Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single-arm, Open-label Phase II Trial.

OBJECTIVE: To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma. SUMMARY BACKGROUND DATA: Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear. METHODS: In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection. RESULTS: Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7-57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery. CONCLUSIONS: This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.

Organ-preservation (chemo)radiotherapy for T4 laryngeal and hypopharyngeal cancer: is the effort worth?

PURPOSE: We aimed to analyze the oncological and functional outcomes of chemoradiation for T4 laryngeal and hypopharyngeal cancer. METHODS: Patients treated between 2008 and 2015 with chemoradiation (n = 39) were retrospectively analyzed for oncological and functional (laryngo-esophageal dysfunction-free survival, LED-FS) outcomes and compared with 32 consecutive patients treated primarily with total laryngectomy (TL). LED was scored as event in case of local failure, TL for any reason, persistent tracheotomy and/or feeding tube dependency 2 years after chemoradiation. RESULTS: The 5-year local control (LC) rates in the chemoradiation and TL groups were 64 and 87%, respectively (p = 0.030). The disease-free survival was 54 and 59% (p = 0.810), and overall survival (OS) was 46 and 47% (p = 1.00). In the chemoradiation group, the 5-year cumulative incidence of LED-FS was 46%, but was significantly worse in patients with poor pre-treatment laryngeal function, compared to those without (20% and 74%, respectively, p = 0.001). Furthermore, patients with LED have significantly worse OS compared to those without (32% and 65%, respectively, p = 0.041). Multivariate analysis showed that primary treatment type is significantly predictive for LC, while tumor site and extra-capsular extension were predictive for OS. Poor pre-treatment laryngeal function is the only significant predictive factor for LED. CONCLUSIONS: TL resulted in significantly better LC, as compared to chemoradiation in T4 laryngeal and hypopharyngeal cancer patients and the LED-FS is worse in patients with poor pre-treatment laryngeal function. These patients might benefit more from primary treatment with TL followed by radiotherapy. These issues should be taken into consideration, as patients are counseled about different primary treatment options.

Surgical consensus guidelines on sentinel node biopsy (SNB) in patients with oral cancer.

BACKGROUND: The eighth international symposium for sentinel node biopsy (SNB) in head and neck cancer was held in 2018. This consensus conference aimed to deliver current multidisciplinary guidelines. This document focuses on the surgical aspects of SNB for oral cancer. METHOD: Invited expert faculty selected topics requiring guidelines. Topics were reviewed and evidence evaluated where available. Data were presented at the consensus meeting, with live debate from panels comprising expert, nonexpert, and patient representatives followed by voting to assess the level of support for proposed recommendations. Evidence review, debate, and voting results were all considered in constructing these guidelines. RESULTS/CONCLUSION: A range of topics were considered, from patient selection to surgical technique and follow-up schedule. Consensus was not achieved in all areas, highlighting potential issues that would benefit from prospective studies. Nevertheless these guidelines represent an up-to-date pragmatic recommendation based on current evidence and expert opinion.

Local control in sinonasal malignant melanoma: Comparing conventional to hypofractionated radiotherapy.

BACKGROUND: The purpose of this study was to analyze the effect of fractionation schedule on local control in postoperative radiotherapy (RT) for sinonasal malignant melanoma. METHODS: Sixty-three patients who were treated with surgery and postoperative RT in 4 accredited head and neck cancer centers in the Netherlands between 1998 and 2013 were retrospectively studied. Outcomes with conventional fractionation (2-2.4 Gy per fraction; n = 27) were compared to hypofractionation (4-6 Gy per fraction; n = 36). The primary endpoint was local control and the secondary endpoint was toxicity. RESULTS: Comparable local control rates were found after 2 and 5 years (63% vs 64% and 47% vs 53%; P = .73 for, respectively, conventional fractionation vs hypofractionation). Local recurrences were predominantly present ipsilateral (92%) and within the irradiated volume (88%). Late toxicity grade ≥ 3 was observed in 2 of 63 patients, 1 patient in both groups. CONCLUSION: Radiotherapy fractionation schedule did not influence the local control rate or the incidence of late toxicity in patients treated with surgery and RT for sinonasal malignant melanoma in this retrospective analysis. Due to this retrospective nature and the limited number of patients, strong recommendations cannot be made. Expected toxicity, patient convenience, and workload may be taken into account for the choice of fractionation schedule until conclusive evidence becomes available.

Clinical relevance of quality of life outcome in cochlear implantation in postlingually deafened adults.

OBJECTIVES: To evaluate the benefits of cochlear implantation in postlingually deafened adults and estimate the clinical relevance of these benefits. STUDY DESIGN: Prospective intervention study. SETTING: Tertiary referral hospital. PATIENTS: Forty-four postlingually deafened adults. INTERVENTIONS: Cochlear implantation with a Clarion CII HiFocus 1 or HiRes 90K. MAIN OUTCOME MEASURES: The Health Utility Index Mark II (HUI2) and Nijmegen Cochlear Implant Questionnaire were administered to quantify health-related QoL (HRQoL); utilities were obtained from the HUI2 and time trade-off instrument. Speech perception scores were analyzed. Patient factors were correlated with postimplant HRQoL and speech perception scores. Clinical significant benefit was estimated using the minimal clinically significant difference (MID) and effect size (ES). RESULTS: The results show a significant improvement in HRQoL and speech perception (p < 0.001). The improvement in HRQoL is mainly obtained in the first months after implantation and is largest in the categories concerning physical functioning (hearing). A shorter duration of deafness (p = 0.003) and higher educational level (p = 0.015) were significant predictors of better speech perception. Cochlear implantation proved to be a cost-effective procedure. By using the MID and ES, we found important clinical improvements on 6 health domains of the Nijmegen Cochlear Implant Questionnaire and on the sensation domain of the HUI2 in most patients; all but 1 of the ESs were large. CONCLUSION: Cochlear implants have a large and significant positive impact on HRQoL and speech perception and are cost-effective. These improvements are clinically relevant as measured by the MID.