Hedgehog Inhibitors Beyond Clinical Complete Response in Basal Cell Carcinoma: Should I Stop or Should I Go?

INTRODUCTION: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. MATERIALS AND METHODS: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10). RESULTS: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01). CONCLUSIONS: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC.

Management of radiation-induced oral mucositis in head and neck cancer patients: a real-life survey among 25 Italian radiation oncology centers.

AIM: Radiation-induced oral mucositis (RIOM) is the most frequent side effect in head and neck cancer (HNC) patients treated with curative radiotherapy (RT). A standardized strategy for preventing and treating RIOM has not been defined. Aim of this study was to perform a real-life survey on RIOM management among Italian RT centers. METHODS: A 40-question survey was administered to 25 radiation oncologists working in 25 different RT centers across Italy. RESULTS: A total of 1554 HNC patients have been treated in the participating centers in 2021, the majority (median across the centers 91%) with curative intent. Median treatment time was 41 days, with a mean percentage of interruption due to toxicity of 14.5%. Eighty percent of responders provide written oral cavity hygiene recommendations. Regarding RIOM prevention, sodium bicarbonate mouthwashes, oral mucosa barrier agents, and hyaluronic acid-based mouthwashes were the most frequent topic agents used. Regarding RIOM treatment, 14 (56%) centers relied on literature evidence, while internal guidelines were available in 13 centers (44%). Grade (G)1 mucositis is mostly treated with sodium bicarbonate mouthwashes, oral mucosa barrier agents, and steroids, while hyaluronic acid-based agents, local anesthetics, and benzydamine were the most used in mucositis G2/G3. Steroids, painkillers, and anti-inflammatory drugs were the most frequent systemic agents used independently from the RIOM severity. CONCLUSION: Great variety of strategies exist among Italian centers in RIOM management for HNC patients. Whether different strategies could impact patients' compliance and overall treatment time of the radiation course is still unclear and needs further investigation.

Management of loco-regionally advanced squamous laryngeal cancer in elderly patients.

PURPOSE: To describe the management and outcomes of loco-regionally advanced (stages III-IV) laryngeal cancer (LRALC) in elderly patients. METHODS: Clinical records of 88 LRALC patients treated at our Institution from 2002 to 2017 were retrospectively reviewed. Patients were divided in 2 subgroups: age > 65 years (elderly) and age ≤ 65 years (controls). Survivals were estimated with Kaplan-Meier method and compared with log-rank test, multivariate analysis were performed with Cox proportional hazard methods. RESULTS: Eighty-eight LRALC patients were included: 45 elderly and 43 controls. Median follow-up was 55.3 months. Median age was 66 years (range 41-84) in the overall population, 72 years (range 66-84) in the elderly cohort. The majority (98%) of elderly patients had at least one comorbidity (ACE27 1-3), while ACE27 was 0 in 37% of controls (p = 0.0001). ECOG PS was 0 in 42% of elderly vs 79% of controls (p = 0.0029). Clinical stage (TNM eighth edition) was III in 67%, IVA in 22% and IVB in 11%. Treatment consisted in total laryngectomy (TL) in 55%, chemo-radiation in 29%, exclusive radiotherapy in 9%, and conservative surgery in 7%. In elderly patients 2-year disease-free and overall survivals were 58% and 74%, respectively. Multivariate analysis performed on the overall group of 88 patients showed that age (HR 1.07, p = 0.0006) and TNM (for both 7th and 8th Editions HR 0.27 for stage III vs IV, p = 0.0005) maintained an independent statistical significant association with OS. CONCLUSIONS: In this monocentric cohort, age and TNM confirmed their independent prognostic role in LRALC patients. Organ-preservation is still an unmet need in a significant portion of elderly patients.

Patients with adenoid cystic carcinomas of the salivary glands treated with lenvatinib: Activity and quality of life.

BACKGROUND: The treatment of patients with recurrent and/or metastatic (R/M) salivary gland adenoid cystic carcinoma (ACC) remains an unmet need. METHODS: Patients with R/M disease with a history of clinical or symptomatic disease progression within 6 months and a maximum of 1 previous line of chemotherapy or a multiple kinase inhibitor received oral lenvatinib at a dose of 24 mg/day. The primary endpoint was the objective response rate; secondary endpoints included quality of life (QOL) (according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items [EORTC QLQ-C30] and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module Head and Neck Module [EORTC QLQ-H&N35]), progression-free survival and overall survival, duration of response, and toxicities. RESULTS: Twenty-eight patients with R/M ACC were enrolled. Among 26 evaluable patients, 3 partial responses (11.5%) were reported. Target lesion reductions between 23% to 28% were observed in 4 of 20 patients with stable disease. Treatment-related adverse events were frequent (all grades, 96%; grade≥3 in 50% of cases according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events). The dose of lenvatinib was reduced in 24 patients, whereas in 21 patients the dose was reduced within the first 12 weeks and 4 patients maintained the full dose throughout treatment. The QOL deteriorated between baseline and 6 months with regard to Fatigue and Dry Mouth. There was no evidence of changes in Swallowing and Physical Functioning. At a median follow-up of 29 months, 2 patients remained on treatment, 10 patients were off protocol for disease progression and were alive with disease, and 14 patients had died of disease progression. The median overall survival, progression-free survival, and duration of response were 27 months, 9.1 months, and 3.1 months, respectively. CONCLUSIONS: Lenvatinib appears to have modest activity in ACC. Toxicities are common but manageable and QOL was found to deteriorate in some domains.

PD-L1 Expression in Unresectable Locally Advanced or Metastatic Skin Squamous Cell Carcinoma Treated with Anti-Epidermal Growth Factor Receptor Agents.

BACKGROUND: Recurrent or metastatic (R/M) skin squamous cell carcinoma (sSCC) not amenable of surgery or irradiation may benefit from systemic therapies. Epidermal growth factor receptor (EGFR) inhibitors and, more recently, immune checkpoint blockers (ICBs) showed activity in R/M sSCC. In this study, we aimed at exploring the possible role of PD-L1 expression in predicting response to anti-EGFR agents. METHODS: Patients affected by R/M sSCC, treated with pan-HER inhibitor dacomitinib or with platinum-based chemotherapy with cetuximab (CT-cet) from 2010 to 2016, were considered. PD-L1 expression was assessed with immunohistochemistry on tumor cells (TCs) and on microenvironment (TC and tumor-infiltrating lymphocyte [IC] scores, respectively). Prognostic role of PD-L1 and the correlation with response to EGFR inhibitors and survival were analyzed. RESULTS: Twenty-eight R/M sSCCs were analyzed (19 treated with dacomitinib, 9 with CT-cet). TC and IC were negative in 82 and 45% of cases, respectively; 15% sSCCs were both TC and IC positive. Progression-free survival (PFS) was longer in IC-positive cases (median 7.5 months vs. 2.1 in IC0, p = 0.02). No statistically significant differences were observed between PD-L1 expression and both overall survival and response rates. CONCLUSION: PD-L1 expression in microenvironment predicted better PFS. The combination of EGFR inhibitors and ICB could help deepening the knowledge about the interrelations between the EGFR and PD-1/PD-L1 pathways.

Preemptive treatment with Xonrid®, a medical device to reduce radiation induced dermatitis in head and neck cancer patients receiving curative treatment: a pilot study.

PURPOSE: The purpose of this study was to investigate efficacy, safety and tolerability of Xonrid®, a new medical device, in preventing radiation dermatitis associated with head and neck cancer (HNC) radiotherapy (RT). METHODS: In this monocentric, prospective pilot study, adult consecutive HNC patients who were planned to receive curative RT with or without chemotherapy were enrolled. Patients were instructed to apply Xonrid® on the irradiated area during treatment continuing until 2 weeks after the completion of RT or the development of severe skin toxicity. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 scale. The patient reported outcome measures included the Skindex-16 questionnaire and patient satisfaction. Skin reflectance spectra were analyzed to objectively evaluate dermatitis. RESULTS: In total, 41 subjects were enrolled (30 males, median age 60 years). No skin adverse events were recorded either in the skin area where the product was applied or in the nearby skin over the entire period of administration. At the end of RT, nine patients (22%) presented G1, 31 (76%) G2, and one patient (2%) G3 skin toxicity (after 5 weeks). Seven and 20 patients reached skin maximum toxicity at the fourth week and after the seventh week, respectively. An increasing trend of median spectrophotometry scores along with skin toxicity grades was observed. A correlation between Skindex-16 scores and skin toxicity grade during treatment was found. CONCLUSIONS: Our study results suggest that Xonrid® is well tolerated, safe, and effective in minimizing and delaying high-grade radiation dermatitis in HNC patients.

Postoperative radiotherapy with volumetric modulated arc therapy of lacrimal gland carcinoma: two case reports and literature review.

AIMS: To evaluate technical issues and clinical outcomes after postoperative volumetric-modulated arc therapy (VMAT) in two cases of malignant lacrimal gland cancer. PATIENTS & METHODS: Patients were treated by postoperative VMAT and post-treatment clinical outcomes were followed-up to 18 months. RESULTS: Dosimetric results were acceptable and acute toxicity was manageable in both patients. No evidence of disease was found at latest follow-up. One patient underwent corneal transplant for central corneal ulceration, experiencing reduction of visual acuity. CONCLUSION: Postoperative VMAT for treatment of lacrimal gland tumors offers improved outcome, with manageable side effects. In the context of photon beam radiotherapy, VMAT emerged as a valuable treatment option for these malignant tumors.

Critical analysis of locoregional failures following intensity-modulated radiotherapy for nasopharyngeal carcinoma.

AIM: To analyze the patterns of locoregional failure following intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) at our institution, as part of an internal quality assurance program. We aimed to investigate the potential existence of a correlation between any part of the IMRT process and clinical outcome. METHODS & MATERIALS: A total of 106 non-metastatic NPC patients consecutively treated with IMRT (with or without chemotherapy) were analyzed. Radiotherapy was administered using a sequential or simultaneous integrated boost approach at the total prescribed dose of 66-70 Gy (2.00-2.12 Gy per fraction). MRI studies of recurrences were recorded with the planning computed tomography studies to identify volume of failure. Recurrence-related characteristics were analyzed with respect to the original treatment. Failures were classified as 'in-field', 'marginal' or 'out-field' if at least 95, 20-95 or less than 20% of the volume of failure, respectively, was within 95% of the total prescription dose. RESULTS: With a median follow-up of 43.4 months, 5-years local control, regional control, locoregional control and overall survival rates were 87.7, 88.0, 83.5 and 81.3% respectively. A total of 21 failures were registered in 15 patients. In particular, ten failures (47.6%) were classified as 'in-field' (seven local failures and three regional failures [RFs]), nine failures (42.9%) as 'marginal' (five local failures and four RFs) and only two failures (9.5%) as 'out-field' (both RFs). The most relevant causes of failures were suboptimal target definition and target coverage as well as a longer than planned overall treatment time. CONCLUSION: IMRT determines excellent outcome in NPC patients. However, great attention in all IMRT steps is necessary to reduce potential causes of failure.

The association of cemiplimab plus sonidegib for synchronous cutaneous squamous cell carcinoma and basal cell carcinoma of the head and neck: Two case reports.

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are the most frequent cancers in humans, with cumulative ultraviolet radiation exposure, aging, and immunodepression as the main risk factors. In most cases, these malignancies arise in the head and neck area, and they can be treated with locoregional therapies. A minority of cases require systemic therapy. Currently, Sonic Hedgehog inhibitors (i.e., vismodegib and sonidegib) have been approved for advanced BCC, while the PD-1 checkpoint inhibitor cemiplimab has been approved as a first-line treatment for cSCC and as a second-line treatment for BCC. Nevertheless, there is a clinical need for an effective and safe systemic therapies for advanced synchronous (syn) BCC/cSCC not amenable to local treatments. International guidelines do not provide specific recommendations for patients affected by this condition, and no case reports on the full-dose association of these medications have been previously reported. Here, we present the cases of two elderly patients affected by synBCC/cSCC of the head and neck, who received combined therapy with cemiplimab and sonidegib at full dose and standard schedule, achieving remarkable clinical benefit and long-term responses, without major adverse events. The instance of a feasible treatment for patients with advanced synBCC/cSCC will become increasingly frequent with the advancement of life expectancy in the global population, and the synergistic activity of targeted therapies and immunotherapy-administered either in association or sequentially-deserves to be further explored.

Multidisciplinary management of pregnancy-associated and early post-partum head and neck cancer patients.

Background: Pregnancy-associated cancer (PAC) occurs during pregnancy or within 12 months after the delivery. Head and neck cancer (HNC) during pregnancy is infrequent, therefore diagnosis and personalized therapy are intricate. Methods: We investigated outcomes of 15 PAC patients (5 salivary, 4 nasopharyngeal, 3 thyroid, 2 oral cavity, one HPV-related carcinoma) diagnosed in the period 2005-2019. A literature review on PAC is provided. Results: Median gestational age at PAC diagnosis was 28 weeks (range: 16-40 weeks) in ten cases, at 5 months after delivery (range: 1 week-6 months) in the remaining five. Treatments included surgery (3 during pregnancy, 5 after childbirth), chemoradiation (8), and 3 patients with upfront metastatic disease received chemotherapy. Median survival was 6.6 years (eight women remain with no evidence of disease six years after diagnosis). Conclusion: All patients received state-of-the-art therapy, with encouraging long-term results, highlighting treatment safety in women with HNC during pregnancy.

Long-lasting responses with chemotherapy followed by T-cell therapy in recurrent or metastatic EBV-related nasopharyngeal carcinoma.

Background: Refractory or metastatic nasopharyngeal carcinoma (NPC) patients have a poor prognosis due to the lack of effective salvage treatments and prolonged survival by means of combination chemotherapy being described only for a minority of younger patients with oligometastatic disease. Targeting the Epstein - Barr virus (EBV) proteins expressed in NPC cells has been shown to be a feasible strategy that could help control systemic disease. Patients and Methods: Between 2011 and 2014, 16 patients with recurrent/metastatic EBV-NPC received first-line chemotherapy (CT) followed by 2 doses of autologous cytotoxic EBV specific T-lymphocytes (15-25 x 107 total cells/dose, 2 weeks apart), based on our previous studies showing the feasibility and efficacy of this infusion regimen. Cumulative overall survival (OS) and median OS were analysed in the whole population and according to specific clinical and biological parameters. Results: All patients received the planned T-cell therapy schedule, 9 after reaching partial (n=5) or complete (n=4) disease remission with CT, and 7 after failing to obtain benefit from chemotherapy. No severe adverse events were recorded. Patients who received cytotoxic T-lymphocytes (CTLs) had a cumulative 10-year OS of 44%, with a median OS of 60 months (95% CI 42-62). Patients responding to CT, with oligometastatic disease (<3 disease sites), and plasma EBV-DNA <1000 copies/mL had a better outcome. Conclusions: Autologous EBV-specific CTLs transplanted following conventional first-line CT demonstrated promising efficacy with several patients obtaining long-lasting disease control. The rationale provided by this study, with the crucial role likely played by the timing of CTL administration when trying to induce synergy with conventional treatment needs to be confirmed in a prospective controlled trial.

Pre-treatment risk factors to predict early cisplatin-related nephrotoxicity in locally advanced head and neck cancer patients treated with chemoradiation: A single Institution experience.

OBJECTIVES: Cisplatin is essential in the curative treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC) patients. The assessment of risk factors to predict an early cisplatin-induced nephrotoxicity could help in better managing one of the most relevant cisplatin-related dose-limiting factors. MATERIAL AND METHODS: We retrospectively collected data of LA-HNSCC patients treated at our Institution from 2008 to 2019. Patients received cisplatin in a curative setting concurrently with radiation. Acute Kidney Injury (AKI) was assessed as a dichotomous variable (CreaIncr) based on pre-treatment values, and values recorded at days 6-20 post-first cycle of cisplatin. Univariable logistic regression models were performed to investigate associations between CreaIncr and clinical characteristics. A multivariable logistic model on a priori selected putative covariates was performed. RESULTS: Of the 350 LA-HNSCC treated patients, 204 were analyzed. Ninety (44 %) suffered from any grade AKI (grade I 51.1 %): out of them, 84.4 % received high-dose cisplatin (100 mg/m2 q21). On the univariable logistic regression model, male sex, age, serum uric acid, creatinine, concomitant drugs, and cisplatin schedule were significantly associated with a higher rate of AKI. At multivariable model, age (p = 0.034), baseline creatinine (p = 0.027), concomitant drugs (p = 0.043), and cisplatin schedule (one-day bolus or fractionated high-dose vs. weekly; p = 0.001) maintained their significant association. CONCLUSIONS: Identifying pre-treatment risk factors in LA-HNSCC patients may improve decision-making in a setting where cisplatin has a curative significance. A strict monitoring of AKI could avoid cisplatin dose adjustments, interruptions, and treatment delays, thus limiting a negative impact on outcomes.

Monitoring patients with head and neck cancer for flu-like symptoms during the COVID-19 pandemic.

OBJECTIVE: To capture and monitor flu-like symptoms in relation to the clinical characteristics and the oncologic treatment of a large head and neck cancer (HNC) patient cohort during the Coronavirus disease 2019 (COVID-19) pandemic. METHODS: Patients were monitored through by 2 rounds of interviews. Clinical characteristics of patients with no symptoms (group 0) and of those reporting ⩾1 (group A), ⩾3 (group B), or ⩾5 symptoms (group C) were analyzed. Patients with ⩾1 symptom at both interviews were defined as group A2. RESULTS: Five hundred patients with HNC were analyzed. A higher frequency of patients with the following characteristics was observed in group A vs group 0: active treatment (40% vs 24%, p = 0.0002), gastrostomy (6% vs 2%, p = 0.027), recent active treatment (48% vs 29%, p < 0.0001), and higher number of concomitant medications (p = 0.01). A lower median age was observed in group B vs group no-B (patients with fewer than three symptoms) (59 vs 63.55 years, p = 0.016) and in group A2 vs group no-A2 (patients without at least one symptom at both interviews) (56 vs 63 years, p = 0.021); patients in group B received more recent active treatment than those in group no-B and in group A2 vs those in group no-A2 (p = 0.024 and 0.043, respectively); patients in group B had a lower body mass index than those in group no-B (22.4 vs 23.93 kg/m2, p = 0.0066). CONCLUSIONS: This work is based on patient-reported symptoms and signs independently of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. In the future, these results might serve as a a benchmark for clinicians triaging and managing patients with HNC during infectious outbreaks involving flu-like symptoms.

HER2 status in recurrent/metastatic androgen receptor overexpressing salivary gland carcinoma patients.

Background: Overexpression of human epidermal growth factor receptor type 2 (HER2) occurs in almost 25-30% of androgen receptor (AR)-positive salivary gland carcinomas (SGCs), notably salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified (NOS). In the last years, several studies have reported the clinical benefit of HER2 directed therapies in this setting. This work aims at describing the natural history of AR-positive recurrent/metastatic (R/M) SGC patients, based on HER2 amplification status. Methods: Consecutive R/M AR-positive SGC patients accessing our Institution from 2010 to 2021 were analyzed. Descriptive statistics and survival analyses were performed to present the clinical characteristics of the selected patients and the outcomes, based on HER2 status. A specific focus was dedicated to patients developing metastases to the central nervous system (CNS). Results: Seventy-four R/M AR-positive SGC patients (72 men) were analyzed. Median follow-up was 36.18 months (95% CI 30.19-42.66). HER2 status was available in 62 cases (84%) and in 42% the protein was overexpressed (HER2+). Compared with patients with HER2- SGCs, in patients with HER2+ disease, HR for disease recurrence was 2.97 (95% CI 1.44-6.1, p=0.003), and HR for death from R/M disease was 3.22 (95% CI 1.39-7.49, p=0.007). Moreover, the HER2+ group showed a non-significant trend towards a higher prevalence of CNS metastases (40% vs. 24%, p=0.263). Patients developing CNS metastases had shorter survival than those who did not; at bivariate analysis (covariates: CNS disease and HER2 status), HER2 status demonstrated its independent prognostic significance. Discussion: In our patient population, HER2 amplification was a negative prognostic factor, and it was associated with a non-statistically significant higher risk of developing CNS metastasis. Further studies are needed to explore the potential clinical benefit of tackling the two biological pathways (AR and HER2) in patients affected by this rare and aggressive malignancy.

The Interplay between Age and Viral Status in EBV-Related Nasopharyngeal and HPV-Related Oropharyngeal Carcinoma Patients.

Background. The aim of this work was to analyze the interplay between age and viral status on the outcomes in loco-regionally advanced oropharyngeal and nasopharyngeal cancer patients treated with radiotherapy and different chemotherapy combinations. Methods. A retrospective (2006−2017) analysis was performed on non-metastatic loco-regionally advanced oropharyngeal (both HPV+ and HPV−) and EBV+ nasopharyngeal cancer patients (young: <65 years vs. elderly: ≥65 years) treated with radiotherapy with or without chemotherapy. The impact of age and viral status on overall (OS) and disease-free survival (DFS) were studied with multivariable models, which were adjusted for smoking, stage, comorbidities, chemotherapy dose intensity and treatment strategy. Results. We analyzed 324 patients (146 HPV+ oropharynx, 63 HPV−, 115 nasopharynx). Elderly patients had more comorbidities, and received less intensive treatments when compared to younger subjects. Although OS and DFS were shorter in older patients, after adjustment for stage, smoking, comorbidities, treatment strategy and dose intensity, no significant differences in terms of survival were observed according to age (65 vs. 50 years of age: HR 1.89, 95% CI 0.45−7.84 for HPV+ OPC; HR 0.91, 95% CI 0.29−2.89 for HPV− OPC; HR 1.99, 95% CI 0.9−4.39 for NPC; p = 0.395). Conclusions. Several potential age-related (comorbidities, treatment intensity) and disease-related (stage) confounding factors play a prognostic role with differential impacts on both virus and non-virus-related tumors. In HPV+ oropharyngeal cancer and in EBV+ nasopharyngeal cancer patients, age should be considered as the expression of an array of host- and tumor-related features rather than an independent prognostic factor.

Comparing BamHI-W and CE-marked assays to detect circulating Epstein-Barr Virus (EBV) DNA of nasopharyngeal cancer patients in a non-endemic area.

OBJECTIVES: Plasma Epstein-Barr Virus (EBV)-DNA is a well-established prognostic biomarker in nasopharyngeal carcinoma (NPC). Different methods for assessment include single-copy gene targeted, European Conformity (CE)-marked assays, which are mostly employed in non-endemic settings, vs multiple-copy gene targeted, in-house BamHI-W based assays, which currently represent the most widely used method for EBV-DNA quantification. To date, evidence concerning the commutability of these different assays is still limited. MATERIALS AND METHODS: From August 2016 to March 2018, 124 plasma and 124 whole blood (WB) samples from 93 NPC patients were collected at different time-points for each patient. EBV-DNA viral load was quantified in pre- (n = 12) and post-treatment (n = 9), follow-up (n = 53), and recurrent/metastatic (R/M) (n = 50) phase. For each sample, one in-house BamHI-W vs three different CE-marked plasma assays were compared; the performance of plasma vs WB matrix was also assessed. Quantitative agreement of EBV-DNA values was evaluated by linear correlation and Bland-Altman analysis. RESULTS: A statistically significant (p = 0.0001) agreement between all CE-marked and the BamHI-W assays was found using plasma matrix, regardless of clinical phase. The results obtained in copies/ml were comparable to those expressed in IU/ml. When using WB matrix, the number of positive detections increased in the post-treatment phase. CONCLUSIONS: Our retrospective comparison supported an agreement between Plasma BamHI-W and CE-marked assays in measuring EBV-DNA for non-endemic NPC patients. There were no significant interferences from different measurement units (IU/ml vs copies/ml). Further evaluations are needed to better clarify the role of WB.

Outpatient palliative care referral system (PCRS) for patients with advanced cancer: an impact evaluation protocol.

INTRODUCTION: Early palliative care (PC) in the clinical pathway of advanced cancer patients improves symptom control, quality of life and has a positive impact on overall quality of care. At present, standardised criteria for appropriate referral for early PC in oncology care are lacking. The aim of this project is to develop a set of standardised referral criteria and procedures to implement appropriate early PC for advanced cancer patients (the palliative care referral system, PCRS) and test its impact on user perception of quality of care received, on patient quality of life and on the use of healthcare resources. SETTING: Selected oncology clinics and PC outpatient clinic. METHODS AND ANALYSIS: A scoping literature review and an expert consultation through a nominal group technique will be used to revise existing referral tools and to develop a new one, the PCRS. 25 patients will be enrolled in a pilot study to assess feasibility of the implementation of PCRS; 10 interviews with patients and healthcare professionals will be carried out to evaluate applicability.A pretest-post-test quasiexperimental study involving 150 patients before implementation of the PCRS and 150 patients after implementation will be carried out.Patient satisfaction with care received, quality of life and use of resources, and caregiver satisfaction with care will also be assessed to explore the impact of the intervention. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the Institutional Review board of the Fondazione IRCCS Istituto Nazionale Tumori; approval reference INT201/19.Results will be disseminated through open access publications and through scientific communication presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04936568.

Bleeding complications in patients with squamous cell carcinoma of the head and neck.

Hemorrhage in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) may be attributed to chemotherapy and local tumor irradiation. Evidence of the relationship between hemorrhage in R/M HNSCC and targeted therapies, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors, or immune checkpoint inhibitors, is limited. We aimed to identify epidemiological and clinical data related to the occurrence of hemorrhage in R/M HNSCC and to explore its relationship with various therapies. We describe information obtained from literature searches as well as data extracted from a commercial database and a database from the author's institution (Istituto Nazionale dei Tumori of Milan). Evidence suggests that most bleeding events in R/M HNSCC are minor. Clinical trial safety data do not identify a causal association between hemorrhage and anti-EGFR agents or immune checkpoint inhibitors. In contrast, anti-VEGF agents are associated with increased, and often severe/fatal, hemorrhagic complications.

Immunotherapy in head and neck squamous cell carcinoma and rare head and neck malignancies.

The dismal prognosis of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) prompted recent advances in the field of therapeutic approaches beyond cytotoxic cancer therapy. In recent years, the deeper and increasing knowledge on the genomic landscape and the upcoming new data on immunotherapy enacted by HNSCCs have led to successful therapeutic targeting of the immune system. Immune checkpoint inhibitors (ICIs) have changed state of the art in R/M patients and could have a potential role even in early disease. The purpose of this work is to summarize the role of immunotherapy for R/M HNSCC in clinical practice, with insights about future perspectives. Updated immunotherapy results in other R/M head and neck cancers such as thyroid, salivary glands, nasopharynx, sinonasal cancers, and nuclear protein in testis (NUT) are presented.

Local therapies for liver metastases of rare head and neck cancers: a monoinstitutional case series.

INTRODUCTION: Transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) are established procedures for treating hepatocellular cancer and selected malignancies with liver metastasis. The aim of this study is to describe a monoinstitutional case series of local approaches in patients with liver metastases from rare head and neck cancers (HNCs). METHODS: This is a retrospective series of adult patients with HNC treated with liver locoregional approaches (TACE or RFA) at our institution from 2007 to 2018. In case of chemoembolization, the preferred chemotherapeutic drug was doxorubicin. Response according to RECIST (Response Evaluation Criteria in Solid Tumors) was assessed with contrast-enhanced computed tomography scans. RESULTS: Thirty-four patients were treated (20 men, median age 58 years) with TACE (27), transarterial embolization (2), or RFA (7). Primary tumours were salivary gland (21), thyroid (6), nasopharyngeal (5), and sinonasal cancers (2). Seventeen patients (50%) had a single metastatic liver nodule; 70% of the remaining 17 patients had at least three liver metastases. The median diameter of the metastatic liver mass undergoing treatment was 39 mm (range 11-100 mm). Median follow-up was 27.6 months. Response rate was 35% (3% complete, 32% partial response). Median progression-free survival and overall survival were 6.9 and 19.6 months, respectively. Treatment-related adverse events occurred in 59% of patients (21% grade ⩾ 3; no grade 5). DISCUSSION: This retrospective case series demonstrates that locoregional radiologic approaches for rare HNCs with liver metastases are feasible. These procedures deserve further prospective studies before being considered safe and active in these malignancies where the availability of effective systemic treatments is lacking.