Single vs. multiple fraction non-inferiority trial of stereotactic ablative radiotherapy for the comprehensive treatment of oligo-metastases/progression: SIMPLIFY-SABR-COMET.

BACKGROUND: Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience. METHODS: This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival. DISCUSSION: This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Upfront Versus Delayed Systemic Therapy in Patients With Oligometastatic Cancer Treated With SABR in the Phase 2 SABR-5 Trial.

PURPOSE: The optimal sequencing of local and systemic therapy for oligometastatic cancer has not been established. This study retrospectively compared progression-free survival (PFS), overall survival (OS), and SABR-related toxicity between upfront versus delay of systemic treatment until progression in patients in the SABR-5 trial. METHODS AND MATERIALS: The single-arm phase 2 SABR-5 trial accrued patients with up to 5 oligometastases across SABR-5 between November 2016 and July 2020. Patients received SABR to all lesions. Two cohorts were retrospectively identified: those receiving upfront systemic treatment along with SABR and those for whom systemic treatment was delayed until disease progression. Patients treated for oligoprogression were excluded. Propensity score analysis with overlap weighting balanced baseline characteristics of cohorts. Bootstrap sampling and Cox regression models estimated the association of delayed systemic treatment with PFS, OS, and grade ≥2 toxicity. RESULTS: A total of 319 patients with oligometastases underwent treatment on SABR-5, including 121 (38%) and 198 (62%) who received upfront and delayed systemic treatment, respectively. In the weighted sample, prostate cancer was the most common primary tumor histology (48%) followed by colorectal (18%), breast (13%), and lung (4%). Most patients (93%) were treated for 1 to 2 metastases. The median follow-up time was 34 months (IQR, 24-45). Delayed systemic treatment was associated with shorter PFS (hazard ratio [HR], 1.56; 95% CI, 1.15-2.13; P = .005) but similar OS (HR, 0.90; 95% CI, 0.51-1.59; P = .65) compared with upfront systemic treatment. Risk of grade 2 or higher SABR-related toxicity was reduced with delayed systemic treatment (odds ratio, 0.35; 95% CI, 0.15-0.70; P < .001). CONCLUSIONS: Delayed systemic treatment is associated with shorter PFS without reduction in OS and with reduced SABR-related toxicity and may be a favorable option for select patients seeking to avoid initial systemic treatment. Efforts should continue to accrue patients to histology-specific trials examining a delayed systemic treatment approach.

Solitary Plasmacytoma of the Jugular Foramen: A Case Report and Review of the Differential Diagnosis.

Jugular foramen tumours are uncommon, deeply located, and eloquently situated, making their diagnosis and management challenging. Paragangliomas and other benign tumours comprise the large majority of lesions in this region, but malignant tumours are occasionally identified. We report a unique case of a solitary plasmacytoma of the jugular foramen resembling a jugulotympanic paraganglioma. A solitary plasmacytoma of the jugular foramen is both rare in location and in disease presentation, as most plasma cell neoplasms are diagnosed as multiple myeloma. Our 75-year-old patient presented with symptoms typical for a jugular foramen tumour. Although there are radiographic features which help differentiate paragangliomas from other benign and malignant tumours, plasmacytomas are highly vascular and can demonstrate a local infiltrative spread which can mimic the radiographic appearance of a paraganglioma. Clinicians should consider plasma cell neoplasms in the differential when faced with an unusual presentation of a jugular foramen lesion. Our patient was treated with definitive radiotherapy to 45 Gy, which was very effective local treatment for the solitary plasmacytoma.

Should organs at risk (OARs) be prioritized over target volume coverage in stereotactic ablative radiotherapy (SABR) for oligometastases? a secondary analysis of the population-based phase II SABR-5 trial.

BACKGROUND AND PURPOSE: Stereotactic ablative radiotherapy (SABR) for oligometastases may improve survival, however concerns about safety remain. To mitigate risk of toxicity, target coverage was sacrificed to prioritize organs-at-risk (OARs) during SABR planning in the population-based SABR-5 trial. This study evaluated the effect of this practice on dosimetry, local recurrence (LR), and progression-free survival (PFS). METHODS: This single-arm phase II trial included patients with up to 5 oligometastases between November 2016 and July 2020. Theprotocol-specified planning objective was to cover 95 % of the planning target volume (PTV) with 100 % of the prescribed dose, however PTV coverage was reduced as needed to meet OAR constraints. This trade-off was measured using the coverage compromise index (CCI), computed as minimum dose received by the hottest 99 % of the PTV (D99) divided by the prescription dose. Under-coverage was defined as CCI < 0.90. The potential association between CCI and outcomes was evaluated. RESULTS: 549 lesions from 381 patients were assessed. Mean CCI was 0.88 (95 % confidence interval [CI], 0.86-0.89), and 196 (36 %) lesions were under-covered. The highest mean CCI (0.95; 95 %CI, 0.93-0.97) was in non-spine bone lesions (n = 116), while the lowest mean CCI (0.71; 95 % CI, 0.69-0.73) was in spine lesions (n = 104). On multivariable analysis, under-coverage did not predict for worse LR (HR 0.48, p = 0.37) or PFS (HR 1.24, p = 0.38). Largest lesion diameter, colorectal and 'other' (non-prostate, breast, or lung) primary predicted for worse LR. Largest lesion diameter, synchronous tumor treatment, short disease free interval, state of oligoprogression, initiation or change in systemic treatment, and a high PTV Dmax were significantly associated with PFS. CONCLUSION: PTV under-coverage was not associated with worse LR or PFS in this large, population-based phase II trial. Combined with low toxicity rates, this study supports the practice of prioritizing OAR constraints during oligometastatic SABR planning.

Treatment With Stereotactic Ablative Radiotherapy for Up to 5 Oligometastases in Patients With Cancer: Primary Toxic Effect Results of the Nonrandomized Phase 2 SABR-5 Clinical Trial.

Importance: After the publication of the landmark SABR-COMET trial, concerns arose regarding high-grade toxic effects of treatment with stereotactic ablative body radiotherapy (SABR) for oligometastases. Objective: To document toxic effects of treatment with SABR in a large cohort from a population-based, provincial cancer program. Design, Setting, and Participants: From November 2016 to July 2020, 381 patients across all 6 cancer centers in British Columbia were treated in this single-arm, phase 2 trial of treatment with SABR for patients with oligometastatic or oligoprogressive disease. During this period, patients were only eligible to receive treatment with SABR in these settings in trials within British Columbia; therefore, this analysis is population based, with resultant minimal selection bias compared with previously published SABR series. Interventions: Stereotactic ablative body radiotherapy to up to 5 metastases. Main Outcomes and Measures: Rate of grade 2, 3, 4, and 5 toxic effects associated with SABR. Findings: Among 381 participants (122 women [32%]), the mean (SD; range) age was 68 (11.1; 30-97) years, and the median (range) follow-up was 25 (1-54) months. The most common histological findings were prostate cancer (123 [32%]), colorectal cancer (63 [17%]), breast cancer (42 [11%]), and lung cancer (33 [9%]). The number of SABR-treated sites were 1 (263 [69%]), 2 (82 [22%]), and 3 or more (36 [10%]). The most common sites of SABR were lung (188 [34%]), nonspine bone (136 [25%]), spine (85 [16%]), lymph nodes (78 [14%]), liver (29 [5%]), and adrenal (15 [3%]). Rates of grade 2, 3, 4, and 5 toxic effects associated with SABR (based on the highest-grade toxic effect per patient) were 14.2%; (95% CI, 10.7%-17.7%), 4.2% (95% CI, 2.2%-6.2%), 0%, and 0.3% (95% CI, 0%-0.8%), respectively. The cumulative incidence of grade 2 or higher toxic effects associated with SABR at year 2 by Kaplan-Meier analysis was 8%, and for grade 3 or higher, 4%. Conclusions and Relevance: This single-arm, phase 2 clinical trial found that the incidence of grade 3 or higher SABR toxic effects in this population-based study was less than 5%. Furthermore, the rates of grade 2 or higher toxic effects (18.6%) were lower than previously published for SABR-COMET (29%). These results suggest that SABR treatment for oligometastases has acceptable rates of toxic effects and potentially support further enrollment in randomized phase 3 clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02933242.

Association Between EGFR and ALK Mutation Status on Patient-Reported Symptoms After Palliative Radiation for Bone Pain in NSCLC.

Introduction: After palliative radiotherapy for bone metastases from NSCLC, up to 30% of patients may derive no symptomatic benefit, and there are a lack of biological predictors for this. The purpose was to investigate whether EGFR and ALK genetic rearrangements were associated with greater rates of pain response to palliative radiotherapy. Methods: Patients were identified from a prospectively collected patient-reported outcomes database for all patients with lung cancer treated with conventional palliative radiotherapy for bone metastases from 2013 to 2016 in the province of British Columbia. Patients were divided on the basis of mutational status into the following: EGFR and ALK wild type (WT), EGFR mutation present (EGFR+), or ALK mutation present (ALK+). Patient-reported outcomes of global pain severity were collected before and after radiotherapy and on an ordinal scale of 0 to 4, with 0 representing no bone pain and 4 representing the maximal possible bone pain. The primary outcome was the rate of partial pain response (any improvement in score), and the secondary outcome was the rate of complete pain response (final pain score of 0). Stepwise, multivariable logistic analysis was used to compare response rates between treatment courses for different mutational statuses. Results: The final cohort consisted of 388 treatment courses for 329 unique patients. For the WT, EGFR+, and ALK+ groups, there were 180, 63, and nine treatment courses, respectively. There were 92 patients with no ALK and EGFR testing. The most common treatment fractionations were 8 Gy in one fraction (188 of 388) and 20 Gy in five fractions (160 of 388), and use of multifraction radiotherapy did not differ between mutation status groups (p = 0.3). Partial pain response rates were as follows: WT 63%, EGFR+ 75%, and ALK+ 78%. On multivariable analysis, rates of partial response were higher for EGFR+ (OR = 5.4, p < 0.001) and for ALK+ (OR = 12.8, p = 0.008) in comparison to WT. Complete response rates were as follows: WT 20.5%, EGFR+ 35%, and ALK+ 67%. On multivariable analysis, complete response was not significantly increased in EGFR+ compared with WT (OR = 1.6, p = 0.127). ALK+ mutation status was associated with a higher rate of complete response compared with WT (OR = 5.2, p = 0.031). Conclusions: There was an association between EGFR+ and ALK+ tumors and increased rates of partial pain response to palliative radiotherapy.

Lung cancer epidermal growth factor receptor mutations and radiotherapy response: A multicentre clinical study.

PURPOSE: To examine the impact of epidermal growth factor receptor (EGFR) mutations on objective response to palliative lung radiotherapy in patients with metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A multicentre retrospective study was conducted of patients with metastatic NSCLC diagnosed between March 2010 and June 2012 who received palliative radiotherapy to the chest. Patients included for study had baseline imaging and follow-up imaging 1-3 months after radiotherapy. The primary endpoint was 1-3 month local objective imaging response by the Response Evaluation Criteria in Solid Tumours (RECIST). Patients were divided into EGFR mutation positive (EGFR+) and EGFR wild type (WT) cohorts for analysis. RESULTS: There were 121 patients for study inclusion: 89 (74%) were EGFR WT and 32 (26%) were EGFR+. The response rate between EGFR WT and EGFR+ cohorts was not significantly different (49 vs. 63%, p = 0.21). On multivariate analysis, initiation of a tyrosine kinase inhibitor (TKI) after radiotherapy was associated with a higher rate of response (OR: 5.07, 95%CI: 1.08-23.69, p = 0.039) but EGFR mutation status was not. For the EGFR+ cohort, patients with disease progression after initial management on a TKI had a worse response rate compared to patients who were TKI-naïve before starting radiotherapy (30 vs. 77%, p = 0.018). Local control was not statistically different between the EGFR cohorts. CONCLUSION: The EGFR mutation status alone was not an independent predictor of objective radiographic response to palliative thoracic radiotherapy. Acquired resistance to TKI therapy may be associated with disease cross-resistance to palliative radiotherapy.

Type and timing of systemic therapy use predict overall survival for patients with brain metastases treated with radiation therapy.

INTRODUCTION: This study aimed to investigate whether systemic therapy (ST) use surrounding radiation therapy (RT) predicts overall survival (OS) after RT for patients with brain metastases (BMs). METHODS: Provincial RT and pharmacy databases were used to review all adult patients in British Columbia, Canada, who received a first course of RT for BMs between 2012 and 2016 (n = 3095). Multivariate analysis on a randomly selected subset was used to develop an OS nomogram. RESULTS: In comparison to the 2096 non-recipients of ST after RT, the median OS of the 999 recipients of ST after RT was 5.0 (95% Confidence interval (CI) 4.1-6.0) months longer (p < 0.0001). Some types of ST after RT were independently predictive of OS: targeted therapy (hazard ratio (HR) 0.42, CI 0.37-0.48), hormone therapy (HR 0.45, CI 0.36-0.55), cytotoxic chemotherapy (HR 0.71, CI 0.64-0.79), and immunotherapy (HR 0.64, CI 0.37-1.06). Patients who discontinued ST after RT had 0.9 (CI 0.3-1.4) months shorter median OS than patients who received no ST before or after RT (p < 0.0001). In the multivariate analysis of the 220-patient subset, established prognostic variables (extracranial disease, performance status, age, cancer diagnosis, and number of BMs), and the novel variables "ST before RT" and "Type of ST after RT" independently predicted OS. The nomogram predicted 6- and 12-month OS probability and median OS (bootstrap-corrected Harrell's Concordance Index = 0.70). CONCLUSIONS: The type and timing of ST use surrounding RT predict OS for patients with BMs.

SUPR-3D: A randomized phase iii trial comparing simple unplanned palliative radiotherapy versus 3d conformal radiotherapy for patients with bone metastases: study protocol.

BACKGROUND: Bone metastases in the lower spine and pelvis are effectively palliated with radiotherapy (RT), though this can come with side effects such as radiation induced nausea and vomiting (RINV). We hypothesize that high rates of RINV occur in part because of the widespread use of inexpensive simple unplanned palliative radiotherapy (SUPR), over more complex and resource intensive 3D conformal RT, such as volumetric modulated arc therapy (VMAT). METHODS: This is a randomized, multi-centre phase III trial of SUPR versus VMAT. We will accrue 250 patients to assess the difference in patient-reported RINV. This study is powered to detect a difference in quality of life between patients treated with VMAT vs. SUPR. DISCUSSION: This trial will determine if VMAT reduces early toxicity compared to SUPR and may provide justification for this more resource-intensive and costly form of RT. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03694015 . Date of registration: October 3, 2018.

Population-based phase II trial of stereotactic ablative radiotherapy (SABR) for up to 5 oligometastases: SABR-5.

BACKGROUND: Oligometastases refer to a state of disease where cancer has spread beyond the primary site, but is not yet widely metastatic, often defined as 1-3 or 1-5 metastases in number. Stereotactic ablative radiotherapy (SABR) is an emerging radiotherapy technique to treat oligometastases that require further prospective population-based toxicity estimates. METHODS: This is a non-randomized phase II trial where all participants will receive experimental SABR treatment to all sites of newly diagnosed or progressing oligometastatic disease. We will accrue 200 patients to assess toxicity associated with this experimental treatment. The study was powered to give a 95% confidence on the risk of late grade 4 toxicity, anticipating a < 5% rate of grade 4 toxicity. DISCUSSION: SABR treatment of oligometastases is occurring off-trial at a high rate, without sufficient evidence of its efficacy or toxicity. This trial will provide necessary toxicity data in a population-based cohort, using standardized doses and organ at risk constraints, while we await data on efficacy from randomized phase III trials. TRIAL REGISTRATION: Registered through clinicaltrials.gov NCT02933242 on October 14, 2016 prospectively before patient accrual.

Adenocarcinoma of the Lung with Miliary Metastases and Primary Resistance Exon 20 Mutations.

Epidermal growth factor receptor (EGFR) exon 20 mutations are seldom tested for in part because they are less common than other EGFR driver mutations and are not associated with sensitivity to EGFR tyrosine kinase inhibitors. We report two cases of lung adenocarcinoma with EGFR exon 20 mutations and a presentation of diffuse, tiny, innumerable lung and brain nodules resembling miliary metastases. Clinicians should be aware of this pattern of presentation in patients with primary resistance EGFR exon 20 mutations.

Visual Outcomes and Local Control After Fractionated Stereotactic Radiotherapy for Optic Nerve Sheath Meningioma.

PURPOSE: To review the outcomes of patients with optic nerve sheath meningiomas (ONSM) treated with fractionated stereotactic radiotherapy. METHODS: Patient characteristics, treatment, and outcomes were analyzed for all patients with primary and secondary ONSM treated from 2001 to 2012. Clinically significant visual acuity change was defined as a 2-line change on the Snellen eye chart from pre-fractionated stereotactic radiotherapy. RESULTS: Forty-one patients were treated: 23 patients with primary ONSM and 18 patients with secondary ONSM. The median age at diagnosis was 56 years. The median visual follow up was 3.8 years and the median radiologic follow up was 4.4 years. At diagnosis, 36% had normal vision (20/20-20/40), 10% had mild impairment (<20/40-20/60), 20% had moderate visual impairment (<20/60-20/200), 27% had severe impairment (<20/200), and 7% had no light perception. Common acute side effects were headache (32%) and nausea (15%); 15% of patients required corticosteroids during stereotactic radiotherapy. Chronic toxicities included retinopathy (7%), pituitary dysfunction (13%), chronic ocular pain (5%), and cataracts (2%). Visual acuity was stable in 65%, improved in 27%, and decreased in 8% of patients. Visual fields were stable in 70%, improved in 21%, and reduced in 9%. Actuarial 5-year local control rates were 100% for primary ONSM and 88% for secondary ONSM. Actuarial 5-year visual preservation rates were 100% for primary ONSM and 86% for secondary ONSM. CONCLUSIONS: Fractionated stereotactic radiotherapy for primary and secondary ONSM was well tolerated and provides excellent local control and visual preservation. Longer follow up is required to determine the risk of late ocular and pituitary sequelae.

Population-Based Study of Stereotactic Radiosurgery or Fractionated Stereotactic Radiation Therapy for Vestibular Schwannoma: Long-Term Outcomes and Toxicities.

PURPOSE: To examine long-term local control of vestibular schwannoma and side effects in patients treated with stereotactic radiosurgery (SRS) and fractionated stereotactic radiation therapy (SRT) in British Columbia. METHODS AND MATERIALS: From August 1998 to May 2009, 207 patients were treated with radiation therapy (RT) at British Columbia Cancer Agency. 136 (66%) received SRS, and 71 (34%) received SRT. Dose prescriptions were 50 Gy/25 fractions for SRT and 12 Gy/1 fraction for SRS. Our multidisciplinary provincial neuro-stereotactic conference recommended SRT for tumors >3 cm and for patients with serviceable hearing (Gardner-Robertson classes I and II). RESULTS: Median follow-up was 7.7 years to the last MRI and 6.4 years to the last clinical assessment. Local control for SRS versus SRT was 94% versus 87% at 5 years and 90% versus 85% at 10 years (P=.2). Five- and 10-year actuarial rates of RT-induced trigeminal nerve dysfunction were 25% and 25% after SRS, compared with 7% and 12% after SRT (P=.01). Five- and 10-year actuarial rates of RT-induced facial nerve dysfunction were 15% and 15% after SRS, versus 13% and 15% after SRT (P=.93). In the 49 patients with serviceable hearing at baseline who were treated with SRT, hearing preservation was 55% at 3 years, 37% at 5 years, and 29% at 7 years. In multivariable analysis, better pretreatment ipsilateral pure tone average was significantly associated with hearing preservation (hazard ratio 1.03; 95% confidence interval 1.00-1.07; P=.04). CONCLUSIONS: Both SRS and SRT provided excellent long-term local control of vestibular schwannoma. Stereotactic radiosurgery was associated with higher rates of trigeminal nerve dysfunction. Even with a fractionated course, hearing preservation declined steadily with long-term audiometric follow-up.

The incidence of symptomatic brain metastases from extra-pulmonary small cell carcinoma: Is there a role for prophylactic cranial irradiation in a clinically relevant population cohort?

BACKGROUND AND PURPOSE: To examine the incidence and outcomes of patients with brain metastases from extra-pulmonary small cell carcinoma (EPSCC) and assess the indication for prophylactic cranial irradiation (PCI). MATERIALS AND METHODS: A Provincial cancer registry was used to conduct a retrospective, population-based study of patients diagnosed with EPSCC between January 1997 and December 2011. The primary end point was the incidence of brain metastases. The secondary endpoint was overall survival. A "PCI Eligible" cohort was defined to provide an estimation of the incidence of brain metastases in clinically relevant patients. RESULTS: In 287 patients, the primary sites were 21% gastrointestinal, 34% genito-urinary, 14% gynecologic, 5% head/neck and 25% unknown primary. Thirty-five (12.5%) patients had brain metastases: 12 (4.2%) at initial diagnosis and 23 (8%) later in the disease course. In PCI Eligible patients, the 3-year cumulative incidence of new brain metastases was 5.5% for M0 stage disease and 26.3% for M1 disease. There was no significant difference in the incidence of brain metastases between primary sites. CONCLUSIONS: The incidence of brain metastases in patients with EPSCC is comparatively low, even in a cohort of patients that were suitable for PCI. Based on our analysis, we cannot recommend PCI for patients with EPSCC.

Miliary metastases are associated with epidermal growth factor receptor mutations in non-small cell lung cancer: a population-based study.

BACKGROUND: Miliary metastases are characterized by metastatic nodules that are diffuse, innumerable and small. The purpose of this study was to examine the incidence, prognostic significance and impact of epidermal growth factor receptor (EGFR) mutations for miliary metastases from non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Patients were identified from a Provincial cancer registry (British Columbia, Canada) for the period 2010-2012. Inclusion criteria were stage IV NSCLC at presentation and conclusive EGFR mutation testing. Miliary metastases were defined by subjective and objective radiographic criteria. The primary endpoint was the incidence of miliary lung, brain and liver metastases. Secondary endpoints were survival and the prognostic implication for each site of miliary metastases. RESULTS: For 543 patients, the total number of brain, lung and liver metastases were 165 (30.4%), 290 (53.4%) and 67 (12.3%), respectively. The EGFR mutation positive (EGFR+) subgroup had a significantly higher 3-year cumulative incidence of miliary brain (4.1 vs. 0.5%, p = .015) and miliary lung (11.6 vs. 3.3%, p < .001) metastases compared to EGFR wild type (WT). A greater proportion of metastases from EGFR + cancers were miliary for brain (8.5 vs. 1.7%, p = .035) and lung (18.9 vs. 6.9%, p = .003) sites. Only non-miliary brain (HR = 1.45) and liver (HR = 1.70) metastases predicted for poor overall survival. CONCLUSIONS: Mutations in EGFR were associated with a higher rate of miliary brain and lung metastases. The presence of miliary metastases did not predict for poor overall survival.

Salvage Stereotactic Radiosurgery for Multiple Brain Recurrences: How Much is Enough?

Stereotactic radiosurgery (SRS) can be used as a salvage treatment in selected patients with recurrent brain metastases after previous brain radiation. We report the case of a patient with metastatic lung adenocarcinoma who experienced recurrence numerous times in the brain and was successfully treated each time with SRS. For this patient, brain imaging surveillance helped identify metastases early for salvage SRS. We have also included a discussion of published literature regarding the neurocognitive toxicity of repeated courses of SRS.

EGFR mutation status on brain metastases from non-small cell lung cancer.

OBJECTIVES: The purpose of this study was to examine the impact of EGFR mutations on the incidence of brain metastases in patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A retrospective, population-based study was conducted using a provincial cancer registry to identify patients with metastatic NSCLC. Patients with diagnostic EGFR mutation testing were divided into EGFR mutation positive (EGFR+) and EGFR wild type (WT) cohorts. The primary endpoint was the incidence of brain metastases. Cumulative incidence curves were estimated using the competing risk method. The secondary endpoint was overall survival. RESULTS: For 543 patients there were 121 EGFR+ and 422 EGFR WT. The cumulative incidence of brain metastases was 39.2% for EGFR+ patients compared to 28.2% for EGFR WT (p=0.038; HR 1.4). In multivariate analysis, younger age and EGFR+ status were significant factors for developing brain metastases. The median survival for the EGFR+ and EGFR WT cohorts were 22.4 and 7.9 months (p<0.001), respectively. In multivariate analysis, poor performance status and brain metastases were factors significant for worse survival. CONCLUSIONS: There is a higher incidence of brain metastases for patients with EGFR+ metastatic NSCLC, even when adjusted for differences in survival, compared to EGFR WT. For patients with and without brain metastases, survival prognosis with stage IV NSCLC is much longer with EGFR+ disease.

Volumetric Radiosurgery for 1 to 10 Brain Metastases: A Multicenter, Single-Arm, Phase 2 Study.

PURPOSE: Interest is growing in treating multiple brain metastases with radiosurgery. We report on the effectiveness and tolerability of volumetric radiosurgery (VRS). METHODS AND MATERIALS: We enrolled patients with a ≥6-month estimated life expectancy and 1 to 10 brain metastases with a diameter of ≤3 cm at 5 cancer centers. Volumetric radiosurgery was delivered in 5 fractions with 98% target coverage, prescribed as 95% of 50 Gy (47.5 Gy in 5 fractions) to the metastases with no margin and 95% of 40 Gy (38 Gy in 5 fractions) to their 2-mm planning target volumes, concurrent with 20 Gy to the whole brain planning target volume. The treatment was delivered with daily image guidance using conventional linear accelerators and volumetric modulated arc therapy. A magnetic resonance imaging scan was obtained every 3 months. The primary endpoint was the 3-month objective response in the brain according to the Response Evaluation Criteria in Solid Tumors, version 1.1. The principal secondary endpoint was 1-year actuarial control of treated metastases. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. The present study is registered with ClinicalTrials.gov (clinicaltrials.gov identifier NCT01046123). RESULTS: From July 2010 to May 2013, 60 patients underwent VRS with 47.5 Gy in 5 fractions for 12 metastases in the thalamus and basal ganglia (deep metastases) and 207 non-deep metastases. The median follow-up period was 30.5 months, and the median survival was 10.1 months. For the 43 patients assessable at 3 months, the objective response in the brain was 56%. The treated metastases were controlled in 88% of patients at 1 year and 84% at 3 years. Overall survival did not differ for patients with 4 to 10 versus 1 to 3 metastases (hazard ratio 1.18, P=.6). The crude incidence of severe radionecrosis (grade 3-5) was 25% (3 of 12) per deep metastasis, 1.9% (4 of 219) per non-deep metastasis, and 10% (6 of 60) per patient. CONCLUSIONS: For non-deep brain metastases, 47.5 Gy in 5 fractions was tolerable. Volumetric radiosurgery was effective for long-term control of treated brain metastases.

Stereotactic Radiosurgery for Metastases in Eloquent Central Brain Locations.

BACKGROUND: To examine stereotactic radiosurgery (SRS) following whole brain radiotherapy for metastases in eloquent, central brain locations: brainstem, thalamus, and basal ganglia. METHODS: We conducted a retrospective review of patients with metastases in eloquent, central brain locations who were treated with SRS between January 2000 and April 2012. All patients had whole brain radiotherapy. Patients eligible for SRS had one to three brain metastases, metastasis size ≤4 cm, and Karnofsky performance status ≥70. Local progression-free survival and overall survival were calculated using the Kaplan-Meier method. RESULTS: For 24 patients, the median age was 50 years (range, 36-73). Metastases by location were: 11 brainstem, 9 thalamus, and 5 basal ganglia. The median metastasis size was 15 mm (range, 2-33) and the median SRS dose prescription was 15 Gy (range, 12-24). The median local progression-free survival was 13.7 months and median overall survival was 16.4 months. Compared with a cohort of 188 patients with noneloquent brain metastases receiving a median dose of 24 Gy, overall survival of 10.8 months was not significantly different (p=0.16). The only symptomatic complication was grade 2 headache in 8.3%. Asymptomatic adverse radiologic events were radionecrosis in two (8.3%), peritumoural edema in four (16.7%), and hemorrhage in one patient (4.2%). CONCLUSIONS: Lower SRS marginal doses do not appear to compromise survival in patients with eloquently located brain metastases compared with higher doses for other brain metastases, with minimal symptomatic complications.

High-grade glioma radiation therapy target volumes and patterns of failure obtained from magnetic resonance imaging and 18F-FDOPA positron emission tomography delineations from multiple observers.

PURPOSE: The objective of this study was to compare recurrent tumor locations after radiation therapy with pretreatment delineations of high-grade gliomas from magnetic resonance imaging (MRI) and 3,4-dihydroxy-6-[(18)F]fluoro-L-phenylalanine ((18)F-FDOPA) positron emission tomography (PET) using contours delineated by multiple observers. METHODS AND MATERIALS: Nineteen patients with newly diagnosed high-grade gliomas underwent computed tomography (CT), gadolinium contrast-enhanced MRI, and (18)F-FDOPA PET/CT. The image sets (CT, MRI, and PET/CT) were registered, and 5 observers contoured gross tumor volumes (GTVs) using MRI and PET. Consensus contours were obtained by simultaneous truth and performance level estimation (STAPLE). Interobserver variability was quantified by the percentage of volume overlap. Recurrent tumor locations after radiation therapy were contoured by each observer using CT or MRI. Consensus recurrence contours were obtained with STAPLE. RESULTS: The mean interobserver volume overlap for PET GTVs (42% ± 22%) and MRI GTVs (41% ± 22%) was not significantly different (P=.67). The mean consensus volume was significantly larger for PET GTVs (58.6 ± 52.4 cm(3)) than for MRI GTVs (30.8 ± 26.0 cm(3), P=.003). More than 95% of the consensus recurrence volume was within the 95% isodose surface for 11 of 12 (92%) cases with recurrent tumor imaging. Ten (91%) of these cases extended beyond the PET GTV, and 9 (82%) were contained within a 2-cm margin on the MRI GTV. One recurrence (8%) was located outside the 95% isodose surface. CONCLUSIONS: High-grade glioma contours obtained with (18)F-FDOPA PET had similar interobserver agreement to volumes obtained with MRI. Although PET-based consensus target volumes were larger than MRI-based volumes, treatment planning using PET-based volumes may not have yielded better treatment outcomes, given that all but 1 recurrence extended beyond the PET GTV and most were contained by a 2-cm margin on the MRI GTV.