Long-term results from a clinical study of xevinapant plus chemoradiotherapy in people with high-risk locally advanced squamous cell carcinoma of the head and neck: a plain language summary.

Squamous cell carcinoma of the head and neck (SCCHN) is the most common type of head and neck cancer. About half of the people with locally advanced (LA) SCCHN will have surgery to remove their cancer. For people who do not have surgery, chemoradiotherapy is the standard treatment, with the aim of fully removing the cancer. However, in many people, this treatment does not completely kill the cancer. This summary presents the main results of a phase 2 study of a medicine called xevinapant, which is under investigation as a potential future medicine for people with this type of cancer. In this study, researchers wanted to find out whether xevinapant plus chemoradiotherapy could stop the cancer from growing back or getting worse in the years after treatment completion in people with LA SCCHN. They also looked at whether people with this type of cancer had side effects from taking this medicine. Short-term results were collected 18 months after treatment with chemoradiotherapy ended. These results showed that people who received xevinapant plus chemoradiotherapy were less likely to have their cancer grow back, or get worse in the part of the body where it was first found, than people who received liquid placebo-which looked and tasted the same as the active medicine (in this case, xevinapant), but did not contain any medicine-plus chemoradiotherapy. Researchers then continued to collect information for a longer amount of time (at least 3 years). They wanted to see if treatment with xevinapant plus chemoradiotherapy was stopping the cancer from growing back or getting worse and helping people live longer. After this, people were monitored for a further 2 years to see if they were alive 5 years after treatment. The results showed that people with this type of cancer who were treated with xevinapant plus chemoradiotherapy were less likely to die, lived longer on average, and were less likely to have their cancer get worse. A phase 3 study, named TrilynX, in a larger group of people, is currently taking place to confirm the results of this study. Clinical Trial Registration: NCT02022098 (Debio 1143-201 Dose-finding and Efficacy Phase I/II Trial) (ClinicalTrials.gov)

Current trends in initial management of hypopharyngeal cancer: The declining use of open surgery

Squamous cell carcinoma of the hypopharynx represents a distinct clinical entity. Most patients present with significant comorbidities and advanced‐stage disease. The overall survival is relatively poor because of high rates of regional and distant metastasis at presentation or early in the course of the disease. A multidisciplinary approach is crucial in the overall management of these patients to achieve the best results and maintain or improve functional results. Traditionally, operable hypopharyngeal cancer has been treated by total (occasionally partial) laryngectomy and partial or circumferential pharyngectomy, followed by reconstruction and postoperative radiotherapy in most cases. Efforts to preserve speech and swallowing function in the surgical treatment of hypopharyngeal (and laryngeal) cancer have resulted in a declining use of total laryngopharyngectomy and improved reconstructive efforts, including microvascular free tissue transfer. There are many surgical, as well as nonsurgical, options available for organ and function preservation, which report equally effective tumor control and survival. The selection of appropriate treatment is of crucial importance in the achievement of optimal results for these patients. In this article, several aspects of surgical and nonsurgical approaches in the treatment of hypopharyngeal cancer are discussed. Future studies must be carefully designed within clearly defined populations and use uniform terminology and standardized functional assessment and declare appropriate patient or disease endpoints. These studies should focus on improvement of resultsx, without increasing patient morbidity. In this respect, technical improvements in radiotherapy such as intensity‐modulated radiotherapy, advances in supportive care, and incorporation of newer systemic agents such as targeted therapy, are relevant developments. © 2010 Wiley Periodicals, Inc. Head Neck, 2012Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90087/1/21613_ftp.pd

A Rare Case of Radiation-Induced Osteosarcoma of the Ethmoid Sinus

Radiation therapy has been recognized as a useful modality of treatment in head and neck malignant tumors. However, radiation over 10 Gy may predispose to secondary tumors. Radiation-induced osteosarcoma of the ethmoid sinus is unusual. These tumors may present long after radiation with epistaxis. Computed tomography, magnetic resonance imaging, and biopsy are the modalities of diagnosis. We report a case of radiation-induced osteosarcoma of the ethmoid sinus 9 years after initial exposure. We describe the clinical presentation, the radiological findings, and the management

A GORTEC survey on low-risk CTV-P2 delineation in head and neck cancers.

An international consensus was established in 2018 to standardise practice using geometric (5 + 5 mm) expansion around GTV-P for definitive radiotherapy of squamous cell carcinomas of the head and neck (HNC). The GORTEC (French HNC Oncology and Radiotherapy Group) conducted a survey to assess the level of agreement about CTV-P2 delineation using a "formalised consensus method". The 32 proposals of the 2018 consensus on CTV-P2 and 6 additional GORTEC proposals were submitted to 13 GORTEC radiation oncologists (RO). Proposals were rated as "suitable" for median scores ≥7, "unsuitable" for scores ≤3.5 or "uncertain." The degree of agreement was high (≥85 %), moderate (75-84 %) or low (<75 %). Suitable proposals were reviewed by 40 other RO for final recommendations. The 2018 proposals were "uncertain" with low degrees of agreement (41.5-69 %), except for T1 tumors, which had 89 % agreement. Five out of 6 GORTEC proposals were "suitable" and one "uncertain." The final recommendation was "suitable and to be retained" by 97.5 % of RO, as follows: To obtain CTV-P2, GORTEC recommends applying a "geo-anatomical" approach. Using the geometric concept, 10 mm-isotropic margins are applied to the GTV, for all locations but the hypopharynx (10 mm antero-posterior, laterally and 15 mm craniocaudally). CTV-P2 is further modified using the anatomical concept (anatomical barriers, dissemination routes) and accounting the benefit/risk balance and proximity of organs at risk. The GORTEC survey derived from the 2018 international CTV-Ps delineation consensus suggests a "geo-anatomical" approach for the delineation of CTV-P2 in HNC

Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412):a randomised, double-blind, phase 3 trial

Background: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC.Methods: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting.Findings: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1–52·3). Median event-free survival was not reached (95% CI 44·7 months–not reached) in the pembrolizumab group and 46·6 months (27·5–not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68–1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis).Interpretation: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches.Funding: Merck Sharp &amp; Dohme, a subsidiary of Merck &amp; Co, Rahway, NJ, USA.</p

ACR Appropriateness Criteria® Locoregional therapy for resectable oropharyngeal squamous cell carcinomas

BackgroundThere are no level I studies to guide treatment for resectable oropharyngeal squamous cell carcinoma (SCC). Treatment toxicities influence management recommendations. Ongoing investigations are examining deintensified treatments for human papillomavirus (HPV)‐associated oropharyngeal SCC.MethodsThe Appropriateness Criteria panel, using modified Delphi methodology, produced a literature summary, an assessment of treatment recommendations, and cases to illustrate their use.ResultsA multidisciplinary team produces optimum results. Based on HPV status, smoking history, and staging, patients are divided into groups at low, intermediate, and high‐risk of death. In the future, treatment recommendations may be influenced by HPV status, which has changed the epidemiology of oropharyngeal SCC.ConclusionT1 to T2N0M0 resectable oropharyngeal SCC can be treated with surgery or radiation without chemotherapy. Patients with T1‐2N1‐2aM0 disease can receive radiation, chemoradiation, or transoral surgery with neck dissection and appropriate adjuvant therapy. Patients with T1‐2N2b‐3M0 disease should receive chemoradiation or transoral surgery with neck dissection and appropriate adjuvant therapy. Concurrent chemoradiation is preferred for T3 to T4 disease. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1299–1309, 2016Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/133590/1/hed24447.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133590/2/hed24447_am.pd

Evidence‐based review of treatment options for patients with glottic cancer

Evidence‐based medicine integrates the best available data in decision making, with the goal of minimizing physicians' and patients' subjectivity. In 2006, the American Society of Clinical Oncology edited clinical practice guidelines for the use of larynx preservation strategies. The objective of this review was to evaluate the current levels of evidence for glottic squamous cell carcinoma. Current guidelines for early stage glottic cancer are based on low‐level evidence. Conservation surgery (open or transoral) and radiation therapy are all valid options for T1 and selected T2 lesions. For advanced lesions, surgery and combined chemotherapy and radiation are options. High‐level evidence favors combined chemotherapy and radiation therapy or altered fractionation radiation therapy as nonsurgical strategies for organ preservation, compared with radiation therapy alone. The optimal combination of chemotherapy, targeted therapy, and radiation therapy remains to be demonstrated, however, and for high‐volume tumors, total laryngectomy may still be warranted. © 2011 Wiley Periodicals, Inc. Head Neck, 2011Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87151/1/21528_ftp.pd

Environmental and Molecular Drivers of the α-Gal Syndrome

The α-Gal syndrome (AGS) is a type of allergy characterized by an IgE antibody (Ab) response against the carbohydrate Galα1-3Galβ1-4GlcNAc-R (α-Gal), which is present in glycoproteins from tick saliva and tissues of non-catarrhine mammals. Recurrent tick bites induce high levels of anti-α-Gal IgE Abs that mediate delayed hypersensitivity to consumed red meat products in humans. This was the first evidence that tick glycoproteins play a major role in allergy development with the potential to cause fatal delayed anaphylaxis to α-Gal-containing foods and drugs and immediate anaphylaxis to tick bites. Initially, it was thought that the origin of tick-derived α-Gal was either residual blood meal mammalian glycoproteins containing α-Gal or tick gut bacteria producing this glycan. However, recently tick galactosyltransferases were shown to be involved in α-Gal synthesis with a role in tick and tick-borne pathogen life cycles. The tick-borne pathogen Anaplasma phagocytophilum increases the level of tick α-Gal, which potentially increases the risk of developing AGS after a bite by a pathogen-infected tick. Two mechanisms might explain the production of anti-α-Gal IgE Abs after tick bites. The first mechanism proposes that the α-Gal antigen on tick salivary proteins is presented to antigen-presenting cells and B-lymphocytes in the context of Th2 cell-mediated immunity induced by tick saliva. The second mechanism is based on the possibility that tick salivary prostaglandin E2 triggers Immunoglobulin class switching to anti-α-Gal IgE-producing B cells from preexisting mature B cells clones producing anti-α-Gal IgM and/or IgG. Importantly, blood group antigens influence the capacity of the immune system to produce anti-α-Gal Abs which in turn impacts individual susceptibility to AGS. The presence of blood type B reduces the capacity of the immune system to produce anti-α-Gal Abs, presumably due to tolerance to α-Gal, which is very similar in structure to blood group B antigen. Therefore, individuals with blood group B and reduced levels of anti-α-Gal Abs have lower risk to develop AGS. Specific immunity to tick α-Gal is linked to host immunity to tick bites. Basophil activation and release of histamine have been implicated in IgE-mediated acquired protective immunity to tick infestations and chronic itch. Basophil reactivity was also found to be higher in patients with AGS when compared to asymptomatic α-Gal sensitized individuals. In addition, host resistance to tick infestation is associated with resistance to tick-borne pathogen infection. Anti-α-Gal IgM and IgG Abs protect humans against vector-borne pathogens and blood group B individuals seem to be more susceptible to vector-borne diseases. The link between blood groups and anti-α-Gal immunity which in turn affects resistance to vector-borne pathogens and susceptibility to AGS, suggests a trade-off between susceptibility to AGS and protection to some infectious diseases. The understanding of the environmental and molecular drivers of the immune mechanisms involved in AGS is essential to developing tools for the diagnosis, control, and prevention of this growing health problem