Glottic Cancer Treatment & Management
- Author: Andrew M Coughlin, MD; Chief Editor: Arlen D Meyers, MD, MBA more...
Radiation is the primary nonsurgical treatment for early-stage glottic tumors (ie, T1, T2). Although radiotherapy techniques and doses may vary, a standard course of radiation for glottic cancer usually consists of a total of 60-70 Gy administered in single daily fractions over 6 weeks. Advantages of radiotherapy include the avoidance of surgery and the subsequent hospitalization. A useful voice is preserved in 80-95% of patients who were treated with radiation for an early glottic tumor. Of these patients, 80-90% are reported to have good-to-excellent voice quality. Radiation failures can be salvaged successfully with surgery; however, complication rates may be higher than with primary surgical procedures. Some patients who were initially candidates for conservative laryngeal surgery may no longer be candidates after unsuccessful radiation therapy and may require total laryngectomy.
Disadvantages to the use of radiation include long treatment course, early and late adverse effects associated with radiation, and difficulty in diagnosing recurrent or second primary tumors in the irradiated larynx. Early adverse effects of radiation include mucositis, dermatitis, xerostomia, dysphagia/odynophagia, radiation exposure, and weight loss. Late complications can include xerostomia, hypothyroidism, carotid artery stenosis, pharyngeal strictures, osteoradionecrosis of the mandible, and radiation-induced sarcoma.
In the early 1980s, chemotherapy regimens for the treatment of laryngeal carcinoma were introduced, and a correlation between chemosensitivity and radiosensitivity was identified. Induction chemotherapy became a way to identify those patients who were likely to have a good response to radiotherapy.
In 1991, the Veterans Administration Larynx Study Group published the results of a study in which patients with laryngeal cancer were assigned randomly to treatment with standard surgery and postoperative radiation or 2 cycles of induction chemotherapy. Patients in the chemotherapy arm who demonstrated less than a partial response or disease progression after 2 cycles of chemotherapy underwent surgery, and those who showed partial or complete response underwent an additional cycle of chemotherapy followed by irradiation. Long-term follow-up revealed no differences in survival rates between the 2 arms, and 31% of the total population were able to retain the larynx (66% of 4-y survivors).
More recently, a study by the Radiation Therapy Oncology Group (RTOG) compared concurrent chemoradiation therapy, induction chemotherapy followed by radiation therapy, and radiation therapy alone. They showed that laryngeal preservation at 2 years was 88% vs 75% vs 70%, respectively, significantly in favor of concurrent chemoradiation therapy. When looking specifically at disease free and overall survival, however, no significant difference was observed between concurrent and induction chemotherapy groups. Despite a lack of survival benefit, the authors now generally deliver cisplatin concurrently with radiation therapy on days 1, 21, and 42 of therapy, with the overriding goal of laryngeal preservation.
Depression complicates head and neck cancer treatment in 20-40% of patients. Recently, a randomized, placebo-controlled, double-blinded study comparing prophylactic antidepressant therapy with placebo for patients undergoing surgery or radiation therapy for advanced head and neck cancer was performed by Lydiatt et al. This study showed that if escitalopram was started prior to treatment and continued for 16 weeks, patients in the experimental arm had a significantly lower depression rate (10% vs 24.6%) and their quality of life was better than the placebo group up to 3 months after cessation of therapy. On subgroup analysis, this was especially true for those undergoing radiation therapy; however, the surgery subgroup also trended towards lower rates of depression. Treatment of depression can improve quality of life and likely also improves survival. Therefore, prophylactic antidepressants should be strongly considered as an adjuvant to standard therapy.
To become more selective in the attack of tumors, and in response to the often substantial morbidity associated with combination therapy, the recent use of monoclonal antibodies that inhibit key aspects in tumor growth has proliferated. The potential advantage is a change in the type and severity of adverse events. For example, radiation therapy with cetuximab, a monoclonal antibody against the epidermal growth factor receptor, has been shown to be more effective than radiation alone. What has not been demonstrated is a direct comparison of cetuximab and radiation versus standard platinum-based chemotherapy and radiation. There are several studies comparing cetuximab to standard cisplatin based regimens; however, these studies are still ongoing. Therefore, cisplatin remains the standard of care.
Endoscopic management of premalignant lesions and stage I-II glottic carcinomas can be performed during direct laryngoscopy using an operative microscope. Lesions are excised with either microlaryngoscopic instruments or a carbon dioxide laser.[6, 7] These procedures are usually performed on an outpatient basis. The use of endoscopic techniques for more extensive lesions has been touted by German investigators and is currently being investigated in the United States. The use of this technique must take into account the skill of the operating surgeon, the ability of the larynx to be visualized, and the state of disease in the neck. If the patient can be treated without the use of adjuvant radiation therapy, endoscopic surgery may provide a reasonable alternative to total laryngectomy or combination chemotherapy and radiation. The key appears to be in proper patient selection.
Vertical partial laryngectomy is indicated in the treatment of tumors that arise on the true vocal cord with limited involvement of the anterior commissure. In this type of resection, most of the ipsilateral thyroid cartilage, the true vocal cord, and portions of the subglottic mucosa and false vocal cord are removed. Closing the strap muscles over the defect can create a pseudocord. All patients require a tracheotomy, which is generally left in place for 3-7 days postoperatively. In the case of anterior commissure involvement, a frontolateral partial laryngectomy may be considered. This procedure extends the resection to the contralateral cord, including the anterior commissure. Contraindications for both types of vertical partial laryngectomy include tumor involvement of the interarytenoid area, subglottic extension greater than 10 mm, and poor medical condition, especially significant pulmonary disease.
Total laryngectomy is the standard for treatment of advanced laryngeal cancer. Adequate treatment of tumors that have invaded beyond the confines of the larynx involves resection of the disease with a margin of normal extralaryngeal tissue. In this procedure, the entire larynx, hyoid bone, and overlying strap muscles are resected in an en bloc manner. Generally, the ipsilateral thyroid gland is removed with the specimen, especially in cases of extrathyroidal extension. Care is taken to preserve the parathyroid glands in situ to prevent postoperative hypoparathyroidism and hypocalcemia. This is much more difficult in salvage operations and in those patients with bulky neck disease that must be resected with the specimen.
Pharyngotomy incisions are made with a margin of approximately 1.5 cm of mucosa that is healthy in appearance. The inferior tracheal margin should also have at least 1.5 cm of mucosa that appears healthy. The margin status is intraoperatively confirmed with frozen section. Pharyngeal closures are accomplished primarily or with flap augmentation. Careful skin-mucosal approximation creates a permanent tracheal stoma.
With any head and neck malignancy, the elective treatment of cervical lymph nodes is generally recommended when the risk of occult nodal disease is at least 15-20%. For stage I and II glottic cancer, the risk of cervical lymph node metastasis is low, ranging from 1-8% in most series. Given this low rate of occult metastasis, elective neck treatment is usually not indicated in these patients. With later-stage disease, the risk for nodal disease increases to 20-30%. Elective treatment of the neck is recommended for late-stage disease (ie, T3, T4). The nodal groups at risk for laryngeal cancer include levels II, III, and IV, with rare involvement of levels I and V. The elective treatment of the neck in glottic cancer usually consists of selective removal of the nodes in levels II, III, and IV; however, radiotherapy is also a possible treatment option.
Most necks with clinical disease can be managed with an ipsilateral selective or modified radical neck dissection, depending on the extent of the disease. Consider bilateral neck dissection when managing glottic lesions that approach midline and when bilateral disease is clinically present in the neck.
In salvage settings, the need for elective treatment of the neck has been evaluated recently in an article by Basheeth et al. They showed that only 8% of the 45 patients treated with salvage neck dissection had positive pathologic nodal disease. Of these, all 3 patients were initially staged with T4 tumors. More concerning is that 67% of patients with bilateral neck dissections developed major postoperative complications such as pharyngocutaneous fistulas, hematomas, or wound infections, whereas only 30% of patients with unilateral or no neck dissection developed major postoperative complications. Therefore, we would argue that unless there is gross positive neck disease present at the time of salvage surgery, neck dissection is not necessary.
Endoscopic laser resection
See the list below:
A small 5.5 or 6.0 laser safe tube is used for intubation, with the proximal cuff being filled with saline and the distal cuff with methylene blue.
The patient is turned 90° to his or her right, and a direct laryngoscopy is performed with the laser safe laryngoscope. Once adequate visualization of the vocal cords is obtained, the patient is suspended on the Mayo stand and the operative microscope is used to better visualize the cords.
If it is difficult to adequately visualize the cords on direct laryngoscopy, make sure that the neck is flexed and head is extended appropriately. A large piece of tape can also be used to secure a 2 x 2 gauze placed on the cricoid cartilage to the bed so that constant cricoid pressure is obtained.
Proper eye protection must be applied to the patient, and wet towels are used to cover the patients face/skin to prevent inadvertent injury by the laser.
Endoscopic resection using the CO 2 laser is then performed, removing the tumor, followed by peripheral margin analysis.
Each technique is different for a total laryngectomy with regards to the sequence of steps; however, the basic procedure is outlined below.
An apron incision is made through the skin, subcutaneous fat, and platysma. If a tracheostomy exists prior to surgery, this is generally incorporated into the incision.
Subplatysmal flaps are raised just above the hyoid superiorly and to the clavicle inferiorly.
The fascia overlying the sternocleidomastoid muscle is then reflected medially until the jugular vein and carotid sheath are identified.
This dissection plane is continued medially over the carotid artery, and the strap muscles are elevated off of the thyroid.
Inferiorly, the strap muscles are sacrificed near the sternum and the paratracheal fat is divided to completely expose the trachea.
The thyroid is divided through the isthmus, and, unless it is being resected with the specimen, it is reflected laterally into the neck.
With the trachea completely exposed, a tracheotomy is performed; however, the incision is carried circumferentially through the ring.
Once the membranous portion of the trachea is reached, the incision is carried superiorly in a teardrop shape to obtain additional mucosa for stoma maturation.
Vicryl or silk sutures are then used to suture the inferior skin flap to the cartilaginous trachea in a modified vertical mattress fashion.
The party wall is identified between the esophagus and trachea, and this plane is dissected bluntly up to the level of the cricoid cartilage.
The thyroid ala is then palpated and the pharyngeal constrictors are released. Care is taken to dissect the perichondrium of the inner cortex to preserve piriform sinus mucosa.
The above steps are performed on the opposite side of the neck.
Superiorly, the hyoid bone is palpated and the bovie is used to skeletonize the superior portion of the entire bone laterally.
A pharyngotomy is then performed in the midline for purely endolaryngeal tumors and the epiglottis is delivered into the neck.
Mucosal cuts are then made into the piriform sinus, aiming medially towards the postcricoid mucosa and esophageal inlet bilaterally.
This cut is then connected to the previously dissected inferior party wall region and the specimen is removed.
Finally, a Dobhoff tube is placed under direct visualization and the pharynx is closed either primarily with a running Connell stitch or with inverting interrupted sutures. The pharynx can also be closed with an interposed free flap or pedicled myocutaneous pectoralis onlay flap to reinforce the pharyngeal closure.
See the list below:
Most patients can be discharged home immediately following surgery, unless there are concerns about aspiration postoperatively. This is generally more common for T2-3 tumors that require larger excisions.
Total and partial laryngectomy
See the list below:
Admission to the ICU is rarely indicated unless the patient is ventilator dependent postoperatively.
Normal postoperative care includes ambulation, daily laboratory tests as appropriate, drain measurement, and wound care on the inpatient floor.
Thyroid replacement is given if the entire gland is removed, and the authors monitor for signs of hypocalcemia.
Postoperative antibiotics are not used unless there are signs of infection or a free flap has been used to close the defect. In these cases, 3 days of antibiotics are given.
Prophylaxis with a sequential compression device, enoxaparin, and senna docusate are used to prevent perioperative complications.
Humidified oxygen with or without an indwelling stomal tube is used to help with postoperative crusting.
Tube feeds are started on postoperative day 1 and continued for about 5-7 days, at which point a swallowing trial is performed to evaluate for leak. If no leak exists, patients are advanced to a full liquid diet and generally discharged home.
For salvage cases with or without free flap reconstruction, the authors generally wait 2 weeks to assess swallowing function.
Any wound breakdown is treated with local moist dressing changes twice a day.
Following surgery or radiation treatment, patients are monitored closely for healing and for the development of complications. Both the patient and family members often need significant assistance and reassurance as they adjust to the physical and functional changes that occur with treatment of this disease. After healing is complete and adjuvant treatment is completed, patients undergo a complete head and neck examination every 3 months. If the larynx remains, careful attention is directed to the larynx.
One of the most difficult areas of practice for the head and neck surgeon or radiation therapist is follow-up of the irradiated larynx. Postradiation edema makes the recognition of recurrence very difficult. The dilemma of whether to perform an examination under anesthesia with biopsy, imaging studies, or periodic clinical examination is perplexing. Each carries its own pros and cons.
Examination under anesthesia with biopsy is the criterion standard for proving recurrence. However, the risk of further swelling, chondronecrosis, and precipitation of a tracheostomy makes this a decision not to be entered into lightly (particularly because laryngeal reflux, candidiasis, and continued trauma from cigarette smoke may further complicate the clinical picture). Serial examination provides the clinician with a picture over time and carries the least morbidity from the actual procedure.
The role of CT scanning and MRI may provide an adjunct to clinical follow-up. Changes on CT scans and MRI after radiation are frequent and often difficult to differentiate between edema, infection, and recurrence. Like clinical examination, changes over time may provide the best use of these studies. The role of PET scanning is currently being defined. Sensitivity and specificity of PET alone are generally in the same range as CT or MRI and still leave the clinician to choose between biopsy and follow-up.
The emerging role of PET/CT is also under investigation. Preliminary data suggest that it may have enhanced sensitivity over CT scanning, MRI, or PET scan alone. The proper timing of the examination is still uncertain, with some reports suggesting that PET/CT can be performed 3-4 months following completion of radiation and others suggesting a year's wait. Rarely are the art of medicine and the necessity of judgment more critical than in the evaluation of the postirradiated larynx.
Two years after completion of treatment, follow-up examinations are decreased to every 4 months. Follow-up examinations scheduled at 6-month intervals can be started at 4 years after completion of treatment, and yearly examinations can be started at 5 years after completion of treatment. Yearly chest radiography and liver function testing are important screens for second primary tumors (eg, lung cancer) and distant metastases. Thyroid function testing should also be performed yearly, especially in those patients treated with radiation therapy, because the risk of acquired post-treatment hypothyroidism approaches 50-60%.
During the course of radiotherapy, patients may experience a number of acute adverse effects, including mucositis, loss of taste, xerostomia, dysphagia, skin burns, and desquamation. Approximately 10% of patients who undergo radiation require gastrostomy feeding tubes for nutritional support. Patients who receive concomitant chemotherapy and radiation are much more likely to require a gastrostomy feeding tube. Some patients require unplanned breaks in therapy because of adverse effects, which can compromise treatment efficacy and cure rates. One study showed that a 5-day delay in completing radiotherapy was associated with a 3.5-8% reduction in local control for laryngeal cancers.
Late complications associated with radiation therapy include permanent xerostomia, poor wound healing, soft tissue fibrosis, dental caries, chondritis, and rarely, osteoradionecrosis of the mandible. Persistent dysphagia, aspiration, and laryngeal edema are serious complications that occur most often in patients with advanced disease. Similar complications are observed in patients who undergo adjuvant radiation therapy following surgery and usually occur with a higher frequency.
Endoscopic procedures are less invasive and have fewer complications than more extensive laryngeal surgery. A tracheotomy is rarely required in patients who undergo endoscopic resections. Aspiration can occur postoperatively; however, aspiration is rare and depends on the extent of tissue resection and the location of the tumor.
Most patients who undergo a vertical partial laryngectomy undergo tracheotomy at the same time, but they are usually decannulated within the first month. Complications are generally dependent on the extent of surgical resection. Acute complications include wound infection, fistula formation, and glottic incompetence with aspiration. Granulation tissue formation can result in an inferior voice outcome. Endoscopic laser resection can remove granulation tissue effectively, and control of acid reflux may prevent recurrence. Postoperative laryngeal stenosis is very difficult to treat and may result in permanent tracheotomy.
Early complications following total laryngectomy include hematoma formation, wound infection, wound dehiscence, and pharyngocutaneous fistula. Development of a hematoma can cause a separation of the pharyngeal suture line and may require a return to the operating room for evacuation. Wound infections and dehiscence are treated with antibiotic coverage and local wound care, including daily packing. A persistent nonhealing wound dehiscence may require flap coverage for definitive management.
Pharyngocutaneous fistula is a relatively frequent complication following total laryngectomy, with an incidence of 30-75% with primary closure in the salvage setting depending on the series of patients evaluated. Multiple studies have examined predisposing factors for the development of pharyngocutaneous fistula. Although results are conflicting, poor nutritional status, previous radiation, positive surgical margins, concurrent medical disease, and intraoperative blood transfusion have been found to be associated with higher fistula rates. A recent study of 359 patients at 8 institutions undergoing salvage laryngectomy showed significantly higher fistula rates with primary closure (34%) compared with vascularized free flap interposition (25%) and primary closure with pectoralis onlay flap (15%).
Management of a pharyngocutaneous fistula consists of restriction of oral intake, antibiotic coverage, and wound care, including packing. Re-exploration of the neck and attempted surgical closure can be considered but is often unsuccessful. Diverting fistulas away from the tracheal stoma and away from the carotid arteries is beneficial. Additional incisions closer to the site of the fistula (usually near the base of tongue) and use of a wound vac can shorten the fistulous tract. Wound vac placement in the head and neck region is often very difficult and therefore not often used. In situations in which the patient has persistent fistulas, particularly over the carotid arteries that have been irradiated and are at risk for rupture, neck re-exploration and placement of a pectoralis myofascial flap is ultimately the definitive management.
The most common late complications following total laryngectomy are stomal stenosis, pharyngoesophageal stenosis and stricture, and hypothyroidism. A stomal button or standard tracheotomy tube can sometimes prevent stomal stenosis. Consider these devices, especially in patients who undergo postoperative radiation. Stenosis, stricture of the neopharynx, or tumor recurrence can cause late onset of dysphagia in a patient who has undergone total laryngectomy. Evaluate new dysphagia with endoscopy and biopsy to rule out tumor. Benign strictures can usually be dilated effectively. Hypothyroidism occurs in 50% of patients following total laryngectomy and in 65% of patients after combined therapy of radiation and surgery.
Potential complications following neck dissection include hematoma, wound infection and dehiscence, and chylous fistula. The first 3 complications are managed as discussed previously. A chylous fistula occurs when the thoracic duct on the left side of the neck or the major chylous drainage on the right is disrupted and not recognized at the time of the operation. In most cases, the fistula is recognized intraoperatively; however, a fistula is suspected postoperatively when drain output increases after a diet is started. Conservative management includes wound drainage, pressure dressings, and a low-fat diet. Occasionally, surgical exploration is required.
Carotid artery rupture is the most serious complication associated with neck dissection, and the outcome with this event can be fatal. Wound infection, flap dehiscence, and salivary fistula, especially in a previously irradiated neck, can result in carotid artery exposure. Coverage of the carotid with a pedicle or free vascularized flap may help prevent a catastrophic outcome. Cerebral edema, blindness, and occasionally, death can result following bilateral neck dissections, especially in radical dissections when both internal jugular veins are ligated.
Outcome and Prognosis
The overall 5-year survival rate for early glottic carcinoma (ie, T1, T2) independent of treatment modality is 85-95%, which is quite encouraging. Nodal metastases in early disease decrease survival rates closer to 60%. T3 tumors without neck disease are associated with a 65% 5-year survival rate, which drops to 50% when nodal metastases are present. Invasive glottic tumors (ie, T4) are associated with a 40% 5-year survival rate in the absence of nodal disease and a 10-30% survival rate with nodal metastases, depending on the extent of disease.
Currently, no well-developed randomized controlled trials comparing endoscopic surgery and radiation therapy have been performed. Most studies that have been performed are retrospective case control studies from single institution experiences and only one meta-analysis was performed.
In 2012 Yoo et al performed a systematic review regarding the treatment of T1 glottic tumors. They incorporated one meta-analysis, 15 cohort studies, and two cross-sectional studies and found no overall survival differences between surgery and radiation therapy. Local control, however, was disputed in two studies showing 89% and 90.1% for surgery versus 75% and 69.5%, respectively, in radiation-treated patients when T1a tumors specifically were evaluated (P < .005 and P < .001).[12, 13] Laryngeal preservation rates were also significantly better with surgery compared with radiation therapy in the systematic review by Yoo et al in 5 studies, with only 1 favoring radiation.
Quality of life is also very important with regard to laryngeal cancer, and voice quality is an important parameter. With regard to early glottic cancers, there is great controversy over the question of whether radiation therapy or surgery provides a better outcome. Acoustic analysis and Voice Handicap Index (VHI) are two parameters that have been used to assess function and quality of life after treatment of glottic cancer.
Cohen et al in 2006 performed a meta-analysis of six studies with 208 patients in the surgery group and 91 patients in the radiation group. The vast majority of patients had T1a disease. Posttreatment VHI scores were equivalent between the groups. These findings were substantiated by another meta-analysis performed by Abdurehim et al in 2011 that showed equivalent acoustic parameters: jitter, shimmer, maximal phonation time, and air flow rate. They did identify significantly better fundamental frequency in the radiation therapy group; however, the VHI was not different between the two groups. Ultimately, patient selection and experience are key when making decisions about endoscopic resection and radiation therapy for early glottic tumors.
A study by Khaja et al of treatment trends for glottic carcinoma in situ in the United States between 1988 and 2012 found that the survival rate for the disease did not significantly change over this period. The study, which used data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, reported that surgery was most frequently employed as the initial treatment but that the use of radiation therapy increased over time.
A study by Graciano et al comparing outcomes in partial laryngectomy versus radiotherapy for glottic cancer found that the two modalities were not significantly different with regard to distant metastasis rates, disease-free period, laryngeal rescue-free time, and overall 5-year survival; severe complication rates were similar as well. The study included 62 patients.
Future and Controversies
Initially described over 125 years ago, total laryngectomy is the current criterion standard for the treatment of advanced glottic carcinoma. Since that time, great advances have been made in the preservation of the larynx in early-stage disease and in moderately advanced cancers. Future directions in the treatment of early glottic malignancy will likely involve further definition of the role of endoscopic resections and innovative radiation protocols, with further emphasis on preservation of the voice. In order to define these roles, better multicenter randomized controlled trials directly comparing surgery and radiation therapy are warranted. Advanced disease may continue to require total laryngectomy for control, but combined-modality treatment and chemoradiation protocols are being defined that could improve survival and potentially preserve the larynx in select patients.
Several recent studies have used quality-of-life surveys to evaluate the impact of treatment of laryngeal carcinoma.[2, 18] Communication and swallowing disorders were found to result in a decreased quality of life. The 2 main factors in determining quality of life are cancer control and survival; therefore, in order to compare quality of life between procedures, survival must be equivalent. Because several options for treatment of laryngeal cancer exist, many of which have similar effectiveness, future patient quality-of-life evaluations may help define the ideal treatment for this disease.
Since the Veteran Administration laryngeal trial was published, there have been no randomized prospective trials that have included both surgical and chemoradiation arms to assess not only survivability but also quality of life. As we know, each type of treatment diminishes quality of life in different ways, with laryngectomy most affecting voice function and chemoradiation mostly affecting swallowing.
Currently, the University of Minnesota is running a multi-institutional prospective observational trial comparing swallowing outcomes in patients with cartilage-invading T3 and T4 tumors who are treated with either surgery and postoperative radiation therapy or concurrent chemoradiation therapy. The primary outcome is swallowing function 12 months after treatment using the MD Anderson Dysphagia Inventory. Voice handicap index (VHI), University of Washington-Quality of Life survey, and the SF-36 battery are also being used to assess secondary outcomes and to determine if there are subgroups of patients who would benefit from one treatment over another. This study should help stratify advanced-stage laryngeal cancer patients specifically with respect to T stage.
Gene therapy, which involves the introduction of genes into the body with the goal of treating a disease, is an exciting new field. Both genetic and acquired disease can be treated theoretically with gene therapy. Gene therapy in the treatment of cancer involves the introduction of genes into cells to direct the production of proteins that target malignant cells. These proteins are released at a specific location within the body to target diseased tissues and minimize toxicity to normal tissues. Gene therapy is still in experimental stages but holds promise for the treatment of head and neck cancer.
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