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Background: Desmoid tumors can cause morbidity due to local invasion, potentially being fatal when fast growth compromises vital structures. In this context, a timely treatment response is required. This study aims to compare the activity of sorafenib and anthracycline-containing regimens during the first year of treatment., Methods: The authors conducted a multi-institutional retrospective analysis of desmoid tumor patients treated with either sorafenib or an anthracycline-containing regimen over 1 year. The primary end point was the overall response rate (ORR). The secondary end points were time to response (TTR), progression-free survival (PFS), and adverse events., Results: From 2005 to 2022, 80 patients received sorafenib and 51 received an anthracycline-containing regimen with similar baseline characteristics. The 1-year ORR was 37% for anthracycline and 13% for sorafenib (p = .016). Median best response was -9% (range, -73 to 51) for anthracycline and -4% (range, -69 to 126) for sorafenib. Median TTR was 5.6 months (95% confidence interval [CI], 3.4-7.8) for anthracycline and 8.7 months (95% CI, 6.3-11.1) for sorafenib (p = .2). One-year PFS was 73% (95% CI, 60-86) for anthracycline and 59% (95% CI, 47-71) for sorafenib (p = .3). Common grade 1-2 adverse events for sorafenib were hand-foot syndrome (40%), diarrhea (25%), and fatigue (22%); for anthracycline, they were nausea (31%), fatigue (16%), and rash (14%). Grade 3 events were higher in the anthracycline group, 27% versus 14% (p < .05)., Conclusion: Anthracycline-based therapy provided a greater 1-year response rate than sorafenib but was associated with a higher rate of serious adverse events. Higher-risk desmoid tumors, which need a more timely response, might benefit from anthracycline-based therapies, whereas average-risk tumors could benefit from sorafenib., (© 2024 American Cancer Society.)

Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE., Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ- CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires., Results: 44 patients enrolled and 42 started trametinib. TAZ- CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094-19.0], median PFS was 10.4 months (95%CI, 7.1-NA), and 2-year OS rate was 33.3%(95%CI, 19.1-58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib., Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552., (©2024 American Association for Cancer Research.)

Context.—: The characteristic molecular signature for both atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma is amplified sequences derived from chromosome 12q13-15, including MDM2 proto-oncogene (MDM2). As the progression of atypical lipomatous tumor/well-differentiated liposarcoma to the more aggressive dedifferentiated liposarcoma has the potential to adversely affect patient outcomes, the extent of the latter component might be important to evaluate., Objective.—: To investigate the correlation between clinicopathologic characteristics, including tumor size, modified Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade, molecular data, and outcomes in 123 surgically resected MDM2-amplified liposarcomas., Design.—: Pathology reports and clinical records were reviewed. A log-rank test was used to compare the survival trends, and univariate logistic regression was performed to identify variables associated with adverse events (distant metastasis and/or death), from which the P value was derived to construct a multivariate regression model., Results.—: In univariate analysis, the largest single dimension of the dedifferentiated component, the percentage of cells with gain of chromosome 12, mitotic count, and the presence of modified FNCLLC grade 3 were associated with adverse events. In multivariate analysis, the largest single dimension of the dedifferentiated component (odds ratio: 1.169; 95% CI: 1.053, 1.299; P = .003), and a higher mitotic count (odds ratio: 1.133; 95% CI: 1.037, 1.237; P = .006) were correlated with adverse events. There was no statistically significant association between current local recurrence status, overall largest tumor dimension, overall tumor volume, MDM2 copy number, or MDM2 to chromosome 12 centromere probe ratio and adverse outcomes., Conclusions.—: Staging dedifferentiated liposarcoma based on the size of the dedifferentiated component better predicts the outcome., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

To assess epidemiology, clinical presentation, treatment and overall survival of adult patients with renal sarcomas, the 2004-2016 SEER and NCDB databases were queried for adult patients diagnosed with renal sarcoma, calculating average annual age-adjusted incidence rates (AAIR) and average annual percentage change (AAPC) as well as overall survival (OS). In n = 1279 included renal sarcoma patients, AAIR remained constant over the study period (average 0.53 cases/1million; AAPC = 0.7, p = 0.6). Leiomyosarcoma (AAIR 0.14 cases/1 million) and malignant rhabdoid tumors (0.06 cases/1 million) were most common. Sarcoma histiotypes demonstrated considerable heterogeneity regarding demographic and cancer-related variables. Patients presented with advanced local extent (T3 33.3%; T4 14.2%) or distant metastases (29.1%) and commonly underwent surgical resection (81.6%). Longer OS was independently associated with younger age, female sex, lower comorbidity index, low T stage, negative surgical margins, absence of tumor necrosis or distant metastases and leiomyosarcoma histiotype (multivariable p < 0.05 each). Treatment efficacy varied according to sarcoma histiotype (interaction p < 0.001). Accounting for 0.25% of renal malignancies, renal sarcomas include 43 histiotypes with distinct epidemiology, clinical presentation, outcomes and sensitivity to systemic therapy, thereby reflecting soft-tissue sarcoma behavior. Renal sarcoma treatment patterns follow recommendations by renal cancer guidelines with surgical resection as the cornerstone of therapy., (© 2024. The Author(s).)

Background: Primary cardiac soft tissue sarcomas (CSTS) affect young adults, with dismal outcomes., Objectives: The aim of this study was to investigate the clinical outcomes of patients with CSTS receiving immune checkpoint inhibitors (ICIs)., Methods: A retrospective, multi-institutional cohort study was conducted among patients with CSTS between 2015 and 2022. The patients were treated with ICI-based regimens. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates were determined according to Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events version 5.0., Results: Among 24 patients with CSTS, 17 (70.8%) were White, and 13 (54.2%) were male. Eight patients (33.3%) had angiosarcoma. At the time of ICI treatment, 18 patients (75.0%) had metastatic CSTS, and 4 (16.7%) had locally advanced disease. ICIs were administered as the first-line therapy in 6 patients (25.0%) and as the second-line therapy or beyond in 18 patients (75.0%). For the 18 patients with available response data, objective response rate was 11.1% (n = 2 of 18). The median PFS and median OS in advanced and metastatic CSTS (n = 22) were 5.7 months (95% CI: 2.8-13.3 months) and 14.9 months (95% CI: 5.7-23.7 months), respectively. The median PFS and OS were significantly shorter in patients with cardiac angiosarcomas than in those with nonangiosarcoma CSTS: median PFS was 1.7 vs 11 months, respectively ( P  < 0.0001), and median OS was 3.0 vs 24.0 months, respectively ( P  = 0.008). Any grade treatment-related adverse events occurred exclusively in the 15 patients with nonangiosarcoma CSTS (n = 7 [46.7%]), of which 6 (40.0%) were grade ≥3., Conclusions: Although ICIs demonstrate modest activity in CSTS, durable benefit was observed in a subset of patients with nonangiosarcoma, albeit with higher toxicity., Competing Interests: Dr Abdel-Wahab is supported by a K01 Mentored Research Scientist Development Award from the National Institute of Allergy and Infectious Diseases (grant K01AI163412) and has received the University of Texas MD Anderson Cancer Center Institutional Research Grant, Division of Internal Medicine Development Award, Survivorship Seed Money Award, Prioritizing Research Innovation and Mentoring Excellence Award, and Melanoma SPORE Career Enhancement Program Award. Dr Nassar has received honoraria from OncLive, TEMPUS, and the Korean Society for Medical Oncology; and has received consulting fees from Guidepoint Global. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported., Methods: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action., Results: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1., Conclusions: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments., Methods: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival., Results: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%)., Conclusions: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.)., (Copyright © 2023 Massachusetts Medical Society.)

A man in his 70s with a history of fatigue, abdominal pain, and a palpable abdominal mass was found to have a peritoneal desmoid tumour. One year after diagnosis, he was prescribed sorafenib to limit tumour growth. Two months later, he developed dyspnoea on exertion and lower extremity weakness and was reported to have supine hypertension and orthostatic hypotension. On formal autonomic testing, he was noted to have severely impaired sympathetic responses and marked orthostatic hypotension without appropriate chronotropic response. A decision to hold sorafenib was made, and treatment was started with graduated compression stockings, liberal fluid and sodium intake, and midodrine. The patient had a modest and gradual improvement in his symptoms. To our knowledge, this is the first reported case of orthostatic hypotension related to sorafenib or any vascular endothelial growth factor inhibitors., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: There is limited understanding of the role of postdischarge medical oncology follow-up during care transition periods. Our study describes the care transition patterns and the association between postdischarge medical oncology appointments and downstream health care use at a tertiary academic center., Methods: We conducted a retrospective cohort study of 25,135 medical oncology admissions between 2018 and 2020 at Yale New Haven Hospital. We examined the association between postdischarge medical oncology appointment timing with 30-day all-cause readmissions and emergency department (ED) visits using multivariable logistic regression models and propensity score-matched analyses., Results: Compared with admissions without appointment within 30 days, admissions with postdischarge medical oncology appointment within 30 days were associated with lower rates of all-cause 30-day readmission (odds ratio [OR] = 0.56, 95% CI, 0.52 to 0.59; P < .001) and ED visit (OR = 0.56, 95% CI, 0.52 to 0.59; P < .001). Admissions with appointment ≤ 14 days were associated with lower rates of 30-day readmission (OR = 0.28, 95% CI, 0.25 to 0.32; P < .001) and ED visit (OR = 0.56, 95% CI, 0.52 to 0.63; P < .001) compared with those with appointment within 15-30 days. Similar patterns in health care use were seen with propensity score matching. Subgroup analyses of cancer types with the most admissions observed similar trends between 30-day readmission and ED visits with appointment timing., Conclusion: Timely postdischarge medical oncology appointments were associated with significantly lower likelihood of 30-day readmission and ED visits, suggesting a potential role for postdischarge follow-up as an intervention to decrease health care use.

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.

Background: Paclitaxel, carboplatin, and cetuximab (PCC) has shown promise as induction chemotherapy and in patients with metastatic/recurrent head and neck cancer (HNC). Given its tolerability, the regimen is used in frail and elderly patients., Methods: Software generated the cohort of adult patients with HNC treated with PCC in 2014-2019. Modified RECIST response rate (RR), progression-free survival (PFS), and overall survival (OS) were calculated for the metastatic/recurrent group, and successful induction rate and RR for the induction group. These were also calculated in the elderly/frail subset (EF): age ≥75, performance status ≥2, albumin <3.5., Results: Fifty-two percent of patients experienced ≥grade 3 toxicities. For metastatic/recurrent disease (N = 58), RR was 22%, mean PFS was 7.1 months. Mean OS was 15.2 months. In the induction cohort (N = 22), 86% reached their endpoint. The RR was 64%. There were no significant differences for EF., Conclusions: PCC is well-tolerated with good induction success rate and reasonable PFS/OS in metastatic/recurrent disease., (© 2022 Wiley Periodicals LLC.)

Leiomyosarcomas (LMS) are diverse, rare, and aggressive mesenchymal soft tissue sarcomas. Epigenetic alterations influence multiple aspects of cancer, however epigenetic profiling of LMS has been limited. The goal of this study was to delineate the molecular landscape of LMS for subtype-specific differences (uterine LMS (ULMS) vs soft tissue LMS (STLMS)) based on integrated analysis of DNA methylation and gene expression to identify potential targets for therapeutic intervention and diagnosis. We identified differentially methylated and differentially expressed genes associated with ULMS and STLMS using DNA methylation and RNA-seq data from primary tumors. Two main clusters were identified through unsupervised hierarchical clustering: ULMS-enriched cluster and STLMS-enriched cluster. The integrated analysis demonstrated 34 genes associated with hypermethylation of the promoter CpG islands and downregulation of gene expression in ULMS or STLMS. In summary, these results indicate that differential DNA methylation and gene expression patterns are associated with ULMS and STLMS. Further studies are needed to delineate the contribution of epigenetic regulation to LMS subtype-specific gene expression and determine the roles of the differentially methylated and differentially expressed genes as potential therapeutic targets or biomarkers., Competing Interests: CONFLICTS OF INTEREST N.A. has received grant funding from Cepheid and Astex and has served as consultant to Ethicon. N.A. has licensed methylation biomarkers to Cepheid. H.D. is/was scientific advisor/consultant for Daiichi Sankyo, Inc., Deciphera, Eisai-Differentiated Thyroid Cancer (DTC), Bristol-Myers Squibb and Lilly. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The other authors declare no conflict of interest., (Copyright: © 2021 Hasan et al.)

Background: EBRT in resected, nonmetastatic anaplastic thyroid cancer (ATC) remains undefined. We evaluated patterns/outcomes with EBRT and chemotherapy in this setting., Methods: This retrospective analysis included patients identified from the National Cancer Database with nonmetastatic ATC from 2004 to 2014 who underwent non-palliative resection., Results: Our analysis included 496 patients, including 375 who underwent adjuvant EBRT (among whom 198 received concurrent chemotherapy). The median age was 68 years. On MVA, EBRT was associated with sex (OR 0.5, 95% CI 0.3-0.8, P = .002) and income (OR 2.2, 95% CI 1.4-3.3, P < .001). EBRT was associated with longer OS on UVA (12.3 vs 9.1 months, P = .004) and MVA (HR 0.7 [CI 0.6-0.9], P = .004). Concurrent chemoradiation was associated with longer OS on UVA (14.0 vs 9.1 months, P = .003) and MVA (HR 0.6 [CI 0.5-0.8], P < .001)., Conclusion: Adjuvant EBRT is associated with longer OS in resected, nonmetastatic ATC, with additional improved survival with concurrent chemotherapy., (© 2020 Wiley Periodicals, Inc.)

Background: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care., Methods: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated., Results: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%)., Conclusions: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

Background: Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma., Patients and Methods: Subjects with metastatic or unresectable chemotherapy-naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m 2 on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 2-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete)., Results: Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths., Conclusion: Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression-free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: DNA methylation in human papillomavirus-associated (HPV + ) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV + HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV + HNSCC. Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV + HNSCC. Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV + HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV + HNSCC, activated IFN response in some HPV + head and neck cancer cells, and inhibited the ability of HPV + xenografted tumors to invade mouse blood vessels. Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. Clin Cancer Res; 23(23); 7276-87. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Importance: Men with metastatic prostate cancer who have a poor response to initial androgen-deprivation therapy (ADT), as reflected by a prostate-specific antigen (PSA) level higher than 4.0 ng/mL after 7 months of ADT, have a poor prognosis, based on historical controls., Objective: To determine the efficacy of abiraterone acetate with prednisone in these high-risk patients with a suboptimal response to hormonal induction., Design, Setting, and Participants: A phase 2 single-arm study was conducted through the National Clinical Trials Network-Southwest Oncology Group. Eligible patients had metastatic prostate cancer and a PSA level higher than 4.0 ng/mL between 6 and 12 months after starting ADT. The PSA level could be rising or falling at the time of enrollment, but had to be higher than 4.0 ng/mL. No previous chemotherapy or secondary hormonal therapies were allowed, except in patients receiving a standard, first-generation antiandrogen agent with a falling PSA level at the time of enrollment; this therapy was continued in this cohort. Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily was administered to all participants. A total of 41 men were enrolled between the trial's activation on August 9, 2011, and closure on August 1, 2013. Data analysis was conducted from March 21 to November 29, 2016., Interventions: Abiraterone acetate, 1000 mg, once daily by mouth with prednisone, 5 mg, by mouth twice daily., Main Outcomes and Measures: The primary end point was a PSA level of 0.2 ng/mL or lower within 12 months of starting abiraterone acetate plus prednisone. A partial response (PR) was a secondary end point, defined as a PSA level reduction to lower than 4.0 ng/mL but higher than 0.2 ng/mL., Results: Of the 41 men enrolled, 1 did not receive any protocol treatment and was excluded from analysis. The median (range) age of the 40 participants was 66 (39-85) years. Five (13%) patients achieved a PSA level of 0.2 ng/mL or lower (95% CI, 4%-27%). Thirteen (33%) additional patients achieved a partial response, with a reduction in the PSA level to lower than 4.0 ng/mL but higher than 0.2 ng/mL. Sixteen (40%) patients had no PSA response and 6 (15%) were not assessable and assumed to be nonresponders. The median progression-free survival was 17.5 months (95% CI, 8.6-25.0 months) and the median overall survival was 25.8 months (95% CI, 15.7-25.8 months). There was 1 incident each of grade 4 adverse events of alanine aminotransferase level elevation and rectal hemorrhage. Eleven patients reported grade 3 adverse events., Conclusions and Relevance: This study did not reach its prescribed level of 6 PSA responses of 0.2 ng/mL or lower, although 5 responses were observed. The overall survival and progression-free survival rates observed in this trial are encouraging compared with historical controls. The therapy was generally well tolerated, without any clear signal of any unexpected adverse effects.

Importance: The current American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system, developed for human papillomavirus (HPV)-unrelated disease, discriminates poorly when applied to HPV-related oropharyngeal squamous cell cancer (OPSCC), leading to calls for a new staging system., Objective: To compare the prognostic ability of the AJCC/UICC seventh edition staging system; a recently proposed system, the International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S); and a novel objectively derived system for HPV-related OPSCC using a national database of patients primarily treated with either radiation or surgery., Design, Setting, and Participants: In this observational study, patients with HPV-related nonmetastatic OPSCC were identified in the National Cancer Database between 2010 and 2012. Recursive partitioning analysis (RPA) was used to derive the proposed-RPA staging system. The data were analyzed from March to May 2016., Main Outcomes and Measures: Overall survival was calculated using the Kaplan-Meier method. The performance of the 3 systems was compared using published criteria, and internal validation using bootstrap methods was performed. Survival differences between stage groups were evaluated using the log-rank test., Results: A total of 5626 patients (86.0% male; median [range] age, 58 [21-90] years) were identified. The median (range) follow-up was 28.5 (0.1-58.8) months. A novel staging system (proposed-RPA) consisting of stage IA, T1-2N0-2a; stage IB, T1-2N2b-3; stage II, T3N0-3; stage III, T4a-bN0-3 resulted in 3-year overall survival rates of 91%, 87%, 81%, and 70%, respectively. This system, as well as the ICON-S, significantly prognosticated for survival when either primary surgery or primary radiation subgroups were examined (log-rank P < .001 for all). The AJCC/UICC system, ICON-S, and proposed-RPA all significantly predicted survival outcomes when analyzed globally (log-rank P < .001 for all). The AJCC/UICC system could not differentiate between survival when stages I and IVA were compared, however (log-rank P = .17). On comparative performance evaluation for survival prediction, the proposed-RPA provided superior prognostication compared with the other systems., Conclusions and Relevance: We validated the ICON-S staging as prognostic, overall, and in primary radiation therapy and surgery subgroups, but ultimately found that a staging system consisting of stage IA, T1-2N0-2a; stage IB, T1-2N2b-3; stage II, T3N0-3; and stage III, T4a-bN0-3 (with stage IV representing M1 disease) outperformed the others. The proposed-RPA is an alternative staging system that should be evaluated for potential adoption as part of the next AJCC/UICC staging system.

Background: The optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated., Methods: A phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography., Results: Twenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease., Conclusions: Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors., (© 2015 American Cancer Society.)

Li-Fraumeni syndrome is a rare cancer predisposition syndrome classically associated with remarkably early onset of cancer in families with a typical spectrum of malignancies, including sarcoma, breast cancer, brain tumors, and adrenocortical carcinoma. Because the risks of cancer development are strikingly high for Li-Fraumeni syndrome, aggressive cancer surveillance is often pursued in these individuals. However, optimal screening methods and intervals for Li-Fraumeni syndrome have yet to be determined. In addition, there may be a significant psychosocial burden to intensive cancer surveillance and some prevention modalities. Here, we describe a case of a young woman with a de novo mutation in TP53 and multiple malignancies, with her most recent cancers found at early, curable stages due to aggressive cancer screening. The potential benefits and risks of intensive cancer surveillance in hereditary cancer syndromes is discussed.

This case confirms the observation that urothelial carcinomas can secrete beta-hCG, and that beta-hCG can potentially be used as a marker of a patient's clinical response to treatment. Prospective studies are clearly warranted by these observations.

Purpose of Review: Anaplastic thyroid cancer is the most aggressive solid tumor known to humans. Even when found in a localized form, the prognosis is grave. For metastatic disease, there has been little effect on survival using traditional chemotherapy., Recent Findings: Over a five-decade interval, there has been little progress in the treatment of this malignancy. However, targeted agents represent a new mode of treatment, and some studies have shown encouraging preclinical results. Combretastatin has shown activity in phase 1 and phase II trials; although the registration phase III study failed to meet its accrual goals, it did appear to show some benefit, especially in younger patients., Summary: Combinations of this compound and other targeted agents may prove to be a breakthrough in an otherwise untreatable cancer.

Medullary thyroid cancer (MTC) represents an aggressive form of thyroid malignancy. Some may occur spontaneously or can be associated with Multiple Endocrine Neoplasia syndromes, or Familial Medullary Thyroid Cancer syndrome. In these patients, the protooncogene RET (rearranged during transfection) is mutated. In patients who have unresectable or metastatic disease, the long term prognosis is poor. New treatments for this disease have focused on the use of targeted agents that inhibit the receptor tyrosine kinase of RET. One of these treatments, Vandetanib (Caprelsa, Astra Zeneca), recently has received approval from the Food and Drug Administration for the treatment of patients with progressive locally advanced and/or metastatic disease. This review highlights the studies that led to the drug's approval, and discusses on the potential financial costs of treatment and side effects of this therapy. The main clinical studies evaluating Vandetanib for the treatment of other solid tumors will also be reviewed.

Vandetanib (ZD6474) became the first systemic agent to be approved for the treatment of metastatic or locally advanced medullary thyroid cancer. It was a proof of principle, because it is an orally bioavailable medication that targets the growth factors felt to be important in the pathogenesis of this disease, ie, the rearranged during transfection proto-oncogene and vascular endothelial growth factor receptor. It was tested initially in two Phase II studies at doses of 100 mg and 300 mg daily. Although activity was seen at both doses, the higher dose was chosen for a randomized, placebo-controlled Phase II study. This trial, which accrued more than 300 patients, showed a statistically significant benefit for the group taking vandetanib compared with those taking placebo medication. Progression-free survival for the vandetanib arm has not been reached, compared with 19 months for the placebo arm. The main toxicity appears to be diarrhea, although some patients experienced significant side effects, including torsades de pointes and sudden cardiac death. Therefore, it is now necessary for practitioners to enroll in a Risk Evaluation Mitigation Strategy before being allowed to prescribe this medication, to reduce the risk of serious side effects occurring.

Vandetanib (ZD6474) is an orally bioavailable small molecule tyrosine kinase inhibitor of multiple growth factor receptors, including RET (Rearrange during transfection), vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR). The activity against RET and VEGF made it a good choice in the treatment of medullary thyroid cancer (MTC). As there is considerable cross talk between growth factor pathways, dual inhibition with such agents has become an attractive strategy, in the treatment of many malignancies with encouraging Phase II clinical trial data to date. Vandetanib was tested in two Phase II trials in the treatment of patients with medullary thyroid cancer at doses of 100 mg and 300 mg daily respectively. The encouraging results of these 2 trials led to a randomized phase II trial comparing this medication to placebo using a crossover design. More than 300 patients were included in this study, which ultimately showed a significant improvement in progression-free survival in patients taking vandetanib. Based on these results, the Oncology Drug Advisory Committee (ODAC) of the Food and Drug Administration (FDA) recommended that vandetanib be approved for the treatment of patients with unresectable locally advanced or metastatic medullary thyroid cancer.

Vandetanib (ZD6474) is an oral small molecule inhibitor of multiple intracellular receptor kinases, including the vascular endothelial growth factor receptor (VEGFR) -2 and epidermal growth factor receptor (EGFR). Both VEGFR and EGFR pathways have emerged as instrumental in the growth and metastasis of multiple malignancies, including non-small cell lung cancer (NSCLC). Indeed, inhibitors of each pathway have been approved by the US Food and Drug Administration for use in advanced NSCLC. As there is considerable cross talk between these pathways, dual inhibition with such agents has become an attractive strategy, with encouraging Phase II clinical trial data to date. The convenience of one oral agent targeting both pathways is clear, and clinical trials have established the maximum tolerated daily dose of vandetanib, with data from randomized Phase III trials emerging. This report will review completed and ongoing NSCLC clinical trials evaluating vandetanib, and speculate on the future of this agent in NSCLC.

Introduction: Thyroid cancer is a rare disease with an incidence of around 37,000 cases per year. However, its incidence is rising faster than many other cancers and for men this disease ranks highest overall in the rate of increase (2.4% annual increase) in cancer deaths. As the number of radioactive iodine-resistant thyroid cancers increases, the need for newer treatments has become more important. Axitinib is one of many new small molecule inhibitors of growth factor receptors that have shown promise in the treatment of many cancers. It targets the vascular endothelial growth factor receptors 1, 2 and 3., Aims: The goal of this article is to review the published evidence for the use of axitinib in the treatment of thyroid cancer and define its therapeutic potential., Evidence Review: The major evidence of axitinib activity has appeared in meeting report abstracts. One phase II study has been published. This included patients with any histological type of thyroid cancer that was not amenable to treatment with radioactive iodine., Clinical Potential: To date, in phase II clinical studies axitinib has demonstrated antitumor activity in advanced refractory thyroid cancer. As a monotherapy it resulted in a 30% response rate with another 38% of patients having stable disease. Axitinib appears to have a good tolerability profile, with hypertension being the most common grade 3 or greater side effect.

The treatment of thyroid cancer is evolving. The molecular mechanisms of carcinogenesis for many thyroid cancers have been investigated, and have yielded targets for potential therapies. These targets include VEGFR in the treatment of all thyroid cancers, BRAF in the treatment of papillary thyroid cancer, and RET in the treatment of medullary thyroid cancer (MTC). Many promising drugs that target one or more of these proteins are currently being evaluated, including sorafenib and sunitinib, both of which are still under development for the treatment of thyroid cancer but which have been approved for use in other malignancies. In addition, compounds such as vandetanib (AstraZeneca plc) and XL-184 (Bristol-Myers Squibb Co/Exelixis Inc) have demonstrated activity in early-phase clinical trials of MTC and are being tested further in randomized trials.

Systemic therapy for advanced non-small cell lung cancer (NSCLC) has evolved over the last two decades, with modest improvements in quality of life and overall survival. A plateau has been reached with traditional chemotherapy, and efforts are now being directed at developing molecularly targeted agents. To date, three such agents have been found to improve overall survival in advanced NSCLC. Erlotinib, a small-molecule inhibitor of the epidermal growth factor receptor, was approved by the US FDA in 2004 as second- or third-line treatment for advanced NSCLC. Bevacizumab, an antibody to vascular endothelial growth factor, a key mediator of angiogenesis, received approval in 2006, after a randomized trial reported a median survival of 1 year when bevacizumab was added to first-line chemotherapy. More recently, cetuximab, an antibody to the epidermal growth factor receptor, was found to improve outcome when added to chemotherapy, and FDA approval is anticipated. Several additional agents are currently being evaluated in randomized trials, with encouraging results from early studies. These and other studies are prospectively investigating predictive clinical and molecular characteristics, with the ultimate goal of individualizing therapy in advanced NSCLC.

Purpose of Review: Endocrine tumors are often overlooked in medical oncology discussions, as many of them are effectively cured by surgery alone or surgery plus an ablative radiation therapy. For the rare aggressive endocrine cancers that are widely metastatic or rapidly progressive, however, the role of the medical oncologist becomes more important. To date, conventional chemotherapy has not had a significant impact on the natural history of these malignancies. This has led to the evaluation of novel compounds; some of which have already entered into randomized clinical trials. This review will focus on the advances made in the treatment of advanced thyroid cancer, the commonest of endocrine malignancies., Recent Findings: A growing understanding of molecular oncology has allowed the development of targeted agents in different types of thyroid cancer. Some agents presently being evaluated in clinical trials include inhibitors of angiogenesis (sorafenib, CA4P, axitinib and vandetanib), the epidermal growth factor receptor (gefitinib, vandetanib) and RET protein (vandetanib). Preliminary results from these studies will be reviewed in this paper., Summary: The recent explosion of targeted agents available for study has generated enthusiasm for oncologists treating thyroid cancer. Antiangiogenesis strategies in particular appear promising. RET inhibition in medullary thyroid cancer is also being explored. Further clinical trials will determine which of these will enter the clinic in the near future.