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A double-blind phase III trial of immunomodulating nutritional formula during adjuvant chemoradiotherapy in head and neck cancer patients: IMPATOX.
Boisselier, P, Kaminsky, MC, Thézenas, S, Gallocher, O, Lavau-Denes, S, Garcia-Ramirez, M, Alfonsi, M, Cupissol, D, de Forges, H, Janiszewski, C, et al
The American journal of clinical nutrition. 2020;(6):1523-1531
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Abstract
BACKGROUND In a previous phase II study an immunonutrient supplement was found to reduce severe acute toxicities for head and neck squamous cell cancer (HNSCC) patients treated with concomitant cisplatin and radiotherapy. OBJECTIVES The primary objective of the present study was to evaluate efficacy of the same immunonutrient supplement on severe mucositis. Secondary objectives included tolerance, compliance to oral supplementation, chemotherapy interruptions and delays, quality of life, and progression-free survival (PFS) and overall survival (OS) at 1, 2, and 3 y. METHODS Between November 2009 and June 2013, 180 HNSCC patients eligible for adjuvant chemotherapy after surgery with curative intent were included in our double-blind phase III multicenter trial. They were assigned to receive oral supplementation (3 sachets/d) of either a formula enriched with l-arginine and omega-3 (n-3) fatty and ribonucleic acids (experimental arm), or an isocaloric isonitrogenous control (control arm), for 5 d before each of 3 cycles of cisplatin. Intention-to-treat (ITT) and per-protocol (PP) analyses were undertaken, along with subgroup analyses of ≥75% compliant patients, to compare the incidence of acute mucositis (Radiation Therapy Oncology Group and WHO scales) and 36-mo survival. RESULTS At 1 mo after terminating chemoradiotherapy (CRT), no differences were observed in the incidence of grade 3-4 mucositis between treatment groups, in the ITT, PP (172 patients), and subgroup (≥75% compliance, n = 112) analyses. The immunomodulating supplement did not significantly improve survival in the ITT and PP analyses at 3 y after CRT. Among ≥75% compliant patients, however, OS at 3 y was significantly improved in the immunomodulating formula group (81%; 95% CI: 67%, 89%) compared with controls (61%; 95% CI: 46%, 73%; P = 0.034), as well as PFS (73%; 95% CI: 58%, 83% compared with 50%; 95% CI: 36%, 63%; P = 0.012). CONCLUSIONS Although this immunomodulating formula failed to reduce severe mucositis during CRT, the findings suggest that the long-term survival of compliant HNSCC patients was improved.This trial was registered at clinicaltrials.gov as NCT01149642.
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Rationale and design of a randomised controlled trial investigating the effect of multidisciplinary nutritional rehabilitation for patients treated for head and neck cancer (the NUTRI-HAB trial).
Kristensen, MB, Wessel, I, Beck, AM, Dieperink, KB, Mikkelsen, TB, Møller, JK, Zwisler, AD
Nutrition journal. 2020;(1):21
Abstract
BACKGROUND Eating problems frequently affect quality of life and physical, psychological and social function in patients treated for head and neck cancer (HNC). Residential rehabilitation programmes may ameliorate these adverse effects but are not indicated for all individuals. Systematic assessment of rehabilitation needs may optimise the use of resources while ensuring referral to rehabilitation for those in need. Yet, evidence lacks on which nutrition screening and assessment tools to use. The trial objectives are: 1) To test the effect of a multidisciplinary residential nutritional rehabilitation programme compared to standard care on the primary outcome body weight and secondary outcomes health-related quality of life, physical function and symptoms of anxiety and depression in patients curatively treated for HNC and 2) To test for correlations between participants' development in outcome scores during their participation in the programme and their baseline scores in Nutritional Risk Screening 2002 (NRS 2002), the Scored Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF), and M. D. Anderson Dysphagia Inventory (MDADI) and to assess sensitivity, specificity and predictive values of the three tools in relation to a clinically relevant improvement in outcome scores. METHODS In a randomised controlled trial, 72 patients treated for HNC recruited through a nationwide survey will be randomised to a multidisciplinary residential nutritional rehabilitation programme or to a wait-list control group. Data are collected at baseline, three and six months. Primary outcome is change in body weight, and secondary outcomes include changes in quality of life, physical function and symptoms of anxiety and depression. Potential correlations between intervention effect and baseline scores in NRS 2002, PG-SGA-SF and MDADI will be tested, and sensitivity, specificity and predictive values of the three tools in relation to a clinically relevant improvement in outcome scores will be assessed. DISCUSSION This is the first randomised controlled trial to test the effect of a multidisciplinary residential nutritional rehabilitation programme in patients treated for HNC. Recruitment through a nationwide survey gives a unique possibility to describe the trial population and to identify potential selection bias. As the trial will explore the potential of different nutrition screening and assessment tools in the assessment of rehabilitation needs in patients treated for HNC, the trial will create knowledge about how selection and prioritisation of nutritional rehabilitation aimed at patients treated for HNC should be offered. The results may contribute to a better organisation and use of existing resources in benefit of patients treated for HNC. TRIAL REGISTRATION The trial is registered by The Danish Data Protection Agency (registration 2012-58-0018, approval number 18/14847) and the Regional Committees on Health Research Ethics for Southern Denmark (journal number 20182000-165). ClinicalTrials.gov Identifier: NCT03909256. Registered April 9, 2019.
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Hypoxia dynamics on FMISO-PET in combination with PD-1/PD-L1 expression has an impact on the clinical outcome of patients with Head-and-neck Squamous Cell Carcinoma undergoing Chemoradiation.
Rühle, A, Grosu, AL, Wiedenmann, N, Mix, M, Stoian, R, Niedermann, G, Baltas, D, Werner, M, Weber, WA, Kayser, G, et al
Theranostics. 2020;(20):9395-9406
Abstract
Tumor-associated hypoxia influences the radiation response of head-and-neck cancer (HNSCC) patients, and a lack of early hypoxia resolution during treatment considerably deteriorates outcomes. As the detrimental effects of hypoxia are partly related to the induction of an immunosuppressive microenvironment, we investigated the interaction between tumor hypoxia dynamics and the PD-1/PD-L1 axis in HNSCC patients undergoing chemoradiation and its relevance for patient outcomes in a prospective trial. Methods: 49 patients treated with definitive chemoradiation for locally advanced HNSCC were enrolled in this trial and received longitudinal hypoxia PET imaging using fluorine-18 misonidazole ([18F]FMISO) at weeks 0, 2 and 5 during treatment. Pre-therapeutic tumor biopsies were immunohistochemically analyzed regarding the PD-1/PD-L1 expression both on immune cells and on tumor cells, and potential correlations between the PD-1/PD-L1 axis and tumor hypoxia dynamics during chemoradiation were assessed using Spearman's rank correlations. Hypoxia dynamics during treatment were quantified by subtracting the standardized uptake value (SUV) index at baseline from the SUV values at weeks 2 or 5, whereby SUV index was defined as ratio of maximum tumor [18F]FMISO SUV to mean SUV in the contralateral sternocleidomastoid muscle (i.e. tumor-to-muscle ratio). The impact of the PD-1/PD-L1 expression alone and in combination with persistent tumor hypoxia on locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) was examined using log-rank tests and Cox proportional hazards models. Results: Neither PD-L1 nor PD-1 expression levels on tumor-infiltrating immune cells influenced LRC (HR = 0.734; p = 0.480 for PD-L1, HR = 0.991; p = 0.989 for PD-1), PFS (HR = 0.813; p = 0.597 for PD-L1, HR = 0.796; p = 0.713 for PD-1) or OS (HR = 0.698; p = 0.405 for PD-L1, HR = 0.315; p = 0.265 for PD-1). However, patients with no hypoxia resolution between weeks 0 and 2 and PD-L1 expression on tumor cells, quantified by a tumor proportional score (TPS) of at least 1%, showed significantly worse LRC (HR = 3.374, p = 0.022) and a trend towards reduced PFS (HR = 2.752, p = 0.052). In the multivariate Cox regression analysis, the combination of absent tumor hypoxia resolution and high tumoral PD-L1 expression remained a significant prognosticator for impaired LRC (HR = 3.374, p = 0.022). On the other side, tumoral PD-L1 expression did not compromise the outcomes of patients whose tumor-associated hypoxia declined between week 0 and 2 during chemoradiation (LRC: HR = 1.186, p = 0.772, PFS: HR = 0.846, p = 0.766). Conclusion: In this exploratory analysis, we showed for the first time that patients with both persistent tumor-associated hypoxia during treatment and PD-L1 expression on tumor cells exhibited a worse outcome, while the tumor cells' PD-L1 expression did not influence the outcomes of patients with early tumor hypoxia resolution. While the results have to be validated in an independent cohort, these findings form a foundation to investigate the combination of hypoxic modification and immune checkpoint inhibitors for the unfavorable subgroup, moving forward towards personalized radiation oncology treatment.
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A randomized phase 2 study of temsirolimus and cetuximab versus temsirolimus alone in recurrent/metastatic, cetuximab-resistant head and neck cancer: The MAESTRO study.
Seiwert, TY, Kochanny, S, Wood, K, Worden, FP, Adkins, D, Wade, JL, Sleckman, BG, Anderson, D, Brisson, RJ, Karrison, T, et al
Cancer. 2020;(14):3237-3243
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Abstract
BACKGROUND Patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3-kinase signaling in preclinical models of EGFR resistance. METHODS In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC with documented progression on cetuximab (in any line in the recurrent/metastatic setting) received 25 mg of temsirolimus weekly plus cetuximab at 400/250 mg/m2 weekly (TC) or single-agent temsirolimus (T). The primary outcome was progression-free survival (PFS) in the TC arm versus the T arm. Response rates, overall survival, and toxicity were secondary outcomes. RESULTS Eighty patients were randomized to therapy with TC or T alone. There was no difference for the primary outcome of median PFS (TC arm, 3.5 months; T arm, 3.5 months). The response rate was 12.5% in the TC arm (5 responses, including 1 complete response [2.5%]) and 2.5% in the T arm (1 partial response; P = .10). Responses were clinically meaningful in the TC arm (range, 3.6-9.1 months) but not in the T-alone arm (1.9 months). Fatigue, electrolyte abnormalities, and leukopenia were the most common grade 3 or higher adverse events and occurred in less than 20% of patients in both arms. CONCLUSIONS The study did not meet its primary endpoint of improvement in PFS. However, TC induced responses in cetuximab-refractory patients with good tolerability. The post hoc observation of activity in patients with acquired resistance (after prior benefit from cetuximab monotherapy) may warrant further investigation.
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Topical Fluorides for Head and Neck Cancer Patients Subjected to Surgical Resection and Radiation Therapy in Resource Restraint Settings.
Sheikh, A, Khan, FR, Tabassum, S
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2020;(2):205-209
Abstract
Patients undergoing surgical resection and ionizing radiations for the treatment of head and cancer may lead a challenging life even after the cure of the disease; because these procedures can adversely affect the oral mucosa, salivary gland, bone, masticatory musculature, and the dentition. Especially, if major salivary glands are exposed to high dose radiation, an irreversible xerostomia may occur that can lead to rampant dental caries. Treatment of these complications demands high cost and time; and is often unaffordable for the patients in the resource constraint setting rendering them to compromise on their quality of life. The healthcare providers should work together in a team to prevent or manage these complications and improve the lives of the patients. This review paper focuses on the significance of low cost fluoride treatment for salvaging the dentition among patients who have had developed head and neck carcinoma and later got subjected to surgical resection and radiation therapy.
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Electrochemotherapy in the head and neck area: an addition to the treatment armamentarium.
de Bree, R, Wessel, I
Current opinion in otolaryngology & head and neck surgery. 2020;(2):112-117
Abstract
PURPOSE OF REVIEW Electrochemotherapy (ECT) is increasingly used in different settings in head and neck cancer patients when conventional treatment options are not available. RECENT FINDINGS Recent improvements of electroporation and ECT include new advanced electrode probes, the combination with intratumorally injected supraphysiological doses of calcium and an update of the standard operating procedures. SUMMARY ECT is a treatment modality that combines administration of a chemotherapeutic drug, for example, bleomycin, with electroporation therapy (EPT). EPT uses brief, high-intensity, pulsed electrical currents to enhance the uptake of cytotoxic drugs by producing a transient increase in cell wall permeability. ECT increases the effect of cytostatic drugs, is independent on histology of the lesion, enables treatment to previously treated areas, preserves healthy tissue, has no significant side effects (low-dose chemotherapy) and enables repeated treatments. ECT can be combined with other treatment modalities and is an addition to the current treatment options of head and neck cancer. ECT is not only able to palliate symptoms but can also provide complete responses and curation.
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The role of allied healthcare professionals in head and neck cancer surveillance: A systematic review.
Rocke, J, Mclaren, O, Hardman, J, Garas, G, Smith, ME, Ishii, H, Constable, J, Tikka, T, Wie Liu, Z, Williams, R, et al
Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery. 2020;(1):83-98
Abstract
OBJECTIVES The roles of Allied Health Care Professionals (AHPs) in Head and Neck Cancer (HNC) are wide ranging but not clearly defined. Inter-regional variability in practice results from a lack of standardisation in approaches to the Multidisciplinary Team (MDT) make-up and structure. Traditionally, the follow-up of HNC patients is clinician led with multiple scheduled follow-up appointments. The increasing population of HNC patients provides logistical, monetary and efficiency challenges. This systematic review presents the roles of the multiple AHP sub-groups in HNC with the aim of presenting how their differing skill sets can be integrated to modernise our approach in follow-up. DESIGN We searched MEDLINE, Embase, the Cochrane Library, NIHR Dissemination Centre, The Kings Fund Library, Clinical Evidence, National Health Service Evidence and the National Institute of Clinical Excellence to identify multiple subgroups of AHPs (Dentists, Speech and Language Therapists, Dieticians, Physiotherapists, Psychologists, Clinical Nurse Specialists) and evidence of their role in HNC follow-up. Evidence not directly relating to HNC follow-up was excluded. SETTING AND PARTICIPANTS This Systematic Review was undertaken online by the Integrate (UK ENT Trainee National Collaborative) Head and Neck Subcommittee. MAIN OUTCOME MEASURES Most evidence was of low-quality, and the broad nature of the protocol provided a wide variety of study models. Two authors screened the articles for relevance to the topic before final analysis. RESULTS The main role identified was improvement in Quality of Life and symptom control rather than detecting recurrence. We also demonstrate that it is possible to stratify HNC follow-up patients using their received treatment modality and Distress Thermometers to identify groups who will require more intensive AHP input. CONCLUSIONS HNC follow-up covers a broad group of patients with differing needs. As such, a blanket approach to this phase of treatment is likely to be less effective than a patient-led model where the group of AHPs are employed on a needs basis rather than at set time points. This will likely lead to greater patient satisfaction, earlier detection of recurrence and efficiency savings.
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The effects of zinc on radiation-induced dysgeusia: a systematic review and meta-analysis.
Chi, WJ, Myers, JN, Frank, SJ, Aponte-Wesson, RA, Otun, AO, Nogueras-González, GM, Li, Y, Geng, Y, Chambers, MS
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2020;(12):1-12
Abstract
PURPOSE Many head and neck cancer patients who receive radiation therapy experience radiation-induced dysgeusia (RID), which has no standard treatment. The only supplement controlled clinical trials have evaluated for the treatment of RID is zinc. However, the results of these and other studies investigating the use of zinc for RID have been inconsistent. To assess the validity of zinc as a treatment for RID, we conducted a systematic literature search and performed a meta-analysis to determine the extent to which zinc affects RID incidence and the degree to which ongoing RID responds to zinc. METHODS We searched the Ovid MEDLINE, Ovid Embase, PubMed, and Cochrane Library databases to identify studies investigating the use of zinc-based therapy for RID in head and neck cancer patients treated with radiation that were published between January 1, 2003, and November 9, 2017. Using American Society of Clinical Oncology criteria, we selected studies with a high level of evidence for inclusion in the meta-analysis. RESULTS Of the 32 full-text articles eligible for inclusion, three were included in the final review and meta-analysis. The meta-analysis showed that, compared with placebo, zinc reduces the incidence of RID (risk ratio, 0.72; 95% confidence interval, 0.67-0.92) but does not improve taste acuity more rapidly following radiation therapy (risk ratio, 2.58; 95% confidence interval, 0.97-6.88). CONCLUSION Our findings indicate that zinc-based therapy reduces the incidence of RID but has a minimal effect on ongoing RID. Our findings also highlight the need for additional evidence-based research on this topic.
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Evaluation of the Erythrocyte Membrane in Head and Neck Cancer Patients.
De Souza Gonçalves, B, Toledo, MM, Colodette, NM, Chaves, ALF, Muniz, LV, Ribeiro, RIMA, Dos Santos, HB, Cortes, VF, Soares, JMA, Barbosa, LA, et al
The Journal of membrane biology. 2020;(6):617-629
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous and complex disease, both from a clinical and molecular point of view. The prolonged use of alcohol and tobacco, along with the release of tumor secretions can modulate blood cells, such as erythrocytes. Here, this study was conducted with 24 patients diagnosed with HNSCC and an equal number of healthy individuals are matched by age and gender. The levels of lipid peroxidation were measured using the individual plasma, while for lipid concentrations, identification and quantification Na, K-ATPase activity and osmotic fragility, the red blood cell concentrate were used. The release of TBARS was significantly higher in patients with HNSCC. The lipid profile assays demonstrated a rearrangement of the erythrocyte membrane due to a decrease in total phospholipids and phosphatidylethanolamine followed by an increase in total cholesterol and phosphatidylcholine. Na, K-ATPase activity also increased. Erythrocytes were more fragile in patients with HNSCC than in health individuals. Therefore, the membrane of erythrocytes were rearranged and Na, K-ATPase function altered in the HNSCC patients. Our findings suggests that the alcohol, tobacco and tumor secretion modulate in a specific manner that the erythrocytes membranes of these patients making this system a potential tool for HNSCC biomarker of tumor progression.
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A randomized phase III trial for alleviating radiation-induced xerostomia with chewing gum.
Kaae, JK, Stenfeldt, L, Hyrup, B, Brink, C, Eriksen, JG
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2020;:72-78
Abstract
BACKGROUND AND PURPOSE Xerostomia is frequently reported after radiotherapy (RT) for head and neck cancer (HNC). The aim of this study was to reduce symptoms of radiation-induced xerostomia in HNC survivors, in which the experimental arm used chewing gum for a month. Primary endpoint was changes in scoring of dry mouth as defined by EORTC QLQ-H&N35 between arms. MATERIALS AND METHODS Participants with any grade of physician-assessed xerostomia, ≥ six month after RT, disease-free and able to chew gum were, for a month, randomized (2:1) to: (Arm A) daily chewing gum or (Arm B) standard care. Xerostomia-related QOL was assessed using EORTC QLQ-H&N35 and GRIX questionnaires along with measurement of salivary flow and viscosity at inclusion and after one month. The study was registered on ClinicalTrials.gov (NCT03302676). RESULTS Ninety-one participants were eligible for analysis (Arm A, n = 55; Arm B, n = 36). Comparing categorized scores for symptoms between arms, reduction of dry mouth was significantly higher for Arm A than Arm B (p = 0.05). A reduction in dry mouth scores was observed for xerostomia assessed by EORTC QLQ-H&N35 (question 41) for both arms. Salivary flow increased and viscosity decreased upon five minutes of stimulation within both arms (p < 0.001, respectively), however no significantly difference was observed between arms. CONCLUSION Categorized scores found reduction of dry mouth to be significantly higher in Arm A than Arm B, but no difference was seen for salivary flow rate and viscosity.