Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine-refractory (RAIR) thyroid cancer ...and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.
This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.
Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3-18.5) with a 2-year PFS of 23.6% (95% CI, 10.5-39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8-85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations.
-mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.
Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine.
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Objectives
Accurate pre-treatment imaging determination of extranodal extension (ENE) could facilitate the selection of appropriate initial therapy for HPV-positive oropharyngeal squamous cell ...carcinoma (HPV + OPSCC). Small studies have associated 7 CT features with ENE with varied results and agreement. This article seeks to determine the replicable diagnostic performance of these CT features for ENE.
Methods
Five expert academic head/neck neuroradiologists from 5 institutions evaluate a single academic cancer center cohort of 75 consecutive HPV + OPSCC patients. In a web-based virtual laboratory for imaging research and education, the experts performed training on 7 published CT features associated with ENE and then independently identified the “single most (if any) suspicious” lymph node and presence/absence of each of the features. Inter-rater agreement was assessed using percentage agreement, Gwet’s AC1, and Fleiss’ kappa. Sensitivity, specificity, and positive and negative predictive values were calculated for each CT feature based on histologic ENE.
Results
All 5 raters identified the same node in 52 cases (69%). In 15 cases (20%), at least one rater selected a node and at least one rater did not. In 8 cases (11%), all raters selected a node, but at least one rater selected a different node. Percentage agreement and Gwet’s AC1 coefficients were > 0.80 for lesion identification, matted/conglomerated nodes, and central necrosis. Fleiss’ kappa was always < 0.6. CT sensitivity for histologically confirmed ENE ranged 0.18–0.94, specificity 0.41–0.88, PPV 0.26–0.36, and NPV 0.78–0.96.
Conclusions
Previously described CT features appear to have poor reproducibility among expert head/neck neuroradiologists and poor predictive value for histologic ENE.
Key Points
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Previously described CT imaging features appear to have poor reproducibility among expert head and neck subspecialized neuroradiologists as well as poor predictive value for histologic ENE
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Although it may still be appropriate to comment on the presence or absence of these CT features in imaging reports, the evidence indicates that caution is warranted when incorporating these features into clinical decision-making regarding the likelihood of ENE
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Background
Osteoradionecrosis of the jaw (ORN) is an infrequent yet potentially devastating complication of radiation therapy to the head and neck region. Treatment options include antimicrobial ...therapy, local sequestrectomy, resection, and the use of hyperbaric oxygen (HBO). Published data on ORN are difficult to compare because of the lack of a universally accepted classification and staging system, and the literature on the use of HBO to either prevent or successfully manage ORN is controversial and inconclusive. Therefore, we aimed to establish a standard approach for using HBO at our institution.
Materials and Methods
A literature search was conducted of articles published in the English language between January 1980 and January 2016. Retrieved articles were evaluated by two independent reviewers. Isolated case reports, s, case series, review articles, and cohort studies without a control group were excluded; summary data were extracted from the remaining studies. A panel of experts from Head and Neck Oncology and Oral Medicine from the Dana‐Farber Cancer Institute and Brigham and Women's Hospital reviewed the summary data and established multidisciplinary guidelines on the use of HBO for the prevention and management of ORN.
Results
Seven studies were evaluated and reviewed by the multidisciplinary panel. There was no consistent evidence in support of HBO for either the prevention or management of ORN.
Conclusion
Based on the available evidence and expert opinion, routine use of HBO for the prevention or management of ORN is not recommended and is rarely used at our institution.
Implications for Practice
The Division of Head and Neck Oncology of Dana‐Farber/Brigham and Women's Cancer Center does not recommend the routine use of HBO for the prevention or management of ORN. Adjunctive HBO may be considered for use on a case‐by‐case basis in patients considered to be at exceptionally high risk who have failed conservative therapy and subsequent surgical resection.
Osteoradionecrosis of the jaw is a complication of radiation therapy to the head and neck region. Many preventive strategies for osteoradionecrosis have been proposed that have yet to be validated by high‐level evidence. The use of hyperbaric oxygen has been suggested as a means for prevention and treatment, and this study aimed to establish a standard approach for using hyperbaric oxygen at one institution.
Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition ...anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L) before and after salvage surgery to improve disease-free survival (DFS).
In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling.
Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (
= 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8-71.7) and 1-year OS was 85.7% (95% CI, 66.3-94.4). Two-year DFS and OS were 64% and 80% among pathologic responders.
(Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.
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Cemiplimab is approved for treating locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). Solid organ transplant recipients have been excluded from immunotherapy trials, given ...concern for allograft rejection despite their increased risk of skin cancers. Chronic immunosuppression is necessary to prevent organ rejection but may attenuate antitumor response with PD-1 inhibitors.
We report a phase I study of cemiplimab for kidney transplant recipients (KTRs) with advanced CSCC. After cross-taper to a mammalian target of rapamycin (mTOR) inhibitor and pulsed dose corticosteroids (prednisone 40 mg once daily, the day before and on days 1-3 of each cycle, followed by 20 mg once daily on days 4-6, then 10 mg once daily until the day before each subsequent cycle), patients received cemiplimab 350 mg intravenously once every 3 weeks for up to 2 years and were assessed for response every 8 weeks. The primary end point was the rate of kidney rejection, with key secondary end points including rate and duration of response, and survival.
Twelve patients were treated. No kidney rejection or loss was observed. A response to cemiplimab was observed in five of 11 evaluable patients (46%; 90% CI, 22 to 73), including two with durable responses beyond a year. Median follow-up was 6.8 months (range, 0.7-29.8). Treatment-related grade 3 or greater adverse events occurred in five patients (42%), including diarrhea, infection, and metabolic disturbances. One patient died of angioedema and anaphylaxis attributed to mTOR inhibitor cross-taper.
mTOR inhibitor and corticosteroids represent a favorable immunosuppressive regimen for KTRs with advanced CSCC receiving immunotherapy. This combination resulted in durable antitumor responses with no kidney rejection events (funded by Regeneron Pharmaceuticals ClinicalTrials.gov identifier: NCT04339062).
The programmed death-1 (PD-1) immune checkpoint inhibitor pembrolizumab is currently approved in the US for the first-line (1L) treatment of recurrent or metastatic head and neck squamous cell ...carcinoma (R/M HNSCC), either alone or in combination with platinum and 5-fluorouracil (5-FU). However, the toxicity of 5-FU has motivated the study of alternate combinations that replace 5-FU with a taxane. The objective of the current study was to describe the baseline characteristics, treatment patterns and sequences, and real-world outcomes of individuals receiving pembrolizumab + platinum + taxane as 1L treatment for R/M HNSCC in the US.
This was a retrospective study of US adults ≥18 years of age receiving pembrolizumab + platinum + taxane as 1L treatment for R/M HNSCC, using electronic health record data from a nationwide de-identified database. Real-world overall survival (rwOS), time on treatment (rwToT), and time to next treatment (rwTTNT) outcomes were assessed using Kaplan-Meier analysis.
The study population comprised 83 individuals (80.7% male) with a median age of 64 years. The most common tumor site was the oropharynx (48.2%); 70.0% of these tumors were HPV-positive. A total of 71.1% of the study population had an Eastern Cooperative Oncology Group performance status of 0-1 at index date, 71.8% had a combined positive score for programmed death ligand-1 (PD-L1) expression of ≥1, and 30.8% had a score of ≥20. The median (95% CI) rwOS was 14.9 (8.8-23.3) months, rwToT was 5.3 (4.0-8.2) months, and rwTTNT was 8.7 (6.8-12.3) months. Among the 24 individuals who received a subsequent therapy, the most common second-line therapies were cetuximab-based (
= 9) or pembrolizumab-containing (
= 8) regimens.
The rwOS and other real-world outcomes observed for this study population further support pembrolizumab + platinum + taxane combination therapy as a potential 1L treatment option for R/M HNSCC.
Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression ...alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti-PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti-PD-1/L1 response.
Pembrolizumab, a PD-1 immune checkpoint inhibitor, is approved as first-line (1L) treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) as monotherapy or in ...combination with platinum and 5-fluorouracil chemotherapy. Limited data exist on the use of these regimens in real-world settings.
Our primary objectives were to describe baseline characteristics and real-world overall survival (rwOS), time on treatment (rwToT), and time to next treatment (rwTTNT) among individuals with R/M HNSCC receiving approved 1L pembrolizumab therapies. We also aimed to identify baseline factors associated with choice of 1L pembrolizumab therapy and with rwOS.
This was a retrospective cohort study of adults with R/M HNSCC receiving 1L pembrolizumab monotherapy or pembrolizumab plus chemotherapy. We used Kaplan-Meier analyses to assess real-world outcomes, logistic regression modeling to identify factors associated with choice of 1L pembrolizumab therapy, and Cox proportional hazards models to identify factors associated with rwOS.
The study population included 431 individuals receiving 1L pembrolizumab monotherapy and 215 receiving 1L pembrolizumab plus chemotherapy. The use of 1L pembrolizumab monotherapy was associated with higher baseline combined positive score for PD-L1 expression, older age, higher Eastern Cooperative Oncology Group performance status (ECOG PS), laryngeal tumor site, and human papillomavirus (HPV)-positive tumor status. The pembrolizumab monotherapy group had a median (95% CI) rwOS of 12.1 (9.2-15.1) months, rwToT of 4.2 (3.5-4.6) months, and rwTTNT of 6.5 (5.4-7.4) months. Among this group, HPV-positive tumor status and lower ECOG PS were associated with longer rwOS, and oral cavity tumor site with shorter rwOS. The pembrolizumab plus chemotherapy cohort had a median (95% CI) rwOS of 11.9 (9.0-16.0) months, rwToT of 4.9 (3.8-5.6) months, and rwTTNT of 6.6 (5.8-8.3) months. In this group, HPV-positive tumor status was associated with longer rwOS.
This study adds to clinical trial data by summarizing real-world treatment outcomes with 1L pembrolizumab-containing therapies in a more heterogeneous population. Overall survival outcomes in both treatment groups were similar to those observed in the registration clinical trial. These findings support the use of pembrolizumab as standard of care for R/M HNSCC.
Circulating tumor tissue-modified viral (TTMV) human papillomavirus (HPV) DNA is a dynamic, clinically relevant biomarker for HPV-positive oropharyngeal squamous cell carcinoma. Reasons for its wide ...pretreatment interpatient variability are not well understood.
To characterize clinicopathologic factors associated with TTMV HPV DNA.
This cross-sectional study included patients evaluated for HPV-positive oropharyngeal squamous cell carcinoma at Dana-Farber Cancer Institute in Boston, Massachusetts, between December 2019 and January 2022 and who were undergoing curative-intent treatment.
Clinicopathologic characteristics including demographic variables, tumor and nodal staging, HPV genotype, and imaging findings.
Pretreatment circulating TTMV HPV DNA from 5 genotypes (16, 18, 31, 33, and 35) assessed using a commercially available digital droplet polymerase chain reaction-based assay, considered as either detectable/undetectable or a continuous score (fragments/mL).
Among 110 included patients, 96 were men (87%) and 104 were White (95%), with a mean (SD) age of 62.2 (9.4) years. Circulating TTMV HPV DNA was detected in 98 patients (89%), with a median (IQR) score of 315 (47-2686) fragments/mL (range, 0-60 061 fragments/mL). Most detectable TTMV HPV DNA was genotype 16 (n = 86 88%), while 12 patients (12%) harbored other genotypes. Circulating TTMV HPV DNA detection was most strongly associated with clinical N stage. Although few patients had clinical stage N0 disease, only 4 of these 11 patients (36%) had detectable DNA compared with 94 of 99 patients (95%) with clinical stage N1 to N3 disease (proportion difference, 59%; 95% CI, 30%-87%). Among patients with undetectable TTMV HPV DNA, more than half (7 of 12 58%) had clinical stage N0 disease. The TTMV HPV DNA prevalence and score increased with progressively higher clinical nodal stage, diameter of largest lymph node, and higher nodal maximum standardized uptake value on positron emission tomography/computed tomography. In multivariable analysis, clinical nodal stage and nodal maximum standardized uptake value were each strongly associated with TTMV HPV DNA score. Among 27 surgically treated patients, more patients with than without lymphovascular invasion had detectable TTMV HPV DNA (12 of 12 100% vs 9 of 15 60%).
In this cross-sectional study, circulating TTMV HPV DNA was statistically significantly associated with nodal disease at HPV-positive OPSCC diagnosis. The few patients with undetectable levels had predominantly clinical stage N0 disease, suggesting assay sensitivity for diagnostic purposes may be lower among patients without cervical lymphadenopathy. Mechanisms underlying this association, and the use of this biomarker for surveillance of patients with undetectable baseline values, warrant further investigation.
Abstract Purpose: Many patients with locoregionally advanced human papillomavirus–negative head and neck squamous cell carcinoma (HNSCC) relapse. ctDNA has the potential to identify minimal residual ...disease, but its clinical utility for virus-negative HNSCC is not well understood. Experimental Design: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera, Natera) during clinical care of patients treated for predominantly newly diagnosed human papillomavirus–negative HNSCC. Signatera utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes posttreatment with disease outcomes. Results: Testing was successful in 100/116 (86%) patients (median age: 65 years, 68% male, 65% smokers); testing failed in 16 (14%) because of insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III to IV disease (82, 71%), whereas 17 (15%) had distant metastases. Pretreatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03–4049.69 mean tumor molecules/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At a median follow-up of 5.1 months (range: 0.2–15.1), 55 (55%) had >1 test result (range: 1–7; 194 samples). Of 55 patients, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive versus ctDNA negative posttreatment (HR, 7.33; 95% confidence interval, 3.12–17.2; P < 0.001); 1-year overall survival was 89.1% versus 100%, respectively (HR, 7.46; 95% confidence interval, 0.46–119.5; P = 0.155). Conclusions: Tumor-informed ctDNA testing is feasible in nonviral HNSCC. ctDNA positivity is an indicator of disease progression and associated with inferior survival. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy in HNSCC.
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