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Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma.

ABSTRACT: In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in sphingolipid metabolism and signaling pathways, mediates antiproliferative responses, and its level increases in response to radiotherapy and chemotherapy. However, when ceramide is metabolized, prosurvival factors, such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glucosylceramide, are produced, reducing the antitumor effects of ceramide. The activities of ceramide- and sphingosine-metabolizing enzymes are also associated with radio- and chemo-resistance. Ceramide analogs and low molecular-weight compounds targeting these enzymes exert anticancer effects. Synthetic ceramides and a therapeutic approach using ultrasound have also been developed. Inhibitors of ceramide- and sphingosine-metabolizing enzymes and synthetic ceramides can function as sensitizers of radiotherapy and chemotherapy for HNSCC.

SUBMITTER: Yura Y

PROVIDER: S-EPMC7463798 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma.

Yura Yoshiaki Y Masui Atsushi A Hamada Masakazu M

Cancers 20200726 8

In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in sphingolipid metabolism and signaling pathways, mediates antiproliferative responses, and its level increases in response to radiotherapy and chemotherapy. However, when ceramide is metabolized, ...[more]

PMID: 32722626

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Project description:BackgroundFormer meta-analyses have shown a survival benefit for the addition of chemotherapy (CHX) to radiotherapy (RT) and to some extent also for the use of hyperfractionated radiation therapy (HFRT) and accelerated radiation therapy (AFRT) in locally advanced squamous cell carcinoma (SCC) of the head and neck. However, the publication of new studies and the fact that many older studies that were included in these former meta-analyses used obsolete radiation doses, CHX schedules or study designs prompted us to carry out a new analysis using strict inclusion criteria.MethodsRandomised trials testing curatively intended RT (> or =60 Gy in >4 weeks/>50 Gy in <4 weeks) on SCC of the oral cavity, oropharynx, hypopharynx, and larynx published as full paper or in abstract form between 1975 and 2003 were eligible. Trials comparing RT alone with concurrent or alternating chemoradiation (5-fluorouracil (5-FU), cisplatin, carboplatin, mitomycin C) were analyzed according to the employed radiation schedule and the used CHX regimen. Studies comparing conventionally fractionated radiotherapy (CFRT) with either HFRT or AFRT without CHX were separately examined. End point of the meta-analysis was overall survival.ResultsThirty-two trials with a total of 10 225 patients were included into the meta-analysis. An overall survival benefit of 12.0 months was observed for the addition of simultaneous CHX to either CFRT or HFRT/AFRT (p < 0.001). Separate analyses by cytostatic drug indicate a prolongation of survival of 24.0 months, 16.8 months, 6.7 months, and 4.0 months, respectively, for the simultaneous administration of 5-FU, cisplatin-based, carboplatin-based, and mitomycin C-based CHX to RT (each p < 0.01). Whereas no significant gain in overall survival was observed for AFRT in comparison to CFRT, a substantial prolongation of median survival (14.2 months, p < 0.001) was seen for HFRT compared to CFRT (both without CHX).ConclusionRT combined with simultaneous 5-FU, cisplatin, carboplatin, and mitomycin C as single drug or combinations of 5-FU with one of the other drugs results in a large survival advantage irrespective the employed radiation schedule. If radiation therapy is used as single modality, hyperfractionation leads to a significant improvement of overall survival. Accelerated radiation therapy alone, especially when given as split course radiation schedule or extremely accelerated treatments with decreased total dose, does not increase overall survival.

Project description:BackgroundOral cavity (OC), oropharyngeal (OP), hypopharyngeal (HP), and laryngeal (LA) squamous cell carcinoma (SCC) have a high incidence of regional lymph node metastasis (LNM). Elective irradiation for clinically node-negative neck is routinely administered to treat lymph nodes harboring occult metastasis. However, the optimal elective irradiation schemes are still inconclusive. In this study, we aimed to establish individualized elective irradiation schemes for the ipsilateral and contralateral node-negative neck of these four types of cancer.MethodsFrom July 2005 to December 2018, 793 patients with OC-SCC, 464 with OP-SCC, 413 with HP-SCC, and 645 with LA-SCC were recruited retrospectively. Based on the actual incidence of LNM and the tumor characteristics, risk factors for contralateral LNM, as well as node level coverage schemes for elective irradiation, were determined using logistic regression analysis. Additionally, we developed a publicly available online tool to facilitate the widespread clinical use of these schemes.ResultsFor the ipsilateral node-negative neck, elective irradiation at levels I-III for OC-SCC and levels II-IVa for OP-, HP- and LA-SCC are generally recommended. In addition, level VIIa should be included in patients with OP-SCC. Multivariate analyses revealed that posterior hypopharyngeal wall and post-cricoid region involvement were independently associated with level VIIa metastasis in HP-SCC (all P < 0.05). For the contralateral node-negative neck, multivariate analyses revealed that ipsilateral N2b2-N3, tumors with body midline involvement, and degree of tumor invasion were the independent factors for contralateral LNM (all P < 0.05). In patients who require contralateral neck irradiation, levels I-II are recommended for OC-SCC, and additional level III is recommended for patients with ipsilateral N3 disease. Levels II-III are recommended for OP-, HP-, and LA-SCC, and additional level IVa is recommended for patients with advanced T or ipsilateral N classifications. Furthermore, additional level VIIa is recommended only for OP-SCC with T4 and ipsilateral N3 disease.ConclusionBased on our findings, we suggest that individualized and computer-aided elective irradiation schemes could reduce irradiation volumes in OC-, OP- and HP-SCC patients, as compared to current guidelines, and could thus positively impact the patients' quality of life after radiotherapy.

Project description:Importance:Accurate, accessible predictions of posttreatment hearing loss for patients with head and neck cancer prior to the initiation of treatment are a necessary part of informed patient decision-making. Objective:To develop a prediction model for postradiotherapy and/or post-cisplatin chemotherapy hearing loss for patients with head and neck cancer. Design, Setting, and Participants:A retrospective cohort study was conducted at a tertiary academic medical center among 242 patients (482 ears) with head and neck cancer who were treated with radiotherapy and/or cisplatin from October 1, 2014, to July 31, 2018, and had follow-up audiometric data available. Exposures:Radiotherapy and cisplatin chemotherapy. Main Outcomes and Measures:Patient hearing level, as measured by the mean of pure tone audiometry at 1, 2, and 4 kHz on completion of treatment. A multivariable mixed model for predicting the posttreatment pure tone average was developed using only information available to clinicians at the beginning of treatment. Results:A total of 242 patients (482 ears; 56 women and 186 men; mean [SD] age, 60 [10] years) were included in the analysis. All patients in the study received radiotherapy, and 105 (43.4%) received cisplatin chemotherapy. The mean (SD) total cumulative cisplatin dose was 298 (109) mg/m2. Patients' ears received a mean (SD) cochlear radiotherapy dose of 15 (13) Gy. The fixed-effects predictions from the predictive model agreed with 77% (95% CI, 73%-81%) of the variability in the posttreatment pure tone average. This predictive model also had a sensitivity of 80% and a specificity of 75% for predicting an observed posttreatment pure tone average greater than 35 dB (area under the receiver operating characteristic curve, 0.85). Conclusions and Relevance:To our knowledge, this study develops the first accurate prediction model of posttreatment hearing in patients with head and neck cancer that is feasible for use in the clinical setting before the initiation of treatment. This research confirms that exposure of the cochlea to cisplatin chemotherapy and radiotherapy is associated with hearing loss in patients with head and neck cancer. Finally, this research motivates future studies of ototoxic effects to better understand the adverse effects of head and neck cancer treatment.

Dataset Information

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma.

Publications

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma.

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