Search

The incidence of multiple primary malignancies (MPM) has increased in recent decades. Our aim was to evaluate incidence, clinical features, and survival in cases of spinal metastases from MPM in which one of the malignancies is lung cancer.We retrospectively reviewed an institutional database of lung cancer patients with spinal metastasis and extracted all cases of MPM.Among 275 patients who had spinal metastasis with lung cancer as one of the diagnoses, 21 (7.6%) patients with MPM were identified. Mean patient age was 68.5 years (95% confidence interval [CI], 65.3-71.7). The most common cancers diagnosed in addition to lung cancer were breast cancer (5 patients, 24%), upper aerodigestive tract cancer (4 patients, 19%), and prostate cancer (4 patients, 19%). Eighteen (86%) patients walked independently, and 3 (14%) patients walked with help. Seventeen (80.9%) patients had a good Karnofsky performance scale score. The median survivals from the date of first cancer diagnosis, last cancer diagnosis, and spinal metastasis diagnosis were 109.8 months (95% CI, 23.5-196.1), 17.8 months (95% CI, 5.8-29.8), and 10.3 months (95% CI, 5.4-15.2), respectively. Actual rates of survival at 6 months, 12 months, and 24 months from the date of spinal metastasis diagnosis were 81%, 42.9%, and 23.8%, respectively.The present study is the first series to our knowledge to show that survival of patients with spinal metastasis and MPM involving lung cancer is not clearly inferior to that of patients with spinal metastasis and lung cancer alone.

Background Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Methods This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15–21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Results Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1–9) BM were treated with SRS. Median follow-up was 16.0 months (0.43–25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3–69.6%) and 61.3% (95% CI 45.1–83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2–4 months (P = .0007). Conclusions The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

The novel coronavirus of 2019 has had a broad impact of the delivery of healthcare, including cancer care. We chose to quantify the impact in the radiation oncology department of the largest academic center in the hardest hit city in Canada. With the approval of our ethics review board, data on each patient treated from March 13, 2020 to August 10, 2020 were compared to patients treated during the same period in 2019. We compared the case mix, delay from treatment decision to treatment start, and number of fractions per patient. We reviewed prospectively collected information regarding deviations from our usual practice. During the pandemic the caseload was reduced by 12%, this was more pronounced in prostate and CNS tumors. The average number of fractions per patient was reduced from 12.3 to 10.9. This reduction was most marked in prostate, breast, gastro-intestinal, and palliative cases. When physicians were questioned, they reported that 17% of treatment plans deviated from their usual practice because of the pandemic. The most common deviations were related to changes in department policies (77%) vs. patient-specific deviations (20%) or changes requested by the patient (3%). Rare deviations were due to patients contracting COVID-19 (2 patients). At its worse, the wait list contained 27% of patients who had a delay to radiotherapy of more than 28 days. However, the average wait time increased little (19.6 days vs. 18.2 days) as more pressing cases were prioritized. In an unprecedented health crisis, our radiation oncology department was able to reduce resource utilization, notably by decreasing the number of fractions per patient. It will be important to follow these patients&rsquo, health outcomes for insight into these practices. More quantitative tools to simulate and plan future practice changes in response to resource constraints will be implemented.

Background A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline. Methods In this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment. Results The APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014). Conclusions Patients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

Summary Needle tract seeding is a potential, albeit rare, complication following transcutaneous biopsies, leading to the seeding of tumor cells along the path of the needle. Biopsies of adrenal masses are not routinely recommended and are only indicated, after exclusion of pheochromocytoma, when an adrenal metastasis of a primary extra-adrenal cancer is suspected or when pathological confirmation of inoperable adrenocortical cancer (ACC) may impact treatment. Despite guideline recommendations to avoid primary adrenal biopsy, very few needle tract seeding cases have been reported and none were in the context of an ACC. We report the occurrence of needle tract seeding in a patient following adrenal transcutaneous biopsy leading to ACC abdominal wall recurrence. Learning points Needle tract seeding is a rare complication of transcutaneous biopsy. It may increase morbidity and impact overall survival. It has yet to be documented in adrenocortical carcinoma (ACC). Adrenal masses can be accurately evaluated for malignancy using a combination of conventional and metabolic imaging, such as CT and fluorodeoxyglucose-PET, obviating the need for biopsies. Adrenal mass biopsy is not indicated in ACC unless advanced ACC is diagnosed, and a pathological confirmation would impact management.

Purpose This study aimed to evaluate if the F18-fluorodeoxyglucose positron emission tomography (F18-FDG PET) response after two weeks of chemoradiation for locoregionally advanced esophageal cancer (staged Tumor (T) 3 and/or Nodes (N)+ Metastases (M) 0) was linked to the pathologic response for patients undergoing surgery, to disease-free survival (DFS) or overall survival (OS). Materials and Methods Between March 2006 and September 2017, 40 patients were prospectively enrolled in our study, gave written consent, and had PET scans performed before treatment and after two weeks of chemoradiation. One patient did not undergo his two-week PET without informing study coordinators and was excluded from analyses. Results The median age at diagnosis was 62 years. Seventy-two percent of patients had N+ disease. Median OS for the entire group was 24 months. Five-year overall survival was 17%. Survival curves for patients with no PET response, minor PET response, or good PET response overlapped and were not statistically different. For the 25 patients who underwent surgery, the positive predictive value (PPV) of the PET response relative to the pathologic response was 75% and the negative predictive value (NPV) was 62%. In study patients, the crude recurrence rate was 68% and there was no correlation between PET response and DFS. Conclusion In our study, interim PET response after two weeks of chemoradiation for locoregionally advanced esophageal cancer was not predictive of outcome or pathologic response. Based on our data and current literature, interim PET should not be used to alter treatment (whether to escalate neo-adjuvant treatment or omit surgery).

OBJECTIVE Gamma Knife radiosurgery is recognized as an efficient intervention for the treatment of refractory trigeminal neuralgia (TN). The CyberKnife, a more recent frameless and nonisocentric radiosurgery alternative, has not been studied as extensively for this condition. This study aims to evaluate the clinical outcomes of a first CyberKnife radiosurgery (CKRS) treatment in patients with medically refractory TN. METHODS A retrospective cohort study of 166 patients (168 procedures) with refractory TN treated from 2009 to 2021 at the Centre Hospitalier de l’Université de Montréal was conducted. The treatment was performed using a CyberKnife (model G4, VSI, or M6). The treatment median maximum dose was 80 (range 70.0–88.9) Gy. RESULTS Adequate pain relief, evaluated using Barrow Neurological Institute pain scale scores (I–IIIb), was achieved in 146 cases (86.9%). The median latency period before adequate pain relief was 35 (range 0–202) days. The median duration of pain relief for cases with a recurrence of pain was 8.3 (range 0.6–85.0) months. The actuarial rates of maintaining adequate pain relief at 12, 36, and 60 months from the treatment date were 77.0%, 62.5%, and 50.2%, respectively. There was new onset or aggravation of facial numbness in 44 cases (26.2%). This facial numbness was predictive of better maintenance of pain relief (p < 0.001). The maintenance of adequate pain relief was sustained longer in idiopathic cases compared with cases associated with multiple sclerosis (MS; p < 0.001). CONCLUSIONS In the authors’ experience, CKRS for refractory TN is efficient and safe. The onset or aggravation of facial hypoesthesia after treatment was predictive of a more sustained pain relief, and idiopathic cases had more sustained pain relief in comparison with MS-related cases.

This study aimed to assess systemic and local risk factors for the development of osteoradionecrosis (ORN) of the jaws and its incidence in patients with head and neck cancer undergoing radiotherapy (RT). This was a retrospective cohort study of 620 adults following irradiation for head and neck cancer in 2011 or 2012. Among 181 patients who did not require any tooth extractions, the incidence of ORN was 0.5%. Among 266 patients with a total of 1491 tooth extractions (mean, 5.5 teeth per patient) performed before RT, the incidence of ORN was 3.7%. In all cases, ORN was observed in extraction sites located in the field of radiation. No extractions were performed during RT. Fifteen patients underwent extractions both before and after RT. Of the 53 tooth extractions performed after RT (20 patients; mean, 2.7 teeth per patient), 15 were in the field of radiation. No case of ORN was reported in that group. Among 168 edentulous patients, the incidence of ORN was 1.8%. Within the limitations of this study, the results suggest that the incidence of ORN can be minimized with a meticulous pre-RT dental examination, a comprehensive treatment plan, and diligent post-RT follow-up examinations conducted by an experienced multidisciplinary team.

Background: Tumor Treating Fields (TTFields) therapy is a loco-regional, noninvasive treatment approved for newly diagnosed (nd)/recurrent (r) glioblastoma (GBM) and mesothelioma. Approval for ndGBM was based on the pivotal phase 3 EF-14 study where TTFields therapy/temozolomide (TMZ), administered in the adjuvant setting, significantly improved PFS and OS vs TMZ monotherapy. TTFields therapy-related adverse events (AEs) were mostly mild-to-moderate skin reactions, with no evidence of TTFields therapy-related systemic toxicity. Radiotherapy (RT) concomitant with TTFields therapy demonstrated an increased therapeutic effect in preclinical models. Supplementary evidence from two pilot phase 2 studies demonstrated that concomitant administration of TTFields therapy with standard of care RT/TMZ was feasible and well-tolerated. Here we present a phase 3 study examining the efficacy and safety of TTFields therapy concomitant with RT/TMZ in patients with ndGBM. Materials and Methods: TRIDENT (EF-32; NCT04471844) is a global, randomized, phase 3 study of patients ≥18 years of age (≥22 years in the US) with histologically confirmed ndGBM, ≥3 months life expectancy, ≥70 Karnofsky Performance Status, and adequate organ function. Patients will be stratified by the extent of resection and methylation status of the MGMT promoter. Approximately 950 patients will be assigned 1:1 to continuous TTFields therapy (200 kHz, ≥18 h/day) concomitant with RT/TMZ (experimental arm) or RT/TMZ alone (control arm). Patients will first receive 6 weeks of experimental or control therapy, TTFields therapy will then be added to the control group and all patients will receive 6 cycles of maintenance TMZ and continuous TTFields therapy. Once initiated, TTFields therapy use will continue until second disease progression (PFS2) or until 24 months (if clinically able) from the time of randomization. The primary endpoint is median OS; secondary endpoints include 1- and 2- year OS rates, PFS, 6- and 12-month PFS rates, and PFS2 (all per Response Assessment in Neuro-Oncology [RANO]), overall radiological response (per RANO), severity and frequency of AEs, quality of life (QoL; per European Organisation for Research and Treatment of Cancer QoL Questionnaires), neurological function (per Neurological Assessment in Neuro-Oncology scale), and tumor pathology post study treatments (when available). The ability of TTFields therapy to prolong OS in a dose-dependent manner is an exploratory endpoint. The primary endpoint is based on the hypothesis that TTFields therapy/RT/TMZ can significantly improve OS (vs RT/TMZ) and will be tested using a stratified log-rank test. The sample size is calculated for a hazard ratio of Citation Format: Wenyin Shi, Lawrence Kleinberg, Suriya A. Jeyapalan, Samuel A. Goldlust, Seema Nagpal, Leonardo Lustgarten, Stephanie E. Combs, David Roberge, Ryo Nishikawa, David Reardon, Rachel Grossman, Martin Glas. TRIDENT phase 3 study (EF-32): First-line Tumor Treating Fields (TTFields; 200 kHz) therapy concomitant with chemo-radiation, followed by maintenance TTFields/temozolomide in newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT061.

Introduction Identifying, segmenting, measuring, and following multiple brain metastases treated with radiosurgery can be time consuming and error prone. Machine learning has shown promise for automated detection and segmentation. Recently, a U-Net inspired model combining volume aware loss functions and volume aware sampling methods was trained in an industrial-academic partnership. A total of 530 clinically annotated T1 gadolinium MRIs were used. Initial validation showed a high sensitivity (91%) with an average of 0.66 false positives per MRI. The goal of the present work was to characterize those “false positives” which may represent clinically undetected metastases. METHODS The images used for model development were clinically annotated for radiosurgery planning. Lesions had first been identified by a radiologist, second by clinicians during tumor board review, third by the treating radiation oncologist and the treating neurosurgeon (potentially after segmentation by a trainee) and finally by fellow radiation oncologists during quality assurance rounds. Despite these multiple checks, 10 patients (2%) had brain lesions considered potential clinical misses when all “false positives” were manually reviewed by a single investigator. Further detailed review including prior and subsequent imaging was used to arbitrate the nature of these lesions. RESULTS Among the 10 cases, four were confirmed as undetected metastases: two lesions required subsequent radiosurgery and 2 patients died prior to further imaging. The six other lesions were adjudicated as true “false positives” (typically vascular). CONCLUSION The multi-tier radiosurgery workflow at our institution left very few unidentified brain metastases (0.8%). Despite this low error rate, our AI algorithm still detected two lesions that required further treatment. Future investigations will focus on potential roles of AI in simplifying and accelerating our workflow. It also remains to be established if more undetected metastases would be seen in community settings where workflows include fewer sequential imaging reviews.

Detection of brain metastases (BM) and segmentation for treatment planning could be optimized with machine learning methods. Convolutional neural networks (CNNs) are promising, but their trade-offs between sensitivity and precision frequently lead to missing small lesions.Combining volume aware (VA) loss function and sampling strategy could improve BM detection sensitivity.Retrospective.A total of 530 radiation oncology patients (55% women) were split into a training/validation set (433 patients/1460 BM) and an independent test set (97 patients/296 BM).1.5 T and 3 T, contrast-enhanced three-dimensional (3D) T1-weighted fast gradient echo sequences.Ground truth masks were based on radiotherapy treatment planning contours reviewed by experts. A U-Net inspired model was trained. Three loss functions (Dice, Dice + boundary, and VA) and two sampling methods (label and VA) were compared. Results were reported with Dice scores, volumetric error, lesion detection sensitivity, and precision. A detected voxel within the ground truth constituted a true positive.McNemar's exact test to compare detected lesions between models. Pearson's correlation coefficient and Bland-Altman analysis to compare volume agreement between predicted and ground truth volumes. Statistical significance was set at P ≤ 0.05.Combining VA loss and VA sampling performed best with an overall sensitivity of 91% and precision of 81%. For BM in the 2.5-6 mm estimated sphere diameter range, VA loss reduced false negatives by 58% and VA sampling reduced it further by 30%. In the same range, the boundary loss achieved the highest precision at 81%, but a low sensitivity (24%) and a 31% Dice loss.Considering BM size in the loss and sampling function of CNN may increase the detection sensitivity regarding small BM. Our pipeline relying on a single contrast-enhanced T1-weighted MRI sequence could reach a detection sensitivity of 91%, with an average of only 0.66 false positives per scan.3 TECHNICAL EFFICACY: Stage 2.

Background: Antiplatelet therapy is a cornerstone in the management of carotid artery disease following carotid endarterectomy (CEA). There is a paucity of data regarding the effect of dual antiplatelet therapy (DAPT) on restenosis rates. Methods: A retrospective review of patients who underwent CEA from January 1, 2007 to December 31, 2013 was performed at a single center. Study groups consisted of subjects who received DAPT and those who received single antiplatelet therapy (SAPT) following CEA. Restenosis was evaluated by carotid duplex. Severity and timing of restenosis, postoperative complications, and reinterventions were compared between study groups. Results: Between January 1, 2007 and December 31, 2013, 1453 patients underwent CEA. The SAPT group consisted of 245 patients and the DAPT group consisted of 1208 patients. No difference in restenosis was identified between groups at less than 6 weeks (6.5% vs. 11.7% 50-79% stenosis, 0% vs. 2.2% 80-99% stenosis, 2.2% vs. 0.6% occlusion, p = 0.368), and 6 weeks to 2 years (20.6% vs. 17.9% 50-79% stenosis, 1.1% vs. 1.0% 80-99% stenosis, 1.6% vs. 0.4% occlusion, p = 0.242). A higher rate of restenosis in SAPT was found greater than 2 years from surgery (68.4% vs. 82.4% 50% stenosis vs. 17.6% of the DAPT group (adjusted OR 0.48, 95% CI 0.30-0.76, p = 0.002). In a propensity matched-population, 32.7% of the SAPT group demonstrated restenosis vs. 13.7% of the DAPT group (adjusted OR 0.35, 95% CI 0.16-0.77, p = 0.009). There was no difference in the need for reintervention between study groups (DAPT 3.8% vs SAPT 3.3%, p = 0.684). Conclusion: Following CEA, patients on DAPT exhibited lower rates of late restenosis. Despite this finding, a clinical difference in reintervention was not found during this study period.

PURPOSE Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non–small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

Purpose The geometry of an immobilization device such as a headrest can cause undesired computed tomography (CT) artifacts that may affect both volume definition and dosimetry in radiotherapy of the brain. The purpose of this work was to reduce CT artifacts caused by a standard hard plastic hollow radiotherapy headrest. This was to be achieved through design and prototyping of a custom‐made head support. Methods A series of CT scans were acquired of both a water phantom and an anthropomorphic head phantom which were resting on custom‐made three‐dimensional (3D) printed supports. All custom‐made supports were made of polylactic acid (PLA) plastic filament and printed by fused deposition modeling (FDM) 3D printing technology. Initial designs were studied with a water phantom using a simplified support with straight and curved shapes both at the edges and as infill patterns. Imaging of a 3D printed clinical prototype was then compared to our standard headrest using an anthropomorphic head phantom. Results The presence of dark streaks inside both phantoms was seen on the CT images for headrests involving supports with straight shapes at the edges or as infill patterns. Such artifacts were ascribed to the exponential edge‐gradient effect (EEGE). No such artifact was observed when the support was designed with a combination of curved edges and infill patterns. Conclusion When developing immobilization accessories for use in CT scanners, more attention could be paid to artifact attenuating design elements. This work illustrates the usefulness of 3D printing in prototyping radiotherapy accessories and solving concrete clinical problems.

PurposeBrain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.Methods and materialsA multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively.ResultsMedian survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01).ConclusionsMS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

Purpose For nonoperable stage I non-small cell lung cancer, stereotactic body radiation therapy (SBRT) has emerged as a standard treatment option. We aimed to compare the clinical outcomes of lung SBRT between patients with versus without pathologic cancer diagnosis. Methods and Materials We included patients treated by SBRT for a single pulmonary lesion between July 2009 and July 2017. Patients in the clinical diagnosis group had a positron emission tomography/computed tomography scan showing hypermetabolism, growth of the mass on sequential computed tomography, and were not eligible for biopsy, refused biopsy, or had an inconclusive biopsy. For each of those patients, a matched pair in the pathologic diagnosis group was identified by matching for patient, treatment, and tumoral characteristics. We performed a power calculation to estimate the sample size required to detect a difference arising from a 5% or 15% rate of benign processes in the group without pathology. Results A total of 924 lung SBRT treatments were performed among 878 patients from 2009 to 2017. Within this population, 131 patients were treated based on clinical findings. They were matched with 131 patients with a pathologic diagnosis who received treatment. At 3 years, no significant differences were observed in overall survival (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.7-2.1), local control (HR, 0.9; 95% CI, 0.4-2), or regional (HR, 0.5; 95% CI, 0.2-1.4) or distant recurrence (HR, 0.6; 95% CI, 0.3-1.1). Conclusions In our population, we found no clinically significant difference in patterns of recurrence or survival after lung SBRT for patients who had received clinical versus pathological diagnoses. There was, however, a trend toward more distant recurrences in the pathologic diagnosis group. Our power calculation suggests that data from multiple institutions would be required to rule out a difference in outcomes due to 5% to 15% of clinically diagnosed cases being treated for benign processes.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

LBA492 Purpose: To determine if more patients (pts) with painful liver cancer have improved pain 1 month following radiation therapy (RT), compared to best supportive care (BSC). Methods: This multi-centre, phase III trial randomized pts with painful hepatocellular carcinoma (HCC) or liver metastases (LM) 1:1 to BSC alone or with single fraction RT (8 Gy). Eligible pts had end-stage disease unsuitable for local, regional or systemic therapies, > 4 weeks since chemotherapy or TACE, > 2 weeks since targeted therapy or immunotherapy, and no planned systemic therapy. The primary objective was to determine if the proportion of pts with improved liver cancer pain "intensity at worst" on Brief Pain Inventory (BPI) by ≥2 points from baseline to 1 month was higher following RT vs. BSC alone. Secondary endpoints included proportion of pts 1) alive at 3 months, 2) with improvement ≥2 points in BPI at 1 and 3 months, 3) with a 25% reduction in opioids at 1 month and 4) with improved quality of life (QOL): Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) hepatobiliary subscale (HBS) change score ≥5 and Trial Outcome Index ≥7 at 1 month. Results: Sixty-six pts were randomized, 43 with LM (12 colorectal, 5 breast, 4 pancreas, 3 lung, 19 other), 23 with HCC. 59% had ECOG performance status 2 or 3, 64% Child Pugh (CP) score A vs. 36% CP B or C. The clinical target volume irradiated was the whole liver or near whole liver (median 2013 cc). Forty-two pts (24 on RT and 18 on BSC) completed baseline and 1-month assessments. The average baseline pain at worst score was 7/10. A significant improvement in the primary endpoint, ‘worst’ pain score on BPI, from baseline to 1 month was seen in 67% of pts on RT and 22% on BSC (p = 0.004). The proportion of pts with improved ‘worst’ pain at 1 month, with no increase in opioid use was 21% on RT vs 0% with BSC (p = 0.07). From baseline to 1 month, the proportion of pts with a significant improvement in BPI “pain at its least” was higher for pts on RT vs. BSC (63% vs. 28%, p = 0.03), as was BPI “percentage relief in pain by treatment” (59% vs. 25%, p = 0.04). A sensitivity analysis of all pts, treating those with no 1 month assessment as having ‘no improvement’, found improvements in BPI ‘worst’ pain in 49% of pts on RT and 12% for BSC alone (p = 0.002). Eleven patients on the BSC arm crossed over to receive RT at 1 month. A trend to improvement in FACT HBS post RT vs BSC was seen at 1 month (p = 0.07), with no statistically significant difference in other FACT-Hep subscales. The proportion of pts with grade ≥2 AE (CTCAEv4.0) at day 30 was 58% on RT vs 33% on BSC (p = 0.05). Grade ≥3 AE were uncommon. There was a trend for improved 3 month survival with RT (51% vs. 33% for BSC alone, p = 0.07). Conclusions: Single fraction RT (8 Gy) improves hepatic pain in the majority of patients with end-stage HCC or liver metastases, with a trend to improved survival. This research is funded by the Canadian Cancer Society (Grant #703547). Clinical trial information: NCT02511522 .

Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly.A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA.Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P.01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies.Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

ImportanceLong-term outcomes of radiotherapy are important in understanding the risks and benefits of therapies for patients with brain metastases.ObjectiveTo 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.Design, Setting, and ParticipantsThis 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.InterventionsStereotactic radiosurgery or WBRT.Main Outcomes and MeasuresIntracranial tumor control, toxic effects, cognitive deterioration, and QOL.ResultsFifty-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.Conclusions and RelevanceThe 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.Trial RegistrationClinicalTrials.gov Identifier: NCT01372774; ALLIANCE/CCTG: N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group)

BACKGROUND Tumor Treating Fields therapy (TTFields; 200 kHz) comprise alternating electric fields that disrupt cancer cell division, and is approved for newly diagnosed glioblastoma (ndGBM), recurrent GBM and mesothelioma. In the phase 3 EF-14 trial, TTFields/temozolomide (TMZ) significantly increased overall survival (OS) and progression-free survival (PFS) vs TMZ alone in patients with ndGBM. TTFields-related adverse events (AEs) were mainly dermatological with no increases in systemic toxicity. In preclinical models, the addition of TTFields to radiotherapy (RT) increased the therapeutic effect. Additionally, TTFields added to RT/TMZ was reported as feasible and well-tolerated in 2 clinical pilot phase 2 studies. MATERIALS AND METHODS TRIDENT (EF-32; NCT04471844) is an international, phase 3 randomized trial comparing TTFields (200 KHz, ≥18 h/day)/RT/TMZ vs RT/TMZ alone. Adult patients (N=950; ≥18 years of age [≥22 years of age; US]) with histologically confirmed ndGBM, Karnofsky Performance Status ≥70, life expectancy ≥3 months, adequate organ function and eligible for RT/TMZ will be enrolled. Patients will be stratified by extent-of-resection and MGMT promoter methylation status and randomized 1:1 to receive continuous TTFields/RT/TMZ or RT/TMZ during the investigational period. Subsequently, all patients will receive TTFields/6 cycles of maintenance TTFields/TMZ; TTFields will continue for 24 months or until second disease progression per Response Assessment in Neuro-Oncology (RANO). The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1- and 2-year survival rates, overall radiological response (RANO), PFS6, PFS12, severity and frequency of AEs and quality-of-life, OS per TTFields duration-of-usage. The study is powered at 80% to detect a hazard ratio of

BACKGROUND The assessment of BM response to WBRT and its impact on NCF in clinical trials has been limited by lack of standardized imaging protocols. NRG-CC001 is a randomized clinical trial requiring pre-specified MRI protocols at baseline and 6-months, providing a uniform dataset to investigate if RR correlates with NCF changes. METHODS NRG-CC001 randomized patients with BM to hippocampal avoidance WBRT (HA-WBRT) or WBRT. NCF was analyzed using 6-month standardized change scores and deterioration, defined using the reliable change index. Chi-square and t-tests were used for pretreatment characteristic comparisons. Inter-rater reliability between central and institutional assessment of RR was assessed with weighted kappa, κ. Linear regression was used to test trends in NCF change scores across types of response and multivariable logistic regression was used to test the association of RR to NCF deterioration. RESULTS 149 and 135 patients were evaluable for RR and NCF assessment, respectively. Pretreatment characteristics were well-balanced, except for post-high school education (70.6% HA-WBRT vs. 52.5% WBRT, p=0.023). Inter-rater reliability between central and institutional assessment of RR was fair (κ=0.36). There was no difference between arms in RR (p=0.41) with overall rates of 14.1% CR, 42.2% PR, 17% SD, and 26.7% PD. Patients with CR had improved 6-month NCF change as measured by HVLT-R Total Recall (p=0.0005), HVLT-R Delayed Recall (p=0.0003), HVLT-R Delayed Recognition (p=0.011), TMT-B (p=0.033), COWA (p=0.016), and Clinical Trial Battery Composite score (p=0.0011). Multivariable analysis demonstrated less deterioration in HVLT-R Delayed Recall for CR (p=0.019) and PR (p=0.0086) vs. SD/PD and HVLT-R Recognition for PR (p=0.031) vs. SD/PD. CONCLUSIONS HA-WBRT and WBRT result in similar RR at 6-months. CR or PR is associated with better NCF preservation. This suggests investigation into treatment escalation for patients with SD/PD may provide further NCF benefit along with HA-WBRT and memantine.Grant support from NCI-UG1CA189867 and U24CA180803.

Highlights • Brain metastases in GI cancer patients are not uncommon. • Survival varies widely within this cohort. • New identified prognostic factors are incorporated in an updated prognostic index. • This index, the GI-GPA, will better estimate survival. • The GI-GPA is useful in treatment selection and stratification of clinical trials., Background Patients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985–2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database. Methods An IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA. Results Median survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0–1, 1.5–2, 2.5–3.0 and 3.5–4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0). Conclusions Brain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com.

Purpose We present a concise description of an in-house decision aid software called “C entral 3D” that allows a quick and robust lung tumor classification between central and peripheral as defined by the Radiation Therapy Oncology Group (RTOG) 0813. Methods and materials Twenty cases of lung tumors were selected for this study and four radiation oncologists blindly classified them as peripheral versus central without assistance of our software. All discordant cases were reviewed using C entral 3D and prompt consensus was obtained. Results Many authors have stressed the importance of adopting risk adaptive fractionation schedule with lower biological equivalent dose when treating centrally-located high risks lesions. C entral 3D addresses the limitation of current treatment planning systems to represent image data in fixed planes and can help radiation oncologists to fully characterize these pulmonary lesions.