|Year : 2017 | Volume
| Issue : 1 | Page : 3-12
Transoral surgery in early-stage laryngeal cancer
Somiah Siddiq, Vinidh Paleri
Department of Otolaryngology-Head and Neck Surgery, Newcastle Upon Tyne Foundation Hospitals NHS Trust, Newcastle Upon Tyne, NE7 7DN, UK
|Date of Web Publication||27-Jul-2017|
Department of Otolaryngology-Head and Neck Surgery, Newcastle Upon Tyne Foundation Hospitals NHS Trust, Newcastle Upon Tyne, NE7 7DN
Source of Support: None, Conflict of Interest: None
Single modality treatment is advocated for early laryngeal cancer, providing superior functional outcome and crucially options for further treatment in the event of local tumor recurrence. Options include surgery (mainly in the form of endolaryngeal techniques) or radiotherapy. With no prospective direct randomized controlled trials available, the choice of treatment following multidisciplinary discussion rests on a combination of tumor, patient and local expertise factors, with ultimately patient choice taking precedence. However, recently published data support the case for primary surgery on the basis of both organ preservation and health economics in early laryngeal cancer. We present an evidence-based review of the current literature in the management of primary and recurrent early laryngeal cancer.
Keywords: Early-stage laryngeal cancer, glottic, organ preservation, supraglottic, transoral surgery
|How to cite this article:|
Siddiq S, Paleri V. Transoral surgery in early-stage laryngeal cancer. J Head Neck Physicians Surg 2017;5:3-12
| Introduction|| |
Over 150,000 cases of laryngeal cancer are diagnosed each year in the world, with highest rates observed in Southern and Eastern Europe. Proven risk factors are smoking and alcohol, with greater incidence in men compared to women. The majority (75%) of laryngeal cancers arise from the glottis and thus present early due to the resulting hoarseness once vocal cords are involved. This, coupled with the rarity of cervical metastases, results in overall 5-year survival rates of >85%. The aim of treatment for early laryngeal cancer is to cure with one of the two modalities, with minimal complications or long-term adverse sequelae. Currently, modalities that exist include both endolaryngeal surgery (less so open partial laryngectomy [OPL]) and radiotherapy (RT). Generally, both modalities of treatment are thought to offer similar oncological results.
| Management of Early-Stage Laryngeal Cancers|| |
Early laryngeal cancer (T1/T2) can effectively be managed with single modality treatment in the form of either surgery or RT. Over the last two decades, a paradigm shift in the management of early laryngeal cancers has seen endoscopic resection techniques in the form of transoral laser microsurgery (TLM) and more recently transoral robotic surgery (TORS) increasingly being used as a primary treatment option for early glottic and supraglottic cancer.
Although never conclusively proven, surgery is considered to lead to inferior voice outcomes, especially in patients with anterior commissure lesions. However, surgery has distinct advantages including shorter treatment times (TLM for glottic cancer is often offered as a day-case procedure), ability to determine prognostic factors of the primary tumor including margin status, perineural and vascular spread, lymph node status, and extracapsular spread, while preserving options for adjuvant or salvage treatment. The latter is significant when one considers that only 50% of supraglottic cancers can be successfully salvaged with total laryngectomy following primary radiation therapy.
While RT causes no anatomic change to the organ, it involves several weeks of daily treatment with the associated impact on swallowing secondary to mucositis. A systemic review including data from 6181 patients identified that 80% of patients receiving RT suffered from mucositis, resulting in hospitalization and modification of RT regimens in 16% and 11% of patients, respectively. Furthermore, there is now a recognition that acute toxicities persist into the long term although this is often underestimated. For instance, even in the setting of advanced nonlaryngeal head and neck cancer where the larynx receives subradical radiation doses, RT has been shown to have significant deleterious effects on voice when assessed at 8 years after treatment. Notwithstanding the above, RT is preferred in patients within those with unfavorable anatomy (e.g., limited neck extension, trismus, or prominent upper dentition that prevents adequate endoscopic exposure of the larynx for TLM or TORS), significant medical comorbidity or poor pulmonary reserve.
| Pathways of Cancer Spread|| |
Tumors restricted to the free margin of the true vocal cords may spread along the entire length of the epithelial surface of the cord with restriction of vocal cord mobility once there is infiltration of the underlying thyroarytenoid (vocalis) muscle.
Careful assessment of the anterior commissure lesions, supplemented by imaging, is crucial due to the anatomical proximity of the thyroid cartilage at this site. Although, initially, the lack of perichondrium at the insertion of Broyles ligament was thought to result in inevitable thyroid cartilage invasion, whole organ serial section studies suggest the ligament serves more of a barrier than a potential avenue for tumour spread; invasion of cartilage is more likely in tumors extending superiorly and inferiorly via the subglottic wedge and thereby the cricothyroid membrane. Direct spread may occur via the anterior commissure to the opposite cord or posteriorly to involve the arytenoid cartilage.
Lateral spread into the paraglottic space results once Reinke's space is transgressed with cranial and caudal spread resulting from breach of the thyroglottic ligament (floor of the ventricle) and conus elastics inferiorly. Inferior extension via the paraglottic space may result in extralaryngeal spread via the cricothyroid membrane and subsequently thyroid gland and soft tissues of the neck. Although the laryngeal framework is an effective barrier to invasion, areas of ossification (inferior rim of the thyroid cartilage and the superior rim of the cricoid cartilage) are at highest risk of invasion resulting in a portal of exit via the cricothyroid membrane.
Lymphatic spread of glottic cancers is less common due to lack of submucosal lymphatics. Estimates of lymph node metastases by disease stage are <5% (T1) and 7% (T2).
Supraglottic cancers tend to remain locally confined (even with preepiglottic or nodal spread) to their subsite until relatively late. Several studies have shown that approximately 50% of supraglottic cancers spread to the glottic region. The presence of foramina within the epiglottic cartilage makes this less of a barrier to spread. However, invasion of the hyoid is rare (2%–4%), and as a result, it can often be preserved. “Suprahyoid supraglottic” carcinomas tend to invade the preepiglottic space and the deep muscles of the tongue and spread mucosally into the piriform fossae rather than into the paraglottic space. Supraglottic tumors also have a propensity for bilateral nodal metastasis. In reports of advanced disease, supraglottic carcinoma has a positive nodal rate of over 60%, compared with much lower rates of 20% in advanced glottic cases. This has a major influence on the decision to perform elective neck dissections for these patients.
| Clinical Presentation|| |
Fortunately, early glottic cancer presents with voice change by affecting the wave pattern over the vocal cord. Therefore, any person with hoarseness persisting for 3 weeks or more should be assessed urgently. With increasing size, hoarseness worsens, and once vocal cord fixation ensues, both dyspnea and a variable degree of aspiration become apparent. With more advanced disease, the risk of airway obstruction increases with evident stridor and potential otalgia. In early glottic cancer, neck nodes are rarely the presenting complaint and if evident may represent extension into the supraglottis or deep invasion and extension.
Small supraglottic cancers not involving the glottis may present with globus or foreign body sensation. Hemoptysis may become more predominant if the lesion is more exophytic in nature. Voice alteration may result in a “hot potato” voice as tumor increases in size with hoarseness if extension involves the vocal cords. Spread laterally may result in otalgia, odynophagia, and true dysphagia. Unlike glottic cancers, neck nodes may be the first presentation in supraglottic cancers.
| Assessment and Staging|| |
Following appropriate history, flexible laryngoscopy examination in the clinic setting assists in the assessment of vocal cord movement, extent of involvement including critical areas, such as the anterior commissure and subtle signs suggestive of subglottic extension, such a salivary pooling in the pyriform sinus. Videostroboscopy laryngeal examination may provide an estimation of depth of invasion and thereby potential extent of resection preoperatively, which may inform the decision-making process.
Cross-sectional imaging in the form of computerized tomography (CT) or magnetic resonance imaging (MRI) including chest imaging should be undertaken. Although rare, cervical metastases may be of concern if there is invasion outside of the glottis and in supraglottic cancers where a high percentage of patients present with clinically positive or occult bilateral nodal metastases. MRI has been shown to exhibit a higher accuracy than CT on T-staging of laryngeal cancer with anterior vocal commissure involvement; however, combined utility of both MRI and CT assists in improving the accuracy of thyroid cartilage involvement.
For staging purposes, examination under anesthesia is crucial and should routinely include the use of rigid (0° and angled 30° and/or 70°) endoscopes with tissue biopsy for histological assessment for definitive diagnosis.
In the setting of recurrent laryngeal cancer, the true extent of tumor is often underestimated clinically due to laryngeal edema and submucosal spread. Studies where whole organ sectioning has been employed indicate approximately 50% accuracy of pretreatment clinical and radiologic staging, with >90% being understaged. Newer MR techniques such as diffusion-weighted MR may offer greater precision in differentiating tumor, edema, and scar tissue but do require a higher level of experience for appropriate interpretation. Of the currently available optical imaging techniques, narrow band imaging is most commonly implemented in clinical practice. This technique exploits selected wavelengths of light to enhance the vascular pattern of mucosa and submucosa, identifying superficial carcinomas due to their aberrant vascular pattern, and has been shown to better define surgical margins, tumor staging, and early detection of primary, residual, or recurrent disease compared to white light endoscopy.
| Management|| |
Function and survival
For T1/T2aN0 lesions of the glottis, single modality treatment in the form of radiation or surgery offers comparable voice outcomes. Furthermore, no significant statistical difference in overall survival, disease-free survival, or local control is seen between TLM and RT.
In a meta-analysis of 362 patients with a mean follow-up time of 47 months, where voice outcomes measured using the vocal handicap inventory (VHI), no significant difference in posttreatment VHI scores was detected between RT and surgery. Systematic reviews have identified no advantages in voice outcomes for patients with T1 glottic cancer treated by RT compared to TLM.,, A recently updated Cochrane systematic review comparing RT, open surgery, and endolaryngeal excision (with or without laser) for early (T1, T2a) glottic laryngeal cancer concluded that all are presently accepted modalities of treatment with similar survival advantages. Although one trial that satisfied inclusion criteria was identified, it was associated with a high risk of bias. In an assessment of voice quality after treatment of early vocal cord cancer, a randomized trial comparing laser surgery with radiation therapy concluded that overall voice quality between the groups was rated similar, but voice was breathier and the glottal gap was wider in patients treated with laser surgery than in those who received radiation therapy. Patients treated with radiation therapy reported less hoarseness-related inconvenience in daily living 2 years after treatment.,
In the UK, the Early Stage glottic cancer: Endoscopic excision or Radiotherapy feasibility trial was set up to compare TLM with RT in laryngeal cancer staged T1 but failed to recruit the required number of patients. A detailed qualitative analysis identified several reasons for failure, with the major reason for low recruitment being that patients declined to be randomized, favoring the practical benefits of TLM over RT. These included completion of treatment as a day-case procedure while RT involved several weeks of daily treatment. Furthermore, postoperative recovery after TLM for T1 glottic cancers results in rapid recovery with minimal impact on swallowing, voice, and rapid return to normal activities.
Unsurprisingly, voice outcomes following endolaryngeal surgery are dependent upon the depth and extent of resection, which is the basis for the European Laryngological Society (ELS) classification [Table 1]. Voice-quality outcomes are better for superficial (ELS 1 and 2) resections and equivalent to RT compared to extended/deeper resections (ELS 3–6). Having said this, vocal function may return to preoperative levels in patients who undergo resections that are type III cordectomy.
|Table 1: European laryngological society classification of cordectomies for glottic carcinomas|
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It is common practice for mid-cord lesions to be offered TLM, with RT reserved for larger lesions where the impact on voice may be greater. TLM is less often used when tumor involves the anterior commissure or extends across two sites (T2), where voice quality following RT is superior, although cure rates are at least equivalent. Concerns in relation to lesions involving the anterior commissure include invasion of the thyroid cartilage in up to 20% at presentation, and the higher risk of local disease recurrence following partial laryngectomy, particularly following transoral laser resection.
In a population-based analysis of 10,429 patients with localized laryngeal cancer (90% T1 and T2; 10% T3) from the Surveillance, Epidemiology and End Results (SEER) database between 1995 and 2009, Misono et al. observed that while single modality treatment increased over the years (radiation or local surgery), combined modality treatment decreased, with these changes being statistically significant. Compared with radiation only (which was the reference category), patients who underwent “local surgery only” or “local surgery and radiation” had lower hazards of death (P< 0.0006 and P < 0.0001, respectively), with the survival differences persisting beyond 5 years of treatment. Whereas the 5-year disease-specific survival rates for the “local surgery” and “local surgery and radiation” groups were 91% and 90%, respectively, the 5-year survival rate for the “radiation only” group was 83%. This raises further questions regarding the presumed equivalence of the two treatment modalities.
Approximately one-third of patients with supraglottic cancer are diagnosed as Stage I or II, and similar to early glottic cancers, T1/T2 supraglottic cancers may be treated with single modality treatment.
With the increasing use of TLM and more recently TORS, endoscopic partial laryngectomy [Table 2] has become more popular, superseding traditional open supraglottic partial laryngectomy approaches. The advanced optics with three-dimensional imaging system, range of motion with the bimanual control of the robotic arms, additional suction and retraction by the surgical assistant, providing a total of four dissecting instruments during the transoral resection, the ability to work without the target being in the line of sight, and the possibility of en bloc resection are potential advantages of TORS over TLM. In 2007, Weinstein et al. reported the first three cases of TORS supraglottic partial laryngectomy and several series have since described the use of TORS for supraglottic cancers with comparable oncologic and functional outcomes to TLM.,,,
|Table 2: European Laryngological Society classification of transoral resections for supraglottic carcinomas|
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A very recent systematic review on transoral surgery versus intensity-modulated RT (IMRT) for early supraglottic cancer highlighted the lack of high-quality evidence but concluded excellent local control rates averaging 86% in endolaryngeal surgery as a definitive therapy for T1 and T2 supraglottic cancers. Furthermore, when comparing the single IMRT study included within the review, local control rates for T2 tumors were better for endolaryngeal surgery compared to IMRT (83% vs. 70%).
In a recent SEER database study of 2631 patients with early-stage supraglottic cancer, comparison was made between partial laryngeal surgery and neck dissection to definitive RT. In patients with T2N0 cancer, partial laryngeal surgery and neck dissection led to significantly better 5-year disease-specific survival (86% vs. 60%; hazards ratio [HR] = 0.31, P < 0.001) and overall survival (77% vs. 45%; HR = 0.36, P < 0.001) compared to radiation therapy. The authors acknowledged that the lower survival in the RT group was probably due to occult cervical metastases. Although these data predate IMRT and do not report upon swallowing and quality of life outcomes, it does raise questions regarding the common perception that either modality offers equivalent oncologic outcomes in early supraglottic cancers.
Organ preservation in early laryngeal cancer
Retrospective studies, have previously highlighted that laryngeal preservation rates are higher in the primary-surgery setting for early laryngeal cancers. A meta-analysis of several studies suggested surgery was associated with increased laryngectomy-free survival compared to RT in T1a glottic cancers. Organ preservation for early laryngeal cancer is often not discussed during the decision-making process for treatment but is significant in the setting of Stage II disease where T2 cancers have a significantly higher risk of local recurrence.
In a series of 260 patients with T2 laryngeal squamous cell carcinoma (LSCC), organ preservation following RT was 81% and 74% for T2a and T2b tumors, respectively. A meta-analysis of 21 studies for T2a and T2b laryngeal tumors treated by radiation therapy found mean local control at 5 years of 76.2% (standard deviation 10.2%) and 64.4% (10.2%), respectively. When considering four of the 21 papers published in the last decade from this study (n = 653), local 5-year control rates range between 70% and 80%, suggesting no significant improvement in control rates. The 3-year risk of recurrence for T2 cancer in a single-center series of 1615 patients with laryngeal cancer of all stages was 27.3%. Therefore, in the setting of primary RT as a treatment modality for T2 LSCC, at least 25% of patients will suffer local disease recurrence, a figure also supported by large population cohort studies. Although selected patients may be salvaged with partial laryngectomy procedures most are not suitable, resulting in a total laryngectomy with obvious impact on voice, swallow, and overall quality of life.
Local disease recurrence with transoral procedures for early laryngeal cancers occurs in 7%–15% of patients. However, unlike patients who recur following RT, a greater armamentarium of retreatment options to aid larynx preservation exists including OPL, repeat TLM/TORS, and/or RT. Organ preservation rates of 84%–96% for T2N0 tumors were demonstrated in three large case series with >100 patients in each series,,, with no difference in survival rates between the two modalities of treatment. A recent systematic review 48 papers pooled data from 1156 patients treated by TLM and 3191 treated with RT showed similar local control rates.
A recent review concluded that there was higher chance of laryngeal preservation if surgery was used as the initial treatment modality in T2 tumors, with the caveat that the voice outcomes may be poorer in surgically treated patients. However, a potential sacrifice in voice quality to retain a functional larynx in the long-term may be acceptable compromise to many patients and should form part of the discussions during the decision-making process.
Health economics and early glottic cancer
Surgery for early-stage laryngeal cancer has been shown to be more cost-effective than RT in several studies. A recent analysis compared TLM against RT in the management of early-stage (T1a, T1b, and T2) glottic cancer to identify the most cost-effective treatment modality within the UK National Health Service (NHS). A Markov decision model [Figure 1] was populated using data from updated systematic reviews and meta-analyses, with attributable costs from NHS sources and a de novo health economics model generated. The study concluded that over a 10-year time horizon, RT as the initial treatment strategy was more expensive (£2,654 vs. £623) and less effective (QALY reduction of 0.141 and 0.04 in T1a and T1b–T2 laryngeal cancer, respectively) than TLM. The dominance of TLM for T1a cancers was unchanged on sensitivity analysis in most modeled scenarios, while for T1b-T2 laryngeal cancers, RT became more cost-effective when TLM costs were increased and when a QALY gain was assumed for RT. Considering both the oncologic and health economic data, NICE guidelines on upper aerodigestive tract cancer published in 2016 recommended that TLM is offered as the first-choice intervention for patients with T1a glottic cancer.
|Figure 1: Markov decision model for patients receiving radiation therapy as first treatment for early glottic cancer|
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TLM was found to dominate RT with higher QALYs and reduced costs in a cost-effectiveness analysis in the Canadian health-care system. A study of the itemized average costs of RT and TLM in the American health-care system in 2001 showed RT to be 15.5 times more costly. Mean-associated costs for RT were found to be twice as high as those for TLM (€8233 and €4434, respectively) including costs of treating possible recurrences in a recent cost-effectiveness study within the Netherlands. Finally, using the 5-year survival rate as the “effect” in a cost-effectiveness analysis within the Spanish healthcare setting, it was found that TLM offered a saving of €1342.68/year. It is very likely that similar outcomes will be found if such an analysis were to be performed in the Indian health-care setting.
Recurrent laryngeal cancer
Recurrent laryngeal cancer following RT poses multiple challenges as it tends to be more aggressive, arises in a field where lymphatic drainage is unpredictable and associated with poor control rates. Therefore, in the setting of radiorecurrent laryngeal cancer, the option of a salvage total laryngectomy is often considered as it is technically reproducible with predictable outcomes.,,
OPLs [Table 3] have been demonstrated to be oncologically sound procedures in the salvage setting with a high larynx preservation rate. The pooled estimates of 26 studies in a systemic review and meta analysis assessing the role of open conservation laryngeal surgery in radiorecurrent laryngeal cancers showed local control rate of 86.9% (95% confidence interval [CI], 84%–89.5%) at 24 months for 560 patients, disease-free survival rate of 91.2% (95% CI, 88.2%–93.9%) for 352 patients, and overall survival rate was 83.1% (95% CI, 79.1%–86.7%) for 360 patients. However, OPL procedures are less often used due to limited expertise and less predictable functional outcomes.
|Table 3: European Laryngological Society classification of open partial laryngectomies|
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TLM has an established role in the management of primary early laryngeal cancer; however, its role in the recurrent setting is less well defined. Pathways of spread of tumor in recurrent cancer play a significant factor in predicting endoscopic curability; salvage TLM was possible in 86% when recurrence occurred in the same area, 74% when the recurrence occurred in adjacent sites with multifocal distribution and was not possible in cases of submucosal recurrence or when extension occurred into the visceral spaces or cartilaginous framework of the larynx. Unlike primary cancers, the conventional margins taken during TLM resection may not be applicable in radiorecurrent disease, where margins are difficult to assess in a previously irradiated larynx, reflected by recurrence rates of up to 58% following the first laser resection. Furthermore, recurrent disease is often clinically understaged with a higher stage noted following pathological examination.,
Although salvage TLM has been shown to be oncological sound with high larynx preservation rate, in a recent systematic review and meta-analysis, inferior control rates were noted compared to OPL. The pooled mean estimate of local control at 24 months after first TLM (n = 249) was 56.9%, 30% less compared to the 24-month local control rates for OPL in recurrent cancers with a relatively lower mean larynx preservation rate of 72.3% for TLM versus 84% for OPL. The latter reflects the higher locoregional failure following TLM and the lower threshold for resorting to a total laryngectomy.
Hence, in cases where the recurrence is limited to the mid-cord with no concern of submucosal spread, TLM may be an option, otherwise where appropriate patients should be offered OPL or where not suitable a total laryngectomy.
| Conclusions|| |
With the absence of randomized controlled trials, ongoing therapeutic debate in the setting of early laryngeal cancer continues. However, until such studies become available, alternate determinants to optimal treatment modality should be considered including cost utility, long-term functional outcomes, and complication rates. Considering the current data, surgery should be considered the primary modality for early laryngeal cancer (T1a, T1b, and selected T2 cases). In carefully selected recurrent early laryngeal cancer, OPL should be given serious consideration. Considering the current data, surgery [Figure 2] and [Figure 3] should be considered the primary modality for early laryngeal (T1a, T1b and selected T2 cases). In carefully selected recurrent early laryngeal cancer, OPL should be given serious consideration [Figure 4].
|Figure 3: Management algorithm for T1/T2 Supraglottic cancer. This algorithm is largely applicable to patients with early stage neck disease. TLM, transoral laser microsurgery; TORS, transoral robotic surgery. *CRT for positive margins, and extranodal extension; RT for multiple nodes, level IV or V nodal disease, perineural invasion, vascular embolism|
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|Figure 4: Management algorithm for Recurrent early laryngeal cancer. TLM, transoral laser microsurgery; OPL, open partial laryngectomy|
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Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]