A Combined Neutron and Proton Regimen for Advanced Salivary Tumors: Early Clinical Experience.

Background and objective  Fast neutron radiotherapy (NRT) is a high linear energy transfer (LET) particle therapy that offers a local control (LC) advantage over low-LET X-rays in the treatment of advanced and unresectable salivary gland malignancies. However, in tumors approximating the base of skull (BOS), target volumes may be underdosed to minimize toxicity to the central nervous system (CNS). In this setting, a proton beam boost to the underdosed part of the tumor may improve LC. We report our early experience with a hybrid neutron-proton approach in patients with BOS involvement. Materials and methods We retrospectively reviewed 29 patients with locally advanced and unresectable salivary gland tumors involving the BOS between 2014-2018. The median age of the patients was 56 years, with the majority of them having adenoid cystic carcinomas (ACC) (79%) with advanced T4a/b disease (86%), pathologic perineural invasion (PNI) (55.2%), and orbital invasion (34.5%). Five patients (17.2%) were cases of re-irradiation. Surgical resection was attempted in 15 patients (51.7%), of which none achieved negative margins. The median neutron dose was 18.4 neutron Gray (nGy) with a sequential proton boost (PB) with a median dose of 25 Gy [relative biological effectiveness (RBE)] (range: 16-45 Gy). Toxicity was graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Descriptive statistics and the Kaplan-Meier method were used. Results At a median follow-up of 18.9 months [interquartile range (IQR): 6.1-32.5], the entire cohort's overall survival (OS) was 93.1%, progression-free survival (PFS) was 79.3%, and LC was 89.7%. Among patients who were not re-irradiated (n=24), the most commonly recorded acute grade 3 toxicities were mucositis (50%) and dermatitis (37.5%). There was no documented acute grade 4/5 events. Late grade 3/4 events included trismus (n=1), hearing loss (n=2), visual loss (n=6), and bone necrosis (n=1). There were no reported late grade 5 events in de novo patients. Conclusion In this challenging cohort with a poor prognosis, early outcomes for a hybrid neutron-proton approach were found to be promising. Further studies involving longer follow-ups with a larger cohort of patients are required to validate our findings.

Neutrophil-lymphocyte ratio kinetics in patients with advanced solid tumours on phase I trials of PD-1/PD-L1 inhibitors.

BACKGROUND: Although the neutrophil-lymphocyte ratio (NLR) is prognostic in many oncological settings, its significance in the immunotherapy era is unknown. Mechanistically, PD-1/PD-L1 inhibitors may alter NLR. We sought to characterise NLR kinetics in patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors. METHODS: Electronic records of patients treated with PD-1/PD-L1 inhibitors on phase I trials across three sites were reviewed. A high NLR (hNLR) was predefined as >5. Univariate logistic regression models were used for toxicity, response analyses and Cox models for overall survival (OS) and progression-free survival analyses. Landmark analyses were performed (cycle two, three). Longitudinal analysis of NLR was performed utilising a mixed effect regression model. RESULTS: The median OS for patients with hNLR was 8.5 months and 19.4 for patients with low NLR, (hazard ratio [HR] = 1.85, 95% confidence interval [CI] 1.15-2.96, p = 0.01). On landmark analysis, hNLR was significantly associated with inferior OS at all time points with a similar magnitude of effect over time (p < 0.05). On multivariate analysis, NLR was associated with OS (HR 1.06, 95% CI 1.01-1.11, p = 0.01). NLR did not correlate with increased immune toxicity. Longitudinally, NLR correlated with response: NLR decreased by 0.09 (95% CI: -0.15 to -0.02; p = 0.01) per month in responders compared with non-responders. CONCLUSIONS: hNLR at baseline and during treatment is adversely prognostic in patients with advanced malignancies receiving PD-1/PD-L1 blockade. Importantly, NLR reduced over time in responders to immunotherapy. Taken together, these data suggest that baseline and longitudinal NLR may have utility as a unique biomarker to aid clinical decision-making in patients receiving immunotherapy.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.