Recent advancements in computational power, machine learning, and artificial intelligence technology have enabled automated evaluation of medical images to generate quantitative diagnostic and prognostic biomarkers. Such objective biomarkers are readily available and have the potential to improve personalized treatment, precision medicine, and patient selection for clinical trials. In this article, we explore the merits of the most recent addition to the “-omics” concept for the broader field of head and neck cancer – “Radiomics”. This review discusses radiomics studies focused on (molecular) characterization, classification, prognostication and treatment guidance for head and neck squamous cell carcinomas (HNSCC). We review the underlying hypothesis, general concept and typical workflow of radiomic analysis, and elaborate on current and future challenges to be addressed before routine clinical application.
Background We conducted a correlative study for E2399, a function preservation trial for resectable locally advanced oropharynx and larynx cancer, to prospectively assess effects of chemoradiation (CCR) on quality of life (QOL), swallowing and voice. We correlated the results of swallow assessments done via questionnaires and objective assessments by modified barium swallow (MBS). Methods The Functional Assessment of Cancer-HN (FACT-HN), the Performance Status Scale – Head and Neck (PSS-HN), swallow assessments (including modified barium swallow studies), and voice assessments: Voice Handicap Index (VHI), the Voice Disability Assessment (VDA), and American Speech-Language Hearing Association’s Functional Communication Measure (FCM) were conducted at baseline and periodically post-treatment for 2 years. Results Baseline QOL and swallowing function predicted overall survival. Patients experienced a marked decrease in QOL, swallowing, and speech post CCR although the decrease in vocal function was modest. Function and QOL returned towards baseline in the majority of patients by 12 months post treatment. Less than 10% of patients had severe dysphagia and were PEG dependent at 12 months post treatment. There was a high degree of correlation between the FACT-HN and PSS-HN swallow items. Statistically significant correlations were found between subjective and objective measures of swallow function. Conclusions Patients experience marked loss in swallowing function post CCR which returned to baseline in the majority of patients. The correlations between the FCM and self-report swallow items on the PSS and FACT-HN appear to be sufficiently strong to justify their use as a surrogate marker for swallowing disability in large therapeutic trials.
Background Human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than HNSCC due to other risk factors. However, there is significant heterogeneity within HPV-associated HNSCC and 25% of these patients still do poorly despite receiving aggressive therapy. We currently have no good molecular tools to differentiate and exclude this “high-risk” sub-population and focus on “low-risk” patients for clinical trials. This has been a potential barrier to identifying successful de-escalation treatment strategies in HPV-associated HNSCC. We conducted an analysis of molecular markers with a well-known role in the pathogenesis of HPV-associated HNSCC and hypothesized that these markers could help independently predict recurrence and prognosis in these patients and therefore help identify at the molecular level “low-risk” patients suitable for de-escalation trials. Methods We analyzed 24 tumor specimens of patients with p16+ HNSCC who underwent definitive resection as primary treatment. Tissue microarray (TMA) was generated from the 24 pathology blocks and immunohistochemistry (IHC) was performed using highly specific antibodies for our chosen biomarkers (PI3K-PTEN, AKT pathway, mTOR, 4EBP1, S6, and pAMPK, ERCC-1). Transcriptome data was also obtained for 7 p16+ HNSCC patients from The Cancer Genome Atlas (TCGA). Data from the TMA and TCGA were analyzed for association of relapse-free survival (RFS) and overall survival (OS) with protein and gene expression of the chosen biomarkers. Results Increased pAMPK protein activity by IHC and AMPK gene expression by TCGA gene expression data was correlated with improved RFS with a trend towards statistical significance. Conclusions This data suggests that increased pAMPK activity and expression may portend a better prognosis in HPV-associated HNSCC undergoing primary definitive resection. However, these findings require validation in larger studies.
Cancer burden in sub-Saharan Africa is on the rise with one-third of cancers estimated to be caused by infectious agents. Head and neck squamous cell cancer (HNSCC) is the sixth most common malignancy in sub-Saharan Africa and includes tumors in the Upper Aero-digestive Tract (UADT). The established risk factors are tobacco and alcohol exposure with a recent recognition of the role of Human Papilloma Virus (HPV). The HPV related HNC is seen predominantly in the oropharynx, presents at a younger age and has a better prognosis. With a rapidly increasing incidence of these cancers in the developed world, it was important to study HPV in HNC in Uganda. The HPV can be detected using P16 immunohistochemistry as a surrogate marker thus making it suitable for screening. The study aimed at establishing the presence of HPV and the commonly affected sites in UADT squamous cell carcinoma (SCC) at Uganda Cancer Institute (UCI) using P16 immunohistochemistry. This was a cross sectional study in which 59 patients with histologically proven SCC from the oral cavity, oropharynx, larynx and hypopharynx were recruited. These patients’ demographics and clinical data were collected. Tissue sections from retrieved histology samples were stained by Haematoxylin and Eosin to reconfirm SCC. Subsequently, P16 expression was determined using P16 immunohistochemistry. Seventy-one patients were enrolled and 59 patients with confirmed SCC of the sites of interest were analyzed. The majority (79.7%) of the participants were male and over 50 years. 59.3% were tobacco smokers, 66.1% used alcohol, 52.2% used both. Only 27.1% used none of the substances. Only 27.1% of the participants were HIV positive. Most of the tumors were in the larynx (37.3%) and 64.4% were overall TNM stage 4. The overall prevalence of HPV in UADT SCC at UCI was 20.3, 95%CI 10.9–32.8. The oropharynx had the highest prevalence (30.8%). The prevalence of HPV in UADT SCC at UCI is significant at 20.3%. The most affected site, is the oropharynx. Vigilant HPV screening of these sites with confirmation where possible is recommended.
Comprehensive molecular characterization of head and neck squamous cell carcinoma (HNSCC) has led to the identification of distinct molecular subgroups with fundamental differences in biological properties and clinical behavior. Despite improvements in tumor classification and increased understanding about the signaling pathways involved in neoplastic transformation and disease progression, current standard-of-care treatment for HNSCC mostly remains to be based on a stage-dependent strategy whereby all patients at the same stage receive the same treatment. Preclinical models that closely resemble molecular HNSCC subgroups that can be exploited for dissecting the biological function of genetic variants and/or altered gene expression will be highly valuable for translating molecular findings into improved clinical care. In the present review, we merge and discuss existing and new information on established cell lines, primary two- and three-dimensional ex vivo tumor cultures from HNSCC patients, and animal models. We review their value in elucidating the basic biology of HNSCC, molecular mechanisms of treatment resistance and their potential for the development of novel molecularly stratified treatment.
Background: The latency of the swallowing reflex is an important factor causing dysphagia in head and neck cancer patients. Although there are many reports comparing voluntary swallowing function before and after treatment, few studies have focused on the latency of the swallowing reflex, which is a risk factor for pneumonia due to silent aspiration. The aim of this retrospective study was to clarify the changes in the latency of the swallowing reflex before and after treatment. Methods: The latency of the swallowing reflex was quantified using the time from the injection of 1 ml of distilled water into the pharynx through a nasal catheter to the onset of swallowing. Results: The latency time of the swallowing reflex was significantly decreased 3 months after treatment compared to before treatment. A significant reduction was also observed in patients with pharyngeal cancer who underwent chemoradiation therapy. Conclusions: This retrospective study showed that a delayed swallowing reflex improved with treatment in advanced head and neck cancer patients. Trial registration number: The Institutional Review Board of Tohoku University Hospital (Number 2014-1-274).
Angiogenesis is an integral aspect of the growth and proliferation of solid tumors, including head and neck squamous cell carcinoma (HNSCC), and has potential implications in prognosis and treatment of both localized and recurrent/metastatic HNSCC. Therefore, there has been a significant interest in utilizing anti-angiogenic agents either alone or in combination with currently approved and emerging therapies. A phase III randomized trial (E1305) of chemotherapy with or without bevacizumab in the first-line treatment of recurrent/metastatic HNSCC showed an increased response rate and longer progression-free survival but fell short in demonstrating a statistically significant improved survival with bevacizumab. Moreover, toxicity, especially bleeding, was increased. Nevertheless, the study of other anti-angiogenic agents and novel combinations with other therapies, including immunotherapy, remains of interest. Several clinical trials are currently underway.
There remains up to a 50% recurrence rate in advanced p16- head and neck squamous cell carcinoma with current standard of care treatment. In an attempt to improve survival, multiple trials administering induction or neoadjuvant chemotherapy have been conducted but none demonstrated improved overall survival. The established efficacy of immune checkpoint inhibitors in the recurrent and metastatic setting has produced widespread interest in their neoadjuvant use. To survey the landscape of active neoadjuvant immunotherapy trials in head and neck squamous cell carcinoma and summarize and synthesize currently available outcomes from these trials. Neoadjuvant immunotherapy has proven safe and well tolerated in head and neck squamous cell carcinoma with encouraging efficacy results, including relatively high rates of pathologic response. Ongoing studies offer an opportunity to study immune responses in vivo. PD-L1 positivity, high tumor mutational burden and infiltration of NK cells, CD8, CD26 and Tim3 positive lymphocytes at time of surgery have been correlated with pathologic responses. We await updated reports of disease free survival and overall survival data and results of ongoing phase III studies utilizing neoadjuvant immunotherapy to determine if this treatment paradigm will have a place in the standard of care treatment in head and neck squamous cell carcinoma.
As the number of indicated malignancies for which immune checkpoint inhibitor therapy such as pembrolizumab grows the descriptions of associated immune-related adverse events (irAEs) increases as well. On rare occasions immunotherapy can lead to development of Hemophagocytic Lymphohistiocytosis (HLH) which is a potentially lethal inflammatory disorder characterized by histiocyte activation and cytokine storm. At this time no cases of HLH developing in head and neck squamous cell carcinoma (HNSCC) patients receiving pembrolizumab have been reported. Here we describe the first documented case of pembrolizumab-induced HLH in a 61 year-old male with metastatic HNSCC after having received multiple prior cycles of pembrolizumab without event. Following cycle 14 the patient developed fever associated with new pancytopenia and transaminitis prompting hospital admission. Infectious workup was negative, his metastatic lesions were found to be stable, and there was no evidence of new malignancy. Further workup demonstrated hyperferritinemia and bone marrow biopsy demonstrated hemophagocytosis concerning for pembrolizumab-induced HLH. Etoposide and dexamethasone therapy was initiated leading to clinical improvement and safe discharge. Immunotherapy is a groundbreaking therapeutic intervention for patients with malignancy, however by nature of their mechanism carry a risk of inflammatory side effects. In rare circumstances these inflammatory reactions include potentially deadly syndromes such as HLH. As immunotherapeutics such as pembrolizumab become more widely utilized increased awareness of complications such as HLH is clinically relevant.
For many years, head and neck squamous cell carcinoma (HNSCC) has been considered as a single entity. However, in the last decades HNSCC complexity and heterogeneity have been recognized. In parallel, high-throughput omics techniques had allowed picturing a larger spectrum of the behavior and characteristics of molecules in cancer and a large set of omics web-based tools and informative repository databases have been developed. The objective of the present review is to provide an overview on biological, prognostic and predictive molecular signatures in HNSCC. To contextualize the selected data, our literature survey includes a short summary of the main characteristics of omics data repositories and web-tools for data analyses. The timeframe of our analysis was fixed, encompassing papers published between January 2015 and January 2019. From more than 1000 papers evaluated, 61 omics studies were selected: 33 investigating mRNA signatures, 11 and 13 related to miRNA and other non-coding-RNA signatures and 4 analyzing DNA methylation signatures. More than half of identified signatures (36) had a prognostic value but only in 10 studies selection of a specific anatomical sub-site (8 oral cavity, 1 oropharynx and 1 both oral cavity and oropharynx) was performed. Noteworthy, although the sample size included in many studies was limited, about one-half of the retrieved studies reported an external validation on independent dataset(s), strengthening the relevance of the obtained data. Finally, we highlighted the development and exploitation of three gene-expression signatures, whose clinical impact on prognosis/prediction of treatment response could be high. Based on this overview on omics-related literature in HNSCC, we identified some limits and strengths. The major limits are represented by the low number of signatures associated to DNA methylation and to non-coding RNA (miRNA, lncRNA and piRNAs) and the availability of a single dataset with multiple omics on more than 500 HNSCC (i.e. TCGA). The major strengths rely on the integration of multiple datasets through meta-analysis approaches and on the growing integration among omics data obtained on the same cohort of patients. Moreover, new approaches based on artificial intelligence and informatic analyses are expected to be available in the next future.
Although there have been dramatic improvements in radiotherapy for head and neck squamous cell carcinoma (HNSCC), including robust intensity modulation and daily image guidance, these advances are not able to account for inherent structural and spatial changes that may occur during treatment. Many sources have reported volume reductions in the primary target, nodal volumes, and parotid glands over treatment, which may result in unintended dosimetric changes affecting the side effect profile and even efficacy of the treatment. Adaptive radiotherapy (ART) is an exciting treatment paradigm that has been developed to directly adjust for these changes. Adaptive radiotherapy may be divided into two categories: anatomy-adapted (A-ART) and response-adapted ART (R-ART). Anatomy-adapted ART is the process of re-planning patients based on structural and spatial changes occurring over treatment, with the intent of reducing overdosage of sensitive structures such as the parotids, improving dose homogeneity, and preserving coverage of the target. In contrast, response-adapted ART is the process of re-planning patients based on response to treatment, such that the target and/or dose changes as a function of interim imaging during treatment, with the intent of dose escalating persistent disease and/or de-escalating surrounding normal tissue. The impact of R-ART on local control and toxicity outcomes is actively being investigated in several currently accruing trials. Anatomy-adapted ART is a promising modality to improve rates of xerostomia and coverage in individuals who experience significant volumetric changes during radiation, while R-ART is currently being studied to assess its utility in either dose escalation of radioresistant disease, or de-intensification of surrounding normal tissue following treatment response. In this paper, we will review the existing literature and recent advances regarding A-ART and R-ART.
Compared to HPV-negative head and neck squamous cell carcinomas (HNSCCs), HPV-positive HNSCCs are associated with a favorable prognosis in part due to their improved treatment sensitivity. Inactivating mutations in NSD1 were shown to be a favorable prognostic biomarker in laryngeal cancers. Here, we characterize NSD1 mutations from the expanded The Cancer Genome Atlas (TCGA) HNSCC cohort (n = 522) and examine their prognostic implications based on HPV status of the tumor. We also begin to examine if NSD1 regulates response to platinum-based drugs and other DNA-damaging agents. TCGA HNSCC samples were segregated by HPV and NSD1 mutations using cBioPortal and patient survival was determined. Pathogenicity of mutations was predicted using UMD-Predictor. NSD1-depleted cell lines were established by transfection with control or shRNAs against NSD1, followed by puromycin selection, and confirmed by qRT-PCR. Cell sensitivity to DNA damaging agents was assessed using short-term proliferation and long-term clonogenic survival assays. Among 457 HPV(−) tumors, 13% contained alterations in the NSD1 gene. The majority (61.3%) of NSD1 gene alterations in HPV(−) specimens were truncating mutations within or before the enzymatic SET domain. The remaining alterations included homozygous gene deletions (6.7%), missense point mutations (30.7%) and inframe deletions (1.3%). UMD-Predictor categorized 18 of 23 missense point mutations as pathogenic. For HPV(+) HNSCC (n = 65), 6 NSD1 mutations, comprised of two truncating (33%) and 4 missense point (66%) mutations, were identified. Three of the 4 missense point mutations were predicted to be pathogenic or probably pathogenic by UMD-Predictor. Kaplan-Meier survival analysis determined significantly improved survival of HPV(−) HNSCC patients whose tumors harbored NSD1 gene alterations, as compared to patients with wild-type NSD1 tumors. Interestingly, the survival effect of NSD1 mutations observed in HPV-negative HNSCC was reversed in HPV(+) tumors. Proliferation and clonogenic survival of two HPV(−) cell lines stably expressing control or NSD1 shRNAs showed that NSD1-depleted cells were more sensitive to cisplatin and carboplatin, but not to other DNA damaging drugs. Genetic alterations in NSD1 hold potential as novel prognostic biomarkers in HPV(−) head and neck cancers. NSD1 mutations in HPV(+) cancers may also play a prognostic role, although this effect must be examined in a larger cohort. NSD1 downregulation results in improved sensitivity to cisplatin and carboplatin, but not to other DNA-damaging agents, in epithelial cells. Increased sensitivity to platinum-based chemotherapy agents associated with NSD1 depletion may contribute to improved survival in HPV(−) HNSCCs. Further studies are needed to determine mechanisms through which NSD1 protects HPV(−) HNSCC cells from platinum-based therapy, as well as confirmation of NSD1 effect in HPV(+) HNSCC.
The genomic landscape of head and neck cancer has been reported through The Cancer Genome Atlas project. We attempt to determine if high-risk human papillomavirus (HPV) or frequently mutated genes are correlated with survival in an oral cancer cohort. Patient demographic data along with data from final pathology was collected. Tumor DNA was analyzed using a custom Illumina targeted sequencing panel. Five high-risk HPV types were tested by qPCR. Statistical analyses were used to identify associations between patient outcome and mutational status. High-risk HPV types were identified in 7% of cases; HPV status was not associated with survival. Mutations were identified in TP53, TERT promoter, & PIK3CA. Mutations in TP53 were significantly associated with poorer overall survival on multi-variate analysis (p = 0.03). Mutations in TP53 were associated with poor patient survival. Expanding our sample size may identify further predictors of outcome to direct customized cancer care.
Patients with head and neck cancer (HNC) experience significant physical and psychological distress, which have a negative impact on their quality of life (QOL). Few strategies have been studied to help improve QOL in this patient population.In this article, we review the existing literature for intervention studies that focus on improving QOL and/or mood in HNC patients. Our review yielded 14 studies that met criteria. Types of interventions included educational, psychosocial, physical and psychological symptom management, mindfulness, pharmacologic, exercise, and telemedicine. Although the majority of the studies had small sample sizes or other methodological limitations, many showed preliminary feasibility and acceptability with some positive impacts on QOL and/or mood.Larger studies are warranted with more robust randomized designs to determine efficacy of interventions to improve QOL and/or mood in patients with HNC. Additionally, future studies must also consider strategies for implementation and dissemination of these interventions into the health care system to improve the physical and psychological burden of HNC as a population.
The optimal treatment for regional lymphatic recurrences from head and neck cancer has not been fully established. In order to explore the therapeutic benefit of surgical resection and adjuvant brachytherapy, the authors reviewed their experience utilizing interstitial brachytherapy (IBT) at the M. D. Anderson Cancer Center. A retrospective chart review of the 51 patients who received salvage surgical resection of lymphatic recurrences and adjuvant IBT between 1993 and 2012 at the M. D. Anderson Cancer Center was undertaken. All patients underwent neck dissection with complete resection and intraoperative placement of afterloading brachytherapy catheters. Soft tissue reconstruction was performed as necessary. The technical aspects of IBT were reviewed, and the overall and disease free survival rates and the recurrence rates were determined. All patients had received external beam radiation (EBRT) as part of their initial treatment to a median dose of 66 Gy; 40 and 68% of the patients also had a neck dissection or chemotherapy, respectively. The cumulative regional recurrence probability is 28 and 38% at 5 years and 10 years. All of the patients underwent salvage neck dissection and IBT, with 81% also undergoing soft tissue reconstruction. The median dose delivered to the tumor bed was 60 Gy over a median duration of 4.5 days. There were 21 early adverse events, 8 of which were severe, and 19 late adverse events, 6 of which were severe. The most common early and late adverse events due to surgery and brachytherapy were dysphagia (7.1%) and true vocal cord paralysis (17.9%), respectively. There were no perioperative deaths or carotid hemorrhages. Nineteen patients developed recurrence including regional recurrence and distinct metastasis. The median time to recurrence is 130 months using Kaplan-Meier product limit method. The 2-year disease-free survival rate was 58%. The 2-year, 5-year, and 10-year overall survival rates were 69, 56, and 46%, respectively. Regional recurrences in previously irradiated tissues after the definitive treatment of primary head and neck cancers represent a challenging problem. We demonstrated that salvage neck dissection with IBT provided encouraging regional control and survival rates, while maintaining relatively low acute and long-term toxicity rates.
Human papillomavirus-associated oropharyngeal cancer (HPV-OSCC) is rapidly increasing in incidence and has unique epidemiologic, molecular, and biologic characteristics. Standard combined modality therapies for head and neck cancer confer a significant risk of morbidity. However, patients with HPV-OSCC are diagnosed at a younger age and have a superior prognosis; this spurs the development of treatment deintensification trials that attempt to decrease treatment-related morbidity without compromising efficacy. The De-Escalate-HPV is a randomized phase 3 study that compares the standard treatment, radiation and cisplatin, with radiation and epidermal growth factor receptor (EGFR) inhibitor cetuximab in patients with low-risk HPV-OSCC. In this commentary, we aim to discuss the results of the De-Escalate-HPV study.
Background: Significant weight loss and malnutrition are common in patients with head and neck cancer, despite advances in treatment and development of evidenced-based guidelines. The aim of this study was to assess adherence to evidenced-based guidelines and investigate nutrition outcomes during and post radiation treatment in head and neck cancer patients. Methods: This was a two-year retrospective cohort study of 209 head and neck cancer patients (85% male) treated with ≥20 fractions of radiation (mean dose = 64.8 Gy delivered over 31.9 fractions) at an Australian tertiary hospital. Results: Regarding guideline adherences, 80% of patients were seen by a dietitian weekly during treatment and 62% of patients were seen bi-weekly for six-weeks post-treatment. Average weight loss was 6.7% during treatment and 10. 3% three-months post treatment. At the end of treatment, oropharyngeal and oral cavity patients had lost the most weight (8.8, 10.9%), with skin cancer and laryngeal patients losing the least weight (4.8, 2.9%). Gastrostomy patients (n = 60) had their tube in-situ for an average of 150 days and lost an average of 7.7 kg (9.4%) during treatment and 11. 5 kg (13.5%) from baseline to three-months post treatment. The number of malnourished patients increased from 15% at baseline to 56% at the end of treatment, decreasing to 30% three-months post treatment. Conclusions: Despite high adherence to evidenced-based guidelines, large discrepancies in weight loss and nutritional status between tumor sites was seen. This highlights the opportunity for further investigation of the relationship between tumor site, nutritional status and nutrition interventions, which may then influence future evidenced-based guidelines.
Airline crew are exposed to ionizing radiation as part of their occupation and have a documented increased risk of melanoma and cataracts. However, whether their occupation predisposes them to an increased risk of thyroid cancer is not established. The purpose of this systematic review and meta-analysis was to assess the risk of thyroid cancer in airline cockpit and cabin crew compared with the general population.
