11123 Background: We tested the primary question whether the addition of cetuximab to postoperative radiotherapy (IMRT) results in poorer patient reported outcomes (PROs) at 12 months compared to IMRT alone. We also examined changes in PROs over time. Methods: Randomized and eligible patients who consented to quality of life (QOL) assessment completed PROs measured by 5 instruments, prior to treatment (baseline) and at 3, 12, and 24 months after IMRT. Instruments included: 1) Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN), a multidimensional QOL instrument for use with head and neck cancer patients; 2) University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) covering mouth/throat dryness and its impact on oral health-related QOL; 3) Dermatology Life Quality Index (DLQI) for skin-related changes; 4) EuroQol (EQ-5D-3L) covering usual activities and perceived current health state; 5) Performance Status Scale for Head and Neck Cancer (PSS-HN) assessing normalcy of diet, public eating, and understandability of speech. Higher scores on XeQOLS and DLQI indicate worse QOL; otherwise higher scores indicate better QOL for other measures. For FACT-HN, XeQOLS, DLQI, and EQ-5D-3L, changes from baseline were compared by Van Elteren test, and for PSS-HN, the % ≤ 50 was compared by Z test. 158 patients per arm provided 80% power to test the difference between IMRT + cetuximab and IMRT alone. Changes in PROs over time were evaluated using mixed models. Two-sided tests were used with α=0.05. Results: 499 of 577 eligible patients (86%) consented to QOL. There were no significant differences between treatment arms (IMRT vs. IMRT + cetuximab) for all PRO measures in change from baseline to 3 or 12 months post-IMRT (see table). At 24 months, the change from baseline was significantly different for DLQI (p=0.02), but the difference was not clinically meaningful; other PROs were not significantly different. There were no significant differences between treatment arms for PSS-HN diet, eating, or speech at any time point (see table). Regarding treatment effect over time, in both treatment groups, all PRO measures showed greatest decline at 3 months followed by improvement towards baseline by 24 months. Conclusions: Treatment with IMRT + cetuximab was not associated with worse PROs compared to IMRT alone. Furthermore, findings demonstrate important recovery trends in QOL with return to baseline for most measures in both study arms. Clinical trial information: NCT00956007 . Results at 12 months. Instrument (score range) IMRT IMRT+Cetuximab p-value FACT-HN (0-148) n 122 132 Mean change -0.41 1.31 0.94 XeQOLS (0-4) n 105 114 Mean change 0.52 0.46 0.99 DLQI (0-30) n 121 133 Mean change -0.07 0.44 0.23 EQ-5D-3L (0-1) n 108 117 Mean change 0.01 0.02 0.87 PSS-HN diet (0-100) n 130 141 % ≤ 50 37.7 39.7 0.73 PSS-HN eating (0-100) n 130 141 % ≤ 50 20.0 15.6 0.34 PSS-HN speech (0-100) n 131 140 % ≤ 50 10.7 7.9 0.42

The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma.

The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma.

The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma.

This review summarizes the current role of radiotherapy for the treatment of cutaneous melanoma in the definitive, adjuvant, and palliative settings, and combinations with immunotherapy and targeted therapies. Definitive radiotherapy may be considered for lentigo maligna if surgery would be disfiguring. High risk, resected melanoma may be treated with adjuvant radiotherapy, but the role is poorly defined since the advent of effective systemic therapies. For patients with metastatic disease, immunotherapy and targeted therapies can be delivered safely in tandem with radiotherapy to improve outcomes. Radiotherapy and modern systemic therapies act in concert to improve outcomes, especially in the metastatic setting. Further prospective data is needed to guide the use of definitive radiotherapy for lentigo maligna and adjuvant radiotherapy for high-risk melanoma in the immunotherapy era. Current evidence does not support an abscopal response or at least identify the conditions necessary to reliably produce one with combinations of radiation and immunotherapy.

The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma.

Supplementary Data from Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition

Cancers of the head and neck region are associated with high symptom burden and elevated levels of psychological distress. Radiotherapy (RT) is a common treatment for patients with head and neck cancer (HNC) that is associated with psychological distress related to the immobilizing nature of the treatment, frequency of treatment delivery, and side effects. Guided imagery is a relaxation technique that is beneficial in reducing psychological distress in patients with other cancer diagnoses but has not been studied in this patient population. The purpose of this study is to evaluate the feasibility and acceptability of a brief guided imagery intervention (guided imagery for treatment, GIFT) to reduce RT-related anxiety and depression in patients with HNC relative to treatment as usual (TAU). Patients with HNC planning to receive RT will be recruited to participate in a randomized controlled trial evaluating a brief, two-session guided imagery intervention (GIFT) relative to TAU alone. Primary aims include acceptability and feasibility evaluated through quantitative and qualitative methods. Measures of anxiety and depression, symptom burden, health-related quality of life, and anxiolytic medication use will be collected at baseline, during treatment, and at 1-month follow-up. There are no published interventions of guided imagery for anxiety and depression in patients with HNC despite its efficacy in other populations of patients with cancer. This proposed project evaluates the feasibility and acceptability of an intervention that has the potential to reduce psychological distress in a vulnerable population. Additionally, we will preliminarily examine the impact of behavioral intervention on psychological distress and the use of anxiolytic medication, a novel area of study. Clinicaltrials.gov NCT03662698 ; registered on 9/6/2018.

Purpose: The abnormal function of tumor blood vessels causes hypoxia fueling disease progression and conferring treatment resistance. The local level of oxygen experienced by a cell will determine its response, making it critical to understand tissue oxygen levels with a spatial resolution on the order of the size of a cell. While microenvironment normalization strategies alleviate global hypoxia, how local oxygen levels change are not known because there are no in vivo techniques to longitudinally assess tumor vessels and interstitial oxygen in tumors with sufficient resolution. Understanding the heterogeneity of oxygen levels after microenvironmental normalization will help improve the efficacy of various normalization strategies. Experimental Design: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular weight palladium porphyrin probe to measure perfused vessels, oxygen tension and their spatial correlations in vivo in mouse skin, bone marrow, and tumors. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to microenvironmental normalization. Results: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen carrying ability than normal skin, most tumors had inefficient vessels. Further, inter-vessel heterogeneity in tumors coincided with heterogeneous response to microenvironmental normalizing agents. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persist, even with global reductions in hypoxia. Conclusions: We present the first study to examine the high-resolution spatial and temporal response of tumor vessels to two agents known to improve vascular perfusion globally. Our measurements demonstrate that the heterogeneities in the local imbalance of pro- and anti-angiogenic signaling lead to spatially heterogeneous changes in vessel structure and function. Microscale dynamic vascular changes should be considered in optimizing the dose and schedule of microenvironment normalizing therapies to improve function. Citation Format: John Martin, Ryan Lanning, Dai Fukumura, Timothy Padera, Rakesh Jain. Multiphoton phosphorescence quenching microscopy reveals kinetics of tumor oxygenation during anti-angiogenesis and angiotensin signaling inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB557.

Abstract Purpose: The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies. Experimental Design: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan). Results: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia. Conclusions: High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

Inflammatory changes and residual disease are difficult to distinguish after high dose, definitive radiotherapy of head and neck malignancies. FDG uptake located within a high dose field may more likely represent inflammatory changes, and FDG uptake outside of the radiation field could represent unsuspected and under treated disease. In situ knowledge of the precise radiotherapy fields, therefore, may be useful in distinguishing these etiologies. This study aimed to evaluate the clinical feasibility of rapid integration of radiation treatment field images during follow-up FDG PET/CT imaging. Twenty head and neck cancer patients who underwent radiation therapy were identified. A MIM based workflow was created which fused the radiation treatment CT, including the planning volumes and isodose curves, into the follow-up imaging. Two board certified physicians, blinded to treatment outcome, reviewed the follow-up exams, half with the treatment information and half without. Each exam was scored for recurrent or residual disease, confidence of the read and a qualitative assessment to the overall usefulness of the treatment plan. Interpretation accuracy improved from 80 to 90% with integration of the treatment plan. Similarly, the sensitivity improved from 71% to 86%, while the specificity increased from 85% to 92%. Confidence also increased by 0.7 on a 5 point scale for both readers. Data demonstrate the clinical feasibility of rapidly incorporating radiation treatment dosimetry into follow-up FDG PET/CT exams in patients with head and neck cancer. Preliminary results demonstrated a simple, efficient method which improved accuracy of interpretation and overall reader confidence.