Genetics of Head and Neck Cancer: Advances in Molecular Research

6021 Background: An oral fluoropyrimidine, S-1, has shown high efficacy against head and neck cancer (HNC), with a response rate of 34%. We investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin and S-1 (TPS) in patients (pts) with locally advanced or recurrent/metastatic HNC. Methods: Eligibility criteria were histologically proven HNC, PS 0–1, age ≤75 years, adequate organ function, and no prior chemotherapy. Treatment consisted of 1-hour infusion of docetaxel at escalating doses of 50, 60 and 70 mg/m2, 2-hour infusion of cisplatin at 70 mg/m2/day on day 1, and S-1 twice daily on days 1–14 at escalating doses of 40, 60, and 80 mg/m2/day. This regimen was repeated every 3 or 4 weeks. Pts with locally advanced HNC received concurrent chemoradiotherapy after completion of 3 cycles of TPS. Results: Forty pts were enrolled, consisting of 33 males and 7 females with a median age of 50 years (range 22–74 years). Twenty-nine cases were locally advanced cancer and 11 were metastatic cancer. 116 cycles (median = 3, range 1–6) were administered in 6 dose levels. Grade 3 or 4 hematological toxicities were neutropenia (59%), febrile neutropenia (13%), and anemia (8%), whereas no grade 3 or 4 thrombocytopenia was seen. Two dose-limiting toxicities (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg/m2/day every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 pts treated at dose level 6 (TPS: 70/70/60 mg/m2/day every 3 weeks), three DLTs were seen, namely one grade 3 diarrhea, one grade 3 ALT/AST and one grade 2 creatinine elevation. Of a total of 40 pts, 6 achieved a complete response and 22 a partial response according to RECIST, giving an overall response rate of 70%. Conclusions: The TPS combination was well tolerated. The recommended phase II dose was determined to be TPS at 70/70/60 mg/m2/day every 3 weeks. Antitumor activity was highly promising, and warrants further investigation. No significant financial relationships to disclose.

Nivolumab is expected to further prolong survival and improve the quality of life (QOL) of patients with a poor prognosis of head and neck cancer. However, only a few studies have been conducted regarding the QOL of recurrent or metastatic head and neck cancer patients treated with nivolumab using real-world data. This study aimed to examine the effect of nivolumab on the QOL of these patients using real-world data. This study included patients with recurrent metastatic head and neck cancer who received nivolumab at the Department of Otolaryngology and Head and Neck Surgery, Tokyo Medical University Hospital from May 1, 2017, to December 31, 2021. Among them, 50 patients who self-assessed their QOL were included in this study. The primary endpoint was the QOL evaluation score, and secondary endpoints were overall survival (OS), progression-free survival (PFS), response rate, and immune-related adverse events. OS and PFS were evaluated using the Kaplan-Meier method. No significant reduction in QOL was observed before or after nivolumab administration. The median OS time was 20.1 months, and 1-year OS rate was 76.4%. The median PFS time was 4.2 months, and 1-year PFS rate was 31.0%. The comparison of patient QOL before and after nivolumab use suggested that patient QOL was not compromised. The results were not inferior to those of other studies in terms of treatment efficacy and safety.

Preface. List of Contributors. 1. Overview of Head and Neck Cancer G. Masters, B. Brockstein. 2. Epidemiology, Staging and Screening of Head and Neck Cancer A. Argiris, C. Eng. 3. Oral Preneoplasia and Chemoprevention of Squamous Cell Carcinoma of the Head and Neck O. Kucuk. 4. Early Stage Head and Neck Cancer Surgery S.J. Charous. 5. Radiation Therapy in the Management of Early-Stage Head and Neck Cancer R.W. Hinerman, et al. 6. Advanced Head and Neck Cancer-Surgery and Reconstruction B.G. Bentz, D.H. Kraus. 7. Modified Fractionated Radiotherapy in Head and Neck Squamous Cell Carcinoma (HNSCC) and Re-irradiation in Recurrent Head and Neck Carcinomas R.De Crevoisier, et al. 8 Organ Preservation-Induction Chemotherapy A.D. Colevas. 9. Organ Preservation for Advanced Head and Neck Cancer, Comcomitant Chemoradiation B. Brockstein. 10. Unresectable, Locoregionally Advanced Head and Neck Cancer F. Rosen. 11. Nasopharyngeal Cancer A.T.C. Chan, et al. 12. Treatment of Metastatic Head and Neck Cancer: Chemotherapy and Novel Agents E.S. Kim, B.S. Glisson. 13. New Therapies for Locoregionally Advanced and Locoregionally Recurrent Head and Neck Cancer B.L. Wenig. 14. Quality of Life and Late Toxicities in Head and Neck Cancer M.A. List, J. Stracks. 15. Oral, Dental, and Supportive Care in the Cancer Patient H. Staffileno, L. Reeder. Index.

Tobacco and alcohol are well-established risk factors for head and neck squamous cell carcinomas (HNSCC), but it can also develop in individuals not exposed to them. However, only a small proportion of tobacco exposed individuals have developed HNSCC, and there is an emerging tumoral population who lack exposure to these mentioned risk factors, suggesting that others factors can play a role in head and neck carcinogenesis. Over the past two decades, the role of high-risk human papilloma virus (HPV) has been studied through several studies worldwide, and data supporting its role as a causative agent in the development and progression of a subset of HNSCC has been controversial, with considerable variability in frequency depending on the population studied, tumor localization, quality of samples and technical resources utilized for HPV detection. As is the case in cervical and anogenital carcinomas, the most frequently detected high-risk HPVs in HNSCC are the 16 and 18 genotypes. The tonsils and oropharynx are the specific sites associated with higher risk of HPV oncogenic transformation, and investigations suggest that HPV infection in these anatomic sites is an independent risk factor for carcinogenesis. The establishment and maintenance of HPV genomes in the squamous epithelium and HPV-related HNSCC cancer is believed to be originated by oncogenic potential of HPV integration into host DNA genome and their ability to manipulate cell cycle regulators, resulting in deregulated expression of oncoproteins such as E6, which promotes degradation of the tumor suppressor protein p53, allowing cells to evade cell cycle checkpoints, and also E7, which binds to retinoblastoma protein (pRb) and could promote the entrance in S1 phase of cell cycle, leading to disruption of normal cell cycle controls. Following cell division, infected cells leave the basal layer, migrate towards the suprabasal regions and begin to differentiate. Increased understanding of cervical pathogenesis has led to confirmation of HPV as an etiological agent for cancers and consequently to the development of preventive vaccines targeting HPV antigens for the control of cervical cancer. The HPV vaccine was developed as a result of the achievement of core technologies able to produce virus-like

The purpose of this study was to assess free-flap viability in patients treated for recurrent head and neck cancers. A 10-year retrospective review identified 121 patients who had had prior head and neck cancers extirpated for cure, who subsequently presented with documented recurrent cancers that were removed, and who then underwent reconstruction with free flaps. The charts of these patients were reviewed for patient demographics, tumor types, location, flaps used for reconstruction, size of area requiring reconstruction, length of operation, previous radiation, and all postoperative morbidity and mortality. The time to recurrence ranged from 21/2 months to 21 years. The majority of tumors treated were squamous cell carcinomas (n = 82). Most of them were located intraorally (n = 75). Radiation therapy had been delivered to 88 patients before their free-flap reconstructions. In this series, 31 percent of all patients required additional surgery for complications, 14 percent of free flaps were lost, and 4 percent of patients died within 30 days of their operation. The significant findings were that a flap that was >4 cm in diameter was related to flap loss (p = 0.03 by the chi2 method) and that flap loss was related to operative times greater than 11 hours (p = 0.03 by the chi2 method). It was concluded that recurrent head and neck cancers with large postextirpation defects that required prolonged operative times yielded a significantly high tendency toward flap failure.

The ubiquitin-proteasome system has a crucial role in maintaining and regulating cellular homeostasis including carcinogenesis. UBE2Q2, also designated Ubci, is one of the ubiquitin-conjugating enzymes (E2), and it has been reported that mRNA of UBE2Q2 is highly expressed in human head and neck squamous cell carcinoma, particularly hypopharyngeal carcinoma. However, the involvement of UBE2Q2 in carcinogenesis has not been fully elucidated. Most cases of head and neck carcinoma are treated with cis-diamminedichloroplatinum (II; CDDP) or docetaxel, which are the most effective chemotherapeutic agents against squamous cell carcinomas. Nevertheless, some head and neck cancers develop resistance to these drugs, although the causes and mechanisms remain unknown. In this study, we found high expression levels of UBE2Q2 in human head and neck carcinoma cell lines and cancer tissues by using an anti-UBE2Q2 antibody at the protein level. We also found that the expression level of UBE2Q2 is decreased in cell lines and cancer tissues that have resistance to CDDP or docetaxel and in cancer tissues treated with CDDP or docetaxel. Furthermore, we found that overexpression of UBE2Q2 affects cell proliferation and anchorage-independent cell growth. These findings suggest that UBE2Q2 is a novel oncosuppressor that inhibits tumor growth and is related to the resistance to anticarcinoma agents and that UBE2Q2 likely functions as a novel diagnostic tool and a potentially therapeutic target for head and neck squamous cell carcinoma.

Advanced and recurrent head and neck cancers often present with distant metastasis. The most common sites include lung, liver and bones. The propensity for metastasis depends upon the site of the primary disease as well. Cancers of hypopharynx and nasopharynx both have high propensity for distant meta stasis. Positron emission tomographycomputed tomography is done in many of these situations to assess distant metastasis, especially in locally advanced and recurrent cases. The positive predictive value of PET-CT in predicting distant metastasis in recurrent head and neck cancers is 60%. This low positive predictive value is attributed to inflammation, infections, and post RT changes. The present case report highlights that PET positive lesions should be interpreted with caution as they can be false positive and can be mistaken for metastasis and, hence, a potentially curative patient can be treated as one with palliative intent. How to cite this article Joshi P, Chaturvedi P, Agarwal JP, Kane S. Pitfall of Positron Emission Tomography-Computed Tomography in assessing Metastasis in a Recurrent Head and Neck Cancer. Int J Head Neck Surg 2015;6(1):14-16.

Interstitial and endocavitary brachytherapy are well-accepted kinds of radiotherapy that are commonly used in recurrent head and neck cancer. Most reports about brachytherapy in the successful treatment of head and neck tumors used low-dose-rate brachytherapy. There are only a few reports about high-dose-rate brachytherapy (HDRBT) in head and neck cancer patients. After 10 years of experience with HDRBT with Ir 192, we have analyzed the results regarding response rates, survival time, and side effects. Between 1991 and 2000, 90 consecutive patients (68 men, 22 women) were treated with interstitial (68 patients) or intracavitary (22 patients) HDRBT in the head and neck area. Primary tumor locations were as follows: oropharynx (n = 26), tongue/floor of mouth (n = 22), nasopharynx (n = 10), nose/paranasal sinuses (n = 9), salivary glands (n = 5), hypopharynx (n = 5), CUP syndrome (n = 5), and others (n = 8). High-dose-rate brachytherapy was administered in 51 patients with recurrent disease and in 32 patients with residual tumor after primary radiochemotherapy. Seven patients were given exclusive HDRBT in a primary palliative situation. The single dose per fraction ranged from 1.5 to 7.5 Gy (median value, 5 Gy), and the total HDRBT dose ranged from 4.0 to 42.0 Gy (median value, 17.5 Gy). The overall remission rate was 81% with a 46% rate of complete remissions. We observed no change in or progression of tumor in 17 cases (19%). The rate of complete remissions (and median overall survival time) was different in the three therapy groups: in case of recurrent disease, 28% (6 mo); in case of residual tumor, 84% (25 mo); and in primary palliative brachytherapy, 0% (1 mo). Late toxicities III and IV (radiation treatment oncology group score) occurred in 6 of 90 (6.7%) patients. High-dose-rate brachytherapy proved to be an effective treatment modality in locoregional recurrent head and neck cancer. In cases with persistent or residual tumor after primary radiochemotherapy a local boost with brachytherapy can improve the chance of cure of tumor disease.

Administering reirradiation for the treatment of recurrent head and neck cancers is extremely challenging. These tumors are hypoxic and radioresistant and require escalated radiation doses for adequate control. The obstacle to delivering this escalated dose of radiation to the target is its proximity to critical organs at risk (OARs) and possible development of consequent severe late toxicities. With the emergence of highly sophisticated technologies, intensity-modulated radiotherapy (IMRT) and stereotactic body radiotherapy have shown promising outcomes. Proton beam radiotherapy has been used for locally recurrent head and neck cancers because of its excellent physical dose distribution, exploring sharp Bragg peak properties with negligible entrance and exit doses. To further improve these results, carbon ion radiotherapy (CIRT) has been explored in several countries across Europe and Asia because of its favorable physical properties with minimal entrance and exit doses, sharper lateral penumbra, and much higher and variable relative biological efficacy, which cannot be currently achieved with any other form of radiation. Few studies have described the role of CIRT in recurrent head and neck cancers. In this article, we have discussed the different aspects of carbon ions in reirradiation of recurrent head and neck cancers, including European and Asian experiences, different dose schedules, dose constraints of OARs, outcomes, and toxicities, and a brief comparison with proton beam radiotherapy and IMRT.

An integrated study on the role of human papillomaviruses (HPV) in cervical cancer has been conducted. Out of a total of 433 cases of cervical cancer, HPV-DNA was detected in 342 (79%) using the polymerase chain reaction (PCR). The incidence of HPV infection was not significantly related to histological types, although a lower incidence was noted in adenocarcinoma cases. The incidence of lymph node (LN) metastasis in adenosquamous carcinoma (55.6%) was significantly higher than in squamous cell carcinoma (SCC) and adenocarcinoma. HPV 16 was detected significantly more often in SCC than in adenocarcinoma. In contrast, HPV 18 was detected more often in adenocarcinoma than in SCC. As a whole, pelvic LN metastases were found in 24.3% of HPV+ cases, significantly higher than 11% of HPV- cases. However, the significant association of HPV-DNA with LN metastasis was only noted in stage I but not stage II. As far as histological types were concerned, the incidence of positive LN was: HPV+ SCC > HPV- SCC (p < 0.01), whereas HPV- adenocarcinoma > HPV+ adenocarcinoma (p = 0.12). Genotypes of HPV did not have any effect on nodal status. The presence of types of HPV were not associated with tumor size and distribution of clinical stage. Our results suggest that the prognostic significance of HPV-DNA on nodal status is dependent on histological types while the genotypes of HPV cannot account for prognostic significance in cervical cancer.

6031 Background: Multiple genomic alterations were described in HNC, including squamous cell carcinomas (SCC), salivary gland (SG) and nasopharyngeal (NF) tumors. Tumor molecular profiling (TMP) may increase therapeutic alternatives in early trials for pts with refractory metastatic (met) HNC. We evaluate the impact of matched/unmatched therapy (mT/uT) in HNC with potentially targetable alterations. Methods: From 2010-16, 47 met HNC pts were treated in 57 early trials after TMP. Clinical benefit was measured by: time to progression (TTP); clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] &gt; 4months [m]); progression-free survival [PFS] ratio≥1.3 (PFS under molecular therapeutics/PFS upon last prior chemotherapy [pT]). Results: Median age was 51 years; median number of pT lines was 1 (0-5). In total, 26 SCC, 11 SG, 8 NF and 2 nasosinusal pts (mostly with lymph nodes and lung met) were treated with small kinases (SK) inhibitors (inh) (50%; main targets PI3K/HER/FGFR), immune-oncology (IO) drugs (40%, PD-1/PD-L1), angiogenesis inh (5%) or chaperone, cytidine analog, RNA polymerase (5%). 14/57 trials were mT including CDKinh (1 CDKN2A mutation [mut]), PI3Kinh (5 PIK3CA mut, 2 PTEN mut), PI3K/MEKinh (1 NRAS mut), HERinh (1 ERBB3mut), FGFRinh (2 FGFR1mRNA high, 1 FGF3/4/19 ligand amplified) and porcupine inh (1 ZNFR3mut). Distribution by tumor: IO (16 SCC/5 NF), SKmT (8SG/4SCC/2NF) and SKuT (9SCC/4SG). Responses: 1CR in SCC (IO), 5 PR in SCC (4 IO, 1 FGFRinh), 3 PR in NF (1 cytidin analog, 1 IO, 1 PI3K/MEKinh). Benefit: median TTP 9.33m (CI95% 7-20) with upward trend in NF and SG vs SCC (HR 0.6;p = 0.28), without differences according to target therapies (HR 0.8; p = 0.9); CBR of 58%, without differences by tumor type (p = 0.42) or therapy (SKmT, SKuT, IO; p = 0.5); 60% with PFS ratio≥1.3, significantly higher in SCC and SG (p = 0.016), particularly with IO drug and SKmT, respectively. Conclusions: Considering our preselected fit population as bias selection, individualized treatment selection with novel therapeutics based on TMP, especially in NF and SG irrespective of targets (SKmT, SKuT, IO), and in SCC with IO drugs, seems to confer substantial clinical benefit.

IntroductionAlcohol and tobacco are the most important risk factors for head and neck cancers (HNC). However, in some countries, it has been observed an increase in incidence rates, particularly among...

The role of human papillomavirus (HPV) on head and neck squamous cell carcinoma (HNSCC) survival in regions with low HPV prevalence is not yet clear. We evaluated the HPV16 infection on survival of HNSCC Brazilian patient series. This cohort comprised 1,093 HNSCC cases recruited from 1998 to 2008 in four Brazilian cities and followed up until June 2009. HPV16 antibodies were analyzed by multiplex Luminex assay. In a subset of 398 fresh frozen or paraffin blocks of HNSCC specimens, we analyzed for HPV16 DNA by L1 generic primer polymerase chain reaction. HNSCC survival according to HPV16 antibodies was evaluated through Kaplan-Meier method and Cox regression. Prevalence of HPV16 E6 and E6/E7 antibodies was higher in oropharyngeal cancer than in other head and neck tumor sites. HPV16 DNA positive in tumor tissue was also higher in the oropharynx. Seropositivity for HPV16 E6 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer. The presence of HPV16 E6/E7 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer survival. The death risk of oropharyngeal squamous cell carcinoma patients HPV16 E6/E7 antibodies positive was 78 % lower than to those who test negative. Oropharyngeal squamous cell carcinoma is less aggressive in the HPV16 E6/E7 positive serology patients. HPV16 E6/E7 antibody is a clinically sensible surrogate prognostic marker of oropharyngeal squamous cell carcinoma.

BackgroundAnti-PD1 inhibitors have been approved for the treatment of recurrent or metastatic head and neck cancer (HNC), as a result of Global Phase III trials. However, the clinical outcomes of immune checkpoint inhibitors in patients who are not eligible for clinical trials or have various medical conditions have not been fully elucidated.MethodsWe retrospectively reviewed 46 patients with recurrent or metastatic HNC who received pembrolizumab or nivolumab between June 2016 and June 2019.ResultsThirty-five patients had head and neck squamous cell carcinoma (HNSCC) affecting the oropharynx, oral cavity, hypopharynx, larynx, nasal cavity, or paranasal sinuses, and eleven patients had nasopharyngeal cancer (NPC). The median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.8 months, respectively, for patients with HNSCC, and 4.3 months and 11.8 months, respectively, for patients with NPC. The objective response rate (ORR) in all patients was 21%. Of 30 patients with HNSCC, 5 patients achieved complete response and 2 achieved partial response (ORR 23%); 1 of 8 NPC patients achieved partial response (13%). Patients who previously underwent radiotherapy had better OS than those who did not (median OS, 7.6 months vs. 2.3 months, p = 0.006). OS was longer in patients treated with pembrolizumab than in those treated with nivolumab (median OS, 11.8 months vs. 6.8 months, p = 0.017).ConclusionConsistent with previous reports, immune checkpoint inhibitors showed promising efficacy in patients with previously treated recurrent or metastatic HNC in a real-world setting.

Background: Head and neck cancers (HNC) constitute the sixth common type of malignancies worldwide and can affect a wide range of anatomical regions. The role of the herpes simplex virus (HSV) in oral squamous cell carcinoma (OSCC) has been previously investigated. Objectives: The objective of the current study was to evaluate the molecular epidemiology of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) in patients with HNC. Methods: A total of 156 patients with HNC were chosen including 90 biopsies and 66 formalin-fixed paraffin-embedded (FFPE) samples. HNC was confirmed and affected different anatomical regions. HSV detection was performed by a polymerase chain reaction (PCR) and HSV typing was assessed by a multiplex PCR. Results: The 156 HNC specimens included 35 (22.4%) larynx, 29 (18.6%) tongue, 6 (3.8%) glands (parotid and tonsil), 12 (7.6%) nasopharynx, 9 (5.7%) pharynx, 33 (21%) vocal cord, 3 (1.9%) palatine, glottis 17 (10.8%), nasal 2 (1.3%), mandibular 4 (2.5%), lip 4 (2.5%), neck 1 (0.6%), and face 1 (0.6%). The mean ± SD of the patients’ age was 60.3 ± 12.65, where 121 (77.1%) were male. The HSV was detected in 4 (2.6%) samples and 75% of HSV positive samples were HSV-1. Conclusions: The rate of HSV infection in Iranian patients with HNC was 2.6% with the majority being HSV-1 (75%). As a preliminary study in Iranian patients with HNC, cancer location was not statistically significant. Further investigations are needed to assess the role of HSV in HNC.