 brain metastases. The routine use of adjuvant WBRT remains debatable, as although greater distant brain control rates are observed, there is no impact on survival, and modern outcomes suggest adverse effects from WBRT on patient cognition and quality of life. With dramatic technologic advances in radiation oncology facilitating the adoption of SRS into mainstream practice, the optimal management of patients with multiple brain metastases is now being put forward. Practice is evolving to SRS alone in these patients despite a lack of level 1 evidence to support a clinical departure from WBRT. The purpose of this review is to summarize the current state of the evidence for patients presenting with limited and multiple metastases, and to present an in-depth analysis of the technology and dosimetric issues specific to the treatment of multiple metastases.

The Relapsed - Memorial Sloan - Kettering Cancer Center (R-MSKCC) Prognostic Score Is a Risk-Stratification Model for the Central Nervous System (CNS) Involvement at Relapse in Patients with Diffuse Large B Cell Lymphoma (DLBCL) in the Rituximab Era

Background: Introduction of Rituximab has shown a remarkable improvement on survival for the patients with diffuse Large B cell Lymphoma (DLBCL). However, involvement of central nervous system (CNS) at relapse in these patients is still an issue and a mostly fatal with a median survival of 2.5 - 4 months when they treated with conventional therapies. The Memorial Sloan - Kettering Cancer Center (MSKCC) prognostic score has been used as a statistically powerful model to patients with newly diagnosed primary central nervous system lymphoma (PCNSL) before rituximab introduction. By contrast, effective prognostic model for the relapsed DLBCL patients with CNS involvement in the rituximab era is unclear. The purpose of this study was to address treatment response and detailed prognosis of CNS recurrence of DLBCL after initial treatment with Rituximab contained chemotherapy.Patients and Methods: In total, 560 newly diagnosed de novo DLBCL patients treated with R-Results: Among the 25 patients assessed in this study, median age was 61 years (range, 34-81 years) at relapse.Sixteen (64%) patients were male. Primary sites at initial diagnosis were mostly extra-nodal sites such as nasal cavity, paranasal sinuses, skin, primary effusion, breasts, testes, ovaries, gastro-intestine, kidneys, adrenal glands, and bone in 88% (22/25) of the patients. The cell of origin of germinal center (GC) subtype by Hans algorithm were shown in 47.6% (10/25). All patients other than one with stage I were to receive 6 to 8 cycles of R-CHOP and the patient with stage I were to receive combined modality therapy with 3 cycles of R-CHOP followed by involved field radiation therapy as an initial treatment. Only two patients received intrathecal prophylaxis. The median interval between the initial diagnosis and CNS relapse was 22 months (range, 1-100 months). The patients status at relapse were 44% of (11/25) first complete response (CR), 32% of (8/25) first partial response (PR), 20% (5/25) of second CR, and 4% (1/25) of second PR after the latest chemotherapy. There were 15 patients (60%) with brain intra- parenchymal lesions identified by brain imaging and the others (40%) with leptomeningeal infiltration revealed with cerebrospinal fluid analysis. Front-line treatment for relapse at CNS lesion was chemotherapy with or without whole brain radiotherapy (WBRT) in 13 patients (52%). A total of 6 patients (24%) received WBRT without chemotherapy. The others received the best supportive care. In addition, most patients through those three groups received intrathecal chemotherapy with MTX, Ara-C, and prednisone. The median overall survival (OS) after CNS relapse was 7 months (95% CI: 5-12) for the whole population, 12 months for chemotherapy group, 6.5 months for WBRT group, and 2 months for BSC group (p = 0.02). To date 22 patients (88%) had died. At univariate analysis significant prognostic factors for overall survival were age at relapse (P=0.02), elevated b2- microglobulin (b2-MG) (p=0.03), and response for the latest chemotherapy (p=0.01) that was only a significant factor in multivariate analysis. Thus we established Relapsed-MSKCC prognostic score consisting of age < 50, KPS >=70, and response for the latest chemotherapy; add 1 to MSKCC score if they did not achieve CR after the latest therapy. The median OS in patients with a R-MSKCC prognostic score of 1 was not reached, and differed significantly from the 13 months in patients with a R-MSKCC score of 2, 8 months in patients with a R-MSKCC score of 3, and 2 months in patients with a R-MSKCC score of 4 (P=0.01).Conclusions: The Survival of CNS recurrence in patients with DLBCL remains lethal. R-MSKCC prognostic score may predict survival better in these patients. [Display omitted] DisclosuresNishimura:Chugai pharmaceutical co.LTD: Consultancy. Terui:Yanssen: Honoraria. Mishima:Chugai: Consultancy. Yokoyama:Chugai: Consultancy. Hatake:Meiji-Seika: Consultancy; Kyowa Kirin: Honoraria, Research Funding; Otsuka: Consultancy; Chugai: Research Funding.

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy.

In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death.

Central nervous system involvement in breast cancer patients: Is the therapeutic landscape changing too slowly?

Central nervous system (CNS) involvement from breast cancer (BC) has been historically considered a relatively rare event. However, the development of new therapeutic strategies with a better control of extra-cranial disease and a longer overall survival (OS) has determined an increased incidence of brain metastases. Patients with HER2-positive or triple negative BC have higher occurrence of CNS involvement than patients with luminal-like disease. Moreover, after development of brain metastases, the prognosis is highly influenced by biological subtype. In patients with multiple brain metastases who experience important neurological symptoms, palliative treatment, with or without whole brain radiation therapy (WBRT), needs to be considered the first step of a multidisciplinary therapeutic approach. Patients with a good performance status and 1-3 brain lesions should be considered for radical surgery; patients technically inoperable with 4-5 metastases smaller than 3cm may undergo stereotactic radiosurgery. The role of systemic therapy in the management of patients with brain metastases is controversial. Preliminary data suggest that systemic therapy after WBRT may improve survival in BC patients with brain lesions. In patients with HER2-positive disease, several retrospective or post hoc analyses showed a longer brain progression-free survival with trastuzumab in combination with or followed by other anti-HER2 drugs (such as pertuzumab, lapatinib, and T-DM1). Until now, no new strategies or drugs are available for triple-negative and luminal-like BC.

A phase 2 study of radiosurgery and temozolomide for patients with 1 to 4 brain metastases

PurposeTo determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1 to 4 brain metastases treated with radiosurgery without whole-brain radiation therapy (WBRT). Methods and materialsTwenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase 2 trial of radiosurgery (15-24 Gy) and adjuvant temozolomide. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. ResultsTwenty-five patients were enrolled between 2002 and 2005; 3 were not evaluable for determining DBF. Of the remaining 22 patients, tumor types included non-small cell lung cancer (n = 8), melanoma (n = 7), and other (n = 7). Extracranial disease was present in 10 (45%) patients. The median number of tumors at the time of radiosurgery was 3 (range, 1-6). The median overall survival was 31 weeks. The median radiographic follow-up for patients who did not develop DBF was 33 weeks. Six patients developed DBF. The 1-year actuarial risk of DBF was 37%. ConclusionsIn this study, there was a relatively low risk of distant brain failure observed in the nonmelanoma subgroup receiving temozolamide. However, patient selection factors rather than chemotherapy treatment efficacy are more likely the reason for the relatively low risk of distant brain failure observed in this study. Future trial design should account for these risk factors.

Determining the Optimal Management of Patients With Limited-Brain Metastases: A Cost Analysis Approach

Multiple radiation therapy treatment options exist for patients with limited (1-3) brain metastases including stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT). The natural history, treatment patterns, and cancer-related costs for these patients were analyzed to determine the benefit, if any, of WBRT in the modern era. From 2011-2013, 144 patients were treated with primary SRS, and 22 patients were treated with SRS+WBRT for limited-brain metastasis, at the discretion of the treating physician. A retrospective review was performed of the patient records for determination of clinical outcomes and patterns of failure. Cost analyses were performed using detailed institutional cost data captured by the cancer institute during inpatient and outpatient hospital encounters, including direct and indirect diagnosis-related costs. Survival times were calculated using the Kaplan-Meier method from date of initial radiation procedure. The median age at brain metastasis diagnosis for all patients was 63.5 years, the median KPS was 80, and the median time from diagnosis of the patient's primary disease to brain metastasis was 6.1 months. The 1-year overall survival and distant brain recurrence-free survival were 46% and 50% for patients treated with primary SRS, and 26% and 70% for those treated with SRS+WBRT, respectively (P=.14 and .09). Of the patients treated with primary SRS, 35 (24%) underwent an additional SRS session, 10 (7%) underwent ≥ 2 SRS sessions, and 15 (10%) patients were treated with salvage WBRT at the time of each intracranial relapse. Eight patients (6%) treated with primary SRS and 3 patients (14%) treated with SRS+WBRT were diagnosed with radiation necrosis. Neurologic death occurred in 19 patients (13%) treated with SRS and 6 (27%) treated with SRS+WBRT. The median total cost of care for all patients was $81,142 (R: $8,649 - $429,912): $84,501 for those undergoing primary SRS over a median of 31 clinical encounters and $54,033 ($12,828 - $226,426) over a median of 20 clinical encounters for those undergoing SRS+WBRT (P=.16). The median total cost of care per month survival was similar between the two groups ($10,356 SRS vs $10,285 GKS+WBRT, P=.74). Although patients with limited-brain metastases are at increased risk for distant intracranial failure without upfront WBRT, primary SRS provides comparable local control, risk of neurologic death, and overall survival with a lower risk of treatment-related toxicity. Even when accounting for additional close monitoring, more frequent imaging, and need for salvage therapies for patients undergoing primary GKS, the cost of care per month and overall cost of care remain comparable between single modality and multi-modality radiation treatments.

Phase 3 Trials of Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for 1 to 4 Brain Metastases: Individual Patient Data Meta-Analysis

To perform an individual patient data (IPD) meta-analysis of randomized controlled trials evaluating stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT) for patients presenting with 1 to 4 brain metastases. Three trials were identified through a literature search, and IPD were obtained. Outcomes of interest were survival, local failure, and distant brain failure. The treatment effect was estimated after adjustments for age, recursive partitioning analysis (RPA) score, number of brain metastases, and treatment arm. A total of 364 of the pooled 389 patients met eligibility criteria, of whom 51% were treated with SRS alone and 49% were treated with SRS plus WBRT. For survival, age was a significant effect modifier (P=.04) favoring SRS alone in patients ≤50 years of age, and no significant differences were observed in older patients. Hazard ratios (HRs) for patients 35, 40, 45, and 50 years of age were 0.46 (95% confidence interval [CI] = 0.24-0.90), 0.52 (95% CI = 0.29-0.92), 0.58 (95% CI = 0.35-0.95), and 0.64 (95% CI = 0.42-0.99), respectively. Patients with a single metastasis had significantly better survival than those who had 2 to 4 metastases. For distant brain failure, age was a significant effect modifier (P=.043), with similar rates in the 2 arms for patients ≤50 of age; otherwise, the risk was reduced with WBRT for patients >50 years of age. Patients with a single metastasis also had a significantly lower risk of distant brain failure than patients who had 2 to 4 metastases. Local control significantly favored additional WBRT in all age groups. For patients ≤50 years of age, SRS alone favored survival, in addition, the initial omission of WBRT did not impact distant brain relapse rates. SRS alone may be the preferred treatment for this age group.

Local control of brain metastasis: treatment outcome of focal brain treatments in relation to subtypes.

PurposeTo investigate treatment options for local control of metastasis in the brain, we compared focal brain treatment (FBT) with or without whole brain radiotherapy (WBRT) vs. WBRT alone, for breast cancer patients with tumor relapse in the brain. We also evaluated treatment outcomes according to the subtypes.MethodsWe conducted a retrospective review of breast cancer patients with brain metastasis after primary surgery. All patients received at least one local treatment for brain metastasis. Surgery or stereotactic radiosurgery was categorized as FBT. Patients were divided into two groups: the FBT group received FBT±WBRT, whereas the non-FBT group received WBRT alone. Subtypes were defined as follows: hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HR-positive/HER2-positive, HR-negative/HER2-positive, and triple-negative (TN). We examined the overall survival after brain metastasis (OSBM), brain metastasis-specific survival (BMSS), and brain metastasis-specific progression-free survival (BMPFS).ResultsA total of 116 patients were identified. After a median follow-up of 50.9 months, the median OSBM was 11.5 months (95% confidence interval, 9.0-14.1 months). The FBT group showed significantly superior OSBM and BMSS. However, FBT was not an independent prognostic factor for OSBM and BMSS on multivariate analyses. In contrast, multivariate analyses showed that patients who underwent surgery had improved BMPFS, indicating local control of metastasis in the brain. FBT resulted in better BMPFS in patients with HR-negative/HER2-positive cancer or the TN subtype.ConclusionWe found that patients who underwent surgery experienced improved local control of brain metastasis, regardless of its extent. Furthermore, FBT showed positive results and could be considered for better local control of brain metastasis in patients with aggressive subtypes such as HER2-positive and TN.

A Multi-institutional Predictive Nomogram for Distant Brain Failure in Patients Treated with Upfront Stereotactic Radiosurgery Without Whole Brain Radiation Therapy

Primary radiosurgical management of brain metastases without whole brain radiation therapy (WBRT) has been popularized as a means of avoiding the cognitive toxicities associated with WBRT. We present a predictive nomogram as a clinically useful tool to determine the likelihood of distant brain failure (DBF) at different time points after radiosurgery. This is a multi-institutional retrospective cohort of 1098 patients. Between 2000 and 2013, 1098 patients were treated with stereotactic radiosurgery (SRS) without WBRT for primary management of newly diagnosed brain metastases across 5 major academic radiosurgery centers. These patients included breast cancer (n = 143), non-small cell lung cancer (n = 492), melanoma (n = 173), and renal cell carcinoma (n = 94). Patients with GI and GYN primaries were excluded from analysis due to small numbers. Factors including histology, status of systemic disease at time of SRS, burden of systemic disease, number of metastases and lowest marginal dose were evaluated. A Cox proportional hazard regression model was used to determine covariates that predicted for time to DBF. From the univariate and multivariate Cox regression results, a nomogram was constructed using the RMS package. An internal validation was performed using a bootstrapping method to produce calibration plots at multiple time points. A concordance index (Harrell’s c-index) was used to evaluate the predictive discrimination of the model. Across institutions, the median number of lesions treated was 1 (range 1-13). The median time to DBF was 11 months. The concordance index (c-index) was 0.655 with the actual and predicted events identifying risk tendencies that are contained within the current model. Calibration curves delineating the predicted and observed probabilities of DBF were concordant and within the 95% confidence intervals for the 3, 6, and 9 month time points. Dominant factors predicting for early DBF in our model were > 4 metastases vs 1-3 (HR = 1.37, p value = 0.0015), squamous cell lung cancer vs adenocarcinoma (HR = 2.23, p < 0.0001), and melanoma (1.33, p = 0.0099) histologies. Table 1 displays the nomogram output for 4 sample cases. The concordance index suggests the nomogram may be predictive, but may need to include additional institutions as an external validation dataset before being widely used clinically. This effort is likely feasible, and will ultimately provide a clinically useful tool for helping to determine which patients may benefit from upfront radiosurgery.Oral Scientific Abstract 275; TableSample Nomogram PatientsCase NumberAgeGenderHistologyNumber of Metastates at SRSStatus of Extracranial Disease6 Months Probability of Freedom From DBF9 Month Probability of Freedom From DBF145FHer2(+) Breast1none88%84%250MLung Adenocarcinoma3none82%76%365MLung Squamous Cell Carcinoma4stable46%32%475MRenal Cell Carcinoma2stable68%58% Open table in a new tab

Therapeutic effect of stereotactic radiotherapy for brain metastases of non-small cell lung cancer

Objective To analyze the effect of stereotactic radiotherapy(SRT) with or without whole brain radiotherapy(WBRT) in the treatment of hmited number brain metastases of non-small cell lung cancer (NSGLC).Methods 75 NSCLC patients with brain metastases within 4 lesions were retrospectively analyzed.35cases were treated with SRT alone and 40 cases were treated with SRT + WBRT.The therapeutic effects,overall survival and radiotherapeufic side effects of the two groups were compared.Results The total effective rate of SRT group and WBRT + SRT group were 91.5％ and 87.5％ respectively.There was no significant difference between the two groups (P ＞0.05).For all the patients,the median overall survival time was 14.7 months.There was no difference between SRT alone group and SRT + WBRT group (13.7 months vs 15.4 months,P =0.180).There was no serious side effectin in two groups.Conclusions Stereotactic radiotherapy was an effective and safe treatment for limited number brain metastases of NSCLC.The patients who accepted SRT alone or SRT + WBRT had the similar overall survival time. Key words: Brain metastases; Non-small cell lung cancer; Whole brain radiotherapy; Stereotactic radiotherapy

Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study

We aimed to examine whether stereotactic radiosurgery without whole-brain radiotherapy (WBRT) as the initial treatment for patients with five to ten brain metastases is non-inferior to that for patients with two to four brain metastases in terms of overall survival. This prospective observational study enrolled patients with one to ten newly diagnosed brain metastases (largest tumour <10 mL in volume and <3 cm in longest diameter; total cumulative volume ≤15 mL) and a Karnofsky performance status score of 70 or higher from 23 facilities in Japan. Standard stereotactic radiosurgery procedures were used in all patients; tumour volumes smaller than 4 mL were irradiated with 22 Gy at the lesion periphery and those that were 4-10 mL with 20 Gy. The primary endpoint was overall survival, for which the non-inferiority margin for the comparison of outcomes in patients with two to four brain metastases with those of patients with five to ten brain metastases was set as the value of the upper 95% CI for a hazard ratio (HR) of 1·30, and all data were analysed by intention to treat. The study was finalised on Dec 31, 2012, for analysis of the primary endpoint; however, monitoring of stereotactic radiosurgery-induced complications and neurocognitive function assessment will continue for the censored subset until the end of 2014. This study is registered with the University Medical Information Network Clinical Trial Registry, number 000001812. We enrolled 1194 eligible patients between March 1, 2009, and Feb 15, 2012. Median overall survival after stereotactic radiosurgery was 13·9 months [95% CI 12·0-15·6] in the 455 patients with one tumour, 10·8 months [9·4-12·4] in the 531 patients with two to four tumours, and 10·8 months [9·1-12·7] in the 208 patients with five to ten tumours. Overall survival did not differ between the patients with two to four tumours and those with five to ten (HR 0·97, 95% CI 0·81-1·18 [less than non-inferiority margin], p=0·78; pnon-inferiority<0·0001). Stereotactic radiosurgery-induced adverse events occurred in 101 (8%) patients; nine (2%) patients with one tumour had one or more grade 3-4 event compared with 13 (2%) patients with two to four tumours and six (3%) patients with five to ten tumours. The proportion of patients who had one or more treatment-related adverse event of any grade did not differ significantly between the two groups of patients with multiple tumours (50 [9%] patients with two to four tumours vs 18 [9%] with five to ten; p=0·89). Four patients died, mainly of complications relating to stereotactic radiosurgery (two with one tumour and one each in the other two groups). Our results suggest that stereotactic radiosurgery without WBRT in patients with five to ten brain metastases is non-inferior to that in patients with two to four brain metastases. Considering the minimal invasiveness of stereotactic radiosurgery and the fewer side-effects than with WBRT, stereotactic radiosurgery might be a suitable alternative for patients with up to ten brain metastases. Japan Brain Foundation.

A nomogram for predicting distant brain failure in patients treated with gamma knife stereotactic radiosurgery without whole brain radiotherapy

We review our single institution experience to determine predictive factors for early and delayed distant brain failure (DBF) after radiosurgery without whole brain radiotherapy (WBRT) for brain metastases. Between January 2000 and December 2010, a total of 464 patients were treated with Gamma Knife stereotactic radiosurgery (SRS) without WBRT for primary management of newly diagnosed brain metastases. Histology, systemic disease, RPA class, and number of metastases were evaluated as possible predictors of DBF rate. DBF rates were determined by serial MRI. Kaplan-Meier method was used to estimate rate of DBF. Multivariate analysis was performed using Cox Proportional Hazard regression. Median number of lesions treated was 1 (range 1-13). Median time to DBF was 4.9 months. Twenty-seven percent of patients ultimately required WBRT with median time to WBRT of 5.6 months. Progressive systemic disease (χ(2)= 16.748, P < .001), number of metastases at SRS (χ(2) = 27.216, P < .001), discovery of new metastases at time of SRS (χ(2) = 9.197, P < .01), and histology (χ(2) = 12.819, P < .07) were factors that predicted for earlier time to distant failure. High risk histologic subtypes (melanoma, her2 negative breast, χ(2) = 11.020, P < .001) and low risk subtypes (her2 + breast, χ(2) = 11.343, P < .001) were identified. Progressive systemic disease (χ(2) = 9.549, P < .01), number of brain metastases (χ(2) = 16.953, P < .001), minimum SRS dose (χ(2) = 21.609, P < .001), and widespread metastatic disease (χ(2) = 29.396, P < .001) were predictive of shorter time to WBRT. Systemic disease, number of metastases, and histology are factors that predict distant failure rate after primary radiosurgical management of brain metastases.