Originally published as JCO Early Release 10.1200/JCO.2006.07.4559 on July 10 2006

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American Society of Clinical Oncology Clinical Practice Guideline for the Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer

David G. Pfister, Scott A. Laurie, Gregory S. Weinstein, William M. Mendenhall, David J. Adelstein, K. Kian Ang, Gary L. Clayman, Susan G. Fisher, Arlene A. Forastiere, Louis B. Harrison, Jean-Louis Lefebvre, Nancy Leupold, Marcy A. List, Bernard O. O'Malley, Snehal Patel, Marshall R. Posner, Michael A. Schwartz, Gregory T. Wolf

From the American Society of Clinical Oncology, Alexandria, VA

Address reprint requests to American Society of Clinical Oncology, Cancer Policy and Clinical Affairs, 1900 Duke Street, Suite 200, Alexandria, VA 22314; e-mail: guidelines{at}asco.org

	ABSTRACT

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PURPOSE: To develop a clinical practice guideline for treatment of laryngeal cancer with the intent of preserving the larynx (either the organ itself or its function). This guideline is intended for use by oncologists in the care of patients outside of clinical trials.

METHODS: A multidisciplinary Expert Panel determined the clinical management questions to be addressed and reviewed the literature available through November 2005, with emphasis given to randomized controlled trials of site-specific disease. Survival, rate of larynx preservation, and toxicities were the principal outcomes assessed. The guideline underwent internal review and approval by the Panel, as well as external review by additional experts, members of the American Society of Clinical Oncology (ASCO) Health Services Committee, and the ASCO Board of Directors.

RESULTS: Evidence supports the use of larynx-preservation approaches for appropriately selected patients without a compromise in survival; however, no larynx-preservation approach offers a survival advantage compared with total laryngectomy and adjuvant therapy with rehabilitation as indicated.

RECOMMENDATIONS: All patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.

	INTRODUCTION

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In 2005, an estimated 9,880 new cases of laryngeal cancer will be diagnosed in the United States, accounting for 3,770 deaths.¹ Squamous cell carcinoma is the predominant histologic type, and approximately 40% of patients will have stage III or IV disease when first evaluated.² Most cases of laryngeal cancer are associated with a history of tobacco and/or alcohol use, so the treatment of patients is complicated by medical comorbidity and the development of second primary cancers.^3-5 Given the fundamental role the larynx plays in human speech and communication, determining the optimal management of laryngeal cancers must involve consideration of both survival and the functional consequences of a given treatment approach. The potential morbidity of curative treatment is a special consideration when total laryngectomy, either for primary therapy or as salvage treatment, is the recommendation. Total laryngectomy is widely recognized as one of the surgical procedures most feared by patients. Social isolation, job loss, and depression are common sequelae.^6,7 Pioneering work on patient preferences showed that approximately 25% of healthy individuals interviewed were willing to trade a 20% absolute difference in survival for the opportunity to save their voice.⁸ Different voice rehabilitations exist,⁹ but many patients are dissatisfied with the results and report associated restrictions in their daily lives. Although the impact of the procedure on voice often receives the greatest attention, the presence of the stoma may adversely affect quality of life as much, if not more.¹⁰ Accordingly, there has been keen interest in the development and refinement of organ-preservation therapies, such as radiation therapy alone, the combination of chemotherapy and radiation therapy (chemoradiotherapy therapy), and function-preserving partial laryngectomy procedures. With all three of these approaches, total laryngectomy is reserved for tumor recurrence.

The American Society of Clinical Oncology (ASCO) fully appreciates the controversy about how to best achieve the dual goals of cure and preservation of function for patients with laryngeal cancer. As a service to patients, to its members, and to practicing physicians generally, ASCO convened an Expert Panel under the auspices of the Health Services Committee to develop recommendations regarding the appropriate application of larynx-preservation therapies.

Accordingly, ASCO considers adherence to this guideline to be voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. In addition, the guideline describes administration of therapies in clinical practice; it cannot be assumed to apply to interventions performed in the context of clinical trials, given that clinical studies are designed to test innovative and novel therapies in a disease and setting for which better therapy is needed. Because guideline development involves a review and synthesis of the latest literature, a practice guideline also serves to identify important questions for further research and those settings in which investigational therapy should be considered.

	QUESTIONS

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The following questions about squamous cell laryngeal cancer were addressed by the Panel:

(1) What are the larynx-preservation treatment options for limited stage (T1, T2) primary site disease that do not compromise survival? What are the considerations in selecting among them?

(2) What are the larynx-preservation treatment options for advanced stage (T3, T4) primary site disease that do not compromise survival? What are the considerations in selecting among them?

(3) What is the appropriate treatment of the regional cervical nodes for patients with laryngeal cancer who are treated with an organ-preservation approach?

(4) Are there methods for prospectively selecting patients with laryngeal cancer to increase the likelihood of success of larynx preservation?

	METHODS

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The members of the Expert Panel were selected for their expertise in clinical medicine; medical, radiation, and surgical oncology; diagnostic imaging; clinical research; outcomes/health services research; and related disciplines (biostatistics, quality of life) with a focus on expertise in head and neck and laryngeal cancer (Appendix A). To enhance the focus of the published guideline on the implications for clinical practice, the methodology of the guideline development is available online, at both www.jco.org and www.asco.org.

	GUIDELINE FOR LARYNX-PRESERVATION TREATMENT

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We have summarized the recommended treatment strategies by T stage, along with the basis for the recommendations and the quality of the supporting evidence (Table 1). A complete review of the literature and discussion of study results are available online.

The recommendations to address these questions are based on evidence from prospective and retrospective cohort studies.^11-75 The recommendations for T2 N+ disease are based on data from randomized controlled trials of chemoradiotherapy therapy (with either induction or concurrent chemotherapy compared with radiation therapy alone or surgery followed by adjuvant radiation therapy).^77,78 The outcomes assessed included overall survival, disease-free survival, rates of laryngeal preservation, local-regional control, toxicity of therapy, and cost.

Limited-stage disease represents a spectrum. Treatment selection can be challenging, as the evidence base for most decisions is derived from nonrandomized studies and various factors need to be considered when choosing therapy. Selected examples for glottic cancer are illustrative. If voice outcome is predicted to be good after endoscopic laser resection for a T1 glottic cancer (eg, a superficial tumor located in the middle third of the cord, especially on its free edge), then use of this modality is more efficient and thus preferred. However, lesions that are indistinct, especially those arising in the context of widespread, abnormal-appearing mucosa, are more suitable for radiation therapy than for surgery. Radiation therapy is preferred by many clinicians for treatment of T2 glottic carcinoma characterized as superficial on radiographic imaging, with preserved cord mobility, as local control rates are high and anticipated functional outcomes are good. But some investigators have noted compromised survival after the failure of radiation therapy in T2 glottic carcinoma indicating the importance of obtaining initial local control.^56,59 As such, supracricoid partial laryngectomy with cricohyoidoepliglottopexy remains a reasonable alternative for patients with a T2 glottic carcinoma who after pretreatment counseling would be willing to sacrifice voice quality in an effort to improve local control. Induction chemotherapy has been investigated as treatment for patients with limited-stage laryngeal cancer. However, insufficient data are currently available to recommend such an approach outside the context of a clinical trial.

Recommendations

• All patients with T1-T2 laryngeal cancer should be treated, at least initially, with intent to preserve the larynx.
  
• T1-T2 laryngeal cancer can be treated with radiation or larynx-preservation surgery with similar survival outcomes. Selection of treatment depends on patient factors, local expertise, and the availability of appropriate support and rehabilitative services. Every effort should be made to avoid combining surgery with radiation therapy because functional outcomes may be compromised by combined-modality therapy; single-modality treatment is effective for limited-stage, invasive cancer of the larynx.
  
• Surgical excision of the primary tumor with intent to preserve the larynx should be undertaken with the aim of achieving tumor-free margins; so-called narrow-margin excision followed by postoperative radiation therapy is not an acceptable treatment approach.
  
• Local tumor recurrence after radiation therapy may be amenable to salvage by organ-preservation surgery, but total laryngectomy will be necessary for a substantial proportion of patients, especially those with index T2 tumors.
  
• Concurrent chemoradiotherapy therapy may be used for larynx preservation for selected patients with stage III, T2 N+ cancers when total laryngectomy is the only surgical option, when the functional outcome after larynx-preservation surgery is expected to be unsatisfactory, or when surgical expertise in such procedures is not available.
  
• Limited-stage laryngeal cancer constitutes a wide spectrum of disease. The clinician must exercise judgment when recommending treatment in this category. For a given patient, factors that may influence the selection of treatment modality include extent and volume of tumor; involvement of the anterior commissure; lymph node metastasis; the patient's age, occupation, preference, and compliance; availability of expertise in radiation therapy or surgery; and history of a malignant lesion in the head and neck.
  

What are the larynx-preservation treatment options for advanced stage (T3, T4) primary site disease that do not compromise survival? What are the considerations in selecting among them?
Evidence base. The recommendations to address these questions are based on evidence from randomized controlled trials of different radiation fractionation schedules,⁷⁶ chemoradiotherapy therapy (either induction or concurrent) compared with radiation therapy alone or surgery followed by adjuvant radiation therapy,^77-85 on meta-analysis or other secondary analysis of data from randomized clinical trials,^{86-88,102,105,108} and on prospective and retrospective cohort studies.^{22,58,89-101,103,104,106,107} The outcomes evaluated included overall survival, disease-free survival, rates of laryngeal preservation, local-regional control, toxicity of therapy, and cost.

Recommendations

• Organ-preservation surgery, concurrent chemoradiotherapy therapy, and radiation therapy alone, all with further surgery reserved for salvage, offer potential for larynx preservation without compromising survival. Anticipated success rates for larynx preservation, associated toxicities, and suitability for a given patient will vary among these approaches. Selection of a treatment option will depend on patient factors, local expertise, and the availability of appropriate support and rehabilitation services.
  
• All patients should be evaluated regarding their suitability for a larynx-preservation approach, and they should be apprised of these treatment options. No larynx-preservation approach offers a survival advantage compared with total laryngectomy and appropriate adjuvant treatment (Table 2).
  
• A minority of patients with T3-T4 primary site disease will be suitable for specialized organ-preservation procedures, such as a supracricoid partial laryngectomy. The addition of postoperative radiation therapy will compromise anticipated functional outcomes. Induction chemotherapy before organ-preservation surgery is not recommended outside of a clinical trial.
  
• Concurrent chemoradiotherapy therapy offers a significantly higher chance of larynx preservation than does radiation therapy alone or induction chemotherapy followed by radiation, albeit at the cost of higher acute in-field toxicities (Table 3).
  
• The best available evidence supports the use of cisplatin as the drug of choice in this setting.
  
• There is insufficient evidence to indicate that survival or larynx-preservation outcomes are improved by the addition of induction chemotherapy before concurrent treatment or the use of concurrent chemotherapy with altered fractionated radiation therapy in this setting.
  
• For patients who desire larynx-preservation therapy but are not candidates for organ-preservation surgery or chemoradiotherapy therapy, radiation therapy alone is an appropriate treatment. With this last approach, survival is similar to that associated with chemoradiotherapy therapy when salvage surgery is incorporated, but the likelihood of larynx preservation is lower.
  

The recommendations to address this question are based on evidence from derivative analyses of randomized controlled trials of chemoradiotherapy (either induction or concurrent) compared with radiation therapy alone or surgery followed by adjuvant radiation therapy,^125,140 a randomized trial comparing the different types of neck dissection,¹¹³ and on prospective and retrospective cohort studies.^{25,35,66,109,124,126-139,141,142} With respect to adjuvant therapy, evidence was drawn from randomized controlled trials of radiation therapy compared with concurrent chemoradiotherapy.^143-145 The outcomes assessed included overall survival, disease-free survival, local-regional control, and toxicity of therapy.

Recommendations

• Most patients with T1-T2 lesions of the glottis and clinically negative cervical nodes (N0) do not require routine elective treatment of the neck.
  
• Patients with advanced lesions of the glottis and all patients with supraglottic lesions should have elective treatment of the neck, even if clinically N0.
  
• Patients with clinically involved regional cervical nodes (N1) who are treated with definitive radiation therapy or chemoradiotherapy therapy and who have a complete clinical response do not require elective neck dissection. Neck dissection should be performed for patients who do not have a complete clinical response to radiation therapy.
  
• Surgical treatment of the neck is recommended for patients with N2 or N3 disease who are treated with definitive radiation therapy or chemoradiotherapy therapy, regardless of response. Some surgeons and patients are reluctant to risk the morbidity of neck dissection, given the prospect of a negative pathologic diagnosis in most cases, but there is no standard imaging approach in this setting that has been validated to significantly improve on this decision-making process. Salvage surgery for recurrent disease in the neck is rarely successful if subsequently required in this setting. These two points should be discussed with all patients who have an apparent complete clinical response to radiation therapy or chemoradiotherapy therapy and choose to be followed up with expectant observation.
  
• Patients with clinically involved cervical nodes who are treated with surgery for the primary lesion should have neck dissection. If there are poor-risk features, adjuvant concurrent chemoradiotherapy therapy is indicated.
  

Are there methods for prospectively selecting patients with laryngeal cancer to increase the likelihood of successful larynx preservation?
Evidence base. The recommendations addressing this question are based on evidence from prospective and retrospective cohort studies of clinical, radiographic, and/or pathologic parameters associated with clinical outcomes^{44,47,62,73,89,91,146,147,149,151-168} and on derivative analyses of a randomized controlled trial.^{148,150,169-171} The outcomes assessed included overall survival, disease-free survival, local-regional control, and rates of laryngeal preservation.

Recommendations

• There are no validated markers that consistently predict outcomes of larynx-preservation therapy. However, patients with tumor penetration through cartilage into soft tissues are considered poor candidates for a larynx-preservation approach. Primary surgery, usually total laryngectomy, is commonly recommended in this setting.
  
• Selection of therapy for an individual patient requires assessment by a multidisciplinary team, as well as consideration of patient comorbidity, psychosocial situation and preferences, and local therapeutic expertise.
  
• Continued cigarette smoking appears to be associated with a worse outcome after radiation therapy. Patients should be encouraged to abstain from smoking after diagnosis and throughout treatment.
  

	FINAL COMMENTS

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Larynx-preservation therapy is intended to offer improved function and quality of life for patients with laryngeal cancer, without compromising survival. Our review of the data indicated that there is commonly more than one treatment option to consider. A thorough discussion of the risks and benefits of larynx-preservation therapy is crucial. Organ-preservation treatments can be difficult to administer, given that many patients have underlying medical comorbidity. Optimal patient selection increases the likelihood of a successful outcome. Effective application of larynx-preservation treatment requires special expertise and a specialized support team. A typical treatment team will include expertise in head and neck surgery, radiation therapy, medical oncology, pathology, nursing, speech and swallowing physiology/rehabilitation, audiology, social services, nutrition, tobacco cessation, and management of relevant medical comorbidities.

Many important management decisions have not been addressed by randomized trials or require further clarification. Reliable biologic markers and imaging techniques to facilitate assessment of patient prognosis and response to therapy are needed to guide therapy and select the patients most appropriate for organ-preserving approaches. Defining optimal treatment combinations, including the role of neoadjuvant/induction, concurrent, and adjuvant therapy, as well as newer targeted therapies, is a priority. The role of more targeted radiation approaches and newer fractionation schedules, the timing of surgery for persistent disease, and optimal surveillance for recurrence and prevention of second primary cancers are key research areas. Practical assessments and interventions for nutrition, speech, swallowing, risk-factor modification, and rehabilitation/reconstruction are needed. The Expert Panel believes that commitment to and support of relevant and important randomized studies will be fundamental to addressing these issues. The thoughtful incorporation of relevant correlative studies, such as tissue-specific investigations, into the design of randomized studies will maximize the value of the latter.

When treatments yield similar survival end points, other outcomes, such as function, quality of life, and cost, become increasingly relevant. For example, speech and swallowing are highly complex, finely coordinated neuromuscular processes, and may be disrupted by both the disease itself and its therapy. Preservation of the laryngeal structure is not considered a functional success if persistent dysphagia, aspiration, or chronic tracheostomy results from organ-preserving therapy. All organ-sparing therapies are not the same with regard to their anticipated functional and quality of life outcomes. Yet, as is the case with more traditional biomedical end points, randomized, primary site-specific data comparing patient-reported outcomes are limited.

Available information highlights some issues to consider. Differences in outcome between surgical and radiation-based approaches are not necessarily found on all quality-of-life domains,^26,102 and some that do may be primary site dependent.¹⁷² How each patient perceives an adverse sequela of treatment is variable. Permanent gastrostomy or stoma is often a greater concern to patients than loss of speech^10,173; other quality-of-life domains (eg, emotional, social, financial) besides the functional one may be affected by the disease and its treatment and deserve attention. Underestimation of substantial functional morbidity and treatment-related toxicities such as dysphagia is a risk if patients are not followed up for longer time periods.^30,174-176 Careful assessment of such outcomes is crucial to guide subsequent protocol development in hopes of minimizing the morbidity of treatment without compromising efficacy.^177,178

The thoughtful incorporation of valid pretreatment and longitudinal post-treatment functional and quality-of-life assessments will enhance the value of future larynx-preservation studies. Validated technologies are already available to quantitate such end points.^9,179 Considering patient-reported outcomes in a broader sense than has historically been the case, particularly in organ-preservation studies where treatment is randomly assigned, will provide useful information and facilitate clinical decision-making and subsequent improvement in treatment protocols.

	Appendix

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	Authors' Disclosures of Potential Conflicts of Interest

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Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

^* No significant financial relationships to disclose.

	Author Contributions

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Conception and design: David G. Pfister, Gregory S. Weinstein, William M. Mendenhall, David J. Adelstein, K. Kian Ang, Gary L. Clayman, Susan G. Fisher, Arlene A. Forastiere, Louis B. Harrison, Jean-Louis Lefebvre, Nancy Leupoid, Marcy A. List, Bernard O. O’Malley, Marshall R. Posner, Michael A. Schwartz, Gregory T. Wolf Collection and assembly of data: David G. Pfister, Scott A. Laurie, Gregory S. Weinstein, William M. Mendenhall, David J. Adelstein, K. Kian Ang, Gary L. Clayman, Susan G. Fisher, Arlene A. Forastiere, Louis B. Harrison, Jean-Louis Lefebvre, Nancy Leupold, Marcy A. List, Bernard O. O'Malley, Snehal Patel, Marshall R. Posner, Michael A. Schwartz, Gregory T. Wolf Data analysis and interpretation: David G. Pfister, Scott A. Laurie, Gregory S. Weinstein, William M. Mendenhall, David J. Adelstein, K. Kian Ang, Gary L. Clayman, Susan G. Fisher, Arlene A. Forastiere, Louis B. Harrison, Jean-Louis Lefebvre, Nancy Leupold, Marcy A. List, Bernard O. O'Malley, Snehal Patel, Marshall R. Posner, Michael A. Schwartz, Gregory T. Wolf Manuscript writing: David G. Pfister, Scott A. Laurie, Gregory S. Weinstein, William M. Mendenhall, David J. Adelstein, K. Kian Ang, Gary L. Clayman, Susan G. Fisher, Arlene A. Forastiere, Louis B. Harrison, Jean-Louis Lefebvre, Nancy Leupold, Marcy A. List, Bernard O. O'Malley, Snehal Patel, Marshall R. Posner, Michael A. Schwartz, Gregory T. Wolf Final approval of manuscript: David G. Pfister, Scott A. Laurie, Gregory S. Weinstein, William M. Mendenhall, David J. Adelstein, K. Kian Ang, Gary L. Clayman, Susan G. Fisher, Arlene A. Forastiere, Louis B. Harrison, Jean-Louis Lefebvre, Nancy Leupold, Marcy A. List, Bernard O. O'Malley, Snehal Patel, Marshall R. Posner, Michael A. Schwartz, Gregory T. Wolf

 

	ACKNOWLEDGMENTS

 
The Expert Panel members wish to thank Dr David M. Brizel, Dr George P. Browman, Dr Brian Burkey, Dr Avraham Eisbruch, Dr Jan S. Lewin, Dr Bruce D. Minsky, Dr James Netterville, Dr Michael N. Neuss, Dr Jay Piccirillo, Dr Andy Trotti, Dr Jan B. Vermorken, Dr Jamie H. Von Roenn, Dr Randal S. Weber, and Dr Ernest Weymuller for their thoughtful reviews of earlier drafts.

The Expert Panel members also wish to express their gratitude to Dr Karen Fu and Dr Yungpo Bernard Su for their constructive input and assistance in preparation of the guideline.

	NOTES

 
The unabridged version of this article can be found at www.asco.org/guidelines/larynx/unabridged

Adopted on February 28, 2006, by the American Society of Clinical Oncology.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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