Faculty Bibliography

BACKGROUND:Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab. METHODS:We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual. FINDINGS/RESULTS:Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported. INTERPRETATION/CONCLUSIONS:Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial. FUNDING/BACKGROUND:AstraZeneca.

OBJECTIVE:Radiobiological models have been used to calculate the outcomes of treatment plans based on dose-volume relationship. This study examines several radiobiological models for the calculation of tumor control probability (TCP) of intensity modulated radiotherapy plans for the treatment of lung, prostate, and head and neck (H&N) cancers. METHODS:Dose volume histogram (DVH) data from the intensity modulated radiotherapy plans of 36 lung, 26 prostate, and 87  H&N cases were evaluated. The Poisson, Niemierko, and Marsden models were used to calculate the TCP of each disease group treatment plan. The calculated results were analyzed for correlation and discrepancy among the three models, as well as different treatment sites under study. RESULTS:The median value of calculated TCP in lung plans was 61.9% (34.1-76.5%), 59.5% (33.5-73.9%) and 32.5% (0.0-93.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in prostate plans was 85.1% (56.4-90.9%), 81.2% (56.1-88.7%) and 62.5% (28.2-75.9%) with the Poisson, Niemierko, and Marsden models, respectively. The median value of calculated TCP in H&N plans was 94.0% (44.0-97.8%) and 94.3% (0.0-97.8%) with the Poisson and Niemierko models, respectively. There were significant differences between the calculated TCPs with the Marsden model in comparison with either the Poisson or Niemierko model (p < 0.001) for both lung and prostate plans. The TCPs calculated by the Poisson and Niemierko models were significantly correlated for all three tumor sites. CONCLUSION/CONCLUSIONS:There are variations with different radiobiological models. Understanding of the correlation and limitation of a TCP model with dosimetric parameters can help develop the meaningful objective functions for plan optimization, which would lead to the implementation of outcome-based planning. More clinical data are needed to refine and consolidate the model for accuracy and robustness. Advances in knowledge: This study has tested three radiobiological models with varied disease sites. It is significant to compare different models with the same data set for better understanding of their clinical applicability.

It is estimated that approximately 24% of the US population has at least one tattoo. However, tattoo ink ingredients include heavy metals (high atomic number Z) that are not regulated, which can cause skin reactions. This study investigates the dosimetric effects in surface dose due to high-Z elements in tattoo ink under electron beam irradiation. Four commercially available tattoo ink colors, black, red, yellow, and blue were chosen. The elemental composition of the tattoo ink samples was analyzed using X-ray Fluorescence (XRF). An ultrathin-window parallel plate ion chamber was used to measure the surface dose perturbation (ratio of ionizations with and without tattoo ink) for 6 - 20 MeV electron beams. The elemental concentration in the tattoo ink samples showed high-Z elements, with Z ranging from 11 to 92. The dose perturbation ranged from 1.4% up to 6% for the yellow ink for the 6 MeV electron beam, with similar values across the rest of the electron energies, whereas the black, red, and blue inks presented up to 3% dose perturbation for the same range of energies. Based on this initial study, we conclude that commercially available tattoo inks contain large amounts of high-Z metals that may contribute to dose perturbation. Therefore treatment of superficial lesions with electron beams in a tattooed area should be monitored for signs of early skin reaction during radiation therapy treatments.

Introduction Oral mucositis (OM) is one of the most debilitating adverse effects in patients undergoing cancer treatment. Physiologically, chemotherapy (CT) and radiotherapy (RT) evoke a profound inflammatory response, resulting in mucosal injury, which can result in an increased susceptibility to infection. Objectives The objective of this pilot study was to asses the effects of a novel oral care protocol on OM severity and to evaluate salivary cytokines in head and neck cancer patients undergoing RT or CT/RT at the NYU Langone Laura and Isaac Perlmutter Cancer Center. Methods A total of ten participants were included in this study, and randomized to an InterventionGroup (IG), or ControlGroup (CG). Subjects assigned to the CG received a standard of care oral hygiene on a bi-weekly basis. Subjects assigned to the IG received the Oral Mucosal Deterging and Dental Prophylaxis (OMDP) protocol weekly, which consisted of a periodontal surface debridement and cleansing and deterging of the oral mucosa surfaces. Results Salivary inflammatory biomarkers, noted in levels of IFN-gamma, IL10, IL12p70, IL13, TNFalpha and IL-6 had a significant increase in the CG and reduced or stayed the same under the IG. Although not statistically significant, a tendency of pain decrease was observed in the IG and difficulty in swallowing was statistically significant when both groups were compared (p = 0,016). Conclusions These results suggest that overall inflammation was consistently higher as compared to baseline in the CG, providing encouragement for the effectiveness of the oral care protocol as a coadjutant treatment for this population

Introduction Mucosal damage secondary to cancer therapy occurs in 30% of patients receiving standard chemotherapy and 80% of patients receiving high dose chemotherapy. Mucositis is painful, interferes with nutrition, hydration, and often causes delay or reduction in chemotherapy. 20%of CLABSIs at NYU Langone Health (NYULH) in 2015 were secondary to mucosal translocation Objectives The goal of the NYULH Interprofessional Mucositis Workgroup is to decrease the incidence of mucositis in adult and pediatric oncology patients. Methods An interprofessional team of inpatient and outpatient, adult and pediatric medical providers, dentists, nurse practitioners, nurses, pharmacists, and IT collaborated to develop a standardized NYULH mucositis guideline for prevention and treatment. Results An evidenced-based standardized guideline for mucositis prevention and treatment across adult and pediatric inpatient and outpatient was developed. Conclusions This project suggests that interprofessional collaboration is an effective strategy for development and implementation of a standardized guideline for both pediatric and adult inpatients and outpatients

Oral mucositis (OM) is among the most common, painful, and debilitating toxicities of cancer regimen-related treatment, resulting in the formation of ulcers, which are susceptible to increased colonization of microorganisms. Novel discoveries in OM have focused on understanding the host-microbial interactions, because current pathways have shown that major virulence factors from microorganisms have the potential to contribute to the development of OM and may even prolong the existence of already established ulcerations, affecting tissue healing. Additional comprehensive and disciplined clinical investigation is needed to carefully characterize the relationship between the clinical trajectory of OM, the local levels of inflammatory changes (both clinical and molecular), and the ebb and flow of the oral microbiota. Answering such questions will increase our knowledge of the mechanisms engaged by the oral immune system in response to mucositis, facilitating their translation into novel therapeutic approaches. In doing so, directed clinical strategies can be developed that specifically target those times and tissues that are most susceptible to intervention.