Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study.

INTRODUCTION: Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT. METHODS: Patients were randomized to twice-daily oral nirogacestat (150 mg) or placebo, taken in continuous 28-day cycles. Investigator-identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow-up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle-stimulating hormone (FSH) to within normal limits (WNL) (≤20.4 mIU/mL). RESULTS: Of 92 randomized females, 73 in the safety population were FORP (n = 36 nirogacestat, n = 37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off-treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow-up. CONCLUSION: Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient.

Advanced parental cancer and adolescents: Parenting issues and challenges.

BACKGROUND: An estimated 609,820 child-rearing adults in 2023 died from advanced cancer, affecting 153,675 dependent children. Although children are known to suffer significant distress when a parent is diagnosed with cancer, few studies have described parents' views of their adolescent's behavioral response to their advanced cancer or what the parent did to interpret or manage that response. OBJECTIVES: To describe patient-reported concerns about their adolescent and how they responded to their adolescent's behavior. METHODS: Single occasion interviews were administered to 6 adolescent-rearing parents with Stage IV cancer. Interviews were analyzed using inductive content analysis by trained coders. Trustworthiness of results was protected through peer debriefing, coding to consensus, and maintaining an audit trail. RESULTS: The core construct that explained study data was Being There without Taking Over, comprised of 4 domains: Struggling to Read My Child, Attempting to Talk with My Child about My Cancer, Trying to Maintain Optimism, and Understanding My Child. CONCLUSIONS: Parents were deeply concerned about the impact of their advanced cancer on their adolescent but were unable to distinguish between cancer-related distress and adolescent angst. They feared initiating cancer-related discussions and struggled with their own feelings of guilt and parental inadequacy but did not turn to professionals for help. SIGNIFICANCE OF RESULTS: Adolescent-rearing patients with advanced disease need to be triaged into services that offer a framework from which parents can interpret their child's behavior and learn ways to have adolescent-appropriate conversations about the cancer. Such services should also help parents gain skills to manage feelings of parental inadequacy and guilt. In the absence of services, parents struggle and do not know how to interpret and respond to their adolescent's cancer-related behavior.

Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020.

Importance: Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema. Comprehensive data describing its incidence and presentation patterns are needed. Objective: To describe the incidence, presenting characteristics, and change over time of angiosarcoma in the US. Design, Setting, and Participants: This retrospective cross-sectional study used data from the US Cancer Statistics (USCS) National Program of Cancer Registries-Surveillance, Epidemiology, and End Results Combined Database, which captures more than 99% of newly diagnosed cancers in the US. The study included all 19 289 patients in the US with a new diagnosis of angiosarcoma between 2001 and 2020 captured in the USCS database. Statistical analysis was performed from June to September 2023. Main Outcomes and Measures: Incidence of angiosarcoma, demographics of patients with angiosarcoma, and extent of disease at presentation. Results: The study included 19 289 patients (median age, 71 years [IQR, 59-80 years]; 10 506 women [54.5%]) with a new diagnosis of angiosarcoma. The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P = .001), to 3.3 cases per 1 000 000 person-years (95% CI, 3.1-3.5 cases per 1 000 000 person-years), and an increase in the population at risk. In 2020, the reported incidence rate (3.0 cases per 1 000 000 person-years) and cases of angiosarcoma (n = 1159) were modestly lower than in 2019. Overall, 72.3% of cases of angiosarcoma (n = 13 955) were cutaneous, subcutaneous, or breast angiosarcomas; 24.4% were visceral (n = 4701); and 3.3% were located in unknown or rare primary sites (n = 633). Secondary breast and chest wall angiosarcomas among women represented the largest contribution to increasing incidence. Among breast angiosarcomas, 99.2% (2684 of 2705) were in women and 71.9% (1944 of 2705) were secondary. A total of 80.4% of chest wall or thorax cases among women (1861 of 2316) were secondary vs 26.5% among men (112 of 422), and 63.9% of upper extremity cases among women (205 of 321) were secondary vs 26.8% (56 of 209) among men (P = .001). Rates of secondary angiosarcoma in the abdomen and lower extremities were similar between men and women. The incidence rate of visceral angiosarcoma was also found to be increasing (1.5% per year; P = .001). Conclusions and Relevance: This cross-sectional study describes angiosarcoma presentation patterns and incidence rates in the US over a 20-year period and shows that the number of cases in men and women increased, with the greatest increase among women with secondary angiosarcoma of the chest, breast, and upper extremity. These data increase awareness of a rare but highly morbid disease and highlight the need for improved early detection of angiosarcoma among patients at high risk, such as women with a history of breast cancer.

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma: A Phase 1 Nonrandomized Controlled Trial.

Importance: Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts. Objective: To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions. Design, Setting, and Participants: This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022. Interventions: Two doses of IT GLA-SE (5 µg and 10 µg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion. Main Outcomes and Measures: Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes. Results: Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, -25%; range, -100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion -39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype. Conclusions and Relevance: In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02180698.

Secondary Breast Angiosarcoma After a Primary Diagnosis of Breast Cancer: A Retrospective Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database.

OBJECTIVES: Angiosarcoma is a rare complication of breast-conserving therapy. This study evaluated the change in incidence between 1992 and 2016 of secondary breast angiosarcoma (SBA) in patients with a history of breast cancer and the impact of management strategies for the original breast carcinoma on angiosarcoma treatment. METHODS: Breast cancer and angiosarcoma cases were abstracted from the Surveillance, Epidemiology, and End Result (SEER) database. SBAs were defined as angiosarcomas located in the breast occurring after a prior breast cancer diagnosis. Primary breast angiosarcomas (PBAs) were defined as an angiosarcoma diagnosis listed as "one primary only." Incidence rates were estimated using a proportion of the US total population. Survival was analyzed by the Kaplan-Meier method, and Cox proportional hazard models were used to assess the association of clinicopathologic characteristics on overall survival. RESULTS: Between 1992 and 2016, 193 cases of SBA were reported in the SEER dataset in patients with a prior history of breast cancer. The incidence of breast angiosarcoma in patients with a prior diagnosis of breast cancer increased 3-fold from about 10 cases per 100,000 person-years to about 30 cases per 100,000 person-years over this same period ( P =0.0037). For treatment of SBA (n=193), almost all (95%) had surgery. Nine percent received radiation (compared with 35% of patients with PBA, P <0.001) and 23% received chemotherapy (vs. 45% for PBA, P =0.11). CONCLUSIONS: We demonstrate an increasing incidence of SBA over the study period. These data can help inform shared decision-making for optimal management of locoregional breast cancer and raise awareness of secondary angiosarcoma.

Gender disparities in health-related quality of life (HRQoL) in patients with cutaneous T-cell lymphoma.

Patients with cutaneous T-cell lymphoma (CTCL) often experience debilitating symptoms that impair health-related quality of life (HRQoL). Existing evidence for HRQoL differences with respect to gender is conflicting. Objective: To investigate potential gender differences in HRQoL for patients with CTCL. Methods: We performed a cross-sectional study to assess HRQoL in patients with CTCL by partnering with the Cutaneous Lymphoma Foundation to distribute an electronic survey from February to April 2019. Results: A total of 292 patient responses (66% women, mean age 57 years) were included in the analysis. Most of the cohort had early-stage (IA-IIA) (74%; 162/203) mycosis fungoides (MFs) (87%; 241/279), followed by Sézary syndrome (SS) (12%; 33/279). Women with CTCL experienced significantly worse HRQoL compared with men (Skindex-16: 51±26 vs. 36±26, P ≤ 0.001; FACT-G: 69±21 vs. 77±16, P = 0.005). This gender difference was present even when controlling for stage of disease. Women experienced worse HRQoL in all three of the Skindex-16 subscales (symptoms: ß = 14.0, P ≤ 0.001; emotions: ß = 15.1, P ≤ 0.001; functioning: ß = 11.3, P = 0.006), but only two of the four FACT-G subscales (physical: ß =-2.8, P ≤ 0.001; emotional: ß = -2.0, P = 0.004). Limitations: Due to the method of distribution of the survey, we were unable to estimate a participant response rate. Participants' diagnosis and stage were self-reported. Conclusion: In this cohort women with CTCL experienced significantly worse HRQoL when compared to men. Additional studies are necessary to determine what factors contribute to this gender disparity.

Incidence, demographics, and survival of malignant hemangioendothelioma in the United States.

BACKGROUND: Malignant hemangioendothelioma is an endothelial cancer with heterogeneous clinical behavior that can range from indolent to aggressive, of which the majority are epithelioid (EHE). Its incidence and demographics have not been previously well defined in a large cohort. METHODS: This retrospective analysis used the US Cancer Statistics National Program of Cancer Registries - Surveillance Epidemiology End Results (SEER) combined database to identify patients in the US newly diagnosed with hemangioendothelioma between the years of 2001 and 2017 (n = 1986). Survival analyses were performed on a subset of patients within the SEER-18 database with survival information available (n = 417). Outcomes included incidence, demographics of patients newly diagnosed with hemangioendothelioma, extent of disease at presentation, and overall survival. RESULTS: The incidence of hemangioendothelioma in the US is 0.4 cases per million person-years. Although cases rose to 122 newly diagnosed in the year 2017 (90 EHE, 32 other hemangioendothelioma), incidence rates were stable. Skin and connective tissues were the most common presenting sites (33.4%), followed by liver (24.5%), lung (17.6%), and bone (12.5%). Median age at diagnosis was 55 years; 27.2% of patients were pediatric, adolescent, or young adult (<40 years). At presentation, 36.4% of patients had localized disease; 21.6% presented with regional and 41.7% with distant metastases. Observed survival at 3 years was 79.7%, 70.7%, and 46.0% for patients presenting with local, regional, and distant disease and most deaths occurred within the first 2 years. CONCLUSIONS: Malignant hemangioendothelioma is ultra-rare but meaningfully impacts affected patients. These data may provide benchmarks for comparison of new approaches to hemangioendothelioma therapy and highlight poor survival outcomes.

ADCC's Improving Goal Concordant Care Initiative: Implementing Primary Palliative Care Principles.

BACKGROUND: High-quality, timely goals of care communication (GOCC) may improve patient and caregiver outcomes and promote care that is consistent with patient preferences. PROBLEM: Cancer patients, and their loved ones, appreciate GOCC; however, oncologists often lack formal communication training, institutional support and structures necessary to promote the delivery, documentation, and longitudinal follow-up of GOCC. PROPOSED SOLUTION: The Alliance of Dedicated Cancer Centers (ADCC), representing 10 U.S. academic cancer hospitals, undertook the Improving Goal Concordant Care Initiative (IGCC). This national, 3-year implementation initiative was designed in Fall 2019 by a workgroup of quality, oncology, and palliative care leaders, as well as patient and family advisory committee members (PFAC). IGCC addresses systemic gaps by requiring four core components for participation: 1) Implementation of a formal communication skills training (CST) program, 2) Structured GOCC documentation in the electronic medical record that is visible to all clinicians, 3) Expectations regarding the timing and patient populations for GOCC, and 4) Implementation of a measurement framework. METHOD: Dyads of palliative and oncology leaders committed to attend regularly scheduled, ADCC-led, virtual meetings during the design and implementation phase, incorporating PFAC feedback at every stage. Using the RE-AIM framework, we describe process and outcome evaluation measures defined by implementation and measures workgroups and collected routinely, including: CST completion; trainee evaluation response rate, trainee-reported quality of CST, trainee changes in self-efficacy and distress; percent of high-priority patients participating in GOCC, and patient-reported response to the "Heard and Understood" scale (HU). IGCC's impact will be assessed using claims-based utilization metrics near the end of life (EOLM) and followed longitudinally. Qualitative evaluations near the completion of IGCC will provide insight into perceived barriers, enabling factors, and sustainability. OUTCOMES: Implementation of all IGCC components has begun at all sites. ADCC-wide, 35% of MD/DOs have completed CST (range by site: 8%-100%). CST is highly rated; in Quarter 3, 2022, 93%-100%, 90%-100% and 87%-100% of respondents reported above average to excellent CST quality, likelihood to use the skills and likelihood to recommend CST to others, respectively. Clinician self-efficacy and distress ratings are expected in late 2023. All sites have identified patient populations and continue to refine automated triggers and timelines; uptake of GOCC documentation has been slow. Eight of 10 sites have submitted patient-reported HU data. EOLM data are expected for all sites in early 2024. LESSONS LEARNED: Flexibility in implementation with shared definitions, measures, and learnings about approaches optimizes the ability of all centers to collaborate and make progress in improving GOCC. Flexibility adds to the complexity of understanding intervention effectiveness, the critical intervention components and the fidelity necessary to achieve specific outcomes.

Bolus versus Continuous Intravenous Delivery of Doxorubicin in Soft-Tissue Sarcomas: Post Hoc Analysis of a Prospective Randomized Trial (SARC021/TH CR-406).

PURPOSE: Continuous intravenous infusion (CIV) of doxorubicin (DOX) versus bolus (BOL) may minimize dose-dependent DOX cardiomyopathy, but it is unclear whether this advantage is evident as employed in typical soft-tissue sarcoma (STS) treatment. The impact of administration mode on adverse events (AE) and efficacy were compared using data from a randomized trial of DOX-based therapy (SARC021/TH CR-406). EXPERIMENTAL DESIGN: In this post hoc analysis, CIV versus BOL was at discretion of the treating physician. Likelihood of AEs, and objective responses were assessed by adjusted logistic regression. Progression-free (PFS) and overall survival (OS) were compared using Kaplan-Meier, log-rank test, and adjusted Cox regression. RESULTS: DOX was administered by BOL to 556 and by CIV to 84 patients. Proportions experiencing hematologic, non-hematologic, or cardiac AEs did not differ by administration mode. Hematologic AEs were associated with age, performance status, and cumulative DOX. Non-hematologic AEs were associated with age, performance status, and cumulative evofosfamide. Cardiac AEs were only associated with cumulative DOX; there was no interaction between DOX dose and delivery mode. PFS and OS were similar (median PFS 6.14 months BOL vs. 6.11 months CIV, P = 0.47; median OS 18.4 months BOL vs. 21.4 months CIV, P = 0.62). PFS, OS, and objective responses were not associated with delivery mode. CONCLUSIONS: CIV was not associated with superior outcomes over BOL within DOX dosing limits of SARC021. Cardiac AEs were associated with increasing cumulative DOX dose. While not randomized with respect to DOX delivery mode, the results indicate that continued investigation of AE mitigation strategies is warranted.

A phase II trial of regorafenib in patients with advanced Ewing sarcoma and related tumors of soft tissue and bone: SARC024 trial results.

BACKGROUND: Regorafenib is one of several FDA-approved cancer therapies targeting multiple tyrosine kinases. However, there are few subtype-specific data regarding kinase inhibitor activity in sarcomas. We report results of a single arm, phase II trial of regorafenib in advanced Ewing family sarcomas. METHODS: Patients with metastatic Ewing family sarcomas (age ≥ 18, ECOG 0-2, good organ function) who had received at least one line of therapy and experienced progression within 6 months of registration were eligible. Prior kinase inhibitors were not allowed. The initial dose of regorafenib was 160 mg oral days 1-21 of a 28-day cycle. The primary endpoint was estimating progression-free rate (PFR) at 8 weeks employing RECIST 1.1. RESULTS: Thirty patients (median age, 32 years; 33% women [10 patients]; bone primary, 40%; extraskeletal primary, 60%) enrolled at 14 sites. The most common grade 3 or higher toxicities were hypophosphatemia (5 grade 3, 1 grade 4), hypertension (2 grade 3), elevated ALT (2 grade 3). Sixteen patients required dose reductions, most often for hypophosphatemia (n = 7 reductions in 6 patients); two stopped regorafenib for toxicity. There was one death unrelated to treatment in the 30-day post-study period. Median progression-free survival (PFS) was 14.8 weeks (95% CI 7.3-15.9); PFR at 8 weeks by Kaplan-Meier analysis was 63% (95% CI 46-81%). The RECIST 1.1 response rate was 10%. Median OS was 53 weeks (95% CI 37-106 weeks). CONCLUSIONS: Regorafenib has modest activity in the Ewing family sarcomas. Toxicity was similar to that seen in approval studies.

Assessment of Oncology Advanced Practice Professional Willingness to Participate in Medical Aid in Dying.

Importance: In 2021, New Mexico passed legislation allowing nurse practitioners and physician assistants (referred to herein as advanced practice professionals [APPs]) to prescribe medications for medical aid in dying (MAID). Other US states with existing MAID laws (eg, Washington) are also considering expanding MAID prescribing authority to APPs. There is a lack of research exploring APP knowledge of, willingness to, and comfort with acting as a prescribing or consulting clinician for MAID. Objective: To assess perspectives of oncology APPs regarding MAID, including their willingness to prescribe and/or consult for MAID and factors associated with willingness. Design, Setting, and Participants: This cross-sectional, self-report survey study used data collected from APPs working at a comprehensive cancer center in Washington State in fall 2021. Main Outcomes and Measures: The primary survey question was whether APPs would be willing to participate in death with dignity, the term used for MAID in Washington. Survey questions evaluated how influential specific factors were on APP views on MAID as well as respondents' knowledge of and comfort with aspects of the MAID process. Results: Of 167 eligible APPs, 77 (46.1%) responded to the survey. Most respondents (68 [88.3%]) reported their race and ethnicity as White; 72 (93.5%) identified as a woman. Medical oncology (28 [36.4%]) was the most common field of practice, and 21 respondents (27.3%) reported having practiced as an APP for 6 to 10 years. Of all respondents, 61 (79.2%) reported having at least 1 patient who inquired about MAID; depending on the question, less than a third of respondents (5.0%-27.0%) endorsed feeling knowledgeable or very knowledgeable about any aspect of the MAID process. In this study, 39 APPs (50.6%) endorsed being willing to participate in MAID either as a consulting or prescribing clinician, whereas 31 (40.3%) were uncertain of whether they would participate. Willingness to participate was associated with having had more patients pursue MAID (33 of the 39 willing participants [84.6%] vs 15 of the 31 unsure participants [48.4%] reported having 1 or more patients pursue MAID). Higher knowledge and comfort scores were both significantly associated with increased odds of being willing to participate (odds ratio, 1.14 per 1-point score increase [95% CI, 1.03-1.27]; P = .01) vs unsure (1.18 [95% CI, 1.07-1.30; P = .001). Conclusions and Relevance: The results of this survey study suggest that oncology APPs may require preparation for the addition of MAID to their scope of practice. This study also raises questions for future research regarding support for APPs who may be considering participation in MAID but question their role or want physician involvement.

Demographics, Outcomes, and Risk Factors for Patients with Sarcoma and COVID-19: A CCC19-Registry Based Retrospective Cohort Study.

BACKGROUND: Patients with sarcoma often require individualized treatment strategies and are likely to receive aggressive immunosuppressive therapies, which may place them at higher risk for severe COVID-19. We aimed to describe demographics, risk factors, and outcomes for patients with sarcoma and COVID-19. METHODS: We performed a retrospective cohort study of patients with sarcoma and COVID-19 reported to the COVID-19 and Cancer Consortium (CCC19) registry (NCT04354701) from 17 March 2020 to 30 September 2021. Demographics, sarcoma histologic type, treatments, and COVID-19 outcomes were analyzed. RESULTS: of 281 patients, 49% (n = 139) were hospitalized, 33% (n = 93) received supplemental oxygen, 11% (n = 31) were admitted to the ICU, and 6% (n = 16) received mechanical ventilation. A total of 23 (8%) died within 30 days of COVID-19 diagnosis and 44 (16%) died overall at the time of analysis. When evaluated by sarcoma subtype, patients with bone sarcoma and COVID-19 had a higher mortality rate than patients from a matched SEER cohort (13.5% vs 4.4%). Older age, poor performance status, recent systemic anti-cancer therapy, and lung metastases all contributed to higher COVID-19 severity. CONCLUSIONS: Patients with sarcoma have high rates of severe COVID-19 and those with bone sarcoma may have the greatest risk of death.

Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461). RESULTS: Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION: Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma.

PURPOSE: Leiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA approved for leiomyosarcoma and liposarcoma. This study aimed to evaluate the safety and efficacy of trabectedin with anti-PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma. PATIENTS AND METHODS: A single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced leiomyosarcoma and liposarcoma. The phase I portion evaluated safety and feasibility of trabectedin (1, 1.2, and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was objective response rate (ORR) by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression. RESULTS: 33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In Phase 1, dose-limiting toxicities (DLT) were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended Phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800-mg avelumab. Of 23 patients evaluable at RP2D, 3 (13%) had partial response (PR) and 10 (43%) had stable disease (SD) as best response. Six-month PFS was 52%; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells versus those with SD (0.182 vs. 0.067, P = 0.02) or progressive disease (0.182 vs. 0.064, P = 0.01). CONCLUSIONS: Although the trial did not meet the primary objective response rate endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.

Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells.

PURPOSE: To characterize changes in the soft-tissue sarcoma (STS) tumor immune microenvironment induced by standard neoadjuvant therapy with the goal of informing neoadjuvant immunotherapy trial design. EXPERIMENTAL DESIGN: Paired pre- and postneoadjuvant therapy specimens were retrospectively identified for 32 patients with STSs and analyzed by three modalities: multiplexed IHC, NanoString, and RNA sequencing with ImmunoPrism analysis. RESULTS: All 32 patients, representing a variety of STS histologic subtypes, received neoadjuvant radiotherapy and 21 (66%) received chemotherapy prior to radiotherapy. The most prevalent immune cells in the tumor before neoadjuvant therapy were myeloid cells (45% of all immune cells) and B cells (37%), with T (13%) and natural killer (NK) cells (5%) also present. Neoadjuvant therapy significantly increased the total immune cells infiltrating the tumors across all histologic subtypes for patients receiving neoadjuvant radiotherapy with or without chemotherapy. An increase in the percentage of monocytes and macrophages, particularly M2 macrophages, B cells, and CD4+ T cells was observed postneoadjuvant therapy. Upregulation of genes and cytokines associated with antigen presentation was also observed, and a favorable pathologic response (≥90% necrosis postneoadjuvant therapy) was associated with an increase in monocytic infiltrate. Upregulation of the T-cell checkpoint TIM3 and downregulation of OX40 were observed posttreatment. CONCLUSIONS: Standard neoadjuvant therapy induces both immunostimulatory and immunosuppressive effects within a complex sarcoma microenvironment dominated by myeloid and B cells. This work informs ongoing efforts to incorporate immune checkpoint inhibitors and novel immunotherapies into the neoadjuvant setting for STSs.

Is Chemotherapy Associated with Improved Overall Survival in Patients with Dedifferentiated Chondrosarcoma? A SEER Database Analysis.

BACKGROUND: Dedifferentiated chondrosarcoma is a chondrosarcoma subtype associated with high rates of recurrence and a poor prognosis. Others have proposed treatment of dedifferentiated chondrosarcoma using osteosarcoma protocols, including perioperative chemotherapy. However, the rarity of this condition poses difficulties in undertaking single- institution studies of sufficient sample size. QUESTION/PURPOSE: Is perioperative chemotherapy associated with improved overall survival in patients with dedifferentiated chondrosarcoma? METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) 1973 to 2016 database for patients with a diagnosis of dedifferentiated chondrosarcoma (n = 308). As dedifferentiated chondrosarcoma was only classified as a distinct entity in SEER starting in 2000, only patients treated in 2000 and later were included. We excluded from our analyses those patients with distant disease at diagnosis, a primary site of disease other than bone or joints, and those who did not receive cancer-directed surgery. These criteria yielded 185 dedifferentiated chondrosarcoma patients for inclusion. We used Kaplan-Meier analyses and Cox proportional hazards models to assess the association of clinical, demographic, and treatment characteristics on overall survival (OS). RESULTS: After controlling for confounding variables, including age, sex, tumor size, stage, grade, location, and radiation treatment status, and after adjusting for missing data, no overall survival benefit was associated with receipt of chemotherapy in patients with dedifferentiated chondrosarcoma (hazard ratio 0.75 [95% confidence interval 0.49 to 1.12]; p = 0.16). CONCLUSION: Chemotherapy treatment of dedifferentiated chondrosarcoma was not associated with improved OS. These results must be viewed cautiously, given the limited granularity of information on chemotherapy treatment, the concerns regarding chemotherapy misclassification in SEER data, and the small sample of patients with dedifferentiated chondrosarcoma, all of which limit the power to detect a difference. Our findings are nevertheless consistent with those of prior reports in which no benefit of chemotherapy could be detected. Lack of clear benefit from perioperative chemotherapy in dedifferentiated chondrosarcoma argues that it should be used only after careful consideration, and ideally in the context of a clinical trial. LEVEL OF EVIDENCE: Level III, therapeutic study.

Association of Physician Orders for Life-Sustaining Treatment With Inpatient Antimicrobial Use at End of Life in Patients With Cancer.

BACKGROUND: Antimicrobial utilization at end of life is common, but whether advance directives correlate with usage is unknown. We sought to determine whether Washington State Physician Orders for Life Sustaining Treatment (POLST) form completion or antimicrobial preferences documented therein correlate with subsequent inpatient antimicrobial prescribing at end of life. METHODS: This was a single-center, retrospective cohort study of adult patients at a cancer center who died between January 1, 2016, and June 30, 2019. We used negative binomial models adjusted for age, sex, and malignancy type to test the relationship between POLST form completion ≥30 days before death, antimicrobial preferences, and antimicrobial days of therapy (DOT) per 1000 inpatient-days in the last 30 days of life. RESULTS: Among 1295 eligible decedents with ≥1 inpatient-day during the last 30 days of life, 318 (24.6%) completed a POLST form. Of 318, 120 (37.7%) were completed ≥30 days before death, 35/120 (29.2%) specified limited antimicrobials, 55/120 (45.8%) specified full antimicrobial use, and 30/120 (25%) omitted antimicrobial preference. Eighty-three percent (1070/1295) received ≥1 inpatient antimicrobial. The median total and intravenous (IV) antimicrobial DOT/1000 inpatient-days were 1077 and 667. Patients specifying limited antimicrobials had significantly lower total antimicrobial DOT (adjusted incidence rate ratio [IRR], 0.68; 95% CI, 0.49-0.95; P = .02) and IV antimicrobial DOT (IRR, 0.57; 95% CI, 0.38-0.86; P = .008) compared with those without a POLST. CONCLUSIONS: Indicating a preference for limited antimicrobials on a POLST form ≥30 days before death may lead to less inpatient antimicrobial use in the last 30 days of life.

NCCN Guidelines® Insights: Palliative Care, Version 2.2021.

Palliative care has evolved to be an integral part of comprehensive cancer care with the goal of early intervention to improve quality of life and patient outcomes. The NCCN Guidelines for Palliative Care provide recommendations to help the primary oncology team promote the best quality of life possible throughout the illness trajectory for each patient with cancer. The NCCN Palliative Care Panel meets annually to evaluate and update recommendations based on panel members' clinical expertise and emerging scientific data. These NCCN Guidelines Insights summarize the panel's recent discussions and highlights updates on the importance of fostering adaptive coping strategies for patients and families, and on the role of pharmacologic and nonpharmacologic interventions to optimize symptom management.

Integrative medicine use in patients with cutaneous T-Cell lymphoma: A cross-sectional survey study.

OBJECTIVES: To characterize patterns of integrative medicine (IM) use and health-related quality of life (HRQoL) in patients with cutaneous T-cell lymphoma (CTCL). DESIGN: Cross-sectional, online survey, created in conjunction with the Cutaneous Lymphoma Foundation (CLF). SETTING: A link to the online survey was posted on the CLF Facebook page and emailed to the CLF listserv; 372 survey responses were received. MAIN OUTCOME MEASURES: The study outcomes were IM use, cancer symptoms, and HRQoL measured via the Skindex-16 and Functional Assessment of Cancer Therapy-General (FACT-G). RESULTS: A total of 292 patient responses (66 % female, median age 59y) were included in analysis. 87 % had mycosis fungoides and 12 % had Sézary syndrome. A majority (59 %) of patients reported using IM for their CTCL, with 48 % using IM to treat their disease and 47 % using IM to manage their symptoms. The most commonly used IM were vitamins/minerals (32 %), prayer/meditation (26 %), diet (24 %), and exercise/yoga (22 %). Higher itch scores were reported by patients using IM compared to non-users (31 (IQR 10-62) and 18 (IQR 3-46) respectively; p = 0.002). HRQoL was worse among patients who reported IM use; median Skindex-16 scores were 54 (IQR 28-72) among IM users compared to 33 (IQR 19-57) for non-IM users (p < 0.001). CONCLUSIONS: IM use is common among patients with CTCL, particularly those with worse itching and worse HRQoL. IM interventions require further study given use by CTCL patients to treat disease and ameliorate symptoms.

Outcomes of Patients with Sarcoma and COVID-19 Infection: A Single Institution Cohort Analysis.

Outcomes for patients (pts) with sarcoma and COVID-19 are unknown. This is a single institution retrospective study of adults with sarcoma and COVID-19. Ten pts [median age 60 (range 24-69)] were identified. Five were hospitalized; two died from COVID-19 complications; another died from sarcoma. Time between last systemic treatment dose and COVID-19 diagnosis was 6-41 days in pts who died. 5 underwent prior radiation (RT); time between RT and COVID-19 diagnosis was 20-62 days for pts who died. All three pts with WBC differential data (two died) were lymphopenic. Efforts to capture outcomes for a larger cohort are urgently needed.