Background
The role of chemotherapy in extremity/trunk soft‐tissue sarcoma (ET‐STS) is controversial, even for patients at high risk for distant recurrence and death (those with high‐grade tumors ...≥5 cm in size). This study examines the impact of integrating chemotherapy with neoadjuvant radiotherapy (RT) on overall survival (OS) for patients with high‐risk ET‐STS.
Methods
The National Cancer Data Base was queried for adult patients with high‐risk ET‐STS who received neoadjuvant RT and limb salvage surgery between 2006 and 2014. Patients were stratified into RT and chemoradiotherapy (CRT) cohorts. OS for the RT and CRT cohorts was analyzed with the Kaplan‐Meier method, log‐rank tests, and Cox proportional hazards models. Propensity score matching (PSM) analysis was used to account for a potential treatment selection bias between the cohorts.
Results
A total of 884 patients were identified: 639 (72.3%) in the RT cohort and 245 (27.7%) in the CRT cohort. The unadjusted 5‐year Kaplan‐Meier OS rate was significantly higher in the CRT cohort: 72.0% versus 56.1% (P < .001). Neoadjuvant chemotherapy was associated with improved OS in univariate and multivariable analyses (hazard ratio HR, 0.57; 95% confidence interval CI, 0.41‐0.78; P < .001). PSM identified 2 evenly matched cohorts of 212 patients each. The 5‐year matched Kaplan‐Meier OS rates were 69.8% and 55.4% for the CRT and RT cohorts, respectively (P = .002). The addition of neoadjuvant chemotherapy remained prognostic for OS on PSM (HR, 0.56; 95% CI, 0.39‐0.83; P = .003).
Conclusions
The addition of chemotherapy to neoadjuvant RT was associated with improved OS for patients with high‐risk ET‐STS. In the absence of randomized data evaluating CRT versus RT, these findings warrant further investigation.
The addition of chemotherapy to neoadjuvant radiotherapy is associated with improved survival for patients with high‐risk extremity/trunk soft‐tissue sarcoma in this large, multicenter data set. In the absence of randomized data comparing these modalities, these findings are encouraging and warrant further investigation.
AbstractPurposePalbociclib is a selective cyclin-dependent kinase 4/6 inhibitor approved for metastatic ER+/HER2- breast cancer. Preclinical evidence suggests a possible synergistic effect of ...palbociclib when combined with radiation therapy (RT); however, the toxicity of this pairing is unknown. We report preliminary results on the use of this combination.Methods and MaterialsRecords of patients treated with palbociclib at our institution from 2015 to 2018 were retrospectively reviewed. Patients who received RT for symptomatic metastases concurrently or within 14 days of palbociclib were included. Local treatment effect was assessed by clinical examination and subsequent computed tomography/magnetic resonance imaging. Toxicity was graded based on Common Terminology Criteria for Adverse Events version 5.0.ResultsA total of 16 women received palliative RT in close temporal proximity to palbociclib administration. Four patients received palbociclib before RT (25.0%), 5 concurrently (31.3%), and 7 after RT (43.8%). The median interval from closest palbociclib use to RT was 5 days (range, 0-14). The following sites were irradiated in decreasing order of frequency: bone (11 axial skeleton 9 vertebra and 2 other; 4 pelvis; 3 extremity), brain (4: 3 whole brain RT and 1 stereotactic radiosurgery), and mediastinum (1). The median and mean follow-up time is 14.7 and 17.6 months (range, 1.7-38.2). Pain relief was achieved in all patients. No radiographic local failure was noted in the 13 patients with evaluable follow-up imaging. Leukopenia, neutropenia, and thrombocytopenia were seen in 4 (25.0%), 5 (31.3%), and 1 (6.3%) patient before RT. After RT, 5 (31.3%), 1 (6.3%), and 3 (18.8%) patients were leukopenic, neutropenic, and thrombocytopenic, respectively. All but 2 (grade 2) hematologic toxicities were grade 1. No acute or late grade 2+ cutaneous, neurologic, or gastrointestinal toxicities were noted. Toxicity results did not differ based on disease site, palbociclib-RT temporal association, or irradiated site.ConclusionsThe use of RT in patients receiving palbociclib resulted in minimal grade 2 and no grade 3+ toxicities. This preliminary work suggests that symptomatic patients receiving palbociclib may be safely irradiated.
BackgroundUveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint ...blockade with nivolumab and ipilimumab is not well defined.MethodsWe conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.Results89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).ConclusionsDual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.
Immune checkpoint inhibitors (ICI) predispose patients to immune-related adverse events (irAEs). Although hepatitis is a potentially lethal toxicity, the timing and outcomes have not been well ...described. In this retrospective study, patients from six international institutions were included if they were treated with ICIs and developed immune-related hepatitis. Patient and tumor characteristics, and hepatitis management and outcomes were evaluated. Of the 164 patients included, most were male (53.7%) with a median age of 63.0 years. Most patients had melanoma (83.5%) and stage IV disease (86.0%). Median follow-up was 585 days; median OS and PFS were not reached. The initial grade of hepatitis was most often grade 2 (30.5%) or 3 (45.7%) with a median time to onset of 61 days. Patients were most commonly asymptomatic (46.2%), but flu-like symptoms, including fatigue/anorexia (17.1%), nausea/emesis (14.0%), abdominal/back pain (11.6%), and arthralgias/myalgias (8.5%) occurred. Most patients received glucocorticoids (92.1%); the median time to improvement by one grade was 13.0 days, and the median time to complete resolution was 52.0 days. Second-line immunosuppression was required in 37 patients (22.6%), and steroid-dose re-escalation in 45 patients (27.4%). Five patients (3%) died of ICI-hepatitis or complications of hepatitis treatment. Ninety-one patients (58.6%) did not resume ICI; of 66 patients (40 grade 1/2, 26 grade 3/4) that were rechallenged, only 25.8% (n = 17) had recurrence. In this multi-institutional cohort, immune-related hepatitis was associated with excellent outcomes but frequently required therapy discontinuation, high-dose steroids, and second-line immunosuppression. Rechallenge was associated with a modest rate of hepatitis recurrence.
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems ...idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4
T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45RO
GZMB
Ki67
) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV
lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4
and CD8
T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
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11054
Background: Large, high-grade extremity/trunk (ET) non-rhabdomyosarcoma soft-tissue sarcoma (STS) is at high risk for distant recurrence and death. The integration of chemotherapy ...(C) to standard of care neoadjuvant radiotherapy (RT) remains controversial, even for these patients. This study examines the impact of adding C to neoadjuvant RT on overall survival (OS) in high risk ET-STS. Methods: The National Cancer Data Base (NCDB) was queried for patients ≥18 years with high risk (≥5 cm + high grade) non-rhabdomyosarcoma ET-STS (WHO histology) who received neoadjuvant RT and limb sparing surgery from 2006-2014. Patients were next stratified based upon receipt of C (RT and CRT cohorts). Overall survival (OS) for RT vs CRT cohorts was analyzed using the Kaplan-Meier (KM) method, log-rank test, and Cox proportional hazards models. Propensity score-matched analysis (PSM) was employed to account for potential treatment selection bias between cohorts. Results: A total of 848 (71.1%) and 344 (28.9%) patients received RT and CRT, respectively. Patient cohorts were well-balanced except for the CRT cohort having higher rates of treatment in the West (22.1% vs 10.6%) & Midwest (28.3% vs 22.7%), Charlson-Deyo CD score 0 vs ≥1 (85.5% vs 79.4%), younger age (≤50) (45.9% vs 21.7%), synovial sarcoma histology (18.9% vs 3.2%), earlier year of diagnosis (2006-2010) (39.5% vs 32.3%), and positive lymphovascular invasion (2.0 vs 1.51%), (p < 0.05 each). The KM 5-year OS was significantly higher in the CRT vs RT cohort: 69.2% vs 58.1% on univariate (p < 0.0001) and multivariate analysis (Hazard Ratio HR: 0.66; 95% Confidence Interval CI: 0.52-0.85; p = 0.001) even after adjusting for age, race, income, CD score, histology, tumor size, tumor grade, and primary site (lower extremity; upper extremity; trunk). PSM identified evenly matched cohorts of 300 patients each with respect to age, income, CD score, histology, grade, tumor size, and primary site. The addition of neoadjuvant C remained prognostic for OS on PSM (HR: 0.74 0.56-0.99, p = 0.042). Conclusions: The addition of C to neoadjuvant RT was associated with improved OS in patients with high risk non-rhabdomyosarcoma ET-STS in the NCDB. These hypothesis generating results support prospective evaluation.
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11009
Background: Gender & racial/ethnic leadership disparities have been independently identified in academic hematology/oncology (HO) and radiation oncology (RO). Here, we evaluate ...gender and racial/ethnic intersectionality from the trainee to the leadership level. Methods: All ACGME accredited HO and RO training program websites were queried to identify constituent trainees, academic faculty, program directors (PD) and department chairs (DC), with a leadership position defined as PD or DC. Individual gender & race/ethnicity was determined using externally validated software tools (Gender-API, NamSor, & Onolytics), publicly available descriptors, and image review. We grouped individuals into 6 categories: White Male (WM), White Female (WF), Asian Male (AM), Asian Female (AF), Underrepresented Groups in Medicine (as defined by AAMC) Male (URMM) and Female (URMF). The chi-squared goodness-of-fit test was applied to examine if deviations exist between the observed vs. expected proportions of gender/race dyads in trainees, PD, and DC compared to academic faculty. Results: We identified 7,722 individuals from 2019-2020: 1,759 trainees (HO=1525; RO=234), 5,726 faculty (HO=4834; RO=892), 242 PD (HO=149; RO=93) and 237 DC (HO=144; RO=93). Leadership positions were most often comprised by WM (52.6%), and least often comprised by URMF (2.9%). Combined HO/RO analysis revealed significant differences in the observed representation of trainees & DC vs expected levels based on total faculty, respectively: WM (33.7% & 60.3% vs. 42.3%), WF (19.2% & 13.9% vs. 22.3%), AM (20.75% & 16.9% vs. 16.4%), AF (17.9% & 2.5% vs. 12.7%), URMM (4.09% & 5.5% vs. 3.5%) and URMF (4.3% & 0.8% vs. 2.8%), p<0.01. No differences were seen between PD vs total faculty. On subset analysis, there were significant differences observed in HO programs at the trainee, PD and DC levels compared to total faculty, whereas significant differences in RO programs were seen only at the DC level Table. Conclusions: Gender & racial/ethnic disparity is present in academic oncology. Specifically, women of all races/ethnicities are proportionally underrepresented in DC positions in HO and RO programs. These data can serve as a benchmark to raise awareness and monitor progress towards a more balanced workforce in oncology.Table: see text
Women are underrepresented in medical leadership positions; however, representation of women among academic oncology leadership is unknown.
To evaluate representation of women overall and in ...leadership positions in academic medical oncology (MO), radiation oncology (RO), and surgical oncology (SO) programs and to examine the association of women leadership with overall faculty representation of women per program.
In this cross-sectional study, MO, RO, and SO training program websites were queried from October 2018 through June 2019. All faculty from 265 of 273 accredited MO, RO, and SO training programs (97.1%) were included.
Gender.
Observed proportions of women in leadership positions compared with the expected proportion of overall women faculty in MO, RO, and SO were assessed. Rates of representation of women across each MO, RO, and SO program's faculty based on the presence or absence of a woman in a leadership position were compared.
Of 6030 total faculty, only 2164 (35.9%) were women. Total representation of women among MO, RO, and SO faculty was 37.1% (1563 of 4215), 30.7% (389 of 1269), and 38.8% (212 of 546), respectively. Women composed only 21.7% (30 of 138), 11.7% (11 of 94), and 3.8% (1 of 26) of MO, RO, and SO chair positions, respectively. The observed proportion of women in chair positions was significantly lower than the expected proportion for MO, RO, and SO. In all, 47.9%, 33%, and 18.5% of MO, RO, and SO programs, respectively, had at least 1 woman in a leadership position (program director or chair). Programs with 1 or more women in a leadership position were associated with a higher mean (SD) percentage of women faculty than those without at least 1 woman leader in MO (40.7% 12.5% vs 33.1% 11.0%; P < .001) and RO (36.2% 13.3% vs 23.4% 12.3%; P < .001) but not SO (40.2% 15.4% vs 31.4% 16.9%; P = .29).
Gender disparity exists in academic MO, RO, and SO faculty, which is magnified at the chair level. Programs in MO and RO with a woman physician in a leadership position were associated with a higher percentage of women faculty, but this was not true for SO. These data will serve as a benchmark to monitor progress toward a more balanced workforce.
The field of tumor immunology has faced many complex challenges over the last century, but the approval of immune checkpoint inhibitors (anti-cytotoxic T-lymphocyte-associated protein 4 CTLA4 and ...anti-programmed cell death-1 PD-1/PD-ligand 1 PD-L1) and talimogene laherparepvec (T-VEC) for the treatment of metastatic melanoma have awakened a new wave of interest in cancer immunotherapy. Additionally, combinations of vaccines and oncolytic viral therapies with immune checkpoint inhibitors and other systemic agents seem to be promising synergistic strategies to further boost the immune response against cancer. These combinations are undergoing clinical investigation, and if successful, will hopefully soon become available to patients. Here, we review key basic concepts of tumor-induced immune suppression in malignant melanoma, the historical perspective around vaccine development in melanoma, and advances in oncolytic viral therapies. We also discuss the emerging role for combination approaches with different immunomodulatory agents as well as new developments in personalized immunization approaches.
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