Methodology for the development of National Multidisciplinary Management Recommendations using a multi-stage meta-consensus initiative.

BACKGROUND: Methods for developing national recommendations vary widely. The successful adoption of new guidance into routine practice is dependent on buy-in from the clinicians delivering day-to-day patient care and must be considerate of existing resource constraints, as well as being aspirational in its scope. This initiative aimed to produce guidelines for the management of head and neck squamous cell carcinoma of unknown primary (HNSCCUP) using a novel methodology to maximise the likelihood of national adoption. METHODS: A voluntary steering committee oversaw 3 phases of development: 1) clarification of topic areas, data collection and assimilation, including systematic reviews and a National Audit of Practice; 2) a National Consensus Day, presenting data from the above to generate candidate consensus statements for indicative voting by attendees; and 3) a National Delphi Exercise seeking agreement on the candidate consensus statements, including representatives from all 58 UK Head and Neck Multidisciplinary Teams (MDT). Methodology was published online in advance of the Consensus Day and Delphi exercise. RESULTS: Four topic areas were identified to frame guideline development. The National Consensus Day was attended by 227 participants (54 in-person and 173 virtual). Results from 7 new systematic reviews were presented, alongside 7 expert stakeholder presentations and interim data from the National Audit and from relevant ongoing Clinical Trials. This resulted in the generation of 35 statements for indicative voting by attendees which, following steering committee ratification, led to 30 statements entering the National Delphi exercise. After 3 rounds (with a further statement added after round 1), 27 statements had reached 'strong agreement' (n = 25, 2, 0 for each round, respectively), a single statement achieved 'agreement' only (round 3), and 'no agreement' could be reached for 3 statements (response rate 98% for each round). Subsequently, 28 statements were adopted into the National MDT Guidelines for HNSCCUP. CONCLUSIONS: The described methodology demonstrated an effective multi-phase strategy for the development of national practice recommendations. It may serve as a cost-effective model for future guideline development for controversial or rare conditions where there is a paucity of available evidence or where there is significant variability in management practices across a healthcare service.

TLM Outcomes in Elderly Patients with Glottic Pre-Malignancy and Early Malignancy; A 12-Year Retrospective Study.

INTRODUCTION: UK population ageing and associated cancer risk predicts an increase in the prevalence of laryngeal cancer in elderly patients. Whilst trans-oral laser microsurgery (TLM) has been demonstrated to achieve excellent control of early disease with few complications, data specifically related to its safety and efficacy in older patients is lacking. We report the largest series to date. OBJECTIVES: To assess the safety and efficacy of TLM in elderly patients with glottic pre-malignancy and early malignancy. METHODS: A retrospective review and statistical analysis of the clinical records of patients aged 70 or over undergoing TLM for early and premalignant glottic disease. RESULTS: The records of 106 patients over the age of 70 were identified. Thirteen records were excluded, 4 due to failure to meet the inclusion criteria (stage I/II disease, primary site of lesion in the glottis) and 9 due to incomplete follow up data capture. Most surgeries (>70%) were performed as a day case or overnight admission, with only 2 admissions >2 days. One patient required hospital readmission with dysphagia, resulting in an altered diet. No patients required tracheostomy or tube feeding. No treatment related deaths or intensive care admissions were observed. Ten patients had recurrent disease within 5 years; 1 received radiotherapy, 1 underwent salvage laryngectomy, the remainder had further TLM without complication. Five-year disease specific survival rates were >90%. CONCLUSION: Our results demonstrate that TLM is safe and effective for elderly patients, with outcomes comparable to those reported in large, non-age selected cohorts. Although our patients underwent more conservative cordectomy types (I-III) than those with similar disease stages reported elsewhere, our recurrence rates were not higher. This supports the oncological effectiveness of surgery whilst reducing the risk of associated functional compromise.

Bone marrow metastasis/carcinomatosis in head and neck squamous cell carcinoma.

BACKGROUND: Literature on bone marrow carcinomatosis in head and neck squamous cell carcinoma (HNSCC) is sparse. This work aims to augment understanding on its characteristic features, clinical presentation, investigations, treatment and outcomes. METHODS: Comprehensive literature review of all published cases of metastasis of HNSCC to the bone marrow with regard to clinical presentation, diagnosis, treatment and survival outcomes of this disease. Each of these factors is discussed forming an up-to-date review on the subject. RESULTS: Eight case reports were identified, seven males and one female with an age range of 35-64 years. Primary sites were from the oral cavity (n = 4), oropharynx (n = 3) and supraglottis (n = 1). Six were stage four disease with nodal involvement, one case stage two and one case with unknown staging. Two of the oropharyngeal cancers were p16 positive, and one p16 status was not documented. Five patients presented with back pain, two patients had ecchymoses with bleeding, and one presented with sepsis and thrombocytopaenia. Three patients had proven disseminated intravascular coagulation. Four patients were treated with palliative chemoradiotherapy, one had palliative radiotherapy, one had radiotherapy and dendritic cell vaccine immunotherapy, and two died from the disease prior to any treatment. Various facets of presentation and management are discussed. CONCLUSION: Bone marrow carcinomatosis from HNSCC is rare. It can present with a variety of non-specific symptoms, and a high index of suspicion is required to be able to diagnose the condition promptly. Aggressive chemotherapy is the treatment of choice but prognosis remains poor.

Endoscopic video-assisted transoral (EVAT) surgery of the oropharynx: clinical, oncological and functional outcomes.

PURPOSE: Transoral surgery for suspected or proven oropharyngeal malignancies has increased significantly with the practice of transoral laser microsurgery (TLM) and transoral robotic surgery (TORS). An accepted alternative technique is endoscopic video-assisted transoral (EVAT) surgery. Our aim is to review the clinical, oncological and functional outcomes of this technique at our institution. METHODS: 56 consecutive patients undergoing EVAT surgery as part of their cancer work up or treatment were reviewed, focusing on clinical, oncological, and functional outcomes. RESULTS: Patients had primary oropharyngeal cancer or carcinoma of unknown primary (CUP) staged between T0-T3 and N0-N3. EVAT surgery identified a primary in 47.1% of CUP with p16 positive disease. Major haemorrhage occurred in 1.8%, with eight post-operative complications. 8.9% of patients developed locoregional recurrence. Mean MD Anderson Dysphagia Inventory score was 76.4 following EVAT surgery, 68.8 after EVAT surgery + radiotherapy and 67.1 after EVAT surgery + chemoradiotherapy CONCLUSION: Early clinical, oncological and functional outcomes following EVAT surgery are comparable to TLM and TORS. LEVEL OF EVIDENCE: 4 (case series).

Endoscopic video-assisted transoral resection of lateral oropharyngeal tumors.

Endoscopic, video-assisted transoral resection of oropharyngeal tumors is a novel technique carried out using common instruments present in most otolaryngology departments. The technique facilitates oropharyngeal resection akin to transoral robotic surgery (TORS) without the need for a robot. A dual surgeon approach, analogous to that of endoscopic skull base surgery is used. Each surgeon can actively participate in the resection with several key advantages over current techniques. The technique is applicable to departments internationally especially where the use of a robot is prohibited by cost or availability. This is especially important given the resection of oropharyngeal tumours offers the opportunity of single modality treatment or reduced intensity adjuvant treatment compared to traditional non-surgical therapy.

Tamoxifen-induced cytotoxicity in breast cancer cells is mediated by glucose-regulated protein 78 (GRP78) via AKT (Thr308) regulation.

Glucose regulated protein 78 (GRP78) has recently been suggested to be associated with drug resistance in breast cancer patients. However, the precise role of GRP78 in drug resistance and the involved signaling pathways are not clearly understood. In the present study, we show that among a panel of drugs, namely Paclitaxel (TAX), Doxorubicin (DOX), 5-fluorouracil (5-FU), UCN-01 and Tamoxifen (TAM) used, TAM alone up-regulated the expression of GRP78 significantly and induced apoptosis in MCF-7 and MDA-MB-231 cells. Interestingly, inhibition of GRP78 by a specific pharmacological inhibitor, VER-155008 augmented TAM-induced apoptosis, and overexpression of GRP78 rendered the cells resistant to TAM-induced cell death suggesting a role for GRP78 in TAM-induced cytotoxicity. Mechanistically, the expression of phosphorylated AKT as determined by Western blot analyses revealed that TAM selectively upregulated phosphorylation of AKT at Thr308 but not at Ser473, and siRNA silencing of GRP78 resulted in inhibition of AKT phosphorylation at Thr308 but not at Ser473. Further, a GRP78 inhibitor, VER155008 inhibited TAM-induced phosphorylation of GSK3ß, a downstream substrate of AKT. These results, thus suggests a role for GRP78 in TAM-induced AKT activation. Additionally, co-localization studies by immunofluorescence, and immunoprecipitation experiments demonstrated a complex formation of AKT and GRP78. Furthermore, in glucose-free medium, the cells were sensitized to TAM-induced cell death that was associated with reduced AKT phosphorylation at Thr308, thus strengthening the association of AKT regulation with drug response. Collectively, our findings identify a role of GRP78 in AKT regulation in response to TAM in breast cancer cells.

Short, sharp shock public health campaign had limited impact on raising awareness of laryngeal cancer.

Laryngeal cancer has poorer outcomes if diagnosed at a later stage. Improving awareness could encourage earlier presentation and improve outcomes. This study aimed to evaluate a public engagement campaign targeted at raising awareness of laryngeal cancer. An epidemiological study identified high-risk populations in the region. A target population as well as a matched control population was selected. A cancer awareness survey combined with focus groups guided the design of a 3-month multimedia campaign. The survey was repeated post-campaign to evaluate the campaign effectiveness. The study identified populations with the highest rates of laryngeal cancer and late stage disease at presentation. The surveys performed revealed a limited effect of the multimedia campaign in raising awareness of the signs and symptoms of laryngeal cancer. Recall of the campaign also faded rapidly. This is the first public awareness campaign aimed at laryngeal cancer carried out in the UK. The results suggest that short-term campaigns have a limited effect and a more prolonged approach should be considered.

Inferior turbinate surgery for nasal obstruction in allergic rhinitis after failed medical treatment.

BACKGROUND: Allergic rhinitis is a highly prevalent disease that results from an IgE-mediated hypersensitivity reaction of the nasal mucosa to inhaled allergens. It is primarily treated by allergen avoidance and medical treatment, but when these measures fail to control symptoms then surgery to the inferior turbinates of nose is often performed. It is unclear whether these procedures are beneficial in the long term or indeed whether the risks outweigh the benefits. OBJECTIVES: To assess the effectiveness of inferior turbinate surgery on unrelieved or partially relieved nasal obstruction in patients after maximal medical treatment of proven allergic rhinitis, to compare the results using different surgical techniques and to measure short and long-term results. SEARCH STRATEGY: We searched the following databases from their inception for published, unpublished and ongoing trials: the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2); PubMed; EMBASE; CINAHL; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; BIOSIS Previews; CNKI; mRCT (Current Controlled Trials); ClinicalTrials.gov; ISRCTN; ICTRP (International Clinical Trials Registry Platform); Cambridge Scientific Abstracts; Google and additional sources for published and unpublished trials. We modelled subject strategies for databases on the search strategy designed for CENTRAL. The date of the most recent search was 6 July 2010. SELECTION CRITERIA: Randomised controlled trials of inferior turbinate surgery versus continued medical treatment for proven allergic rhinitis, or comparisons between one technique of inferior turbinate surgery versus another technique, after maximal medical treatment. DATA COLLECTION AND ANALYSIS: Both authors independently screened the search results and assessed the full text of potentially relevant studies. We attempted to contact trial authors for additional information. MAIN RESULTS: There were no studies that fulfilled the inclusion criteria of the review. AUTHORS' CONCLUSIONS: This review highlights the need for randomised controlled trials to evaluate the role of inferior turbinate surgery for nasal obstruction in allergic rhinitis after failed medical treatment. Future trials needs to be rigorous in design and delivery, separate adults from paediatric patients, not combine allergic with non-allergic patients and last long enough to determine long-term results and complications.

Recent changes in the treatment of patients with advanced laryngeal cancer.

Since the original data from the Department of Veterans Affairs Laryngeal Cancer Study Group demonstrated that nonsurgical therapy could achieve survival rates comparable to total laryngectomy in selected cases, there has been a progressive increase in employment of nonsurgical therapy for the management of advanced laryngeal cancer. Both neoadjuvant chemotherapy followed by conventionally fractionated or hyperfractioned radiotherapy for chemotherapy responders, or simultaneously administered chemoradiation has resulted in a significant number of patients who achieved cure while preserving their larynges. Nevertheless, combined chemotherapy and external beam radiation is associated with a variety of acute and chronic sequelae that can have a debilitating impact on function and quality of life. Although no therapeutic option is without risk, the decision regarding the modality of therapy for a patient with advanced laryngeal cancer should prompt a careful review of the current surgical techniques available for treatment. Data on quality of life and aging, as well as advances in minimally invasive surgical techniques, are available today that were not available at the time of the Veterans study. Selection of optimal therapy is often complex and raises the question whether the pendulum may have swung too far in the direction of nonsurgical therapy for advanced laryngeal cancer. This article reviews the current options available for a patient with advanced laryngeal cancer and discusses the impact of therapy.

Soft tissue deposits in neck dissections of patients with head and neck squamous cell carcinoma: prospective analysis of prevalence, survival, and its implications.

BACKGROUND: Soft tissue deposits of squamous cell carcinoma in the necks of patients with squamous cell carcinoma of the upper aerodigestive tract may represent either total effacement of a lymph node by carcinoma or extralymphatic deposits of carcinoma. There are few reports of their clinical or prognostic significance. METHODS: Data from 215 neck dissections from 155 patients with squamous cell carcinoma of the upper aerodigestive tract were studied prospectively to assess the prevalence of soft tissue deposits within the neck. The case notes of these patients were subsequently reviewed to analyze the effect on both the overall survival and recurrence-free survival. RESULTS: The prevalence rate for soft tissue deposits occurring alone was 10.3%; the prevalence rate for soft tissue deposits occurring with extracapsular spread was 13.5%. The overall prevalence rate for soft tissue deposits was 23.9%. There was a statistically significant reduction in actuarial and recurrence-free survival in patients with soft tissue deposits compared with patients with pathologically node-negative necks (P=.001), and in patients with soft tissue deposits compared with those with pathologically node-positive necks without extracapsular spread (P=.001). No statistically significant differences were found between patients with soft tissue deposits and patients with pathologically node-positive necks with extracapsular spread, for actuarial survival or recurrence-free survival. CONCLUSIONS: In this series, soft tissue deposits were associated with an aggressive clinical course and poor survival. It is therefore important that histopathologists agree on a uniform terminology when reporting soft tissue deposits and actively look for their presence when examining neck dissection specimens.

Upper aerodigestive tract squamous cell carcinoma: distribution of extracapsular spread and soft tissue deposits in the neck.

OBJECTIVE: Extracapsular spread (ECS) and soft tissue deposits (STD) of squamous cell carcinoma (SCC) in the neck of patients with metastatic SCC of the upper aerodigestive tract have been shown to adversely affect actuarial and disease-free survival. No studies to date have detailed the distribution of ECS and STD within the neck. MATERIAL AND METHODS: A total of 215 neck dissections from 155 patients were prospectively collected and analysed for the presence of both STD and ECS. As no classification for STD exists, their distribution was classified according to the nodal levels used for classification of cervical lymph nodes as described by the Memorial Sloan-Kettering Cancer Center. RESULTS: A total of 81 neck dissections from 59 patients were found to have either metastatic lymph nodes with ECS, STD or both. The distribution of lymph node metastasis, ECS and STD was very similar. Level II was most frequently affected, with Levels III and IV being affected less frequently. There were very few lymph node metastases to Level V, and this level contained no evidence of either ECS or STD. CONCLUSION: The method of pathological assessment of neck dissection specimens and reporting on the presence of ECS and STD has not been formalized. By analysing neck dissection specimens in the manner described we can report on the presence or absence of ECS and STD with increased accuracy. This has considerable implications for patient management.

Cervical node metastases in squamous cell carcinoma of the upper aerodigestive tract: the significance of extracapsular spread and soft tissue deposits.

BACKGROUND: Literature regarding the prognostic significance of extracapsular spread and soft tissue deposits in cervical lymph node metastases of squamous cell carcinoma of the upper aerodigestive tract shows variable results. METHODS: We analyzed 215 prospectively collected neck dissections from 155 patients with upper aerodigestive tract squamous cell carcinoma to assess the prevalence of extracapsular spread and soft tissue deposits and to assess their effect on survival. RESULTS: Both extracapsular spread and soft tissue deposits significantly reduced survival (actuarial and recurrence free) compared with pN0 necks (p <.001) and pN+ve necks without extracapsular spread (p <.0025). There was no statistically significant difference between pN+ve necks without soft tissue deposits or extracapsular spread compared with those with pN0 necks (p =.24). Multivariate analysis revealed comparable results. CONCLUSIONS: Microscopic and macroscopic extracapsular spread and soft tissue deposits are of prognostic significance for survival and recurrence-free survival in patients with upper aerodigestive tract squamous cell carcinoma.

Cervical metastases in upper aerodigestive tract squamous cell carcinoma: histopathologic analysis and reporting.

BACKGROUND: Accurate histopathologic assessment of neck dissections is of paramount importance. Retrospective analyses of the distribution of lymph node metastases have formed the rationale for elective neck dissection. However, standard techniques for examination of neck dissection specimens may have difficulty in correctly recognizing node levels and may also miss micrometastases, microscopic extracapsular spread, and soft tissue deposits. METHODS: Two hundred thirty-seven neck dissections were performed in 173 patients with squamous cell carcinoma of the upper aerodigestive tract between August 1995 and November 2000. The neck dissections were separated into node levels peroperatively, sectioned at 6 microm thickness, and stained with hematoxylin and eosin. RESULTS: Eleven thousand three hundred forty-nine lymph nodes were identified and examined. The mean yield per neck dissection was 50.4 (range, 12-131); 21.4% had extracapsular spread, 11.0% had soft tissue deposits, and 13.3% had both. A third of the metastatic nodes were 3 mm or less in diameter. CONCLUSIONS: The accurate pathologic staging of the neck in patients with upper aerodigestive tract squamous cell cancer is important for providing prognostic information and optimizing the treatment plan for the patient. Accurate staging also allows the changing patterns of disease to be monitored and allows equitable comparison of patients in clinical trials and among surgical units.