Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN).

Background: To investigate the activity and safety of afatinib in the preoperative treatment of squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: This study was an open-label, randomized, multicenter, phase II window of opportunity trial. Treatment-naïve SCCHN patients selected for primary curative surgery were randomized (5 : 1 ratio) to receive afatinib during 14 days (day -15 until day -1) before surgery (day 0) or no treatment. Tumor biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and magnetic resonance imaging (MRI) were carried out at diagnosis and just before surgery. The primary end point was metabolic FDG-PET response (according to EORTC guidelines). Other end points included response assessment based on the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, dynamic contrast-enhanced (DCE)-MRI, diffusion weighted (DW)-MRI, safety, and translational research (TR). Results: Thirty patients were randomized: 25 to afatinib and 5 to control arm. Of the 23 eligible patients randomized to afatinib, 16 (70%; 95% CI: 47% to 87%) patients had a partial metabolic FDG-PET response (PMR). Five patients (22%; 95% CI: 8% to 44%) showed a partial response by RECISTv1.1. Responses assessed via DCE-MRI and DWI-MRI did not show a strong association with PMR or RECIST. One patient discontinued afatinib after 11 days for grade 3 diarrhea with subsequent renal failure and 24 days delay in surgery. No grade 4 toxicities or surgical comorbidities related to afatinib were reported. TR results indicated that PMR was more frequent in the tumors with high Cluster3-hypoxia score expression and with TP53 wild type. Conclusion: Afatinib given for 2 weeks to newly diagnosed SCCHN patients induces a high rate of FDG-PET partial metabolic response and partial response according to RECISTv1.1. Afatinib can be safely administered before surgery. Although exploratory, the hypoxic gene signature needs further investigations as a predictive biomarker of afatinib activity. Clinical trial registration: ClinicalTrials.gov: NCT01538381.

Incidence of medication-related osteonecrosis of the jaw in patients treated with both bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs. PATIENTS AND METHODS: We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence. RESULTS: Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0-18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1-29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033). CONCLUSION: With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone.

Safety and efficacy of adjunctive therapy in the treatment of odontogenic keratocyst: a systematic review.

The odontogenic keratocyst (OKC) is a common cystic lesion in the jaw. Its management, however, is highly debated with no consensus on the best treatment option. Clinicians base their approach on treatment efficacy and associated morbidity. Management often consists of enucleation with peripheral ostectomy and adjunctive therapy to prevent recurrence. The aim of our systematic review was to evaluate the safety and efficacy of these different modalities. Embase, Medline, and Cochrane were searched according to the PRISMA guidelines for articles that presented non-syndromic patients with histopathologically confirmed OKC treated with 5-fluorouracil (5FU), Carnoy's solution (CS), or modified Carnoy's solution (MCS) as adjunctive therapy after enucleation and peripheral ostectomy. The outcomes of interest were safety (measured as adverse events) and efficacy (expressed as recurrence). Risk of bias was evaluated using the Newcastle-Ottawa scale. Four studies were included and 62 patients were evaluated. The results show that recurrence occurred only in patients treated with MCS. Reported adverse events were mostly limited to paraesthesia that could be permanent (in the CS and MCS treatment groups) or transient (across all adjunctive therapies). With the prohibition of CS, both MCS and 5FU are promising replacement adjunctive therapies. From a safety and efficacy perspective we consider 5FU, which was associated with the lowest recurrence and fewest adverse events, to be the most viable option. More high-evidence prospective studies, such as randomised controlled trials, with a longer follow-up period are necessary to draw definite conclusions.

Medication-related osteonecrosis of the jaw in oncological patients with skeletal metastases: conservative treatment is effective up to stage 2.

There is currently no widespread strategy for treating medication-related osteonecrosis of the jaw (MRONJ), so our aim was to evaluate retrospectively the outcome of a minimally invasive treatment protocol for patients with both MRONJ and cancer. We designed a retrospective cohort study of patients with cancer who had been diagnosed with MRONJ after treatment with denosumab or bisphosphonates given intravenously. Primary outcome measures were improvement in the clinical stage of MRONJ and the time course to its resolution. Secondary outcome measures included the incidence of risk factors and patterns of treatment. Seventy-nine patients with 109 lesions were enrolled, and their characteristics, presentation of the lesions, complications, and relations to previous oral interventions were recorded. Treatment depended on the stage of disease, and included conservative medical, and minimally-invasive surgical, procedures. There was complete healing and resolution of disease in 38/57 stage 1 lesions, 30/47 stage 2 lesions, and 3/5 stage 3 lesions. The symptoms improved in 16/47 stage 2 lesions, and 2/5 stage 3 lesions. Fifteen of the stage 1 lesions, and one of the stage 2 lesions, failed to respond. Despite the possibility of an aggressive approach to the treatment of MRONJ, conservative treatment remains the first line of defence as regression is obvious, with evidence of no evolution to a higher stage. In our experience surgical intervention is recommended in persistent stage 3 MRONJ that has failed to respond to conservative treatment.

Osteoradionecrosis and medication-related osteonecrosis of the jaw: similarities and differences.

The purpose of this study was to compare medication-related osteonecrosis of the jaw (MRONJ) with osteoradionecrosis (ORN). Group 1 comprised 74 MRONJ patients (93 lesions) and group 2 comprised 59 ORN patients (69 lesions). Patient characteristics, clinical presentation of the lesions, the presence of complications, and the relationship with previous dental extractions were analyzed for both groups. Significant differences were found between the groups with regard to the characteristics of the patient populations, extraction as the precipitating event, the type of initial complaint, the prevalence of pain, and the location of the lesions. In the ORN group, significantly more patients complained of pain (P=0.0108) compared with the MRONJ group. Furthermore, significantly more pathological fractures (P<0.0001) and skin fistulae (P<0.0001) occurred in the ORN group. The treatment was more often conservative in the MRONJ group than in the ORN group (61.3% vs. 36.2%). Despite similarities in terms of imaging, risk factors, prevention, and treatment, MRONJ and ORN are two distinct pathological entities, as highlighted by the differences in patient characteristics, the initial clinical presentation, course of the disease, and outcome.