43 02

Many T3 and T4 hypopharynx cancers that are treated surgically will require total laryngectomy with efforts to preserve a posterior strip of the hypopharynx spanning the oropharynx to the esophagus. This preserved posterior wall of the hypopharynx may be tubed and closed on itself in selected cases. In the past it was common practice to accept primary reconstruction of this segment as adequate for swallowing with closure over a nasogastric tube. More recently primary closure has been discouraged for cases with less than a 3 to 3.5 cm width of posterior pharyngeal wall mucosa to tube on itself. Most commonly superior swallowing results when the anterior and lateral walls of the remaining hypopharynx are reconstructed with either pedicled or free flap reconstruction.
For more bulky tumors of the hypopharynx, total laryngopharyngectomy is required and refers to removal of the larynx and the entire hypopharynx. This procedure creates a gap between the oropharynx and esophagus that can be reconstructed with a tubed fasciocutaneous flap such as the radial forearm free flap or lateral thigh flap, a free jejunum, or a tubed pedicled myocutaneous flap. The myocutaneous flaps are technically difficult to tube due to the bulk of the fat and muscle underlying the skin paddle.
Laryngopharyngectomy with esophagectomy may be performed if the hypopharynx cancer extends inferior to the cricopharyngeus to ensure the inferior margin. In this case, reconstruction with a gastric pull-up or colon interposition are options used to restore the conduit for food and saliva extending from the oropharynx to the stomach.

Postoperative Radiation Therapy

In light of the deeply infiltrative nature of advanced hypopharynx cancers that are treated with initial surgical resection, the vast majority of patients are recommended to undergo adjuvant radiation therapy in an effort to enhance locoregional control rates. Classical indications for postoperative radiation include T4 primary tumors, close or positive microscopic margins, cartilage/bony invasion, >1 metastatic lymph node, or the presence of extracapsular extension (ECE). Conventional therapy involves the use of shrinking field techniques, as described previously, to deliver 54 to 63 Gy to all areas at risk and a boost to 60 to 66 Gy to regions of ECE and/or positive margins. The entire cervical nodal chain from the skull base to the clavicle bilaterally should be included. IMRT techniques may be considered in an attempt to reduce radiation dose to normal tissue structures such as the contralateral parotid gland and thereby preserve better salivary function.
Recently, the role of concurrent chemotherapy along with postoperative radiation has been evaluated in prospective randomized trials by the RTOG and European Organization for Research and Treatment of Cancer (EORTC). Eligibility criteria in the RTOG trial included patients with two or more positive nodes, ECE, or microscopically positive margins. All patients received 60 Gy alone or with concurrent cisplatin 100 mg/m2 every 3 weeks. This trial demonstrated an improvement in locoregional control and DFS for patients who received concurrent chemoradiotherapy. However, no significant benefit in absolute survival was confirmed (Table 43.7) (20). The EORTC conducted a similar trial that included patients with stage III (except T3 N0 larynx), stage IV, and patients with stage I or II with positive margins, lymphovascular invasion, and perineural invasion. All patients received 66 Gy alone or with cisplatin at 100 mg/m2 every 3 weeks. This trial demonstrated a significant improvement in progression-free survival and overall survival with the addition of chemotherapy (6) (Table 43.8).

Although the studies above identify that the addition of cisplatin chemotherapy to postoperative radiation can improve tumor control outcome for specific categories of high-risk patients, it is clear that this modest benefit comes at the expense of additional toxicity. Careful clinical judgment regarding the selection of patients most likely to tolerate and thereby benefit from this approach is warranted. In the definitive treatment setting, there is mounting evidence that patients >70 years of age derive little to no benefit from the addition of systemic chemotherapy to radiation in head and neck cancer (9,55). This is quite likely to be true in the postoperative head and neck cancer treatment setting as well. The inadvertent introduction of treatment breaks during the adjuvant radiation course can easily compromise the potential benefits of the combined modality therapy in this setting.
There is considerable interest in the use of molecular targeted therapies in the treatment of head and neck cancer patients. The most mature clinical data set in head and neck cancer involves the use of EGFR inhibitors such as cetuximab (monoclonal antibody against the EGFR). An international phase III trial comparing high-dose radiation alone versus radiation plus cetuximab in advanced head and neck cancer patients confirmed a locoregional control improvement (10% at 3 years) and overall survival advantage (10% at 3 years) with the addition of cetuximab (7). A relatively small subset of patients with hypopharynx cancer were enrolled in this study of 424 patients, and this subset did not demonstrate a clear advantage with use of the EGFR inhibitor treatment. Ongoing trials to examine the potential value of adding cetuximab to concurrent chemoradiation approaches in advanced head and neck cancer are in progress in both the definitive and high-risk postoperative settings.
Definitive Radiation Therapy
There are several reasons why hypopharynx cancer patients who are technically resectable may not undergo primary surgery. These include age (eg, patients >70 or 80 years old), the presence of significant medical comorbidities and/or patient unwillingness to accept total laryngectomy. Curative-intent radiation or chemoradiation is often pursued in these settings. Conventional radiation therapy commonly involves a shrinking three-field technique to deliver ~70 Gy in 2 Gy daily fractions to areas of gross disease and 50 to 60 Gy to areas of microscopic disease. If patients are scheduled to undergo postradiotherapy neck dissection, then gross nodal disease can be limited to 60 to 63 Gy. If patients are not candidates for postradiotherapy neck dissection, then gross nodal disease should be carried to 70 Gy. Altered fractionation regimens such as hyperfractionation or accelerated fractionation should be considered for patients being treated with radiation alone, as this approach has been demonstrated to improve the likelihood of locoregional tumor control (31).
In patients with adequate performance status, concurrent chemoradiation strategies using platinum-based chemotherapy should be considered. The most comprehensive meta-analysis to examine the benefit of chemotherapy in advanced head and neck cancer confirms a small but significant survival advantage for the use of chemotherapy, with the best gains observed with the use of concurrent platinum-based regimens (8%) (9,55).
P.967


P.968

However, this meta-analysis also confirms a steadily decreasing benefit for the use of chemotherapy with advancing patient age, such that no advantage is observed for patients >70 years of age. This same loss of statistical benefit for patients >70 years of age is also observed for the outcome gains derived from altered fractionation over conventional fractionation. Therefore, once daily radiation regimens (conventional technique or IMRT) may be quite reasonable for hypopharynx patients >70 years of age (or selected patients with modest performance status) rather than intensified fractionation regimens or the use of concurrent chemotherapy.

Recently, there has been renewed interest in the concept of induction chemotherapy approaches for patients with locoregionally advanced head and neck cancer, particularly with the introduction of taxane-containing regimens that offer promise to improve tumor response rates. Two randomized trials have been reported that compare induction 5-fluorouacil (5-FU) and cisplatin versus 5-FU, cisplatin, plus a taxane (37,73). Preliminary reports suggest a significant improvement in overall response rate with the addition of a taxane. In an effort to simultaneously enhance locoregional disease control and reduce distant metastases, several phase III trials are in progress that compare this sequential approach (triple agent induction chemotherapy followed by concurrent chemoradiation) versus concurrent chemoradiation (current standard of care) for patients with locoregionally advanced head and neck cancer (1). These aggressive approaches certainly appear worthy of controlled clinical investigation for head and neck subsites such as the hypopharynx, where the overall outcomes are poor and both locoregional control and distant metastases present a formidable challenge. Nevertheless, maturation of these trials is important before the ad hoc adoption of such complex, costly, and toxic treatment strategies. Careful assessment of tumor control, survival, and long-term functional outcome dovetailed with quality of life evaluation will be important to help place these regimens in the best perspective for advanced head and neck cancer patients.

Management of hypopharynx cancer has gradually evolved over the past decades to reflect the steady advancement of nonsurgical therapy. Data from the NCDB Benchmark reports addressing 3,519 cases diagnosed in 2000 to 2001 reveals the combination of radiation and chemotherapy to be the most common initial treatment overall (32.5%) for all stages of hypopharynx cancer (Fig. 43.10). Radiation as a single modality therapy was the most common initial treatment for stage I hypopharynx cancer (34%) followed by surgery alone (19.4%) as next most common (Fig. 43.11A). Chemoradiation was the most common treatment for stage II (34.4%), stage III (37%), and stage IV (35.7%) disease (Figs. 43.11B–D) (53).
Unresectable, Nonmetastatic Disease
The management of patients with unresectable locoregional disease without distant metastases is dependent on patient performance status. A patient with a good performance status may be offered definitive radiotherapy or concurrent chemotherapy as discussed above. In a randomized Intergroup trial of unresectable head and neck cancers, the addition of high-dose cisplatin to radiation was found to improve survival versus radiation alone, although at the expense of increased toxicity (2) (Table 43.9). However, patients with poor performance status who are not considered candidates for aggressive radiation or chemoradiation approaches should be managed with palliative intent. This may include short-course radiation regimens such as 4 to 5 Gy of five fractions over 1 to 2 weeks with a repeat of the same 3 weeks hence if favorable initial tolerance and response is achieved. Systemic chemotherapy alone can be considered, although for poor performance status patients, best supportive care with medical therapy and airway control may also be appropriate.
P.969


Metastatic Disease
As many as one quarter of hypopharynx cancer patients will develop metastatic disease at some point in their clinical course. In this setting, treatment is palliative and should be delivered to maximize or help maintain quality of life. If patients are having difficulty with local pain, bleeding, or swallowing, palliative short-course radiation therapy can be delivered as described above. Surgery may also provide a reasonable palliative option for selected patients who have incurable disease but significant symptoms related to their localized disease. If aspiration of secretions (despite no food by mouth status and enteral feedings) persists, laryngopharyngectomy may afford a reasonable option to discuss with the patient and family members. Similarly, complete stenosis of the pharynx or upper esophagus due to tumor (or following treatment) may leave a patient with constant need for suctioning his or her own secretions. In selected patients, laryngopharyngectomy with gastric pull-up may be a reasonable palliative option. Finally, G-tube placement can be considered for patients who do not wish to pursue palliative radiation therapy or surgery. Many patients in this setting will benefit from narcotic analgesics for pain management.
Patients with adequate or good performance status should be considered for palliative chemotherapy. Several agents have shown response for recurrent and metastatic (head and neck) cancer including cisplatin, carboplatin, 5-FU, methotrexate, docetaxel, or combination regimens based on platinum or taxane and the more recent introduction of molecular targeted therapies including the EGFR inhibitors (17,19). A randomized trial has been reported comparing the efficacy of cisplatin
P.970

alone compared with two multiagent regimens: (a) cisplatin and 5-FU and (b) cisplatin, 5-FU, bleomycin, and vincristine. Although the combination regimens demonstrated higher tumor response rates, this did not translate into a significant difference in median survival between the three arms. The combination arms were more toxic (16). In the 1990s there was significant interest in incorporating taxanes into regimens for recurrent and metastatic head and neck cancer. A randomized trial comparing cisplatin and 5-FU to cisplatin and paclitaxel demonstrated similar response rates, median survival, and 1-year survival. The cisplatin and 5-FU arm was more toxic to administer (33). There has also been significant interest in incorporating targeted therapies such as the EGFR inhibitors for head and neck cancer patients with metastatic or recurrent disease. These agents generally elicit modest response rates when given as single agents. For example, cetuximab, gefitinib, and erlotinib have generated response rates of 13%, 11%, and 4%, respectively as single agents in head and neck cancer (18,62,72). There is interest in combining traditional cytotoxic chemotherapy agents with targeted agents to improve overall outcomes. A trial comparing cisplatin alone or in combination with cetuximab demonstrated improved response rates with cetuximab, but no significant improvement in progression-free survival or overall survival (13).
P.971


Complicazioni
Chirurgia
The complications from surgery generally fall within the confines of bleeding, infection, reaction to the anesthesia, and damage to structures around or in the field of surgery. The damage to the laryngopharynx that occurs in the course of removing those tissues involved by cancer necessarily interferes with key laryngeal functions: breathing, swallowing, and speaking.
If an effort is made to preserve laryngeal function, some compromise may be required. A long-term tracheotomy, no food by mouth status with the use of gastrostomy feedings, and/or significant dysphonia are not uncommon for patients with hypopharynx cancer treated with conservation laryngeal surgery. These same complications may attend the more comprehensive laryngopharyngectomy as well. Stenosis of the neopharynx, difficulty with alaryngeal speech, and stomal stenosis may compromise the same functions ordinarily ascribed to the larynx. For all open surgical approaches, the risk of a salivary fistula is greatest for those patients previously treated with radiation. Although salivary fistulas are rare with endoscopic approaches, they have occurred in cases requiring aggressive laser resection.
Radioterapia
During a course of head and neck radiation therapy, there are predictable side effects that are experienced by the majority of patients: mucositis, fatigue, loss of taste acuity, radiation dermatitis, and xerostomia. Typically patients will begin to experience mucositis during the 3rd week of radiotherapy. This initially manifests as mucosal blanching within the treatment field, but can progress to patchy or confluent mucositis. Initially patients can be treated with an over-the-counter pain reliever, but once patients develop grade II or III mucositis, they will commonly require narcotic analgesics for adequate pain control. The combination of dysphagia and mucositis can result in significant nutritional compromise, necessitating intravenous hydration and parenteral nutritional supplementation. Nausea associated with treatment can also further complicate the nutritional status. These acute toxicities can become particularly pronounced in the setting of intensified radiation fractionation schedules and/or combined chemoradiotherapy. Patients may require prophylactic antiemetics. In patients receiving concurrent radiotherapy and platinum-based chemotherapy, there is clear potential for myelosuppression; therefore, blood counts should be monitored regularly. Signs or symptoms of infection should be addressed promptly. Finally, xerostomia can become problematic during the course of radiation. Ultimately, patients can be reassured that the majority of these side effects, with the exception of xerostomia, are temporary and will resolve several weeks to months following completion of therapy.
As noted, one of the acute side effects of radiotherapy that can become permanent is xerostomia. Chemical and physical modifiers of the radiation response have been utilized to reduce long-term xerostomia. The free-radical scavenger amifostine has the potential to reduce radiation effects on normal tissues if administered just prior to each radiation fraction. A randomized phase III trial demonstrated a reduction in the severity of the acute and chronic grade 2 or higher xerostomia in patients who received amifostine during RT (11). Dose-limiting toxicities commonly include hypotension and nausea. However, more recent reviews have called into question the ultimate value of amifostine in patients with advanced head and neck cancer, and currently there is no universal standard recommendation across treatment centers for the use of this radioprotector (40,76).
IMRT or tomotherapy techniques allow the clinician to physically modify the radiation dose distribution in an effort to spare critical normal tissues. This approach has been used increasingly for (head and neck) cancer patients to reduce radiation dose to the major salivary glands. A dosimetric analysis comparing radiation dose to the parotid gland and postradiation salivary function demonstrates that limiting mean dose to the parotid gland to <26 Gy is associated with improved postradiation salivary function (25).
In some cases, hypopharynx cancer patients who complete a course of radiation therapy will be noted to have persistent laryngeal edema on subsequent follow-up visits. Although in the early posttreatment phase (in fact up to 24 months), significant or newfound edema should raise suspicion regarding the possibility of persistent or recurrent disease, the majority of patients who receive high-dose radiation across major segments of the larynx and hypopharynx will manifest some degree of edema, mucosal congestion, and eventual fibrosis (see Fig. 43.4B). Generally, this collateral damage is a tolerable chronic toxicity with modest impact on patient quality of life. However, in approximately 10% to 15% of patients, this edema is severe enough to cause significant airway and swallow function compromise requiring tracheostomy.
Outcomes
There are several institutional reports of radiation therapy alone in the management of hypopharynx cancer. It is difficult to compare directly the results between surgically treated patients and radiation treated patients because there is often a selection bias whereby some patients are selected for surgery and others referred for radiotherapy. The University of Florida has systematically reported their results with radiation alone for patients with hypopharynx cancer (Tables 43.10, 43.11 and 43.12) (3,27).
In an effort to examine the potential for organ preservation in patients with advanced cancers of the hypopharynx, the EORTC conducted a randomized trial for patients who would require total laryngectomy as a surgical approach. This trial randomly allocated patients to induction chemotherapy with cisplatin and 5-florouracil followed by definitive radiation versus primary surgical resection and postoperative radiation. With a median follow-up of 10 years, this trial demonstrated no significant difference in 5- or 10-year overall survival or progression-free survival. Of note, two thirds of living patients in the chemoradiotherapy arm were able to retain their larynx (43).
P.972


Long-Term Follow-Up
Regardless of whether patients undergo primary surgery or radiation therapy, there is value in close posttreatment surveillance by head and neck surgeon and radiation oncologist. During the first 6 months after treatment, patients should be followed every 4 to 6 weeks with clinical examination, including fiberoptic nasopharyngoscopy. Recommended guidelines include a follow-up visit every 1 to 3 months during the first year, every 2 to 4 months for the second year, every 4 to 6 months for years 3 through 5, and every 6 to 12 months thereafter. Additionally, if the patient received comprehensive head and neck radiation, the serum thyrotropin should be measured every 6 to 12 months. Imaging evaluation of the neck most commonly with CT or MRI scan are obtained at 3 to 6 month intervals during the first 2 years or as indicated based on clinical findings. Functional imaging with 18FDG-PET can sometimes prove valuable to help differentiate posttreatment fibrosis from persistent or recurrent disease.
A study by Hermans et al. (36) examined findings on CT scan of the neck 3 to 4 months following completion of radiation therapy for patients with larynx or hypopharynx cancer to examine correlation with long-term outcome. The authors suggest that in patients achieving complete radiographic resolution of all pretreatment disease, the likelihood of subsequent local failure is very small. These patients might therefore undergo routine clinical examination with repeat imaging reserved for instances where the clinical examination becomes suspicious for recurrence. For patients who achieved <50% reduction in tumor volume or retained a mass ≥1 cm on the posttreatment imaging study, the likelihood of local failure was 100% and 30%, respectively. In these patients, repeat CT at 3 to 4 months, FDG PET, or biopsy is therefore recommended. Preliminary reports indicate that the results of the first post-RT FDG-PET scan may be a strong predictor of developing locoregional disease recurrence (78).

In the posttreatment setting of hypopharynx cancer patients, the involvement of an experienced head and neck radiologist is highly desirable for optimal interpretation of imaging results. Soft-tissue changes following ablative surgery and reconstruction or following high-dose radiation or chemoradiation with resultant edema and fibrosis can be very difficult to differentiate from tumor, particularly for the inexperienced reader.
Management of Recurrence
After completion of treatment, patients should be followed closely for signs of recurrent or persistent disease. If recurrence is suspected, this should generally be confirmed by biopsy. If biopsy is confirmatory, then the patient should undergo complete restaging to assess the extent of disease. In the setting of local or regional disease alone, patients treated with initial radiation or chemoradiation can be considered for surgical salvage therapy. Although salvage surgery following comprehensive head and neck radiation and chemotherapy presents several resection and reconstructive healing challenges for the surgeon, selected patients may still derive long-term benefit from this approach. Recurrent patients who initially received comprehensive head and neck radiation have traditionally not been considered good candidates for repeat high-dose radiation in light of normal tissue tolerances. However, with the advent of highly conformal radiation delivery techniques, selected patients may benefit from reirradiation approaches in conjunction with systemic chemotherapy (77). Many patients with recurrent disease, however, are not good candidates for aggressive surgery or radiation salvage therapy and are best served with systemic chemotherapy and/or best supportive care approaches.
In the setting of distant metastatic disease, further treatment will focus on palliative goals. If the patient is experiencing significant local symptoms in the setting of asymptomatic distant metastases, palliative surgery or radiation may still warrant

P.973

consideration. Most patients with distant metastatic disease and adequate performance status should be considered for systemic therapy and/or best supportive care options.
Quality of Life
Assessment of parameters including functional status, organ preservation, treatment cost, and patient-assessment of quality of life play an increasingly important role in the evaluation of overall treatment efficacy. For larynx and hypopharynx cancer patients, a focus of contemporary clinical investigation has been the study of treatments designed to preserve laryngeal function for patients traditionally treated with total laryngectomy. A frequently cited but somewhat controversial study by McNeil et al. (46) employed a questionnaire administered to healthy individuals and concluded that some might forgo total laryngectomy in favor of alternative therapy even if this choice diminished their ultimate chance for cure. A more recent report by El-Deiry et al. (26) evaluated long-term quality of life in a matched pair analysis comparing the surgical and nonsurgical treatment of patients with advanced head and neck cancer involving the oropharynx, hypopharynx, and larynx. Although patients in the surgery arm demonstrated worse speech outcomes than those treated with chemoradiation, this difference did not carry over to the overall quality of life score. These investigators concluded that, although it seems reasonable that organ preservation (nonsurgical) treatment will uniformly result in a higher quality of life, the complexities of human adjustment and multitude of potential treatment effects render this assumption invalid for many patients.
There have been relatively few prospective assessments of quality of life following treatment for head and neck cancer. In a subset of locally advanced patients requiring radical surgery such as total laryngectomy and partial pharyngectomy, the functional deficits are predictable. However, for patients undergoing “organ preservation” with radiation alone or in combination with chemotherapy, it can be difficult to assess the true extent and quality of organ preservation. Regardless of the primary treatment approach, these patients often require long-term speech, swallow, and dental rehabilitation. A study from Meyer et al. (49) retrospectively assessed speech intelligibility and quality of life in survivors of head and neck cancer. A total of 64 patients were enrolled; 31 underwent RT alone, five surgery alone, and 28 received both. All patients underwent comprehensive subjective and objective testing of speech function and quality of life. They found significant subjective and objective deficits in speech and quality of life even 5 years after completion of therapy. Terrell et al. (69) reported the results of a self-administered health survey of 570 patients at a Veteran's Administration hospital that demonstrated that the single most notable event having a negative impact on Quality of life was placement of a feeding tube. This was followed by medical comorbid conditions, presence of a tracheotomy tube, chemotherapy, and neck dissection.
A prospective study on quality of life utilizing the EORTC QLQ-C30 and QLQ-head and neck 35 questionnaires was conducted in Sweden on 357 patients. This study found that quality of life issues were significantly associated with the site of origin, with stage at diagnosis being the most important predictor. Additionally, patients with hypopharynx cancer exhibited the poorest quality of life (35). A study from the University of South Carolina compared swallow related quality of life after surgery or radiotherapy for head and neck cancer using a dysphagia risk factor survey, the MD Anderson Dysphagia Inventory (MDADI). They found significantly better scores on the emotional and functional components of the MDADI for patients undergoing chemoradiation compared to those undergoing surgery followed by radiation (34).
Conclusion
Patients with cancers of the hypopharynx commonly present with advanced disease associated with varying degrees of compromise in speech and/or swallow function. Many hypopharynx cancer patients also carry significant medical and social comorbidities. Typically, small T1–2 lesions can be managed with either primary radiation or surgery with similar clinical outcome. For intermediate stage disease that would require laryngopharyngectomy for the surgical approach, an increasingly preferred treatment option is combined chemoradiation that has demonstrated equivalence to immediate surgery in cancer survival, however, with improved organ preservation and functional outcome. For bulky hypopharynx tumors with significant airway compromise, laryngeal distortion, and cartilage destruction, it is generally best to proceed with definitive surgery with postoperative radiation or chemoradiation. Despite an aggressive approach in the overall management of hypopharynx cancer patients, ultimate cure rates remain quite poor. There are relatively few early stage patients, and for many advanced stage patients it is difficult to achieve long-term control. Even for those patients with excellent response to therapy, there exists a continuous risk for the development of second malignancies, particularly of the upper aerodigestive track with long-term follow-up. Posttreatment patients often require aggressive speech and swallow therapy to maximize their functional outcome. There is significant interest in the incorporation of molecular targeted therapies in combination with traditional cytotoxic therapy and radiation in an effort to improve outcomes.