Omission Of Whole Brain Radiotherapy Research Articles

PB2117: TEN-YEAR SINGLE CENTER EXPERIENCE TREATING PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: CAN RADIOTHERAPY BE OMITTED?

Background: Primary central nervous system lymphoma (PCNSL) is a rare form of lymphoma confined to the central nervous system (CNS) that is characterized by an aggressive course, high rates of treatment resistance and short overall survival. In recent decades, the treatment of PCNSL has undergone significant changes; its standard treatment consists of combined immunochemotherapy regimens that should include high-dose methotrexate (HD-MTX) and/or cytarabine, followed by consolidative autologous hematopoietic cell transplantation (AHCT). HD-MTX–based chemotherapy followed by consolidative whole brain radiotherapy (WBRT) has, historically, been the standard of care. In elderly and comorbid patients who are not candidates for AHCT, maintenance therapy with procarbazine or temozolomide is often used. Aims: We aim to describe a single center’s ten-year experience treating PCNSL. Methods: Retrospective study of patients with PCNSL treated in a single center from 2011 to 2021, describing the demographic, clinical features and outcomes. Data was collected from clinical records and analyzed with IBM SPSS 25.0. Results: Twenty patients, 11 (55%) female, with a median age of 61 years (range 44-77) were identified. 65% had an Eastern Cooperative Oncology Group performance status (ECOG) of 0, 25% of 1, 5% had an ECOG of 2 and 5% had an ECOG of 4. International Extranodal Lymphoma Study Group (IELSG) score was 0-1 in 7/35%, 2-3 in 11/55% and 4-5 in 2/10%; 17/85% presented with parenchymal disease, 2/10% with leptomeningeal disease only, and 1/5% with both; only one patient had eye involvement at presentation. Frontline therapy consisted of chemotherapy only (with or without rituximab) in 14 patients while 6 had chemotherapy plus WBRT; all patients received methotrexate (MTX)-based regimens (Ferreri, MATRix, DeAngelis, R-MP and R-MPV-A). Overall response was obtained in 12/60% patients (complete response in 10/50% and partial response in 2/10%). 8/40% patients relapsed, at a median time of 4.2 months after completion of therapy; 7/87.5% relapsed with parenchymal disease and 1/12.5% with mixed parenchymal and leptomeningeal disease. Median follow up was 12.1 months, median overall survival (OS) was 25.3 months and median progression-free survival (PFS) was 4.4 months. In univariate analysis (log rank), age, sex, ECOG, presence of deep brain lesions and IELSG score did not significantly impact OS and PFS, whereas radiotherapy use was significantly associated with improved OS (63.7 vs. 13.0 months; p-value 0.002) and PFS (36.1 vs. 3.3 months; p-value 0.016; Image). Univariate Cox regression analysis showed significant PFS improvement with radiotherapy use (HR 0.12; 95% CI 0.02-0.92, p-value 0.042), but no statistically significant OS improvement; in our cohort, no other variables significantly impacted survival. All surviving patients who underwent WBRT have shown cognitive impairment in neuropsychological tests. Image:Summary/Conclusion: Based on our analysis, age, ECOG and IELSG score did not significantly impact OS and PFS, whereas WBRT use was significantly associated with improved PFS, suggesting that the omission of WBRT may not be associated with improved survival, although its use should be weighed against potentially limiting neurotoxicity.

Radiotherapy for brain metastases from small-cell lung cancer in distinct clinical indications and scenarios.

Management of brain metastases (BM) from small-cell lung cancer (SCLC) is complex and not supported by a strong evidence from prospective clinical trials. Owing to the different clinical and pathological characteristics of SCLC, patients with this histology were not included in the prospective studies on the value of whole-brain radiotherapy (WBRT) and local surgical or ablative radiation treatment like stereotactic radiosurgery (SRS). Chemotherapy also represents a major part of the armamentarium against BM from SCLC due to the well-recognized chemoresponsiveness of this cancer and the frequent presentation of BM with extracranial progression. WBRT in combination with chemotherapy has long been a standard approach in this setting. However, data on the neurocognitive toxicity and the lack of documented impact on overall survival of WBRT in the management of BM from other solid tumors, as well as the increasing availability of the stereotactic radiotherapy technologies, has led to the increasing use of SRS with omission of WBRT also in SCLC. In the current review the use of different modalities of radiotherapy and ways of combining radiotherapy with chemotherapy for BM from SCLC will be presented for distinct clinical situations: presentation of BM synchronous with primary, metachronous presentation of BM—without previous prophylactic cranial irradiation (PCI) vs. after PCI, and asymptomatic BM found at the staging before PCI.

Stereotactic radiosurgery in the management of brain metastases

A treatment relying solely on stereotactic radiosurgery (SRS), with the omission of whole brain radiotherapy (WBRT), is now increasingly applied to the patients with brain metastases that are limited in number, however, it has not been reached a general agreement if patients really receive benefit from this strategy. In response to this situation, we, Japanese Radiation Oncology Study Group (JROSG), carried out a prospective randomized control trial in which SRS-alone approach was compared with WBRT+SRS for patients with 1-4 brain metastases. This study proved that there was no significant difference in survival, mode of death (neurologic versus systemic), and functional preservation rate between two treatment arms. However, the omission of WBRT significantly increased the frequency of brain tumor recurrence, and as a result, salvages brain treatments were more frequently required among patients allocated to SRS-alone arm. In the analyses of neurocognitive function, it was shown that the brain tumor recurrence as well as late radiation toxicities could be a cause of the deterioration of neurocognitive function. Those results indicate that SRS-alone treatment can be a treatment option for 1-4 brain metastases, however frequent monitoring of the brain tumor status should be warranted in order to detect recurrence of brain metastases before they became symptomatic.

AT-59 * HIGH-DOSE MTX-BASED CHEMOTHERAPY FOR PRIMARY CNS LYMPHOMA: WITH OR WITHOUT WHOLE BRAIN RADIOTHERAPY? FINAL ANALYSIS OF G-PCNSL-SG-1

BACKGROUND: This is the final report of the G-PCNSL-SG-1 trial after a median follow-up of 81.2 months. METHODS: G-PCNSL-SG-1 (www.clinicaltrials.gov {type:clinical-trial,attrs:{text:NCT00153530,term_id:NCT00153530}}NCT00153530) had randomised immunocompetent patients with newly diagnosed PCNSL to high-dose methotrexate (HDMTX) - based chemotherapy followed by whole-brain radiotherapy (WBRT) or chemotherapy alone. We hypothesized that the omission of WBRT from first-line treatment would not compromise overall survival (OS; primary endpoint), using a non-inferiority design with a margin of 0.9. FINDINGS: Of 551 patients who entered the study 524 fulfilled the eligibility criteria, 410 entered the post-HDMTX phase (intention-to-treat, ITT population), and 320 were treated per protocol (PP). OS with versus without WBRT was different neither in the ITT (HR 0.997, 95%CI 0.79-1.26, p = 0.98) nor in the PP population (HR 1.03, 95%CI 0.79-1.35, p = 0.82). In the ITT population CR patients experienced neither a progression-free survival (PFS) benefit from the last HDMTX-based CHT (PFS-2) (HR 0.84, 95% CI 0.60-1.19, p = 0.33) nor an OS benefit (HR 1.13, 95% CI 0.77-1.66, p = 0.53) with WBRT. In CR patients of the PP population, WBRT conferred a benefit for PFS-2 (HR 0.68, 95%CI 0.46-1.01, p = 0.057), but no OS benefit (HR 1.06, 95%CI 0.69-1.63, p = 0.78). In non-CR patients of the ITT population, a benefit of PFS-2 (HR 0.58, 95%CI 0.44-0.77, p < 0.001), but not of OS (HR 0.86, 95%CI 0.64-1.16, p = 0.32) was found with WBRT; in non-CR patients of the PP population, WBRT conferred a benefit of PFS-2 over CHT alone (HR 0.41, 95%CI 0.29-0.57, p < 0.001) and a trend for OS, too (HR 0.76, 95%CI 0.54-1.08, p = 0.12). INTERPRETATION: Despite improvement in PFS, particularly in patients without CR to HDMTX-based CHT, no significant difference in OS was found when WBRT was omitted from primary therapy in this long-term follow-up analysis. The PFS afforded by WBRT has to be balanced against its long-term toxicity.

2010: neuro-oncology is moving!

The first randomized phase III trial in patients with primary central nervous system lymphoma was reported for the first time at the 2010 annual meeting of the American Society of Clinical Oncology, and concluded that the omission of whole brain radiotherapy from first-line treatment does not compromise survival. Two randomized trials investigated tailored treatment strategies for elderly patients with glioma and reached opposite conclusions. Novel treatment approaches in recurrent glioblastoma with alternating tumour treatment fields (NovoTTF), or antiangiogenic agents (cilengitide and bevacizumab) have been reported and updated. The role of vascular endothelial growth factor-inhibiting strategies in the management of recurrent glioma remains unclear and controversial.

High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial

High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m(2)) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m(2)) on days 3-5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530. 551 patients (median age 63 years, IQR 55-69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8-39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5-46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80-1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6-25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3-16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors.

Should whole-brain radiotherapy be considered standard of care in newly diagnosed primary central nervous system lymphoma? The G-PCNSL-SG1 randomized phase IV trial.

8008 Background: High-dose methotrexate (HDMTX) is considered the standard of care for patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The role of whole-brain radiotherapy (WBRT) has remained controversial. Delayed neurotoxicity limits its acceptance as a standard of care. Methods: Immunocompetent patients with newly diagnosed PCNSL were randomized to chemotherapy followed by WBRT (arms A1, B1) or chemotherapy alone (A2, B2). After randomization, all patients were to receive 6 cycles HDMTX (4 g/m2, D1, biweekly) from 1999-2007 and HDMTX plus ifosfamide (1.5 g/m2, D3-D5, biweekly) thereafter. Patients achieving a complete response (CR) received either consolidating WBRT with 45 Gy in 1.5 Gy fractions (arm A1) or no further treatment (A2). Patients without CR received salvage WBRT (B1) or salvage chemotherapy using HD-cytarabine (B2) (4 × 3 g/m2/ 48 h, × 3 weeks). The goal of the trial was to demonstrate that the omission of WBRT from first-line treatment does not compromise o...

Brain metastases: current management and new developments

To review the state-of-the-art and new developments in the management of patients with brain metastases. Treatment decisions are based on prognostic factors to maximize neurologic function and survival, while avoiding unnecessary therapies. Whole-brain radiotherapy (WBRT) is the treatment of choice for patients with unfavorable prognostic factors. Stereotactic radiosurgery (SRS) or surgery is indicated for patients with favorable prognostic factors and limited brain disease. In single brain metastasis, the addition of either stereotactic radiosurgery or surgery to WBRT improves survival. The omission of WBRT after surgery or radiosurgery results in a worse local and distant control, though it does not affect survival. The incidence of neurocognitive deficits in long-term survivors after WBRT remains to be defined. New approaches to avoid cognitive deficits following WBRT are being investigated. The role of chemotherapy is limited. Molecularly targeted therapies are increasingly employed. Prophylaxis with WBRT is the standard in small-cell lung cancer. Many questions need future trials: the usefulness of new radiosensitizers; the role of local treatments after surgery; and the impact of molecularly targeted therapies on subgroups of patients with specific molecular profiles. Quality of life and cognitive functions are recognized as major endpoints in clinical trials.

Neurocognitive Function of Patients with Brain Metastasis Who Received Either Whole Brain Radiotherapy Plus Stereotactic Radiosurgery or Radiosurgery Alone

To determine how the omission of whole brain radiotherapy (WBRT) affects the neurocognitive function of patients with one to four brain metastases who have been treated with stereotactic radiosurgery (SRS). In a prospective randomized trial between WBRT+SRS and SRS alone for patients with one to four brain metastases, we assessed the neurocognitive function using the Mini-Mental State Examination (MMSE). Of the 132 enrolled patients, MMSE scores were available for 110. In the baseline MMSE analyses, statistically significant differences were observed for total tumor volume, extent of tumor edema, age, and Karnofsky performance status. Of the 92 patients who underwent the follow-up MMSE, 39 had a baseline MMSE score of < or =27 (17 in the WBRT+SRS group and 22 in the SRS-alone group). Improvements of > or =3 points in the MMSEs of 9 WBRT+SRS patients and 11 SRS-alone patients (p = 0.85) were observed. Of the 82 patients with a baseline MMSE score of > or =27 or whose baseline MMSE score was < or =26 but had improved to > or =27 after the initial brain treatment, the 12-, 24-, and 36-month actuarial free rate of the 3-point drop in the MMSE was 76.1%, 68.5%, and 14.7% in the WBRT+SRS group and 59.3%, 51.9%, and 51.9% in the SRS-alone group, respectively. The average duration until deterioration was 16.5 months in the WBRT+SRS group and 7.6 months in the SRS-alone group (p = 0.05). The results of the present study have revealed that, for most brain metastatic patients, control of the brain tumor is the most important factor for stabilizing neurocognitive function. However, the long-term adverse effects of WBRT on neurocognitive function might not be negligible.

Prospective study of stereotactic radiosurgery without whole brain radiotherapy in patients with four or less brain metastases: incidence of intracranial progression and salvage radiotherapy.

This prospective study was conducted to evaluate the treatment outcome after stereotactic radiosurgery (SRS) alone with special attention to its influence on intracranial freedom from progression (FFP), local control, time to whole brain radiotherapy (WBRT), and survival. Forty-one patients with brain metastases who met the inclusion criteria were enrolled in this prospective cohort and treated by SRS alone between January 1998 and September 2001. The overall local control rate was 76%. The one year actuarial intracranial FFP was 33%. Ten patients (24%) had relapse at treated site. Twenty-three patients (56%) had intracranial progression with a median time of 4.25 months (1-24.6). Salvage radiotherapy was given in 21 patients (51%). Only 12 (29%) patients required WBRT with the median time to WBRT after SRS of 4.85 months. Nine patients (22%) underwent additional SRS at the median time of 5 months after the first procedure. The median survival was 10 months. At the time of follow up, 16 patients (39%) were still alive with a range of 6-31 months. This prospective study suggests that the omission of WBRT in the initial treatment of patients with SRS for four or less brain metastases may allow up to 70% of patients to avoid WBRT.

Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases

Purpose: To evaluate the usefulness of whole brain radiotherapy (WBRT) and of the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) for brain metastases among patients receiving stereotactic radiosurgery (SRS). Methods and Materials: A retrospective analysis was performed on 135 patients who underwent linear accelerator (Linac) ( n = 73) or Gamma Knife ( n = 62) SRS for newly diagnosed brain metastases at the Cleveland Clinic Foundation between 8/89 and 12/98. Univariate and multivariate analyses were performed to evaluate the effects of age, primary site, control of the primary, interval to development of brain metastases (disease-free interval [DFI]), number of brain metastases, presence of extracranial metastases, Karnofsky performance status (KPS), treatment of brain metastases, and RPA class on overall survival. Results: Application of the RPA classification revealed 29 patients fit the criteria for class I, 96 for class II, and 10 for class III. All of the patients underwent SRS. Fifty-seven patients also received WBRT at the time of initial presentation (SRS and immediate WBRT), and 78 patients received WBRT only if CNS relapse occurred (SRS alone). The median survival for all patients was 7.9 months (range: 1.1–90.1), and was 11.2 months for RPA class I compared to 6.9 months for RPA classes II–III ( p = 0.016). Median survival was 10.5 months following SRS alone compared to 6.4 months following SRS and WBRT ( p = 0.07). On univariate analysis, KPS ≥ 80% ( p = 0.002) and absence of systemic disease ( p = 0.013) were also associated with longer survival, whereas control of the primary, DFI, and number of brain metastases did not have an impact. Multivariate analysis revealed only RPA class ( p = 0.023) to be an independent predictor for overall survival, whereas treatment group ( p = 0.079) was only marginally significant. At 2 years, immediate WBRT improved control at the original site of metastases (80% vs. 52%, p = 0.03) and prevention of new metastatic sites within the brain, 74% vs. 48% ( p = 0.06). The 2-year intracranial disease-free survival was 60% following SRS and WBRT compared to only 34% following SRS alone ( p = 0.03). Conclusions: Despite the inherent biases to select more favorable patients for SRS, the RPA class retains its prognostic value. Omission of WBRT from the initial management was not detrimental in terms of overall survival; however, progressive disease occurred in over 50% of patients treated in this manner. Further studies are required to determine which, if any, patients should be considered for SRS with WBRT held in reserve.

Radiosurgery for brain metastases: is whole brain radiotherapy necessary?

Purpose: Because whole brain radiotherapy (WBRT) may cause dementia in long-term survivors, selected patients with brain metastases may benefit from initial treatment with radiosurgery (RS) alone reserving WBRT for salvage as needed. We reviewed results of RS ± WBRT in patients with newly diagnosed brain metastasis to provide background for a prospective trial. Methods and Materials: Patients with single or multiple brain metastases managed initially with RS alone vs. RS + WBRT (62 vs. 43 patients) from 1991 through February 1997 were retrospectively reviewed. The use of upfront WBRT depended on physician preference and referral patterns. Survival, freedom from progression (FFP) endpoints, and brain control allowing for successful salvage therapy were measured from the date of diagnosis of brain metastases. Actuarial curves were estimated using the Kaplan-Meier method. Analyses to adjust for known prognostic factors were performed using the Cox proportional hazards model (CPHM) stratified by primary site. Results: Survival and local FFP were the same for RS alone vs. RS + WBRT (median survival 11.3 vs. 11.1 months and 1-year local FFP by patient 71% vs. 79%, respectively). Brain FFP (scoring new metastases and/or local failure) was significantly worse for RS alone vs. RS + WBRT (28% vs. 69% at 1 year; CPHM adjusted p = 0.03 and hazard ratio = 0.476). However, brain control allowing for successful salvage of a first failure was not significantly different for RS alone vs. RS + WBRT (62% vs. 73% at 1 year; CPHM adjusted p = 0.56). Conclusions: The omission of WBRT in the initial management of patients treated with RS for up to 4 brain metastases does not appear to compromise survival or intracranial control allowing for salvage therapy as indicated. A randomized trial of RS vs. RS + WBRT is needed to assess survival, quality of life, and cost in good-prognosis patients with newly diagnosed brain metastases.