This article reviews the management of laryngeal and hypopharyngeal squamous cell carcinoma. Available therapies for early and late stage cancers are discussed, and the literature is reviewed. The indications and outcomes of surgical and nonsurgical modalities are discussed and compared.
Key points
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Multidisciplinary management, including surgery, radiation, and medical oncology, with speech and swallow therapy, is essential for optimal outcomes in laryngeal and hypopharyngeal cancers.
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Transoral surgical techniques provide equal or better oncologic and functional outcomes compared with open surgical techniques and definitive radiation for appropriate candidates.
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Multimodality therapy is essential to achieve control in advanced disease.
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Organ preservation protocols using concurrent chemoradiation result in similar oncologic outcomes while maintaining laryngeal preservation for select tumors compared with initial total laryngectomy.
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Long-term surveillance allows for early detection of second primary tumors and management of the sequelae of therapy.
Introduction
A multidisciplinary approach to patients with squamous cell carcinoma of the larynx and hypopharynx is essential. These tumors and their treatment affect a patient’s ability to communicate, swallow, and function in society. When managing patients with these diseases, the physician should be mindful of the importance of maintaining quality of life, in addition to the importance of a definitive cure. Long-term survivorship, a primary goal, should be balanced with the known sequelae of therapy.
Introduction
A multidisciplinary approach to patients with squamous cell carcinoma of the larynx and hypopharynx is essential. These tumors and their treatment affect a patient’s ability to communicate, swallow, and function in society. When managing patients with these diseases, the physician should be mindful of the importance of maintaining quality of life, in addition to the importance of a definitive cure. Long-term survivorship, a primary goal, should be balanced with the known sequelae of therapy.
Patient evaluation overview
A thorough pretreatment assessment is essential for a patient with potential laryngeal or hypopharyngeal cancer. Smoking and alcohol history should be elicited and addressed. Severe malnourishment should be addressed immediately with enteral feeding tube placement, because nutritional status affects treatment outcomes. Physical examination should include inspection for second primary lesions, palpation and inspection of the neck, and flexible or indirect nasopharyngolaryngoscopy. Early tracheotomy may be needed for airway protection or management, and dental evaluation, with necessary dental work, should be performed before radiation.
Additional diagnostic tests are also important in the workup of patients with laryngopharyngeal cancers. Patients with limited early stage glottic cancers, without involvement of the anterior commissure, may be spared imaging, however. Hypopharyngeal, supraglottic, and subglottic tumors have a high risk of nodal disease or early local extension due to anatomic factors and therefore should undergo imaging of the neck with computed tomography (CT) with intravenous iodinated contrast or MRI in equivocal cases. PET-CT is useful for diseases of unknown primary, equivocal nodal disease, and advanced cases where distant or nodal metastases are suspected. Laryngeal swallowing function and possible aspiration should be evaluated with a modified barium swallow study before initiation of treatment. For early stage laryngeal cancer without nodal disease, chest radiography is adequate to evaluate for second primary tumors. For hypopharynx cancer, chest CT or PET-CT may be necessary for a complete evaluation. Panendoscopy should be performed to assess the dimensions and extent of the lesion, to assess for second primary disease, and to perform a biopsy for pathologic analysis ( Fig. 1 ).
General principles of therapy
Laryngeal and hypopharyngeal cancers are defined by their subsites, which portend patterns of spread and outcome ( Table 1 ). Larynx and hypopharynx cancers are staged according to American Joint Committee on Cancer criteria. Early stage cancers are initially managed with single-modality therapy such as radiation or surgical resection for accessible lesions. Advanced cases are usually treated with multiple modalities. Organ-preservation protocols involve radiation and chemotherapy, reserving total laryngectomy (TL) for salvage therapy.
| Laryngeal Subsites | Hypopharyngeal Subsites | ||
|---|---|---|---|
| Supraglottis | Glottis | Subglottis | |
| True vocal folds Anterior commissure Posterior commissure | Pyriform sinus Posterior and lateral Postcricoid space | |
Radiation therapy in early stage disease
Principles of Radiotherapy in Head and Neck Cancer
Radiotherapy (RT) is a cornerstone of therapy for head and neck cancer. RT is frequently curative as a single-modality treatment in early stage laryngeal and hypopharyngeal cancers and may be used in combination with surgery or chemotherapy in advanced cases.
External Beam Radiotherapy
External beam RT is the most common form of radiation in the treatment of head and neck tumors. Typical radiation doses for definitive therapy are 66 to 70 Gy. Intensity-modulated radiation therapy is a form of external beam radiation that is intended to minimize radiation doses to uninvolved, critical structures. Various fractionation and dosing schedules exist for the delivery of radiation in head and neck cancers. Hyperfractionated radiation can deliver higher total doses of radiation over the same time course as standard radiation. Accelerated radiation delivers the same dose as standard RT but in a shorter time frame. Hyperfractionated dosing may improve long-term oncologic outcomes.
Proton delivery is an emerging and promising external beam radiation technique that improves dose distribution. Proton therapy may decrease radiation dose to normal tissues while maintaining or improving the dose to targeted tissues, potentially reducing xerostomia and swallowing dysfunction. Unfortunately, particle accelerators required for proton therapy are not widely available, and the applications of proton therapy in head and neck cancers are still experimental.
Radiotherapy for Early Stage Glottic Tumors
Radiation alone is the most common treatment for early stage glottic cancers. Oncologic outcomes and preservation of function are excellent. Large retrospective reviews have demonstrated high local control and laryngeal preservation rates at 5 years in patients with early glottic laryngeal cancers treated with definitive RT. A review of outcomes for early glottis cancers treated with definitive radiation or transoral laser microsurgery (TLM) is provided ( Table 2 ). Expectant management of the neck is indicated in N0 early glottic cancers. Primary early stage glottic cancers have a very low rate of nodal metastases, observed to be 0% to 5% in T1 and T2 tumors confined to the glottis. The following factors are associated with worse outcomes after definitive RT for early stage glottic cancers:
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Involvement of the anterior commissure
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Treatment interruptions and a protracted treatment course
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Impaired vocal fold mobility
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Larger tumor size and higher histologic grade
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Smoking during treatment
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Pretreatment hemoglobin less than or equal to 13 g/dL.
| Early Glottic Cancer | ||||||
|---|---|---|---|---|---|---|
| Author, Year | N | Treatment | OS (%) | DFS (%) | LC (%) | Recurrence (N) |
| Tis | ||||||
| Smee et al, 2010 | 24 | RT | 87.5 | 75 | 2 | |
| Garcia-Serra et al, 2002 | 30 | RT | 100 | 88 | 3 | |
| Spayne et al, 2001 | 67 | RT | 100 | 98 | 1 | |
| Peretti et al, 2010 | 71 | TLM | 100 | 93 | 16 | |
| Roedel et al, 2009 | 35 | TLM | 100 | 93 | 4 | |
| Damm et al, 2000 | 29 | TLM | 100 | 87 | 4 | |
| T1 | ||||||
| Stoeckli et al, 2003 | RT | 88 | 93 | 85 | ||
| Sjogren et al, 2008 | 108 | RT | 80 | 92 | 75 | 34 |
| Smee et al, 2010 | 356 | RT | 95 | 83 | 61 | |
| Cellai et al, 2005 | 831 | RT | 77 | 95 | 84 | 121 |
| Franchin et al, 2003 | 232 | RT | 66 | 90 | 91 | 27 |
| Peretti et al, 2010 | 404 | TLM | 99 | 95 | 54 | |
| Motta et al, 2005 | 432 | TLM | 85 | 97 | 96 | 58 |
| Stoeckli et al, 2003 | TLM | 85 | 96 | 86 | ||
| Sjogren et al, 2008 | 70 | TLM | 84 | 99 | 89 | 7 |
| T2 | ||||||
| Stoeckli et al, 2003 | RT | 78 | 88 | 67 | ||
| Smee et al, 2010 | 142 | RT | 85 | 72 | 40 | |
| Frata et al, 2005 | 256 | RT | 59 | 86 | 73 | 62 |
| Garden et al, 2003 | 230 | RT | 73 | 92 | 72 | 67 |
| Peretti et al, 2010 | 109 | TLM | 98 | 87 | 24 | |
| Motta et al, 2005 | 236 | TLM | 77 | 86 | 87 | 84 |
| Grant et al, 2007 | 21 | TLM | 93 | 93 | 93 | 1 |
| Stoeckli et al, 2003 | TLM | 83 | 83 | 89 | ||
| T3 | ||||||
| Mendenhall et al, 1997 | 75 | RT | 51 | 78 (DSS) | 63 | 25 |
| Johansen et al, 2002 | 128 | RT | 43 | 63 (DSS) | 63 | 62 |
| Canis et al, 2014 | 122 | TLM | 59 | 84 (DSS) | 58 | 21 |
| Vilaseca et al, 2010 | 51 | TLM | 73 | 86 (DSS) | 88 | 27 |
| Motta et al, 2005 | 51 | TLM | 64 | 72 (DSS) | 70 | 21 |
| Grant et al, 2007 | 10 | TLM | 64 | 40 (DSS) | 45 | 6 |
Radiotherapy for Early Stage Supraglottic Tumors
RT as a single-modality treatment is feasible and effective for early and moderately advanced supraglottic cancers. Bulky lesions with pretreatment airway compromise may not be appropriate for initial definitive RT. Tumor volume greater than 6 cubic centimeters on pretreatment CT is a poor prognostic indicator. Because of the high risk of lymphatic spread in supraglottic cancers, nodal basins in the neck, at minimum levels of II to IV, should be included in the radiation field. A review of outcomes for T1 and T2 supraglottic tumors is provided ( Table 3 ). Five-year local control with definitive RT for T1–T2 supraglottic tumors ranges between approximately 40% and 95%, but significantly higher ultimate control rates can be achieved when including salvage surgery. Voice preservation with RT has been reported to be 96% to 100% in T1 and 80% to 86% in T2 lesions.
| Supraglottic Cancer | ||||||
|---|---|---|---|---|---|---|
| Author, Year | N | Treatment | OS (%) | DFS (%) | LC (%) | Recurrence (N) |
| T1 | ||||||
| Johansen et al, 2002 | 154 | RT | 55 | 71 | 67 | 56 |
| Daugaard et al, 1998 | 220 | RT | 50 | |||
| Nakfoor et al, 1998 | 23 | RT | 78 | 96 | ||
| Carl et al, 1996 | 161 | RT | 58 | |||
| Hinerman et al, 2002 | 18 | RT | 100 | 0 | ||
| Grant et al, 2007 | 8 | TLM | 100 | 80 | 100 | 1.0 |
| Motta et al, 2004 | 45 | TLM | 91 | 97 | 98 | 12 |
| Iro et al, 1998 | 39 | TLM | 86 | 8 | ||
| Ambrosch et al, 1998 | 12 | TLM | 100 | 0 | ||
| Zeitels et al, 1994 | 13 | TLM | 100 | 0 | ||
| T2 | ||||||
| Johansen et al, 2002 | 86 | RT | 52 | 74 | 73 | 32 |
| Daugaard et al, 1998 | 134 | RT | 41 | |||
| Nakfoor et al, 1998 | 73 | RT | 82 | 86 | ||
| Hinerman et al, 2002 | 109 | RT | 85 | 12 | ||
| Grant et al, 2007 | 14 | TLM | 74 | 91 | 100 | 1 |
| Motta et al, 2004 | 61 | TLM | 88 | 94 | 90 | 21 |
| Iro et al, 1998 | 54 | TLM | 75 | 7 | ||
| Ambrosch et al, 1998 | 34 | TLM | 89 | 4 | ||
| Zeitels et al, 1994 | 6 | TLM | 100 | 0 | ||
| T3 | ||||||
| Johansen et al, 2002 | 87 | RT | 45 | 52 | 43 | 44 |
| Daugaard et al, 1998 | 147 | RT | 30 | |||
| Nakfoor et al, 1998 | 51 | RT | 64 | 76 | ||
| Hinerman et al, 2002 | 87 | RT | 62 | |||
| Grant et al, 2007 | 8 | TLM | 67 | 73 | 100 | 0 |
| Motta et al, 2004 | 18 | TLM | 81 | 81 | 90 | 7 |
| Vilaseca et al, 2010 | 96 | TLM | 46 | 62 | 70 | 29 |
Radiotherapy for Early Stage Subglottic and Hypopharyngeal Carcinoma
Subglottic and hypopharyngeal tumors frequently present at an advanced stage because of anatomic features that encourage early spread of disease. Treatment typically involves multiple modalities, and lesions are rarely treated with RT alone. Primary carcinoma of the subglottis has a 50% overall survival and 63.2% disease-free survival with RT alone for early stage disease. Elective management of the neck is indicated in clinically N0 cases, including the central neck and upper mediastinum in subglottic cancer and level V and retropharyngeal nodes in hypopharyngeal cancer. Large tumor volume and extension to the pyriform apex in hypopharynx cancers are poor predictors of outcome. Ultimately, the risks of recurrence, second malignancy, and distant metastases are high, and multimodality therapy is the norm in subglottic and hypopharyngeal cancers.
Complications of RT include edema, chondritis, chondronecrosis, laryngeal scarring and stenosis, and stenosis of the cervical esophagus. Rarely, persistent edema of the larynx and supraglottic structures may delay diagnosis of persistent or recurrent disease. Edema may become obstructive and result in the necessity of a tracheotomy or feeding tube.
Combination therapies
Chemoradiotherapy (CRT) protocols were developed with the aim of laryngeal preservation in appropriate patients. Patients who are not candidates may be elderly or have a poor performance status, whereby straightforward surgical management with TL may provide more rapid return to swallowing function.
Chemoradiotherapy for Advanced Laryngeal and Hypopharyngeal Cancers
Two landmark articles guide the standard management of advanced laryngeal cancers: the Veteran’s Affairs (VA) study and the Radiation Therapy Oncology Group (RTOG) 91-11. The VA study, published in 1991, randomized 332 patients with stage III and IV laryngeal cancers to either TL and adjuvant RT (TL + postoperative radiotherapy [PORT]) or induction chemotherapy followed by radiation (ICRT). The 2-year survival rates were similar between the TL + PORT group and the ICRT group (68%), but there was a 64% rate of laryngeal preservation in the ICRT. Of note, the rate of locoregional recurrence was higher in the ICRT group than the surgery group (12% vs 2%). The conclusion was that induction chemotherapy results in higher laryngeal preservation rates without compromising patient survival.
The RTOG 91-11 study randomized 547 patients with advanced laryngeal cancers to ICRT, concurrent chemoradiotherapy (CCRT), or RT alone. Failures received salvage TL. The 5-year survival rates were similar among the 3 arms, but CCRT resulted in the highest laryngeal preservation rate (84%) and local control (78%). Although acute toxic effects were much higher in the chemotherapy arms, late toxic effects were comparable in all 3 groups. The study concluded that CCRT may result in superior outcomes than ICRT or RT alone. At 10-year follow-up, CCRT maintained higher laryngeal preservation and locoregional control rates but had worse overall survival and more seemingly unrelated deaths when compared with ICRT (30.8% vs 20.8%). This finding may be a random occurrence or related to older RT techniques administered in this 2-decade-old study, but it is unclear whether these deaths may in fact be due to late effects of concurrent therapy.
Despite this evidence, caution should be used when generalizing the results to all patients. Patients were accrued for those studied 20 to 30 years ago, before advances in RT and surgical techniques. Long-term results demonstrating increased rates of unexplained deaths in CCRT is of significant concern. As CRT-based organ preservation protocols have been increasingly used, the overall survival for laryngeal cancer has actually declined during this same time period, especially for T3N0M0 glottic cancers. Recent evidence suggests that there may in fact be a survival advantage with initial surgical therapy. Despite this suggestion, organ preservation with CCRT is recommended as the initial treatment of T3 and T4 laryngeal and hypopharyngeal cancers without significant cartilage invasion, base of tongue involvement, or extension into the neck soft tissues.
Since the publication of these studies, there seemed to be a reduced role for open surgery in all laryngeal cancers. Recently, however, the pendulum seems to be swinging back toward the importance of initial surgical management for T4 tumors. Cost-effectiveness may also become a consideration. TL with PORT is nearly $3000 less than organ preservation protocols for chemoradiation in advanced laryngeal cancers.
Postoperative Radiotherapy and Chemoradiotherapy
Postoperative adjuvant therapy is indicated when there is an increased risk of locoregional or distant recurrence of disease after resection. Adjuvant therapy can be considered in patients who have undergone conservation surgery or TL for advanced disease with the following high-risk features :
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T3 or T4 disease
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Perineural invasion
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Lymphoid or vascular invasion
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N2 disease or greater
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Positive (or close, <5 mm) resection margins
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Extracapsular extension of nodal disease (ECS)
PORT significantly improves overall survival, locoregional control, and disease-specific survival in patients with high-risk features compared with surgery alone. PORT is adequate for patients with moderately increased risk, but those with highest-risk features (positive, or close, margins, and ECS) should receive postoperative CCRT.
Postoperative CCRT has been demonstrated to improve outcomes in multiple large, randomized studies. In 2004, the European Organisation for Research and Treatment of Cancer (EORTC) (22931) and RTOG (9501) simultaneously published randomized trials comparing postoperative CCRT to PORT alone in high-risk patients. The addition of chemotherapy significantly improved locoregional control compared with PORT alone (82% vs 69% in the EORTC trial; 82% vs 72% in the RTOG trial). Of note, a significant increase in acute toxicities was noted with the addition of chemotherapy. The RTOG trial cited a 77% incidence of acute adverse effects of grade 3 or greater acute adverse effects in the CCRT group, compared with 34% incidence in the PORT group ( P <.001), with 4 deaths directly associated with CCRT. When the data from these 2 studies were pooled, extracapsular extension and positive surgical margins were the only factors that significantly benefitted from the addition of postoperative CCRT. The 10-year follow-up of the RTOG 9501 trial also reported that only patients with positive margins and ECS significantly benefitted from the addition of chemotherapy.
Monoclonal antibodies such as cetuximab (Erbitux, developed by Merck, under license from ImClone) may be used as a single agent or in combination with other modalities in advanced, recurrent, or metastatic head and neck cancers. Cetuximab produces modest improvements in the duration of locoregional control and overall survival. However, recent studies suggest that the addition of cetuximab to standard CCRT is of questionable benefit with significant toxicity and should not be used routinely.
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