Missak Haigentz

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.

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.

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

Adenoid cystic carcinoma of the head and neck--An update

This article provides an update on the current understanding of adenoid cystic carcinoma of the head and neck, including a review of its epidemiology, clinical behavior, pathology, molecular biology, diagnostic workup, treatment and prognosis. Adenoid cystic carcinoma is an uncommon salivary gland tumor that may arise in a wide variety of anatomical sites in the head and neck, often with an advanced stage at diagnosis. The clinical course is characterized by very late recurrences; consequently, clinical follow-up should extend at least >15 years. The optimal treatment is generally considered to be surgery with postoperative radiotherapy to optimize local disease control. Much effort has been invested into understanding the tumors molecular biological processes, aiming to identify patients at high risk of recurrence, in hopes that they could benefit from other, still unproven treatment modalities such as chemotherapy or biological therapy.

Future of the TNM classification and staging system in head and neck cancer

Staging systems for cancer, including the most universally used TNM classification system, have been based almost exclusively on anatomic information. However, the question arises whether staging systems should be based on this information alone. Other parameters have been identified that should be considered for inclusion in classification systems like the TNM. This is all the more important, as a shift toward nonsurgical treatments for head and neck cancer has been made over the years. For these treatment modalities tumor/biologic characteristics next to anatomic information may be particularly important for treatment choice and outcome. The shortcomings of the current TNM classification system will be discussed, along with suggestions for improvement and expansion of the TNM system based on tumor, patient, and environment‐related factors. Further improvement of the TNM classification is expected to result in better treatment choices, outcome and prognostication of patients with head and neck cancer.

Erlotinib, an effective epidermal growth factor receptor tyrosine kinase inhibitor, induces p27KIP1 up-regulation and nuclear translocation in association with cell growth inhibition and G1/S phase arrest in human non-small-cell lung cancer cell lines.

Erlotinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been shown to have potent antitumor effects against human non-small-cell lung cancer (NSCLC) cell growth; however, the mechanism of such an effect is not elucidated. Here, we demonstrate that erlotinib-induced cell growth inhibition in EGFR high-expressing human H322 NSCLC cells was accompanied by G1/S phase arrest, which was largely caused by a decrease in expression of G1/S-related cyclins, suppression of activities of cyclin-dependent kinase (CDK) 2 and CDK4, induction of CDK inhibitor p27KIP1, and retinoblastoma hypophosphorylation. To further understand the role of p27KIP1 in G1/S arrest and cell growth inhibition by erlotinib, we determined its effect on the expression of p27KIP1 at transcriptional and posttranscriptional levels. Studies using real-time reverse transcription-polymerase chain reaction analysis and p27 promoter-driven luciferase reporter showed that erlotinib treatment resulted in the promotion of p27 gene transcription. In addition, erlotinib treatment led to an increase in p27KIP1 half-life by inhibiting p27KIP1 phosphorylation at Thr187 and by down-regulating Skp2 expression. Furthermore, immunofluorescence staining and cell fractionation showed that erlotinib treatment led to p27KIP1 translocation to the nucleus. Knockdown of p27KIP1 expression with p27KIP1 small interfering RNA significantly abrogated erlotinib-induced G1 phase arrest and cell growth inhibition, suggesting that induction of p27KIP1 is required for G1 arrest and cell growth inhibition by erlotinib. It is noteworthy that we found that G1 arrest and p27KIP1 up-regulation by erlotinib occurred in the tested sensitive cell lines but to a lesser extent in the resistant cell lines. Taken together, these results suggest that erlotinib inhibits human NSCLC cell growth predominantly by inducing p27KIP1 expression and by suppressing cell-cycle events involved in the G1/S transition.

Contemporary management of cancer of the oral cavity

Oral cancer represents a common entity comprising a third of all head and neck malignant tumors. The options for curative treatment of oral cavity cancer have not changed significantly in the last three decades; however, the work up, the approach to surveillance, and the options for reconstruction have evolved significantly. Because of the profound functional and cosmetic importance of the oral cavity, management of oral cavity cancers requires a thorough understanding of disease progression, approaches to management and options for reconstruction. The purpose of this review is to discuss the most current management options for oral cavity cancers.

Contemporary management of lymph node metastases from an unknown primary to the neck: II. a review of therapeutic options.

Although uncommon, cancer of an unknown primary (CUP) metastatic to cervical lymph nodes poses a range of dilemmas relating to optimal treatment. The ideal resolution would be a properly designed prospective randomized trial, but it is unlikely that this will ever be conducted in this group of patients. Accordingly, knowledge gained from retrospective studies and experience from treating patients with known head and neck primary tumors form the basis of therapeutic strategies in CUP. This review provides a critical appraisal of various treatment approaches described in the literature. Emerging treatment options for CUP with metastases to cervical lymph nodes are discussed in view of recent innovations in the field of head and neck oncology and suitable therapeutic strategies for particular clinical scenarios are presented. For pN1 or cN1 disease without extracapsular extension (ECE), selective neck dissection or radiotherapy offer high rates of regional control. For more advanced neck disease, intensive combined treatment is required, either a combination of neck dissection and radiotherapy, or initial (chemo)radiotherapy followed by neck dissection if a complete response is not recorded on imaging. Each of these approaches seems to be equally effective. Use of extensive bilateral neck/mucosal irradiation must be weighed against toxicity, availability of close follow‐up with elective neck imaging and guided fine‐needle aspiration biopsy (FNAB) when appropriate, the human papillomavirus (HPV) status of the tumor, and particularly against the distribution pattern (oropharynx in the majority of cases) and the emergence rate of hidden primary lesions (<10% after comprehensive workup). The addition of systemic agents is expected to yield similar improvement in outcome as has been observed for known head and neck primary tumors. Head Neck, 2013