Definitive treatment options for advanced laryngeal cancer include surgery, radiotherapy, chemoradiotherapy, or a combination of these.
Surgical options may range from minimally invasive transoral laser or robotic surgical resection, to open partial laryngectomy, to total laryngectomy. However, for many cases of advanced larynx cancer, the only feasible option is total laryngectomy. In the past, this operation was considered to be the gold standard treatment for advanced laryngeal cancers.15 However, while it offers excellent local control, it is associated with significant functional and psychological sequelae.
More recently, there have been major changes in treatment paradigms for advanced laryngeal cancer. The result has been a major decrease in the number of patients treated with surgery alone, and a major increase in the number of patients treated with radiotherapy and chemoradiotherapy. The major driver for these changes has been the publication of clinical trials reporting high rates of larynx preservation after using chemoradiotherapy protocols to treat advanced laryngeal cancer.14,16 However, simultaneous with this shift in treatment paradigm, new concerns have emerged after the recent publication of data which would appear to show a reduction in larynx cancer survival over recent decades.17
An important factor which facilitates non-surgical treatment of advanced laryngeal cancer is the anatomy of the larynx and the impact of this on the pattern of post-radiotherapy recurrences. Thus, due to the anatomical constraints of the larynx, and the barriers to invasion provided by the laryngeal cartilages and membranes, when cancers which are originally confined to the larynx fail initial treatment with radiotherapy, the recurrent cancers also tend to remain confined to the larynx. Because of this, post-radiotherapy recurrences are usually amenable to surgical salvage by means of total laryngectomy with a reasonable expectation of disease control. This is in contrast to most other head and neck cancers, which are much less likely to be salvageable if they recur after initial non-surgical treatment.
Conservation Laryngeal Surgery
Conservation surgery (transoral laser or robotic surgery, or open partial laryngectomy) is an excellent option for many patients with early (T1/2N0) larynx cancers, offering excellent oncologic control and functional outcomes.18–20
For advanced cancers, the role of conservation surgery is much more limited to cases which are either early T stage, but with concurrent cervical metastases, or select small-volume T3 cases.
One of the drawbacks with conservation surgery for advanced laryngeal cancer is the risk of greater functional deficit and higher risk of complications with more extensive resections. For example, resection of one arytenoid cartilage during supracricoid laryngectomy has been shown to lead to increased risk of aspiration pneumonia, longer time to decannulation of tracheostomy tube, and poorer voice.21–25 Thus, the functional advantages of conservation surgery over non-surgical treatment may be less clear-cut. Another concern is that, in patients with palpable neck disease, concurrent neck dissection will need to be undertaken with the surgery, and postoperative radiotherapy will in most cases be recommended to optimize regional control. The administration of postoperative radiotherapy may also adversely affect functional outcomes, although as long as the dose to the larynx is kept at 50 Gy, the adverse impact should be within acceptable limits.26,27 Finally, in the case of cancers undergoing open partial laryngectomy, patients will need to consent to proceeding to possible immediate total laryngectomy based on intraoperative findings and frozen sections. Total laryngectomy may also need to be considered in cases with positive margins at final histology. The risk of positive margins and possible need for total laryngectomy is more likely to be an issue for locally advanced primary tumors than for smaller primary tumors. However, given that many such cases are likely to be also amenable to treatment with radiotherapy or chemoradiotherapy with a reasonable expectation of good outcome, getting patients’ consent for an operation which may end up with total laryngectomy may be a “hard sell.”
Nevertheless, for well-selected cases of “intermediate-stage” laryngeal cancer, conservation laryngeal surgery effected either by transoral laser or open partial surgical techniques can offer excellent oncological and functional outcomes.28–32 Cases most suitable for a conservative surgical approach will be those staged T3 based on minor pre-epiglottic or paraglottic space invasion or minor inner lamina of thyroid cartilage erosion, without full restriction of vocal mobility (indicating absence of arytenoid fixation), in motivated patients with good performance status and pulmonary reserve.
The Veterans Administration (VA) study in 1991 marked a major change in attitudes toward treatment of advanced laryngeal cancer.14
This was a randomized controlled trial comparing two treatment arms. Inclusion criteria were patients with stage 3 or 4 laryngeal cancer. The first arm underwent 2–3 cycles of induction chemotherapy, followed by definitive radiotherapy provided there was tumor response to chemotherapy. Non-responders underwent immediate total laryngectomy. The second arm underwent total laryngectomy with postoperative radiotherapy. Two-year survival was equal in both arms (68%); however, 36% of the non-surgical arm retained their larynx. Thus, this study was taken as evidence to support the use of primary chemoradiotherapy as treatment for advanced laryngeal cancer, on the basis that it offered patients an equal survival, but with a two-thirds likelihood of retaining their larynx.
The VA study was followed by a further landmark study, the Radiation Therapy Oncology Group (RTOG) 91-11 study published by Forastiere et al. in 2003.16 This comprised a three-arm randomized controlled trial on patients with stage 3/4 laryngeal cancer. The first arm consisted of induction chemotherapy followed by radiation; the second consisted of concurrent chemoradiotherapy; and the third consisted of radiotherapy alone. This study showed a superior locoregional control and laryngeal preservation rate in the concurrent chemoradiotherapy group, although there was no difference in overall survival and a higher incidence of severe toxicity in the concurrent chemoradiotherapy arm. This study was a major driver for primary chemoradiation to become the first-line treatment for most patients with advanced laryngeal cancer.
Both the VA study and the Forastiere study have been criticized on a number of grounds. One was the inclusion of some patients with early-stage primary tumors, but considered to have advanced laryngeal cancer on the basis of cervical metastatic disease. For example, nearly half of patients in both studies had mobile vocal cords. Given that the end-point of these trials was laryngeal preservation, this may have biased the results toward showing a better outcome from non-surgical treatment. Indeed, a French randomized controlled trial limited to patients with T3 primary tumors, which compared total laryngectomy to induction chemotherapy followed by radiotherapy in responders (or total laryngectomy in non-responders), demonstrated a significantly better survival in the group undergoing immediate surgery.33
Another criticism was the short follow-up, with only 2-year survival data reported in the original papers. In a recent update to the RTOG 91-11 study, 10-year survival data are reported. These results are very interesting insofar as while they confirm a superior laryngeal preservation rate and locoregional control for patients treated with concurrent versus induction chemotherapy, there was no significant difference in laryngectomy-free survival. Differences in overall survival were not significantly different; however, there was a trend toward a worse survival in the arm treated with concurrent chemoradiotherapy, which was attributable to an increased number of deaths which were apparently unrelated to the index cancer in the concurrent chemoradiotherapy group.34 These long-term findings might suggest that the increased incidence of toxicity in the concurrent chemoradiation group may be consequential in leading to increased mortality in the ensuing years.
The final criticism is that while these studies reported an impressive laryngeal preservation rate among patients treated non-surgically, little information was given regarding the function of the preserved larynx. In recent years, this has emerged as a major concern in patients treated with primary chemoradiotherapy. Secondary analyses of patients enrolled in clinical trials of chemoradiotherapy in head and neck cancer have reported severe late toxicity in 39%–43% of evaluable patients,35,36 with laryngopharyngeal primary site, older age, and advanced T stage being predictors for worse outcome.35 A systematic review of studies reporting on the incidence of pharyngo-esophageal stricture after radiotherapy reported an overall incidence of stricture of 7.6%, but rising to 16.7% in the intensity-modulated radiotherapy group (where most patients also received chemotherapy), and also being three times higher in prospective than retrospective studies,37 while rates of permanent gastrostomy tube use as high as one-third have been reported.38 In particular, for patients with dysfunctional larynges prior to treatment commencement, a dysfunctional larynx post treatment is to be expected.
Since the publication of the RTOG study, further studies have been performed investigating the role of TPF (taxane, cisplatin, and 5-fluorouracil) versus PF (cisplatin and 5-FU), as was used in the RTOG trial, for induction treatment. Pointreau et al. reported a better response rate to induction treatment (80% versus 59%), and better 3-year laryngeal preservation (70% versus 57.5%) with TPF induction versus PF induction followed by radiotherapy in patients with SCC of the larynx or hypopharynx. Differences in overall and disease-free survival were not significantly different.39 This was consistent with earlier findings from Posner et al. who found TPF induction followed by chemoradiotherapy to have superior survival in patients with head and neck cancer from all sites.40 These findings, along with the long-term findings of the RTOG 91-11 study, have led to a renewed interest in sequential chemoradiotherapy. However, the drawback of a more prolonged treatment regime may be reduced compliance, particularly among patients with poorer performance status. On the other hand, response to induction chemotherapy may be a very useful predictor of response to radiotherapy, and so may help select patients with very advanced tumors for definitive surgical versus non-surgical management.41,42
Thus it is clear that the major advantages of radiotherapy or chemoradiotherapy for treatment of advanced laryngeal cancer are avoidance of an operation and anatomic preservation of the larynx, with no definite compromise in overall survival.14,43,44 On the other hand, the disadvantages include a high incidence of severe acute toxicity, and a high incidence of long-term laryngeal functional problems, particularly in patients treated with concurrent chemoradiotherapy.35–38 There also appears to be a reduced likelihood of local control for patients with T4 tumors with gross cartilage destruction or extralaryngeal extension. Thus, consideration toward primary total laryngectomy should be given in these patients. Furthermore, among patients who develop local recurrence and require salvage laryngectomy, there is an increased incidence of pharyngocutaneous fistula and major complications in the post-radiotherapy setting.45
At most institutions, radiotherapy or chemoradiotherapy is the treatment of choice for most T3 laryngeal cancers. The decision to enhance the radiotherapy with chemotherapy will depend mainly on the patient’s general condition, medical co-morbidity, and ability to tolerate chemotherapy. Frail patients or patients with medical co-morbidity are best treated by radiotherapy alone; the possible benefit in local control by adding chemotherapy in such patients may be more than offset by the increased risk of local recurrence due to breaks in treatment caused by acute toxicity. For patients aged >70 years, the addition of chemotherapy has not been shown to offer any benefit over radiotherapy alone, while functional outcomes have been reported to be even worse. Another consideration may be whether there is likely to be a conservation surgical option in the event of treatment failure. Whereas conservation laryngeal surgery may be an option in some highly selected patients with recurrent laryngeal cancer after radiotherapy, this will almost never be feasible in the post-chemoradiotherapy setting due to the very high risk of breakdown.
Primary Total Laryngectomy
Total laryngectomy remains the gold standard treatment for locally advanced T4 laryngeal cancers with gross cartilage destruction or extralaryngeal extension, as well as for treatment of locally recurrent laryngeal cancers after primary non-surgical treatment. The rationale for primary total laryngectomy in advanced T4 cases is the decreased likelihood of complete response with radiotherapy or chemoradiotherapy;46
the lack of evidence regarding non-surgical management of such cases, as large volume T4 cases were excluded from many of the organ preservation studies;16
the reduced success rate of salvage laryngectomy in the setting of extralaryngeal disease; and the increased incidence of major complications after salvage laryngectomy.45
In the past, primary total laryngectomy was also recommended in patients with bulky T3 tumors. With the advent of organ preservation protocols and evidence from the VA and RTOG studies, the number of total laryngectomies performed for T3 disease has reduced substantially. However, there is probably still an important role for primary total laryngectomy in selected patients with T3 primary tumors. An example of a case where primary total laryngectomy would be a very reasonable option is that of a young patient with good intelligence and social support, who has a T3 bulky transglottic SCC with fixed vocal cord fixation, a compromised airway, and questionable cartilage destruction on CT scan. The major arguments in favor of consideration of total laryngectomy in such a cases include adverse characteristics of primary tumor which may increase the risk of persistence or local recurrence, including large size,47 vocal cord fixation,13,48 and transglottic tumor extent; the presence of pre-treatment laryngeal dysfunction which portends a higher risk of permanent laryngeal dysfunction after even successful non-surgical treatment; and good patient performance status, intelligence, motivation, and social support which predicts a better likelihood of good speech and other functional outcomes after total laryngectomy.
Total laryngectomy is a major operation with significant functional, social, and psychological consequences for the patient. The major functional impact is due to loss of voice. The best method for speech rehabilitation would appear to be surgical voice restoration with tracheo-esophageal speech after tracheo-esophageal prosthesis placement.49 A high success rate for surgical voice restoration is reported by many authors;50–52 however, other studies which have endeavored to capture and follow up all patients undergoing total laryngectomy report the use of successful tracheo-esophageal speech in around half of patients.49 Of those who do not achieve successful tracheo-esophageal speech, some will achieve reasonable esophageal speech. Speech outcomes with use of electrolarynx are generally poor. Up to one quarter of all patients do not achieve intelligible speech at all.49 Other issues after total laryngectomy include the presence of a stoma in the neck, with attendant need to take precautions to avoid water getting in and keeping it clean; less effective coughing, and inability to perform a Valsalva maneuver during abdominal straining or lifting; and loss of sense of smell. Most patients undergoing primary laryngectomy without pharyngeal resection have satisfactory swallowing. Dysphagia is more common after salvage laryngectomy which is usually related to post-radiotherapy stricturing.
Total laryngectomy has been reported to be effective in 67%–81% of patients with T3 tumors,53–55 and 55% of patients with T4 tumors.54 Local recurrence may take the form of stomal or peristomal recurrence, which is believed to arise from metastatic paratracheal nodes, or pharyngeal/base of tongue/esophageal recurrence, which probably arises due to unrecognized submucosal extension or local lymphovascular invasion.56 Risk factors for local recurrence include transglottic or subglottic tumor extent,54 lymph node metastases,54–56 poor differentiation,54 lymphovascular invasion,56 preoperative tracheostomy,55,56 and positive resection margins.56
With the increasing role of non-surgical management in the treatment of advanced larynx cancer, total laryngectomy is increasingly becoming as a salvage treatment for cases which fail radiotherapy or chemoradiotherapy. Salvage laryngectomy is associated with an increased risk of major complications including pharyngocutaneous fistula,45
enlargement of the tracheo-esophageal puncture site,57
and dysphagia. Additional risk factors for these complications in the salvage setting include interval since radiotherapy45
and concomitant performance of bilateral neck dissection.45
In an effort to reduce the risk of these complications, several authors have advocated elective use of pectoralis major myogenous flaps, placed in onlay fashion, or free flaps interposed between the pharynx and skin/stoma.58
The use of a pectoralis major myogenous flap to bolster the pharyngeal repair has been reported by some authors to reduce the incidence of pharyngocutaneous fistula, and shorten time to healing in cases which do fistulize.59,60
On the other hand, other authors found no significant difference in the incidence of fistula between patients undergoing and not undergoing pectoralis major flap.45,61
However, these studies were all retrospective, so it is not possible to exclude bias due to cases considered at higher risk of fistula having undergone pectoralis major flap.