The present study describes the optimization of 68Ga radiolabeling with PAMAM dendrimer–DOTA conjugate. A conjugate (PAMAM–DOTA) concentration of 11.69 µM, provided best radiolabeling efficiency of more than 93.0% at pH 4.0, incubation time of 30.0 min and reaction temperature ranging between 90 and 100 °C. The decay corrected radiochemical yield was found to be 79.47 ± 0.01%. The radiolabeled preparation ([68Ga]-DOTA–PAMAM-D) remained stable (radiolabeling efficiency of 96.0%) at room temperature and in serum for up to 4-h. The plasma protein binding was observed to be 21.0%. After intravenous administration, 50.0% of the tracer cleared from the blood circulation by 30-min and less than 1.0% of the injected activity remained in blood by 1.0 h. The animal biodistribution studies demonstrated that the tracer excretes through the kidneys and about 0.33% of the %ID/g accumulated in the tumor at 1 h post injection. The animal organ's biodistribution data was supported by animal PET imaging showing good ‘non-specific’ tracer uptake in tumor and excretion is primarily through kidneys. Additionally, DOTA–PAMAM-D conjugation with αVβ3 receptors targeting peptides and drug loading on the dendrimers may improve the specificity of the 68Ga labeled product for imaging and treating angiogenesis respectively.

BackgroundOral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects, notably impaired ability to eat, drink and talk. The development of new chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients. ObjectivesTo determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal cancer results in improved survival, disease free survival, progression free survival, locoregional control and reduced recurrence of disease. To determine which regimen and time of administration (induction, concomitant or adjuvant) is associated with better outcomes. Search methodsElectronic searches of the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE, EMBASE, AMED were undertaken on 1st December 2010. Reference lists of recent reviews and included studies were also searched to identify further trials. Selection criteriaRandomised controlled trials where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and which compared the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration, were included. 1 Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy (Review)

Background. In Ontario, Canada, patient reported outcomes (PRO) evaluation through Edmonton Symptom Assessment System (ESAS) has been integrated into clinical workflow since 2007. As stage IV non-small cell lung cancer (NSCLC) is associated with substantial disease and treatment-related morbidity, this province-wide study investigated moderateto-severe symptom burden in this population. Methods. ESAS collected from stage IV NSCLC patients diagnosed between 2007-2018 linked to Ontario provincial healthcare system database were studied. ESAS acquired within 12 months following diagnosis were analyzed and the proportion reporting moderate-to-severe scores (ESAS ≥4) in each domain was calculated. Predictors of moderateto-severe scores were identified using multivariable Poisson regression models with robust error variance. Results. Of 22,799 patients, 13,289 (58.3%) completed ESAS (84,373 assessments) in the year following diagnosis. Patients with older age, high comorbidity, and not receiving active cancer therapy had lower ESAS completion. Majority (94.4%) reported at least 1 moderate-to-severe symptoms. Most prevalent were tiredness (84.1%), low wellbeing (80.7%), low appetite (71.7%), and shortness of breath (67.8%). Most symptoms peaked at diagnosis, while declining, remained high in the following year.On multivariable analyses, comorbidity, low income, non-immigrants, and urban residency were associated with moderate-to-severe symptoms. Moderate-to-severe scores in all ESAS domains aside from anxiety were associated with radiotherapy within 2 weeks prior, while drowsiness, low appetite and wellbeing, nausea, and tiredness were associated with systemic therapy within 2 weeks prior. Conclusion. This province-wide PRO analysis showed moderate-to-severe symptoms were prevalent and persistent among metastatic NSCLC patients, underscoring the need to address supportive measures in this population especially around treatments. The Oncologist ;9999:• • Implications for Practice: This is the largest patient reported outcome (PRO) results among lung cancer patients worldwide. Our results demonstrated the worse moderate-to-severe symptoms among stage IV non-small cell lung cancer patients compared to other patients with metastatic, other malignancies such as breast, gastric, or esophageal cancers assessed with similar methodology. These patients symptom severity also peaked early, and persistently high during 1 year follow-up. Symptoms burden was also associated with recent radiation and systemic treatments. This emphasized the importance of early and sustained PRO collection to detect actionable symptom progression, especially around treatments. Moreover, PRO

Background: Clinical benefit scores (CBS) are key elements of the ASCO Value Framework (ASCO-VF) and are weighted based on a hierarchy of efficacy endpoints: hazard ratio for death (HR OS), median overall survival (mOS), HR for disease progression (HR PFS), median progression-free survival (mPFS), and response rate (RR). When HR OS is unavailable, the other endpoints serve as “surrogates” to calculate CBS. CBS are computed from PFS or RR in 39.6% of randomized controlled trials. This study examined whether surrogate-derived CBS offer unbiased scoring compared with HR OS–derived CBS. Methods: Using the ASCO-VF, CBS for advanced disease settings were computed for randomized controlled trials of oncology drug approvals by the FDA, European Medicines Agency, and Health Canada in January 2006 through December 2017. Mean differences of surrogate-derived CBS minus HR OS–derived CBS assessed the tendency of surrogate-derived CBS to overestimate or underestimate clinical benefit. Spearman’s correlation evaluated the association between surrogate- and HR OS–derived CBS. Mean absolute error assessed the average difference between surrogate-derived CBS relative to HR OS–derived CBS. Results: CBS derived from mOS, HR PFS, mPFS, and RR overestimated HR OS–derived CBS in 58%, 68%, 77%, and 55% of pairs and overall by an average of 5.62 (n=90), 6.86 (n=110), 29.81 (n=101), and 3.58 (n=108), respectively. Correlation coefficients were 0.80 (95% CI, 0.70–0.86), 0.38 (0.20–0.53), 0.20 (0.00–0.38), and 0.01 (–0.18 to 0.19) for mOS-, HR PFS–, mPFS-, and RR-derived CBS, respectively, and mean absolute errors were 11.32, 12.34, 40.40, and 18.63, respectively. Conclusions: Based on the ASCO-VF algorithm, HR PFS–, mPFS-, and RR-derived CBS are suboptimal surrogates, because they were shown to be biased and poorly correlated to HR OS–derived CBS. Despite lower weighting than OS in the ASCO-VF algorithm, PFS still overestimated CBS. Simple rescaling of surrogate endpoints may not improve their validity within the ASCO-VF given their poor correlations with HR OS–derived CBS.

The introduction of oral vascular endothelial growth factor receptor tyrosine kinase inhibitors therapy has been associated with major improvements in outcome for patients with metastatic kidney cancer. Each drug has been licensed with rigid dosing criteria that are not optimal for all patients. This paper reviews the growing body of evidence suggesting that individualized dosing based on toxicity may be associated with optimal drug exposure for each patient and improved outcome both in the metastatic and adjuvant setting.

12092 Background: Stage IV NSCLC patients have significant disease and treatment-related morbidity. In Ontario, Canada, cancer patients complete Edmonton Symptom Assessment System (ESAS) questionnaires, a tool that elicits patients’ self-reported severity of common cancer-associated symptoms at clinical encounters. ESAS domains are: anxiety, depression, drowsiness, appetite, nausea, pain, shortness of breath, tiredness and well-being. The purpose of this study is to examine moderate-to-severe symptom burden in the 12 months following a diagnosis of stage IV NSCLC. Methods: Using administrative databases and unique encoded identifiers, stage IV NSCLC diagnosed between January 2007 and September 2018 were evaluated for symptom screening with ESAS in the 12 months following diagnosis. Proportion of patients reporting moderate-to-severe score (i.e. ESAS ≥4) in each domain within 12 months were calculated. Patients reporting moderate-to-severe within the different ESAS domains of were plotted over time. Multivariable (MV) Poisson regression models with potential covariates such as age, sex, Elixhauser comorbidity index, income quintiles, and lung cancer treatments received were constructed to identify factors associated with moderate-to-severe symptoms. Results: Of 22,799 stage IV NSCLC patients, 13,289 (58.3%) had completed ESAS (84,373 unique assessments) in the year following diagnosis. Patients with older age, high comorbidity, and not receiving active cancer therapy were less likely to complete ESAS. Most (94.4%) reported at least 1 moderate-to-severe score. Most prevalent moderate-to-severe ESAS symptoms within 12 months after diagnosis were tiredness (84.1%), lack of wellbeing (80.7%), low appetite (71.7%), and shortness of breath (67.8%); nausea was the least prevalent (34.6%). Most symptoms peaked at diagnosis and persisted in the year after diagnosis. On adjusted MV analyses, patients with high comorbidity, low income, and urban residency were associated with increased moderate-to-severe symptoms. Moderate-to-severe scores in all ESAS symptoms were associated with delivery of radiotherapy within 2 weeks prior, while moderate-to-severe nausea, drowsiness, tiredness, low appetite, and lack of wellbeing were associated with delivery of systemic therapy within preceding 2 weeks. Conclusions: In this population-based analysis of stage IV NSCLC PROs in the year following diagnosis, moderate-to-severe symptoms were highly prevalent and persistently high, underscoring the need to address supportive requirements in this at-risk population.

620 Background: Up to one-third of patients with mRCC can present with asymptomatic brain metastases (BM). Timely identification of BM allows for the delivery of early local interventions, which may lead to improved patient outcomes. To investigate the potential utility of routine intra-cranial imaging, we compared the outcomes of mRCC patients with asymptomatic versus symptomatic BM. Methods: Using the Canadian Kidney Cancer information system (CKCis) database, we identified mRCC patients diagnosed with BM between 2011 and 2018. This cohort was divided into two groups dependent on the presence or absence of neurological symptoms. Baseline patient demographics, clinico-pathological disease characteristics and survival data were extracted. Statistical analysis was through chi-square tests, analysis of variance and Kaplan-Meier method to characterize survival outcomes. Results: 269 mRCC patients with BM were identified with the majority presenting with symptomatic disease (n=163; 61%). No significant differences in clinico-pathological disease characteristics were identified. Median overall survival (OS) from mRCC diagnosis for asymptomatic patients was 33.4 months (interquartile range, IQR 27.8-64.4) versus 34.5 months (20.4-43.4) for symptomatic patients (p=0.35). Median OS from time of BM diagnosis revealed a trend favoring asymptomatic, as compared to symptomatic, patients [24.5 (17.6-24.9) vs. 13.1 months (9.0-20.6), p=0.06]. Factors associated with worse OS from time of BM diagnosis included presentation with symptomatic BM [hazard ratio, HR (95% CI): 1.40 (1.03-1.90), p=0.034] and International Metastatic Renal Cell Carcinoma Consortium Database (IMDC)-characterized intermediate/poor risk disease [HR (95% CI): 1.47 (1.01-2.13), p=0.045]. Conclusions: Routine intra-cranial imaging may lead to earlier identification of BM in mRCC. However, further investigation as to whether this practice improves survival is warranted.

TPS6114 Background: Lymphatic mapping identifies neck lymph nodes at risk for cancer spread in patients with lateralized oropharyngeal (OPC) squamous cell carcinoma. We hypothesize that a lymphatic mapping guided approach to radiotherapy (RT) treatment of the contralateral neck will enable safe de-escalation of therapy with acceptable disease control with potential benefits in RT related toxicity, QOL, swallowing function and economics. Methods: HN.11 is a Canadian Cancer Trials Group international multi-centre, non-inferiority randomized phase III trial comparing a lymphatic mapping-guided approach for management of the contralateral neck (experimental) vs. bilateral neck radiation therapy (RT) (control). The primary objective is to determine if a lymphatic mapping-guided approach for management of the contralateral neck has a non-inferior disease-free survival (DFS) compared to bilateral neck RT. Secondary objectives: To compare swallowing related QOL, xerostomia, isolated contralateral neck failure, overall survival, loco-regional failure, distant metastases, RT-related toxicities, patient reported adverse events (PRO CTCAE), gastrostomy tube usage, and economics indicators (resource utilization, lost productivity, financial toxicity, EQ5D). Exploratory objectives: Swallowing function using video fluoroscopic swallow studies, head and neck-cancer specific QOL, patterns of lymphatic drainage, radiomic prediction of contralateral lymphatic drainage, correlation of tumour somatic mutations and ctDNA with disease recurrence. Statistical Design: The target sample size is 510 patients. The experimental arm will be considered non-inferior if the upper limit of the one sided 95% confidence interval (CI) of the estimated hazard ratio (HR) does not exceed 1.46 (non-inferiority margin of 6.5% for 2-year DFS). In the primary intention-to-treat (ITT) analysis, the study has 81% power, with a one-sided type I error rate of 5%, assuming 5 years of accrual, 3-years of follow up to observe 178 DFS events, and a 5% loss to follow up. If non-inferiority is demonstrated in the ITT analysis, a secondary per-protocol analysis will be performed, analyzing those patients treated as per their allocation, with 80% power to detect non-inferiority of the experimental arm assuming a conservative 10% cross-over from the experimental to the control arm (i.e. failed lymphatic mapping). Conduct to Date: Study activation September 29, 2022. First enrollment was February 10, 2023. Supported by Canadian Cancer Society, Canadian Institutes of Health Research, National Cancer Trials Network (NCTN). Clinical trial information: NCT05451004 .