Transoral laser microsurgery and radiotherapy for oropharyngeal squamous cell carcinoma: Equitable survival and enhanced function compared with contemporary standards of care.

INTRODUCTION: We describe the 5-year oncological and functional outcomes of transoral laser microsurgery, neck dissection (TLM + ND) and adjuvant radiotherapy (PORT) used to treat patients with oropharyngeal carcinoma. The effectiveness of external carotid artery (ECA) ligation in reducing post-operative bleeding, and fibrin glue following ND in reducing wound drainage and length of hospital stay is reported. MATERIALS AND METHODS: This retrospective case review of consecutive patients undergoing TLM between 2006 and 2017 used the Kaplan-Meier Estimator and Log-Rank Test for univariate, time-to-event analyses, and Cox-Proportionate Hazard modelling for multivariate analysis. RESULTS: 264 consecutive patients were included. Mean follow-up was 49.4 months. 219 (82.9%) patients received PORT. Five-year overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) rates were 74.9%, 73.7%, and 86.2%, respectively. Five-year locoregional control was 89.4%. 65.5% of cases were Human papillomavirus associated (HPV+), for whom OS, DFS and DSS was 85.6%, 84.7% and 92.7%, respectively, and demonstrated significantly higher OS (hazard ratio (HR) 0.28, CI 0.16-0.49, p < 0.0001), DFS (HR 0.28, CI 0.17-0.47, p < 0.0001) and DSS (HR 0.2, CI 0.09-0.44, <0.001). Post-operative oropharyngeal bleeding occurred in 23 patients (8.7%), of which 5 were major/severe, in patients without ECA ligation. Fibrin glue significantly reduced neck drain output (p < 0.001), and length of hospital stay (p < 0.001). One-year gastrostomy dependence rate was 2.3%. CONCLUSIONS: TLM + ND + PORT results in favourable 5-year survival and locoregional control rates, and low feeding tube dependency rates. ECA ligation and fibrin glue appear to reduce major post-operative haemorrhage, wound drainage and length of hospital stay.

Lenvatinib and sorafenib for differentiated thyroid cancer after radioactive iodine: a systematic review and economic evaluation.

BACKGROUND: Thyroid cancer is a rare cancer, accounting for only 1% of all malignancies in England and Wales. Differentiated thyroid cancer (DTC) accounts for ≈94% of all thyroid cancers. Patients with DTC often require treatment with radioactive iodine. Treatment for DTC that is refractory to radioactive iodine [radioactive iodine-refractory DTC (RR-DTC)] is often limited to best supportive care (BSC). OBJECTIVES: We aimed to assess the clinical effectiveness and cost-effectiveness of lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany) for the treatment of patients with RR-DTC. DATA SOURCES: EMBASE, MEDLINE, PubMed, The Cochrane Library and EconLit were searched (date range 1999 to 10 January 2017; searched on 10 January 2017). The bibliographies of retrieved citations were also examined. REVIEW METHODS: We searched for randomised controlled trials (RCTs), systematic reviews, prospective observational studies and economic evaluations of lenvatinib or sorafenib. In the absence of relevant economic evaluations, we constructed a de novo economic model to compare the cost-effectiveness of lenvatinib and sorafenib with that of BSC. RESULTS: Two RCTs were identified: SELECT (Study of [E7080] LEnvatinib in 131I-refractory differentiated Cancer of the Thyroid) and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer). Lenvatinib and sorafenib were both reported to improve median progression-free survival (PFS) compared with placebo: 18.3 months (lenvatinib) vs. 3.6 months (placebo) and 10.8 months (sorafenib) vs. 5.8 months (placebo). Patient crossover was high (≥ 75%) in both trials, confounding estimates of overall survival (OS). Using OS data adjusted for crossover, trial authors reported a statistically significant improvement in OS for patients treated with lenvatinib compared with those given placebo (SELECT) but not for patients treated with sorafenib compared with those given placebo (DECISION). Both lenvatinib and sorafenib increased the incidence of adverse events (AEs), and dose reductions were required (for > 60% of patients). The results from nine prospective observational studies and 13 systematic reviews of lenvatinib or sorafenib were broadly comparable to those from the RCTs. Health-related quality-of-life (HRQoL) data were collected only in DECISION. We considered the feasibility of comparing lenvatinib with sorafenib via an indirect comparison but concluded that this would not be appropriate because of differences in trial and participant characteristics, risk profiles of the participants in the placebo arms and because the proportional hazard assumption was violated for five of the six survival outcomes available from the trials. In the base-case economic analysis, using list prices only, the cost-effectiveness comparison of lenvatinib versus BSC yields an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £65,872, and the comparison of sorafenib versus BSC yields an ICER of £85,644 per QALY gained. The deterministic sensitivity analyses show that none of the variations lowered the base-case ICERs to < £50,000 per QALY gained. LIMITATIONS: We consider that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib and sorafenib. CONCLUSIONS: Compared with placebo/BSC, treatment with lenvatinib or sorafenib results in an improvement in PFS, objective tumour response rate and possibly OS, but dose modifications were required to treat AEs. Both treatments exhibit estimated ICERs of > £50,000 per QALY gained. Further research should include examination of the effects of lenvatinib, sorafenib and BSC (including HRQoL) for both symptomatic and asymptomatic patients, and the positioning of treatments in the treatment pathway. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017055516. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

WHAT WAS THE PROBLEM?: Differentiated thyroid cancer is a common type of thyroid cancer. For many patients, radioactive iodine is an effective treatment; however, for some patients, the treatment stops working or becomes unsafe. Two new drugs, lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany), may be new treatment options. WHAT DID WE DO?: We reviewed the clinical evidence of lenvatinib and sorafenib. We also estimated the costs and benefits of treatment. WHAT DID WE FIND?: Compared with no treatment, treatment with lenvatinib or sorafenib may increase the time that people live with thyroid cancer before their disease gets worse; however, both drugs are expensive and may have unpleasant side effects. WHAT DOES THIS MEAN?: At their published (undiscounted) prices, lenvatinib or sorafenib may not be considered to provide good value for money to the NHS.

A systematic review of lenvatinib and sorafenib for treating progressive, locally advanced or metastatic, differentiated thyroid cancer after treatment with radioactive iodine.

BACKGROUND: Treatment with radioactive iodine is effective for many patients with progressive, locally advanced or metastatic, differentiated thyroid cancer. However, some patients become refractory to treatment. These types of patients are considered to have radioactive iodine refractory differentiated thyroid cancer (RR-DTC). METHODS: We searched Embase, MEDLINE, PubMed and the Cochrane Library from January 1999 through January 2017. Reference lists of included studies and ongoing trial registries were also searched. Reports of randomized controlled trials (RCTs), prospective observational studies, and systematic reviews/indirect comparisons were eligible for inclusion. In the absence of direct clinical trial evidence comparing lenvatinib versus sorafenib, we assessed the feasibility of conducting an indirect comparison to obtain estimates of the relative efficacy and safety of these two treatments. RESULTS: Of 2364 citations, in total, 93 papers reporting on 2 RCTs (primary evidence), 9 observational studies and 13 evidence reviews (supporting evidence) were identified. Compared to placebo, RCT evidence demonstrated improvements with lenvatinib or sorafenib in median progression-free survival (PFS) and objective tumour response rate (ORR). Overall survival (OS) was confounded by high treatment crossover (≥75%) in both trials. Adverse events (AEs) were more common with lenvatinib or sorafenib than with placebo but the most common AEs associated with each drug differed. Primarily due to differences in the survival risk profiles of patients in the placebo arms of the RCTs, we considered it inappropriate to indirectly compare the effectiveness of lenvatinib versus sorafenib. ORR and AE findings for lenvatinib and sorafenib from the supporting evidence were broadly in line with RCT evidence. Health-related quality of life (HRQoL) data were limited. CONCLUSIONS: Lenvatinib and sorafenib are more efficacious than placebo (a proxy for best supportive care) for treating RR-DTC. Uncertainty surrounds the extent of the impact on OS and HRQoL. Lenvatinib could not reliably be compared with sorafenib. Choice of treatment is therefore likely to depend on an individual patient's circumstances.

Voice outcomes for early laryngeal cancer.

PURPOSE OF REVIEW: Treatment options for early laryngeal cancer are well established with good local control and 5-year survival. The commonest treatments are radiotherapy or transoral laser microsurgery (TLM). There are advantages and disadvantages of the different modalities, but debate continues regarding the voice outcomes posttreatment. This review will focus on early glottic carcinoma and voice outcomes following the different treatments. RECENT FINDINGS: TLM and radiotherapy are both likely to affect voice quality, but the extent of voice change depends on different factors. These factors can be divided into patient, tumour and treatment factors. Recent meta-analyses data show similar voice outcomes for either modality in the treatment of early glottic carcinoma. However, larger tumours and those involving the anterior commissure are associated with worse voice outcomes. SUMMARY: There are various considerations for the patient and clinician before deciding on the preferred treatment for early glottic carcinoma. Although both TLM and radiotherapy will affect voice outcomes, the recent meta-analyses show similar voice outcomes for either modality in the treatment of early glottic carcinoma. There are numerous variables in the published studies hindering direct comparisons. These include heterogeneous patient groups, different treatment standardization and methods of voice analysis.

The impact of MGMT methylation and IDH-1 mutation on long-term outcome for glioblastoma treated with chemoradiotherapy.

BACKGROUND: Increasingly, biomarkers have been identified that correlate with improved overall and progression-free survival (OS and PFS) in glioblastoma, including MGMT methylation status and mutations in the IDH1 gene. In this study, we investigated the clinical and biological factors associated with long-term survival in glioblastoma patients treated with chemoradiotherapy. METHOD: Demographic and clinical data were collected for all patients with glioblastoma diagnosed between May 2004 and September 2007, treated with chemoradiotherapy and with associated tissue samples available for biomarker analysis. MGMT methylation was determined by pyrosequencing. IDH1 mutation was identified by R132H immunohistochemistry. Univariate Cox regression analysis of factors associated with survival and Kaplan-Meier survival analysis was performed using the SPSS statistics package. RESULTS: One hundred patients were included in the study. Median follow-up was 12.2 months (range 1.6-102.4). Median OS was 12.1 months (95 % CI: 10.8-13.3) and median PFS was 8.2 months (95 % CI: 6.8-9.5). The 2-, 3- and 5-year survival was 18, 9 and 6 % respectively. Three patients are still alive at 7.4, 8.3 and 8.5 years after diagnosis. Cox proportional-hazards regression identified independent prognostic factors for OS, female (p = 0.019), MGMT methylation (p < 0.0001) and IDH1 mutation (p = 0.023), and for PFS, MGMT methylation (p = 0.001) and IDH1 mutation (p = 0.018). Kaplan-Meier survival analysis showed that MGMT(methylated)/IDH1(+ve) was associated with a significantly longer OS 66.8 months (95 % CI: 0.0-167.8) and PFS 16.9 months (95 % CI: 11.1-22.7) when compared with MGMT(methylated)/IDH1(-ve) OS 15.5 months (95 % CI: 11.6-19.4) and PFS 9.4 months (95 % CI: 8-10.8) (log-rank, P = 0.000) and MGMT(unmethylated)/IDH1(-ve) OS 11.1 months (95 % CI: 8.5-13.7) and PFS 6.3 months (95 % CI: 4.4-8.3) (log-rank, p = 0.000). CONCLUSIONS: While the importance of MGMT methylation is well established, we demonstrate that the combination of MGMT(methylated)/IDH1(+ve) is associated with considerably longer OS and PFS in this series of chemoradiotherapy-treated glioblastoma tumours. The long-term cognitive function and quality of life in these long-term survivors warrant investigation.

Transoral laser microsurgery for oropharyngeal squamous cell carcinoma: A paradigm shift in therapeutic approach.

BACKGROUND: The contemporary treatment of oropharyngeal squamous cell carcinoma (SCC) is an area of debate. We report outcomes of a minimally invasive approach involving transoral laser microsurgery (TLM). METHODS: A consecutive series of patients (n = 153) undergoing primary TLM for oropharyngeal SCC from 2006 to 2013 was studied. Human papillomavirus (HPV) status was determined by p16 immunohistochemistry and high-risk HPV DNA in situ hybridization. Survival analyses were evaluated using Kaplan-Meier statistics. RESULTS: Tumor subsites included tonsil (n = 94; 61.5%), tongue base (n = 38; 24.8%), and soft palate (n = 21; 13.7%), with the majority being American Joint Committee on Cancer (AJCC) stage III/IVa (n = 124; 81.0%) and HPV-positive (n = 101; 66.0%). Three-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were 84.5%, 91.7%, and 78.2%, respectively. HPV-positivity portended favorable oncologic outcomes. One-year gastrostomy tube (G-tube) dependency was 1.3%. CONCLUSION: To the best of our knowledge, this is the largest single-center TLM oropharyngeal SCC series to date. Our data suggest that TLM +/- postoperative radiotherapy (PORT) results in at least as good oncologic outcomes as chemoradiotherapy (CRT), while conferring swallowing function advantages. © 2016 Wiley Periodicals, Inc. Head Neck , 2016 © 2016 Wiley Periodicals, Inc. Head Neck 38:1263-1270, 2016.

Management of cerebral metastasis: evidence-based approach for surgery, stereotactic radiosurgery and radiotherapy.

Brain metastases constitute a significant disease burden and have a major impact on morbidity and mortality. This review discusses the relative merits of open surgery, whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS), which have been used alone and in combination with varying degrees of success for the treatment of newly diagnosed brain metastasis. Treatment aims to provide disease control with a good quality of life, although prolonged survival may not always be achieved. Decision to treat is based on several prognostic factors including age, performance status and control of the primary cancer. The recently developed disease-specific graded prognostic assessment (DS-GPA) scales can aid in clinical decision making for individual patients. Whole brain radiotherapy remains the mainstay of treatment and provides effective palliation. Omission of WBRT results in worse local and distant control, though not survival. Local tumour control can be achieved by either resection of stereotactic radiosurgery (SRS). In long-term survivors WBRT may cause cognitive decline and SRS is being explored as an alternative method of disease control. Increasingly, quality of life and neuro-cognitive function are being used as end-points in clinical trials.

Phase II trial of intratumoral BCNU injection and radiotherapy on untreated adult malignant glioma.

DTI-015 (BCNU dissolved in ethanol) utilizes solvent facilitated perfusion (SFP) for intratumoral drug delivery. A phase II clinical trial of DTI-015 and fractionated external beam radiotherapy on newly diagnosed, malignant gliomas investigated early changes in tumour physiology and metabolism, clinical outcome and safety. Pre- and post DTI-015 injection neuro-imaging included computed tomography (CT) cerebral blood flow and volume, glucose and thallium single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Clinical status was determined before and after DTI-015, prior to radiotherapy and 3 monthly thereafter until progression (defined by Macdonald criteria). Primary endpoint was radiographic response. Secondary endpoints were progression free (PFS) and overall survival (OS). Twelve patients were enrolled; eight glioblastoma multiforme (GBM), four anaplastic astrocytoma (AA). Three days after DTI-015 injection, mean tumour blood flow (Paired t-test; P < 0.001) and blood volume (Paired t-test; P = 0.001) were significantly reduced. There was a significant decrease in glucose utilization (Paired t-test; P < 0.001) and thallium uptake (Paired t-test; P < 0.001) at 6 days. Tumour blood volume had a sustained reduction (Paired t-test; P = 0.001) at 26 days after DTI-015. There were two serious adverse events. Two patients with AA achieved a partial response. Median PFS was 39 weeks for AA and 27 weeks for GBM; median OS for GBM was 47 weeks and 132 weeks for AA. The imaging data forms a biological basis for understanding the effects of high dose BCNU delivered intratumorally by SFP, and suggests early effects on tumour vasculature and metabolism.