Robert P. Takes

Current trends in initial management of oropharyngeal cancer: the declining use of open surgery

The role of open surgery for management of laryngeal cancer has been greatly diminished during the past decade. The development of transoral endoscopic laser microsurgery (TLS), improvements in delivery of radiation therapy (RT) and the advent of multimodality protocols, particularly concomitant chemoradiotherapy (CCRT) have supplanted the previously standard techniques of open partial laryngectomy for early cancer and total laryngectomy followed by adjuvant RT for advanced cancer. A review of the recent literature revealed virtually no new reports of conventional conservation surgery as initial treatment for early stage glottic and supraglottic cancer. TLS and RT, with or without laser surgery or CCRT, have become the standard initial treatments for T1, T2 and selected T3 laryngeal cancer. Photodynamic therapy (PDT) may have an emerging role in the treatment of early laryngeal cancer. Anterior commissure involvement presents particular difficulties in application of TLS, although no definitive conclusions have been reached with regard to optimal treatment of these lesions. Results of TLS are equivalent to those obtained by conventional conservation surgery, with considerably less morbidity, less hospital time and better postoperative function. Oncologic results of TLS and RT are equivalent for glottic cancer, but with better voice results for RT in patients who require more extensive cordectomy. The preferred treatment for early supraglottic cancer, particularly for bulkier or T3 lesions is TLS, with or without postoperative RT. The Veterans Administration Study published in 1991 established the fact that the response to neoadjuvant CT predicts the response of a tumor to RT. Patients with advanced tumors that responded either partially or completely to CT were treated with RT, and total laryngectomy was reserved for non-responders. This resulted in the ability to preserve the larynx in a significant number of patients with locally advanced laryngeal cancer, while achieving local control and overall survival results equivalent to those achieved with initial total laryngectomy. Following this report, similar “organ preservation” protocols were employed in many centers. By 2003, results of the RTOG 93-11 trial, utilizing CCRT as initial treatment, were published, demonstrating a higher rate of laryngeal preservation with this protocol. Surgery was reserved for treatment failures. This concept changed the paradigm for management of advanced laryngeal cancer, greatly reducing the number of laryngectomies performed. While supracricoid laryngectomy has been employed for selected patients, total laryngectomy is the usual procedure for salvage of failure after non-surgical treatment.

CD44 Expression Predicts Local Recurrence after Radiotherapy in Larynx Cancer

Purpose: To find molecular markers from expression profiling data to predict recurrence of laryngeal cancer after radiotherapy. Experimental Design: We generated gene expression data on pre-treatment biopsies from 52 larynx cancer patients. Patients developing a local recurrence were matched for T-stage, subsite, treatment, gender and age with non-recurrence patients. Candidate genes were then tested by immunohistochemistry on tumor material from a second series of 76 patients. Both series comprised early stage cancer treated with radiotherapy alone. Finally, gene expression data of eight larynx cancer cell lines with known radiosensitivity were analyzed. Results: Nineteen patients with a local recurrence were matched with 33 controls. Gene sets for hypoxia, proliferation and intrinsic radiosensitivity did not correlate with recurrence, whereas expression of the putative stem cell marker CD44 did. In a supervised analysis, probes for all three splice variants of CD44 on the array appeared in the top 10 most significantly correlated with local recurrence. Immunohistochemical analysis of CD44 expression on the independent validation series confirmed CD44s predictive potential. In 8 larynx cancer cell lines, CD44 gene expression did not correlate with intrinsic radiosensitivity although it did correlate significantly with plating efficiency, consistent with a relationship with stem cell content. Conclusions: CD44 was the only biological factor tested which significantly correlated with response to radiotherapy in early stage larynx cancer patients, both at the mRNA and protein levels. Further studies are needed to confirm this and to assess how general these findings are for other head and neck tumor stages and sites. Clin Cancer Res; 16(21); 5329–38. ©2010 AACR.

Comorbidity in head and neck cancer: A critical appraisal and recommendations for practice

Comorbidity, the presence of additional illnesses unrelated to the tumor, has a significant impact on the prognosis of patients with head and neck cancer. In these patients, tobacco and alcohol abuse contributes greatly to comorbidity. Several instruments have been used to quantify comorbidity including Adult Comorbidity Evaluation 27 (ACE 27), Charlson Index (CI) and Cumulative Illness Rating Scale. The ACE 27 and CI are the most frequently used indices. Information on comorbidity at the time of diagnosis can be abstracted from patient records. Self-reporting is less reliable than record review. Functional status is not a reliable substitute for comorbidity evaluation as a prognostic measure. Severity as well as the presence of a condition is required for a good predictive instrument. Comorbidity increases mortality in patients with head and neck cancer, and this effect is greater in the early years following treatment. In addition to reducing overall survival, many studies have shown that comorbidity influences disease-specific survival negatively, most likely because patients with high comorbidity tend to have delay in diagnosis, often presenting with advanced stage tumors, and the comorbidity may also prompt less aggressive treatment. The impact of comorbidity on survival is greater in younger than in older patients, although it affects both. For specific tumor sites, comorbidity has been shown to negatively influence prognosis in oral, oropharyngeal, laryngeal and salivary gland tumors. Several studies have reported higher incidence and increased severity of treatment complications in patients with high comorbidity burden. Studies have demonstrated a negative impact of comorbidity on quality of life, and increased cost of treatment with higher degree of comorbidity. Our review of the literature suggests that routine collection of comorbidity data will be important in the analysis of survival, quality of life and functional outcomes after treatment as comorbidity has an impact on all of the above. These data should be integrated with tumor-specific staging systems in order to develop better instruments for prognostication, as well as comparing results of different treatment regimens and institutions.

Surgical margins in head and neck cancer: a contemporary review.

Adequate resection margins are critical to the treatment decisions and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). However, there are numerous controversies regarding reporting and interpretation of the status of resection margins. Fundamental issues relating to the basic definition of margin adequacy, uniform reporting standards for margins, optimal method of specimen dissection, and the role of intraoperative frozen section evaluation, all require further clarification and standardization. Future horizons for margin surveillance offer the possible use of novel methods such as “molecular margins” and contact microscopic endoscopy, However, the limitations of these approaches need to be understood. The goal of this review was to evaluate these issues to define a more rational, standardized approach for achieving resection margin adequacy for patients with HNSCC undergoing curative resection.

HUMAN PAPILLOMAVIRUS INFECTIONS IN LARYNGEAL CANCER

Although the association and clinical significance of human papillomavirus (HPV) infections with a subset of head and neck cancers, particularly for oropharyngeal carcinoma, has recently been well documented, the involvement of HPV in laryngeal cancer has been inadequately evaluated. Herein we review the currently known associations of HPV infections in diseases of the larynx and their potential for oncogenicity. Using several methods of detection, HPV DNA has been detected in benign (papillomatosis), indolent (verrucous carcinoma), and malignant (squamous cell carcinoma) lesions of the larynx. Consistent with the known oncogenic risk of HPV infections, common HPV types associated with laryngeal papillomatosis include low‐risk HPV types 6 and 11, with high‐risk HPV types 16 and 18 more commonly present in neoplastic lesions (verrucous carcinoma and squamous cell carcinoma). Although a broad range of prevalence has been noted in individual studies, approximately 25% of laryngeal squamous cell carcinomas harbor HPV infections on meta‐analysis, with common involvement of high‐risk HPV types 16 (highest frequency) and 18. Preliminary results suggest that these high‐risk HPV infections seem to be biologically relevant in laryngeal carcinogenesis, manifested as having viral DNA integration in the cancer cell genome and increased expression of the p16 protein. Despite this knowledge, the clinical significance of these infections and the implications on disease prevention and treatment are unclear and require further investigation.

Current trends in initial management of hypopharyngeal cancer: The declining use of open surgery

Squamous cell carcinoma of the hypopharynx represents a distinct clinical entity. Most patients present with significant comorbidities and advanced‐stage disease. The overall survival is relatively poor because of high rates of regional and distant metastasis at presentation or early in the course of the disease. A multidisciplinary approach is crucial in the overall management of these patients to achieve the best results and maintain or improve functional results. Traditionally, operable hypopharyngeal cancer has been treated by total (occasionally partial) laryngectomy and partial or circumferential pharyngectomy, followed by reconstruction and postoperative radiotherapy in most cases.

Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches

In an era of advanced diagnostics, metastasis to cervical lymph nodes from an occult primary tumor is a rare clinical entity and accounts for approximately 3% of head and neck malignancies. Histologically, two thirds of cases are squamous cell carcinomas (SCCs), with other tissue types less common in the neck. With modern imaging and tissue examinations, a primary tumor initially undetected on physical examination is revealed in >50% of patients and the site of the index primary can be predicted with a high level of probability. In the present review, the range and limitations of diagnostic procedures are summarized and the optimal diagnostic workup is proposed. Initial preferred diagnostic procedures are a fine‐needle aspiration biopsy (FNAB) and imaging. This allows directed surgical biopsy (such as tonsillectomy), based on the preliminary findings, and prevents misinterpretation of postsurgical images. When no primary lesion is suggested after imaging and panendoscopy, and for patients without a history of smoking and alcohol abuse, molecular profiling of an FNAB sample for human papillomavirus (HPV) and/or Epstein–Barr virus (EBV) is important. Head Neck, 2013

Advances and applications of oral cancer basic research.

Cancer of the oral cavity accounts for almost 3% of cancer cases in the world. The incidence varies widely reflecting geographic differences in exposure to risk factors. The recent rise in younger age groups and females seen in many countries is of particular concern. Treatment and management of complications, locoregional recurrence and further primary tumors result in high morbidity and mortality especially when the disease is advanced stage at initial diagnosis. Progress in cancer research has provided abundant new knowledge about cellular processes and molecular biology underlying oral carcinogenesis and tumor progression. The present review attempts to summarize the current most widely-used research approaches and their application in the prevention, diagnosis, effective treatment, and improved outcome of oral cancer.

Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: A diagnostic meta-analysis

BACKGROUND The aim of the study was to systematically assess the accuracy of a sentinel lymph node biopsy (SLNB) in cT1/T2N0 oral cavity and oropharyngeal squamous cell carcinoma patients. METHODS We searched electronic databases, including EMBASE and MEDLINE (Pubmed) up to November 7 2012, by combining oral cancer keywords with sentinel node biopsy keywords. We included diagnostic accuracy studies which used neck dissection as a reference test for the sentinel node biopsy. Study characteristics and measures of accuracy were extracted. Diagnostic accuracy was calculated from 2 × 2 tables. RESULTS 21 Studies (847 patients) could be included. Most of these patients had oral cavity squamous cell carcinoma (OCSCC). The pooled data showed an overall sensitivity of 0.93 [95% CI 0.90-0.95]. Subgroup analysis showed no significant differences in subgroups. CONCLUSION The high sensitivity of SLNB supports a role in the diagnostic work-up of OCSCC.

Chemotherapy and targeted therapy in adenoid cystic carcinoma of the head and neck: a review.

Adenoid cystic carcinoma (ACC) is an uncommon tumor usually arising in the head and neck region, mainly in the salivary glands. It demonstrates an indolent prolonged course and is characterized by perineural invasion. Primary treatment of local and locoregional disease consists mainly of surgery and/or irradiation. During follow‐up these patients frequently develop local recurrences and distant metastases, especially in the lung, although long‐term survival is possible. The role of chemotherapy in ACC is limited, and studies with only a limited number of patients are performed. In this article we review the literature on chemotherapy regimens, including monotherapy and combination chemotherapy schedules, as well as the new targeted therapies.