Combination Of Whole Brain Radiotherapy Research Articles

Outcome of whole brain irradiation with a dose-escalated simultaneous-integrated boost in patients with multiple large and/or diffuse brain metastases: real live data and review of the literature

BackgroundWe retrospectively investigate feasibility and safety of whole brain radiotherapy (WBRT) including a simultaneous-integrated boost technique (WBRT-SIB) in a cohort of patients with a very poor prognosis suffering from multiple and/or large brain metastases, unfavorable primary histology, poor performance status and/or symptomatic BMs.Materials and MethodsThirty-five patients with high brain tumor burden, extracranial metastases and low life-expectancy were treated with WBRT-SIB mostly with 35-42 Gy/14 fractions. All metastases were boosted in patients with up to 12 BMs. In patients with > 12 BM, large and/or small metastases in critical brain regions were boosted up to a maximum of 12 SIB volumes.ResultsThe median number of BM was 8 (range 2–45) and the median BM diameter was 12 mm (range 4–90 mm). Fifteen (43%) patients had ≥ 10 BMs and 25 patients presented with a Karnofski index ≤ 80%. Primary tumor histology was NSCLC (n = 13), SCLC (n = 11), breast cancer (n = 7), melanoma (n = 2), other (n = 2). The median iPFS was not reached, and 12- and 18-months iPFS were 75% and 50%, respectively. Overall, seven patients had intracranial progression: two patients within the SIB and WBRT area, one patient only within the SIB region and four patients had new BMs in the WBRT volume alone. The median iPFS for non-SCLC patients was 17 months and the 12- and 18-month iPFS were 56.8% and 28.4%, respectively. There was no significant OS difference between SCLC-group and non-SCLC patients (p = 0.38). Overall, median OS was 8.7 months and 1-year OS was 25%. The treatment was generally well-tolerated with no observed cases of radionecrosis.ConclusionOur WBRT-SIB approach involves a combination of whole brain radiotherapy and a simultaneous integrated boost to specific tumor volumes, and its effectiveness is compared with other treatment modalities in the literature. Further research, including prospective studies with larger patient cohorts, is necessary to validate and refine the findings.

Effect of whole-brain radiotherapy with platinum-based chemotherapy in non-small cell lung cancer patients with multiple metastases including brain metastases

Current guidelines recommend that cytotoxic chemotherapy be considered first in non-small cell lung cancer (NSCLC) patients with multiple metastases, and whole-brain radiotherapy (WBRT) is not initially recommended even if brain metastases are present. However, cytotoxic chemotherapeutic agents are less effective in brain metastases due to poor blood–brain barrier permeability. We investigated the effect of WBRT in combination with cytotoxic chemotherapy on survival in NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases. From January 2005 to December 2018, histologically confirmed NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases were included in this study. Patients were classified into two groups based on receiving WBRT prior to or concurrently with administration of first-line chemotherapeutic agents or receiving chemotherapy only. We compared intracranial progression-free survival (iPFS) and overall survival (OS). Of the 240 NSCLC patients with brain metastases at diagnosis and an ECOG PS of 2, 67 patients were EGFR, ALK, and PD-L1 negative with multiple metastases including brain metastases. Among those patients, 43 (64.2%) received WBRT prior to or concurrently with platinum-based chemotherapy. Patients who received WBRT prior to or concurrently with chemotherapy had better iPFS (7.7 months [4.8–10.6] vs. 3.5 months [2.1–4.9], p = 0.009) and OS (10.8 months [5.9–15.7] vs. 6.1 months [1.9–10.3], p = 0.038) than those who did not receive WBRT. In multivariate analyses, WBRT was significantly associated with iPFS (HR: 1.94 and 95% CI 1.11–3.40, p = 0.020) and OS (HR: 1.92 and 95% CI 1.08–3.42, p = 0.027). In NSCLC patients who are EGFR, ALK, and PD-L1 negative, have an ECOG PS of 2, and have multiple metastases including brain metastases, WBRT prior to or concurrently with chemotherapy could improve iPFS and OS. Therefore, the combination of WBRT with cytotoxic chemotherapy should be considered in these patients.

216P Lenalidomide maintenance after whole brain radiotherapy in relapsed/refractory primary CNS lymphoma

Prognosis of patients with relapsed primary CNS lymphoma (PCNSL) not eligible for high dose methotrexate salvage is poor. Systemic therapy with agents like temozolomide, ibrutinib, lenalidomide results in overall response rates of 31 to 67% and median PFS from 1.9 to 7.8 months. Whole brain radiotherapy (WBRT) leads to a high overall response rate of 75 to 80% but a short PFS of 9 to 10 months. A combination of WBRT followed by lenalidomide with the aim of prolonging remission seems an attractive strategy.

Functional role of brain-engrafted macrophages against brain injuries

BackgroundBrain-resident microglia have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacological depletion of microglia during whole-brain radiotherapy prevents synaptic loss and long-term recognition memory deficits. However, the origin or repopulated cells and the mechanisms behind these protective effects are unknown.MethodsCD45low/int/CD11b+ cells from naïve brains, irradiated brains, PLX5622-treated brains and PLX5622 + whole-brain radiotherapy-treated brains were FACS sorted and sequenced for transcriptomic comparisons. Bone marrow chimeras were used to trace the origin and long-term morphology of repopulated cells after PLX5622 and whole-brain radiotherapy. FACS analyses of intrinsic and exotic synaptic compartments were used to measure phagocytic activities of microglia and repopulated cells. In addition, concussive brain injuries were given to PLX5622 and brain-irradiated mice to study the potential protective functions of repopulated cells after PLX5622 + whole-brain radiotherapy.ResultsAfter a combination of whole-brain radiotherapy and microglia depletion, repopulated cells are brain-engrafted macrophages that originate from circulating monocytes. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. In addition, brain-engrafted macrophages display reduced phagocytic activity for synaptic compartments compared to microglia from normal brains in response to a secondary concussive brain injury. Importantly, replacement of microglia by brain-engrafted macrophages spare mice from whole-brain radiotherapy-induced long-term cognitive deficits, and prevent concussive injury-induced memory loss.ConclusionsBrain-engrafted macrophages prevent radiation- and concussion-induced brain injuries and cognitive deficits.

Combination of Whole-Brain Radiotherapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Improves Overall Survival in EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases.

Brain metastases (BM) cause morbidity and mortality in patients with non-small cell lung cancer (NSCLC). The use of upfront epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and withholding of whole-brain radiation therapy (WBRT) is controversial. We aim to investigate the impact of WBRT on overall survival (OS). After screening 1384 patients, a total of 141 EGFR-mutated patients with NSCLC and BM were enrolled. All patients received EGFR-TKIs between 2011 and 2015. Ninety-four patients (66.7%) were treated with WBRT (TKI + WBRT group). With a median follow-up of 20.3 months (95% confidence interval (CI), 16.9–23.7), the median OS after the diagnosis of BM was 14.3 months (95% CI, 9.5 to 18.3) in the TKI + WBRT group and 2.3 months (95% CI, 2 to 2.6) in the TKI alone group. On multivariate analysis, WBRT (p < 0.001), female, surgery to primary lung tumor, and surgery to BM were associated with improved OS. The 1-year OS rate was longer in the TKI+WBRT group than that in the TKI alone group (81.9% vs. 59.6%, p = 0.002). In conclusion, this is the first study to demonstrate the negative survival impact from the omission of WBRT in patients with EGFR-mutant NSCLC.

Pre-operative stereotactic radiosurgery treatment is preferred to post-operative treatment for smaller solitary brain metastases

BackgroundWhile the optimal combination of whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) and surgical resection in the treatment of brain metastases, is controversial, the addition of SRS to surgical resction of solitary metastasis may enhance local control while potentially minimizing toxicity associated with adjuvant WBRT. This study seeks to determine whether pre-operative SRS to the lesion versus post-operative SRS to the resection bed may reduce irradiation of adjacent normal brain tissue.MethodsA retrospective study of 12 patients with 13 surgically resected cerebral metastases was performed. The pre-operative contrast-enhancing tumors and post-operative resection cavities plus any enhancing residual disease were contoured to yield the gross target volume (GTV). In turn these GTV’s were uniformly expanded by 3-mm to generate the pre-operative, as well as post-operative planning target volume (PTV.) For each lesion, a 7-static-conformal-beam, non-coplanar plan utilizing 6 MV photons was generated to encompass the PTV within the 85% isodose line. Excess normal brain volume irradiated was defined as the volume outside the GTV receiving the prescribed dose.ResultsWhen lesions were divided into two groups - Group A (pre-operative GTV’s < 15 cc, n = 9) and Group B (pre-operative GTV’s > 15 cc, n = 4) - the average volume of normal brain irradiated was significantly smaller if pre-operative SRS was used for treatment of lesions in Group A (9.5 vs. 16.8 cc, paired t-test, p = 0.0045). In contrast, this volume was smaller for Group B lesions if post-operative SRS was used for treatment of these lesions (27.6 vs. 51.2 cc, p = 0.252). A comparison of groups with respect to mean volume differences between pre- and post-operative SRS was significantly different (two-sample t-test p = 0.016). GTV and the difference between pre- and post-operative volume were highly correlated (Pearson correlation = −0.875, p < 0.0001).ConclusionsPre-operative treatment of smaller metastases may result in reduced radiation dose to normal tissue and, thus, reduced treatment-related morbidity compared to post-operative irradiation of the resection cavity.

Combined treatment for non-small cell lung cancer and breast cancer patients with brain metastases with whole brain radiotherapy and temozolomide: a systematic review and meta-analysis.

Brain metastasis is the leading cause of death among advanced non-small cell lung cancer (NSCLC) and breast cancer patients. The standard treatment for brain metastases is radiotherapy. The combination of radiotherapy and chemotherapy has been tested. However, the management of brain metastases has yet to be successful. Here, we aimed to determine the efficacy and safety of whole brain radiotherapy (WBRT) alone or in combination with temozolomide (TMZ) in NSCLC and breast cancer patients with brain metastases. A systematic review of PubMed, CNKI (China National Knowledge Infrastructure) and WANFANG (WANGFANG data) involving 870 patients were conducted. Fourteen randomized controlled trials (RCTs) were independently identified by two reviewers. The primary outcome measures were objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity. The ORR was better with combination therapy of WBRT and TMZ than with WBRT alone (RR = 1.34, p < 0.00001) and subgroup analysis showed a significantly superior ORR in NSCLC patients (RR = 1.38, p < 0.00001), but not in breast cancer patients (RR = 1.03, p = 0.86). OS and PFS did not significantly differ between combination therapy and WBRT alone. A higher rate of toxicity was observed in combination therapy than in WBRT alone (RR = 1.83, p = 0.0006). No advantages of concurrent WBRT and TMZ were observed in breast cancer patients with brain metastases. Combination therapy was associated with improved ORR in NSCLC patients, especially in Chinese patients. As a "surrogate endpoint" for OS, ORR may allow a conclusion to be made about the management of NSCLC with brain metastases with the combination of WBRT and TMZ. However, it needs to be validated to show that improved ORR predicts the treatment effects on the clinical benefit. The ORR may be valid for a particular indication such as status of MGMT promoter methylation.

Leptomeningeal Metastases in Patients with NSCLC with EGFR Mutations

IntroductionLeptomeningeal metastases (LM) have increased in patients with NSCLC, and prognostic factors and outcomes for LM with EGFR gene mutations have not been well studied. MethodsWe retrospectively analyzed patients with lung cancer from January 2011 to June 2015 at our institute. Treatments and clinical outcomes of LM were reviewed. ResultsLM were diagnosed in 184 (3.4%) of 5387 patients with lung cancer. Patients with LM harboring EGFR mutations (9.4%) were significantly more frequent than those with wild-type EGFR (1.7% [p < 0.001]). The median overall survival (OS) after LM was 8.7 months (95% confidence interval [CI]: 7.3–10.1). Among the 109 patients with common EGFR mutations, the 88 patients who received tyrosine kinase inhibitor (TKI) therapy demonstrated longer OS than those who did not (10.0 months versus 3.3 months [p < 0.001]), but 42 patients who underwent whole brain radiotherapy (WBRT) did not show longer OS than those without WBRT, and a combination of WBRT and TKIs did not add any survival benefit beyond that in patients receiving only TKIs. A multivariate analysis indicated that TKI therapy (p < 0.001, hazard ratio = 0.218) was an independent predictor of favorable survival, whereas poor Eastern Cooperative Oncology Group performance status (p < 0.001, hazard ratio = 3.657) was a predictor of poor survival. ConclusionsLM were much more frequent in patients with NSCLC harboring EGFR mutations. EGFR TKIs were the optimal treatment for LM, and active treatment with WBRT did not prolong OS for EGFR-mutated patients.

Response Evaluation in Brain Metastasis with Whole Brain Radiotherapy and Temozolomide

Background: Approximately 20%–40% of cancer patients develop brain metastases (BM). Whole-brain radiotherapy (WBRT) is the standard treatment for patients with brain metastases. Although WBRT can reduce neurologic symptoms, the median survival following WBRT is between 3 and 6 months. We have compared the clinical response and overall survival with WBRT alone and WBRT with concomitant Temozolomide (TMZ) in patients of brain metastases in this two arm study. Methods: We have enrolled 40 patients, divided into two arms of 20 patients in each arm. First arm patients received only 30 Gy WBRT while second arm received 30 Gy WBRT with concomitant TMZ (75mg/m2/day).The primary end points were objective response rate (ORR), overall survival rate (OSR) and progression free survival rate (PFSR). Results: In Arm-I, 3 patients had a complete response, 7 patients had a partial response and in Arm-II, 5 patients had a complete response, 9 patients had a partial response. The objective response rate was 50%in Arm-I and in Arm-II it was 70%. Overall survival rate was 60%in Arm-I and 70% in Arm-II. In Arm-I overall survival was 6.2 months while in Arm-II it was 7.4 months. The progression free survival was also better in Arm-II (45% vs. 35%). Deaths were more in the Arm-I (40% vs. 30%). Conclusion: Combination of WBRT and TMZ has better clinical response in patients with brain metastases. It improves ORR, OSR, & PFSR.

Whole Brain Radiotherapy-Based Combined Modality Treatment of Brain Metastases from Non-Small Cell Lung Cancer: A Retrospective Analysis of Prognostic Factors

Background: The prognostic factors for patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy (WBRT)-based combined modality therapy were investigated. Materials and Methods: Out of 135 patients treated with WBRT, 47 (34.8%) received a radiation boost, 84 (62.2%) underwent systemic chemotherapy, and 39 (28.9%) were given epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results: The mean survival time was 9.3 months, and the 1-year and 2-year survival rates were 46.3 and 16.1%, respectively. In univariate analysis, improved survival was associated with age < 60 years, no extracranial metastasis, Karnofsky performance score ≥ 70, ≥ 3 cycles of chemotherapy after diagnosis of brain metastases, combined treatment with EGFR-TKIs, and no metastases in the cerebellum. In multivariate analysis, the above prognostic factors maintained significance with the exception of age. In an additional analysis of the 58 patients with 1-3 brain metastases, combination of WBRT with radiation boost was associated with better survival. Conclusion: We confirm previously described prognostic factors. Moreover, we found the absence of cerebellar metastases to be an independent prognostic factor for favorable outcome.

Brain metastases from testicular germ cell tumors: A retrospective analysis

To review our series of testicular germ cell tumors with brain metastases and to establish an optimal treatment strategy for them. Twenty-seven cases of testicular germ cell tumors from three institutions were retrospectively reviewed. Twenty-six were non-seminomatous tumors and only one was a seminoma. Based on the International Germ Cell Consensus Classification, two cases were classified as good prognosis, seven as intermediate prognosis and 18 as poor prognosis. Chemotherapy was carried out in all patients. Additionally, whole-brain radiotherapy was performed in 10 cases, stereotactic radiosurgery in six, whole-brain radiotherapy combined with stereotactic radiosurgery in three and complete surgical resection in five. Three patients received chemotherapy only. Cancer-specific 5- and 10-year survival rates were both 35.9%. The prognosis of those with brain metastases at the time of diagnosis tended to be better than those developing brain metastases during treatment. Those with a single brain metastasis showed significantly better survival than those with multiple brain metastases. No other significant prognostic factor was found at multivariate analysis. Testicular germ cell tumors with brain metastases can be managed with the combination of whole-brain radiotherapy, stereotactic radiotherapy, and/or surgical resection in combination with chemotherapy.

Current Management of Metastatic Brain Disease

Brain metastases are the most common intracranial tumor in adults. The incidence of metastases is thought to be rising due to better detection and treatment of systemic malignancy. More widespread use and improved quality of MRI may lead to early detection of brain metastases. Available evidence suggests that survival is longer and quality of life improved if brain metastases are treated aggressively. This article reviews current therapeutic management used for brain metastases. To select the appropriate therapy, the physician must consider the extent of the systemic disease, primary histology, and patient age and performance status, as well as the number, size, and location of the brain metastases. Available treatment options include whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), surgery, and chemotherapy. Multidisciplinary approaches such as the combination of WBRT with SRS or surgery have shown superior results in terms of survival time, neurocognitive function, and quality of life. The utility and optimal use of chemotherapy and radiosensitizing agents is less clear. It is hoped that further advances and multidisciplinary approaches currently under study will result in improved patient outcomes.

P2-187: Treatment for non small cell lung cancer presenting with synchronous brain metastases

Solitary brain metastases occur in about 50% of patients with brain metastases from non small cell lung cancer. The standard therapy is surgical resection or stereotactic radiosurgery plus whole brain radiotherapy. The optimal treatment for the primary site of newly diagnosed non small cell lung cancer with solitary brain metastases is not well defined. to evaluate the outcome of treatment for patients with newly diagnosis advanced non small cell lung cancer with isolated single synchronous brain metastases. A total of 22 patients with non small cell lung cancer and solitary brain metastases were included. All patients had extensive tumour non small cell lung cancer with involved mediastinal lymph nodes. 4 patients received treatment of their primary lung cancer using radiotherapy, 6 patients treated with chemotherapy and 12 patients treated with both chemotherapy and radiotherapy. The treatment of brain metastases was as follows: 14 patients underwent surgery resection and postoperative whole brain radiotherapy, 4 had surgical resection alone and 4 treated with radiotherapy alone. Survival was measured from the date of the first treatment for malignancy. Overall survival from time of lung cancer diagnoses were 1 year survival rate 36, 3%, 2-year 9%. The better overall survival was achieved in patients treated with chemo and radiotherapy. A total of 6 (27, 2%) patients had failure in brain, including 3 patients who receiving whole brain irradiation alone. Aggressive therapy for both, primary site of non small cell lung cancer and the brain metastases may provide a survival advantages. Better local control of single brain metastases was achieved with a combination of whole brain radiotherapy with surgical resection.

Treatment outcome for patients with primary nonsmall-cell lung cancer and synchronous brain metastasis.

The purpose of this study was to evaluate the outcome of treatment for patients with newly diagnosed nonsmall-cell lung cancer (NSCLC) with an isolated, single, synchronous brain metastasis. A retrospective review was performed evaluating any patient diagnosed between 1982 and 1996 at the Cleveland Clinic Foundation with NSCLC metastatic only to the brain. Patients with multiple brain metastases or with systemic metastases to any other organ were excluded. Survival was measured from the date of the first treatment for malignancy. All hospital records were thoroughly reviewed in a retrospective manner. Thirty-three patients were identified who met the study criteria. Twelve patients had primary disease limited to the lung and hilar nodes, and 21 had more advanced primary disease with involvement of the mediastinum. Treatment of the chest was considered aggressive in 13 patients and palliative in 15. The primary tumor was observed in 5 patients. The management of the brain metastasis was as follows: 21 patients underwent surgical resection and postoperative whole brain radiotherapy (WBRT), 5 underwent stereotactic radiosurgery (SRS) and WBRT, 3 had resection alone, 2 had SRS alone, and 2 underwent WBRT alone. The median overall and disease-free survival for all patients was 6.9 months and 3.3 months, respectively. Overall survival was markedly improved with the addition of WBRT (P = 0.002) and with the aggressive management of the primary tumor (P = 0.005). A total of 9 patients experienced CNS failure, including both patients receiving WBRT alone. CNS failures were divided as follows: 3 local, 5 distant, and 1 local and distant. Two of the 4 patients with a local failure were salvaged, and ultimate local control of the original brain metastasis was achieved in 93.6% of cases. Survival remains poor for patients with Stage IV NSCLC even when metastatic disease is limited to a single site within the brain; however, aggressive therapy of both the lung primary and the brain metastasis may provide a survival advantage. Excellent local control of single brain metastases was achieved with a combination of WBRT with either surgical resection or SRS.

Treatment outcome for patients with primary nonsmall‐cell lung cancer and synchronous brain metastasis

The purpose of this study was to evaluate the outcome of treatment for patients with newly diagnosed nonsmall-cell lung cancer (NSCLC) with an isolated, single, synchronous brain metastasis. A retrospective review was performed evaluating any patient diagnosed between 1982 and 1996 at the Cleveland Clinic Foundation with NSCLC metastatic only to the brain. Patients with multiple brain metastases or with systemic metastases to any other organ were excluded. Survival was measured from the date of the first treatment for malignancy. All hospital records were thoroughly reviewed in a retrospective manner. Thirty-three patients were identified who met the study criteria. Twelve patients had primary disease limited to the lung and hilar nodes, and 21 had more advanced primary disease with involvement of the mediastinum. Treatment of the chest was considered aggressive in 13 patients and palliative in 15. The primary tumor was observed in 5 patients. The management of the brain metastasis was as follows: 21 patients underwent surgical resection and postoperative whole brain radiotherapy (WBRT), 5 underwent stereotactic radiosurgery (SRS) and WBRT, 3 had resection alone, 2 had SRS alone, and 2 underwent WBRT alone. The median overall and disease-free survival for all patients was 6.9 months and 3.3 months, respectively. Overall survival was markedly improved with the addition of WBRT (P = 0.002) and with the aggressive management of the primary tumor (P = 0.005). A total of 9 patients experienced CNS failure, including both patients receiving WBRT alone. CNS failures were divided as follows: 3 local, 5 distant, and 1 local and distant. Two of the 4 patients with a local failure were salvaged, and ultimate local control of the original brain metastasis was achieved in 93.6% of cases. Survival remains poor for patients with Stage IV NSCLC even when metastatic disease is limited to a single site within the brain; however, aggressive therapy of both the lung primary and the brain metastasis may provide a survival advantage. Excellent local control of single brain metastases was achieved with a combination of WBRT with either surgical resection or SRS. Radiat. Oncol. Invest. 7:313–319, 1999. © 1999 Wiley-Liss, Inc.