Journal of Surgical Oncology
REVIEW Current Treatment of Head and Neck Squamous Cell Cancer RYAN BELCHER, MD,1 KATHERINE HAYES, MD,1 STACEY FEDEWA,
MPH,
2
AND
AMY Y. CHEN, MD, MPH1*
1
Department of Otolaryngology-Head and Neck Surgery, Emory University School of Medicine, Atlanta, Georgia 2 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
Head and neck cancer is a heterogenous group of cancers involving the upper aerodigestive tract. In this review article, the most common sites will be discussed, including the oral cavity, oropharynx, hypopharynx, and larynx. Etiology and epidemiology will be discussed followed by staging, treatment, and survival. J. Surg. Oncol. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: squamous cell cancer; head and neck; outcomes; chemotherapy; radiation; surgery
INTRODUCTION In 2013 in the United States there were an estimated 53,640 new cancer cases of the head and neck (oral cavity, pharynx, and larynx) with over 95% of these cases comprised of squamous cell carcinoma. Survival rates have been stable to slightly increasing over the past 3 decades for oral cavity and pharyngeal cancers with the 5‐year survival rate as of 2002–2008 at 65%. In contrast laryngeal cancer has provided a challenge for treatment and outcomes with the 5‐year survival rates decreasing over the past 3 decades from 66% in 1975–1977 to 63% from 2002 to 2008 [1]. Advancements in the management of head and neck cancer have included improved clinical care for these patients. Other advancements in the outcomes of head and neck cancer include the use of robotic assisted surgery, increased use of free tissue transfers, increasing use of postoperative adjuvant external beam radiotherapy since the 1970s, and the use of adjuvant chemotherapy in the 1980s. Targeted molecular therapies are also being utilized. The ultimate goal will be to have therapies individually tailored to the specific genetic components of each patient’s tumor. In this article, the outcomes of head and neck squamous cell cancer (HNSCCA) are discussed by the anatomic sub‐site of disease; oral cavity, oropharynx, hypopharynx, and larynx. Clinical and non‐clinical factors that impact outcome including stage of cancer (early vs. late), patient selection, surgical options, and non‐surgical options (i.e., chemotherapy, radiation therapy) will be discussed.
ORAL CAVITY The oral cavity (OCSCC) represents the most common site of squamous cell carcinoma in the head and neck. This anatomic region includes the lip, alveolar ridge, buccal mucosa, retromolar trigone, floor of mouth, and oral tongue. Overall, the male to female ratio of OCSCC remains 2:1, although this disparity has decreased in recent years due to prolonged alcohol and tobacco use among women. It should be noted that the epidemiology of cancers of the lip differs from other subsites within the oral cavity, being more common among white males and related to prolonged sun exposure. For the remainder of the oral cavity, tobacco, and alcohol use are the most significant risk factors for the development of SCC. Smokeless tobacco and betel nut use are also uniquely implicated in the oral cavity due to direct carcinogenic effects
ß 2014 Wiley Periodicals, Inc.
on adjacent mucosa [2]. Whereas HPV has become a major etiologic factor in tumors of the oropharynx, this relationship is not clear within the oral cavity. Although HPV infection is prevalent in the oral cavity, the prevalence of oncogenic HPV subtypes among tumors in this site is low and their role in carcinogenesis requires further investigation [3]. The oral cavity is readily accessible to physical examination, yet a delay in diagnosis of cancers in the oral cavity can occur due to confusion with benign oral pathology. However, with a high index of suspicion, premalignant lesions including leukoplakia and erythroplakia can be identified within the oral cavity. Leukoplakia has been found to harbor dysplasia or malignancy on histologic evaluation up to 20% of the time; this number increases to well over 50% for erythroplakia. Prompt identification and treatment of these lesions is extremely important. These lesions are often surgically removed with either cold steel or laser treatment although recurrence has been reported up to 20% of the time [4]. A robust area of ongoing research is the use of chemoprevention in patients with premalignant lesions. Proponents of chemoprevention cite the field cancerization model proposed by Slaughter in 1953 and the high frequency of synchronous and metachronous second primaries of the aerodigestive tract as justification for preventative treatment in high risk patients. Several agents including retinoids and beta‐carotene antioxidants have been used with varying success in these patients in an attempt to prevent recurrence and limit development of second primaries [5]. Initial diagnosis and staging is best completed with a thorough history and physical examination with biopsy of suspicious lesions. Due to a relatively high risk of synchronous primary aerodigestive tumors, panendoscopy is often performed as part of a complete workup. Cross sectional imaging is obtained to elucidate extent of soft tissue invasion,
Conflict of interest: none. *Correspondence to: Amy Y. Chen, MD, MPH, Department of Otolaryngology‐Head and Neck Surgery, Emory University School of Medicine, 550 Peachtree St, Atlanta, GA 30308. Fax: þ1‐404‐778‐4295. E‐mail: [email protected] Received 24 March 2014; Accepted 5 June 2014 DOI 10.1002/jso.23724 Published online in Wiley Online Library (wileyonlinelibrary.com).
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bony invasion, and presence of nodal disease. Computed tomography (CT) scan illustrates nodal disease and is the modality of choice for identifying erosion of the mandible or frank medullary bone involvement [6]. Extent of bony involvement is important for staging and for surgical planning. However, it should be noted that soft tissue invasion can be difficult to determine on CT due to significant artifact from dental amalgams. As a result, if there is a question of extent of soft tissue involvement or perineural spread, magnetic resonance imaging (MRI) is preferable. Positron emission tomography (PET) is also employed to evaluate for distant metastatic disease [6]. Staging within the oral cavity is based on the TNM classification (see Appendix). Small tumors without obvious nodal metastases represent early stage I and II cancers, while larger tumors and/or the presence of neck lymphadenopathy represent advanced stage III and IV cancers. Factors that have been linked to poorer outcomes in OCSCC include advanced tumor stage, increased soft tissue depth of invasion, presence of nodal metastases, and extracapsular nodal spread. These factors play a large part in patient selection and the decision making for surgery or non‐surgical treatments [7]. In general, early stage tumors are treated with single modality therapy—either surgery or radiation. Although Lefebvre et al. [8] demonstrated similar outcomes for early tumors treated with primary brachytherapy or surgery, the ease of access to the oral cavity and minimal morbidity of surgery makes surgery the mainstay of treatment. Advanced stage cancers are often treated with combination therapy, usually surgical resection followed by adjuvant radiation with or without chemotherapy. Evidence supporting the use of postoperative adjuvant chemotherapy with cisplatin versus radiation alone for HNSCCA came from two landmark prospective randomized trials published in 2004. Independently, studies designed by the European Organization for Research and Treatment of Cancer (EORTC 22931) and the Radiation Therapy Oncology Group (RTOG 95‐01) demonstrated improved locoregional control and disease‐free survival among HNSCCA patients with high‐risk features who received postoperative chemoradiation (rather than radiation alone) [9,10]. More recently, a study looking specifically at OCSCC showed that the addition of chemotherapy to radiation postoperatively in advanced stage tumors led to a significant increase in 2‐ and 5‐year overall survival compared to adjuvant radiation alone. This was most pronounced among tumors with nodal extracapsular spread, in which a 55% survival advantage was exhibited at 5 years [11]. Although initial primary surgery followed by adjuvant chemoradiation or radiation has classically been the treatment of choice for advanced oral cavity tumors, recent studies query whether definitive concurrent chemoradiation may be an alternative choice in select cases. In a retrospective review, Cohen et al. [12] demonstrated functional and survival outcomes comparable to historical data when T4 tumors—including those with bony invasion were treated with primary concurrent chemoradiation. However, other reviews including restrospective data from Gore et al. [13] in 2014 show a clearly significant improvement in survival among surgically treated patients. Without prospective data available, the role for chemoradiation among patients with oral cavity cancer is currently limited to those with non‐resectable tumors or comorbidities precluding surgery. Surgery remains the mainstay of initial treatment for oral cavity cancer. Smaller lesions are easily accessed transorally, while larger tumors may require mandibulotomy with lip‐split incision or visor flap approach. Preoperative imaging determines the extent of bony involvement and guides surgical planning as to whether marginal or segmental mandibular resection is necessary. Figure 1 shows an axial CT image of a floor of mouth T4aN2bM0 squamous cell carcinoma that has invaded the mandible in multiple areas. Figure 2 is a clinical photo of the lesion in the same patient. When bone invasion is limited to the alveolar process, a marginal mandibulectomy may be performed but medullary invasion necessitates a segmental resection. Surgical defects can be closed in a variety of ways ranging from primary closure to use of free Journal of Surgical Oncology
Fig. 1. Axial computer tomography image showing left mandibular erosion of a floor of mouth T4aN2bM0 squamous cell carcinoma.
tissue transfer. Due to the anatomic complexity of the oral cavity and the crucial role it plays in taste, swallowing, speech, and breathing, reconstructive decisions must take into consideration the associated functional and cosmetic outcomes. The use of vascularized osteocutaneous free tissue, often from the fibula, has become the standard of care following mandibulectomy. In addition, a variety of musculocutaneous and fasciocutaneous vascularized flaps are available for reconstruction of soft tissue defects of varying sizes [14]. Lymphatic drainage of the oral cavity usually occurs first to levels I– III. Early T1 and T2 lesions of the lip, tongue, and floor of mouth with depth of invasion 20% of occult metastases. Byers et al. [15] demonstrated a rate of skip metastases to level IV of 15.8% and advocated for its inclusion with elective neck dissection. In the clinically positive neck, recent studies show no difference in locoregional control or survival when level V is omitted and recommend level I–III or I–IV therapeutic neck dissection based on the burden of nodal disease and surgeon preference [16].
Fig. 2. Photograph taken in clinic setting of same patient in Figure 1. Left floor of mouth T4aN2bM0 squamous cell cancer that has invaded the mandible.
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Fig. 3. Five‐year survival among oral cavity cancer cases by stage (2004–2009). n ¼ 24,676. Log rank test for the significant differences between curves Chi Sq ¼ 1387.20, df ¼ 1, P‐value < 0.0001. Five‐year survival for stage I oral cavity cancer is 72%, stage II 54%, stage III 37%, and stage IV 29% [17]. Tumor stage at the time of patient presentation is the most important prognostic factor, with a significant drop in survival seen with the presence of nodal metastases [14]. Data from 2004 to 2009 was gathered from the Surveillance, Epidemiology, and End Results Program (SEER) for 5‐year survival rates in oral cavity cancer (early stage vs. late stage) and is shown in Figure 3.
In general, multiple modality treatment is the standard of care for advanced OPSCC. Machtay et al. [24] had a single institution study at the University of Pennsylvania with patients with stage III/IV OPSCC treated with surgery and postoperative external beam radiation therapy
OROPHARYNX The oropharynx is crucial for normal speech production, deglutition, and respiration. The oropharynx includes the palatine tonsillar fossa and pillars, soft palate, pharyngeal walls, and the base of tongue. In addition to tobacco and alcohol abuse, HPV infection is a risk factor for development of oropharyngeal squamous cell carcinoma (OPSCC) [18,19]. A worldwide meta‐analysis showed that HPV associated OPSCC is increasing in prevalence from 40.5% in studies before 2000 to 72.2% in studies with patients recruited after 2005 [20]. Initial staging of OPSCC involves an exam under anesthesia with complete inspection and palpation of the tumor. The oropharynx is also implicated most often, specifically tonsillar fossa and base of tongue, when patients present with cervical metastasis and an unknown primary. A panendoscopy is recommended in these cases with bilateral tonsillectomy and bilateral base of tongue biopsies [21]. Stage 1 and Stage 2 OPSCCs can be treated with surgery and/or radiation alone. The choice between the two treatment options is balanced by many factors including patient preference, HPV associated OPSCC, patient comorbidities among many other factors [22]. In addition, a subset of Stage III OPSCCs that are T1 or T2 lesions with N1 disease can be treated with radiation therapy alone [23]. Figure 4 shows an axial CT image of a T2N2bM0 SCCa of the right tonsil. Figure 5 shows a transoral picture of the lesion taken in the clinical setting. Journal of Surgical Oncology
Fig. 4. Axial computer tomography image of right tonsil T2N2bM0 squamous cell cancer. The right tonsil is enlarged and an involved lymph node can be seen on the patient’s right.
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Belcher et al. by the Eastern Cooperative Oncology Group (ECOG) showed that patients with Stage 3 and Stage 4 HPV‐positive HNSCC of the oropharynx is strongly associated with improved therapeutic response and survival compared to patients with HPV‐negative tumors [35]. Five‐year survival rates of HPV‐positive tumor patients is approximately 75–80% compared to 45–50% for HPV‐negative tumor patients [36]. Five‐year survival rates for OPSCC from SEER is depicted in Figure 6.
HYPOPHARYNX
Fig. 5. Transoral picture taken in clinic setting of the right tonsil T2N2bM0 squamous cell carcinoma of same patient in Figure 4. (XRT) that showed the patients have approximately 30% risk of locoregional relapse, a 30% risk of distant relapse, and a 60% risk of having a poor functional outcome. Concurrent chemoradiation (CRT) has steadily increased over the past several years in replacing surgery in the initial treatment of advanced stage OPSCC, especially in those patients with HPV‐positive tumors. Although there has been a lack of trials directly comparing surgery with postoperative radiation to concurrent CRT in OPSCC, the trend to use CRT in oropharynx has grown since the Veterans Affairs Laryngeal Cancer study demonstrated equivalent survival for non‐surgical and surgical treatment for advanced laryngeal cancer [25]. NCCN Guidelines recommend cisplatin alone for advanced OPSCC although several trials have shown concurrent CRT with cisplatin and 5‐fluorouracil to also be an acceptable treatment regimen for patients that receive CRT in OPSCC [26–29]. Surgical resection of the primary can be done via a transoral or transcervical approach. Transcervical approaches are more commonly used for patients with advanced primaries, bony involvement, and salvage surgery. Transoral procedures involving the CO2 laser for OPSCC have been in use since the 1990s but in 2005 transoral robotic surgery (TORS) was introduced and has been gaining popularity ever since. TORS has shown to have low complication rates, improved cosmetic outcome, shortened hospital stays and swallowing function remains high compared to primary open surgery. This technique also improves visualization and adds degrees of freedom to surgical movements [30]. Another added benefit of TORS in early stage tumors of oropharynx is it has shown to avoid the need for adjuvant radiotherapy (RT) in up to 38% of cases without sacrifice of disease control [31]. In another study done by University of Pennsylvania, Weinstein et al. [32] showed that TORS used in advanced OPSCC (Stage III/IV) had comparable oncologic outcomes to CRT studies and even had a disease‐specific survival of 90% at 2 years. Long‐term studies on TORS are still needed to measure outcomes and oncologic benefit. Currently, the robot is only approved for early stage OPSCC by the FDA. The oropharynx lymphatics most often drain to neck levels II–IV and the retropharyngeal lymph nodes (RPLNs). N0 and N1 necks can be treated with the same single modality used on the primary tumor (surgery vs. radiation). In contrast to OCSCC, management of the cervical lymph nodes in OPSCC is most commonly done after concurrent chemoradiation for N2 and N3 necks [10]. Excision of the RPLNs should always be considered in patients with posterior pharyngeal wall involvement or advanced T and N stage tumors [33]. OPSCC staging is outlined in the Appendix. Expected 5‐year survival of patients with Stage I OPSCC is 67%, 46% for Stage 2, 31% for Stage 3, and 32% for Stage 4 [34]. A prospective study performed Journal of Surgical Oncology
The hypopharynx spans from the hyoid bone down to inferior cricoid cartilage and includes the pyriform sinuses, postcricroid area, and pharyngeal wall. Hypopharyngeal squamous cell carcinomas (HPSCC) represent 3–4% of all head and neck cancers in the United States [37]. These patients are most commonly heavy smokers and drinkers. One study showed active tobacco smoking had a stronger risk of cancer in the hypopharynx than it did for oral cavity, oropharynx, and esophagus [38]. These patients commonly have multiple comorbidities because of their tobacco and/or alcohol abuse with up to 77% of these patients presenting with stage III or IV disease [39]. HPSCCs are often intimately associated with the cervical esophagus and the adjacent larynx. Tumors occur in the pyriform sinuses over half of the time and the rich submucosal lymphatic network allows these tumors to spread easily to the surrounding areas [40]. Other characteristics of these tumors include multicentricity resulting in satellite lesions, high incidence of distant metastasis, and early lymphatic spread [41]. Early stage HPSCCs can be treated by surgery or radiation alone with comparable 5‐year overall survival and local disease control rates. Patient selection along with tumor characteristics (e.g., HPV positive), play a major role in deciding between the treatment options. Patients with early stage tumors unfortunately have a higher risk of developing a second primary tumor than do patients with advanced tumors because of their longer survival period [42]. Surgical approaches are most commonly transoral for early stage carcinomas and transcervical for late stage. Early‐stage pyriform sinus tumors can be visualized by a transhyoid approach for a partial laryngopharyngectomy or a supracricroid hemilaryngectomy. Advanced stage pyriform sinus tumors typically require a total laryngectomy and pharyngectomy. Advanced staged posterior hypopharyngeal wall tumors may require a transcervical approach for adequate surgical resection. Transoral surgery approaches can be performed by laser resection or by the more recently developed TORS technique. Transoral laser surgery (TOLS) has been shown to have oncologic results comparable to open surgery. Both TOLS and TORS are not only able to preserve the larynx, but also the pharyngeal sensory nerve plexus, which contributes to a more rapid recovery of patient functions such as swallowing and tracheotomy decannulation [43,44]. Advanced stage tumors can be treated with surgery and postoperative radiation or with CRT. Since the early 1990s, there has been increasing use of non‐surgical treatment with the goal of organ preservation. This trend has grown in part because of the results of the previously mentioned Veteran Affairs Laryngeal Cancer study and the RTOG 09‐ 11 study [25,27]. One study conducted by the European Organization for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Cooperative group compared an organ preservation protocol (induction chemotherapy followed by radiation) and surgery for pyriform sinus cancer [28]. This study found no significant survival differences between the organ preservation and surgery arms. A subsequent study conducted by the European Groupe Oncologie Radiotherapie Tete et Cou (GORTEC) showed that three‐drug therapy consisting of docetaxel, cisplatin, and 5‐floururacil was statistically superior as induction therapy for organ preservation in advanced HPSCC over the two‐drug combination of cisplaitin and 5‐floururacil [45].
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Fig. 6. Five‐year survival among pharyngeal cancer cases by stage, 2004–2009. n ¼ 3,606. Log rank test for the significant differences between curves Chi Sq ¼ 206.33, df ¼ 1, P‐value < 0.0001. The prevalence of neck metastasis on presentation is between 65% and 80% [41,46]. One study demonstrated that patients treated with surgery and radiation with N0 or N1 necks had a 5‐year survival of 54% while those with N2 or greater disease had a 5‐year survival of 20% [47]. Involvement of the retropharyngeal lymph nodes and bilateral drainage are common. If initial surgical resection of the primary is performed, surgical management of the neck is also done at the same time. Ipsilateral SND (II–IV) is recommended for early stage tumors of lateral pyriform sinus. Advanced stage HPSCCs require a bilateral SND and paratracheal nodal dissection. In addition, a mediastinal lymph node dissection is recommended for T4 tumors [48,49]. HPSCC has the worst survival of any primary malignancy of the head and neck mucosa, with a 5‐year overall survival of around 35% [37]. Early stage cancers (Stage 1 and 2) have up to a 71% 5‐year survival rate [43]. Advanced stage HPSCC 5‐year survival is much more dismal and has been reported to be as low as 16% and as high as 47% [50,51]. Five‐year survival rates for hypopharyngeal cancer from SEER data is shown in Figure 7.
LARYNX The larynx is responsible for respiration, the ability to speak, and to protect the airway. The supraglottis, glottis, and subglottis comprise the larynx. Each of these subsites has different embryologic origins; thus, each has different lymphatic drainage patterns and blood supplies. Thus when a laryngeal malignancy is diagnosed, the location in which the cancer originates plays a major role in guiding the treatment. The majority of all the malignancies of the larynx occur in the glottis (64%) and supraglottis (34%) with the subglottis only representing less than 2% of the cases [52]. Risk factors for laryngeal squamous cell carcinoma (LSCC) include tobacco and alcohol. It is estimated that only 5% of laryngeal LSCCs occur in nonsmokers and nondrinkers [53]. With Journal of Surgical Oncology
a decrease in smoking, the incidence of laryngeal cancer has been decreasing [54]. HPV has been reported to be associated with LSCC, but with less frequency that OPSCC [55]. Roughly 60% of all LSCC cases are diagnosed as early stage [56]. A retrospective review by Gourin et al. [57] from 1985 to 2002 found 5‐ year survival rates to be 85% for Stage 1 and 77% for Stage 2. Primary surgery for early stage supraglottic lesions has been shown to be superior in local control rates compared to primary radiotherapy in some studies, but RT is still an acceptable form of treatment especially if visual access of the tumor is not possible or the patient is not a candidate for surgery [58]. Transoral laser microsurgery (TLM) can be used for supraglottic and glottis tumors if adequate visualization of the entire tumor can be achieved. TORS is also an option that shows promise for these cancers but can be limited due to spatial constraints [59]. Early staged glottis tumors can be treated with a cordectomy either with TLM or open surgery. If there is extension to the arytenoids then a hemilaryngectomy can be performed as well. The decision for these treatment modalities is guided by adequate visual access, expectations, tumor stage and site, and expectations of voice quality. Subglottic tumors are extremely rare and mostly result from secondary extensions from glottic cancers. Surgery and XRT are both used for subglottic primaries. Advanced LSCCs are treated with either CRT or total laryngectomy. Figures 8 and 9 show a T4aN0M0 SCC of the left vocal cord. Figure 8 is an axial CT image of the tumor that shows the lesion creating a mass effect on the left vocal cord. Figure 9 was a clinical photo taken with a flexible nasopharyngoscope. Advanced laryngeal tumor treatment shifted after 1991 when the VA Laryngeal Cancer study demonstrated comparable survival for patients treated with TL or organ preservation [25]. Laryngeal preservation rate was 67% [25]. Further studies have shown that Stage 3 and 4 cancers can be treated with CRT or surgery. However, T4 cases should be treated with surgery [57,60].
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Fig. 7. Five‐year survival among hypopharyngeal cancer cases by stage, 2004–2009. n ¼ 2,235. Log rank test for the significant differences between curves Chi Sq ¼ 61.06, df ¼ 1, P‐value < 0.0001. A phase III study by the Radiation Therapy Oncology Group (RTOG) showed that concurrent CRT had significantly better locoregional control rates and 2‐year laryngeal preservation rates when compared to induction CRT and radiation alone. Concurrent CRT is an acceptable
Fig. 8. Axial computer tomography image of left vocal cord T4aN0M0. The fullness can be seen in the left vocal cord, which was biopsied and found to be positive for squamous cell carcinoma. Journal of Surgical Oncology
treatment for advanced LSCC in patients that meet appropriate organ preservation criteria [27]. Patients with laryngeal organ dysfunction prior to treatment should not undergo organ preservation treatments. The supraglottis has more abundant lymphatics than the glottis with a cervical metastasis rate of 33% in T1–T2 tumors of supraglottis. Lymphatic spread in T1–T2 cancers of the glottis is uncommon but more common in primaries larger than T3 [61]. Both sites predictably drain to levels II–IV. In addition to levels II–IV, the glottis also drains into level VI. N0 and N1 necks can be treated the same modality used to treat the primary (radiation or surgery). N2 and N3 nodal disease is best treated with multimodality treatment including surgery, radiation, and chemotherapy.
Fig. 9. Clinical picture taken with nasopharyngolaryngoscopy of the left vocal cord T4aN0M0 squamous cell carcinoma.
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Fig. 10. Five‐year survival among laryngeal cancer cases by stage, 2004–2009. n ¼ 12,577. Log rank test for the significant differences between curves Chi Sq ¼ 1494.06, df ¼ 1, P‐value < 0.0001. As nonsurgical treatment has increased for treatment of laryngeal cancer, the 5‐year survival rate from LSCC in the United States has decreased (66% down to 63%) [1]. Several studies have demonstrated this trend [56,57,60,62]. Figure 10 shows 5‐year survival rates of laryngeal cancer from SEER data. In addition, two studies have reported that LSCC is the only HNSCCA with decreasing survival rates over the past decades [56,63]. Further investigation demonstrated that comorbidity burden is not greater among non‐ patients and thus not the reason for worse survival [64]. Emerging evidence suggest that heterogeneity of non‐surgical care may be the reason for worse outcomes than what has been reported in previous clinical trials [57,63,64].
CONCLUSIONS Head and neck squamous cell cancer is a heterogeneous group of cancers. Etiology, treatment and outcomes are dependent on the subsite. We have outlined in this paper the subsites of oral cavity, oropharynx, hypopharynx, and larynx and the most common pathology, squamous cell cancer. Optimal management of HNSCCA is dependent upon accurate staging and treatment.
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35. Fakhry C, Westra WH, Li S, et al.: Improved survival of patients with human papillomavirus‐positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100:261–269. 36. Ang KK, Harris J, Wheeler R, et al.: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24–35. 37. Cooper JS, Porter K, Mallin K, et al.: National Cancer Database report on cancer of the head and neck: 10‐Year update. Head Neck 2009;31:748–758. 38. Lee YC, Marron M, Benhamou S, et al.: Active and involuntary tobacco smoking and upper aerodigestive tract cancer risks in a multicenter case–control study. Cancer Epidemiol Biomarkers Prev 2009;119:1274–1280. 39. Hoffman HT, Karnell LH, Funk GF, et al.: The National Cancer Database report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg 1998;124:951–962. 40. Martin A, Jackel MC, Christiansen H, et al.: Microsurgery for cancer of the hypopharynx. Laryngoscope 2008;118:398–402. 41. Koo BS, Lim YC, Lee JS, et al.: Management of contralateral N0 neck in pyriform sinus carcinoma. Laryngoscope 2006;116:1268– 1272. 42. Yoshimura R, Kagami Y, Ito Y, et al.: Outcomes in patients with early‐stage hypopharyngeal cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2010;77:1017–1023. 43. Takes RP, Strojan P, Silver CE, et al.: Current trends in initial management of hypopharyngeal cancer: the Declining use of open surgery. Head Neck 2012;34:270–281. 44. Park YM, Kim WS, Virgilio AD, et al.: Transoral robotic surgery for hypopharyngeal squamous cell carcinoma: 3‐Year oncologic and functional analysis. Oral Oncol 2012;48:560–566. 45. Pointreau Y, Garaud P, Chapet S, et al.: Randomized trial of induction chemotherapy with cisplatin and 5‐fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009;101:498–506. 46. Hall SF, Groome PA, Irish J, et al.: The natural history of patients with squamous cell carcinoma of the hypopharynx. Laryngoscope 2008;118:1362–1371. 47. Kraus DH, Zelefsky MJ, Brock HAJ, et al.: Combined surgery and radiation therapy for squamous cell carcinoma of the hypopharynx. Otolaryngol Head Neck Surg 1997;116:637–641. 48. Joo YH, Sun DI, Cho KJ, et al.: The impact of paratracheal lymph node metastasis in squamous cell carcinoma of the hypopharynx. Eur Arch Otorhinolaryngol 2010;267:945–950. 49. Martin AS: Neck and mediastinal node dissection in pharyngolaryngoesophageal tumors. Head Neck 2001;23:772–779. 50. Godballe C, Jorgensen K, Hansen O, et al.: Hypopharyngeal cancer: Results of treatment based on radiation therapy and salvage surgery. Laryngoscope 2002;112:834–838. 51. Steiner W, Ambrosch P, Hess CF, et al.: Organ preservation by transoral laser microsurgery in piriform sinus carcinoma. Otolaryngol Head Neck Surg 2001;124:58–67. 52. Chen AY, Fedewa S, Zhu J: Temporal trends in the treatment of early and advanced‐stage laryngeal cancer in the United States 1985–2007. Arch Otolaryngol Head Neck Surg 2011;137:1017– 1024. 53. Baumann JL, Cohen S, Evjen AN, et al.: Human papillomavirus in early larngeal carcinoma. Laryngoscope 2009;119:1531–1537. 54. Sturgis EM, Cinciripini PM: Trends in head and neck cancer incidence in relation to smoking prevalence: An emerging epidemic of human papillomavirus‐associated cancers. Cancer 2007;110: 1429–1435. 55. Kreimer AR, Clifford GM, Boyle P, et al.: Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review. Cancer Epidemiol Biomarkers Prev 2005;14: 467–475. 56. Hoffman HT, Porter K, Karnell LH, et al.: Laryngeal cancer in the United States changes in demographics, patterns of care, and survival. Laryngoscope 2006;116:1–13. 57. Gourin CG, Conger BT, Sheils C, et al.: The effect of treatment on survival in patients with advanced laryngeal carcinoma. Laryngoscope 2009;119:1312–1317.
Outcomes in Head and Neck Cancer 58. Scola B, Fernandez‐Vega M, Martinez T, et al.: Mangement of cancer of the supraglottis. Otolaryngol Head Neck Surg 2001;124: 195–198. 59. Grant DG, Repanos C, Malpas G, et al.: Transoral laser microsurgery for early laryngeal cancer. Expert Rev Anticancer Ther 2010;10:331–338. 60. Chen AY, Halpern M: Factors predictive of survival in advanced laryngeal cancer. Arch Otolaryngol Head Neck Surg 2007;133: 1270–1276. 61. Yuce I, Cagli S, Bayram A, et al.: Occult metastases from T1–T2 supraglottic carcinoma: Role of primary tumor localization. Eur Arch Otorhinolaryngol 2009;266:1301–1304.
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62. Cosetti M, Yu G, Schantz SP: Five‐year survival rates and time trends of laryngeal cancer in the US population. Arch Otolaryngol Head Neck Surg 2008;134:370–379. 63. Chen AY, Fedewa S, Pavluck A, et al.: Improved survival is associated with treatment at high‐volume teaching facilities for patients with advanced stage laryngeal cancer. Cancer 2011;116: 4744–4752. 64. Zhu J, Fedewa S, Chen A: The impact of comorbidity on treatment (chemoradiation and laryngectomy) of advanced, nondistant metastatic, laryngeal cancer. Arch Otolaryngol 2012;138:1120– 1128.
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REVIEW Current Treatment of Head and Neck Squamous Cell Cancer RYAN BELCHER, MD,1 KATHERINE HAYES, MD,1 STACEY FEDEWA,
MPH,
2
AND
AMY Y. CHEN, MD, MPH1*
1
Department of Otolaryngology-Head and Neck Surgery, Emory University School of Medicine, Atlanta, Georgia 2 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
Head and neck cancer is a heterogenous group of cancers involving the upper aerodigestive tract. In this review article, the most common sites will be discussed, including the oral cavity, oropharynx, hypopharynx, and larynx. Etiology and epidemiology will be discussed followed by staging, treatment, and survival. J. Surg. Oncol. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: squamous cell cancer; head and neck; outcomes; chemotherapy; radiation; surgery
INTRODUCTION In 2013 in the United States there were an estimated 53,640 new cancer cases of the head and neck (oral cavity, pharynx, and larynx) with over 95% of these cases comprised of squamous cell carcinoma. Survival rates have been stable to slightly increasing over the past 3 decades for oral cavity and pharyngeal cancers with the 5‐year survival rate as of 2002–2008 at 65%. In contrast laryngeal cancer has provided a challenge for treatment and outcomes with the 5‐year survival rates decreasing over the past 3 decades from 66% in 1975–1977 to 63% from 2002 to 2008 [1]. Advancements in the management of head and neck cancer have included improved clinical care for these patients. Other advancements in the outcomes of head and neck cancer include the use of robotic assisted surgery, increased use of free tissue transfers, increasing use of postoperative adjuvant external beam radiotherapy since the 1970s, and the use of adjuvant chemotherapy in the 1980s. Targeted molecular therapies are also being utilized. The ultimate goal will be to have therapies individually tailored to the specific genetic components of each patient’s tumor. In this article, the outcomes of head and neck squamous cell cancer (HNSCCA) are discussed by the anatomic sub‐site of disease; oral cavity, oropharynx, hypopharynx, and larynx. Clinical and non‐clinical factors that impact outcome including stage of cancer (early vs. late), patient selection, surgical options, and non‐surgical options (i.e., chemotherapy, radiation therapy) will be discussed.
ORAL CAVITY The oral cavity (OCSCC) represents the most common site of squamous cell carcinoma in the head and neck. This anatomic region includes the lip, alveolar ridge, buccal mucosa, retromolar trigone, floor of mouth, and oral tongue. Overall, the male to female ratio of OCSCC remains 2:1, although this disparity has decreased in recent years due to prolonged alcohol and tobacco use among women. It should be noted that the epidemiology of cancers of the lip differs from other subsites within the oral cavity, being more common among white males and related to prolonged sun exposure. For the remainder of the oral cavity, tobacco, and alcohol use are the most significant risk factors for the development of SCC. Smokeless tobacco and betel nut use are also uniquely implicated in the oral cavity due to direct carcinogenic effects
ß 2014 Wiley Periodicals, Inc.
on adjacent mucosa [2]. Whereas HPV has become a major etiologic factor in tumors of the oropharynx, this relationship is not clear within the oral cavity. Although HPV infection is prevalent in the oral cavity, the prevalence of oncogenic HPV subtypes among tumors in this site is low and their role in carcinogenesis requires further investigation [3]. The oral cavity is readily accessible to physical examination, yet a delay in diagnosis of cancers in the oral cavity can occur due to confusion with benign oral pathology. However, with a high index of suspicion, premalignant lesions including leukoplakia and erythroplakia can be identified within the oral cavity. Leukoplakia has been found to harbor dysplasia or malignancy on histologic evaluation up to 20% of the time; this number increases to well over 50% for erythroplakia. Prompt identification and treatment of these lesions is extremely important. These lesions are often surgically removed with either cold steel or laser treatment although recurrence has been reported up to 20% of the time [4]. A robust area of ongoing research is the use of chemoprevention in patients with premalignant lesions. Proponents of chemoprevention cite the field cancerization model proposed by Slaughter in 1953 and the high frequency of synchronous and metachronous second primaries of the aerodigestive tract as justification for preventative treatment in high risk patients. Several agents including retinoids and beta‐carotene antioxidants have been used with varying success in these patients in an attempt to prevent recurrence and limit development of second primaries [5]. Initial diagnosis and staging is best completed with a thorough history and physical examination with biopsy of suspicious lesions. Due to a relatively high risk of synchronous primary aerodigestive tumors, panendoscopy is often performed as part of a complete workup. Cross sectional imaging is obtained to elucidate extent of soft tissue invasion,
Conflict of interest: none. *Correspondence to: Amy Y. Chen, MD, MPH, Department of Otolaryngology‐Head and Neck Surgery, Emory University School of Medicine, 550 Peachtree St, Atlanta, GA 30308. Fax: þ1‐404‐778‐4295. E‐mail: [email protected] Received 24 March 2014; Accepted 5 June 2014 DOI 10.1002/jso.23724 Published online in Wiley Online Library (wileyonlinelibrary.com).
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bony invasion, and presence of nodal disease. Computed tomography (CT) scan illustrates nodal disease and is the modality of choice for identifying erosion of the mandible or frank medullary bone involvement [6]. Extent of bony involvement is important for staging and for surgical planning. However, it should be noted that soft tissue invasion can be difficult to determine on CT due to significant artifact from dental amalgams. As a result, if there is a question of extent of soft tissue involvement or perineural spread, magnetic resonance imaging (MRI) is preferable. Positron emission tomography (PET) is also employed to evaluate for distant metastatic disease [6]. Staging within the oral cavity is based on the TNM classification (see Appendix). Small tumors without obvious nodal metastases represent early stage I and II cancers, while larger tumors and/or the presence of neck lymphadenopathy represent advanced stage III and IV cancers. Factors that have been linked to poorer outcomes in OCSCC include advanced tumor stage, increased soft tissue depth of invasion, presence of nodal metastases, and extracapsular nodal spread. These factors play a large part in patient selection and the decision making for surgery or non‐surgical treatments [7]. In general, early stage tumors are treated with single modality therapy—either surgery or radiation. Although Lefebvre et al. [8] demonstrated similar outcomes for early tumors treated with primary brachytherapy or surgery, the ease of access to the oral cavity and minimal morbidity of surgery makes surgery the mainstay of treatment. Advanced stage cancers are often treated with combination therapy, usually surgical resection followed by adjuvant radiation with or without chemotherapy. Evidence supporting the use of postoperative adjuvant chemotherapy with cisplatin versus radiation alone for HNSCCA came from two landmark prospective randomized trials published in 2004. Independently, studies designed by the European Organization for Research and Treatment of Cancer (EORTC 22931) and the Radiation Therapy Oncology Group (RTOG 95‐01) demonstrated improved locoregional control and disease‐free survival among HNSCCA patients with high‐risk features who received postoperative chemoradiation (rather than radiation alone) [9,10]. More recently, a study looking specifically at OCSCC showed that the addition of chemotherapy to radiation postoperatively in advanced stage tumors led to a significant increase in 2‐ and 5‐year overall survival compared to adjuvant radiation alone. This was most pronounced among tumors with nodal extracapsular spread, in which a 55% survival advantage was exhibited at 5 years [11]. Although initial primary surgery followed by adjuvant chemoradiation or radiation has classically been the treatment of choice for advanced oral cavity tumors, recent studies query whether definitive concurrent chemoradiation may be an alternative choice in select cases. In a retrospective review, Cohen et al. [12] demonstrated functional and survival outcomes comparable to historical data when T4 tumors—including those with bony invasion were treated with primary concurrent chemoradiation. However, other reviews including restrospective data from Gore et al. [13] in 2014 show a clearly significant improvement in survival among surgically treated patients. Without prospective data available, the role for chemoradiation among patients with oral cavity cancer is currently limited to those with non‐resectable tumors or comorbidities precluding surgery. Surgery remains the mainstay of initial treatment for oral cavity cancer. Smaller lesions are easily accessed transorally, while larger tumors may require mandibulotomy with lip‐split incision or visor flap approach. Preoperative imaging determines the extent of bony involvement and guides surgical planning as to whether marginal or segmental mandibular resection is necessary. Figure 1 shows an axial CT image of a floor of mouth T4aN2bM0 squamous cell carcinoma that has invaded the mandible in multiple areas. Figure 2 is a clinical photo of the lesion in the same patient. When bone invasion is limited to the alveolar process, a marginal mandibulectomy may be performed but medullary invasion necessitates a segmental resection. Surgical defects can be closed in a variety of ways ranging from primary closure to use of free Journal of Surgical Oncology
Fig. 1. Axial computer tomography image showing left mandibular erosion of a floor of mouth T4aN2bM0 squamous cell carcinoma.
tissue transfer. Due to the anatomic complexity of the oral cavity and the crucial role it plays in taste, swallowing, speech, and breathing, reconstructive decisions must take into consideration the associated functional and cosmetic outcomes. The use of vascularized osteocutaneous free tissue, often from the fibula, has become the standard of care following mandibulectomy. In addition, a variety of musculocutaneous and fasciocutaneous vascularized flaps are available for reconstruction of soft tissue defects of varying sizes [14]. Lymphatic drainage of the oral cavity usually occurs first to levels I– III. Early T1 and T2 lesions of the lip, tongue, and floor of mouth with depth of invasion 20% of occult metastases. Byers et al. [15] demonstrated a rate of skip metastases to level IV of 15.8% and advocated for its inclusion with elective neck dissection. In the clinically positive neck, recent studies show no difference in locoregional control or survival when level V is omitted and recommend level I–III or I–IV therapeutic neck dissection based on the burden of nodal disease and surgeon preference [16].
Fig. 2. Photograph taken in clinic setting of same patient in Figure 1. Left floor of mouth T4aN2bM0 squamous cell cancer that has invaded the mandible.
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Fig. 3. Five‐year survival among oral cavity cancer cases by stage (2004–2009). n ¼ 24,676. Log rank test for the significant differences between curves Chi Sq ¼ 1387.20, df ¼ 1, P‐value < 0.0001. Five‐year survival for stage I oral cavity cancer is 72%, stage II 54%, stage III 37%, and stage IV 29% [17]. Tumor stage at the time of patient presentation is the most important prognostic factor, with a significant drop in survival seen with the presence of nodal metastases [14]. Data from 2004 to 2009 was gathered from the Surveillance, Epidemiology, and End Results Program (SEER) for 5‐year survival rates in oral cavity cancer (early stage vs. late stage) and is shown in Figure 3.
In general, multiple modality treatment is the standard of care for advanced OPSCC. Machtay et al. [24] had a single institution study at the University of Pennsylvania with patients with stage III/IV OPSCC treated with surgery and postoperative external beam radiation therapy
OROPHARYNX The oropharynx is crucial for normal speech production, deglutition, and respiration. The oropharynx includes the palatine tonsillar fossa and pillars, soft palate, pharyngeal walls, and the base of tongue. In addition to tobacco and alcohol abuse, HPV infection is a risk factor for development of oropharyngeal squamous cell carcinoma (OPSCC) [18,19]. A worldwide meta‐analysis showed that HPV associated OPSCC is increasing in prevalence from 40.5% in studies before 2000 to 72.2% in studies with patients recruited after 2005 [20]. Initial staging of OPSCC involves an exam under anesthesia with complete inspection and palpation of the tumor. The oropharynx is also implicated most often, specifically tonsillar fossa and base of tongue, when patients present with cervical metastasis and an unknown primary. A panendoscopy is recommended in these cases with bilateral tonsillectomy and bilateral base of tongue biopsies [21]. Stage 1 and Stage 2 OPSCCs can be treated with surgery and/or radiation alone. The choice between the two treatment options is balanced by many factors including patient preference, HPV associated OPSCC, patient comorbidities among many other factors [22]. In addition, a subset of Stage III OPSCCs that are T1 or T2 lesions with N1 disease can be treated with radiation therapy alone [23]. Figure 4 shows an axial CT image of a T2N2bM0 SCCa of the right tonsil. Figure 5 shows a transoral picture of the lesion taken in the clinical setting. Journal of Surgical Oncology
Fig. 4. Axial computer tomography image of right tonsil T2N2bM0 squamous cell cancer. The right tonsil is enlarged and an involved lymph node can be seen on the patient’s right.
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Belcher et al. by the Eastern Cooperative Oncology Group (ECOG) showed that patients with Stage 3 and Stage 4 HPV‐positive HNSCC of the oropharynx is strongly associated with improved therapeutic response and survival compared to patients with HPV‐negative tumors [35]. Five‐year survival rates of HPV‐positive tumor patients is approximately 75–80% compared to 45–50% for HPV‐negative tumor patients [36]. Five‐year survival rates for OPSCC from SEER is depicted in Figure 6.
HYPOPHARYNX
Fig. 5. Transoral picture taken in clinic setting of the right tonsil T2N2bM0 squamous cell carcinoma of same patient in Figure 4. (XRT) that showed the patients have approximately 30% risk of locoregional relapse, a 30% risk of distant relapse, and a 60% risk of having a poor functional outcome. Concurrent chemoradiation (CRT) has steadily increased over the past several years in replacing surgery in the initial treatment of advanced stage OPSCC, especially in those patients with HPV‐positive tumors. Although there has been a lack of trials directly comparing surgery with postoperative radiation to concurrent CRT in OPSCC, the trend to use CRT in oropharynx has grown since the Veterans Affairs Laryngeal Cancer study demonstrated equivalent survival for non‐surgical and surgical treatment for advanced laryngeal cancer [25]. NCCN Guidelines recommend cisplatin alone for advanced OPSCC although several trials have shown concurrent CRT with cisplatin and 5‐fluorouracil to also be an acceptable treatment regimen for patients that receive CRT in OPSCC [26–29]. Surgical resection of the primary can be done via a transoral or transcervical approach. Transcervical approaches are more commonly used for patients with advanced primaries, bony involvement, and salvage surgery. Transoral procedures involving the CO2 laser for OPSCC have been in use since the 1990s but in 2005 transoral robotic surgery (TORS) was introduced and has been gaining popularity ever since. TORS has shown to have low complication rates, improved cosmetic outcome, shortened hospital stays and swallowing function remains high compared to primary open surgery. This technique also improves visualization and adds degrees of freedom to surgical movements [30]. Another added benefit of TORS in early stage tumors of oropharynx is it has shown to avoid the need for adjuvant radiotherapy (RT) in up to 38% of cases without sacrifice of disease control [31]. In another study done by University of Pennsylvania, Weinstein et al. [32] showed that TORS used in advanced OPSCC (Stage III/IV) had comparable oncologic outcomes to CRT studies and even had a disease‐specific survival of 90% at 2 years. Long‐term studies on TORS are still needed to measure outcomes and oncologic benefit. Currently, the robot is only approved for early stage OPSCC by the FDA. The oropharynx lymphatics most often drain to neck levels II–IV and the retropharyngeal lymph nodes (RPLNs). N0 and N1 necks can be treated with the same single modality used on the primary tumor (surgery vs. radiation). In contrast to OCSCC, management of the cervical lymph nodes in OPSCC is most commonly done after concurrent chemoradiation for N2 and N3 necks [10]. Excision of the RPLNs should always be considered in patients with posterior pharyngeal wall involvement or advanced T and N stage tumors [33]. OPSCC staging is outlined in the Appendix. Expected 5‐year survival of patients with Stage I OPSCC is 67%, 46% for Stage 2, 31% for Stage 3, and 32% for Stage 4 [34]. A prospective study performed Journal of Surgical Oncology
The hypopharynx spans from the hyoid bone down to inferior cricoid cartilage and includes the pyriform sinuses, postcricroid area, and pharyngeal wall. Hypopharyngeal squamous cell carcinomas (HPSCC) represent 3–4% of all head and neck cancers in the United States [37]. These patients are most commonly heavy smokers and drinkers. One study showed active tobacco smoking had a stronger risk of cancer in the hypopharynx than it did for oral cavity, oropharynx, and esophagus [38]. These patients commonly have multiple comorbidities because of their tobacco and/or alcohol abuse with up to 77% of these patients presenting with stage III or IV disease [39]. HPSCCs are often intimately associated with the cervical esophagus and the adjacent larynx. Tumors occur in the pyriform sinuses over half of the time and the rich submucosal lymphatic network allows these tumors to spread easily to the surrounding areas [40]. Other characteristics of these tumors include multicentricity resulting in satellite lesions, high incidence of distant metastasis, and early lymphatic spread [41]. Early stage HPSCCs can be treated by surgery or radiation alone with comparable 5‐year overall survival and local disease control rates. Patient selection along with tumor characteristics (e.g., HPV positive), play a major role in deciding between the treatment options. Patients with early stage tumors unfortunately have a higher risk of developing a second primary tumor than do patients with advanced tumors because of their longer survival period [42]. Surgical approaches are most commonly transoral for early stage carcinomas and transcervical for late stage. Early‐stage pyriform sinus tumors can be visualized by a transhyoid approach for a partial laryngopharyngectomy or a supracricroid hemilaryngectomy. Advanced stage pyriform sinus tumors typically require a total laryngectomy and pharyngectomy. Advanced staged posterior hypopharyngeal wall tumors may require a transcervical approach for adequate surgical resection. Transoral surgery approaches can be performed by laser resection or by the more recently developed TORS technique. Transoral laser surgery (TOLS) has been shown to have oncologic results comparable to open surgery. Both TOLS and TORS are not only able to preserve the larynx, but also the pharyngeal sensory nerve plexus, which contributes to a more rapid recovery of patient functions such as swallowing and tracheotomy decannulation [43,44]. Advanced stage tumors can be treated with surgery and postoperative radiation or with CRT. Since the early 1990s, there has been increasing use of non‐surgical treatment with the goal of organ preservation. This trend has grown in part because of the results of the previously mentioned Veteran Affairs Laryngeal Cancer study and the RTOG 09‐ 11 study [25,27]. One study conducted by the European Organization for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Cooperative group compared an organ preservation protocol (induction chemotherapy followed by radiation) and surgery for pyriform sinus cancer [28]. This study found no significant survival differences between the organ preservation and surgery arms. A subsequent study conducted by the European Groupe Oncologie Radiotherapie Tete et Cou (GORTEC) showed that three‐drug therapy consisting of docetaxel, cisplatin, and 5‐floururacil was statistically superior as induction therapy for organ preservation in advanced HPSCC over the two‐drug combination of cisplaitin and 5‐floururacil [45].
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Fig. 6. Five‐year survival among pharyngeal cancer cases by stage, 2004–2009. n ¼ 3,606. Log rank test for the significant differences between curves Chi Sq ¼ 206.33, df ¼ 1, P‐value < 0.0001. The prevalence of neck metastasis on presentation is between 65% and 80% [41,46]. One study demonstrated that patients treated with surgery and radiation with N0 or N1 necks had a 5‐year survival of 54% while those with N2 or greater disease had a 5‐year survival of 20% [47]. Involvement of the retropharyngeal lymph nodes and bilateral drainage are common. If initial surgical resection of the primary is performed, surgical management of the neck is also done at the same time. Ipsilateral SND (II–IV) is recommended for early stage tumors of lateral pyriform sinus. Advanced stage HPSCCs require a bilateral SND and paratracheal nodal dissection. In addition, a mediastinal lymph node dissection is recommended for T4 tumors [48,49]. HPSCC has the worst survival of any primary malignancy of the head and neck mucosa, with a 5‐year overall survival of around 35% [37]. Early stage cancers (Stage 1 and 2) have up to a 71% 5‐year survival rate [43]. Advanced stage HPSCC 5‐year survival is much more dismal and has been reported to be as low as 16% and as high as 47% [50,51]. Five‐year survival rates for hypopharyngeal cancer from SEER data is shown in Figure 7.
LARYNX The larynx is responsible for respiration, the ability to speak, and to protect the airway. The supraglottis, glottis, and subglottis comprise the larynx. Each of these subsites has different embryologic origins; thus, each has different lymphatic drainage patterns and blood supplies. Thus when a laryngeal malignancy is diagnosed, the location in which the cancer originates plays a major role in guiding the treatment. The majority of all the malignancies of the larynx occur in the glottis (64%) and supraglottis (34%) with the subglottis only representing less than 2% of the cases [52]. Risk factors for laryngeal squamous cell carcinoma (LSCC) include tobacco and alcohol. It is estimated that only 5% of laryngeal LSCCs occur in nonsmokers and nondrinkers [53]. With Journal of Surgical Oncology
a decrease in smoking, the incidence of laryngeal cancer has been decreasing [54]. HPV has been reported to be associated with LSCC, but with less frequency that OPSCC [55]. Roughly 60% of all LSCC cases are diagnosed as early stage [56]. A retrospective review by Gourin et al. [57] from 1985 to 2002 found 5‐ year survival rates to be 85% for Stage 1 and 77% for Stage 2. Primary surgery for early stage supraglottic lesions has been shown to be superior in local control rates compared to primary radiotherapy in some studies, but RT is still an acceptable form of treatment especially if visual access of the tumor is not possible or the patient is not a candidate for surgery [58]. Transoral laser microsurgery (TLM) can be used for supraglottic and glottis tumors if adequate visualization of the entire tumor can be achieved. TORS is also an option that shows promise for these cancers but can be limited due to spatial constraints [59]. Early staged glottis tumors can be treated with a cordectomy either with TLM or open surgery. If there is extension to the arytenoids then a hemilaryngectomy can be performed as well. The decision for these treatment modalities is guided by adequate visual access, expectations, tumor stage and site, and expectations of voice quality. Subglottic tumors are extremely rare and mostly result from secondary extensions from glottic cancers. Surgery and XRT are both used for subglottic primaries. Advanced LSCCs are treated with either CRT or total laryngectomy. Figures 8 and 9 show a T4aN0M0 SCC of the left vocal cord. Figure 8 is an axial CT image of the tumor that shows the lesion creating a mass effect on the left vocal cord. Figure 9 was a clinical photo taken with a flexible nasopharyngoscope. Advanced laryngeal tumor treatment shifted after 1991 when the VA Laryngeal Cancer study demonstrated comparable survival for patients treated with TL or organ preservation [25]. Laryngeal preservation rate was 67% [25]. Further studies have shown that Stage 3 and 4 cancers can be treated with CRT or surgery. However, T4 cases should be treated with surgery [57,60].
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Fig. 7. Five‐year survival among hypopharyngeal cancer cases by stage, 2004–2009. n ¼ 2,235. Log rank test for the significant differences between curves Chi Sq ¼ 61.06, df ¼ 1, P‐value < 0.0001. A phase III study by the Radiation Therapy Oncology Group (RTOG) showed that concurrent CRT had significantly better locoregional control rates and 2‐year laryngeal preservation rates when compared to induction CRT and radiation alone. Concurrent CRT is an acceptable
Fig. 8. Axial computer tomography image of left vocal cord T4aN0M0. The fullness can be seen in the left vocal cord, which was biopsied and found to be positive for squamous cell carcinoma. Journal of Surgical Oncology
treatment for advanced LSCC in patients that meet appropriate organ preservation criteria [27]. Patients with laryngeal organ dysfunction prior to treatment should not undergo organ preservation treatments. The supraglottis has more abundant lymphatics than the glottis with a cervical metastasis rate of 33% in T1–T2 tumors of supraglottis. Lymphatic spread in T1–T2 cancers of the glottis is uncommon but more common in primaries larger than T3 [61]. Both sites predictably drain to levels II–IV. In addition to levels II–IV, the glottis also drains into level VI. N0 and N1 necks can be treated the same modality used to treat the primary (radiation or surgery). N2 and N3 nodal disease is best treated with multimodality treatment including surgery, radiation, and chemotherapy.
Fig. 9. Clinical picture taken with nasopharyngolaryngoscopy of the left vocal cord T4aN0M0 squamous cell carcinoma.
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Fig. 10. Five‐year survival among laryngeal cancer cases by stage, 2004–2009. n ¼ 12,577. Log rank test for the significant differences between curves Chi Sq ¼ 1494.06, df ¼ 1, P‐value < 0.0001. As nonsurgical treatment has increased for treatment of laryngeal cancer, the 5‐year survival rate from LSCC in the United States has decreased (66% down to 63%) [1]. Several studies have demonstrated this trend [56,57,60,62]. Figure 10 shows 5‐year survival rates of laryngeal cancer from SEER data. In addition, two studies have reported that LSCC is the only HNSCCA with decreasing survival rates over the past decades [56,63]. Further investigation demonstrated that comorbidity burden is not greater among non‐ patients and thus not the reason for worse survival [64]. Emerging evidence suggest that heterogeneity of non‐surgical care may be the reason for worse outcomes than what has been reported in previous clinical trials [57,63,64].
CONCLUSIONS Head and neck squamous cell cancer is a heterogeneous group of cancers. Etiology, treatment and outcomes are dependent on the subsite. We have outlined in this paper the subsites of oral cavity, oropharynx, hypopharynx, and larynx and the most common pathology, squamous cell cancer. Optimal management of HNSCCA is dependent upon accurate staging and treatment.
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