Squamous cell carcinoma (SCC) of the hypopharynx is rare, consisting of 3%-5% of all head and neck SCC cases [1]. Hypopharynx is characterized with thin mucosal lining (< 1 cm) providing minimal barrier with propensity to submucosal spread. A rich lymphatic network of hypopharynx results in frequent lymph node metastases: ipsilateral nodal metastasis in 60%-80% and contralateral occult nodal metastasis in up to 40% [2] of patients at the time of diagnosis. Stage III or IV in 70%-85% patients are reported in large series, and 5-year survival is only 15%-45% [3].

The preservation of speech and swallowing function in the treatment of laryngeal and hypopharyngeal cancer is important. In early-stage disease, both surgery and radiotherapy (RT) are treatment options that preserve the organ and function [3,4]. For locally advanced hypopharyngeal cancer, traditional approach was laryngopharyngectomy and pharyngeal reconstruction with or without adjuvant RT, resulting in a loss of natural voice production. Addition of chemotherapy to RT alone in advanced cancer improved the outcome compared to surgery plus RT, while allowing larynx preservation [5]. However, no clear guidelines specific to hypopharyngeal cancer are available. Most evidences on laryngeal preservation are from laryngeal cancer or mixed head and neck cancer studies. A few studies reported treatment results dedicated to hypopharyngeal cancer, albeit of mixed population, including early stage cancers and advanced unresectable cancers [6].

We reviewed the treatment outcome of locally advanced resectable SCC of the hypopharynx, with comparative analysis between organ-preserving chemoradiotherapy (CRT) and radical surgery followed by adjuvant RT.

Selecting the optimal treatment strategy for locally advanced hypopharyngeal cancer needs to take into account the extent of the tumor, status of laryngeal function, and patients’ desire for voice preservation. Early stage hypopharyngeal cancer amenable to larynx preservation (most T1N0 and selected T2N0 tumors) may be treated by definitive RT alone or partial laryngopharyngectomy [3,4]. Concurrent CRT or induction chemotherapy, followed by CRT, is recommended for T4b or unresectable tumors [7]. It is the spectrum of disease that fall between these early and very advanced disease groups, namely locally advanced resectable hypopharyngeal cancer, that have several treatment options with no clear advantage of one treatment modality over another.

The current study makes a comparison between larynx preserving CRT and radical surgery followed by adjuvant RT, which are both feasible options for locally advanced resectable hypopharyngeal cancer. The 5-year DFS and OS of 52.1% and 57.4% for all patients were higher than or at least comparable to the results from previous studies [1,5,8]. In this study, the two treatment groups showed comparable DFS and OS. All patients in SRT group underwent adjuvant RT of median 60 Gy with or without concurrent chemotherapy. It is a well-known fact that postoperative RT or CRT improves tumor control in head and neck cancer patients with high risk features [9]. However, the cost of using adjuvant RT or CRT to improve disease control and survival may be substantial, namely increased treatment-related toxicities and prolongation of the total treatment time. Both treatment groups in the current study were subjected to RT; however, it is difficult to compare treatment-related complications attributable exclusively to RT, since all of the patients received multi-modality treatment. On the other hand, the SRT group experienced higher incidence of surgery-related complications, including wound infection, flap failure, stenosis, and fistula, while patients in the CRT group experienced such complications only when patients were subjected to salvage surgery after a local/regional failure (Table 4).

Another treatment-related complication, which is often overlooked, is a reduced rate of successful salvage treatment in case of treatment failure. In Fig. 1A and B, DFS curve for SRT is slightly higher than that of CRT, while OS curve for CRT is higher than that of SRT, especially through the later period of follow-up. Such reversal may have been caused by increased number of treatment-related toxicities, higher rate of unsuccessful salvage, or higher incidence of deaths unrelated to disease progression or toxicity during follow-up in the SRT group. Analysis of treatment outcome after local and/or regional failure suggests that CRT allowed more effective salvage treatment in comparison with SRT (Table 3). In the CRT group, six out of eight patients were salvaged through dissection of the primary tumor or recurrent cervical lymph nodes: salvage efforts were successful with three of these patients still alive without disease and three patients died of intercurrent death without evidence of recurrence. Outcome of salvage treatment in the SRT group was less than favorable. Eight of the 13 patients were treated with chemotherapy or re-irradiation, three patients did not receive any treatment, and only two patients received surgical resection of the recurrent tumor. All patients died of disease progression, except for the two patients who were salvaged successfully with re-irradiation and neck dissection. In a clinical setting, most patients who are treated with surgery for stage III/IV hypopharyngeal cancer also receive adjuvant RT or CRT. Options for salvage treatment after such intensive combined treatment are limited. These patients have already received radical resection of the primary tumor and/or ipsilateral or bilateral neck dissection, followed by radiation of 60 Gy or higher, which delivers maximum tolerable dose to the critical organs, such as pharyngeal swallowing muscles, spinal cord, and parotid glands. Salvage surgery or re-irradiation is extremely difficult, and chemotherapy alone, a remaining option, is often ineffective against gross recurrent tumor. On the other hand, definitive chemoradiotherapy showed disease control and survival that are comparable to the outcome of surgery plus adjuvant RT or CRT, and in the case of a treatment failure, salvage surgery often results in sustained disease control [5]. In a retrospective series, salvage surgery for failure after chemoradiotherapy has shown acceptable oncologic outcome with no local recurrence after salvage surgery [10].

There are concerns for increased toxicity from intensive chemoradiotherapy, such as impairment of pharyngeal swallowing muscles. Radiation dose to hypopharynx was associated with severe late toxicity in accordance to Radiation Therapy Oncology Group (RTOG) analysis [11], and functional outcome of CRT for head and neck cancer was not so promising, despite improved locoregional control [12]. In unsuccessful organ preservation attempts, failures in function preservation may result from either toxicity from aggressive CRT, extensive tumor infiltration into the organ at the time of diagnosis, or from progression of disease. Patients with functional impairment due to tumor infiltration should be excluded from organ preservation candidates. In this study, patients who had resectable tumor (< T4b) and intact laryngeal function were included for analysis, and outcome of larynx preserving CRT was compared to the outcome of radical surgery followed by adjuvant RT/CRT. The function preservation rate of 88.2% in the CRT group with loss of laryngeal function only due to local recurrence or complication of salvage surgery may lead to decisions favoring larynx preserving treatment options.

Previous studies on treatment outcome of head and neck cancer fail to take into account recent advances in treatment modalities and discovery of new prognostic factors. The use of IMRT allowed for a reduction of radiation-induced toxicity, improved local and regional control, and potential for improved survival in hypopharyngeal and other head and neck cancer patients [13]. The most important factors that contribute to morbidity in head and neck cancer patients undergoing intensive CRT are increased risk of dysphagia and aspiration. By more accurate delineation of target volumes and sparing of pharyngeal constrictors and supraglottic larynx, patients treated with IMRT experienced fewer swallowing problems than those treated with conventional RT [14]. Treatment deintensification in patients with human papillomavirus (HPV) positive oropharyngeal cancer is gaining interests [15]. A number of studies reported implication of HPV-positive hypopharyngeal cancer in organ preservation therapy [16,17]. Further investigations may allow deintensification in HPV-positive hypopharyngeal cancer and reduction of treatment-related toxicities while maintaining treatment outcome.

Efforts have been made to employ less than radical surgery for hypopharyngeal cancer. Partial pharyngectomy and even trans-oral resection of the tumor have been attempted with the purpose of organ preservation [3,18]. However, these limited surgery options should be explored with caution, especially in locally advanced cancer of the hypopharynx. In this study, the outcome of patients treated with partial laryngectomy and pharyngectomy was poor compared to the outcome of total laryngectomy. Close and positive resection margin was reported in six (35.3%) and five (29.4%) of the 17 patients who received larynx-sparing surgery and 11 (27.5%) and six (15%) of 40 patients who received total laryngectomy. Local failure occurred in three patients among the 40 who received total laryngectomy (7.5%) and in four among the 17 patients who received less than total laryngectomy (23.5%) (Table 3). Larynx preservation through avoidance of total laryngectomy does not seem to be effective due to its high rate of local failure. The incidence of submucosal extension is up to 58% [19], and pathological studies showed that extent of submucosal involvement measured from the edge of the tumor ranged 10-20 mm superiorly and 10-30 mm inferiorly [20,21], requiring resections margins of 3 cm inferiorly and 2 cm both superiorly and laterally. In locally advanced hypopharyngeal cancer, it is difficult to perform laryngeal preservation surgery while achieving adequate resection margins.

One of the limitations in the current study is the inclusion of a heterogeneous group of patients in the CRT group. The CRT group consists of patients treated with concurrent CRT as well as sequential CRT (induction chemotherapy plus RT or CRT). Recent reports on the induction chemotherapy for laryngeal preservation have shown equivalent outcome between sequential CRT and concurrent CRT [22,23]. The number of cases reviewed in the current study is relatively small, albeit only locally advanced resectable hypopharyngeal cancer cases are included for analysis. Disease characteristics of SCC of the hypopharynx are unique, and optimizing combined modality treatment needs to be explored further with a larger cohort of patients. In the current study, patient characteristics were well balanced between the SRT and CRT groups except for the proportion of female patients, and the use of IMRT were higher in the CRT group. In a univariate analysis, female sex and use of IMRT did not result in significant improvement in DFS and OS (Table 1). Although women have been found to achieve somewhat improved outcomes compared to men, this may in part be due to earlier-stage disease at diagnosis [24]. Moreover, the proportion of female patients (5.5%) was too small to cause a significant difference in the treatment outcome in this study. IMRT is superior over conventional RT in reducing radiation induced toxicities; however, its advantage in patient survival is unclear. In a randomized trial comparing IMRT and conventional RT for the treatment of oropharyngeal and hypopharyngeal SCC, IMRT was superior in preventing xerostomia; however, no significant differences were observed in non-xerostomia late toxicities, locoregional control or overall survival between IMRT and conventional RT [25].

Organ preservation is not to be confused with function preservation. For hypopharyngeal cancer, functions include voice and swallowing, as well as quality of life. In hypopharyngeal cancer with impaired laryngeal function at presentation, laryngopharyngectomy with pharyngeal reconstruction is a preferred option permeating aspiration-free deglutition and prosthetic voice instead of leaving intact but functionless larynx. However, definitive CRT may be preferred in locally advanced resectable hypopharyngeal cancer with intact laryngeal function, providing treatment outcome comparable to surgery plus RT or CRT, while shortening total treatment time and proving a salvage chance in the case of local/regional failure.