Head and Neck Cancer
Arlene Forastiere, M.D., Wayne Koch, M.D., Andrew Trotti, M.D., and David Sidransky, M.D.
Since the subject was last reviewed in the Journal, there have been important advances in the treatment of locally advanced head and neck squamous-cell carcinoma. These new approaches incorporate chemotherapy into initial curative treatment to achieve organ preservation and to improve survival. Moreover, progress in the elucidation of the molecular genetic changes that lead to the development of these tumors should soon bring novel diagnostic and therapeutic procedures into clinical practice. This review will highlight these important advances in the treatment of patients with head and neck cancer (Table 1) and emphasize the ways in which molecular biology is likely to affect the development of future therapies.
Table 1. Head and Neck Cancer in the United States, 1975–1998.
Molecular Progression of Head and Neck Cancer
Neoplasms arise clonally from transformed cells that have undergone specific genetic alterations in proto-oncogenes or tumor-suppressor genes (Table 2). Tabulation of the critical genetic changes in each step of the progression of head and neck cancer from preneoplastic lesions to invasive cancer has allowed the delineation of a model of molecular progression. Loss of chromosomal region 9p21 is the most common of all genetic changes and occurs early in the progression of these tumors. The main effect of this loss is the inactivation of the p16 gene, an inhibitor of cyclin-dependent kinase (CDK) that is important in regulating the cell cycle. This early inactivation is consistent with the finding that keratinocytes in culture often lose p16 function and thus escape senescence. Approximately half of all head and neck cancers contain a mutation of the p53 gene located at 17p13. The loss of p53 function due to a mutation results in a progression from preinvasive to invasive lesions and increases the likelihood of further genetic progression. Amplification of the oncogene cyclin D1, which constitutively activates cell-cycle progression, is seen in about a third of all tumors and is usually associated with invasive disease. Tumor-suppressor genes have not been isolated or characterized for most of the regions that are commonly lost in these tumors.
Table 2. Common Oncogene Alterations Identified in Primary Head and Neck Squamous-Cell Carcinoma.
The model of the molecular progression of head and neck squamous-cell carcinoma demonstrates that tissue with a normal or benign appearance (i.e., minimal dysplasia) can also contain clonal genetic changes (Figure 1). Several studies of head and neck cancer suggest that early genetic changes do not necessarily correlate with observable changes in morphology. Thus, testing for these genetic alterations or ploidy in early lesions may identify patients who are at the greatest risk for progression and lead to more definitive therapy.
Figure 1. Clinical, Pathological, and Molecular Progression of Oral Cancer.
Panel A shows a typical clinical presentation of oral cancer. Benign squamous hyperplasia can often appear similar to normal mucosa. Novel molecular approaches have yielded considerable understanding of the field-cancerization hypothesis originally proposed by Slaughter and colleagues. In most patients, cellular repopulation in geographically distinct areas gives rise to multiple clinical lesions. Although these lesions may have different histopathological patterns, as shown, they are often clonally related, arising from the same cell. The progression from normal-appearing mucosa to invasive cancer is depicted in Panel B. Normal-appearing mucosa already harbors early genetic changes (Panel C), often with loss of 9p21 and inactivation of p16. Further clinical progression through dysplasia is associated with further genetic changes. Carcinoma in situ often harbors most of the genetic changes described in invasive carcinoma. LOH denotes loss of heterozygosity. (Courtesy of Joseph A. Califano.)
Some patients present with cervical nodal metastases from clinically occult primary mucosal lesions. Many of those occult primary tumors are later found within the lymphoepithelium of Waldeyer's ring, especially in the tonsils and the base of the tongue. One recent study demonstrated that clonal genetic changes could be detected in specimens from directed biopsies in patients with this presentation. In more than half the patients, at least one pathologically benign biopsy specimen demonstrated a pattern of genetic alterations identical to that present in the cells from the cervical lymph-node metastases. These data support the notion that pathologically benign mucosa harbors patches of clonal cells that can give rise to metastatic lesions of squamous-cell carcinoma.
Squamous-cell carcinoma of the head and neck is a heterogeneous disease with distinct patterns of presentation and behavior. More than 50 percent of these cancers arising in the oropharynx, particularly in the palatine tonsils and the base of the tongue, contain oncogenic human papillomavirus (HPV) DNA. In a recent study, patients who were HPV-positive were less likely to have tumors that harbored a p53 mutation. These patients had better overall survival and disease-specific survival than HPV-negative patients. These results confirm a large body of earlier literature and suggest that HPV-positive oropharyngeal tumors compose a distinct clinical and pathological disease entity caused at least in part by HPV (Figure 2).
Figure 2. Human Papillomavirus (HPV) in Oropharyngeal Cancers.
Recent studies confirm that oropharyngeal tumors are often HPV-positive and compose a distinct clinical and pathologic disease entity. In Panel A, a typical large tonsillar lesion (arrows) is shown. Panel B shows the typical basaloid appearance often seen in HPV-positive tumors. In Panel C, the same tissue section was subjected to in situ hybridization with an HPV-E7–specific probe. The dark brown spots indicate the presence of HPV DNA in virtually all the neoplastic cells. (Courtesy of Wayne M. Koch and William H. Westra.)
Similarly, the association of head and neck squamous-cell carcinoma with alcohol and tobacco consumption has been clear for many years. Molecular data provide evidence that the carcinogens found in these substances have a causal role, in that the prevalence and spectrum of p53 mutations are significantly greater in cancers in patients who smoke and drink alcohol than in those in patients who abstain from these substances. Laryngeal, hypopharyngeal, and floor-of-mouth cancers rarely develop in patients who do not smoke, whereas the lateral border of the tongue is a common site for head and neck cancer in this nonsmoking group. Nonsmokers are more likely to present with head and neck squamous-cell carcinoma at a relatively young or relatively old age as compared with their smoking counterparts.
Patients with primary cancers who often smoke and drink heavily may present with multiple precancerous and cancerous lesions, so-called field cancerization, throughout the upper aerodigestive tract. Second cancers develop in nonsmokers and smokers with similar frequency, but patients with second primary head and neck squamous-cell carcinomas are much more likely to have abused tobacco and alcohol. Molecular evidence indicates that some, if not all, multiple primary cancers within the upper aerodigestive tract derive from a common clonal progenitor cell that undergoes a common early molecular alteration (Figure 1). This phenomenon has driven pioneering efforts to prevent recurrences through the use of retinoids and related compounds during the past two decades. Novel biomarkers, including the retinoic acid receptor, are promising as indicators of biologic response, but the morphologic regression of these lesions does not necessarily correlate with the abrogation of genetic changes.
Studies have shown that clonal genetic alterations can be identified in blood and other bodily fluids. With the use of a panel of 21 microsatellite markers, clonal genetic changes (loss of heterozygosity, microsatellite instability, or both) were detected in 80 percent of saliva samples from patients with head and neck cancer. DNA from these exfoliated cell samples harbors genetic changes identical to those observed in the primary tumors, whereas samples from smokers without cancer as well as from other controls were negative according to this type of molecular analysis. Thus, a noninvasive test for specific DNA-sequence variants in saliva may someday be useful in identifying either early lesions or patients with cancer.
Clonal genetic changes identical to those found in primary head and neck squamous-cell carcinomas have been identified in circulating plasma or serum; these changes may be useful as a means of monitoring patients with head and neck cancer. For example, Epstein–Barr virus (EBV) has been stongly linked to the development of nasopharyngeal carcinoma. EBV DNA has been found in the serum of patients with nasopharyngeal carcinoma and HPV in a subgroup of patients with other head and neck cancers.The results of quantitative analysis of EBV DNA correlated precisely with disease status and were therefore useful for monitoring and tracking patients. Some tumors do not harbor viral markers but do display promoter hypermethylation, a mechanism for inactivating tumor-suppressor genes; this methylation was detected in the saliva and serum of patients with head and neck cancer and precisely matched the methylation patterns seen in the primary tumors. A panel of such molecular markers could be used to detect early cancer, to detect minimal residual disease, and to help in the monitoring of patients for early recurrence.
The staging of head and neck squamous-cell carcinoma has changed very little in the past decade. Traditional staging methods are weak, and several other systems, including the rating of symptom severity and coexisting conditions by means of the standard tumor–node–metastasis staging method, have been proposed. Computed tomography and magnetic resonance imaging have been universally accepted as vital tools for clinical staging, and newer imaging approaches, including positron-emission tomography and the identification of sentinel nodes by means of lymphoscintigraphy, show promise.
The concept of molecular staging has also been introduced. Genetic alterations can be used to detect rare cancer cells in samples with normal histologic appearance, including lymph nodes and tissue margins at the periphery of the tumor. The molecular analysis of tissue from the margins of head and neck squamous-cell carcinoma has been shown to predict the likelihood of tumor recurrence and to allow determination of the relation between an index lesion of head and neck squamous-cell carcinoma and subsequent lesions. Information derived from these molecular studies may assist clinicians in determining whether to treat a second lesion aggressively with curative intent or to take a palliative approach in the case of distant metastatic disease.
The focus of surgical innovation during the past decade has been on the conservation of organ function and more effective means of reconstruction.
In the management of cancer of the larynx, new surgical procedures have extended the amount of laryngeal tissue that can be resected while preserving the ability of the larynx to protect against aspiration and to produce sound. In supracricoid laryngectomy, nearly the entire larynx is removed, and only the arytenoids and the cricoid cartilage are preserved. These structures, together with the intact base of the tongue, permit the recovery of a breathy but naturally produced voice, an intact airway, and safe deglutition in many cases. Studies of quality of life are needed in order to make direct comparisons between the functional outcomes of these surgical approaches and those of nonsurgical approaches that preserve the larynx.
The debilitating effect of neck dissection on shoulder and neck function is diminished with less radical procedures such as modified comprehensive neck dissection and selective dissection. Selective neck dissection, in which only the anatomical regions that are most likely to contain involved nodes are removed, has been used with increasing frequency. The nodal status in patients with head and neck squamous-cell carcinoma has been established with the use of radionucleotide-tagged technetium injected into the vicinity of a primary mucosal lesion in order to identify the first-echelon lymph nodes that drain that region and permit selective resection.
The reconstruction of tissue to correct defects caused by surgery has been improved with the use of tissue whose characteristics are similar to those of the native organ. For example, radial forearm skin provides enough pliable tissue to reline defects of the oral cavity and pharynx in a manner that does not greatly impede the ability of the remaining musculature to perform articulatory and gustatory functions. Reconstruction for mandibular defects may now be reliably performed with flaps taken from the iliac crest or fibula, with excellent aesthetic and functional results. Oral alimentation often can be resumed after partial or total glossectomy in patients in whom the tongue bulk was replaced with the use of microvascular flaps from the rectus abdominus muscles.
There are two different approaches to parceling a dose of radiation over time — a procedure known as fractionation; these approaches are hyperfractionation and accelerated fractionation. In hyperfractionation, small-dose fractions are delivered two to three times per day in order to take advantage of the more limited damage to normal tissue that is associated with smaller fractions. This approach has often been combined with an escalation of the total dose by 10 to 15 percent over that given with standard fractionation. The accelerated fractionation approach aims to deliver treatment at a rate of accumulation of the weekly dose that is 20 to 50 percent faster than that of standard fractionation; this acceleration substantially shortens the overall duration of treatment in order to reduce the potential for tumor repopulation that may occur between fractions.
A number of phase 3 trials testing both of these approaches have now documented a 10 to 15 percent improvement in local and regional tumor control in patients with middle- and advanced-stage disease without a significant change in overall survival. Although gains in tumor control have been moderate, these trials have confirmed important radiobiologic principles. Selected schedules of both hyperfractionation and accelerated fractionation have now been adopted as treatment options at many large cancer centers and in the community at large.
The presence of oxygen is critical to the ability of radiation to damage DNA and kill cancer cells. Since most head and neck tumors are both acutely and chronically hypoxic, they are relatively resistant to the effects of radiation. Hypoxic-cell radiation sensitizers, such as misonidazole and etanidazole, have been tried but in general do not enhance tumor control. Nimorazole was tested in a randomized trial by the Danish Head and Neck Cancer Study Group and led to improved local and regional control in supraglottic and pharyngeal cancers. The bulk of such trials, however, have been disappointing because they have been unable to demonstrate improvements that translate into improved survival. Sensitizers activated by hypoxia are currently being tested. Other approaches under investigation are the use of sensitizing chemotherapy or growth factors that augment the availability of oxygen in hemoglobin (unpublished data).
The most common approach to the management of advanced head and neck cancer has traditionally been resection and postoperative radiotherapy, but survival and rates of local recurrence have been disappointing. A number of novel approaches are being tried, including the use of risk profiles to define specific target populations at high risk for recurrence and altered fractionation of postoperative radiotherapy. Another strategy to reduce clonal repopulation in the postoperative setting is the use of sensitizing chemotherapy concurrently with radiation.
A previously held dogma that normal tissues can only tolerate a specific maximal lifetime dose of radiation has been challenged by studies in which second doses of radiation of up to twice the expected tolerance of normal tissue have been given with a surprisingly low incidence of serious toxic effects. These clinical data support laboratory investigations that have demonstrated that normal tissue may recover in time, suggesting that it may be possible to give additional doses of radiation in many types of tissue. This approach is currently under investigation by multiple clinical-trial groups.
Treatment of Patients with Recurrent and Metastatic Disease
The goals of treatment for patients for whom cure is no longer an option include prolonging life with various cytotoxic regimens that may achieve measurable reductions in tumor and providing palliation through control of symptoms. Many patients with locally recurrent or metastatic squamous-cell carcinoma of the head and neck have substantial coexisting disease as a consequence of age and tobacco and alcohol abuse, which makes the use of cytotoxic drugs problematic. Tumor recurrence at the primary site in the neck or the base of the skull may result in cranial-nerve dysfunction, pain, impaired speech and swallowing, and airway compromise; the provision of pain control, symptom management, and psychosocial services is integral to optimal palliative care for patients with recurrent or metastatic head and neck cancer.
The cytotoxic drugs most commonly used to treat head and neck cancer are methotrexate, cisplatin, carboplatin, fluorouracil, paclitaxel, and docetaxel. The rate of response, defined as a decrease of at least 50 percent in the dimensions of measurable tumors for a duration of at least one month, is influenced by the amount of previous treatment, the tumor burden, and the patient's performance status. In general, 15 to 30 percent of patients have brief responses to these single agents.
The combination of cisplatin and fluorouracil given by continuous intravenous infusion is the mainstay of treatment. Prospective, multicenter, randomized trials in patients with recurrent disease have shown significantly higher response rates in patients treated with this combination than in those treated with single agents, but there have been no differences in the median duration of survival or the overall survival rates. Randomized trials directly comparing newer regimens, such as paclitaxel or docetaxel plus cisplatin or carboplatin, with the standard cisplatin-and-fluorouracil regimen are in progress.
New agents, including agents that inhibit signal transduction, cell-cycle traversal, programmed cell death, the regulation of transcription, matrix invasion, and angiogenesis, are in development. Therapeutic agents targeted specifically to patients with head and neck cancer include the family of tyrosine kinase inhibitors — in particular, the epidermal growth factor–receptor antagonists, CDK (cyclin-dependent kinase) inhibitors, and replication-competent adenoviruses. More than 90 percent of squamous-cell head and neck cancers overexpress the epidermal growth factor receptor, a transmembrane glycoprotein encoded by c-erbB. Transforming growth factor , epidermal growth factor, and other growth factors bind to the extracellular domain of the epidermal growth factor receptor, stimulating tumor growth through autocrine and paracrine pathways. Thus, monoclonal antibodies directed against epidermal growth factor receptor could block ligand binding and inhibit cell proliferation. The chimeric IgG antibody C225, which has binding affinity equal to that of the natural ligand, can effectively block the effect of epidermal growth factor and transforming growth factor in patients. Enhanced cytotoxicity has been observed when C225 is used in combination with a number of conventional cytotoxic therapies, including cisplatin and paclitaxel. When used in combination with radiotherapy, C225 also enhances the effect of killing tumor cells by inhibiting tumor-cell repopulation. A number of small-molecule drugs that block the epidermal growth factor receptor are in phase 1 and 2 testing.
CDKs phosphorylate key substances that regulate the transitions between cell-cycle phases. Cyclin D is commonly overexpressed in head and neck cancer, and p16, the endogenous inhibitor of CDK4, is commonly deleted or not transcribed. In preclinical testing, the CDK inhibitor flavopiridol repressed the transcription of cyclin D, induced cell-cycle arrest at the transitions between the G2 and M phases and between the G1 and S phases, and induced p53-independent apoptosis. Clinical trials with flavopiridol in head and neck cancer and other solid tumors are in progress. When administered in preclinical studies, another CDK inhibitor, CCI-779 (a structural analogue of the macrocyclic lactone sirolimus, previously called rapamycin), decreased the kinase activity of the CDK4–cyclin D complex in a p53-independent fashion.
Replication-competent adenoviruses have been developed that selectively replicate in and cause lysis of cells deficient in p53 tumor-suppressor activity. An example is ONYX-015, which is constructed with a deletion of the E1b protein and will not proliferate in normal cells but has the capacity to replicate in tumor cells that are deficient in p53. Phase 1 and 2 clinical trials of the intralesional injection of ONYX-015 alone or in combination with systemic chemotherapy suggest that it is effective and that the responses at injected tumor sites are durable.
Three strategies for combining chemotherapy with surgery and radiotherapy are induction chemotherapy, which consists of several courses of chemotherapy before surgery or radiotherapy; the concurrent administration of chemotherapy and radiotherapy; and adjuvant chemotherapy administered after the patient has been rendered free of disease.
Cancers of the Larynx and Hypopharynx
More than a decade ago, induction chemotherapy followed by radiotherapy became a standard treatment option for patients with advanced cancer of the larynx who wanted to preserve their voice. This practice was based on the Veterans Affairs Laryngeal Cancer Study Group trial published in the Journal in 1991. More than 300 patients with stage III or IV cancer of the larynx were randomly assigned to receive induction chemotherapy with cisplatin and fluorouracil followed by radiotherapy (in patients with a response to the chemotherapy) or total laryngectomy and postoperative radiation. In the chemotherapy group, surgery was reserved for patients with no response to the induction chemotherapy and for those with persistent or recurrent disease after radiotherapy. A functioning larynx was preserved in 62 percent of surviving patients treated with chemotherapy, and survival in the chemotherapy group was not significantly different from that in the surgery group. A similarly designed trial in Europe involving patients with cancer of the hypopharynx showed equivalent survival in the surgery group and the induction-chemotherapy group and a rate of larynx preservation of 42 percent. These trials established induction therapy with cisplatin and fluorouracil followed by radiotherapy as an alternative standard of care to preserve the larynx when total laryngectomy would otherwise have been required.
The precise role of chemotherapy, however, could not be determined from these studies, which led to a follow-up trial (R91-11) conducted by the Head and Neck Intergroup in the United States. This trial compared induction chemotherapy, radiotherapy alone, and radiotherapy with concurrent cisplatin. There was a significant advantage of radiotherapy with concurrent cisplatin treatment, with 88 percent of patients preserving their larynx at two years, as compared with 74 percent of those treated with induction chemotherapy (P=0.005) and 69 percent of those treated with radiotherapy alone. These results represent a reduction of nearly 50 percent in the rate of laryngectomy with concurrent treatment as compared with the previous standard of care, and the study has established this approach as the preferred alternative to surgery for patients who desire larynx preservation. Because concurrent treatment is associated with more severe toxic effects, however, it is appropriate to recommend radiotherapy alone for patients with a poor performance status or a limited psychosocial support system.
Cancer of the Oropharynx
The majority of oropharyngeal cancers originate from the base of the tongue and the tonsils, and more than 90 percent are squamous-cell carcinomas. Randomized, controlled trials in patients with locally advanced oropharyngeal cancer have evaluated platinum-based chemotherapy given concurrently with radiotherapy, delivered according to either a standard or an altered fractionation schedule. These studies have demonstrated that such concurrent chemotherapy results in significant improvements in local control, relapse-free survival, and overall survival as compared with radiotherapy alone (Table 3).
Table 3. Randomized Trials of Concurrent Multiagent Chemotherapy and Radiotherapy as Compared with Radiotherapy Alone in Stage III or IV Disease.
Calais and colleagues reported a randomized trial involving 222 patients with stage III or IV cancer of the oropharynx who were treated with either radiotherapy alone (with standard fractionation) or the same radiotherapy delivered concurrently with three courses of chemotherapy with carboplatin and fluorouracil. This study and others demonstrating an improvement in survival with concurrent chemoradiotherapy report differences in local and regional control of 20 to 30 percentage points, which are sufficiently large to alter the likelihood of survival.
These data support the use of concurrent chemotherapy and radiotherapy as the standard of care for the treatment of stage III and IV cancers of the oropharynx when nonsurgical treatment is planned. No randomized trials have been performed comparing the combination of chemotherapy and radiotherapy with surgery. Moreover, these complex treatments have substantial toxicity and are therefore not suitable for all patients. A good performance status, a strong psychosocial support system, and an experienced team of providers are essential for the successful completion of treatment.
Locally Advanced, Unresectable Disease
Patients whose disease cannot be resected with an expectation of achieving tumor-free margins have until recently been treated with radiotherapy alone (Table 3). All of the trials comparing concurrent chemotherapy and radiotherapy with radiotherapy alone have demonstrated statistically significant differences in local and regional control and disease-free survival.
Concurrent chemoradiotherapy is superior to radiotherapy alone and should be the accepted standard of care for patients with locally advanced, unresectable squamous-cell carcinoma of all sites in the head and neck. We make this recommendation with the caveat that patients must have adequate performance status and the support necessary for dealing with the effects of this more complex and toxic therapy. Otherwise, radiotherapy alone is a more appropriate form of care.
Poorly differentiated or undifferentiated nasopharyngeal carcinoma differs from squamous-cell carcinoma of other sites in the head and neck. The rates of local control are high, but distant recurrence is common and is often the cause of death. Autopsy series document distant metastases in 87 percent of patients, mostly to bone, followed in order of frequency by lung, liver, and extraregional nodes. Patients with bulky regional nodes, bilateral involvement, or nodes low in the neck are at greatest risk.
Important advances in treatment have emerged from randomized trials conducted over the past decade. Concurrent chemoradiotherapy has proved superior to the previous standard of care of radiotherapy alone for the treatment of patients with T3, T4, or N1, N2, or N3 disease. Strong positive results in terms of survival — strong enough to cause the trial to be stopped after the first interim analysis — were reported by the Head and Neck Intergroup in its comparison of radiotherapy alone with concurrent cisplatin and radiotherapy followed by three courses of adjuvant cisplatin and fluorouracil. These results led to a change in the standard of care to concurrent treatment. The applicability of these trial results to ethnic groups in which the disease is endemic, such as Asians, is unclear.
Postoperative Adjuvant Chemotherapy
The use of postoperative adjuvant chemotherapy for patients who are at high risk for local and regional recurrence and death from cancer is under evaluation in randomized, controlled trials in both the United States and Europe. Patients with two or more positive regional nodes, extracapsular extension of disease, or positive margins of resection are known to be in a high-risk category. Data from Radiation Therapy Oncology Group trials have shown that the rate of local and regional recurrence at three years is 14 percent for those with none of these risk factors, 27 percent for those with two or more positive nodes or extracapsular extension of tumor, and 49 percent for those with a positive margin with or without other risk factors. The corresponding median durations of survival are 5.6 years, 2.6 years, and 1.5 years. There is no role for adjuvant systemic therapies in patients who are at low risk.
Toxicity of Chemotherapy
The recent revision and expansion of the Common Toxicity Criteria by the National Cancer Institute have improved the standardization of toxicity grading for radiation, chemotherapy, and surgery. Data on speech and swallowing function are now routinely incorporated into clinical trials. Validated psychometric tools for measuring the effects of the tumor burden and the treatment on the quality of life now enable investigators to measure these effects from the patient's perspective. Mucositis is recognized as a major impediment to further intensification of treatment for head and neck cancer.
Another debilitating long-term side effect of radiation to the head and neck region is xerostomia; amifostine given daily by intravenous infusion concurrently with postoperative radiotherapy can reduce xerostomia. Pilocarpine used after radiation has been shown to reduce the sensation of oral dryness but has had no detectable effect on salivary flow. Ongoing studies incorporating amifostine into chemoradiotherapy regimens and trials in which pilocarpine is being given concurrently with radiation are attempts to optimize the effect of these agents. There are additional studies under way to address the long-term side effects as well as the acute toxic effects of combination therapy to the head and neck region.
Head and neck cancer remains a disfiguring disease associated with a high mortality rate. Abstinence from smoking and alcohol is the best approach to prevent its occurrence. New molecular methods of detection may help clinicians diagnose tumors earlier and may provide more accurate staging systems and means of monitoring patients with this type of cancer. Aggressive surgical resection is the cornerstone of therapy, with increasing roles for both radiation and chemotherapy, especially for organ preservation.
Supported by a grant (RO1 DE12588) from the National Institute of Dental and Craniofacial Research and a Lung Spore grant (P50 CA58184).
From the Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore.
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