Squamous Cell Carcinoma Of The Oropharynx Research Articles

Immune checkpoint inhibitor therapy-induced autoimmune polyendocrine syndrome type II and Crohn’s disease: A case report

The development of immune checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease. Unfortunately, ICIs are increasingly implicated in the development of autoimmune diseases. We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab, docetaxel, and cisplatin therapy who developed autoimmune polyendocrine syndrome type II (APS-2) including thyroiditis and type 1 diabetes mellitus and Crohn's disease (CD). He developed thirst, abdominal pain, and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab. Biochemistry confirmed APS-2 and thyrotoxicosis. He was commenced on an insulin infusion. However, his abdominal pain persisted. Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine. He was continued on insulin and mesalazine therapy. Immunotherapy can affect all kinds of organs. When clinical symptoms cannot be explained by a single disease, clinicians should consider the possibility of multisystem damage.

Abstract 6523: A case of stage I HPV-mediated oropharyngeal squamous cell carcinoma (SCC) diagnosed using a multi-cancer early detection (MCED) test

Abstract There are no routine screening tests for head and neck (H&N) cancers, which account for approximately 4% of all cancers in the US. Risk factors for oropharyngeal cancer include smoking and human papillomavirus (HPV) infection. An MCED test that uses a cell-free DNA-based targeted methylation assay and machine learning classifiers to detect a shared cancer signal and predict the cancer signal origin (CSO) is available as a complement to existing single-cancer screening tests. If a cancer signal is detected, the positive result is reported with 1 or 2 CSO prediction(s). We report here a tonsil cancer case detected using an MCED test and review the CSO-guided diagnostic journey. An asymptomatic 74-year-old White male (BMI: 29.9 kg/m2) with history of chronic lymphocytic leukemia (CLL; Rai stage 0; 13q, CD38, and ZAP-70 negative; no treatment was needed) 17 years prior and papillary thyroid cancer (stage IVa; pT3N1bM0; thyroidectomy and radiation therapy; no recurrence) 8 years prior was screened using the MCED test. Patient had an elevated PSA level (9-10 ng/mL) and was a nonsmoker. Fifteen days after a blood sample was collected for analysis, a positive test result (CSO prediction=H&N) was communicated to the patient (Day 1). PET showed abnormal uptake in the right tonsil (Day 28). The patient was referred for an ENT consult and underwent a right lymph node biopsy (Day 54). The biopsy showed invasive moderately differentiated SCC, non-keratinizing, forming a 3 × 2.1 × 1.2 cm mass (Day 57). Patient underwent right tonsillectomy (the surgical margins were negative for invasive or in situ carcinoma) and lymph node dissection (Day 57). The cancer was diagnosed as HPV-mediated p16+, pT2, pN1, cM0 (stage I) SCC of the oropharynx (Day 57). No chemotherapy or radiation was required due to the early stage of detection. The patient will follow-up with ENT and radiation oncology. The MCED test detected a cancer signal and predicted an accurate CSO for an asymptomatic individual with stage I HPV-mediated oropharyngeal SCC. Notably, despite a history of CLL and an elevated PSA level, the test accurately predicted CSO leading to a directed workup diagnosing asymptomatic cancer in less than 2 months, while the cancer was still at stage I. In the case-control Circulating Cell-free Genome Atlas study, the MCED test sensitivity to detect a cancer signal was 63% in stage I H&N cancer. The use of this MCED test led to detection of cancer in a patient with CLL history and treatment (surgery without complications and without chemotherapy or radiation) with curative intent. Citation Format: Janet Vittone, Julia Feygin, Jason Carey. A case of stage I HPV-mediated oropharyngeal squamous cell carcinoma (SCC) diagnosed using a multi-cancer early detection (MCED) test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6523.

Imaging Approach for Cervical Lymph Node Metastases from Unknown Primary Tumor

Neck swelling due to lymph node (LN) metastasis is one of the initial symptoms of head and neck cancer, and in some cases, the primary tumor is not clinically evident. The purpose of imaging for LN metastasis from an unknown primary site is to identify the primary tumor or detect its absence, which leads to the correct diagnosis and optimal treatment. The authors discuss diagnostic imaging approaches for identifying the primary tumor in cases of unknown primary cervical LN metastases. The distribution and characteristics of LN metastases may help locate the primary site. Unknown primary LN metastasis often occurs at nodal levels II and III, and in recent reports, these were mostly related to human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx. Another characteristic imaging finding suggestive of metastasis from HPV-associated oropharyngeal cancer is a cystic change in LN metastases. Other characteristic imaging findings such as calcification may help predict the histologic type and locate the primary site. In cases of LN metastases at nodal levels IV and VB, a primary lesion located outside the head and neck region must also be considered. One clue for detecting the primary lesion at imaging is the disruption of anatomic structures, which can help in identifying small mucosal lesions or submucosal tumors at each subsite. Additionally, fluorine 18 fluorodeoxyglucose PET/CT may help identify a primary tumor. These imaging approaches for identifying primary tumors enable prompt identification of the primary site and assist clinicians in making the correct diagnosis. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Differences between Squamous Cell Carcinomas of the Base of the Tongue and the Tonsils in Prevalence of HPV16 Infection, Its Type, and Clinical Features

Regarding attempts to find de-escalation methods of treatment for patients with HPV16-positive squamous cell carcinoma of the oropharynx (OPSCC), there is an urgent need to identify new prognostic factors which allow physicians to differentiate the prognosis of these patients. The aim of the study is to compare the incidence of transcriptionally active HPV16 infection and its type as well as other epidemiological, clinical, and histopathological features between SCC of the base of the tongue (BOTSCC) and tonsils (TSSCC). The analysis was performed in a group of 63 patients with OPSCC, for which, in our earlier studies, we assessed transcriptionally active HPV16 infection and its type (viral load and viral genome status). Transcriptionally active HPV16 infection was significantly more common in TSSCC (96.3%) than in BOTSCC (3.7%). Patients with TSSCC had significantly higher disease-free survival rates (84.1%) than those with BTSCC (47.4%); the same was true in the subgroup with HPV16 positivity. The obtained results are an important indication for further research on the development of new prognostic and/or predictive factors for patients with HPV16-positive squamous cell carcinomas of the oropharynx.

P24 Analysis of oxidative stress related HPV16-E6*I expression in HPV-positive squamous cell carcinoma of the oropharynx

P24 Analysis of oxidative stress related HPV16-E6*I expression in HPV-positive squamous cell carcinoma of the oropharynx

Impact of Mandated Online Prescription Drug Monitoring Programs on Opiate Analgesic Use and Patient-Reported Pain during Radiotherapy for Oropharyngeal Cancer

<h3>Purpose/Objective(s)</h3> Owing to the dramatic rise in opiate-related deaths, the use of online prescription drug monitoring programs (PDMPs) concurrent with new laws restricting opiate administration has become commonplace across the U.S. Some oncologists, however, have expressed concerns that they may unintentionally limit treatment access to at-risk oncology populations. As opiates are frequently used in the acute management strategies for those undergoing radiotherapy for squamous cell carcinoma of the oropharynx, we sought to evaluate changes in short-term opiate prescription use following the implementation of mandated use of an online PDMP in an outpatient radiation oncology practice. <h3>Materials/Methods</h3> Between July of 2017 and December of 2019, 64 patients with biopsy-confirmed oropharyngeal squamous cell carcinoma undergoing curative-intent radiotherapy were evaluated and divided into two cohorts: (1) 26 patients treated 1 year before and (2) 38 patients treated 1.5 years following mandated PDMP use and implementation of new opiate prescription laws. The primary endpoint was opiate prescriptions during therapy and within 3 months after therapy as well as patient-reported pain per the Defense and Veterans Pain Rating Scale. Opiate doses were treated as the response in a series of chi-square tests using a three-level format: no vs. 40 to 3000 vs. 3000+ MME. Cochran-Mantel-Haenszel chi-square analysis with the row mean score test statistic assessed any proportional shifts in dose rates between strata of selected prognostic factors. <h3>Results</h3> The median total opiate doses were 975 MME and 1025 MME in the pre- and postintervention groups with no significant differences in MMEs prescribed (p=0.8441). There was also no difference in patient-reported uncontrolled pain (p=0.38) between the treatment cohorts. Univariate analysis showed tonsillar/soft-palate subsite (p<0.01) and alcohol use (p=0.04) were associated with higher rates of prescribed opioids. While 75% of patients (n=48) received opiates during their acute care, 78% (n=50) were off all prescription narcotics by 3 months or sooner following treatment. <h3>Conclusion</h3> Although potential concerns that mandated PDMP use would affect opiate utilization, there was no associated change in total opiate use by MME for the management of acute pain during radiotherapy for patients with oropharyngeal squamous cell carcinoma nor differences in patient-reported uncontrolled pain. Furthermore, despite high utilization of opiates during radiotherapy, few patients continued use past 3 months after treatment.

Diagnostic test accuracy of sentinel lymph node biopsy in squamous cell carcinoma of the oropharynx, larynx, and hypopharynx: A systematic review and meta-analysis.

The aim of this meta-analysis was to determine the diagnostic test accuracy of sentinel lymph node biopsy (SLNB) in patients with oropharyngeal, laryngeal, and hypopharyngeal squamous cell carcinoma (SCC). For this purpose, MEDLINE, EMBASE, and Web of Science were searched from inception to March 8, 2022. Included were studies evaluating diagnostic test accuracy of SLNB to identify cervical lymph node metastases with elective neck dissection or follow-up as reference. A bivariate generalized linear mixed model approach was used for the meta-analysis. Nineteen studies were eligible, evaluating 377 cases in total. The pooled estimates of sensitivity and negative predictive value were 0.93 (95% CI: 0.86-0.96) and 0.97 (95% CI: 0.94-0.98), respectively. The excellent accuracy of SLNB justifies a place in the diagnostic workup of patients with larynx and pharynx SCC. Randomized trials are required to demonstrate oncologic safety and benefits on treatment related morbidity and quality of life when omitting elective neck treatment based on SLNB.

New Perspectives in Therapeutic Vaccines for HPV: A Critical Review.

Human Papillomavirus is the main cause of cervical cancer, including squamous cell carcinoma of the oropharynx, anus, rectum, penis, vagina, and vulva. In recent years, considerable effort has been made to control HPV-induced diseases using either prophylactic or therapeutic approaches. A critical review of the literature about the therapeutic Human Papillomavirus vaccine was performed to analyze its efficacy in the treatment of female lower genital tract lesions and its possible perspective application in clinical practice. The most important medical databases were consulted, and all papers published from 2000 until 2021 were considered. We retrieved a group of seven papers, reporting the role of anti HPV therapeutic vaccines against the L2 protein in the order of their efficacy and safety in female lower genital tract disease. In addition, the immune response due to vaccine administration was evaluated. The development of therapeutic vaccines represents an interesting challenge for the treatment of HPV infection of the lower genital tract. Literature data underline that the L2 protein may be an interesting and promising target in the development of therapeutic HPV vaccines, but the possible strengths and the unclear longevity of L2 immune responses are factors to be considered before clinical use.

Comprehensive Viral Genotyping Reveals Prognostic Viral Phylogenetic Groups in HPV16-Associated Squamous Cell Carcinoma of the Oropharynx.

HPV16 genotype is a potential biomarker that could be easily adopted to guide therapeutic decision-making related to deescalation therapy.

Recurrence pattern after chemoradiotherapy for HPV-associated oropharyngeal squamous cell carcinoma with respect to induction chemotherapy and escalated radiation dose-results from a prospective randomized phase II study.

6074 Background: Patients with HPV associated squamous cell carcinoma of the oropharynx have a favorable outcome with respect to tumor control and overall survival (OS) after treatment with chemoradiotherapy (CRT). The leading cause of death in these patients is reported to be peripheral metastases. Because of the favorable outcome for these patients, the medical community tries to find methods to ameliorate treatment intensity, mainly in order to reduce long term morbidity. However, between 10 and 15 % of patients relapse locally in the primary tumor as first site of disease failure. Methods: In this multicentre, randomized, controlled, phase II trial 152 patients with locoregionally advanced oropharyngeal cancer were randomized in a 1:1 ratio to either radiotherapy with cetuximab (arm B) versus the same regimen preceded by 2 cycles of induction chemotherapy (IC) with taxotere/cisplatin/5-FU (arm A). To decrease risk of local failure, an escalated radiation (RT) dose of 74.8 Gy was delivered to T3/T4 tumors and to T2 tumors &gt; 3 cm in the base of tongue. Eligibility criteria included patients 18-75 years, ECOG performance status 0-1 and adequate organ functions. Primary endpoint of the study was to compare PFS between the treatment arms, secondary objectives were recurrence pattern, locoregional control, OS and toxicity. Results: PFS at 2 years was 84.2% (95%CI 76.4-92.8) in arm A and 78.4 (95%CI 69.5-88.3) in arm B (p = 0.20). At the time of analysis there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A there were 3 local, 2 regional and 4 distant relapses as first site of recurrence, and in arm B 4, 4 and 9 relapses in corresponding sites. Local relapse rate as first site of failure was low, i.e. in 4.7%. Local failures constituted 7 relapses out of all 26 (27%), and in 4 of these local failures (57%), the escalated dose was given. In arm B, patients who had no IC, there were more than twice as many patients who had distant metastases as first site of relapse compared to arm A (n.s.). No patient who had a response to IC in the primary tumor or in regional lymph nodes, respectively, measured with CT or MRI, of either CR+CR or CR+PR, had any recurrence, local, regional or distant. So, IC could identify 22 out of 73 evaluable patients (30%) in arm A, who never had any recurrence during follow up. Conclusions: A high incidence of distant metastases as first site of failure is recognized while local failure rate is low. However, despite a high RT dose of 74.8 Gy, delivered to the primary tumor, relapses can appear in this site. Radiological response of tumor to IC could identify patients with no tumor relapse, at least within the first years of follow up, possible candidates for de-escalation treatment protocols. Clinical trial information: 2009-013438-26.

Robotic vs. transoral laser surgery of malignant oropharyngeal tumors-what is best for the patient? : Acontemporary review.

Human papillomavirus (HPV)-associated squamous cell carcinoma of the oropharynx is amalignancy of increasing prevalence. The oncologic community is currently evaluating the safety and efficacy of de-intensifying treatment without compromising oncologic outcomes. Paramount to these treatment algorithms is primary surgery through transoral approaches. This article reviews the literature and concepts pertaining to transoral surgery and describes the two most common techniques, transoral laser microsurgery (TLM) and transoral robotic surgery (TORS).

Estimation of the prevalence of HPV-positive squamous cell carcinoma of the oropharynx on the example of a separate sample in the Russian Federation

Introduction. The increasing incidence of oropharyngeal squamous cell carcinoma observed globally in recent decades gave rise to research in this area. In 2005, human papillomavirus was proved to be an etiological factor of oropharyngeal squamous cell carcinoma. Currently, oropharyngeal squamous cell carcinoma associated with human papillomavirus is believed to have some unique characteristics. The analysis of oropharyngeal squamous cell carcinoma epidemiology appears to be highly relevant.Objective – to assess the incidence and prevalence of oropharyngeal squamous cell carcinoma associated with human papillomavirus in Russia on the example of a certain sample of patients.Materials and methods. We analyzed medical records of 199 oropharyngeal squamous cell carcinoma patients treated in N. N. Blokhin Russian Cancer Research Center between 2016 and 2021. We analyzed the frequency of tumors associated with human papillomavirus, age, sex, tumor spread and stage depending on р16 status.Results. More than half of the patients from our cohort (58.3 %) were р16‑positive. The peak incidence was observed in individuals aged 45 to 64 years (more than 60 % of cases). Males were twice as likely to have р16‑positive tumors than females. A total of 60.9 % of patients with р16‑positive tumors had stage I disease, whereas 51.2 % of patients with p16‑negative tumors had stage IV disease.Conclusion. The results obtained for a sample of Russian patients are comparable with the findings of foreign authors.

Decreased overall survival in patients with locally advanced head and neck cancer receiving definitive radiotherapy and concurrent cetuximab: National Cancer Database analysis.

Recently, randomized trials have questioned the efficacy of cetuximab-based bioradiotherapy compared to chemoradiation for patients with squamous cell carcinoma of the oropharynx, larynx, and hypopharynx (HNSCC). We compared the OS of patients treated with radiotherapy alone (RTonly), chemoradiotherapy (chemoRT), and bioradiotherapy (cetuxRT). Patients with stage III-IVB HNSCC treated with RTonly, chemoRT, or cetuxRT were identified in the National Cancer Database. OS was estimated using Cox proportional hazards. Analyses were conducted on the overall cohort and propensity matched cohorts. 31 014 patients were treated with RTonly (22%), chemoRT (72%), or cetuxRT (6%) from 2013 to 2016. The 2-year OS was 69% for RTonly, 79% for chemoRT, and 66% for cetuxRT (p < 0.001). In the overall and propensity-matched cohorts, chemoRT and RTonly were associated with improved OS as compared to cetuxRT (p ≤ 0.001). Compared to chemoRT or RTonly, cetuxRT is associated with decreased OS for patients with HNSCC, suggesting minimal benefit of bioradiotherapy in this population.

HPV16-A1 Genotype is Associated with Poor Recurrence-Free Survival in HPV16 Associated Squamous Cell Carcinoma of the Oropharynx

<h3>Purpose/Objective(s)</h3> HPV-positive squamous cell carcinoma of the oropharynx (HPV+ OPSCC) is the most prevalent HPV-associated malignancy in the United States and is primarily caused by HPV16. Favorable treatment outcomes have led to increasing interest in treatment de-escalation to reduce treatment-related morbidity. Prognostic biomarkers are needed to identify appropriately low-risk patients for reduced treatment intensity. Large series of complete HPV16 genome sequencing from HPV+ OPSCC tumors are lacking in the literature. Therefore, we sought to test the hypothesis that HPV16 genotype is prognostic of recurrence-free survival (RFS) in HPV16+ OPSCC. <h3>Materials/Methods</h3> Targeted sequencing of 104 patients with HPV16+ OPSCC tumors was performed, providing complete coverage of all HPV16 open reading frames. Clinical features were retrospectively extracted from the medical record. A second cohort of OPSCC patients was sequenced using total RNA sequencing, which identified 89 patients with HPV16+ OPSCC for analysis. <h3>Results</h3> A high degree of coding diversity in the HPV16 was identified, with 93 distinct protein-coding HPV16 genotypes amongst the 104 patients subject to HPV (DNA) sequencing. As found in uterine cervical carcinoma, E7 was the most conserved amongst HPV16 viral genes. Sub-clonal variants were more likely to be non-synonymous and were enhanced for APOBEC-related mutagenesis. The HPV16-A1 sub-lineage was the most prevalent (approximately 70%). Genotypes closely related to HPV16-A1 were associated with increased numbers of copy-number variants in the human genome. Genotypes divergent from HPV16-A1 were strongly associated with favorable RFS as compared to HPV16-A1 (or similar genotypes); this finding was independent of tobacco smoke exposure. HPV16 genotypes divergent from HPV16-A1 were subsequently validated in an independent cohort (subject to RNA sequencing), to be associated with improved RFS in patients with moderate (less than 30 pack-years) and low (no more than 10 pack-years) of tobacco smoke exposure. <h3>Conclusion</h3> HPV16 viral genotype is highly diverse in HPV associated OPSCC. Sequence divergence from the HPV16-A1 reference sequence is strongly associated with improved RFS in patients with moderate to no tobacco smoke exposure. This finding was confirmed in two independent cohorts. HPV16 genotype is a promising potential biomarker that could be easily adopted to guide therapeutic decision-making related to de-escalation therapy. Prognostic genotypic information can be obtained from clinical samples stored in FFPE applying either DNA or RNA sequencing technology.

EVOLVE: Evaluating the Safety of De-escalated Head and Neck Irradiation in HPV Positive Oropharynx Cancer in Non/Minimal Smokers.

<h3>Purpose/Objective(s)</h3> HPV mediated oropharynx cancer in minimal smokers is a favorable disease entity but with high treatment related quality of life burden. Single institutional studies in large academic centers have favorable results with aggressive radiotherapy de-escalation after surgery or after complete response to induction chemotherapy. We hypothesize that radiotherapy can be safely de-escalated in the community cancer center setting. <h3>Materials/Methods</h3> Adults with HPV mediated squamous cell carcinoma of the oropharynx with ≤ 10 pack year smoking history T0-T3N0-N2M0 (AJCC8, including unknown primary p16+ minimal smokers) and with negative margins (if surgical arm) were enrolled on this prospective observational study. Initial surgical resection was performed if an R0 resection was anticipated AND if the surgeon would anticipate a good functional outcome post-operatively. Adjuvant radiotherapy was as per Ma <i>et al</i> JCO 2019. Induction chemotherapy with de-escalated radiotherapy to complete responders was undertaken when surgical resection was not deemed optimal. Platinum eligible induction chemotherapy was as per Marur <i>et al</i> JCO 2017. Platinum ineligible induction chemotherapy was as per Chen <i>et al</i> Lancet Oncology 2017. The primary endpoint was cumulative incidence of local/regional recurrence. Secondary endpoints included quality of life as determined by Head and Neck PRO (FACT-H&N, EORTC QLQ-C30 and H&N35), distant metastasis free survival and overall survival. Preliminary report includes 39 patients with at least 3 months follow-up. Planned accrual is 60 patients. <h3>Results</h3> Median follow-up was 18 months (3-45 months). 31/39 (80%) received initial surgery. 8/39 (20%) received initial induction chemotherapy. 1 withdrew during induction. 100% of patients receiving induction therapy had adequate response to qualify for de-escalation. Cumulative incidence of local/regional recurrence was 3% (1/39). Cumulative incidence of distant metastases was 3% (1/39). Both recurrences occurred in the surgical arm. Overall survival is 100%. No patient in the induction arm required salvage neck dissection or recurred. 1/11 (9%) of patients with extranodal extension (ENE) recurred locally/regionally. 1/11 (9%) patients with ENE recurred distantly. ENE status is unknown in the non-surgical arm. There were no recurrences in the 7 patients with N2 disease. No de-escalated patient required treatment related feeding tube placement. Patient reported quality of life was stable to improved at 12 month follow-up. <h3>Conclusion</h3> In a rural community setting, early results of aggressive de-escalation of radiotherapy demonstrate this approach to be both safe and effective with minimal change in patient reported quality of life. In this favorable disease entity, reported de-escalation results from large academic centers are readily translatable to daily community practice.

Patient derived ex vivo tissue slice cultures demonstrate a profound DNA double-strand break repair defect in HPV-positive oropharyngeal head and neck cancer

BackgroundHPV-positive head and neck squamous cell carcinoma of the oropharynx (OPSCC) are more sensitive towards radiation than HPV-negative OPSCC. Two main theories exist regarding the underlying mechanism. Stronger lymphocyte infiltration points to an enhanced immunogenicity, whereas data from HPV-positive HNSCC cell lines suggest an enhanced cellular radiosensitivity based on a defect in DNA double-strand break (DSB) repair. The critical limitation of the latter theory is that the evidence was largely derived from a small number of established HPV-positive HNSCC cell lines. Methods and materialsFresh patient-derived OPSCC samples were cut in 400 µm sections and cultured on cell culture inserts. Slice cultures were irradiated, in part combined with ATM inhibition, and fixed and frozen after 2 and 24 h. DSBs were analyzed by quantification of 53BP1 foci in nuclei co-stained with the SCC marker p63 via immunofluorescence microscopy. ResultsEx vivo OPSCC tumor slice cultures maintained stable oxygenation and proliferation characteristics for at least 3 days. Areas of p63-positivity in immunofluorescence microscopy matched histologically confirmed tumor cell areas in serial sections, indicating the suitability of p63 as a tumor cell marker. p63-positive nuclei in HPV-positive OPSCC tissues (n = 14) showed profoundly elevated numbers of residual radiation-induced DSBs as compared to those from HPV-negative OPSCC (n = 12) (3 Gy: on average 4.9 vs. 1.2 foci per nucleus; p < 0.0001). Within the HPV-positive subgroup, samples derived from patients with a smoking history of less than 10 pack years demonstrated higher residual DSBs as compared to those derived from patients with 10 or more pack years (3 Gy: on average 6.5 vs. 3.2 foci per nucleus; p = 0.0105). Additional ATM inhibition resulted in a substantial increase in residual foci in all 4 HPV-negative samples tested but strikingly only in 2 out of 11 HPV-positive samples. ConclusionsIn summary, our data provide robust, cell line-independent experimental evidence for an intrinsic DSB repair deficiency in HPV-positive OPSCC, strongly suggesting a meaningful contribution to the enhanced clinical radiosensitivity. The reduced effectiveness of ATM inhibition indicates a defect in the ATM-orchestrated DNA damage response. Lower numbers of residual 53BP1 nuclear foci in the ex vivo assay may identify HPV-positive patients with effective DSB repair who should potentially be excluded from de-intensification approaches.

Accuracy of liquid-based brush cytology and HPV detection for the diagnosis and management of patients with oropharyngeal and oral cancer

ObjectivesThis study aims to evaluate the usefulness of liquid-based brush cytology for malignancy diagnosis and HPV detection in patients with suspected oropharyngeal and oral carcinomas, as well as for the diagnosis of tumoral persistence after treatment.Material and methodsSeventy-five patients with suspicion of squamous cell carcinoma of the oropharynx or oral cavity were included. Two different study groups were analyzed according to the date of the sample collection: (1) during the first endoscopy exploration and (2) in the first control endoscopy after treatment for squamous cell carcinoma. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for malignancy diagnosis as well as for HPV-DNA detection on brush cytologies were assessed.ResultsBefore treatment, the brush cytology showed a sensitivity of 88%, specificity of 100%, and accuracy of 88%. After treatment, it showed a sensitivity of 71%, specificity of 77%, and accuracy of 75%. HPV-DNA detection in cytology samples showed a sensitivity of 85%, specificity of 100%, and accuracy of 91% before treatment and an accuracy of 100% after treatment.ConclusionsLiquid-based brush cytology showed good accuracy for diagnosis of oropharyngeal and oral squamous cell carcinoma before treatment, but its value decreases after treatment. Nevertheless, it is useful for HPV-DNA detection, as well as to monitor the patients after treatment.Clinical relevanceBrush cytology samples are reliable for the detection of HPV-DNA before and after treatment and may be a useful method to incorporate in the HPV testing guidelines.

Quantifying smoking exposure, genomic correlates, and related risk of treatment failure in p16+ squamous cell carcinoma of the oropharynx.

ObjectivesHPV‐associated (p16+) squamous cell carcinoma of the oropharynx (OPSCC) has improved survival as compared to HPV‐negative, smoking‐associated disease. Intermediate outcomes have been noted in patients with p16+ tumors and smoking exposure. However, the extent of smoking exposure required for outcomes to decrease has not been delineated due to low failure rates and poor availability of quantitative tobacco smoke exposure data. Our primary objective is to characterize the dose‐dependent relationship between recurrence‐free survival (RFS) and tobacco smoke exposure in p16+ OPSCC and secondarily correlate tobacco smoke exposure with genomic alterations.MethodsSingle institution chart review was performed of patients diagnosed with p16+ OPSCC from 2003 to 2015. Patients were excluded if staging, treatment details, recurrence status, or smoking exposure in pack‐years were not available. Two hundred and forty‐four patients were included.ResultsPatients with 25 pack‐years or greater smoking history exhibited a dose‐dependent decrease in RFS compared to never smokers. This was robust to multivariate analysis for including staging and demographic factors. Forty‐three patients with available targeted tumor sequencing data were identified. A strong trend was observed for increased C to A transversion mutations above 25 pack‐years, which are known to be associated with exposure to tobacco smoke. Similarly, the proportion of COSMIC Signature 4 mutations were also found to be more common in patients with more than 25 pack‐years of smoking exposure.ConclusionEvidence‐based smoking exposure thresholds are needed to define inclusion criteria for trials of de‐escalation therapy for p16+ OPSCC. Patients with smoking exposure greater than 20 pack‐years have increased risk of recurrence and a distinct pattern of genomic alterations. Further studies are needed to delineate the potential consequences of mild smoking exposure. Smoking‐related mutational signatures may hold potential for biomarker development in p16+ OPSCC.Level of Evidence2B

Recurrence and Quality-of-Life Following Involved Node Radiotherapy for Head and Neck Squamous Cell Carcinoma: Initial Results From the Phase II INRT-Air Trial

Elective neck irradiation (ENI) has long been considered mandatory when treating head and neck squamous cell carcinoma (HNSCC) with definitive radiotherapy (RT). However, ENI is often responsible for the majority of the dose to the salivary glands and swallowing organs-at-risk (OAR), and recent prospective studies have supported reduced elective neck volume and dose. Moreover, with sensitive staging studies and artificial intelligence (AI), our ability to identify occult lymphadenopathy is greatly improving. In this prospective phase II study, we investigated the efficacy and tolerability of eliminating ENI and strictly treating involved and suspicious lymph nodes (LN) with intensity modulated radiation therapy.Patients with newly-diagnosed squamous cell carcinoma of the oropharynx, larynx and hypopharynx were eligible for enrollment, excluding stage I-II glottic larynx. Each LN was characterized as involved or suspicious based on CT (e.g., cross-sectional size, enhancement pattern) and PET criteria and an in-house AI-based classification model. Gross disease and the primary clinical target volume were irradiated to 70 and 63 Gy in 35 fractions, respectively, and suspicious LN were treated to 66.5 Gy. Concurrent chemotherapy was required for stage T3N0-1 and IVA/B patients. The primary endpoint of the study was risk of solitary elective volume LN recurrence (i.e., LN recurrence in a classic ENI field without synchronous in-field or distant failure), with secondary endpoints including patterns-of-failure and patient reported outcomes.Sixty-seven patients were enrolled, with 18 larynx/hypopharynx and 49 oropharynx cancer (88% p16+). In total, 10% and 90% of patients were treated with accelerated RT and chemoRT, respectively. Average contralateral/ipsilateral mean parotid and contralateral submandibular doses were 11.9/18.4 Gy and 34.1 Gy, respectively, and average mean larynx/inferior constrictor/esophagus doses for oropharynx patients were 18.9/12.2/6.7 Gy. With a median follow-up of 12.8 months for surviving patients, there have been no solitary elective volume LN recurrences. Four patients have died from unrelated causes, and one died from in-field local progression. Gastrostomy was placed in 14 (21%), with median removal after 2.8 months for disease-free patients; only one patient is still dependent. Grade 1/2 dermatitis was seen in 90%/10% patients. There was no significant difference in MDADI score between baseline and months 3 and 6 post-RT; for patients with baseline MDADI score > 75, the scores at 3/6 months were 84/83.Preliminary results suggest that eliminating ENI is oncologically sound for HNSCC, with highly favorable OAR dosimetry and promising quality-of-life outcomes. Longer follow-up is needed to confirm these results.

A Novel Immobilization Method Using 3D Printing for the Treatment of Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> Radiation therapy requires immobilization hardware that may produce significant anxiety for a patient under treatment, particularly when covering the face. In cases where such anxiety is treatment limiting, 3D printing can provide for a better tolerated custom immobilization. The technical hurdles, fidelity of positioning, and clinical outcomes are reviewed for the treatment of oropharyngeal cancer in a patient who was unable to tolerate traditional mask-based immobilization. <h3>Materials/Methods</h3> A 3D printer was used to create a custom immobilization cradle for the treatment of squamous cell carcinoma of the oropharynx. This was used in the treatment of a patient who was unable to be simulated despite nine separate attempts, using a variety of open-faced immobilization techniques, anxiolytics, and coaching. Operative management was not feasible due to the patient's habitus and comorbidities. Despite acknowledging the severity of the situation, the patient could not complete simulation. Thus, after he was confirmed to still have locoregionally limited disease, we proposed creation of a 3D-printed cradle for the back of his head and neck, based on CT imaging without immobilization. Three separate attempts were made to complete the printing of the cradle. Major issues stemmed from the need to find a set of support structures that would allow for the proper printing of the area supporting the ears, as well as the back of the head. Ultimately, a dense array of column supports was successful, but still required buttressing of the columns with tape at several points during the print. In total, 664g of polylactic acid filament was used, as well as 525g of polyvinyl alcohol, a water soluble support material. Total print time was just under 78 hours for the final successful print. <h3>Results</h3> The patient was able to tolerate simulation and the full course of fractionated chemoradiotherapy. The cradle provided for a setup requiring mean absolute shift of 0.35 mm in the anterior-posterior direction, 0.17 cm in the cranio-caudal direction, and 0.36 cm in the lateral direction, and a couch kick of 1.28 degrees to bring the patient into alignment on final imaging. The patient is currently in stable condition and following up with both medical oncology and radiation oncology at regular intervals. Imaging and laryngoscopy, conducted at multiple time points following completion, shows him to have no evidence of disease, now at 10 months. <h3>Conclusion</h3> The full uses of 3D printing are still developing, as evidenced by the difficulty of creating a workable print, both in terms of prototyping and the time needed to create a print. The impact of 3D printing within the context of radiation oncology, as well as in other specialties, will undoubtedly continue to increase the variety of viable treatment options available to patients as the technology improves.