Laryngeal Cancer: A Review

Laryngeal cancer is one of the most common cancers of the head and neck in the United States (Baird, Sung, Beadle, & Divi, 2018; Mannelli, Lazio, Luparello, & Gallo, 2018; Taito et al., 2019).  This diagnosis occurs more frequently in men 65 years or older, with a median age of death of 68 years (Obid, Redlich, & Tomeh, 2018).  While laryngeal cancers account for only part of new cancer cases (13,000 new cases), the disease greatly impacts patient’s ability to speak, breath, and swallow (Anis, Razavi, Xiao, & Soliman, 2018; Baird, Sung, Beadle, & Divi, 2018; Forastiere et al., 2018; Obid et al., 2018).  The impact on quality of life makes understanding this type of cancer important.

The course of treatment, and the chances of survival, are influenced by the initial stage of disease (Obid et al., 2018).  Cure rates are between 80-90% for early stage (T1 or T2 tumors), and as low as 40% for more advanced stages (T4) (Obid et al., 2018).  This low cure rate for advanced stages may relate to the variety of different lesions, clinical presentations, biological behaviors and prognosis that clients present with (Mannelli et al., 2018).  Many patients are diagnosed with T3 or T4 or regional nodal metastases, which contribute to the low survival rates (Forastiere et al., 2018).  The advanced stage diagnoses cause an increase in adverse side effects due to necessary treatments such as total or near total laryngectomy, intensive radiotherapy, and chemotherapy (Forastiere et al., 2018).  This report reviews current treatments for all stages of laryngeal cancer.

Literature Review

Although laryngeal cancer is one of the most common cancers of the head and neck, the decrease in the use of tobacco has caused the incidence to decline over the past decade (Baird et al., 2018; Forastiere et al., 2018; Obid et al., 2018).  However, the five-year survival rate of laryngeal cancer has remained steady (Forastiere et al., 2018; Obid et al., 2018).  Therefore, further investigation on the development, treatment and adverse reactions on the patient’s health needs to be completed.

Anatomy of the Larynx

The larynx involves three anatomical regions which help protect the airway and aid in vocalization (Obid et al., 2018).  These regions include the supraglottic larynx, the glottic larynx, and the subglottic larynx (Obid et al., 2018).  The first region, the supraglottic larynx, includes the laryngeal surface of the epiglottis, aryepiglottic folds, arytenoids and false vocal cords (Obid et al., 2018).  This area can cause difficulty in the detection of malignant tumors, with an endoscopic evaluation needed to detect a tumor in this location (Obid et al., 2018).  The next region, the glottic larynx, includes the true vocal cords, involving the paraglottic space, and the anterior and posterior commissures (Obid et al., 2018).  The last anatomical region (subglottic larynx) includes the inferior aspect of the true vocal cords and extends to the inferior edge of the cricoid cartilage (Obid et al., 2018).  The movement of airflow through the larynx is supported by the thyroid cartilage (Obid et al., 2018).  This system maintains the speed of airflow through the system while preventing the collapse of the mucosal surfaces due to an increase in pressure (Obid et al., 2018).  A tumor at any of the above anatomical regions provides a different clinical presentation and challenge for treatment (Obid et al., 2018).

Risk Factors and Diagnosis

The greatest risk factor for the development of laryngeal cancer is chronic exposure to an irritant, including tobacco use, acid reflux, alcohol consumption and environmental exposures (Anis et al., 2018; Muderris, Gul, Doblan, Ergin, & Muderris, 2019; Obid et al., 2018).  These irritants increase inflammation and impair defense mechanisms (i.e. impairing macrophages, dendritic cells, and natural killer cells), which results in an inability to kill bacteria and remove dead cells in this area (Muderris et al., 2019).  This allows mutated cells to spread throughout the area (Muderris et al., 2019).  Due to the inflammation, T-helper 1 and 2 cells accumulate, which causes interleukin (IL-17) to secrete T-helper 17 cells (Muderris et al., 2019).  Study results reveal that patients with laryngeal cancer (as compared to benign laryngeal lesions) have higher levels of interleukin (IL)-17 and IL-22 (Muderris et al., 2019).  Therefore, the role of T-helper cells may be further examined as a part of the development of laryngeal cancer (Muderris et al., 2019).

A physical examination of the neck and an endoscopic evaluation are used to determine the extent of the tumor and the stability of the airway (Obid et al., 2018).  Specifically, this procedure provides information about the obstruction of the airway, the mobility of the vocal cords, and if endotracheal intubation is necessary or feasible (Obid et al., 2018).  The stability of the airway is also assessed through the patient’s ability to breath, use accessory muscles, fatigue, and mental status (Obid et al., 2018).  Depending on the location of the cancerous mass, a patient may present with a neck mass, muffled voice, or a compromised airway (Obid et al., 2018).  Ultimately, the most important factor in determining prognosis is neck dissection, which considers the status of the cervical lymphatics (Obid et al., 2018).

The specific staging classification is determined by the location of the primary tumor, the mobility of the vocal cords, and whether the tumor has metastasized (Obid et al., 2018).  An early stage tumor (T1) describes a primary tumor that is limited to one anatomical area (i.e. supraglottis, true vocal cord involvement, or subglottic) (Obid et al., 2018).  The next stage (T2) describes a tumor that has metastasized to an area outside of the supraglottis or has extended to the vocal cords (Obid et al., 2018).  A T3 tumor (considered advanced stage), when looking at the supraglottic anatomical area, is a tumor that is limited to the larynx, with the tumor extending to the postcricoid area, preepiglottic space, paraglottic space, or inner cortex of the thyroid (Obid et al., 2018).  In the glottic anatomical area, a T3 stage, is limited to the larynx with an affect on the vocal cords, with the tumor extending to the paraglottic space and/or inner cortex of the thyroid cartilage (Obid et al., 2018).  In the subglottic area, a T3 tumor has extended to the larynx with movement toward the vocal cords and/or the inner cortex of the thyroid cartilage (Obid et al., 2018).  Considered the advanced stage of laryngeal cancer, a T4a stage tumor in any of the anatomical areas, has moved throughout the outer cortex of the thyroid cartilage and/or has impacted the tissues beyond the larynx (Obid et al., 2018).  A T4b stage tumor represents an invasion of prevertebral space, carotid artery encasement, or metastasizing to the mediastinal structures in any of the anatomical areas of the larynx (Obid et al., 2018).  A pathological report on the tumor is completed to determine the appropriate diagnosis which informs treatment methods (Locatello et al., 2019; Obid et al., 2018).

Treatment

Previous treatment modalities included resections, intensive radiation, or chemoradiation (Obid et al., 2018).  These extensive treatments resulted in negative impacts on the functions of swallowing, breathing, voice, and a lower quality of life (Kim et al., 2016; Obid et al., 2018).  Today, treatment aims to preserve the larynx and maintain quality of life, which many times necessitates a variety of approaches (i.e. surgery, radiotherapy, and subsequent treatments) (Bernier, 2009; Kim et al., 2016; Obid et al., 2018).  Therefore, a multidisciplinary team of head and neck surgeons, oncologists, radiologists, pathologists and psychologists are necessary to address the complex nature of laryngeal cancer (Locatello et al., 2019).  Factors such as age, medical comorbidities, lymph node metastases, and the extent, volume and location of the primary tumor are all considered when determining if a surgical or nonsurgical approach is more appropriate (Baird et al., 2018; Obid et al., 2018).

Treatment goals for early stage laryngeal cancer (T1 and T2) are to remove the disease while preserving the function of the larynx (Baird et al., 2018; Obid et al., 2018).  Based on these goals, a multi-approach treatment (i.e. surgery, radiation therapy and/or chemoradiation) may be too rigorous, resulting in a negative impact on the function of the larynx (Baird et al., 2018; Obid et al., 2018).  Single modality treatment options may include transoral laser microsurgery, open partial laryngectomy, endoscopic resection or radiation therapy alone (Kim et al., 2016; Obid et al., 2018).  When the risks of surgery outweigh the benefits, radiation alone is considered the standard treatment for these stages (Obid et al., 2018).

Patients diagnosed with advanced stage laryngeal cancer (T3 or T4) a total laryngectomy or chemoradiation are the standard treatments (Baird et al., 2018; Locatello et al., 2019; Mannelli et al., 2018; Obid et al., 2018).  Unfortunately, these treatment options results in a lack of preservation of the larynx, functional deficits, and poorer rates of survival (Baird et al., 2018; Obid et al., 2018).  Voice preservation during treatment planning has caused a push towards preservation surgery and nonsurgical techniques (Mannelli et al., 2018; Obid et al., 2018).  For patients diagnosed with T3 tumors, a laryngeal preservation surgery may be considered with a discussion of the high-risk features that necessitates adjunctive radiation therapy (Obid et al., 2018).  Some patients with T3 tumors may be treated with chemoradiation, with surgery being reserved as a treatment option for cancer recurrence (Locatello et al., 2019; Obid et al., 2018).  However, nonsurgical perseveration techniques do not provide a higher survival rate compared to total laryngectomy (Obid et al., 2018).  Laryngeal cancer may be treated by a variety of surgical procedures, including partial laryngectomy and transoral laser microsurgery (Mannelli et al., 2018; Obid et al., 2018).

Surgical modalities.

Transoral laser microsurgery is a minimally invasive endoscopic treatment that utilizes microsurgical instruments that remove the primary tumor (Baird et al., 2018; Obid et al., 2018).  This approach, when used independently, provides the best post-operative functional benefits (Obid et al., 2018).  The level of functionality is based on the extent of the tumor, vocal cord lesions, and whether the tumors involve the vocal cords (Obid et al., 2018).

The open partial laryngectomy procedure is a conservative procedure that utilizes hemilaryngectomy and supracricoid partial laryngectomy (Mannelli et al., 2018; Obid et al., 2018).  This procedure is utilized as a primary treatment for T3 laryngeal cancer that is not amenable to transoral laser microsurgery (Obid et al., 2018).  A horizontal partial laryngectomy encompasses sectioning the portion of the larynx above the glottis, while preserving the vocal cords and arytenoids (Mannelli et al., 2018; Obid et al., 2018).  This approach is utilized for individuals who have a T3 or T4 stage cancer, with tumors involving one vocal cord and one arytenoid, extending to the base of the tongue (Obid et al., 2018).  A supracricoid partial laryngectomy involves a complete resection of the thyroid cartilage, true and false vocal folds and paraglottic spaces (Obid et al., 2018).

A total laryngectomy is the standard surgical treatment for advanced stage laryngeal cancer (Obid et al., 2018).  This treatment includes the removal of the entire larynx, strap muscles, paratracheal lymphatics, and the ipsilateral thyroid lobe (Obid et al., 2018).  This option offers higher chances of survival but is not amenable to organ preservation (i.e. permanent tracheostoma and loss of voice) (Obid et al., 2018).  Chemotherapy and radiotherapy, other treatment options, are discussed in the next section.

Chemotherapy and radiotherapy.



To preserve the larynx, there has been an increase towards chemoradiation therapy (Mannelli et al., 2018).  However, it should be noted that nonsurgical techniques do not offer a higher survival rate when compared to a total laryngectomy (Mannelli et al., 2018).  Chemotherapy may be utilized as a stand-alone treatment, or in combination with one of the above modalities or radiation (Pignon, Maître, Maillard, & Bourhis, 2009).  Chemotherapy treatment may be administered at different points in relation to radiotherapy.  Chemotherapy administered before radiotherapy is referred to as induction chemotherapy, that administered during radiotherapy is referred to as coadministration, and that administered after radiotherapy is called maintenance therapy (Bernier, 2009).  Induction chemotherapy can help to eradicate micro-metastases and can help increase the survival rate of patients (Gau et al., 2019).  It may also decrease tumor volume, making surgery a viable option for previously inoperable tumors, which may impact the patient’s quality of life (Gau et al., 2019).

The ideal treatment protocol is coadministration, this typically involves administration of 100 mg/m² every 3 weeks during radiation therapy (Haddad et al., 2013).   This treatment causes a shift in the cell-survival rates toward a higher rate of cell-killing, this results in a decrease in the tumor mass, selective toxicity, cytokinetic cooperation, and increased apoptosis (Bernier, 2009; Haddad et al., 2013).   Additionally, this treatment influences DNA replication, specifically in interrupting microtubule function leading to interference with mitosis and eventually cell death (Bernier, 2009).  Drugs such as cisplatin or carboplatin associated with 5-FU or other poly-chemotherapy including either platin or 5-FU may all be utilized during chemotherapy (Bernier, 2009; Haddad et al., 2013; Pignon et al., 2009).  Although coadministration is the ideal choice, this choice is dependent on the tumor’s location and progression (Bernier, 2009; Gau et al., 2019).  This intensive treatment can result in poor treatment adherence, which should be discussed with the patient prior to a treatment protocol being determined (Bernier, 2009).

Radiation may also be utilized as a sole treatment and may be recommended when adverse features are present (i.e. lymphnode metastasis, lymphovascular invasion) (Kim et al., 2016; Obid et al., 2018).  Specifically, the standard radiotherapy treatment (i.e. Conventional radiotherapy or CRT) delivers opposed-lateral radiation beams to the cancerous area (Zumsteg et al., 2015).  This treatment is used to preserve the larynx with patients in which the risks of surgery outweigh the benefit of it, however, it is not an ideal treatment option for many patients (Bernier, 2009; Obid et al., 2018).  CRT may adversely affect functionality of the larynx and surrounding area, leading to aspiration, damage to healthy tissue, fibrosis, and even an increased risk of carotid artery stenosis and stroke (Kim et al., 2016; Zumsteg et al., 2015).  In response to these adverse effects, intensity-modulated radiotherapy (IMRT) is causing a shift in treatment practices (Zumsteg et al., 2015).  This technique delivers high doses of radiotherapy with sharp dose cut-offs which prevent the surrounding normal tissues from being affected (Zumsteg et al., 2015).  However, IMRT is not considered the standard radiotherapy treatment for laryngeal cancer due to the small area (5×5 or 6×6 cm) that is targeted during radiation in laryngeal cancer (Zumsteg et al., 2015).  Further research is needed to evaluate the long-term impact of radiotherapy alone to determine a standard radiotherapy protocol (Zumsteg et al., 2015).  Ultimately, research has shown that the combination of chemotherapy and radiation improve the results of radiotherapy results alone (Bernier, 2009; Zumsteg et al., 2015).

Conclusion

Adverse treatment effects should be considered before a treatment option is chosen.  Specifically, managing laryngeal cancer while understanding the impact that treatment may have on patient’s quality of life is essential (Taito et al., 2019).  The use of radiotherapy has caused adverse long-term reactions including inflammation-induced circulatory disturbances,

dry throat, reduced sensation, voice function, and estraesophageal reflux disease (Anis et al., 2018; Lazarus, 2009; Taito et al., 2019; Zumsteg et al., 2015).  Additionally, research has shown a connection between radiation therapy and carotid artery stenosis and cerebrovascular morbidity two-years post treatment (Kim et al., 2016; Zumsteg et al., 2015).  These factors all affect a patient’s ability to eat, communicate, and survive post-cancer treatment (Kim et al., 2016; Lazarus, 2009).  As technology advances, additional research is necessary to determine the most affective cancer-eliminating practices, while preventing negative impacts to a patient’s quality of life (Kim et al., 2016; Mannelli et al., 2018; Zumsteg et al., 2015)

References

• Anis, M. M., Razavi, M., Xiao, X., & Soliman, A. M. S. (2018). Association of gastroesophageal reflux disease and laryngeal cancer.
  
  World Journal of Otorhinolaryngology-Head and Neck Surgery, 4
  
  (4), 278-281. doi:10.1016/j.wjorl.2017.12.011
• Baird, B. J., Sung, C. K., Beadle, B. M., & Divi, V. (2018). Treatment of early-stage laryngeal cancer: A comparison of treatment options.
  
  Oral Oncology, 87
  
  , 8-16. doi:10.1016/j.oraloncology.2018.09.012
• Bernier, J. (2009). Current state-of-the-art for concurrent chemoradiation.
  
  Seminars in Radiation Oncology, 19
  
  (1), 3-10. doi:10.1016/j.semradonc.2008.09.002
• Forastiere, A. A., Ismaila, N., Lewin, J. S., Nathan, C. A., Adelstein, D. J., Eisbruch, A., . . . Wolf, G. T. (2018). Use of larynx-preservation strategies in the treatment of laryngeal cancer: American society of clinical oncology clinical practice guideline update.
  
  Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 36
  
  (11), 1143-1169. doi:10.1200/JCO.2017.75.7385
• Gau, M., Karabajakian, A., Reverdy, T., Neidhardt, E., & Fayette, J. (2019). Induction chemotherapy in head and neck cancers: Results and controversies.
  
  Oral Oncology
  
  , 95, 164-169. doi:10.1016/j.oraloncology.2019.06.015
• Haddad, R., O’Neill, A., Rabinowits, G., Tishler, R., Khuri, F., Adkins, D., . . . Posner, M. (2013). Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): A randomized phase 3 trial.
  
  Lancet Oncology, The, 14
  
  (3), 257-264. doi:10.1016/S1470-2045(13)70011-1
• Kim, S. H., Lee, Y. S., Kwon, M., Kim, J. W., Roh, J., Choi, S., . . . Nam, S. Y. (2016). Adjuvant role of radiation therapy for locally advanced laryngeal cancer without pathological lymph node metastasis.
  
  Acta Oto-Laryngologica, 136
  
  (7), 703-710.
• Lazarus, C. L. (2009). Effects of chemoradiotherapy on voice and swallowing.
  
  Current Opinion in Otolaryngology & Head and Neck Surgery, 17
  
  (3), 172-178. doi:10.1097/MOO.0b013e32832af12f
• Locatello, L. G., Pietragalla, M., Taverna, C., Bonasera, L., Massi, D., & Mannelli, G. (2019). A critical reappraisal of primary and recurrent advanced laryngeal cancer staging.
  
  Annals of Otology, Rhinology & Laryngology, 128
  
  (1), 36-43. doi:10.1177/0003489418806915
• Mannelli, G., Lazio, M., Luparello, P., & Gallo, O. (2018). Conservative treatment for advanced T3–T4 laryngeal cancer: Meta-analysis of key oncological outcomes.
  
  European Archives of Oto-Rhino-Laryngology, 275
  
  (1), 27-38. doi:10.1007/s00405-017-4799-x
• Muderris, T. K., Gul, F., Doblan, A., Ergin, M., & Muderris, T. (2019). Role of T-helper 17 cell related cytokines in laryngeal cancer.
  
  The Journal of Laryngology and Otology, 133
  
  (5), 394-398. doi:10.1017/S0022215119000689
• Obid, R., BA, Redlich, M., BSN, & Tomeh, Chafeek, MD, MPH. (2018). The treatment of laryngeal cancer.
  
  Oral and Maxillofacial Surgery Clinics, 31
  
  (1), 1-11. doi:10.1016/j.coms.2018.09.001
• Pignon, J., Maître, A. l., Maillard, E., & Bourhis, J. (2009). Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomized trials and 17,346 patients.
  
  Radiotherapy and Oncology, 92
  
  (1), 4-14. doi:10.1016/j.radonc.2009.04.014
• Taito, M., Taito, S., Banno, M., Fujiwara, T., Okamura, H., Tsujimoto, H., . . . Tsujimoto, Y. (2019). Voice rehabilitation for laryngeal cancer after radiotherapy: A systematic review and meta-analysis.
  
  European Archives of Oto-Rhino-Laryngology, 276
  
  (6), 1573-1583. doi:10.1007/s00405-019-05452-2
• Zumsteg, Z. S., Riaz, N., Jaffery, S., Hu, M., Gelblum, D., Zhou, Y., . . . Lee, N. Y. (2015). Carotid sparing intensity-modulated radiation therapy achieves comparable locoregional control to conventional radiotherapy in T1-2N0 laryngeal carcinoma.
  
  Oral Oncology, 51
  
  (7), 716-723. doi:10.1016/j.oraloncology.2015.02.003