Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.

Single-Fraction vs Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases (SAFRON II): The Trans Tasman Radiation Oncology Group 13.01 Phase 2 Randomized Clinical Trial.

IMPORTANCE: Evidence is lacking from randomized clinical trials to guide the optimal approach for stereotactic ablative body radiotherapy (SABR) in patients with pulmonary oligometastases. OBJECTIVE: To assess whether single-fraction or multifraction SABR is more effective for the treatment of patients with pulmonary oligometastases. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, unblinded, phase 2 randomized clinical trial of 90 patients across 13 centers in Australia and New Zealand enrolled patients with 1 to 3 lung oligometastases less than or equal to 5 cm from any nonhematologic malignant tumors located away from the central airways, Eastern Cooperative Oncology Group performance status 0 or 1, and all primary and extrathoracic disease controlled with local therapy. Enrollment was from January 1, 2015, to December 31, 2018, with a minimum patient follow-up of 2 years. INTERVENTIONS: Single fraction of 28 Gy (single-fraction arm) or 4 fractions of 12 Gy (multifraction arm) to each oligometastasis. MAIN OUTCOMES AND MEASURES: The main outcome was grade 3 or higher treatment-related adverse events (AEs) occurring within 1 year of SABR. Secondary outcomes were freedom from local failure, overall survival, disease-free survival, and patient-reported outcomes (MD Anderson Symptom Inventory-Lung Cancer and EuroQol 5-dimension visual analog scale). RESULTS: Ninety participants were randomized, of whom 87 were treated for 133 pulmonary oligometastases. The mean (SD) age was 66.6 [11.6] years; 58 (64%) were male. Median follow-up was 36.5 months (interquartile range, 24.8-43.9 months). The numbers of grade 3 or higher AEs related to treatment at 1 year were 2 (5%; 80% CI, 1%-13%) in the single-fraction arm and 1 (3%; 80% CI, 0%-10%) in the multifraction arm, with no significant difference observed between arms. One grade 5 AE occurred in the multifraction arm. No significant differences were found between the multifraction arm and single-fraction arm for freedom from local failure (hazard ratio [HR], 0.5; 95% CI, 0.2-1.3; P = .13), overall survival (HR, 1.5; 95% CI, 0.6-3.7; P = .44), or disease-free survival (HR, 1.0; 95% CI, 0.6-1.6; P > .99). There were no significant differences observed in patient-reported outcomes. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, neither arm demonstrated evidence of superior safety, efficacy, or symptom burden; however, single-fraction SABR is more efficient to deliver. Therefore, single-fraction SABR, as assessed by the most acceptable outcome profile from all end points, could be chosen to escalate to future studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01965223.

Potentially actionable FGFR2 high-level amplification in thymic sebaceous carcinoma.

Our aim was to investigate sebaceous differentiation in thymus tumours and to identify new actionable genomic alterations. To this end we screened 35 normal and 23 hyperplastic thymuses, 127 thymomas and 41 thymic carcinomas for the presence of sebaceous differentiation as defined by morphology and expression of adipophilin and androgen receptor (AR). One primary thymic carcinoma showed morphology of sebaceous carcinomas (keratinizing and foam cells, calcifications, giant cells), a strong expression of adipophilin and AR together with squamous markers. NGS revealed high-level amplification of fibroblast growth factor receptor 2 (FGFR2). In thymuses and thymomas, no cells with sebaceous morphology were present. Occasionally, macrophages or epithelial cells showed adipophilin-positivity, however, without co-expression of AR. Thymic sebaceous carcinoma should be considered if a thymic carcinoma shows clear or foamy features. Testing for FGFR2 amplification might be warranted when searching for actionable genomic alterations in sebaceous carcinomas in the mediastinum and in other locations.

Sinonasal teratocarcinosarcoma: a case report.

BACKGROUND: Sinonasal teratocarcinosarcoma is a rare and aggressive malignancy with histological features of both carcinosarcoma and teratoma. The optimal management of this malignancy is unclear, with most patients being managed by a combination of surgery and radiotherapy. CASE PRESENTATION: We describe an 83-year-old white woman with sinonasal teratocarcinosarcoma of her left nasal cavity treated with surgical debulking initially with radiological evidence of residual disease which was treated with radiotherapy (60 Gy in 30 fractions). A follow-up examination at 2 years showed no evidence of recurrence. CONCLUSIONS: In cases of sinonasal teratocarcinosarcoma with residual disease post-surgery, radiotherapy alone can be an effective option.

Radiation recall pneumonitis induced by erlotinib after palliative thoracic radiotherapy for lung cancer: Case report and literature review.

Radiation lung injury usually develops 1-6 months after cessation of radiation therapy to the lung. Acute change in the previously irradiated lung after administration of antineoplastic agent is known as radiation recall pneumonitis. Erlotinib is a reversible epidemal growth factor receptor tyrosine kinase inhibitor, which is effective for patients with advanced lung cancer with epidermal growth factor receptor mutations. Here we report a rare case of radiation recall pneumonitis following treatment with erlotinib 4 months after palliative radiotherapy to the lung. A 76-year-old man with non-small cell lung cancer was treated with polychemotherapy, palliative thoracic irradiation (30 Gy in 12 fractions) and erlotinib thereafter. Two months after administration of erlotinib he developed of severe dyspnea, cough, anorexia and lack of energy. CT chest revealed extensive radiation pneumonitis. Erlotinib was ceased and high-dose steroids were started. The symptoms ultimately resolved and erlotinib was resumed cautiously after 11 weeks. On dosimetric analysis, lung V20 and the mean lung dose were 20.33% and 10.7 Gy, respectively, and hence, the risk of radiation pneumonitis is very low. These data indicate that systemic administration of erlotinib after low-dose palliative radiation therapy can be associated with unexpected toxicity when visceral organs are within the radiation field.

Hippocampal avoidance with volumetric modulated arc therapy in melanoma brain metastases - the first Australian experience.

PURPOSE: Volumetric modulated arc therapy (VMAT) can deliver intensity modulated radiotherapy (IMRT) like dose distributions in a short time; this allows the expansion of IMRT treatments to palliative situations like brain metastases (BMs). VMAT can deliver whole brain radiotherapy (WBRT) with hippocampal avoidance and a simultaneous integrated boost (SIB) to achieve stereotactic radiotherapy (SRT) for BMs. This study is an audit of our experience in the treatment of brain metastases with VMAT in our institution. METHODS AND MATERIALS: Metastases were volumetrically contoured on fused diagnostic gadolinium enhanced T1 weighted MRI/planning CT images. Risk organs included hippocampus, optic nerve, optic chiasm, eye, and brain stem. The hippocampi were contoured manually as one paired organ with assistance from a neuroradiologist. WBRT and SIB were integrated into a single plan. RESULTS: Thirty patients with 73 BMs were treated between March 2010 and February 2012 with VMAT. Mean follow up time was 3.5 months. For 26 patients, BMs arose from primary melanoma and for the remaining four patients from non-small cell lung cancer (n= 2), primary breast cancer, and sarcoma. Mean age was 60 years. The male to female ratio was 2:1. Five patients were treated without hippocampal avoidance (HA) intent. The median WBRT dose was 31 Gy with a median SIB dose for BMs of 50 Gy, given over a median of 15 fractions. Mean values for BMs were as follows: GTV = 6.9 cc, PTV = 13.3 cc, conformity index = 8.6, homogeneity index = 1.06. Mean and maximum hippocampus dose was 20.4 Gy, and 32.4 Gy, respectively, in patients treated with HA intent. Mean VMAT treatment time from beam on to beam off for one fraction was 3.43 minutes, which compared to WBRT time of 1.3 minutes. Twenty out of 25 assessable lesions at the time of analysis were controlled. Treatment was well tolerated; grade 4 toxicity was reported in one patient. The median overall survival was 9.40 months CONCLUSIONS: VMAT for BMs is feasible, safe and associated with a similar survival times and toxicities to conventional SRT+/-WBRT. The advantage of VMAT is that WBRT and SRT can be delivered at the same time on one machine.