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Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC).Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review.Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%–49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%–89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9–3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0–not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction.Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications. Clin Cancer Res; 22(1); 44–53. ©2015 AACR.

Purpose: To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses.Experimental Design: Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 × 108 and 1 × 1010 TCID50. In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 × 1010 TCID50. End points were safety, viral replication, immunogenicity, and antitumoral activity.Results: Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease.Conclusions: The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent. Clin Cancer Res; 16(11); 3067–77. ©2010 AACR.

Supplementary Data from Two-Stage Phase I Dose-Escalation Study of Intratumoral Reovirus Type 3 Dearing and Palliative Radiotherapy in Patients with Advanced Cancers

Tumor response

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Purpose: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers.Experimental Design: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 109, 1 × 1010, and 3 × 1010 TCID50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 1010 TCID50 dose characterized the response rate in patients with head and neck cancer.Results: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D.Conclusions: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment. Clin Cancer Res; 18(7); 2080–9. ©2012 AACR.

Highlights • The MR-Linac provides the tools to deliver online MR-guided Adaptive Radiotherapy • Adapt-to-Shape-Lite is a novel radiotherapy planning workflow on the Elekta Unity MR-Linac • Adapt-to-Shape-Lite generated plans that fulfilled 99.9% of mandatory dose constraints • Adapt-to-Shape-Lite workflow can generate plans in relatively short durations • Therefore, we prefer Adapt-To-Shape-Lite as the primary workflow to treat Head-and-Neck cancers, Introduction The Elekta Unity MR-Linac (MRL) has enabled adaptive radiotherapy (ART) for patients with head and neck cancers (HNC). Adapt-To-Shape-Lite (ATS-Lite) is a novel Adapt-to-Shape strategy that provides ART without requiring daily clinician presence to perform online target and organ at risk (OAR) delineation. In this study we compared the performance of our clinically-delivered ATS-Lite strategy against three Adapt-To-Position (ATP) variants: Adapt Segments (ATP-AS), Optimise Weights (ATP-OW), and Optimise Shapes (ATP-OS). Methods Two patients with HNC received radical-dose radiotherapy on the MRL. For each fraction, an ATS-Lite plan was generated online and delivered and additional plans were generated offline for each ATP variant. To assess the clinical acceptability of a plan for every fraction, twenty clinical goals for targets and OARs were assessed for all four plans. Results 53 fractions were analysed. ATS-Lite passed 99.9% of mandatory dose constraints. ATP-AS and ATP-OW each failed 7.6% of mandatory dose constraints. The Planning Target Volumes for 54 Gy (D95% and D98%) were the most frequently failing dose constraint targets for ATP. ATS-Lite median fraction times for Patient 1 and 2 were 40 mins 9 s (range 28 mins 16 s – 47 mins 20 s) and 32 mins 14 s (range 25 mins 33 s – 44 mins 27 s), respectively. Conclusions Our early data show that the novel ATS-Lite strategy produced plans that fulfilled 99.9% of clinical dose constraints in a time frame that is tolerable for patients and comparable to ATP workflows. Therefore, ATS-Lite, which bridges the gap between ATP and full ATS, will be further utilised and developed within our institute and it is a workflow that should be considered for treating patients with HNC on the MRL.

There has been a significant advance in our understanding of the molecular biology of medullary thyroid cancer (MTC) alongside progress in the development of targeted therapies including multikinase and specific rearranged during transfection inhibitors.This review will examine the latest data investigating the impact of the genomics of MTC on the prediction of the natural history of an individual's disease and the determination, selection and timing of treatment interventions.Recent advances in genotyping in MTC and the development of targeted therapies have impacted on the clinical management of both sporadic and hereditary MTC.

At present, no European recommendations for the management of pediatric thyroid nodules and differentiated thyroid carcinoma (DTC) exist. Differences in clinical, molecular, and pathological characteristics between pediatric and adult DTC emphasize the need for specific recommendations for the pediatric population. An expert panel was instituted by the executive committee of the European Thyroid Association including an international community of experts from a variety of disciplines including pediatric and adult endocrinology, pathology, endocrine surgery, nuclear medicine, clinical genetics, and oncology. The 2015 American Thyroid Association Pediatric Guideline was used as framework for the present guideline. Areas of discordance were identified, and clinical questions were formulated. The expert panel members discussed the evidence and formulated recommendations based on the latest evidence and expert opinion. Children with a thyroid nodule or DTC require expert care in an experienced center. The present guideline provides guidance for healthcare professionals to make well-considered decisions together with patients and parents regarding diagnosis, treatment, and follow-up of pediatric thyroid nodules and DTC.

This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of Paediatric patients with differentiated thyroid carcinoma.

Background: Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Since the guidelines for the management of ATC by the American Thyroid Association were first published in 2012, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, and researchers on published evidence relating to the diagnosis and management of ATC. Methods: The specific clinical questions and topics addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of the Task Force members (authors of the guideline). Relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. Results: The guidelines include the diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, targeted/systemic therapy, supportive care during active therapy), approaches to advanced/metastatic disease, palliative care options, surveillance and long-term monitoring, and ethical issues, including end of life. The guidelines include 31 recommendations and 16 good practice statements. Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of ATC. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with ATC.

BACKGROUND: Medullary thyroid cancer (MTC) is a neuroendocrine tumour and a rare variant of thyroid cancer with different aetiology, presentation and treatment to differentiated thyroid cancer. Currently available thyroid cancer-specific quality of life (QoL) tools focus on issues and treatments more relevant to patients with differentiated thyroid cancer and therefore may not address issues specific to a MTC diagnosis and cancer journey. METHOD: This prospective multicentre randomised study involved 204 MTC patients completing four quality of life questionnaires (QOLQ) and stating their most and least preferred. The questionnaires were a general instrument, the EORTC QLQ-C30, two disease-specific tools, the MD Anderson Symptom Inventory (MDASI) thyroid module and the City of Hope Quality of Life Scale/THYROID (amended) and the neuroendocrine questionnaire, EORTC QLQ-GINET21. Patients were randomised to complete the four questionnaires in one of 24 possible orders and then answered questions about which tool they preferred. The primary outcome measure was patients' preferred QoL instrument for describing their concerns and for facilitating communication with their healthcare professional. Secondary analyses looked at differences between preferred QOLQs amongst patient subgroups (WHO performance status [0 and 1+], disease stage: early [T1–3, N0 or N1A], metastatic [T4, any T N1b] and advanced [any T any N M1], and type of MTC [sporadic and inherited]), identification of MTC patients' least preferred questionnaire and clinicians' views on the QoL tools in terms of their ability to highlight problems not otherwise ascertained by a standard clinical review. RESULTS: No evidence of a difference was observed for most preferred QOLQ (p = 0.650). There was however evidence of a difference in least preferred questionnaire in the cohort of 128 patients who stated their least preferred questionnaire (p = 0.042), with 36% (46/128) of patients choosing the EORTC QLQ-GI.NET21 questionnaire. Subgroup analyses showed that there was no evidence of a difference in patients' most preferred questionnaire in sporadic MTC patients (p = 0.637), patients with WHO PS 0 or 1+ (p = 0.844 and p = 0.423) nor when comparing patients with early, advanced local or metastatic disease (p = 0.132, p = 0.463 and p = 0.506, respectively). Similarly, subgroup analyses on patients' least preferred questionnaires showed no evidence of differences in sporadic MTC patients (p = 0.092), patients with WHO PS 0 or 1+ (p = 0.423 and p = 0.276), nor in early or metastatic disease patients (p = 0.682 and p = 0.345, respectively). There was however some evidence to suggest a difference in least preferred questionnaire in patients with advanced local stage disease (p = 0.059), with 43% (16/37) of these patients choosing the EORTC QLQ-GI.NET21 questionnaire. CONCLUSIONS: MTC patients regardless of their performance status, disease aetiology and disease burden did not express a preference for any one particular questionnaire suggesting any of the tools studied could be utilized in this patient cohort. The least preferred questionnaire being a gastrointestinal NET specific tool suggests that diarrhoea was not a significant symptom and concern for the population studied.

Early-stage squamous cell cancer (SCC) of the glottis has a good prognosis. Therefore, patients have long survival outcomes and may potentially suffer from late toxicities of radiotherapy. Radiotherapy with a conventional parallel-opposed-pair or anterior-oblique beam arrangements for stage 1 and 2 glottic SCC have field borders that traditionally cover the entire larynx, exposing organs-at-risk (e.g. carotid arteries, contralateral vocal cord, contralateral arytenoid and inferior pharyngeal constrictor muscles) to high radiation doses. The potential long-term risk of cerebrovascular events has attracted much attention to the dose that carotid arteries receive. Swallow and respiratory motion of laryngeal structures has been an important factor that previously limited reduction of the radiation treatment volume. Motion has been evaluated using multiple imaging modalities and this information has been used to calculate PTV margins for generation of more limited target volumes. This review discusses the current literature surrounding dose-effect relationships for various organs-at-risk and the late toxicities that are associated with them. This article also reviews the currently available data and effects of laryngeal motions on dosimetry to the primary target. We also review the current limitations and benefits of a more targeted approach of radiotherapy for early-stage glottic SCCs and the evolution of CT-based IGRT and MR-guided radiotherapy techniques that may facilitate a shift away from a conventional 3D-conformal radiotherapy approach.

BackgroundPrevious studies have suggested that inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH) and fibrinogen) are prognostic biomarkers in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors (ICIs). We aimed to develop a model that predicts response and survival in patients with relapsed and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy.MethodsAnalysis of 100 consecutive patients with unresectable R/M HNSCC who were treated with ICI. Baseline and on-treatment (day 28) NLR, fibrinogen and LDH were calculated and correlated with response, progression-free survival (PFS) and overall survival (OS) using univariate and multivariate analyses. The optimal cut-off values were derived using maximally selected log-rank statistics.ResultsLow baseline NLR and fibrinogen levels were associated with response. There was a statistically significant correlation between on-treatment NLR and fibrinogen and best overall response. On-treatment high NLR and raised fibrinogen were significantly associated with poorer outcome. In multivariate analysis, on-treatment NLR (≥4) and on-treatment fibrinogen (≥4 ng/mL) showed a significant negative correlation with OS and PFS. Using these cut-off points, we generated an on-treatment score for OS and PFS (0–2 points). The derived scoring system shows appropriate discrimination and suitability for OS (HR 2.4, 95% CI 1.7 to 3.4, pConclusionsNLR and fibrinogen levels are simple, inexpensive and readily available biomarkers that could be incorporated into an on-treatment scoring system and used to help predict survival and response to ICI in patients with R/M HNSCC.

PURPOSE Anaplastic thyroid cancer (ATC), an aggressive malignancy, is associated with a poor prognosis and an unmet need for effective treatment, especially for patients without BRAF mutations or NTRK or RET fusions. Lenvatinib is US Food and Drug Administration–approved for radioiodine-refractory differentiated thyroid cancer and has previously demonstrated activity in a small study of patients with ATC (n = 17). We aimed to further evaluate lenvatinib in ATC. METHODS This open-label, multicenter, international, phase II study enrolled patients with ATC, who had ≥ 1 measurable target lesion, to receive lenvatinib 24 mg once daily. The primary end points were objective response rate (ORR) by investigator assessment per RECIST v1.1 and safety. Responses were confirmed ≥ 4 weeks after the initial response. Additional end points included progression-free survival and overall survival (OS). RESULTS The study was halted for futility as the minimum ORR threshold of 15% was not met upon interim analysis. The interim analysis set included the first 20 patients. The full analysis set includes all 34 enrolled and treated patients. In the full analysis set, one patient achieved a partial response (ORR, 2.9%; 95% CI, 0.1 to 15.3). More than half of the evaluable patients experienced tumor shrinkage; three patients experienced a > 30% tumor reduction. The median progression-free survival was 2.6 months (95% CI, 1.4 to 2.8); the median overall survival was 3.2 months (95% CI, 2.8 to 8.2). The most common treatment-related adverse events (AEs) were hypertension (56%), decreased appetite (29%), fatigue (29%), and stomatitis (29%). No major treatment-related bleeding events or grade 5 treatment-related AEs occurred. CONCLUSION The safety profile of lenvatinib in ATC was manageable, and many AEs were attributable to the progression of ATC. The results suggest that lenvatinib monotherapy may not be an effective treatment for ATC; further investigation may be warranted.

Simple Summary Nivolumab is an anti-PD-1 monoclonal antibody that has been approved in the management of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of progression within 6 months of platinum-based chemotherapy. Most of the evidence regarding the use of nivolumab in this setting is provided within clinical trials with strict inclusion criteria. This multicenter retrospective cohort study evaluates the real-world outcomes of nivolumab use in four major cancer centers in England. This study demonstrates similar progression free survival and overall survival as that seen in the CHECKMATE-141 study. In addition, it demonstrates that nivolumab tends to be well tolerated, with only a 15% rate of immune-related toxicity. Our findings support the findings of other real-world studies that demonstrate improved progression free survival and potentially overall survival for those who have immune-related toxicity. Abstract Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed. Overall, 123 patients were included. The median age was 64 years, the majority of patients were male (80.5%) and had a smoking history (69.9%). Primary outcomes included overall response rate (ORR) of 19.3%, median progression-free survival (PFS) of 3.9 months, 1-year PFS rate of 16.8%, a median overall survival (OS) of 6.5 months and 1-year OS rate of 28.6%. These results are comparable to the CHECKMATE-141 study. Of 27 patients who had PD-L1 status tested, positive PD-L1 status did not significantly affect PFS (p = 0.86) or OS (p = 0.84). Nivolumab was well tolerated with only 15.1% experiencing immune-related toxicities (IRT) and only 6.7% of patients stopping due to toxicity. The occurrence of IRT appeared to significantly affect PFS (p = 0.01) but not OS (p = 0.07). Nivolumab in recurrent/metastatic HNSCC is well tolerated and may be more efficacious in patients who develop IRT.

Background An intact sense of taste provides pleasure, supports sustenance and alerts the body to toxins. Head and neck cancer (HNC) patients who receive radiotherapy (RT) are high-risk for developing radiation-induced taste dysfunction. Advances in RT offer opportunities for taste-preserving strategies by reducing dose to the gustatory organs-at-risk. Methods PubMed, Medline and EMBASE were searched for publications reporting on taste, RT and HNC. Randomised trials, cohort studies and cross-sectional studies were included. Results 31 studies were included in this review. Meta-analysed prevalence of acute taste dysfunction following RT was approximately 96% (95% CI 64 to 100%) by objective measures and 79% (95% CI 65 to 88%) by subjective measures, with the majority of patients showing at least partial recovery. Long-term dysfunction was seen in ~25% of patients. Taste dysfunction was associated with sequalae including weight loss and reduced quality-of-life (QoL). Taste dysfunction was more common when the oral cavity, and specifically the anterior two-thirds of the tongue, was irradiated, suggesting a dose constraint for taste preservation might be feasible. Proton beam therapy and customised bite blocks reduced dose to the gustatory field and subsequent loss of taste. Conclusions Taste dysfunction following RT is common and negatively affects patients’ nutritional status and QoL. Decisions about treatment strategies, including choice of RT modality, dose distribution across the gustatory field and the use of adjuncts like bite blocks may be beneficial. However, evidence is limited. There is a pressing need for randomised studies or large prospective cohort studies with sufficient adjustment for confounders.

BackgroundThe aggressive clinical behavior of poorly differentiated and anaplastic thyroid cancers (PDTC and ATC) has proven challenging to treat, and survival beyond a few months from diagnosis is rare. Although 30%–60% of these tumors contain mutations in the BRAF gene, inhibitors designed specifically to target oncogenic BRAF have shown limited and only short-lasting therapeutic benefits as single agents, thus highlighting the need for improved treatment strategies, including novel combinations.MethodsUsing a BRAFV600E-driven mouse model of ATC, we investigated the therapeutic efficacy of the combination of BRAF inhibition and oncolytic herpes simplex virus (oHSV). Analyses of samples from tumor-bearing mice were performed to immunologically characterize the effects of different treatments. These immune data were used to inform the incorporation of immune checkpoint inhibitors into triple combination therapies.ResultsWe characterized the immune landscape in vivo following BRAF inhibitor treatment and detected only modest immune changes. We, therefore, hypothesized that the addition of oncolytic virotherapy to BRAF inhibition in thyroid cancer would create a more favorable tumor immune microenvironment, boost the inflammatory status of tumors and improve BRAF inhibitor therapy. First, we showed that thyroid cancer cells were susceptible to infection with oHSV and that this process was associated with activation of the immune tumor microenvironment in vivo. Next, we showed improved therapeutic responses when combining oHSV and BRAF inhibition in vivo, although no synergistic effects were seen in vitro, further confirming that the dominant effect of oHSV in this context was likely immune-mediated. Importantly, both gene and protein expression data revealed an increase in activation of T cells and natural killer (NK) cells in the tumor in combination-treated samples. The benefit of combination oHSV and BRAF inhibitor therapy was abrogated when T cells or NK cells were depleted in vivo. In addition, we showed upregulation of PD-L1 and CTLA-4 following combined treatment and demonstrated that blockade of the PD-1/PD-L1 axis or CTLA-4 further improved combination therapy.ConclusionsThe combination of oHSV and BRAF inhibition significantly improved survival in a mouse model of ATC by enhancing immune-mediated antitumor effects, and triple combination therapies, including either PD-1 or CTLA-4 blockade, further improved therapy.

Objective: This study investigates the impact of a restricted craniocaudal (CC) field length of Methods: 110 HNC patients who underwent radical primary or adjuvant radiotherapy were retrospectively analysed. We assessed the proportion of treatment fields with a CC length of Results: 95% of HNC patients had a CC field length Conclusion: The majority of patients with HNC at the Royal Marsden Hospital have anthropometric features compatible with their being treated on the MR-Linac using a single isocentre technique. The absolute CC field size may vary according to primary tumour site, patient factors and neck position. A hyo-sternal neck length cut-off of 14.6 cm in the neutral neck position can be used as a surrogate marker for suitability of treatment on MR-Linac. Advances in knowledge: This paper highlights the potential impact of a restricted CC field in HNC patient selection for the MR-Linac treatment. This is the first report to suggest the use of neck length as a surrogate marker for suitability of treatment on the MR-Linac.

Background Pre-clinical evidence suggests reduced efficacy of anticancer treatment in patients exposed to broad-spectrum antibiotics. It is hypothesised that this phenomenon may be explained by the effects of antibiotics on the composition of the microbiota. To assess this in a clinical setting, we analysed the impact of antibiotics in patients with locally advanced head and neck cancer (LAHNC) treated with curative intent with chemotherapy and radiotherapy (RT). Material and methods Retrospective data for LAHNC patients treated with curative intent (245 induction chemotherapy followed by chemoradiation [CRT], 17 surgery followed by post-operative CRT, six CRT, three RT alone and one RT with concurrent cetuximab) were analysed. We evaluated the impact of antibiotics prescribed during primary anti-cancer treatment on progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS) rates by multivariate Kaplan–Meier and Cox proportional hazards regression analysis. Results Among 272 patients, those receiving antibiotics between within 1 week before and 2 weeks after treatment (N = 124) progressed significantly earlier and had lower OS and DSS rates. In the multivariate analysis, administration of antibiotics was independently associated with reduced PFS (hazards ratio [HR] 1.98, P = 0.001), OS (HR 1.85, P = 0.001) and DSS (HR 1.95, P = 0.004). This effect was maintained with independence of reason for prescription, type and time of antibiotic prescription. The negative impact was greater for patients who received two or more courses of antibiotics. Antibiotic treatment was correlated with increased risk of locoregional relapse. Conclusions Our data suggest a negative impact of antibiotic therapy on treatment outcomes following CRT with curative intent in patients with LAHNC. This potential harm should be considered when prescribing broad-spectrum and prophylactic antibiotics for such patients.

Lenvatinib has been approved for the treatment of advanced differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) following the results of the SELECT trial which demonstrated a significant increase in progression-free survival and a high response rates. The data reported for lenvatinib in RAI-refractory DTC (RAI-R DTC) are the most significant to date in this patient population, with a RECIST objective response rate above 60% and almost 80% reduction in the risk of disease progression. Because the first indication in oncology for lenvatinib is specifically in RAI-R DTC, a period of familiarisation with its safety and efficacy profile is required. This review includes a series of specific recommendations for optimising the management of RAI-R DTC with lenvatinib, as well as specific guidelines for minimising the incidence and severity of adverse events (AEs), which enable dose intensity to be increased and this way maximise the benefits of the drug in the patient population treated. These recommendations were defined at a meeting of experts of different specialities, reviewing available scientific evidence on the drug, as well as their own direct personal experience in daily clinical practice. For toxicity to be properly managed, a multidisciplinary approach is required in which the different medical services, nursing staff and the patient and their careers are all involved. It is essential to assess the suitability of patients who are candidates for lenvatinib, as well as their clinical and physiological status prior to treatment. They must then be closely monitored to prevent and detect possible AEs. The main objective should be to maintain the dose that obtains the maximum therapeutic effect, discontinuing the treatment only if the toxicity becomes unmanageable or there is no clinical benefit.

BACKGROUND: Hypertension (HTN) is an established class effect of vascular endothelial growth factor receptor (VEGFR) inhibition. In the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, HTN was the most frequent adverse event of lenvatinib, an inhibitor of VEGFR1, VEGFR2, VEGFR3, fibroblast growth factor receptor 1 (FGFR1), FGFR2, FGFR3, FGFR4, platelet-derived growth factor receptor (PDGFR), ret proto-oncogene (RET), and stem cell factor receptor (KIT). This exploratory analysis examined treatment-emergent hypertension (TE-HTN) and its relation with lenvatinib efficacy and safety in SELECT. METHODS: In the multicenter, double-blind SELECT trial, 392 patients with progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC) were randomized 2:1 to lenvatinib (24 mg/d on a 28-day cycle) or placebo. Survival endpoints were assessed with Kaplan-Meier estimates and log-rank tests. The influence of TE-HTN on progression-free survival (PFS) and overall survival (OS) was analyzed with univariate and multivariate Cox proportional hazards models. RESULTS: Overall, 73% of lenvatinib-treated patients and 15% of placebo-treated patients experienced TE-HTN. The median PFS for lenvatinib-treated patients with (n = 190) and without TE-HTN (n = 71) was 18.8 and 12.9 months, respectively (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.39-0.88; P = .0085). For lenvatinib-treated patients, the objective response rate was 69% with TE-HTN and 56% without TE-HTN (odds ratio, 1.72; 95% CI, 0.98-3.01). The median change in tumor size for patients with and without TE-HTN was -45% and -40%, respectively (P = .2). The median OS was not reached for patients with TE-HTN; for those without TE-HTN, it was 21.7 months (HR, 0.43; 95% CI, 0.27-0.69; P = .0003). CONCLUSIONS: Although HTN is a clinically significant adverse event that warrants monitoring and management, TE-HTN was significantly correlated with improved outcomes in patients with RR-DTC, indicating that HTN may be predictive for lenvatinib efficacy in this population. (C) 2018 American Cancer Society.

Highlights • Machine learning-based NTCP modelling of acute dysphagia was performed. • The models generated performed well on internal and external validation. • Doses of approximately 1 Gy/fraction were most strongly associated with severe dysphagia. • No spatial variation in radiosensitivity was observed for the pharyngeal mucosa. • These results could inform clinical decision-support and radiotherapy planning., Severe acute dysphagia commonly results from head and neck radiotherapy (RT). A model enabling prediction of severity of acute dysphagia for individual patients could guide clinical decision-making. Statistical associations between RT dose distributions and dysphagia could inform RT planning protocols aiming to reduce the incidence of severe dysphagia. We aimed to establish such a model and associations incorporating spatial dose metrics. Models of severe acute dysphagia were developed using pharyngeal mucosa (PM) RT dose (dose-volume and spatial dose metrics) and clinical data. Penalized logistic regression (PLR), support vector classification and random forest classification (RFC) models were generated and internally (173 patients) and externally (90 patients) validated. These were compared using area under the receiver operating characteristic curve (AUC) to assess performance. Associations between treatment features and dysphagia were explored using RFC models. The PLR model using dose-volume metrics (PLRstandard) performed as well as the more complex models and had very good discrimination (AUC = 0.82) on external validation. The features with the highest RFC importance values were the volume, length and circumference of PM receiving 1 Gy/fraction and higher. The volumes of PM receiving 1 Gy/fraction or higher should be minimized to reduce the incidence of severe acute dysphagia.

Purpose In the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). This prespecified subanalysis investigated the effect of age on the efficacy and safety of lenvatinib. Patients and Methods This randomized, double-blind, phase III study enrolled patients with histologically confirmed RR-DTC stratified by age (≤ 65 or > 65 years). Patients (N = 392) received lenvatinib 24 mg/day (n = 261) or placebo (n = 131). The primary end point was PFS; secondary end points included overall survival (OS), objective response rate, and safety. Results In both treatment arms, median ages were 56 (younger group) and 71 years (older group). PFS benefit was maintained with lenvatinib versus placebo in the younger and older age groups, with median PFS of 20.2 versus 3.2 months (hazard ratio [HR], 0.19; 95% CI, 0.13 to 0.27; P < .001) and 16.7 versus 3.7 months (HR, 0.27; 95% CI, 0.17 to 0.43; P < .001), respectively. PFS did not differ with age in either treatment arm. OS was improved in older lenvatinib-treated patients versus placebo (HR, 0.53; 95% CI, 0.31 to 0.91; P = .020). Younger lenvatinib-treated patients showed significantly higher ORR (72% v 55%; P = .0038), longer time to first dose reduction (3.7 v 1.5 months), and lower proportion of grade ≥ 3 treatment-related adverse events (67% v 89%; P < .001) compared with older patients. Conclusion This subanalysis demonstrated improved PFS with lenvatinib treatment versus placebo in both age groups, although higher toxicity was observed in older patients. Despite the allowance of crossover after disease progression, the OS benefit was observed in older patients, suggesting that lenvatinib should be considered for treatment of patients of any age with RR-DTC.

Background: Patients with head and neck squamous cell carcinoma (HNSCC) undergoing radical chemo-radiation (CRT) frequently receive transfusion with packed red cells (PRCT) during radiotherapy on the basis that PRCT increases tumour oxygenation and overcomes hypoxia-induced radio-resistance. This is likely to be a significant oversimplification given the fact that tumour hypoxia is the result of several intrinsic and extrinsic factors, including many that are not directly related to serum haemoglobin (Hb). Therefore, we have studied the effect of PRCT on tumour oxygenation in a prospective cohort of patients who developed low Hb during radical CRT for HNSCC. Methods: This was a prospective study of 20 patients with HNSCC receiving radical CRT undergoing PRCT for Hb

Purpose Current normal tissue complication probability modeling using logistic regression suffers from bias and high uncertainty in the presence of highly correlated radiation therapy (RT) dose data. This hinders robust estimates of dose-response associations and, hence, optimal normal tissue–sparing strategies from being elucidated. Using functional data analysis (FDA) to reduce the dimensionality of the dose data could overcome this limitation. Methods and Materials FDA was applied to modeling of severe acute mucositis and dysphagia resulting from head and neck RT. Functional partial least squares regression (FPLS) and functional principal component analysis were used for dimensionality reduction of the dose-volume histogram data. The reduced dose data were input into functional logistic regression models (functional partial least squares–logistic regression [FPLS-LR] and functional principal component–logistic regression [FPC-LR]) along with clinical data. This approach was compared with penalized logistic regression (PLR) in terms of predictive performance and the significance of treatment covariate–response associations, assessed using bootstrapping. Results The area under the receiver operating characteristic curve for the PLR, FPC-LR, and FPLS-LR models was 0.65, 0.69, and 0.67, respectively, for mucositis (internal validation) and 0.81, 0.83, and 0.83, respectively, for dysphagia (external validation). The calibration slopes/intercepts for the PLR, FPC-LR, and FPLS-LR models were 1.6/−0.67, 0.45/0.47, and 0.40/0.49, respectively, for mucositis (internal validation) and 2.5/−0.96, 0.79/−0.04, and 0.79/0.00, respectively, for dysphagia (external validation). The bootstrapped odds ratios indicated significant associations between RT dose and severe toxicity in the mucositis and dysphagia FDA models. Cisplatin was significantly associated with severe dysphagia in the FDA models. None of the covariates was significantly associated with severe toxicity in the PLR models. Dose levels greater than approximately 1.0 Gy/fraction were most strongly associated with severe acute mucositis and dysphagia in the FDA models. Conclusions FPLS and functional principal component analysis marginally improved predictive performance compared with PLR and provided robust dose-response associations. FDA is recommended for use in normal tissue complication probability modeling.