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Normal tissue tolerance limits the delivery of both ionizing radiation and cytotoxic chemotherapy for virtually all types of cancer including squamous cell carcinoma of the head and neck (HNSCC). The concept of the therapeutic ratio (TR) is fundamental to the understanding of this issue. The TR can be qualitatively defined as the TCP/NTCP where TCP is the tumor control probability and NTCP is the normal tissue complication probability. Both of these parameters have sigmoid dose-response curves Fig.1. The horizontal separation between these two curves for any given treatment will often determine the efficacy of that treatment. As the curves separate from one another, the likelihood increases that treatment will be effective and not cause an unacceptable level of morbidity. Conversely, the closer together these two curves are, the less the likelihood is that treatment will be effective without causing an unacceptable level of morbidity. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy that is the sixth most common neoplasm worldwide, with close to 5000 new cases diagnosed yearly in the United States (estimated to be 56,520 cases in 2004 [1]) and 600,000 worldwide according to the latest numbers from the International Agency for Research on Cancer, World Health Organization. HNSCC accounts for 2% of all cancer deaths in the United States (2) and is the most common epithelial neoplasm of the upper aerodigestive tract. It constitutes a major health care problem and is clearly associated with well-known risk factors such as tobacco smoking and alcohol use. The management of HNSCC is complex and the morbidity of treatment is life-long. Despite the numerous advances in its treatment, the long-term survival still does not exceed 45% and has only marginally improved over the last decades (3). [ABSTRACT FROM AUTHOR]

Approximately 5% of all cancers arise from the head and neck region (1,2). Patients with head and neck squamous cell cancers (HNSCC) have unique problems related both to the course of their disease and treatment. Pain from surgery and radiation is a particularly difficult problem and becomes a major problem with recurrence due to the high propensity for local erosive metastases in areas that are richly innervated (3). Pain occurs in 31% of patients at presentation but becomes a progressive problem during therapy. Seventy-four percent will experience pain near the end of treatment, and at least one out of four will have significant chronic pain 2 yr after treatment (4-6). Eating disturbances will peak near the end of treatment related to both the disease and the pain of mucositis. Most patients will lose at least 2 kg during treatment. The incidence of mucositis secondary to treatment is as high as 80%, and over half of those receiving intensive radiation combined with chemotherapy will have a grade 3-4 mucositis. Hospitalization owing to mucositis will occur in 16 to 33% of patients treated with radiation. Despite receiving analgesics and topical anesthetics, over one-third of treatment days will be spent in severe pain (7,8). [ABSTRACT FROM AUTHOR]

Quality of life (QOL) has commanded growing attention within oncology in recent years. Adverse changes in functional and behavioral outcomes are a special concern in patients with head and neck squamous cell cancer (HNSCC), because these malignancies disrupt basic aspects of daily life such as eating, respiration, and communication. These difficulties are greatly amplified by demanding treatment toxicities. Thus, there is growing recognition that traditional clinical endpoints such as tumor response and disease-free survival need to be supplemented by indices of QOL. This development has been given further impetus lately by patient advocacy and by the introduction of improved QOL measures. In this chapter, we briefly discuss advances in QOL assessment, review research findings regarding acute and long-term QOL outcomes, and consider important determinants of risk and resilience. [ABSTRACT FROM AUTHOR]

It is generally recognized that the unregulated growth of cancer cells results from sequential acquisition of mutations in genes that control growth and/or differentiation of cells or are involved in protection of the genome. Cancer develops when the accumulation of these alterations allows for a growth advantage over normal surrounding cells (1). The pathogenesis of cancer can be described as follows: Oncogenes are altered normal genes (called protooncogenes) that mediate normal cell growth and differentiation. Gain-of-function (dominant) mutations affect these genes to induce the neoplastic phenotype. Tumor suppressor genes are genes that normally inhibit cellular function. Loss-of-function (recessive) mutations alter their inhibitory properties, leading to unimpeded proliferation. Gene therapy aims to change these genetic alterations so that cancer cell growth can be suppressed. After a gene is transfected into a cell, mRNA is transcribed, and then its protein product is translated. [ABSTRACT FROM AUTHOR]

With about half a million cases diagnosed yearly worldwide (1), head and neck squamous cell cancers (HNSCCs) represent 4 to 5% of all solid malignancies. The prognosis of locally advanced stages, which are found in at least 40% of oral cavity and pharynx carcinomas, remains dismal: in the United States the 5-yr relative survival rates for the period 1989-1995 hardly reached 50%. At the time of diagnosis, distant metastases are found in less than 10% of the cases and until the late 1980s, this disease feature led investigators to focus on local treatment. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma of the head and neck (HNSCC) can be treated with various modalities including radiotherapy, chemotherapy, and surgery. These are often employed in combination, with each playing a substantial and complementary role. Using a multidisciplinary approach, investigators have recently been able to achieve improved survival outcomes for patients with locally advanced, nonmetastatic disease—including both increased long-term survival rates (now approaching 70% in recent reports) (1-]3) and organ preservation (4,5). Nevertheless, in approx 50% of high-risk patients tumors will recur (1-3,6), often with distant metastasis, making the cancer incurable and shifting the treatment goal toward palliation. In addition, short- and long-term toxicities of combination therapy are significant, with xerostomia, esophageal strictures, dysphagia, and increased aspiration risk commonly encountered. [ABSTRACT FROM AUTHOR]

Depending on the site and extent of disease, treatment alternatives for T3-T4 cancers include partial laryngectomy, total laryngectomy, and radiation therapy (RT) alone or combined with adjuvant chemotherapy. The prevailing treatment philosophy varies significantly from one country to another (1). Patients in the United States and Australia are usually treated surgically, which often necessitates total laryngectomy (1). In contrast, patients in Canada and Great Britain are often treated with RT alone, with surgery reserved as salvage treatment for those who experience recurrent disease. Patients treated with RT in the United States sometimes receive induction chemotherapy before RT (2). The rationale for this strategy is based on the Veterans Affairs Laryngeal Cancer Study Group trial which compared induction chemotherapy and RT (in the subset of patients who responded to chemotherapy) with initial laryngectomy and postoperative RT; survival rates were similar, and patients randomized to the induction chemotherapy arm had a higher rate of laryngeal voice preservation (3). A similar trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) evaluated induction chemotherapy followed by RT for patients who had a complete response to treatment for advanced pyriform sinus and aryepiglottic fold malignancies (4). Patients randomized to receive induction chemotherapy had 5-yr survival rates similar to those for patients randomized to undergo initial surgery. Approximately one-third of patients who received induction chemotherapy retained their larynx. More recently, concomitant chemoradiation has gained popularity because it has been shown to improve survival compared with RT alone for patients with local-regionally advanced head and neck cancer. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) of the endemic type (World Health Organization [WHO] type II and III) is considered separately from head and neck squamous cell cancer (HNSCC) because of certain distinctive features that confer a different biological behavior in terms of treatment responses and disease outcome. The most important feature that probably accounts for this difference is its strong association with the Epstein-Barr virus (EBV) (1-]3). This virus is probably the key etiological agent in the pathogenesis of this cancer, with genetic predisposition and other environmental factors as important cofactors (4-13). This is in line with the peculiar geographic distribution and racial predilection of this disease. [ABSTRACT FROM AUTHOR]

Initial efforts to integrate systemic chemotherapy into the definitive management of squamous cell head and neck cancer focused on sequential treatment schedules. Given the impressive response rates seen with multiagent chemotherapy in previously untreated patients, considerable effort went into the study of induction or neoadjuvant treatment schedules (1). Numerous randomized trials have now been completed. Although induction chemotherapy has been generally well tolerated, and appears to decrease the likelihood of distant metastatic disease, no consistent survival benefit has been demonstrated from this treatment approach alone (2). [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma of the head and neck (HNSCC) represents 5% of newly diagnosed cancers in adult patients seen in the United States. Although HNSCC is a highly curable malignancy when diagnosed at an early stage, many patients present with advanced local-regional disease. Locally advanced disease can be separated into either intermediate (stage III; T3N0M0 or T1-3N1M0) or advanced (stage IV; T4N0-1M0 or T1-4N2-3M0) (1). Stage III patients are generally resectable, and although their prognosis is better a stage IV patients, the prognosis for all these patients, particularly those who are unresectable has remained poor (1-8). The potential for surgical resection, whether surgery is advised or not, defines a better prognosis than the presence of unresectable disease. Thus resectability, site, stage, and performance status are the major prognostic factors for patients with HNSCC. Standard therapy with surgery and/or radiotherapy can be associated with significant morbidity and functional disability, particularly when the tumor arises in the larynx, piriform sinus, or oropharynx (9). In addition, despite aggressive local therapy with surgery or radiotherapy, between 50 and 60% will develop locoregional recurrences, and 20 to 30% will develop distant metastases within 2 yr. Only 20 to 45% will remain disease free and alive at 3 yr. [ABSTRACT FROM AUTHOR]

It has been known for more than 20 yr that cisplatin-based combination chemotherapy can achieve overall response rates of 70 to 90%, with complete response rates of 20 to 50% in patients with previously untreated locally advanced head and neck cancer (1,2). The use of chemotherapy prior to radiation or surgery is commonly referred to as induction or neoadjuvant chemotherapy. Investigators hypothesized that the addition of an active induction regimen prior to definitive radiotherapy or surgery would have a significant beneficial impact on the outcome of treatment for patients with locally advanced squamous cell carcinoma of the head and neck. As well as the potential to decrease distant metastases, it was hoped that significant tumor shrinkage could contribute to improved local-regional control, and facilitate organ preservation (3). Early single-arm trials confirmed the activity of platinum-based induction regimens and established that sequential induction chemotherapy and radiation was feasible, without any apparent increase in radiation toxicity (4). [ABSTRACT FROM AUTHOR]

Tumor hypoxia, or the condition of low tumor oxygenation, has been a focus of considerable debate in radiation therapy for almost 50 yr since the pioneering work of Gray and colleagues (1) demonstrating an oxygen dependency in the radiosensitivity of cells and tissues. During this period, interest among researchers has waxed and waned as promising new directions emerged from the laboratory, only to fail in clinical trials. However, with the emergence of new concepts and the development of new tools, the prospect of targeting tumor hypoxia and identifying patients who would most benefit from this approach appears more tangible clinically. This chapter discusses the significance of tumor hypoxia in head and neck squamous cell carcinomas (HNSCC) as well as past, present, and future strategies for targeting this microenvironmental factor. [ABSTRACT FROM AUTHOR]

Fractionation deserves a second look in light of the explosive growth and development of radiation therapy. With the progress we have just seen in the manipulation and delivery of cytotoxic agents in conjunction with radiotherapy, there are now new avenues to explore as the classical dose and fraction size limits may no longer apply. Technological developments in physics, computing, and imaging over the past three decades culminated at the end of the 1990s in the ability to deliver elaborate 3D high-dose volumes to precisely defined targets. The traditional dose limits that are based on the tolerated dose to surrounding normal tissues may no longer be limiting since normal tissues are now avoided to a large extent. Can dose now be safely escalated using altered fractionation? Will the reduced toxicity also permit further exploration of concurrent chemotherapy with altered fractionation? Will molecular image-guided boosts to smaller subvolumes improve tolerance of "hotter" fractionation regimes? Breakthroughs in tumor biology have opened exciting new opportunities to develop specific molecularly targeted strategies to selectively enhance tumor response to radiation. With the nonoverlapping set of toxicities of these agents, can they be safely administered concurrently with more intense radiotherapy fractionation regimes? [ABSTRACT FROM AUTHOR]

Head and neck cancer represents a complex collection of tumors involving mucosal surfaces of the upper aerodigestive tract. Approximately 43,000 cases are diagnosed each year in the United States, representing 3 to 4% of all cancers (1). Worldwide, head and neck cancer represents a much broader oncology problem (∼500,000 annual cases), with tumor development strongly associated with chronic tobacco and alcohol use. [ABSTRACT FROM AUTHOR]

Brachytherapy is an important armament available to the radiation oncologist treating cancers occurring in the head and neck region. It is all the more important in this era of organ preservation and improving quality of life (1,2). There are very few sites in the body where locoregional control is so vital to ultimate quality of life, organ function, and survival as in head and neck cancer. Brachytherapy permits dose intensification specifically to the tumor site while minimizing damage to the surrounding normal tissue and organs (3,4). This leads to an increased therapeutic ratio, while the patient also stands to gain functionally, psychologically, and cosmetically. [ABSTRACT FROM AUTHOR]

The past two decades have seen significant advances in the efficacy of combined chemotherapy and radiation in the management of advanced stage squamous cell carcinoma (SCC) of the head and neck. This is especially true for SCC of the oropharynx, hypopharynx, and larynx. Primary surgery for advanced T-stage tumors, despite sophisticated reconstruction of the surgical defect, may result in a significant impact on speech, swallowing, and respiration. Organ preservation protocols using definitive radiation with or without chemotherapy may provide an effective primary treatment while avoiding the functional and cosmetic morbidity associated with surgery. [ABSTRACT FROM AUTHOR]

Patients afflicted with selected laryngeal and hypopharyngeal cancers have garnered benefit from laryngeal preservation procedures for more than a century. Billroth performed the first hemilaryngectomy for malignancy in 1874 (1). Over the ensuing decades numerous procedures evolved to afford patients the maintenance of speech and swallowing without permanent tracheostomy. In 1947, Alonso (2,3) first described the open supraglottic laryngectomy to spare the true vocal cords and arytenoids by resecting the upper portion of the thyroid cartilage with the supraglottic structures. The procedure was popularized in Europe by Bocca and in the United States by Ogura, Som, and Kirchner (4). The boundaries of resection were pushed further by Majer and Reider (5) in 1959 with the introduction of the supracricoid partial laryngectomy, which provided an alternative to total laryngectomy for patients with selected glottic and supraglottic cancers. Critical review has provided refinements in these procedures. Specific indications have been established based on an improved understanding of surgical anatomy and patterns of tumor spread that have allowed for selected ablation of laryngeal components without the need for total laryngectomy and its associated morbidity. [ABSTRACT FROM AUTHOR]

Chemotherapy in combination with radiation therapy has evolved over the last several decades as an important modality in the treatment of head and neck squamous cell carcinoma. Because of the effectiveness of chemoradiation therapy at controlling disease at the primary site, ablative surgery is generally reserved for surgical salvage if chemoradiation fails to control primary site disease. However, the role of surgery in the treatment of regional neck metastases remains controversial. At the core of this controversy is whether chemoradiation alone is adequate to control neck metastases or whether adjunctive neck dissection should be added for effective control. [ABSTRACT FROM AUTHOR]

Lasers have broad applications in otolaryngology. The myriad possible uses result from the combination of many different anatomic subsites, different types of pathology (both benign and malignant), and several different types of available lasers. A comparison of the KTP laser for hemorrhagic hereditary telangectasias of the nasal cavity, for instance, with photodynamic therapy for esophageal lesions reveals the wide range of applications for laser technology in the head and neck region. It is difficult, however, to make generalizations about laser use when one considers such disparate functions, sites, and pathology. This chapter, then, is limited to a discussion of lasers in the management of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx. [ABSTRACT FROM AUTHOR]

The vast majority of patients with head and neck squamous cell carcinoma (HNSCC) report a history of tobacco and alcohol use. The risk of oral cancer increases as a function of both intensity and duration of each exposure, indicating that alcohol and tobacco act synergistically to promote cancer development (1-3). [ABSTRACT FROM AUTHOR]