Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 ...(PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial.
Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated.
Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ≥2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8–45.8 months). Median progression-free survival was 2.6 months (range 0.5–48.4 months), and median overall survival was 6.0 months (range 0.5–51.6+ months). Responses showed no association with HPV status or PD-L1 expression level.
In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC.
ClinicalTrials.gov number: NCT01375842.
Background
Hematologic markers, such as the neutrophil‐to‐lymphocyte ratio (NLR), characterize the inflammatory response to cancer and are associated with poorer survival in various malignancies. We ...evaluate the effect of pretreatment NLR on overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC).
Methods
Using multiple databases, a systematic search for articles evaluating the effect of NLR on OS in patients with HNSCC was performed. An inverse variation, random‐effects model was used to analyze the data.
Results
A total of 24 of 241 articles, including 6479 patients, were analyzed. The combined hazard ratio for OS in patients with an elevated NLR (range 2.04‐5) was 1.78 (confidence interval CI 1.53‐2.07; P < .0001). The hazard ratios for site‐specific cancer: oral cavity 1.56 CI 1.23‐1.98 (P < .001), nasopharynx 1.66 CI 1.35‐2.04 (P < .001), larynx 1.55 CI 1.26‐1.92 (P < .001), and hypopharynx 2.36 CI 1.54‐3.61 (P < .001).
Conclusion
An elevated NLR is predictive of poorer OS in patients with HNSCC.
The aim of this study is to understand the mechanism of EGFR overexpression in head and neck squamous cell carcinoma (HNSCC). For this reason, expression/mutation of EGFR were analyzed in 30 ...dysplastic head and neck lesions and 148 HNSCC samples of Indian patients along with 3 HNSCC cell lines. In addition, deletion/methylation/mutation/expression of SH3GL2 (associated with EGFR degradation) and CDC25A (associated with dephosphorylation of EGFR) were analyzed in the same set of samples. Our study revealed high frequency of EGFR overexpression (66-84%), low frequency of gene amplification (10-32.5%) and absence of functional mutation in the dysplastic lesions and HNSCC samples. No correlation was found between protein overexpression and mRNA expression/gene amplification status of EGFR. On the other hand, frequent alterations (deletion/methylation) of SH3GL2 (63-77%) and CDC25A (37-64%) were seen in the dysplastic and HNSCC samples. Two novel single nucleotide polymorphism (SNPs) were found in the promoter region of SH3GL2. Reduced expression of these genes showed concordance with their alterations. Overexpression of EGFR and p-EGFR were significantly associated with reduced expression and alterations of SH3GL2 and CDC25A respectively. In-vitro demethylation experiment by 5-aza-2'-deoxycytidine (5-aza-dC) showed upregulation of SH3GL2 and CDC25A and downregulation of EGFR expression in Hep2 cell line. Poor patient outcome was predicted in the cases with alterations of SH3GL2 and CDC25A in presence of human papilloma virus (HPV) infection. Also, low SH3GL2 and high EGFR expression was a predictor of poor patient survival. Thus, our data suggests that overexpression of EGFR due to its reduced degradation and dephosphorylation is needed for development of HNSCC.
Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (HNSCC). Predictive biomarkers have not been established and patient stratification based on molecular ...tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment. From our patient‐derived xenograft platform of HNSCC, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid‐clustering with previously published gene expression data by Keck et al. The models were treated in groups of 5–6 animals with docetaxel, cetuximab, everolimus, cis‐ or carboplatin and 5‐fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after 3 weeks of treatment (RTV). Tumors distributed over the 3 signature‐defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs. BA 0.78 (MS vs. BA, unpaired t‐test, p 0.0002). Cetuximab responders were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the subtypes. In conclusion basal subtype was associated with response to EGFR directed therapy in head and neck squamous cell cancer patient‐derived xenografts.
What's new?
Head and neck squamous cell carcinoma (HNSCC) has multiple subtypes, including basal and classical subtypes, which exhibit elevated expression of epidermal growth factor receptor (EGFR) pathway members. EGFR inhibition is the central action of cetuximab, the only targeted treatment approved for HNSCC. Whether EGFR expression predicts cetuximab response, however, is unclear. In our study, analysis of whole gene expression in patient‐derived xenografts revealed a positive association between the basal subtype of HNSCC and cetuximab response. By contrast, mesenchymal subtype tumors were associated with cetuximab resistance. Functional analyses revealed an enrichment in EGFR pathway gene expression in the basal subtype.
Abstract Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with high morbidity and mortality. Despite advances in cytotoxic therapies and surgical techniques, overall survival ...(OS) has not improved over the past few decades. This emphasises the need for intense investigation into novel therapies with good tumour control and minimal toxicity. Cancer immunotherapy has led this endeavour, attempting to improve tumour recognition and expand immune responses against tumour cells. While various forms of HNSCC immunotherapy are in preclinical trials, the most promising direction thus far has been with monoclonal antibodies (mAbs), targeting growth factor and immune checkpoint receptors. Preclinical and early phase trials have shown unprecedented efficacy with minimal adverse effects. This article will review biological mechanisms of immune escape and implications for immunotherapy in HNSCC.
Objectives/Hypothesis
Poor nutritional status in patients with head and neck squamous cell carcinoma (HNSCC) is associated with tumor progression and survival. This study examined the prognostic ...value of nutritional and hematological markers in patients with HNSCC who received definitive treatments.
Study Design
A prospective observational cohort study.
Methods
This study included 338 consecutive patients who underwent surgery and/or radiotherapy/chemoradiotherapy for treatment‐naïve HNSCC. Body weight and nutritional and hematological parameters were regularly measured before and after treatment. Univariate and multivariate analyses using Cox proportional hazards models were performed to identify factors associated with disease‐free survival (DFS), cancer‐specific survival (CSS), and overall survival (OS).
Results
Body weight, serum total protein and albumin levels, and hematological variables significantly decreased after treatment. Univariate analyses illustrated that age, tumor site, T and N classifications, overall stage, pretreatment serum albumin (<3.5 g/dL) and hemoglobin (<12 g/dL) levels, and neutrophil‐lymphocyte ratio were significantly associated with DFS, CSS, and OS (all P < .05). Multivariate analyses identified age, tumor site, N classification, and pretreatment albumin levels as independent predictors of DFS, CSS, and OS (all P < .05). Patients with low serum albumin levels prior to treatment experienced approximately sixfold increases in the risks of tumor progression and cancer‐specific and overall mortality compared to the findings in their counterparts.
Conclusions
Our results suggest that pretreatment serum albumin levels predict DFS, CSS, and OS in patients who received definitive treatment for HNSCC. These findings might help to predict treatment outcome and guide nutritional intervention in patients with HNSCC.
Level of Evidence
2b. Laryngoscope, 127:E437–E442, 2017
Despite the wide use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in bone defect, its application in treating osteonecrosis of femoral head (ONFH) is yet to be elucidated. The ...heterotopic ossification (HO) after rhBMP-2 usage in some orthopedic surgeries has been reported previously; however, only a few studies describe this complication in the treatment of ONFH.The present study investigated whether the rhBMP-2 application would increase the risk of HO formation in selected ONFH patients with nonvascularized bone grafting surgery and enhance the surgical results of nonvascularized bone grafting as compared to patients who did not receive intraoperative rhBMP-2.A retrospective analysis was performed on 94 patients (141 hips) who, with Association Research Circulation Osseous (ARCO) stages IIb, IIc, and IIIa ONFH, underwent nonvascularized bone grafting surgery. The first 46 patients (66 hips) received intraoperative rhBMP-2. The postoperative radiographic results (X-ray and CT scan) and Harris hip score (HHS) were reviewed in each patient to record the incidence of HO formation and evaluate the clinical efficacy of rhBMP-2, respectively.HO formation frequently occurred in patients receiving intraoperative rhBMP-2 (8/66 hips) than those not receiving the protein (1/75 hips) (P = .02). HHS improved from preoperatively at the final follow-up (P < .01) in the BMP-positive group, with a survival rate of 83.3%. In the BMP-negative group, the HHS improved from preoperatively at the end of the follow-up (P < .01), and the survival rate was 72.0%.rhBMP-2 has osteoinductive property and might serve as an adjuvant therapy in the surgical treatment of ONFH. However, the incidence of HO formation might increase when used in high doses.
Head and neck tumors are malignant tumors that appear in the head and neck. Although much progress has been made in the treatment of head and neck tumors, many challenges remain. The prognosis of ...some advanced cases remains poor and survival and quality of life after treatment face certain limitations. Therefore, further research into the pathogenesis and treatment options for head and neck tumors is important in order to improve the prognosis and quality of life of patients. The Protein Arginine Methyltransferase (PRMT) family is a class of enzymes that are responsible for adding methyl groups to arginine residues in proteins. PRMT family members play important roles in regulating many cellular processes, such as transcriptional regulation, signaling, and cell cycle regulation. Recent studies have shown that the PRMT family also plays an important function in tumorigenesis and development. Here, we found that PRMT family members are significantly overexpressed in head and neck tumors and that PRMT5 may serve as an independent prognostic factor in head and neck tumors. We found that PRMT5-regulated differential genes were significantly enriched in tumor-associated signaling pathways such as IL-17 and p53. And we also found that the expression of PRMT5 in head and neck tumors was significantly correlated with immune cell infiltration, m6A as well as the expression of ferroptosis-related genes, and drug sensitivity. These results suggest that PRMT may play an important role in the development of head and neck tumors.
•Prevalence of HPV positive cancers among OPSCC is increasing.•Cancer stem cells set therapy benchmark for tumour control.•HPV positive HNSCC cancer stem cells are more radiosensitive than HPV ...negative.•Multiple biomarker profiling can more specifically stratify patients for treatment.
Head and neck squamous cell carcinomas (HNSCC) resulting from oncogenic transformations following human papillomavirus (HPV) infection consistently demonstrate better treatment outcomes than HNSCC from other aetiologies. Squamous cell carcinoma of the oropharynx (OPSCC) shows the highest prevalence of HPV involvement at around 70–80%. While strongly prognostic, HPV status alone is not sufficient to predict therapy response or any potential dose de-escalation. Cancer stem cell (CSC) populations within these tumour types represent the most therapy-resistant cells and are the source of recurrence and metastases, setting a benchmark for tumour control. This review examines clinical and preclinical evidence of differences in response to treatment by the HPV statuses of HNSCC and the role played by CSCs in treatment resistance and their repopulation from non-CSCs. Evidence was collated from literature searches of PubMed, Scopus and Ovid for differential treatment response by HPV status and contribution by critical biomarkers including CSC fractions and chemo-radiosensitivity.
While HPV and CSC are yet to fulfil promise as biomarkers of treatment response, understanding how HPV positive and negative aetiologies affect CSC response to treatment and tumour plasticity will facilitate their use for greater treatment individualisation.
•Target volume selection and delineation for both the primary tumor and the lymph nodes are critical steps in the treatment of head and neck tumors with IMRT.•Selection and delineation are optimal ...when reaching the best compromise between a too tight volume that could be associated to an unacceptable rate of local recurrence, and a too large volume.•Sets of guidelines have been proposed aiming at standardizing radiotherapy practices of head and neck cancer patients.
Target volume selection and delineation for both the primary tumor and the lymph nodes are critical steps in the treatment of head and neck tumors with Intensity Modulated Radiation therapy (IMRT). These steps should be based on a probabilistic approach, which is that selection and delineation will be considered as optimal when reaching the best compromise between a too tight volume that could be associated to an unacceptable rate of local recurrence, and a too large volume, which could be associated to an unacceptable rate of treatment morbidity. Failure to do so have been reported to be associated to a higher risk of loco-regional recurrences and/or morbidity after treatment. In this framework, groups of experts proposed sets of guidelines for the radiation oncology community, aiming at standardizing radiotherapy practices of head and neck cancer patients. Although in constant improvement, such guidelines have been shown to translate into more consistent treatment approaches.
This review article summarizes the knowledge accumulated over the years on target volume selection and delineation and tries to reconcile the various schools of thoughts on the topic.
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