Cetuximab-Containing Combinations in Locally Advanced and Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Cetuximab remains to date the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC). The EGFR pathway plays a key role in the tumorigenesis and progression of this disease as well as in the resistance to radiotherapy (RT). While several anti-EGFR agents have been tested in HNSCC, cetuximab, an IgG1 subclass monoclonal antibody against EGFR, is the only drug with proven efficacy for the treatment of both locoregionally-advanced (LA) and recurrent/metastatic (R/M) disease. The addition of cetuximab to radiotherapy is a validated treatment option in LA-HNSCC. However, its use has been limited to patients who are considered unfit for standard of care chemoradiotherapy (CRT) with single agent cisplatin given the lack of direct comparison of these two regimens in randomized phase III trials and the inferiority suggested by metanalysis and phase II studies. The current use of cetuximab in HNSCC is about to change given the recent results from randomized prospective clinical trials in both the LA and R/M setting. Two phase III studies evaluating RT-cetuximab vs. CRT in Human Papillomavirus (HPV)-positive LA oropharyngeal squamous cell carcinoma (De-ESCALaTE and RTOG 1016) showed inferior overall survival and progression-free survival for RT-cetuximab combination, and therefore CRT with cisplatin remains the standard of care in this disease. In the R/M HNSCC, the EXTREME regimen has been the standard of care as first-line treatment for the past 10 years. However, the results from the KEYNOTE-048 study will likely position the anti-PD-1 agent pembrolizumab as the new first line treatment either alone or in combination with chemotherapy in this setting based on PD-L1 status. Interestingly, cetuximab-mediated immunogenicity through antibody dependent cell cytotoxicity (ADCC) has encouraged the evaluation of combined approaches with immune-checkpoint inhibitors in both LA and R/M-HNSCC settings. This article reviews the accumulated evidence on the role of cetuximab in HNSCC in the past decade, offering an overview of its current impact in the treatment of LA and R/M-HNSCC disease and its potential use in the era of immunotherapy

Cetuximab-Containing Combinations in Locally Advanced and Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Cetuximab remains to date the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC). The EGFR pathway plays a key role in the tumorigenesis and progression of this disease as well as in the resistance to radiotherapy (RT). While several anti-EGFR agents have been tested in HNSCC, cetuximab, an IgG1 subclass monoclonal antibody against EGFR, is the only drug with proven efficacy for the treatment of both locoregionally-advanced (LA) and recurrent/metastatic (R/M) disease. The addition of cetuximab to radiotherapy is a validated treatment option in LA-HNSCC. However, its use has been limited to patients who are considered unfit for standard of care chemoradiotherapy (CRT) with single agent cisplatin given the lack of direct comparison of these two regimens in randomized phase III trials and the inferiority suggested by metanalysis and phase II studies. The current use of cetuximab in HNSCC is about to change given the recent results from randomized prospective clinical trials in both the LA and R/M setting. Two phase III studies evaluating RT-cetuximab vs. CRT in Human Papillomavirus (HPV)-positive LA oropharyngeal squamous cell carcinoma (De-ESCALaTE and RTOG 1016) showed inferior overall survival and progression-free survival for RT-cetuximab combination, and therefore CRT with cisplatin remains the standard of care in this disease. In the R/M HNSCC, the EXTREME regimen has been the standard of care as first-line treatment for the past 10 years. However, the results from the KEYNOTE-048 study will likely position the anti-PD-1 agent pembrolizumab as the new first line treatment either alone or in combination with chemotherapy in this setting based on PD-L1 status. Interestingly, cetuximab-mediated immunogenicity through antibody dependent cell cytotoxicity (ADCC) has encouraged the evaluation of combined approaches with immune-checkpoint inhibitors in both LA and R/M-HNSCC settings. This article reviews the accumulated evidence on the role of cetuximab in HNSCC in the past decade, offering an overview of its current impact in the treatment of LA and R/M-HNSCC disease and its potential use in the era of immunotherapy

Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma

Anti-programmed cell death protein 1 (PD-1) agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and are currently being evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides Programmed death ligand-1 (PD-L1) expression, other biomarkers such as immune infiltration, tumor mutational burden or immune-gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review examines the available evidence on emerging immune predictive biomarkers of response to anti-PD-1/PD-L1 therapy in HNSCC, introducing the microbiota and its potential use as a predictive immune biomarker in this disease

The Multidisciplinary Team (MDT) Approach and Quality of Care

The core function of a multidisciplinary team (MDT) is to bring together a group of healthcare professionals from different fields in order to determine patients' treatment plan. Most of head and neck cancer (HNC) units are currently led by MDTs that at least include ENT and maxillofacial surgeons, radiation and medical oncologists. HNC often compromise relevant structures of the upper aerodigestive tract involving functions such as speech, swallowing and breathing, among others. The impairment of these functions can significantly impact patients' quality of life and psychosocial status, and highlights the crucial role of specialized nurses, dietitians, psycho-oncologists, social workers, and onco-geriatricians, among others. Hence, these professionals should be integrated in HNC MDTs. In addition, involving translational research teams should also be considered, as it will help reducing the existing gap between basic research and the daily clinical practice. The aim of this comprehensive review is to assess the role of the different supportive disciplines integrated in an MDT and how they help providing a better care to HNC patients during diagnosis, treatment and follow up

SEOM clinical guidelines for the treatment of head and neck cancer (2020)

Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m2 in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease

Might Oral Human Papillomavirus (HPV) Infection in Healthy Individuals Explain Differences in HPV-Attributable Fractions in Oropharyngeal Cancer? A Systematic Review and Meta-analysis

Background. Differences in oral human papillomavirus (HPV) prevalence and contrasts in HPV-attributable fractions (AFs) in oropharyngeal cancer (OPC) have not been evaluated in depth. Methods. A systematic review was performed to identify studies in which at least 50 healthy individuals were tested for oral HPV infection. Information on sex, age, tobacco/alcohol consumption, sex practices, specimen collection, HPV detection, and population type was extracted. Prevalences were pooled using random-effects models for meta-analyses of binomial data. Correlations were assessed by the Spearman test. Results. Forty-eight reports comprising 28 544 individuals fulfilled inclusion criteria. Global oral HPV prevalence was 4.9%. Estimates were highest in Europe, although regional differences were not statistically significant. HPV16 prevalence was 1.0% globally, and regional differences became statistically significant. A lifetime history of >6 sex partners showed a higher risk of oral HPV infection. The age-specific HPV distribution revealed a prevalence of >= 5% over 40 years of age and a lower prevalence at younger ages. There was no association between oral HPV prevalence and HPV-AFs or age-standardized rates (ASRs) of OPC, genital HPV in healthy women, or tobacco use. Conclusions. Differences in HPV-AFs or ASRs of OPC cannot be explained by differences in the prevalence of oral HPV infection across healthy populations. Consistent research on determinants of oral HPV prevalence, acquisition, clearance, and persistence is warranted

Paclitaxel Plus Cetuximab as Induction Chemotherapy for Patients With Locoregionally Advanced Head and Neck Squamous Cell Carcinoma Unfit for Cisplatin-Based Chemotherapy

ObjectivesInduction chemotherapy (ICT) followed by definitive treatment is an accepted non-surgical approach for locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, ICT remains a challenge for cisplatin-unfit patients. We evaluated paclitaxel and cetuximab (P-C) as ICT in a cohort of LA-HNSCC patients unfit for cisplatin. Materials and MethodsThis is a retrospective analysis of patients with newly diagnosed LA-HNSCC considered unfit for cisplatin-based chemotherapy (age >70 and/or ECOG >= 2 and/or comorbidities) treated with weekly P-C followed by definitive radiotherapy and cetuximab (RT-C) between 2010 and 2017. Toxicity and objective response rate (ORR) to ICT and RT-C were collected. Median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Cox regression analysis was performed to determine baseline predictors of OS and PFS. ResultsA total of 57 patients were included. Grade 3-4 toxicity rate to ICT was 54.4%, and there was a death deemed treatment-related (G5). P-C achieved an ORR of 66.7%, including 12.3% of complete responses (CR). After P-C, 45 patients (78.9%) continued with concomitant RT-C. Twenty-six patients (45.6%) achieved a CR after definitive treatment. With a median follow-up of 21.7 months (range 1.2-94.6), median OS and PFS were 22.9 months and 10.7 months, respectively. The estimated 2-year OS and PFS rates were 48.9% and 33.7%, respectively. Disease stage had a negative impact on OS (stage IVb vs. III-IVa: HR = 2.55 [1.08-6.04], p = 0.03), with a trend towards worse PFS (HR = 1.92 [0.91-4.05], p = 0.09). Primary tumor in the larynx was associated with improved PFS but not OS (HR = 0.45 [0.22-0.92], p = 0.03, and HR = 0.69 [0.32-1.54], p = 0.37, respectively). ConclusionP-C was a well-tolerated and active ICT regimen in this cohort of LA-HNSCC patients unfit for cisplatin-based chemotherapy. P-C might represent a valid ICT option for unfit patients and may aid patient selection for definitive treatment

Predictive Value of Skeletal Muscle Mass in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Patients Treated With Immune Checkpoint Inhibitors

Background Reduced muscle mass has been associated with increased treatment complications in several tumor types. We evaluated the impact of skeletal muscle index (SMI) on prognosis and immune-related adverse events (IrAEs) in a cohort of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immune checkpoints inhibitors (ICI). Methods A single-institutional, retrospective study was performed including 61 consecutive patients of R/M HNSCC diagnosed between July 2015 and December 2018. SMI was quantified using a CT scan at L3 to evaluate body composition. Median baseline SMI was used to dichotomize patients in low and high SMI. Kaplan-Meier estimations were used to detect overall survival (OS) and progression-free survival (PFS). Toxicity was recorded using Common Terminology Criteria for Adverse Event v4.3. Results Patients were 52 men (85.2%) with mean of age 57.7 years (SD 9.62), mainly oral cavity (n = 21; 34.4%). Low SMI was an independent factor for OS in the univariate (HR, 2.06; 95% CI, 1.14-3.73, p = 0.017) and multivariate Cox analyses (HR, 2.99; 95% CI, 1.29-6.94; p = 0.011). PFS was also reduced in patients with low SMI (PFS HR, 1.84; 95% CI, 1.08-3.12; p = 0.025). IrAEs occurred in 29 (47.5%) patients. There was no association between low SMI and IrAEs at any grade (OR, 0.56; 95% CI, 0.20-1.54; p = 0.261). However, grades 3 to 4 IrAEs were developed in seven patients of whom three had low SMI. Conclusions Low SMI before ICI treatment in R/M HNSCC patients had a negative impact on OS and PFS. Further prospective research is needed to confirm the role of body composition as a predictive biomarker in ICI treatment

Human papillomavirus in premalignant oral lesions: no evidence of association in a Spanish cohort

Background: human papillomavirus (HPV) is the cause of a fraction of head and neck squamous cell carcinoma. Although this relation is well-known, it is still not clear the role of HPV in premalignant oral lesions such as oral lichen planus (OLP) and dysplasia. We aimed to evaluate the HPV-DNA prevalence and type distribution in a set of oral biopsies obtained from patients diagnosed with OLP and dysplasia, as well as the role of HPV in these lesions. Methods: a retrospective cohort of all premalignant oral lesions consecutively diagnosed from March 30th 1995 to May 21st 2014 at Hospital of Bellvitge and Odontological University Hospital of Bellvitge was identified and classified in four groups: OLP (groups 1 and 2) and dysplasias (groups 3 and 4) that progressed or not to invasive cancer during follow-up. A random selection targeting 25 cases was aimed to be performed for each group. All selected cases were subjected to pathological evaluation, DNA quality control and HPV-DNA detection. HPV-DNA positive samples were further subject to p16INK4a analysis. Results: a total of 83 cases yielded a valid HPV-DNA result. From those, 7 and 34 cases were OLP that progressed or not to invasive cancer during follow-up, whereas 24 and 18 cases were displasias that progressed or not to invasive cancer during follow-up, respectively. HPV-DNA was detected in 4 samples (3 dysplastic lesions and 1 OLP). Two samples were HPV16 positive (2%), 1 sample HPV18 positive (1%) and 1 sample (1%) was HPV indeterminate. Two out of four HPV-DNA positive cases had high p16INK4a expression and none of the HPV positive cases progressed to invasive cancer during long-term follow-up. CONCLUSIONS: We found a low HPV-DNA attributable fraction in premalignant lesions of the oral cavity, suggesting that HPV is unlikely to play a significant role in oral carcinogenesis in our setting

Oncogenic driver mutations predict outcome in a cohort of head and neck squamous cell carcinoma (HNSCC) patients within a clinical trial

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p<0.01). Mutational and HPV status influences patient survival, being mutated or HPV-negative tumours associated with poor overall survival (p<0.05). No association was found between mutations and clinicopathological features. This study confirmed and expanded previously published genomic characterization data in HNSCC. Survival analysis showed that non-mutated HNSCC tumours associated with better prognosis and lack of mutations can be identified as an important biomarker in HNSCC. Frequent alterations in PI3K pathway in HPV-positive HNSCC could define a promising pathway for pharmacological intervention in this group of tumours