First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: a registry study.

Introduction: Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods: Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results: 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 - 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion: The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

Leptomeningeal neuraxis relapse in glioblastoma is an uncommon but not rare event associated with poor outcome.

BACKGROUND: Spinal neuraxis leptomeningeal metastasis (LM) relapse in glioblastoma is an uncommon event that is challenging to manage. This study aims to determine the incidence, associated factors, and outcome of LM relapse in patients with glioblastoma managed with radical intent. METHODS: Patients managed for glioblastoma using the EORTC-NCIC (Stupp) Protocol from 2007 to 2019 were entered into a prospective ethics-approved database. Follow-up included routine cranial MRI surveillance with further imaging as clinically indicated. LM relapse was determined by MRI findings and/or cerebrospinal fluid analysis. The chi-square test of independence was used to evaluate clinico-pathologic factors associated with increased risk of subsequent LM relapse. Median survival post-LM relapse was calculated using Kaplan-Meier technique. RESULTS: Four-hundred-and-seven patients were eligible, with median follow-up of 60 months for surviving patients. Eleven (2.7%) had LM at first relapse and in total 21 (5.1%) experienced LM in the entire follow-up period. Sites of LM relapse were 8 (38%) focal spinal, 2 (10%) focal brainstem medulla and 11 (52%) diffuse spinal. Median overall survival from initial diagnosis for the entire cohort was 17.6 months (95% CI 16.7-19.0). Median survival from LM relapse to death was 39 days (95% CI: 19-107). Factors associated with LM relapse were age less than 50 years (p < 0.01), initial disease located in the temporal lobe (p < 0.01) and tumours lacking MGMT promoter methylation (p < 0.01). CONCLUSIONS: LM relapse is an uncommon but not rare event in patients managed radically for glioblastoma. It is associated with poor outcome with the majority of patients deceased within two months of recognition.

Challenges and Opportunities With the Use of Hypofractionated Radiation Therapy in Cancer Care: Regional Perspectives From South Korea, Japan, Singapore, and Australia.

Hypofractionated radiotherapy schedules provide higher per-fraction radiation doses delivered in fewer fractions than conventional schedules. This novel delivery method is supported by a large body of clinical trial evidence across various cancer sites in both curative and palliative settings. Hypofractionation is associated with benefits such as lower costs, improved patient access and increased treatment precision, which has led to its inclusion in various treatment guidelines. Despite this, utilization is not uniform across cancer sites and geographic regions due to reasons such as reimbursement models, nuances in healthcare systems, and professional culture. Key factors to ensure patients benefit from access to high quality radiotherapy include publishing clinical evidence, cross-country collaboration to fill knowledge gaps, reviewing reimbursement models, and improving patient advocacy in treatment decision-making.

Large tumour volume reduction of IDH-mutated anaplastic glioma involving the insular region following radiotherapy.

BACKGROUND: The impact of near-total resection of IDH-mutated anaplastic glioma (IDHmutAG) is well-established but there remains uncertainty of benefit in tumours of the insular cortex where the extent of safe resection may be limited. This study aimed to assess tumour volume reduction in patients following IMRT and impact of residual post-surgical volume. METHODS AND MATERIALS: Patients with IDHmutAG involving insular cortex managed with IMRT from 2008 to 2019 had baseline patient, tumour and treatment factors recorded. Volumetric assessment of residual disease on MRI was performed at baseline, month+ 3 and month+ 12 post-IMRT. Potential prognostic factors were analysed for tumour reduction and relapse-free survival, and assessed by log-rank and Cox regression analyses. RESULTS: Thirty two patients with IDHmutAG of the insular cortex were managed with median follow-up post-IMRT of 67.2 months. Pathology was anaplastic astrocytoma (AAmut) in 20, and anaplastic oligodendroglioma (AOD) in 12 patients. Median pre-IMRT volume on T1 and T2Flair was 24.3cm3 and 52.2cm3. Twenty-seven patients were alive with 5-year relapse-free survival of 80%. There was a median 67 and 64% reduction from baseline occurring at 3 months post-IMRT for T1 and T2Flair respectively; and subsequent median 78 and 73% at 12 months. At 12 months AOD patients had median 83% T1 volume reduction compared to 63% in AAmut (p < 0.01). There was no difference on T2Flair volume (p = 0.64). No other pathological factors influenced volume reduction at 12 months. No factors were associated with relapse-free survival including baseline T1 (p = 0.52) and T2Flair (p = 0.93) volume. CONCLUSION: IMRT provides large tumour volume reduction in IDHmutAG of the insular cortex. While maximal safe debulking remains standard of care when feasible, this patient cohort reported no significant negative impact of residual disease volume on relapse-free survival.

MArkerless image Guidance using Intrafraction Kilovoltage x-ray imaging (MAGIK): study protocol for a phase I interventional study for lung cancer radiotherapy.

INTRODUCTION: In radiotherapy, tumour tracking leads the radiation beam to accurately target the tumour while it moves in a complex and unpredictable way due to respiration. Several tumour tracking techniques require the implantation of fiducial markers around the tumour, a procedure that involves unnecessary risks and costs. Markerless tumour tracking (MTT) negates the need for implanted markers, potentially enabling accurate and optimal radiotherapy in a non-invasive way. METHODS AND ANALYSIS: We will perform a phase I interventional trial called MArkerless image Guidance using Intrafraction Kilovoltage x-ray imaging (MAGIK) to investigate the technical feasibility of the MTT technology developed at the University of Sydney (sponsor). 30 participants will undergo the current standard of care lung stereotactic ablative radiation therapy, with the exception that kilovoltage X-ray images will be acquired continuously during treatment delivery to enable MTT. If MTT indicates that the mean lung tumour position has shifted >3 mm, a warning message will be displayed to indicate the need for a treatment intervention. The radiation therapist will then pause the treatment, shift the treatment couch to account for the shift in tumour position and resume the treatment. Participants will be implanted with fiducial markers, which act as the ground truth for evaluating the accuracy of MTT. MTT is considered feasible if the tracking accuracy is <3 mm in each dimension for >80% of the treatment time. ETHICS AND DISSEMINATION: The MAGIK trial has received ethical approval from The Alfred Human Research Ethics Committee and has been registered with ClinicalTrials.gov with the Identifier: NCT04086082. Estimated time of first recruitment is early 2022. The study recruitment and data analysis phases will be performed concurrently. Treatment for all 30 participants is expected to be completed within 2 years and participant follow-up within a total duration of 7 years. Findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04086082; Pre-result.

Volumetric Response of Limited Brain Metastatic Disease to Focal Hypofractionated Radiation Therapy.

Background: This is a retrospective study aimed at assessing the volumetric response, morbidity and failure rates of hypofractionated radiation therapy (HFRT) for definitive focal management of limited brain metastasis. Methods: Patients managed with HFRT for unresected limited metastatic (≤10 lesions) brain disease were entered into an ethics-approved database. Included patients had been deemed unsuitable for surgical resection, and lesions managed with prior radiation therapy were excluded. HFRT was delivered using IMRT or VMAT with 25 Gy or 30 Gy in five fractions. Individual lesions had volumetric assessment performed at three timepoints. The primary endpoint was the change of volume from baseline (GTV0) to one month post-HFRT (GTV1) and to seven months post-HFRT (GTV7). Secondary endpoints were local failure, survival and rates of radiation necrosis. Results: One hundred and twenty-four patients with 233 lesions were managed with HFRT. Median follow-up was 23.5 months with 32 (25.8%) patients alive at censure. Median overall survival was 7.3 months with 36.3% survival at 12 months. Superior survival was predicted by smaller GTV0 (p = 0.003) and increased percentage of volumetric response (p < 0.001). Systemic therapy was delivered to 81.5% of patients. At one month post-HFRT, 206 metastases (88.4%) were available for assessment and at seven months post-HFRT, 118 metastases (50.6%) were available. Median metastasis volume at GTV0 was 1.6 cm3 (range: 0.1-19.1). At GTV1 and GTV7, this reduced to 0.7 cm3 (p < 0.001) and 0.3 cm3 (p < 0.001), respectively, correlating to percentage reductions of 54.9% and 83.3%. No significant predictors of volumetric response following HFRT were identified. Local failure was identified in 4.3% of lesions and radiation necrosis in 3.9%. Conclusion: HFRT is an effective therapy for limited metastatic disease in the brain to maximise initial volumetric response whilst minimising toxicity.

Redo craniotomy or bevacizumab for symptomatic steroid-refractory true or pseudoprogression following IMRT for glioblastoma.

BACKGROUND: There is minimal evidence to support decision making for symptomatic steroid-refractory pseudoprogression or true progression occurring after intensity-modulated radiation therapy (IMRT) for glioblastoma (GBM). This study audited the survival outcome of patients managed with redo craniotomy (RedoSx) or bevacizumab (BEV) for steroid-refractory mass effect after IMRT for GBM. METHODS: Patients with GBM managed between 2008 and 2019 with the EORTC-NCIC Protocol were entered into a prospective database. Patients with symptomatic steroid-refractory mass effect within 6 months of IMRT managed with either RedoSx or BEV were identified for analysis. For the primary endpoint of median overall survival (OS) postintervention, outcome was analyzed in regards to potential prognostic factors, and differences between groups were assessed by log-rank analyses. RESULTS: Of the 399 patients managed with the EORTC-NCIC Protocol, 78 required an intervention within 6 months of IMRT completion for either true or pseudoprogression (49 with RedoSx and 29 with BEV). Subsequently, 20 of the 43 patients managed with RedoSx when BEV was clinically available, required salvage with BEV within 6 months after RedoSx. Median OS postintervention was 8.7 months (95% CI: 7.84-11.61) for the total group; and 8.7 months (95% CI: 6.8-13.1) for RedoSx and 9.4 months (95% CI: 7.8-13.6) for BEV (P = .38). Subsequent use of BEV in RedoSx patients was not associated with improved survival compared with RedoSx alone (P = .10). Age, time from IMRT, and ECOG performance status were not associated with OS. In the RedoSx patients, immunohistochemical features such as Ki-67% reduction correlated with survival. The presence of pure necrosis and residual tumor cells only had improved survival compared with the presence of gross tumor (P < .001). CONCLUSIONS: At time of symptomatic steroid-refractory true or pseudoprogression following IMRT for GBM, BEV was equivalent to RedoSx in terms of OS. Pseudoprogression with residual cells at RedoSx was not associated with worse outcome compared to pure necrosis.

Improving efficiency in the radiation management of multiple brain metastases using a knowledge-based planning solution for single-isocentre volumetric modulated arc therapy (VMAT) technique.

INTRODUCTION: This study aimed to develop a single-isocentre volumetric modulated arc therapy (si-VMAT) technique for multiple brain metastases using knowledge-based planning software, comparing it with a multiple-isocentre stereotactic radiosurgery (mi-SRS) planning approach. METHODS: Twenty-six si-VMAT plans were created and uploaded into RapidPlanTM (RP) to create a si-VMAT model. Ten patients, with 2 to 6 metastases (mets), were planned with a si-VMAT technique utilising RP, and a mi-SRS technique on Brainlab iPlan. Paddick Conformity Index (PCI) was used to compare conformity. The volumes of the brain receiving 15Gy, 12Gy, 10Gy, 7.5Gy and 3Gy were also compared. Retrospective treatment times from the last eight patients treated were averaged for pre-imaging and beam on time to calculate treatment times for both techniques. RESULTS: There was a significant difference in the PCI scores for the mi-SRS plans (M = 0.667, SD = 0.114) and si-VMAT plans (M = 0.728, SD = 0.088), with PCI values suggesting better prescription dose conformity with the si-VMAT technique (P = 0.014). Percentage of total brain volume receiving low-dose wash at four of the five different dose levels was significantly less (P < 0.05) with mi-SRS. Average time to treat a single met with current mi-SRS technique is 25.7 min, with each additional met requiring this same amount of time. The average time to treat 2-3 mets using si-VMAT would be 25.3 min and 4+ metastases 33.5 min. CONCLUSION: A knowledge-based si-VMAT approach was efficient in planning and treating multi metastases while achieving clinically acceptable dosimetry with respect to dose conformity and low-dose fall off.

Introducing Computed Tomography Simulation-Free and Electronic Patient-Reported Outcomes-Monitored Palliative Radiation Therapy into Routine Care: Clinical Outcomes and Implementation Experience.

PURPOSE: Our purpose was to report outcomes of a novel palliative radiation therapy protocol that omits computed tomography simulation and prospectively collects electronic patient-reported outcomes (ePROs). METHODS AND MATERIALS: Patients receiving extracranial, nonstereotactic, linear accelerator-based palliative radiation therapy who met inclusion criteria (no mask-based immobilization and a diagnostic computed tomography within 4 weeks) were eligible. Global pain was scored with the 11-point numerical pain rating scale (NPRS). Patients were coded as having osseous or soft tissue metastases and no/mild versus severe baseline pain (NPRS ≥ 5). Pain response at 4 weeks was measured according to the international consensus (no analgesia adjustment). Transition to ePRO questionnaires was completed in 3 phases. Initially, pain assessments were collected on paper for 11 months, then pilot ePROs for 1 month and then, after adjustments, revised ePROs from 1 year onwards. ePRO feasibility criteria were established with reference to the paper-based process and published evidence. RESULTS: Between May 2018 and November 2019, 542 consecutive patients were screened, of whom 163 were eligible (30%), and 160 patients were successfully treated. The proportion of patients eligible for the study improved from approximately 20% to 50% by study end. Routine care pain monitoring via ePROs was feasible. One hundred twenty-seven patients had a baseline NPRS recording. Ninety-five patients had osseous (61% severe pain) and 32 had soft tissue (25% severe pain) metastases. Eighty-four patients (66%) were assessable for pain response at 4 weeks. In the 41 patients with severe osseous pain, overall and complete pain response was 78% and 22%, respectively. CONCLUSIONS: By study completion, 50% of patients receiving palliative extracranial radiation therapy avoided simulation, streamlining the treatment process and maximizing patient convenience. Pain response for patients with severe pain from osseous lesions was equivalent to published evidence.

Quantification of the geometric uncertainty when using implanted markers as a surrogate for lung tumor motion.

BACKGROUND: Fiducial markers are used as surrogates for tumor location during radiation therapy treatment. Developments in lung fiducial marker and implantation technology have provided a means to insert markers endobronchially for tracking of lung tumors. This study quantifies the surrogacy uncertainty (SU) when using endobronchially implanted markers as a surrogate for lung tumor position. METHODS: We evaluated SU for 17 patients treated in a prospective electromagnetic-guided MLC tracking trial. Tumor and markers were segmented on all phases of treatment planning 4DCTs and all frames of pretreatment kilovoltage fluoroscopy acquired from lateral and frontal views. The difference in tumor and marker position relative to end-exhale position was calculated as the SU for both imaging methods and the distributions of uncertainties analyzed. RESULTS: The mean (range) tumor motion amplitude in the 4DCT scan was 5.9 mm (1.7-11.7 mm) in the superior-inferior (SI) direction, 2.2 mm (0.9-5.5 mm) in the left-right (LR) direction, and 3.9 mm (1.2-12.9 mm) in the anterior-posterior (AP) direction. Population-based analysis indicated symmetric SU centered close to 0 mm, with maximum 5th/95th percentile values over all axes of -2.0 mm/2.1 mm with 4DCT, and -2.3/1.3 mm for fluoroscopy. There was poor correlation between the SU measured with 4DCT and that measured with fluoroscopy on a per-patient basis. We observed increasing SU with increasing surrogate motion. Based on fluoroscopy analysis, the mean (95% CI) SU was 5% (2%-8%) of the motion magnitude in the SI direction, 16% (6%-26%) of the motion magnitude in the LR direction, and 33% (23%-42%) of the motion magnitude in the AP direction. There was no dependence of SU on marker distance from the tumor. CONCLUSION: We have quantified SU due to use of implanted markers as surrogates for lung tumor motion. Population 95th percentile range are up to 2.3 mm, indicating the approximate contribution of SU to total geometric uncertainty. SU was relatively small compared with the SI motion, but substantial compared with LR and AP motion. Due to uncertainty in estimations of patient-specific SU, it is recommended that population-based margins are used to account for this component of the total geometric uncertainty.

PEG site metastasis in oropharyngeal squamous cell carcinoma managed with cetuximab and radiotherapy: A case report.

Percutaneous endoscopic gastrostomy (PEG) tube insertion is commonplace in head and neck cancer (HNC) patients. A rare but serious complication of PEG insertion in HNC is PEG site metastasis (PSM), which may precipitate rapid deterioration. We present the first case of PSM in a HNC patient managed without chemoradiotherapy and/or surgery, but rather with concurrent radiotherapy and cetuximab, followed by second-line pembrolizumab. Following histopathologic diagnosis of PSM, positron emission tomography confirmed primary site recurrence and multiple metastases in the axilla, abdomen and pelvis, managed palliatively with focal abdominal wall radiotherapy, pembrolizumab and carboplatin. The patient deteriorated and passed away 20 months after initial HNC diagnosis, 5 months after confirmation of PSM. Patients and clinicians should be aware of PSM in HNC. Though a proven prevention strategy is yet to be confirmed, prompt PSM diagnosis spares the patient unnecessary antibiotics for presumed infection and suggests the possibility of intra-abdominal metastases.

MLC tracking for lung SABR is feasible, efficient and delivers high-precision target dose and lower normal tissue dose.

BACKGROUND AND PURPOSE: The purpose of this work is to present the clinical experience from the first-in-human trial of real-time tumor targeting via MLC tracking for stereotactic ablative body radiotherapy (SABR) of lung lesions. METHODS AND MATERIALS: Seventeen patients with stage 1 non-small cell lung cancer (NSCLC) or lung metastases were included in a study of electromagnetic transponder-guided MLC tracking for SABR (NCT02514512). Patients had electromagnetic transponders inserted near the tumor. An MLC tracking SABR plan was generated with planning target volume (PTV) expanded 5 mm from the end-exhale gross tumor volume (GTV). A clinically approved comparator plan was generated with PTV expanded 5 mm from a 4DCT-derived internal target volume (ITV). Treatment was delivered using a standard linear accelerator to continuously adapt the MLC based on transponder motion. Treated volumes and reconstructed delivered dose were compared between MLC tracking and comparator ITV-based treatment. RESULTS: All seventeen patients were successfully treated with MLC tracking (70 successful fractions). MLC tracking treatment delivery time averaged 8 minutes. The time from the start of CBCT to the end of treatment averaged 22 minutes. The MLC tracking PTV for 16/17 patients was smaller than the ITV-based PTV (range -1.6% to 44% reduction, or -0.6 to 18 cc). Reductions in mean lung dose (27 cGy) and V20Gy (50 cc) were statistically significant (p < 0.02). Reconstruction of treatment doses confirmed a statistically significant improvement in delivered GTV D98% (p < 0.05) from planned dose compared with the ITV-based plans. CONCLUSION: The first treatments with lung MLC tracking have been successfully performed in seventeen SABR patients. MLC tracking for lung SABR is feasible, efficient and delivers high-precision target dose and lower normal tissue dose.

Geometric uncertainty analysis of MLC tracking for lung SABR.

PURPOSE: The purpose of this work was to report on the geometric uncertainty for patients treated with multi-leaf collimator (MLC) tracking for lung SABR to verify the accuracy of the system. METHODS: Seventeen patients were treated as part of the MLC tracking for lung SABR clinical trial using electromagnetic beacons implanted around the tumor acting as a surrogate for target motion. Sources of uncertainties evaluated in the study included the surrogate-target positional uncertainty, the beam-surrogate tracking uncertainty, the surrogate localization uncertainty, and the target delineation uncertainty. Probability density functions (PDFs) for each source of uncertainty were constructed for the cohort and each patient. The total PDFs was computed using a convolution approach. The 95% confidence interval (CI) was used to quantify these uncertainties. RESULTS: For the cohort, the surrogate-target positional uncertainty 95% CIs were ±2.5 mm (-2.0/3.0 mm) in left-right (LR), ±3.0 mm (-1.6/4.5 mm) in superior-inferior (SI) and ±2.0 mm (-1.8/2.1 mm) in anterior-posterior (AP). The beam-surrogate tracking uncertainty 95% CIs were ±2.1 mm (-2.1/2.1 mm) in LR, ±2.8 mm (-2.8/2.7 mm) in SI and ±2.1 mm (-2.1/2.0 mm) in AP directions. The surrogate localization uncertainty minimally impacted the total PDF with a width of ±0.6 mm. The target delineation uncertainty distribution 95% CIs were ±5.4 mm. For the total PDF, the 95% CIs were ±5.9 mm (-5.8/6.0 mm) in LR, ±6.7 mm (-5.8/7.5 mm) in SI and ±6.0 mm (-5.5/6.5 mm) in AP. CONCLUSION: This work reports the geometric uncertainty of MLC tracking for lung SABR by accounting for the main sources of uncertainties that occurred during treatment. The overall geometric uncertainty is within ±6.0 mm in LR and AP directions and ±6.7 mm in SI. The dominant uncertainty was the target delineation uncertainty. This geometric analysis helps put into context the range of uncertainties that may be expected during MLC tracking for lung SABR (ClinicalTrials.gov registration number: NCT02514512).

The role of large volume re-irradiation with Bevacizumab in chemorefractory high grade glioma.

BACKGROUND AND PURPOSE: Current practice in re-irradiation (reRT) of previously treated high-grade gliomas (HGG) has generally been limited to small volume reRT with stereotactic procedures. Less evidence exists for large volume reRT involving treatment volumes equivalent to that used at initial diagnosis. The primary aim of this study was to investigate the outcome of large volume reRT delivered in combination with Bevacizumab (BEV) in patients with recurrent chemorefractory HGG. METHODS AND MATERIALS: Patients with HGG managed with reRT were entered prospectively into a database. Clinicopathological features were recorded including timing of reRT, use of BEV and Dosimetric data. Median survival following reRT was the primary endpoint and association with clinicopathological factors was assessed with cox regression models. RESULTS: Sixty seven patients in total were managed with reRT, 51 patients had glioblastoma and 16 had anaplastic glioma. The median PTV was 145.3 cm3. Median OS post reRT was 7.8 months (95% CI 6.3-9.2 months) in the total cohort and 7.5 months (95% CI: 6.6-8.3 months) for GBM patients. In multivariate analysis of the whole cohort, IDH1 mutation status (p = 0.041) and ECOG status prior to reRT (<0.001) were significantly associated with OS. In terms of safety and toxicity, the majority of patients (66.5%) were ECOG 0-2 three months after treatment. In total, four episodes of suspected radiation necrosis occurred, all in patients treated without upfront BEV. CONCLUSION: Large volume reRT with bevacizumab is a feasible late salvage option in patients with recurrent HGG and offers meaningful prolongation of survival with low toxicity.

Outcomes for elderly patients 75 years and older treated with curative intent radiotherapy for mucosal squamous cell carcinomas of the head and neck.

BACKGROUND: Elderly patients with mucosal squamous cell carcinomas of the head and neck (mHNSCC) represent a challenging clinical dilemma. METHODS: A retrospective review was performed of patients ≥75 years, treated with curative-intent radiotherapy for mHNSCC in two quaternary Sydney hospitals between 2007 and 2017. RESULTS: Ninety-five patients met inclusion criteria. The median age was 79 years (75-94). Patients received radiotherapy alone (n = 24), concurrent chemoradiotherapy (n = 22), surgery and adjuvant radiotherapy (n = 45), or surgery with adjuvant chemoradiotherapy (n = 4). Median follow-up was 4.5 years, median overall survival (OS) was 3.8 years, and 2-year and 5-year OS were 56% and 43%, respectively. Eastern Cooperative Oncology Group performance status of ≥2 (P < .001) was a statistically significant predictor of reduced OS. Thirty-four patients (36%) required hospitalization, 5 (5%) did not complete radiotherapy, and 9 (9%) were feeding tube dependent beyond 6 months. CONCLUSIONS: Appropriately selected elderly patients can achieve durable outcomes from curative intent radiotherapy with acceptable treatment toxicity.

Validation of the 8th edition UICC/AJCC TNM staging system for HPV associated oropharyngeal cancer patients managed with contemporary chemo-radiotherapy.

BACKGROUND: To compare outcomes of high-risk human papilloma virus-related oropharyngeal squamous cell carcinoma (HPV OPSCC) treated with modern radiation treatment (RT) and daily image-guidance, staged with the 7th versus the 8th Edition (Ed) Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) TNM staging systems. METHODS: All eligible patients with HPV OPSCC treated definitively over a 10-year period (2007-2016) at a single institution were included. Protocols consisting of either RT or chemo-radiation (CRT) (weekly cisplatin or cetuximab) +/- neoadjuvant chemotherapy for those with bulky disease were used. All patients were Fluorine-18-deoxyglucose positron emission tomography (FDG-PET) staged at baseline and at intervals for up to 2 years post-treatment. Patients received parotid-sparing intensity modulated or volumetric modulated arc therapy with simultaneous integrated boost to either 70Gy in 35 fractions or 66Gy in 30 fractions. The overall survival (OS) was determined for each stage using the 7th Ed and subsequently with the updated 8th Ed staging system. RESULTS: One hundred fifty-three patients were analysed. Patient stage groupings varied between the 7th and 8th Eds respectively; Stage I (0.7% vs 64.7%), Stage II (8.5% vs 22.2%), stage III (21.6% vs 12.4%) and stage IV (69.3% vs 0.7%). In the 7th Ed, the 5 year probability of OS for stages I to III was 90%, versus stage IV 85.5%. There was no statistically significant difference between the staging groups (p = 0.85). In the 8th Ed there was a statistically significant difference in 5 year OS for stage I and stage II disease (96.9% vs 77.1% respectively; p < 0.0001), but not between stage II and III disease (p = 0.98). CONCLUSIONS: The new 8th Ed UICC/AJCC TNM staging system better discriminates between stage I and Stage II HPV OPSCC with respect to OS compared with the 7th Ed staging system. Further investigation is required for stage III or IV patients.

Reflecting on survivorship outcomes to aid initial decision making in patients treated for IDH-mutated anaplastic glioma.

BACKGROUND: Patients with anaplastic glioma (AG) harboring an isocitrate dehydrogenase mutation have potential durable survival after intensity-modulated radiotherapy (IMRT) and chemotherapy. Understanding long-term functioning, and the factors that have an impact on later effects, is important for decision making. METHODS: Consecutive patients with AG who received IMRT were reviewed with regard to 6 survivorship domains, including Eastern Cooperative Oncology Group (ECOG) performance status, Medical Research Council (MRC) neurological status, late toxicity, comorbidity, functional status (employment/driving), and psychosocial events. Assessments were performed at baseline before RT; at month +6; and at years +1, +3, and +5 after RT. The primary endpoints were ECOG at year +3 and employment at year +3. RESULTS: A total of 146 patients were included, with a median follow-up of 5.1 years. The 6-year overall survival rate was 78.7% (95% CI, 71.1%-87.0%). Baseline ECOG performance status was 0 to 1 in 82.2% of patients but improved at year +1 (95.7%) and year +3 (97.2%). Employment rates at year +3 and year +5 were 70.1% and 76.5%, respectively, compared with 61.6% at baseline. Worse ECOG performance status at year +3 was related to the anaplastic astrocytoma subtype (P = .001), delayed RT (P = .081), multiple craniotomies performed before RT (P = .002), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), seizures (P = .038), neurocognitive disturbance (P < .001), and the presence of recurrent disease (P = .004). Absent or impaired employment at year +3 was found to be related to older age (P = .007), delayed timing of RT (P = .023), multiple craniotomies prior to RT (P = .005), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), and neurocognitive disturbance (P < .001). CONCLUSIONS: Patients with AG with an isocitrate dehydrogenase mutation have the potential for prolonged survival. Functional status appears to be good in patients who are free of disease progression at 3 to 5 years after IMRT, with >95% of patients having high ECOG performance status and >75% being employed.

Role of delayed salvage bevacizumab at symptomatic progression of chemorefractory glioblastoma.

BACKGROUND: Assess benefit of salvage bevacizumab (BEV) at time of symptomatic progression in patients with refractory glioblastoma (GBM). METHODS: Patients managed with adjuvant long course chemo-radiation therapy for GBM were entered into a prospective database. At chemorefractory symptomatic progression, patients were offered BEV or best supportive care. Re-irradiation (ReRT) was used with BEV in selected patients. BEV continued indefinitely until deterioration limited hospital based infusion. The primary endpoint was median survival calculated from date of decision for BEV to proceed (BEVstart), or decision to decline BEV (BEVreject). RESULTS: Fifty-five patients were managed of which 48 patients have relapsed disease. The median survival post relapse was 6 months (95%CI: 4.6-7.4). At relapse, 28 patients received BEV with only 14% delivered at first relapse. The median number of BEV cycles was 8 (range 1-25). ReRT was subsequently used in 16 (33%) relapsed patients. BEV treated patients were associated with improved median survival post relapse with 9 months vs 3 months (p < 0.01). The median survival from BEV related decision-making at symptomatic refractory progression to death was 4 months (95%CI: 2.0-6.0). BEVstart was associated with improved survival from this date with median survival of 6 months vs 1 month with BEVreject (p < 0.01). Median survival with ReRT from this date was 8 months vs 3 months without ReRT (p = 0.01). In the BEV patients at eventual progression, death occurred at a median of 30 days post BEV cessation. CONCLUSION: In this clinic managing selected patients with chemorefractory progressive glioblastoma, delayed salvage bevacizumab, often in combination with re-irradiation, may provide an increase in survival duration compared with best supportive care.

Both four-dimensional computed tomography and four-dimensional cone beam computed tomography under-predict lung target motion during radiotherapy.

BACKGROUND AND PURPOSE: To test the hypothesis that 4DCT and 4DCBCT-measured target motion ranges predict target motion ranges during lung cancer SABR. MATERIALS AND METHODS: Ten lung SABR patients were implanted with Calypso beacons. 4DCBCT was reconstructed for 29 fractions (1-4fx/patient) from a 1 min CBCT scan. The beacon centroid motion segmented for all 4DCT and 4DCBCT bins was compared with the real-time imaging and treatment beacon centroid ("target") motion range (4SDs) for each fraction. We tested the hypotheses that (1) 4DCT and 4CBCT predict treatment motion range and (2) there is no difference between 4DCT and 4DCBCT for predicting treatment motion range. Phase-wise root-mean-square errors (RMSEs) between imaging and treatment motion and reconstructed motion (4DCT, 4DCBCT) were calculated. Relationships between motion ranges in 4DCT and 4DCBCT and imaging and treatment motion ranges were investigated for the superior-inferior (SI), left-right (LR) and anterior-posterior (AP) directions. Baseline drifts and amplitude variability were investigated as potential factors leading to motion misrepresentation. RESULTS: SI 4DCT, 4DCBCT, imaging and treatment motion ranges were 6.3 ±â€¯3.6 mm, 7.1 ±â€¯4.5 mm, 11.1 ±â€¯7.5 mm and 10.9 ±â€¯6.9 mm, respectively. Similar 4DCT and 4DCBCT under-predictions were observed in the LR and AP directions. Hypothesis (1) was rejected (p < 0.0001). Treatment target motion range was under-predicted in 4DCT by factors of 1.7, 1.9 and 1.7 and in 4DCBCT by factors of 1.5, 1.6 and 1.6 in the SI, LR, and AP directions, respectively. RMSEs were generally lower for end-exhale than inhale. 4DCBCT showed higher correlations with the imaging and treatment target motion than 4DCT and testing hypothesis (2) a statistically significant difference between 4DCT and 4DCBCT was shown in the SI direction (p = 0.03). CONCLUSION: For lung SABR patients both 4DCT and 4DCBCT significantly under-predict treatment target motion ranges.

Focal radiation therapy for limited brain metastases is associated with high rates of local control and low subsequent whole brain radiation therapy.

BACKGROUND: Assess clinical outcomes of focal radiotherapy (RT) in patients with limited brain metastasis (LBM) with whole brain RT (WBRT) avoidance. METHODS: Patients diagnosed with LBM were entered into a database between January 2010 and February 2017. Patients were recommended WBRT avoidance with focal therapy and three-monthly magnetic resonance imaging. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, initial-site failure (ISF), distant brain relapse (DBF), leptomeningeal disease and rate of WBRT. Analysis involved Kaplan-Meier survival estimate with log-rank tests and Cox-regression analysis. RESULTS: One hundred and sixty-six patients were managed with median follow-up of 13 months and median overall survival of 15 months (95% confidence interval (CI) 10.8-19.2). Eighty-three patients had central nervous system (CNS) relapse with median progression-free survival of 11 months (95% CI 6.7-15.3), of which most failures were DBF (83.1%) with 27 ISF (32.5%). Of the ISFs, 12 (43%) had surgery alone, six had chemotherapy alone and nine received RT. Surgery or chemotherapy alone compared with RT had a significantly higher incidence of ISF with a hazard ratio of 4.96 (P < 0.0001, 95% CI 2.10-11.83) and 6.54 (P = 0.001, 95% CI 2.26-18.87), respectively. WBRT was utilized in only 24 patients, with 83% patients free of WBRT at 12 months. On univariate analysis, number of metastases (P = 0.04), symptomatic extracranial disease (P = 0.04) and early CNS relapse within 6 months (P < 0.01) had worse survival. No grade 3-4 toxicity events were noted in 129 patients undergoing RT. CONCLUSION: Focal RT has a low rate of ISF with low toxicity in patients with LBMs. CNS progression was mainly DBF with low rates of salvage WBRT.