Radiotherapy and Chemotherapy of Squamous Cell Carcinomas of the Hypopharynx and Esophagus

Introduction

The hypopharynx and cervical esophagus are contiguous structures, and malignancies arising from them share many features, including certain risk factors, presentation, and treatment approaches. Squamous cell carcinoma (SCC) in these regions often presents at an advanced stage and demonstrates a propensity for local, regional, and distant spread. Treatment for malignancies in this area consists of various combinations of surgery, radiotherapy (RT), and chemotherapy. The optimal combination and sequencing of therapies depend on multiple factors, including stage and location of disease, as well as patient performance status and goals of care. Owing to the need to consider the relative risks and benefits of potential treatment modalities, these patients are often best served by a multidisciplinary team. In this chapter, we will review and contextualize the available evidence for various treatment approaches.

Hypopharyngeal Cancer: General Principles

The hypopharynx comprises the portion of the aerodigestive tract extending from the hyoid bone to the cricoid cartilage and consists of three subsites: the pyriform sinus, postcricoid area, and pharyngeal wall. It is bordered superiorly by the oropharynx and inferiorly by the esophagus. The most commonly involved subsite in the United States, Canada, and much of Europe is the pyriform sinus, although there is geographic variability in the relative frequencies of subsite involvement. The most common type of malignancy arising from the hypopharynx is SCC, although other histologies, including, but not limited to, spindle cell carcinoma, basaloid SCC, adenosquamous carcinoma, and lymphoma, are also observed. SCC of the hypopharynx is relatively rare in the United States and Canada, where it accounts for less than 10% of all head and neck cancers (HNCs) and where its incidence is decreasing. However, hypopharyngeal cancer is more common in certain other countries, including France, India, and Japan.

Hypopharyngeal SCC is more common in men than in women and most often arises in the seventh decade of life. The most important risk factors for hypopharyngeal cancer are tobacco smoking and alcohol consumption, with other factors, such as gastroesophageal reflux and nutritional deficiencies, carrying less significant risk. Postcricoid SCC can arise in the setting of Plummer-Vinson syndrome (also called Paterson-Brown-Kelly syndrome), which, although rare, is more common in women. Emerging evidence suggests that human papillomavirus (HPV) may be an etiologic agent in hypopharyngeal SCC, although much less commonly than in oropharyngeal SCC. While some studies have suggested that HPV positivity may correlate with improved outcomes, this result has not been consistent in all studies, and the prognostic utility of HPV and/or p16 in hypopharyngeal SCC remains poorly understood.

Patients with hypopharyngeal SCC often present with advanced disease, with 50% to 70% presenting with regional lymph node metastases and approximately 70% with at least stage III. One reason for this phenomenon is that hypopharyngeal SCC, owing to its anatomic location, is unlikely to cause significant symptoms until it is locoregionally advanced. A painless, enlarged cervical lymph node is the most common presenting symptom, occurring in approximately 50% of patients. Other presenting symptoms include dysphagia, sore throat, hoarseness because of involvement of the larynx or recurrent laryngeal nerve, and referred otalgia because of involvement of branches of cranial nerve X.

Prognosis of patients with hypopharyngeal SCC is poorer than that of many other HNCs, with an estimated 5-year overall survival for all stages of approximately 30%. This is partially due to the advanced stage at which many patients present but also reflects the prevalence of comorbid conditions and challenges to definitive treatment.

Owing to its relative rarity in comparison with other HNCs, dedicated hypopharyngeal clinical trials are lacking. Therefore, much of the data that guide treatment decisions for hypopharyngeal SCC must be taken from studies that include HNC of multiple sites. This is an important caveat to consider when interpreting and applying results of the studies discussed throughout this chapter.

Treatment of Early-Stage Hypopharyngeal Squamous Cell Carcinoma

Treatment of early-stage hypopharyngeal SCC largely consists of surgery or RT alone. Surgical options for early-stage hypopharyngeal SCC include an open approach via a partial laryngectomy with partial pharyngectomy typically in tumors of the pyriform sinus and partial lateral or posterior hypopharyngectomy in tumors of the hypopharynx anatomically distant from the larynx. A transoral approach via CO ₂ laser surgery is another strategy that has shown acceptable efficacy, although a minority of tumors is amenable to this approach. As is the case with other HNC sites, transoral robotic surgery (TORS) has become increasingly used for hypopharyngeal cancer, with promising results in early-stage disease. Definitive RT alone is another option, with some series demonstrating similar disease control rates and slightly better functional outcomes. In the setting of either upfront surgery or RT, the patient must be counseled on the potential need for adjuvant or salvage treatment.

Historical Treatment of Advanced Hypopharyngeal Squamous Cell Carcinoma

Treatment of resectable, advanced hypopharyngeal SCC has traditionally consisted of surgery and postoperative RT (PORT). While this approach is associated with high rates of locoregional control (approximately 85%), the combination of surgery and RT is relatively morbid. In addition, rates of 5-year overall survival in these patients are low (approximately 35%), which is largely due to high rates of distant metastasis. In an attempt to identify a less morbid treatment, RT alone has been investigated. However, in multiple studies, RT alone was associated with poor rates of disease control and survival. Given these results, methods to improve oncologic and functional outcomes in patients with hypopharyngeal SCC have been pursued.

Chemotherapy in Surgically Treated Hypopharyngeal Squamous Cell Carcinoma

While initially used only as palliative treatment, with the introduction of platinum-based agents in the 1980s, chemotherapy assumed a more prominent role in definitive therapy for HNC. Response rates to platinum-based chemotherapy are quite high in HNC, with partial responses in 40% to 50% of patients, complete responses in 26% to 50%, and any response in 78% to 95%. Despite this, many early studies investigating the addition of chemotherapy either prior to or following surgery and PORT did not show a benefit. In 1990, the European Organisation for Research and Treatment of Cancer (EORTC) Head and Neck Group reported results of a randomized clinical trial that investigated the addition of neoadjuvant vincristine, bleomycin, and methotrexate to surgery and PORT. The authors found no improvement in outcomes from the addition of this preoperative chemotherapy regimen. Similarly, a trial conducted at the Institut Gustave Roussy demonstrated no improvement from the addition of cisplatin and fluorouracil (FU) administered prior to and following surgery and PORT.

As preoperative and postoperative chemotherapy did not improve outcomes in surgically treated patients, efforts then shifted to investigate the addition of concurrent chemotherapy to PORT in high-risk patients. Radiation Therapy Oncology Group (RTOG) 95-01 investigated the addition of cisplatin delivered concomitantly with PORT for patients with HNC with at least one pathologic feature of two or more positive lymph nodes, extracapsular spread, or positive resection margin. In all patients, the addition of chemotherapy was not associated with significantly improved outcomes. However, in patients with either a positive resection margin or extracapsular spread, concurrent chemotherapy and RT (CRT) was associated with decreased rates of 10-year locoregional failure (21.0% vs. 33.1%; P = .02), improved disease-free survival (18.4% vs. 12.3%; P = .05), and improved overall survival (27.1% vs. 19.6%; P = .07).

EORTC 22951 was a similar trial that investigated the addition cisplatin to PORT in patients with stage III/IV HNC with at least one pathologic feature of two or more positive lymph nodes, extracapsular spread, positive margins, vascular embolisms, perineural invasion, or positive lymph nodes in Levels IV or V. In this study, CRT was associated with improved 5-year progression-free survival (47% vs. 36%; P = .04), overall survival (53% vs. 40%; P = .02), and cumulative incidence of local or regional relapses (18% vs. 31%; P = .007). A combined analysis of the EORTC and RTOG trials identified patients with positive margins and/or extracapsular spread as those who derive an overall survival benefit from the addition of chemotherapy to PORT. It is important to note that these trials were conducted in patients with HNC of multiple sites, with only 10% of patients on RTOG 95-01 and 20% of patients on EORTC 22951 having been treated for hypopharyngeal cancer.

In summary, for patients treated surgically for hypopharyngeal SCC, chemotherapy should be used concomitantly with PORT for patients with high-risk features of positive surgical margin and/or extracapsular extension. Routine use of chemotherapy prior to planned surgery or following surgery without high-risk features is not supported. An exception to this recommendation is the use of neoadjuvant chemotherapy for bioselection in larynx-preserving treatment, as discussed in the following sections.