Options for preserving the larynx in patients with advanced laryngeal and hypopharyngeal cancer. (Original Article).

Abstract

The introduction of newer surgical and combined-modality approaches to organ preservation in patients with advanced laryngeal or hypopharyngeal cancer is the most exciting clinical frontier in head and neck cancer treatment today. The use of these techniques at other sites, the exploration of improved methods for patient selection and tumor assessment, and the development of newer combination regimens will need to be rigorously studied in future clinical trials. In all these efforts, the major focus must remain on improving survival. This article reviews the latest developments in organ-preservation strategies and techniques for patients with advanced laryngeal or hypopharyngeal cancer.

Introduction

The goal of preserving laryngeal function and structure has dominated efforts to develop newer treatment approaches to patients with advanced (stage III or IV) cancer of the larynx or hypopharynx. Traditional treatment has consisted of total laryngectomy, usually combined with neck dissection and adjuvant postoperative radiation therapy. In most cases of advanced disease, total laryngectomy has resulted in 2-year cure rates in the range of 60 to 70% for laryngeal cancer and 40 to 50% for hypopharyngeal cancer.

The introduction of neoadjuvant chemotherapy into multidisciplinary management during the late 1970s led to observations that high rates of complete response can be achieved and that some patients who respond to chemotherapy might be cured with subsequent radiation alone. These findings led investigators to conduct two large, carefully performed, randomized, prospective studies of patients with laryngeal (1) and hypopharyngeal (2) cancer. These studies showed that survival rates were not compromised when treatment regimens that included two or three cycles of neoadjuvant cisplatin/5-fluorouracil (5-FU) were used to select patients for definitive radiation therapy. Although planned laryngectomy for nonresponders was an integral part of these treatment regimens, 40 to 65% of patients were able to avoid salvage laryngectomy. These findings opened new frontiers in the development of treatment options for patients with head and neck cancer. In developing these new organ-preservation approaches, researchers have pl aced additional emphasis on quality-of-life issues rather than concentrating exclusively on improvements in survival.

Surgeons who care for patients with laryngeal or hypopharyngeal cancer have pioneered tissue-conservation and -reconstruction techniques that maximize the function of laryngeal remnants following partial laryngeal resections. The horizons of such surgical organ-preservation techniques were recently expanded by the introduction and popularization of supracricoid partial laryngectomy. This relatively new technique, which was developed in Europe, has yielded excellent cure rates for advanced T2 and some T3 cancers. (3,4) Supracricoid partial laryngectomy obviates the need for permanent tracheostomy, does not result in significant swallowing dysfunction, and preserves reasonable voice quality. Selection criteria for such precise resections, however, are complex, and the extent of tumor must be carefully defined.

This article outlines fundamental treatment considerations common to all patients, various alternatives for organ preservation, and principles established thus far for treatment strategies that combine chemotherapy and radiation for organ preservation.

Structure vs function

It is important to differentiate between organ-preservation options that relate to maintenance of structure and those that pertain to maintenance of function. For example, many treatments, both surgical and nonsurgical, can preserve the structure of the larynx but significantly compromise its function. Critical analyses of new treatment approaches that combine chemotherapy and radiation must recognize that the maintenance of the airway (no tracheostomy), swallowing function (no aspiration or feeding tube), and speech are the critical laryngeal functions that have an impact on quality of life. A treatment that does not preserve these functions cannot be considered to be a successful organ-preservation technique, even if the organ remains in situ.

Patients generally value airway and swallowing functions more than they do speech ability. (5) Ill-conceived notions of organ preservation (both surgical and nonsurgical) that result in preservation of nonfunctional laryngeal structures in an attempt to preserve voice should be discouraged. Tracheoesophageal puncture techniques have greatly improved voice restoration rates following total laryngectomy, and most patients are able to speak in a hoarse but natural-sounding voice. Therefore, voice preservation is the least important quality-of-life consideration in the decision-making process.

Standard treatment considerations

In discussing what is experimental and what is "standard of care," it is useful to review some accepted general treatment recommendations and to consider what we have learned from our extensive experience with chemotherapy and radiation for organ preservation:

* All patients should undergo a multidisciplinary evaluation--including endoscopy, adequate biopsy, and radiologic imaging--to fully determine the extent of the tumor.

* Treatment alternatives, success rates, expected morbidity, potential complications, and follow-up requirements must be carefully explained to all patients.

* Methods of maintaining speech, swallowing, and respiration must be fully explained to each patient.

* A head and neck surgical oncologist should supervise tumor staging and follow-up examinations.

* Combined chemotherapy and radiation for organ preservation is indicated only for patients who are facing total laryngectomy.

The proliferation of combined chemotherapy and radiation protocols for head and neck cancer has given rise to a major treatment concern. This concern is that patients who are eligible for a conventional, nonmorbid, single-modality, organ-preserving, curative treatment (e.g., conservation laryngectomy or radiation alone) might instead be treated with an intensive, toxic combination regimen that has not been proven to be superior in randomized comparisons. Moreover, survival can be jeopardized by poor management, inadequate follow-up, or delayed detection of recurrence. All too often, patients with persistent or recurrent laryngeal or hypopharyngeal cancer are referred to surgeons in tertiary care centers following combined chemotherapy and radiation in the hope that some curative salvage resection can be performed. In such situations, the original extent of the tumor is largely unknown, the potential adequacy of salvage resection cannot be assured, life-threatening surgical complications are common, and recurr ent tumors are often unresectable by the time they are clinically detected. Therefore, it is critically important that experimental treatment be differentiated from conventional treatment so that patients can make informed decisions and understand the risks of unconventional treatment, as well as the importance of diligent tumor surveillance.

Organ-preservation options

Patients who face possible total laryngectomy for laryngeal or hypopharyngeal cancer have three options for organ-preservation treatment: organ-preserving surgery, definitive radiation therapy, and neoadjuvant chemotherapy and radiation. A fourth protocol that is being studied, with mixed results, is concurrent chemoradiation.

Organ-preserving surgery. One surgical option is subtotal laryngectomy and/or partial pharyngectomy, which offers several advantages: a precise delineation of the tumor, accurate margin assessment, optimal neck management, and the maintenance of adequate airway and swallowing functions (although the resultant voice quality is usually poor). This type of surgery requires careful patient selection and technical expertise. These procedures are particularly useful in patients who have transglottic cancers and selected glottic or supraglottic cancers that feature limited vocal fold mobility. Postoperative speech and swallowing rehabilitation is necessary for these patients. Local control rates range from 93 to 100% (3,4)

Another alternative to total laryngectomy is the near-total laryngectomy described by Pearson et al. (6) The technique is similar to a total laryngectomy on the more-involved side and a supraglottic laryngectomy on the less-involved side. The surgeon uses a narrow myomucosal strip of larynx to connect the trachea and the pharynx while preserving one functional arytenoid. This creates a dynamic shunt that prevents aspiration and allows speech without the need for a prosthesis, although the patient remains dependent on a tracheostoma for respiration.

Definitive radiation therapy. In general, the results of radiation alone for advanced hypopharyngeal cancer are poor, (7-9) as are the results for patients with laryngeal cancer who have clinically involved neck metastases. (10,11) Some patients who have small primary tumors that are amenable to conservation surgery are occasionally treated with radiation to the primary site in combination with neck dissection. (12 Although radiation obviates the need for primary surgical resection, many patients eventually lose their larynx as a result of local recurrence.

A direct comparison of radiation alone to surgery has not been reported. All definitive radiation approaches rely on successful surgical salvage of local or regional failures in order to achieve survival rates that approach those of primary surgery. Thus, the involvement of the surgeon in staging and surveillance is critical. The long-term toxicity of high-dose radiation is often underappreciated, but it is clear that chronic fibrosis, edema, tissue necrosis, and dysphagia are not uncommon and that their incidence increases with more aggressive accelerated fractionation schemes and with long-term (>5 yr) follow-up.

Neoadjuvant chemotherapy and radiation. Most investigators have now accepted neoadjuvant chemotherapy combined with radiation and surgical salvage as a standard alternative to immediate laryngectomy. (13) This acceptance is based on the results of two published randomized trials: the Department of Veterans Affairs Laryngeal Cancer Study (1) and the European Organization for Research and Treatment of Cancer (EORTC) phase III trial. (2) These two studies showed that patients with advanced laryngeal or hypopharyngeal cancer who were treated with combined chemoradiation and surgical salvage experienced survival rates similar to those who were treated with conventional total laryngectomy. Although neoadjuvant chemotherapy combined with radiation has been embraced by many as a good alternative to immediate laryngectomy, the rate of salvage laryngectomy varies from 30 to 50%; to some, this is unacceptably high. If appropriate and timely surgical salvage cannot be performed, the possible resultant decrease in surviva l cannot be justified.

Survival rates in the VA study illustrate the potential problems that are faced if salvage surgery is not an integral part of treatment. (1) Differences in survival in favor of surgery were 0% at 2 years, 3% at 3 years, 8% at4 years, and 5% after 10 years. (14) None of these differences is statistically significant. This is partly because the survival rate in the chemotherapy group with organ preservation was nearly identical to the survival rate of the surgical salvage group. Duplication of these organ-preservation and survival rates at sites outside the larynx might be more difficult to achieve in cases where barriers to submucosal tumor spread are less well developed and radical surgery is less standardized.

Concurrent chemoradiation. Emerging data from several randomized trials suggest that chemotherapy administered during radiation might improve local control rates (and in some instances even survival rates) to a greater degree than does radiation alone (15-17) The results of a large, well-done meta-analysis by Pignon et al, who looked at the effects of chemotherapy added to locoregional treatment, suggested that a significant survival benefit (8%) was associated with concomitant chemoradiation schedules. (18) Trials with direct comparisons to surgery, however, have not been performed.

The best drugs, schedules, and dosages have not yet been determined for concurrent chemotherapy and radiation. The most widely used regimen incorporates cisplatin with standard fractionation radiation on days 1, 22, and 43 of the radiation schedule. Concerns about concurrent chemotherapy and radiation protocols relate to higher toxicity, a treatment-related mortality rate of 2 to 3%, more severe late toxicity, higher complication rates for salvage surgery, and the risk that radiation treatment might need to be interrupted or the dose might need to be reduced because of the development of mucositis. A number of intensive, multidisciplinary chemoradiation schedules are currently under investigation.

Investigators conducting a recently completed randomized intergroup trial (R91-11) compared the effectiveness of the neoadjuvant approach (in which chemotherapy is used to select patients for radiation, similar to the VA trial) to the effectiveness of definitive radiation alone and of combined concurrent chemoradiation for patients with T3 and selected T4 laryngeal cancers. One would anticipate that patients who underwent concurrent chemoradiation would do better than those who received radiation only. However, according to a recently published report of preliminary results, there was no difference in 2-year survival rates among the three treatment arms. (19) These early findings are disappointing because they do not fulfill the promise of the observations made by Pignon et al. (18)

The R91-11 trial data do suggest that the appearance of distant metastases seemed to be delayed in both of the chemotherapy arms. Moreover, significantly higher rates of laryngeal preservation at 2 years were seen in the concurrent chemoradiation arm (88%) than in the induction arm (74%) and the standard radiation arm (59%). Toxicity in both of the chemotherapy arms was significantly greater than that in the radiation-alone arm, and more of these patients required dose reductions or underwent incomplete definitive radiation courses. A serious concern with the induction arm was the failure to perform planned laryngectomy following a poor response to induction chemotherapy in a large number of patients who were randomized to that group. The treatment strategy for the induction arm differed significantly from that of the other two arms in that the response to chemotherapy was used to select patients for radiation. In the other two arms, all patients received definitive radiation; surgery was not a planned part o f treatment. It will be important to carefully analyze salvage laryngectomy rates, complications, quality of life, and long-term survival among the three groups in this study before any conclusions can be drawn regarding the best standard of therapy.

Another innovative approach that has recently been reported uses a rapid tumor response to a single cycle of induction chemotherapy to select those patients who will undergo concurrent chemotherapy and definitive radiation, as was the case in the R91-11 trial. (20,21) Following radiation therapy, two cycles of additional adjuvant cisplatin/5-FU are administered in an attempt to address disseminated disease. Using this approach, investigators have reported dramatically improved survival rates and decreased late salvage laryngectomy rates compared with those seen following previous organ-preservation regimens.

Many questions still exist regarding organ-preservation treatment approaches that incorporate chemotherapy and radiation. Only the neoadjuvant approach has been prospectively studied in randomized trials. It is unclear whether only those who respond to chemotherapy are good candidates and whether the degree or speed of response to chemotherapy is important. The number of cycles of chemotherapy necessary to achieve success is unclear. The best method of monitoring response and performing tumor surveillance is also unclear. Preliminary data from some centers suggest that serial positron-emission tomography and identification of biologic markers might be useful in selecting patients and for tumor surveillance. Until the answers to such questions are known, there are little data available to define a standard approach. This paucity of data, by necessity, relegates chemoradiation paradigms to an investigational role.

Lessons learned

Despite a lack of definitive data, a number of general principles have emerged from the accumulated experience of numerous investigators. These lessons learned from chemoradiation organ-preservation trials should form the basis for current treatment practice until newer data emerge from future clinical trials:

Comparison of outcomes. There have been no randomized trials conducted in which investigators have compared surgery alone to radiation therapy alone for advanced laryngeal or hypopharyngeal cancer. Thus, comparative outcomes in terms of quality of life, function, and survival are unknown except in the setting of neoadjuvant chemotherapy and radiation. Available data are based on the mature, randomized VA and EORTC studies. (1,2)

Neck management. In patients with advanced locoregional disease, management of the neck is the single most important factor in survival. Therefore, neck management strategies must be comprehensive, and they might differ from those employed in the management of the primary site. For patients with large clinical metastases, planned neck dissections before or after radiation should be considered. (22,23)

Pretreatment imaging. Surgical salvage is an integral part of chemoradiation protocols for organ preservation. Proper staging and pretreatment assessment of tumor extent, planning for potential surgical resection, and tattooing of potential resection margins are critical. Many patients will benefit from pretreatment evaluation by computed tomography or magnetic resonance imaging, particularly to delineate the extent of the tumor in preepiglottic and paraglottic spaces. For some patients who have deeply invasive or submucosal tumors, these radiologic images are the best means of measuring tumor response because surface measurements in such situations are often unreliable.

Follow-up. Clinical surveillance of tumor recurrence and response to therapy is also critical. The success of surveillance is heavily dependent on the skill and experience of the surgeon, and this responsibility cannot be delegated to medical or radiation oncologists or to radiologists alone. Important observations derived from early studies include the finding that fixed vocal folds often remain fixed, even after tumor eradication. The reason is that areas of gross tumor are replaced by scarred and fibrotic tissue. Therefore, the larger the tumor, the less likely it is that normal phonation will be restored.

Aspiration following major tumor regression is uncommon. This might be attributable to the slow disappearance of tissue bulk during tumor regression, which allows patients' protective swallowing mechanisms to adapt to the slow changes in laryngeal anatomy. In the VA trial, no patient required permanent tracheostomy because of aspiration, and only four of 166 (2.4%) required permanent tracheostomy because of chronic laryngeal fibrosis, edema, or chondritis. (1) Three other patients who underwent permanent tracheostomy were never rendered disease-free, and all died of cancer within 6 months of diagnosis (unpublished data, 1991).

Complications. Surgery can be safely performed after chemotherapy without a high risk of complications. On the other hand, the high complication rates following radiation are well known, and even higher rates have been reported following chemoradiation. (24-26) Thus, the identification of potential failures prior to intensive radiation would be beneficial and would avoid unnecessary and redundant therapies.

Patient selection. Concurrent chemoradiation regimens might be superior to radiation alone and superior to induction chemotherapy followed by radiation, particularly since induction chemotherapy has failed to provide a survival advantage. Selection of the most appropriate patients for regimens that carry high toxicity and whose long-term success rates are unknown requires careful patient counseling.

Metastases. Distant metastases remain a major cause of death in patients with advanced laryngeal or hypopharyngeal cancer. (1,2,27) Newer treatments that incorporate systemic therapy will be needed to improve overall survival rates.

References

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