Efficacy and safety of adapalene gel as a reactive treatment for cetuximab-induced skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck: A historical cohort comparison study.

INTRODUCTION: Despite the common occurrence of cetuximab (Cmab)-induced skin toxicity, management strategies are not well established. The traditional mainstay method consists of topical steroids, which, if used excessively, may give rise to other concerns. Alternatively, adapalene can activate epidermal growth factor receptor pathways to potentially alleviate these toxicities. METHODS: We prospectively studied 31 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) who were eligible to use adapalene gel as a reactive treatment for topical steroid-refractory skin toxicity. For comparison, we retrospectively reviewed 99 patients with R/M SCCHN (historical control cohort) whose skin toxicity was mainly treated with topical steroids. We compared the frequency and severity of Cmab-induced skin toxicity, Cmab therapy status (e.g., dose modification), side effects caused by topical steroids and adapalene gel itself, and other medical interventions. RESULTS: Adapalene gel was used by eight patients (25.8%) in the prospective cohort. Patients in the historical control cohort more frequently required escalation of topical steroid potency (34.3% vs. 12.9%, p = 0.022). Although there was no statistically significant difference in the frequency of grade ≥3 facial skin rash and paronychia between the two cohorts, the prospective cohort showed a significantly shorter time to complete recovery from grade 2/3 paronychia (16 vs. 47 days, p = 0.017). Further, while no skin infections were observed in the prospective cohort, 13 patients in the historical control cohort developed skin infections, especially periungual infection (0% vs. 13.1%, p = 0.024). In addition, no patients in the prospective cohort received a dose reduction of Cmab due to skin toxicities, compared to 20 patients in the historical control cohort (0% vs. 20.2%, p = 0.003). No apparent adapalene gel-related side effects were observed. CONCLUSIONS: Adapalene gel may be an effective management option for topical steroid-refractory Cmab-induced skin toxicities and could improve compliance with Cmab therapy.

Preoperative steroid for enhancing patients' recovery after head and neck cancer surgery with free tissue transfer reconstruction: protocol for a phase III, placebo-controlled, randomised, double-blind study (J-SUPPORT 2022, PreSte-HN Study).

INTRODUCTION: There is no established methodology for the perioperative management of head and neck cancer surgery and free tissue transfer reconstruction (HNS-FTR). A single dose of corticosteroid administered immediately before surgery has been shown to reduce postoperative pain and nausea/vomiting after some types of surgery. However, the efficacy of this strategy has not been demonstrated in HNS-FTR, and the increased risk of infectious complications associated with its use cannot be ruled out. This phase III, placebo-controlled, randomised, double-blind, comparative, multicentre study seeks to determine if preoperative administration of corticosteroid hormone has an adjunctive effect in terms of reducing pain and nausea/vomiting after surgery and improving the quality of postoperative recovery. METHODS AND ANALYSIS: Using the minimisation method, patients undergoing HNS-FTR are currently being recruited and randomly assigned to a study arm at a 1:1 allocation rate. The study treatment arm consists of 8.0 mg of dexamethasone phosphate dissolved in 100 mL of saline administered as a single dose by intravenous infusion. These treatments will be administered in a double-blind fashion. All patients will receive perioperative care according to the common multicentre enhanced recovery after surgery programme. The primary endpoint is the quality of postoperative recovery, as determined by the area under the curve (AUC) for total score on the Japanese version of the Quality of Recovery Score (QOR-40J) on postoperative days 2 and 4. The point estimate and CI for the difference in the AUC between the groups on postoperative days 2 and 4 will be calculated. ETHICS AND DISSEMINATION: The study will be performed in accordance with the Declaration of Helsinki and Japan's Clinical Trials Act. The study protocol was approved by the Certified Review Board of National Cancer Center Hospital East (Reference K2021004). TRIAL REGISTRATION NUMBER: The study was registered in the Japan Registry of Clinical Trials (jRCTs031210593; V.3.0, November 2021, available at https://jrct.niph.go.jp/en-latest-detail/jRCTs031210593).

Protocol for a confirmatory trial of the effectiveness and safety of palliative arterial embolization for painful bone metastases.

BACKGROUND: Transcatheter arterial embolization (TAE) has long been used for hemostasis of traumatic or postoperative hemorrhage and embolization of tumors. Previous retrospective studies of TAE for painful bone metastases showed 60%-80% pain reduction with a median time to response of 1-2 days. Compared with radiotherapy and bisphosphonates, time to response appeared earlier than that of radiotherapy or bone-modifying agents. However, few prospective studies have examined TAE for this indication. Here, we describe the protocol for a confirmatory study designed to clarify the efficacy and safety profile of TAE. METHODS: This study will be a multicenter, single-arm confirmatory study (phase 2-3 design). Patients with painful bone metastases from any primary tumor are eligible for enrollment. TAE will be the main intervention. Following puncture of the femoral artery under local anesthesia and insertion of an angiographic sheath, angiography will confirm that the injected region includes tumor vasculature. Catheter position will be adjusted so that the embolization range does not include non-target tissues. Spherical embolic material will then be slowly injected into the artery to embolize it. The primary endpoint (efficacy) is the proportion of subjects with pain relief at 72 h after TAE and the secondary endpoint (safety) is the incidence of all NCI Common Terminology Criteria for Adverse Events version 5.0 Grade 4 adverse events and Grade ≥ 3 necrosis of the central nervous system. DISCUSSION: If the primary and secondary endpoints are met, TAE can be a treatment choice for painful bone metastases. Trial registry number is UMIN-CTR ID: UMIN000040794. TRIAL REGISTRATION: The study is ongoing, and patients are currently being enrolled. Enrollment started in March 2021. A total of 36 patients have participated as of Aug 2022. PROTOCOL VERSION: Ver1.4, 13/07/2022.

Topical steroid versus placebo for the prevention of radiation dermatitis in head and neck cancer patients receiving chemoradiotherapy: the study protocol of J-SUPPORT 1602 (TOPICS study), a randomized double-blinded phase 3 trial.

BACKGROUND: To date, the clinical benefit of topical steroid use has only been demonstrated for radiation dermatitis induced by 50-60 Gy irradiation in breast cancer. However, these agents are also often used clinically for the control of radiation dermatitis induced by high-dose (>60Gy) irradiation with chemotherapy in head and neck cancer. Despite this, the prophylactic efficacy of topical steroids for radiation dermatitis induced by high-dose irradiation is still unclear. The aim of this study is to clarify the benefit of topical steroids in basic nursing care for radiation dermatitis induced by chemoradiotherapy in patients with head and neck cancer. METHODS: The study is being conducted as a multicenter 2-arm randomized double-blinded placebo-controlled Phase 3 trial in Japan. The study was started in May 2017, with participant enrollment between May 2017 and April 2019. Patients scheduled to receive definitive or postoperative chemoradiotherapy for head and neck cancer are eligible for enrollment. All patients will receive chemoradiotherapy, consisting of single agent CDDP and 70-Gy irradiation. Bilateral neck irradiation is mandatory. Supportive care for radiation dermatitis will consist of basic nursing care with topical steroid or placebo. When radiation dermatitis grade 1 is seen or total radiation dose reaches 30 Gy, minimally required intervention will be started as a first step. If radiation dermatitis worsens to grade 2, the irradiated area will be covered with a moderately absorbent surgical pad and steroid or placebo topical cream. The primary endpoint is a comparison of the proportion of patients with ≥ grade 2 radiation dermatitis by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Ethical approval has been obtained from all participating sites. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. DISCUSSION: Evidence supporting the benefit of adding topical steroids in general nursing care for radiation dermatitis induced by high-dose irradiation with chemotherapy is insufficient. This trial aims to clarify the clinical benefit of topical steroid for radiation dermatitis induced by high-dose irradiation with chemotherapy. The trial is ongoing and is currently recruiting. TRIAL REGISTRATION NUMBER: UMIN000027161 . Protocol version 3.0, 18 April 2017.

Predictive Value of Cetuximab-Induced Skin Toxicity in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and NECK.

Background: Skin toxicity is a common adverse event during cetuximab (Cmab) treatment. However, few reports have investigated the correlation between skin toxicity and the efficacy of Cmab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Methods: We retrospectively reviewed 112 R/M SCCHN patients who received palliative chemotherapy with Cmab. Main eligibility criteria included primary disease in the oral cavity, hypopharynx, nasopharynx, oropharynx, or larynx; no prior history of EGFR-directed therapy; receipt of Cmab plus chemotherapy as first-line therapy for recurrent or metastatic disease; and follow-up for more than 90 days. We analyzed the time to first occurrence and time of maximum grade skin toxicity, and its predictive value with regard to treatment efficacy. Results: After a median follow-up of 393 days (range 109-1501 days), 105 (94%) and 20 (18%) patients had skin toxicity of any grade and grade 3, respectively. Among them, 8 patients with grade 3 acneiform rash, skin rash, or paronychia within 90 days after treatment initiation ("early skin toxicity") had improved progression-free survival (PFS) (log-rank test, P = 0.045; 2-year PFS, 25.0 vs. 2.9%) and overall survival (OS) (log-rank test, P = 0.023, 2-year OS, 50.0 vs. 14.4%) compared with those with < grade 3 toxicity. A greater proportion of patients with early skin toxicity than patients without this toxicity could proceed with Cmab maintenance (88 vs. 44%, P = 0.021). Multivariate analysis identified early skin toxicity as an independent predictor of better PFS (hazard ratio [HR] = 0.363, 95% confidence interval [CI] 0.142-0.924, P = 0.034) and OS (HR = 0.187, 95% CI: 0.045-0.781, P = 0.022). Conclusion: Grade 3 Cmab-induced skin toxicity within 90 days was associated with better survival in R/M SCCHN. Effective rash management therefore seems necessary to realize the benefit of Cmab treatment.

Validation of a Liquid Chromatography-Tandem Mass Spectrometric Assay for Quantitative Analysis of Lenvatinib in Human Plasma.

Toward conducting clinical pharmacokinetic studies of an antineoplastic agent, lenvatinib, we developed a liquid chromatography-tandem mass spectrometric assay for its quantitative analysis in human plasma. Analyte (lenvatinib) and internal standard (IS, propranolol) in the plasma were extracted by using acetonitrile and chromatographically separated by using a XTerra MS C18 column with 0.2 mL/min flow and mobile phase starting with 0.1% formic acid in water, followed by increasing percentage of acetonitrile. Detection was performed by using combined reversed-phase liquid chromatography-tandem mass spectrometry (LC/MS-MS) with positive ion electrospray ionization. MS-MS ion transitions used were 427.602>371.000 for lenvatinib and 260.064>116.005 for IS. This study was validated for accuracy, precision, linearity, range, selectivity, lower limit of quantification, recovery, and matrix effect according to the Guideline on Bioanalytical Method Validation in Pharmaceutical Development in Japan. Calibration curve was plotted by using lenvatinib concentrations ranging within 9.6-200 ng/mL, and correlation coefficients (r2) were in excess of 0.997. Intra- and interday accuracy ranged within 95.8-108.3% with mean recoveries of 66.8% for lenvatinib, and precision was <6.7% at all quality control concentration levels. Matrix effect analysis showed extraction efficiency of 15.7% for lenvatinib. Collectively, these findings demonstrate the feasibility of this method to evaluate kinetic disposition of lenvatinib.