Whole Brain Radiotherapy Arm Research Articles

Association of Long-term Outcomes With Stereotactic Radiosurgery vs Whole-Brain Radiotherapy for Resected Brain Metastasis

Long-term outcomes of radiotherapy are important in understanding the risks and benefits of therapies for patients with brain metastases. To determine how the use of postoperative whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) is associated with quality of life (QOL), cognitive function, and intracranial tumor control in long-term survivors with 1 to 4 brain metastases. This secondary analysis of a randomized phase 3 clinical trial included 48 institutions in the US and Canada. Adult patients with 1 resected brain metastases but limited to those with 1 to 4 brain metastasis were eligible. Unresected metastases were treated with SRS. Long-term survivors were defined as evaluable patients who lived longer than 1 year from randomization. Patients were recruited between July 2011 and December 2015, and data were first analyzed in February 2017. For the present study, intracranial tumor control, cognitive deterioration, QOL, and cognitive outcomes were measured in evaluable patients who were alive at 12 months from randomization and reanalyzed in June 2017. Stereotactic radiosurgery or WBRT. Intracranial tumor control, toxic effects, cognitive deterioration, and QOL. Fifty-four patients (27 SRS arm, 27 WBRT arm; female to male ratio, 65% vs 35%) were included for analysis with a median follow-up of 23.8 months. Cognitive deterioration was less frequent with SRS (37%-60%) compared with WBRT (75%-91%) at all time points. More patients declined by 2 or more standard deviations (SDs) in 1 or more cognitive tests for WBRT compared with SRS at 3, 6, and 9 months (70% vs 22%, 46% vs 19%, and 50% vs 20%, respectively). A 2 SD decline in at least 2 cognitive tests was associated with worse 12-month QOL in emotional well-being, functional well-being, general, additional concerns, and total scores. Overall QOL and functional independence favored SRS alone for categorical change at all time points. Total intracranial control for SRS alone vs WBRT at 12 months was 40.7% vs 81.5% (difference, -40.7; 95% CI, -68.1% to -13.4%), respectively. Data were first analyzed in February 2017. The use of SRS alone compared with WBRT resulted in less cognitive deterioration among long-term survivors. The association of late cognitive deterioration with WBRT was clinically meaningful. A significant decline in cognition (2 SD) was associated with overall QOL. However, intracranial tumor control was improved with WBRT. This study provides detailed insight into cognitive function over time in this patient population. ClinicalTrials.gov Identifier: NCT01372774; ALLIANCE/CCTG: N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group).

Radiotherapy (WBRT) or Autologous Stem-Cell Transplantation (ASCT) for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Long-Term Results of the Intergroup Anocef-Goelams Randomized Phase II Precis Study

Introduction: We previously reported the results of the PRECIS trial with a median follow-up of 33 months. Both whole brain radiotherapy (WBRT) and autologous stem cell transplantation (ACST) were effective according to the predetermined threshold. However, more relapses occurred in the WBRT arm. The 2-year event-free survival (EFS) from consolidation (relapse or death defined as event) were 69% (95% CI, 57% to 83%) and 87% (95% CI, 77% to 98%) after WBRT and ASCT, respectively (p = 0.03). Overall survival (OS) was similar in both arms. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT. A longer follow-up is required to better assess the impact of the treatment on relapse, survival and late complications. We report here the results of the PRECIS trial with a median follow-up of 98.3 months [min= 4,1 - max= 131.1], focusing on the per protocol population from time of consolidation.Methods: Immunocompetent patients (18 to 60 years of age) with untreated primary CNS lymphoma (PCNSL) were randomly assigned upfront to receive WBRT (Arm A) or ASCT (Arm B) as consolidation treatment after an induction chemotherapy consisting of two cycles of R-MBVP (rituximab, methotrexate, VP16, BCNU, prednisone) followed by two cycles of R-AraC (rituximab, cytarabine). Intensive chemotherapy consisted of thiotepa (250 mg/m2/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/ fraction). Cognitive functions were prospectively assessed until disease progression and focused on global cognitive function, episodic verbal memory, attention and mental flexibility, and psychoaffective status.Results: 140 patients were randomized (Arm A: N = 70; Arm B: N = 70). Fifty-three and 44 patients completed WBRT and ASCT respectively (per protocol population), including 3 and 5 patients who were in progressive disease (PD) at time of WBRT and ASCT, respectively.8-y EFS from time of consolidation in the per protocol population was 75.9% [63.3-91.0] and 39.9% [26.8-59.3] after ASCT and WBRT, respectively (p = 0.007) (fig 1a). The risk of relapse was significantly decreased after ASCT compared to WBRT (8-y relapse-free interval 94.1% [86.4-100] vs 47.6% [34.2-66.3], (p <0.001) (fig 1b). The 8-year overall survival from time of consolidation was similar in both arms, 63.4% [49.8 - 80.6] and 69.3% [56.7-84.8] in the WBRT and ASCT arms, respectively (fig1c). Among the 24 patients who relapsed after WBRT, 13 patients received subsequent salvage chemotherapy and consolidative ASCT, and seven of these patients were disease-free at last follow-up.Causes of deaths after WBRT (n = 17) were PD (n = 12), neurotoxicity (n = 3), second-line ASCT (n = 2). After ASCT, causes of deaths (n = 14) were treatment-related death (n = 5, including 2 occurring > 100 days post-ASCT, and 2 in patients in PD before ASCT), PD (n = 4), neurotoxicity following salvage WBRT (n = 1), second solid cancer (n = 3) and undetermined in one patient.In multivariate analysis, ECOG, disease status at the end of induction, and protein level in the CSF at diagnosis were independent prognostic factors for OS. Disease status at the end of induction and intraocular involvement at diagnosis were independent prognostic factors for EFS.Cognitive decline that could be fatal was only observed in patients who received WBRT. Imaging analysis of post consolidation leukoencephalopathy is ongoing.Conclusions: Consolidation with ASCT after HD-MTX based induction chemotherapy resulted in an excellent disease control but with a higher treatment-related mortality than WBRT. Severe Cognitive decline and late treatment-induced neurotoxic deaths were observed after WBRT. Intensity of the thiotepa-busulfan-cyclophosphamide regimen used before ASCT should be slightly reduced to improve the benefit/risk ratio of ASCT in first-line treatment of young patients with PCNSL. [Display omitted] DisclosuresSylvain: Sanofi, Celegene, Roche, Abbvie, Sandoz, Janssen, Takeda: Consultancy. Damaj: takeda: Consultancy, Honoraria; roche: Consultancy, Honoraria. Sanhes: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Is Autologous Stem Cell Transplantation a Safe and Effective Alternative to Whole Brain Radiation as Consolidation Therapy in Patients With Primary Central Nervous System Lymphoma?: A Critically Appraised Topic.

High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) is a promising alternative to whole brain radiation therapy (WBRT) in the treatment of primary central nervous system lymphoma (PCNSL). The objective of this study was to critically assess current evidence supporting the use of HD-ASCT as first-line consolidative therapy in PCNSL. The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. A recent, open-label, noncomparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and toxicity of consolidative therapy with HD-ASCT and WBRT in PCNSL in 2 separate treatment arms. A total of 140 patients with newly diagnosed PCNSL between the ages of 18 and 60 years were included. The primary endpoint of 2-year progression-free survival was met in 63% of patients in the WBRT arm and 87% in the HD-ASCT arm. Notably, an overall improvement in neurocognitive scores was observed following HD-ASCT, while WBRT was associated with worsened cognitive outcomes. In young patients with newly diagnosed PCNSL, consolidative therapy with HD-ASCT appears to be associated with less neurocognitive toxicity and may be more effective than WBRT at preventing relapses, however, at the cost of a higher treatment-related mortality.

Induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases: Results of a randomized phase II A-PLUS trial.

1082 Background: Our previous study ( Clin Cancer Res. 2015;21(8):1851) demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for breast cancer (BC) patients (pts) with brain metastases (BM) progressing from WBRT. We conducted a randomized phase II study A-PLUS (NCT02185352) to test whether using BEEP as an induction therapy could enhance the efficacy of WBRT and provide systemic control. Methods: BC pts with measurable BM not suitable for surgery/radiosurgery and had not received WBRT were randomized (2:1) to experimental arm: induction BEEP for 3 cycles (~2 months [ms]) followed by WBRT or control arm: upfront WBRT. The BEEP regimen consists of bevacizumab 15 mg/kg on day 1, and etoposide 70 mg/m2/day on days 2-4, cisplatin 70 mg/m2 on day 2, followed by prophylaxis GCSF, every 21 days. After WBRT in both arms, pts received treatment of physician’s choice except BEEP until BM progression. Stratification was based on the Graded Prognostic Assessment score. Primary endpoint was brain-specific progression free survival (BS-PFS) based on RECIST 1.1, with a total of 108 pts, power of 0.8 at the 2-sided α level of 0.2. Results: Of 112 enrolled pts, 74 were in experimental arm and 38 in control arm. Baseline patient characteristics were generally balanced between arms. With median follow up of 28.7 ms, median BS-PFS was 8.1 vs. 6.5 ms ( p= 0.146; HR 0.71 [95% CI 0.44-1.13]), which met the primary endpoint (pre-defined α level of 0.2). Results of preplanned analysis included: 2-month brain-specific objective response rate of BEEP alone vs. WBRT was 41.9% vs. 52.6% ( p= 0.613); 8-month BS-PFS rate was 48.7% vs. 26.3% ( p= 0.027); median PFS was 6.4 vs. 4.7 ms ( p= 0.071; HR 0.67 [95% CI 0.43-1.04]), and extra-BM PFS was 7.9 vs. 5.0 ms ( p= 0.141; HR 0.71 [95% CI 0.46-1.12]). Median overall survival was 15.6 vs. 13.6 ms ( p= 0.855; HR 0.96 [95% CI 0.59-1.55]), with 31.6% of pts in control arm received BEEP regimen treatment after BM progression. The most common all-grade adverse events (AEs) in experimental arm were neutropenia (30.2%), nausea (27.9%), anemia (27.4%), and leukopenia (24.2%). Most AEs were mild to moderate in severity. Two pts discontinued BEEP treatment due to grade 4 nephrotoxicity and grade 3 infection, respectively. Conclusions: BEEP as induction treatment followed by WBRT for BC pts with BM may improve control of both BM and systemic disease. Further validation by a phase III study is necessary. Clinical trial information: NCT02185352 .

Whole Brain Radiotherapy Versus Stereotactic Radiosurgery in Poor-Prognosis Patients with One to 10 Brain Metastases: A Randomised Feasibility Study

AimsA significant proportion of patients with brain metastases have a poor prognosis, with a life expectancy of 3–6 months. To determine the optimal radiotherapeutic strategy for brain metastases in this population, we conducted a randomised feasibility study of whole brain radiotherapy (WBRT) versus stereotactic radiosurgery (SRS). Materials and methodsPatients with a life expectancy of 3–6 months and between one and 10 brain metastases with a diameter ≤4 cm were enrolled at six Canadian cancer centres. Patients were randomly assigned (1:1) to receive either WBRT (20 Gy in five fractions) or SRS (15 Gy in one fraction). The primary end point was the rate of accrual per month. Secondary feasibility and clinical end points included the ratio of accrued subjects to screened subjects. This trial is registered with ClinicalTrials.gov (number NCT02220491). ResultsIn total, 210 patients were screened to enrol 22 patients into the trial; 20 patients were randomised between the two arms. Two patients did not receive treatment because one patient died and another patient withdrew consent after being enrolled. Patients were accrued between January 2015 and November 2017; the accrual rate was 0.63 patients/month. The most common reasons for exclusion were anticipated median survival outside the required range (n = 40), baseline Karnofsky Performance Score below 70 (n = 28) and more than 10 brain metastases (n = 28). The median follow-up was 7.0 months and the median survival was 7.0 months for all patients in the trial. The median intracranial progression-free survival was 1.8 months in the SRS arm and 9.2 months in the WBRT arm. There were five grade 3+ toxicities in the SRS arm and one grade 3+ toxicity in the WBRT arm; no grade 5 toxicities were observed. The cumulative rates of retreatment were 40% in the SRS arm and 40% in the WBRT arm. ConclusionsA randomised trial evaluating WBRT versus SRS in patients with one to 10 metastases and a poor prognosis is feasible. A slower than expected accrual rate and difficulties with accurate prognostication were identified as issues in this feasibility study. A larger phase III randomised trial is planned to determine the optimal treatment in this patient population.

Concomitant treatment of brain metastases with whole brain radiotherapy and temozolomide protects neurocognitive function and improve quality of life

Purpose: To study the protective effects of a combination of temozolomide (TMZ) and whole brain radiotherapy (WBT) on neurocognition, and its effect on the quality of life (QoL) in patients with brain metastasis (BM) from solid tumors, relative to WBT alone.Methods: A total of 256 BM patients were enrolled and divided into two groups treated with either WBT plus TMZ, or WBRT alone. All patients received 30 Gy WBT, with or without concomitant TMZ (75 mg/m2/day) during the irradiation period, and subsequently up to six cycles of TMZ (150 mg/m2/day).Results: The mean intracranial objective response (IOR) for all patients was 44.80 % while the IOR for WBT arm and WBT+TMZ group arm were 32.48 and 56.56 %, respectively (p = 0.03). The median intracranial overall survival (OS) for all the patients was 7.70 months. The median OS for WBT alone group (6.53 months) was significantly shorter than that of the WBT + TMZ arm (9.57 months). Statistically significant difference in quality of life (QoL) was observed between both arms at six months. Moreover, WBT+TMZ group had higher incidence of toxicity, when compared to WBT-only group.Conclusion: These results suggest that co-application of WBT and TMZ improves intracranial ORR and median OS in BM patients, relative to the use of WBT alone. Although the side effects may be increased as a result of addition of TMZ, toxicity is tolerable and manageable.Keywords: Brain metastasis, Temozolomide, Whole brain radiotherapy, Neurocognition

Effectiveness of temozolomide combined with whole brain radiotherapy for non-small cell lung cancer brain metastases.

BackgroundWe performed a retrospective analysis to compare the efficacy of whole brain radiotherapy (WBRT) combined with temozolomide (TMZ) versus WBRT alone as first‐line treatment for brain metastases (BM).MethodsSeventy‐eight non‐small cell lung cancer patients with BM were observed, including 45 patients who received WBRT plus TMZ (TMZ + WBRT) and 33 patients who received WBRT alone (WBRT). The primary outcome was overall survival (OS). Secondary outcomes included progression‐free survival (PFS), objective response rate (ORR), and adverse events.ResultsThe TMZ + WBRT arm achieved significant improvement in ORR (P = 0.0108) compared to the WBRT arm. PFS in the TMZ + WBRT arm was significantly longer than in the RT arm (6.0 vs. 3.5 months; P = 0.038). OS was not significantly different between the two arms. Although increased adverse reactions were experienced in the TMZ + WBRT arm, patients were tolerant of the side effects. Statistically significant differences in neurocognitive function and quality of life were observed between the arms at six months.ConclusionConcomitant TMZ + WBRT compared to WBRT alone significantly increases ORR and median PFS in patients with BM, but no remarkable difference in median OS was found. Adding TMZ to the treatment strategy could prevent neurocognitive function and quality of life from deteriorating. Although the addition of TMZ increases the incidence of adverse effects, no significant difference was observed. Thus, TMZ is safe and effective.

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases

We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3mg/kg every 3weeks, starting on day 3 of WBRT or 2days after SRS. The ipilimumab dose was escalated to 10mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507. The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3mg/kg (n=7) or 10mg/kg (n=9). The median follow-up was 8months (arm A) and 10.5months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5months and 8months and in arm B was 2.1months and not reached, respectively. Concurrent ipilimumab 10mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

The efficacy and roles of combining temozolomide with whole brain radiotherapy in protection neurocognitive function and improvement quality of life of non-small-cell lung cancer patients with brain metastases

BackgroundBrain metastasis (BM) is a poor prognostic factor for non-small-cell lung cancer (NSCLC). The efficacy and roles of combining temozolomide (TMZ) with whole brain radiotherapy (WBRT) in protection neurocognitive function (NCF) and improvement quality of life (QOL) were investigated and compared with WBRT alone in the treatment of NSCLC patients with BM.MethodsA total of 238 NSCLC patients with BM were reviewed and categorized into WBRT plus TMZ (RCT) arm and WBRT alone (RT), respectively. The efficacy was evaluated with Pearson chi-square or Fisher’s exact tests, Log-rank test and Cox proportional hazards model. NCF was assessed by using revised Hopkins Verbal Learning Test (HVLT-R), Controlled Oral Word Association (COWA) test and Trail-making Test (TMT). QOL was assessed by the Functional Assessment of Cancer Treatment-Lung (FACT-L) Chinese version 4.0 questionnaire.ResultsThe average intracranial objective response (ORR) and disease control rate (DCR) for all the patients were 26.9 and 95.8%, respectively. The intracranial ORR and DCR for RCT and RT arm were 34.9% vs. 20.2% (p = 0.01) and 98.4% vs. 92.7% (p = 0.03), respectively. The median intracranial progression-free survival (PFS) and overall survival (OS) of NSCLC patients with BM were 5.2 and 7.3 months, respectively. The median PFS of RCT arm was significantly longer than that of RT arm (5.9 vs. 4.9 months, p = 0.002). The median OS of the RCT arm was also slightly longer than that of the RT arm (8.5 vs. 5.9 months), but without statistical significance (p = 0.11). Multivariate analysis indicated that TMZ was a significant factor for PFS. Statistically significant differences on NCF and QOL were observed between CRT and RT arms at 5 months. RCT showed a trend of toxicities increase compared with RT, however, the toxicities were tolerable and manageable.ConclusionsAdding TMZ to WBRT in the treatment of NSCLC patients with BM could improve the intracranial ORR, DCR, and median PFS compared with WBRT alone. Although no remarkable difference on median OS was found, adding TMZ could prevent NCF and QOL from worsening. The side effects increased by adding TMZ, but the difference was not statistical significance and toxicities were well tolerated.

Should optimal supportive care alone be the standard of care for brain metastases patients from non-small cell lung cancer, who are not eligible for radiosurgery or surgery?

The Quality of Life after Treatment for Brain Metastases (QUARTZ) trial was a non-inferiority, phase III randomized trial comparing optimal supportive care (OSC) including dexamethasone versus OSC including dexamethasone and whole brain radiotherapy (WBRT). In this trial, 538 patients were recruited from 69 United Kingdom and three Australian centres. The primary outcome was quality-adjusted life-years (QALYs), generated from overall survival and patient completed EuroQOL EQ-5D questionnaires. The mean QALYs was 46.4 days for the OSC and WBRT arm versus 41.7 days for the OSC arm, with a mean difference of 4.7 days (90% CI: −12.7 to 3.3 days). In addition, there was no difference in overall survival (hazard ratio 1.06, 95% CI: 0.90–1.26), overall quality of life or dexamethasone use between the two groups (1).

Whole Brain Radiotherapy (WBRT) Versus Intensive Chemotherapy with Haematopoietic Stem Cell Rescue (IC + HCR) for Primary Central Nervous System Lymphoma (PCNSL) in Young Patients: An Intergroup Anocef-Goelams Randomized Phase II Trial (PRECIS)

BackgroundDespite a significant improvement of therapeutic results with the current immuno-chemotherapies, a consolidation treatment is still required for decreasing the risk of relapse.WBRT has been the historical standard consolidation in PCNSL patients, but IC + HCR has shown encouraging results in non-controlled studies. However, each procedure exposes patients to specific side effects, such as cognitive dysfunctions and treatment-related mortality, respectively. In this trial, we addressed the efficacy and toxicity of a standard chemo-immunotherapy followed by either WBRT or IC+HCR in first-line treatment of PCNSL patients.MethodsImmuno-competent patients (aged 18-60) with newly diagnosed PCNSL and measurable disease were enrolled from 23 French centers. All the patients received 2 cycles of R-MBVP (Rituximab 375 mg/m2 D1, Methotrexate 3 g/m2 D1 and D15, VP16 100 mg/m2 D2, BCNU 100 mg/m2 D3, Prednisone 60 mg/kg/D D1-D5) followed by 2 cycles of R-AraC (Rituximab 375 mg/m2 D1, Cytarabine 3g/m2 D1-D2) as induction chemotherapy. Participants were stratified upfront according to performance status (0-1 vs 2-4) and treating institution and randomly assigned (1:1)to receive either WBRT (Arm A) or IC + HCR (Arm B) as a consolidation treatment. IC consisted in thiotepa (250 mg/mg/m2/d days-9 through-7, busulfan 10 mg/kg (total dose) days-6 through -4, and cyclophosphamide 60 mg/kg/d days -3 and -2). Prospective neuro-cognitive evaluations were planned in both arms. Responses were assessed according to the IPCG criteria. A central review of MRIs was scheduled. The primary end-point was the 2-year progression free survival (PFS). Thirty-eight assessable patients who received the complete study treatment for each treatment were needed. Either of the two arms would be deemed effective if > 24/38 patients are free of disease at 2 year with no major side effects. Analysis was intent to treat, in a non-comparative phase 2 trial design.This study is registered with ClinicalTrials.gov, number NCT00863460.ResultsBetween Oct 2008 and Feb 2014, 140 patients (male: 101; female: 39) were recruited (median age = 55 years, range 22-60) and randomized in Arm A (n=70) or Arm B (n = 70). Sixty-seven patients were assessable in each arm. Two patients withdrew their consent during the induction cycles (Arm A: n = 1; Arm B: n = 1). After two cycles of R-MBVP, overall response rates were 82% (CR + uCR = 24 %) and 77 % (CR + uCR = 23 %) in arm A and arm B respectively. At the end of the induction chemotherapy, ORR was 74 % (CR+ uCR = 44 %) and 67 % (CR+ uCR = 42 %) in arm A and B respectively. WBRT was given to 53 patients in arm A and IC+HCR was given to 44 patients in arm B. After consolidation treatment, ORR was 71 % (56 % CR+ Cru) and 67 % (60 % CR+ Cru) in arm A and B respectively. Five treatment-related deaths were reported, during induction chemotherapy in arm A (n = 2) and after IC+ HCT (n = 3). Median follow-up was 27.2 and 28.6 months in arm A and arm B respectively. Relapses occurred in 21 patients after the end of treatment (arm A: n = 16; Arm B: n = 5) with a median time to relapse of 15.1 and 8.5 months in arm A and B respectively. 2-y PFS in the experimental arm was 86.8% (95 CI, 76.6 to 98.3%). 2-y PFS in arm A will be given after the completion of the ongoing MRI review in this arm. The analysis of the prospective neuropsychological evaluations is pending.Conclusion:This study shows a favorable outcome of patients who received the IC+HCR arm. Improvement of the ORR after induction chemotherapy is still needed. The results of the 2-y PFS in arm A and of the neuropsychological evaluations are awaited to define the further standard of treatment in young patients with PCNSL.Fundings: French Government, Roche, Pierre Fabre [Display omitted] DisclosuresChoquet:Janssen: Consultancy; Celgene: Consultancy. Thyss:Takeda: Research Funding; Millennium: Research Funding. Soussain:Pharmacyclics: Research Funding; Roche: Research Funding; Celgene: Research Funding.

Stereotactic radiotherapy of the tumor bed compared to whole brain radiotherapy after surgery of single brain metastasis: Results from a randomized trial

PurposeTo evaluate if neurological/cognitive function outcomes in patients with resected single brain metastasis (BM) after stereotactic radiotherapy of the tumor bed (SRT-TB) are not inferior compared to those achieved with whole-brain radiotherapy (WBRT). MethodsPatients with total/subtotal resection of single BM were randomly assigned either to SRT-TB (n=29) or WBRT (n=30). SRT-TB arm consisted of 15Gy/1 fraction, or 5×5Gy. WBRT consisted of 30Gy/10 fractions. Neurological/cognitive failure was defined as a decrease of neurological score by one point or more, or a worsening of the MiniMental test by at least 3 points, or neurological death. Cumulative incidence of neurological/cognitive failure (CINCF), neurological death (CIND), and overall survival (OS) were compared. ResultsMedian follow-up was 29months (range: 8–45) for 15 patients still alive. The difference in the probability of CINCF at 6months (primary endpoint) was −8% in favor of WBRT (95% confidence interval: +17% −35%; non-inferiority margin: −20%). In the intention-to-treat analysis, two-year CIND rates were 66% vs. 31%, for SRT-TB and WBRT arm, respectively, p=.015. The corresponding figures for OS were 10% vs. 37%, p=.046. ConclusionsNon-inferiority of SRT-TB was not demonstrated in our underpowered study. More data from randomized studies are needed for confirmation of the value of this method.

Phase II randomized study of whole-brain radiation therapy with or without concurrent temozolomide for brain metastases from breast cancer

BackgroundTo improve the therapeutic index of whole-brain radiation therapy (WBRT) in the treatment of brain metastases (BM) from breast cancer, we investigated the efficacy and safety of WBRT combined with temozolomide (TMZ) in this population. Patients and methodsThis phase II multicenter prospective randomized study included patients with newly diagnosed intraparenchymal BMs from breast cancer, unsuitable for surgery or radiosurgery. All patients received conformal WBRT (3Gy × 10–30Gy), with or without concomitant TMZ administered at a dosage of 75 mg/m2/day during the irradiation period. The primary end point was objective response rate (ORR) 6 weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (modified WHO criteria). Secondary end points were progression-free survival (PFS) and overall survival (OS), neurologic symptoms, and tolerability. ResultsBetween February 2008 and November 2010, 100 patients were enrolled in the study (50 in the WBRT + TMZ arm, 50 in the WBRT arm). Median age was 55 years (29–79). Median follow-up was 9.4 months [1.0–68.1]. ORRs at 6 weeks were 36% in the WBRT arm and 30% in the WBRT + TMZ arm (NS). In the WBRT arm, median PFS was 7.4 months and median OS was 11.1 months. In the WBRT + TMZ arm, median PFS was 6.9 months and median OS was 9.4 months. Treatment was well tolerated in this arm: the most common ≥grade 2 acute toxicity was reversible lymphopenia. ConclusionWBRT combined with TMZ did not significantly improve local control and survival in patients with BMs from breast cancer. Clinicaltrials.govNCT00875355.

A Single Institutional Phase II Randomized Trial of Whole Brain Radiation Therapy with or without Irinotecan for the Treatment of Brain Metastases from Solid Tumours

Background: The relatively suboptimal results of whole brain radiation therapy (WBRT) alone in eradication of brain metastases and an attempt to improve outcomes with WBRT have led to studies combining radiotherapy with chemotherapy drugs that could act as radiosensitizers with a rationale of improving local tumor control. Materials and Methods: This randomized phase II study evaluated the use of Irinotecan concomitant with 37.5 Gray (Gy) of WBRT in 2.5 Gy daily fractions × 5 days each week for 3 weeks versus Whole WBRT alone in patients with brain metastasis (BM) from solid tumors. Fifty patients were randomized to receive either WBRT alone or concomitant with three irinotecan IV infusions 80 mg/m2, 2 hrs before RT on days 1, 8, and 15. Results: The objective response rate (ORR) was significantly improved in patients receiving Irinotecan with radiotherapy versus radiotherapy alone (48% vs. 28%; p = 0.048). The median time to progression of brain metastasis was significantly longer in the irinotecan and WBRT arm as compared to the WBRT arm (8 vs. 5 months; p < 0.001). There was no significant difference in survival between treatment arms (p = 0.361). Irinotecan with radiotherapy was generally well tolerated and did not interfere with the delivery of WBRT. Conclusions: Irinotecan concomitant with WBRT was well tolerated and significantly improved local control of BM compared with WBRT alone. These findings require confirmation in a phase III trial with addition of quality of life assessment.

Hippocampal-Avoidance Whole-Brain Radiation Therapy: A New Standard for Patients With Brain Metastases?

The use of whole-brain radiation therapy (WBRT) for brain metastases was first described in the 1950s. Since that time, WBRT has long been considered the treatment of choice, given its wide availability, ease of delivery, and effectiveness in providing palliation for many patients. Numerous phase III trials have also validated its benefit in improving neurologic signs and symptoms for many patients, with median survival times ranging from 3 to 6 months. Because of the poor outcomes for most patients with brain metastases, some physicians developed a nihilistic view of brain metastases and considered the routine use of WBRT as an obvious approach, given the limited treatment options. As a result, the potential toxicities resulting from WBRT were largely dismissed. However, with the many advances in neurosurgery, imaging, medical oncology, and radiation oncology, the outcomes for some patients have greatly improved, particularly for those with favorable prognostic factors. With this improvement in outcomes and the higher expectations of patients and physicians, the routine use of WBRT has been highly scrutinized, considering its potential impact on neurocognitive function (NCF) and quality of life (QOL). As a result, the optimal management of brain metastases remains one of the most controversial areas of oncology, even among experts. Given the improved outcomes for some patients with brain metastases, the impact of WBRT on NCF has recently been an active area of investigation. A comprehensive phase III trial (PCI-P-120-9801) of WBRT versus WBRT plus motexafin gadolinium, a radiation sensitizer, was performed and included a battery of neurocognitive tests. This study of 401 patients demonstrated that the vast majority of patients with brain metastases (90.5%) had some decline in NCF before initiation of treatment. Neurocognitive test scores and global neurocognitive impairment at baseline were correlated with brain tumor volume and also predicted for survival. Further analysis suggested the adverse impact of tumor progression on NCF was greater than the treatment-related effects of WBRT. In addition, recent neurocognitive data from RTOG (Radiation Therapy Oncology Group) 0214, a phase III randomized trial of observation versus prophylactic cranial irradiation (PCI) for patients with non–small-cell lung cancer, have also suggested a negative impact of PCI. In addition to the neurocognitive effects, the impact of WBRT on QOL and functional independence has also been investigated. Although phase III trials of stereotactic radiosurgery (SRS) and WBRT for patients with a limited number of brain metastases ( four) have shown a significant improvement in local and distant brain control with the addition of WBRT to SRS, the decline in Hopkins Verbal Learning Test–Revised (HVLT-R) scores at 4 months and lack of improvement in the duration of functional independence have further decreased the advocacy for WBRT. In addition, the healthrelated QOL (HRQOL) data from the phase III European Organisation for Research and Treatment of Cancer trial of SRS or surgery with or without WBRT have also introduced additional concerns. In this trial, the WBRT arm had a statistically significant detriment in mean global QOL scores at 9 months and also had lower cognitive function at 8 weeks and 1 year; however, this trial did not formally assess patients with a battery of neurocognitive tests and had only a 45% compliance rate at 1 year. On the basis of the results of these studies and the concerns regarding the effects of WBRT on NCF, strategies to mitigate the late effects of WBRT have been actively explored. Omission of WBRT through the use of SRS is emerging as an attractive treatment approach compared with WBRT, given its inherent advantages, including its multidisciplinary approach, single-session outpatient delivery, minimal recovery time, patient convenience, and more rapid initiation of systemic treatments. Technologic advances in treatment delivery and treatment planning have also facilitated the use of SRS alone as the primary treatment for patients with five lesions. Recently, a prospective observational study of SRS alone in 1,194 patients with one to 10 brain metastases suggested no difference in survival or treatment-related adverse events for patients with two to four and five to 10 lesions. To confirm this and other studies, the North American Gamma Knife Consortium will be performing a prospective randomized trial evaluating NCF of SRS versus WBRT for patients with five metastases (ClinicalTrials .gov NCT01731704). Another approach to minimize the neurocognitive effects of WBRT uses memantine, an N-methyl-D-aspartate receptor antagonist, as a potential neuroprotector, which has been used for patients with mild to moderate dementia in Alzheimer’s disease. RTOG 0614 was a double-blind, placebo-controlled phase III trial of WBRT plus memantine versus WBRT plus placebo. This trial randomly assigned 554 patients to WBRT with or without memantine 10 mg initially then JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 34 DECEMBER 1 2014

Abstract P6-11-01: A randomized phase II clinical trial of whole-brain radiation therapy plus concomitant temozolomide in treatment of brain metastases from breast cancer: Six-month follow-up results

Abstract Background: Despite of therapeutics progress in advanced breast cancer, brain metastases occurrence remain a frequent and delicate situation. The efficacy of whole-brain radiation therapy (WBRT), still considered as the standard local treatment in case of multiple brain metastases, is limited. Recently, several phase II studies have shown some efficacy of the association of WBRT and temozolomide (TMZ), an oral alkylating agent already known as a radiosensitizer, with improved brain control rate (44 to 96%). Patients with breast cancer were underrepresented and none of these trials have studied this combined treatment issue in this specific population. The aim of this study was to assess the efficacy and safety of WBRT combined with temozolomide in the treatment of brain metastases from breast cancer. Materials and Methods: A prospective randomized multicenter phase II study was developed, using a modified two-stage Fleming design. Patients with newly diagnosed intraparenchymal brain metastases from breast cancer, not suitable for surgery nor radiosurgery, were included. All patients received conformational WBRT (3 Gy x 10 to 30 Gy). They were randomized to WBRT plus concomitant TMZ administered 75 mg/m2/day during radiation period versus WBRT alone. The primary endpoint was radiologic objective response at six weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (WHO modified criteria). We also evaluated neurologic symptoms, tolerance, safety, progression free survival (PFS) and overall survival (OS) as secondary endpoints. A longer clinical-brain MRI follow-up was planned, each three months during a two-year period. All of the patients gave their written informed consent to be part of the study, which was approved by the local committee. Results: One hundred patients were enrolled between February 2008 and December 2010 (50 in the WBRT + TMZ arm, 50 in the WBRT arm). The median age was 55 [29 -79]. Eighty (80) patients had brain metastases as single secondary localization. About one third of patients had a triple negative breast cancer subtype (38,3% in the association arm and 35,71% in the WBRT alone arm). There were 26,7% and 14,6% of HER2 positive subtype respectively. The median follow-up was 30 months [range 6-60]. At six months from brain metastases diagnosis (three months after the end of the treatment), objective response rate seems better in the WBRT + TMZ arm: 52% versus 40% in the arm WBRT alone but was not statistically significant (p = 0,54). No complete response was observed. In the WBRT + TMZ group, median PFS and OS at six-months were respectively 55,6% [range 46-7 – 66,0] and 67,7% [range 59,1 – 77,6]. No improvement in neurologic symptoms was noticed. In multivariate analysis, initial TNM status was significantly correlated with PFS and OS. The concurrent use of TMZ with WBRT was well-tolerated. The most frequent upper grade II acute toxicity was reversible leucopenia in the association arm. Conclusion: The addition of temozolomide to WBRT in patients with brain metastases from breast cancer did not improve local control or survival at six months follow-up. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-01.

On the Merits and Limitations of Whole-Brain Radiation Therapy

Brain metastases are a common event in the progression of many human malignancies. In the article that accompanies this editorial, Soffietti et al present data reporting health-related quality of life (HRQOL)outcomesinpatientsenrolledontoEuropeanOrganisationfor Research and Treatment of Cancer (EORTC) trial 22952-26001. This is the first such analysis in a randomized trial of observation or whole-brain radiation therapy (WBRT) after focal therapy (surgery or stereotactic radiosurgery [SRS]). The primary end point results were reported by Kocher et al in 2011 and eloquently editorialized by Mehta in the same issue of Journal of Clinical Oncology. Few topics in oncology have stirred more controversy and partisanship than the appropriate use and role of WBRT in the modern practice of oncology. Deeply held biases have sometimes been defended with a fervor that cannot be easily justified by the scant available evidence. Nonetheless, recent developments have shed some light on the potential merits and limitations of WBRT. All patients with brain metastases typically receive corticosteroids, which will improve edema and neurologic deficits in approximately 70% of patients. Nonetheless, the median survival with corticosteroids alone is approximately 2 months. WBRT has been the mainstay of therapy for patients with intracranial metastases and is associated with increases in the median survival of these patients to approximately 4 to 6 months. In a pooled recursive partitioning analysis of patients treated with WBRT on Radiation Therapy Oncology Group (RTOG) trials, the median survivals were 7, 4, and 2 months, respectively, for patients in the most favorable, intermediate, and poor prognostic subgroups. A cumulative response rate of approximately 60% can be anticipated with WBRT. The debate over the clinical benefit of WBRT versus the potential risks of treatment have led to interest in identifying a group of patients with limited cranial metastases who can be treated adequately with focal therapies alone (surgery or SRS), withholding WBRT until progression (Table 1). Three randomized trials have examined the incremental benefit of adding WBRT to focal therapy alone in patients with limited cranial metastases. Patchell et al reported improved local control (90% v 54%), elsewhere control (86% v 63%), and cumulative intracranial control (82% v 30%) with WBRT compared with observation after surgical resection of a single brain metastasis. There was no improvement in overall survival, but patients in the WBRT arm were less likely to suffer neurologic death. This study is often misinterpreted as a negative study because of the lack of improvement in survival. However, this trial was designed and powered for intracranial disease control; survival was a secondary end point. From the standpoint of intracranial disease control, this was indeed a positive trial, and the findings are congruent with data from the Japanese Radiation Oncology Study Group (JROSG) 99-1 trial. Aoyama et al reported results for 132 patients with one to four brain metastases, each less than 3 cm, who were randomly assigned to SRS alone or WBRT and SRS. The WBRT arm had superior local control, distant brain control, and total intracranial control. Forty-three percent of patients on the SRS-alone arm required salvage therapy, compared with 15% when WBRT was added. Interestingly, this trial demonstrated improvements in local control of the index lesions with WBRT, presumably because of the higher doses received when WBRT was delivered. This finding seems to undermine the rationale for SRS alone (at least on the

Whole-brain radiotherapy in NSCLC patients with brain metastasis: Who benefits and by how much?

e18068 Background: NSCLC patients with brain metastasis have poor survival even with whole brain radiation therapy (WBRT) alone or in combination with surgery (S+WBRT). The aim of the audit was to identify any prognostic factors which can aid treatment decisions. Methods: A retrospective study of patients with brain metastasis from NSCLC, diagnosed between July 2008 and December 2010 was carried out. Patient characteristics, RPA score at the time of presentation, treatment modality, radiotherapy dose fractionation, time to progression, date of death and primary or secondary presentation were collected. The data was analysed using descriptive statistics; overall survival was calculated using the Kaplan-Meier estimates and compared with the Log-rank test. Multivariate analysis was carried using the Proportional Hazards Model. Results: Of the 156 patients included, 52% presented as primary manifestation and 48% as secondary. The mean age of the audit population was 64.4 year, with 60% of patients falling in the RPA II category. Histology was not available in 27 (18%) of the patients. Majority (79%) were treated with WBRT alone, 3 patients had stereotactic radiosurgery in combination with WBRT and 19% had S+WBRT. 9 (6%) patients did not complete WBRT. Median follow up is 3.8 months (0.5-34.5). Overall survival (OS) for the whole group is 4 months. Better survival was seen with S + WBRT (8 vs. 4 months, p &lt;0.01) and primary presentation (5 vs. 4 months, p=0.009). RPA classification significantly influenced survival in the S + WBRT arm (12 months vs. 7 months for RPA I, p=0.009). On multivariate analysis of the various prognostic factors in the WBRT group, RPA classification and higher RT dose (30 Gy/10#) were associated with better survival (OR 2.3 95%CI 1.6-3.4). Patients treated with SRS have the best survival (11 months). Conclusions: RPA classification is the strongest predictor for outcome following treatment for brain metastasis. These findings can assist in better patient selection and optimising radiotherapy dose fractionation to improve survival outcome. It will be interesting to see if QUARTZ trial supports these findings and clarify the benefit of WBRT in patients with NSCLC.

Adjuvant Whole-Brain Radiotherapy Versus Observation After Radiosurgery or Surgical Resection of One to Three Cerebral Metastases: Results of the EORTC 22952-26001 Study

This European Organisation for Research and Treatment of Cancer phase III trial assesses whether adjuvant whole-brain radiotherapy (WBRT) increases the duration of functional independence after surgery or radiosurgery of brain metastases. Patients with one to three brain metastases of solid tumors (small-cell lung cancer excluded) with stable systemic disease or asymptomatic primary tumors and WHO performance status (PS) of 0 to 2 were treated with complete surgery or radiosurgery and randomly assigned to adjuvant WBRT (30 Gy in 10 fractions) or observation (OBS). The primary end point was time to WHO PS deterioration to more than 2. Of 359 patients, 199 underwent radiosurgery, and 160 underwent surgery. In the radiosurgery group, 100 patients were allocated to OBS, and 99 were allocated to WBRT. After surgery, 79 patients were allocated to OBS, and 81 were allocated to adjuvant WBRT. The median time to WHO PS more than 2 was 10.0 months (95% CI, 8.1 to 11.7 months) after OBS and 9.5 months (95% CI, 7.8 to 11.9 months) after WBRT (P = .71). Overall survival was similar in the WBRT and OBS arms (median, 10.9 v 10.7 months, respectively; P = .89). WBRT reduced the 2-year relapse rate both at initial sites (surgery: 59% to 27%, P < .001; radiosurgery: 31% to 19%, P = .040) and at new sites (surgery: 42% to 23%, P = .008; radiosurgery: 48% to 33%, P = .023). Salvage therapies were used more frequently after OBS than after WBRT. Intracranial progression caused death in 78 (44%) of 179 patients in the OBS arm and in 50 (28%) of 180 patients in the WBRT arm. After radiosurgery or surgery of a limited number of brain metastases, adjuvant WBRT reduces intracranial relapses and neurologic deaths but fails to improve the duration of functional independence and overall survival.

Whole-Brain Radiation Therapy Plus Concomitant Temozolomide for the Treatment of Brain Metastases From Non–Small-Cell Lung Cancer: A Randomized, Open-Label Phase II Study

BackgroundA previously published study of temozolomide concurrent with whole-brain radiation therapy (WBRT) reported significant improvement in response rates and a nonsignificant trend toward improved overall survival compared with WBRT alone in patients with brain metastases primarily from lung cancer. This study sought to confirm the benefit of adding temozolomide to WBRT in patients with non–small-cell lung cancer (NSCLC) with brain metastases. Patients and MethodsThis planned phase III study (target = 380 events) was converted to a phase II study (target = 70 events) because of poor enrollment. Patients with NSCLC and ≥ 1 newly diagnosed brain lesion were randomized to WBRT (30 Gy in 10 fractions) alone or combined with temozolomide (75 mg/m2/day) for 21 or 28 days. Endpoints included overall survival and time to central nervous system (CNS) progression. ResultsMedian overall survival and median time to CNS progression was 4.4 and 3.1 months in the WBRT + temozolomide arm (n = 47) versus 5.7 and 3.8 months in the WBRT arm (n = 48). However, there were imbalances in the percentages of patients receiving previous chemotherapy and with synchronous brain metastases. Adding temozolomide to WBRT increased the frequency of nausea, vomiting, alopecia, fatigue, anorexia, and constipation. Most adverse events were mild to moderate. ConclusionThe benefit of adding temozolomide to WBRT was not confirmed; however, the accrual goal for the planned phase III trial was not reached, and the study regimen differed from regimens used previously. Therefore, the role of temozolomide in treating brain metastases remains unresolved.