This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rhee, J. C. Articles by Shin, D. M. Search for Related Content PubMed PubMed Citation Articles by Rhee, J. C. Articles by Shin, D. M.

Advances in Chemoprevention of Head and Neck Cancer

^a Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; ^b Winship Cancer Institute, Emory University, Atlanta, Georgia, USA

Correspondence: Dong M. Shin, M.D., F.A.C.P., Head and Neck Cancer Program, Winship Cancer Institute, Emory University, 1365-C Clifton Road, Atlanta, Georgia 30322, USA. Telephone: 404-778-5990; Fax: 404-778-5520; e-mail: dong_shin{at}emoryhealthcare.org

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
After completing this course, the reader will be able to:

1. Describe the mechanism of carcinogenesis of head and neck cancer.
   
2. Explain chemoprevention with retinoids and other chemopreventive compounds.
   
3. Discuss the published data including phase II and phase III randomized trials.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Head and neck squamous cell carcinoma is a devastating disease with a poor outcome in advanced stages, accounting for approximately 3% of all malignancies, with an estimated 37,200 new cases and 11,000 deaths annually in the U.S. Second primary tumors are estimated to occur at an annual rate of 3%–10% and are significant threats to long-term survivors. Chemoprevention is an appealing strategy, and its success has been demonstrated in breast cancer and familial adenomatous polyposis. High-dose retinoids have been shown to be active against oral premalignant lesions and in prevention of second primary tumors in the head and neck. New targets include the epidermal growth factor receptor, cyclooxygenase-2, and other molecular targets. Challenges in future head and neck cancer chemoprevention investigations include achieving long-lasting efficacy with retinoids and/or new agents, and determining the optimal dose and duration of therapy while maintaining acceptable toxicities.

Key Words. Head and neck cancer • Biochemoprevention • Retinoids • Epidermal growth factor receptor • Cyclooxygenase-2 inhibitors

	INTRODUCTION

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Head and neck squamous cell carcinoma (HNSCC) is a devastating disease with a poor outcome in advanced stages, accounting for approximately 3% of all malignancies, with an estimated 37,200 new cases and 11,000 deaths annually in the U.S. [1]. Tobacco and alcohol are widely recognized risk factors. Some patients will achieve long-term survival, particularly those diagnosed with early-stage disease. However, patients with recurrent disease or distant metastases have a median survival of only 6–8 months [2, 3]. Second primary tumors (SPTs) are estimated to occur at an annual rate of 3%–10% and are significant threats to long-term survivors [4, 5]. Moreover, despite curative therapy for HNSCC, patients may acquire debilitating changes in appearance, speech, swallowing, and breathing. Clearly, preventative strategies are desirable.

Two concepts that have contributed to the understanding of the pathogenesis of head and neck cancer and other epithelial cancers are field cancerization and the multistep process [6–9]. Field cancerization was proposed by Slaughter in the 1950s, when it was observed that tissue adjacent to oral carcinomas revealed dysplasia, carcinoma in situ, and other histologic changes [6]. This was felt to explain the increased risks for SPTs and local recurrences. More recently, the discovery of genetic alterations supports this theory. These events comprise the multistep process, which includes inherited genetic alterations, damage from carcinogens such as tobacco and alcohol, and viral infections [7, 8]. There has been great interest in developing ways to interrupt these processes.

	CHEMOPREVENTION

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Chemoprevention has been studied in several malignancies; however, its success is greatest in breast cancer, where tamoxifen has been shown to decrease the incidence of invasive breast cancer in women at high risk [10]. Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs decreased the risk of colon cancer [11]. In familial adenomatous polyposis, a condition that confers a markedly increased risk of colorectal cancer, the cyclooxygenase-2 (COX-2) inhibitor celecoxib has been shown to decrease the number of colonic polyps by 28% [12]. In other malignancies, such as lung and prostate cancers, several agents have been studied; however, there are no proven strategies.

Oral leukoplakia is a white-plaque mucosal lesion that confers an increased risk for the development of squamous cell carcinoma. Histologically, oral leukoplakia includes hyperplasia, hyperkeratosis, dysplasia, and carcinoma in situ. In 150 patients with leukoplakia followed for a mean duration of 103 months, squamous cell carcinoma developed in 36 (24%). The DNA content of the cells was predictive of the risk for the development of carcinoma [13]. Treatment for oral leukoplakia is removal, when feasible, via surgery or laser therapy. Inherited susceptibility as well as exposure to carcinogens such as tobacco and alcohol result in DNA damage and an increased risk for the development of invasive cancer [14]. Much of what is known about head and neck cancer chemoprevention is based on studies of patients with oral leukoplakia.

	AGENTS IN HEAD AND NECK CANCER CHEMOPREVENTION

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
The most well-studied agents in head and neck cancer chemoprevention include vitamin A, other retinoids, beta-carotene, vitamin E, selenium, and COX-2 inhibitors. In addition, the investigation of biomarkers has led to the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and farnesyl transferase inhibitors (FTIs) that target EGFR and H-ras and are new promising agents for chemoprevention.

	VITAMIN A

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Vitamin A (retinyl palmitate) deficiency was implicated as a cause of head and neck cancer when low levels of serum vitamin A were found twice as often in patients with stage III and IV disease than in healthy individuals [15]. Lower levels of vitamin A were also found in head and neck cancer patients with SPTs compared with those without SPTs, suggesting a possible role in their etiology [16]. The exact mechanism of vitamin A and its derivatives in potential HNSCC prevention is not fully understood; however, it is thought that these agents restore expression of retinoic acid receptor-beta (RAR-ß) mRNA, which may promote normal tissue growth and differentiation [17].

In a randomized controlled trial of smokeless tobacco users and betel nut chewers with oral leukoplakia, participants were given either 200,000 IU of vitamin A weekly for 6 months or placebo. Complete remissions occurred in 57.1% and suppression of the development of new leukoplakia occurred in 100% of the treated group, versus 3% and 21% of the placebo group, respectively. This was confirmed by histologic and cytologic differences between biopsies taken at the beginning and the completion of the trial [18].

These and other studies stimulated interest in the idea that vitamin A and antioxidants could prevent cancer of the upper and lower airways and led to the European Study on Chemoprevention with Vitamin A and N-acetylcysteine (EUROSCAN), a large randomized intervention study in over 2,000 patients with head and neck cancer or lung cancer. In that study, patients were randomized to receive vitamin A (300,000 IU/day followed by 150,000 IU/day in the second year), N-acetylcysteine (600 mg/day for 2 years), both compounds, or no intervention. Unfortunately, recurrence, SPT, and death rates were not better in any of the intervention groups with a median follow-up of 49 months [19].

	OTHER RETINOIDS IN ORAL LEUKOPLAKIA

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Retinoids include vitamin A and its synthetic derivatives and have been shown to have beneficial effects on epithelial cancers in animal studies. Their potential for chemoprevention in head and neck cancer has been studied for several years [20, 21]. Compared with the approximately 15% spontaneous regression rate of oral leukoplakia, Koch achieved complete or partial remissions in 45% of patients with these premalignant lesions treated with one of three retinoids—13-cis-retinoic acid (isotretinoin), trans-beta-retinoic acid, and aromatic retinoid—after follow-up of up to 6 years [22, 23].

In 1986, a landmark trial (Fig. 1) by Hong et al. showed that high doses of isotretinoin were active against oral leukoplakia. There were significant decreases in the sizes of lesions in 16 of 24 patients (67%) receiving 1–2 mg/ kg/body weight/day, compared with only 2 of 20 patients (10%) receiving placebo (p = 0.0002). In addition, clinical response correlated with histologic resolution in nine of those 16 patients. However, toxicities were significant and have, at this point, precluded its clinical use. They included cheilitis, erythema and dryness of the skin, and hypertriglyceridemia, which, in some cases, required reduction or cessation of the drug. Furthermore, over 50% of patients with responses relapsed within 3 months after therapy was stopped. One patient in the treatment group (versus two in the placebo group) developed squamous cell carcinoma; however, since the study lasted only 9 months, it could not be determined whether leukoplakia regression correlated with a decrease in future invasive cancers [24].

View larger version (20K): [in this window] [in a new window]   Figure 1. Study schema and results of high-dose 13-cis-retinoic-acid in oral leukoplakia. Abbreviations: 13-cRA = 13-cis-retinoic acid.

Chiesa et al., in Italy, studied the synthetic retinoid fenretinide (4-HPR) in 115 patients with oral leukoplakia treated surgically. In that 1-year study, 3 of 39 (8%) patients in the treated group and 12 of 41 (29%) patients who received no intervention were found to have local relapses or new lesions. Toxicities included dermatitis and hypertriglyceridemia. Compared with use at higher doses, there were no reports of decreased night vision [26–28]. Updated results from that study reported that toxic effects were minimal and compliance was good [29].

	RETINOIDS FOR SPT PREVENTION IN HEAD AND NECK CANCER

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
In light of the trials of retinoids in oral leukoplakia, the role of retinoids in the adjuvant setting in HNSCC was studied. A phase III study randomized 103 patients with stage I-IV HNSCC to receive either placebo or 50–100 mg/m² isotretinoin daily for 1 year [30]. Although there were no significant differences between the two groups in the number of local, regional, or distant recurrences of the primary cancers, the treatment group had significantly fewer SPTs. After a median follow-up of 32 months, only two patients (4%) in the isotretinoin group, versus 12 (24%) in the placebo group, had SPT (p = 0.005). Toxicities included skin dryness, cheilitis, hypertriglyceridemia, and conjunctivitis. Sixteen of 49 (33%) patients did not complete the 12-month treatment because of adverse effects or noncompliance. Long-term follow-up showed that, in the treatment group, there was a 14% rate of development of an SPT, versus 31% in the placebo group (p = 0.04), after a median of 54.5 months (Fig. 2) [31].

View larger version (20K): [in this window] [in a new window]   Figure 2. Study schema and results of 13-cis-retinoic-acid in HNSCC in the adjuvant setting. Abbreviations: 13-cRA = 13-cis-retinoic acid.

Khuri et al. recently reported data from an intergroup, placebo-controlled, double-blinded study evaluating the efficacy of low-dose isotretinoin (30 mg) in the prevention of SPTs in patients with stage I or stage II HNSCC, as well as the impact of smoking status on SPT development. Starting in 1991, 1,190 patients were randomized to receive either 30 mg of isotretinoin daily or placebo for 3 years. The last patient completed treatment in September 2002. The annual SPT rate was 4.7% in both arms, and there were no significant differences in overall survival or recurrence-free survival. There was a transient, statistically nonsignificant pattern of fewer recurrences with isotretinoin, which was lost after treatment cessation. Continued smoking was shown to have a significant adverse effect on disease-free survival. Molecular tumor characteristics are being analyzed to better distinguish between SPTs and recurrences [33, 34].

The toxicities encountered with high-dose retinoids have prevented them from becoming the standard of care, while low-dose retinoids have been shown to be ineffective. An efficacious schedule with an adequate dose of retinoids has not been achieved.

	BETA-CAROTENE

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Dietary beta-carotene has long been thought to reduce cancer rates [35], and animal studies have shown inhibition of oral carcinogenesis with topical beta-carotene treatment [36]. Earlier studies showed the response rates of oral leukoplakia to beta-carotene to be as high as 44%–71% [37, 38].

A clinical trial of 79 patients with oral leukoplakia receiving antioxidant supplements of 30 mg beta-carotene as well as 1,000 mg ascorbic acid and 800 IU vitamin E or alpha-tocopherol (-TF) for 9 months showed clinical improvements in 56% of those patients [39].

In a randomized, double-blinded, placebo-controlled multicenter trial, 264 patients with early-stage head and neck cancer received either 50 mg beta-carotene or placebo after being curatively treated with radiation and/or surgery [40]. After a median period of 51 months, there were no differences between the two groups in mortality, time to SPT development, or local recurrences.

In the Physician’s Health Study, a large trial that enrolled 22,071 male physicians, 12 years of supplementation with beta-carotene produced neither benefit nor harm in the incidence of malignant neoplasms [41]. Furthermore, the beta-carotene and retinol efficacy trial (CARET) actually showed that the combination of beta-carotene and vitamin A had a relative risk of lung cancer of 1.28 (p = 0.02) and a relative risk of 1.26 of death from cardiovascular disease [42]. Those trials prompted beta-carotene to be removed from chemoprevention trials for oral premalignancy in smokers.

	VITAMIN E AND SELENIUM

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
The antioxidant vitamin E (-TF) prevented the development of cancers in oral cavities in animal studies [43]. A phase II study showed that, among 43 patients with oral leukoplakia who took 400 IU of vitamin E twice daily for 24 weeks, 20 (46%) had clinical responses and nine (21%) had histologic responses [44]. The treatment was well tolerated, without any toxicity higher than grade 2 and with good compliance.

The trace element selenium was proposed to be a potential agent for head and neck cancer chemoprevention when epidemiologic studies showed that death rates for head and neck cancer were lower in regions where soil contained higher levels of selenium [45]. In patients undergoing surgery and/or radiation therapy for head and neck cancer, supplementation with 200 µg of selenium per day was found to be associated with a significantly enhanced cell-mediated immune responsiveness [46].

	BIOCHEMOPREVENTION

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Biochemoprevention therapy combined high-dose isotretinoin, -TF, and interferon-alpha (IFN-). -TF had been chosen because of its synergistic effects with retinoids, its ability to decrease the toxicity of isotretinoin, as well as its minimal side effect profile. In preclinical studies, this three-drug combination showed a markedly better inhibition of cell growth compared with each single agent or two-drug combination. Cell cycle analysis showed that cells were inhibited in the S phase, and a binding assay indicated greater apoptosis by the three-drug combination [47]. A prospective, nonrandomized phase II trial by Papadimitrakopoulou et al. enrolled patients with biopsy-proven advanced premalignant lesions (e.g., mild, moderate, and severe dysplasia) of the oral cavity, oropharynx, and larynx. Participants had serial biopsies and clinical examinations. Among patients with laryngeal dysplasia, 9 of 19 (47%) and 7 of 14 (50%) had complete responses at 6 months and 12 months, respectively. However, patients with oral cavity and oropharynx dysplasia did not achieve such responses—only 1 of 11 (9%) and zero of seven (0%) showed complete responses at 6 and 12 months, respectively. Some patients experienced side effects associated with isotretinoin, but there were no toxicities greater than grade 3 [48]. Seven patients whose pretreatment biopsies expressed a mutant p53 gene were found to have had a reappearance of the wild-type p53 gene in posttreatment biopsies, suggesting biochemoprevention may suppress the mutant p53 gene [49].

Shin et al. conducted a bioadjuvant phase II trial with isotretinoin, -TF, and IFN- for 12 months in patients with locally advanced head and neck cancer [50, 51]. The starting doses were 50 mg/m²/day orally of isotretinoin, 1,200 IU/day orally of -TF, and 3 million units/m² s.c. of IFN- three times weekly. Among the 44 patients, 9% (four patients) developed locoregional recurrence, 5% (2 patients) developed locoregional recurrence and distant metastases, and one patient developed a second primary malignancy (acute promyelocytic leukemia) at a median of 24 months. The 1- and 2-year survival rates were 98% and 91%, respectively. Disease-free survival rates during the same time periods were 91% and 81%, respectively [50]. Long-term follow-up at a median of 49.4 months showed that the overall survival rates at 1 year, 3 years, and 5 years were 98%, 89%, and 81%, respectively. Disease-free survival rates at 1 year, 3 years, and 5 years were 89%, 78%, and 74%, respectively, suggesting that the effect of bioadjuvant therapy is long lasting [51]. This combination was well tolerated, with 86% of patients completing the planned therapy. Toxicities were similar to those previously reported with interferon and isotretinoin and included mild-to-moderate constitutional symptoms and fatigue. Grade 3 toxicities included fatigue in three patients (7%) and peripheral neuropathy in one patient (2%) and required dose reduction. One patient developed visual disturbances with moderate optic neuritis on ophthalmologic examination. The patient’s vision recovered after cessation of the medication [50]. A phase III randomized trial (Fig. 3) is currently being conducted to confirm the phase II results. As a result of the toxicity experienced in the phase II study, the dose of isotretinoin for that study is 40 mg/m²/day orally and the IFN- dose is 2 million units/m² s.c. three times weekly.

View larger version (15K): [in this window] [in a new window]   Figure 3. Study schema of phase III trial of adjuvant biologic therapy in patients with stage III/IV HNSCC. Abbreviation: 13-cRA = 13-cis-retinoic acid.

	NEW TARGETS AND BIOMARKERS OF HNSCC

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

View larger version (17K): [in this window] [in a new window]   Figure 4. Multistep process of the development of HNSCC. Abbreviations: TGF- = transforming growth factor alpha; PCNA = proliferating cell nuclear antigen.

	H-RAS GENE

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Members of the ras gene family are among the most commonly altered protooncogenes in a variety of solid tumors. A mutation in the H-ras gene is found in 27%–61% of squamous cell carcinoma cases and 30% of cases of oral leukoplakia [53, 54]. FTIs inhibit an enzymatic step in the expression of this gene and have been shown to have extensive activity in preclinical studies using HNSCC cell lines, as well as in non-small cell lung cancer lines. A combination of the FTI, L-778,123 and radiotherapy has been studied in locally advanced head and neck cancer patients in the phase I setting, with acceptable toxicities. Two of three patients with HNSCC had no evidence of disease on follow-up computed tomography scans and nasopharyngoscopy [55].

	EPIDERMAL GROWTH FACTOR RECEPTOR

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
The EGFR is a 170-kDa transmembrane protein that plays an important role in organogenesis and tissue homeostasis and is thought to be important in the proliferation and survival of cancer cells [56]. Overexpression of the EGFR has been found in several malignancies, including head and neck, lung, breast, prostate, bladder, and pancreatic cancers [57–61]. Dysregulation of EGFR has been found in 80%–90% of HNSCC specimens and is felt to correlate with a greater risk for disease recurrence [62–66]. Since the EGFR is frequently expressed in HNSCC, blocking the EGFR is an excellent approach to treat and prevent head and neck cancer. One approach to block the EGFR includes targeted agents that inhibit EGFR tyrosine kinase. These TKIs include gefitinib (Iressa^®; AstraZeneca Pharmaceuticals; Wilmington, DE) and erlotinib (Tarceva^TM; Genentech, Inc.; South San Francisco, CA). In phase I trials, gefitinib has shown antitumor activity in patients with non-small cell lung cancer [67]. In 47 patients with recurrent or metastatic HNSCC treated with 500 mg/day gefitinib, the response rate was 10.6% [68]. Gefitinib is generally well tolerated, with the most common adverse events being rash and diarrhea. However, rare cases of interstitial pneumonitis have been reported with gefitinib, which is of concern for its use in the preventative setting [69]. However, the mechanisms involved and the true incidence of interstitial pneumonitis should be further investigated. Preliminary data from a phase II study with 250 mg/day gefitinib support a superior toxicity profile, but conclusions regarding efficacy have not been made [70].

	p53 GENE

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
p53 is a tumor suppressor gene located on the short arm of chromosome 17, and mutations in this gene occur in 43% of HNSCC patients [71]. The expression of p53 protein in HNSCC has been shown to be predictive of shorter survival and may be a valuable marker for identifying individuals at high risk for developing recurrent disease or SPTs [72, 73]. p53 status has also been shown to be an independent indicator of response to neoadjuvant chemotherapy [74]. ONYX-015 is an adenovirus lacking the gene encoding E1B 55kd, which binds to and inactivates p53. ONYX-015 was administered as a mouthwash therapy in a phase II trial for premalignant oral dysplasia. In the first 10 patients treated with weekly therapy, resolution of dysplasia occurred in three patients, as well as histologic improvement in an additional two patients with no toxicity of grade 2 or greater [75]. Further studies are necessary.

	CYCLOOXYGENASE-2 INHIBITORS

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Selective COX-2 inhibitors are promising agents in chemoprevention [76]. COX-2 is thought to enhance the production of vascular growth factors, leading to neoangiogenesis, as well as to mediate cytokines involved in chronic inflammation, resulting in increased epithelial carcinogenesis. Other mechanisms by which COX-2 activity contributes to carcinogenesis include catalyzing the conversion of procarcinogens to carcinogens, decreasing apoptosis, and stimulating the invasive phenotype of cancer cells [77]. COX-2 is expressed in neoplastic cells in head and neck, lung, colon, and breast cancer tissues. Nearly 100-fold greater expression levels of COX-2 were found in HNSCC cells compared with normal oral mucosa [78].

COX-2 inhibitors were first studied as chemopreventative agent in colonic polyps and colorectal cancer [79–81] and have an established use in familial adenomatous polyposis [12]. Potential prevention of breast [82, 83], hepatocellular [84], and bladder cancers [85] has also been proposed.

A randomized animal study by Wang et al. showed a significant difference between the quantity of new vasculature at tumor sites in mice intradermally inoculated with oral carcinoma cells and control mice, suggesting the chemopreventative efficacy of the COX-2 inhibitor celecoxib [86]. Preclinical studies have been performed with celecoxib and the EGFR-TKI AG1478 on cell growth and cell cycle progression of HNSCC cell lines. The combination of the EGFR-TKI and celecoxib synergistically inhibited the growth of the HNSCC cell lines, with apoptosis in 72% with combined treatment, 21%–50% with single-agent therapy, and 8% without treatment [87]. Downstream signaling molecules, mitogen-activated protein kinase, Akt, and signal transducer and activator of transcription (STAT)-3, were also synergistically lower with the combined treatment with an EGFR-TKI and COX-2 inhibitor compared with the single-drug treatment [88]. This combined approach, with EGFR-TKIs and COX-2 inhibitors, has great promise in the future chemoprevention of HNSCC. Our institution is planning a phase I/II chemoprevention trial with celecoxib and erlotinib.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 
Chemoprevention is an attractive strategy in head and neck cancer management, although past trials have not demonstrated its feasibility. Single-agent retinoids are active against oral premalignant lesions, demonstrating a proof of principal that head and neck cancer chemoprevention is possible. Biochemoprevention (isotretinoin, IFN-, -TF) is a promising approach, but its efficacy needs to be determined in phase III trials. Molecular targeted agents such as EGFR-TKIs, FTIs, and COX-2 inhibitors are important potential treatments. Future clinical trials should test these new agents and combinations of these agents. Questions remain regarding the optimal dose and duration of therapy with retinoids and other agents. Other challenges include achieving efficacy while maintaining acceptable toxicity levels and good patient compliance. Although vast advances have been made in the knowledge of head and neck carcinogenesis, chemoprevention for HNSCC remains investigational.

	REFERENCES

Top Learning Objectives Abstract Introduction Chemoprevention Agents in Head and... Vitamin A Other Retinoids in Oral... Retinoids for SPT Prevention... Beta-Carotene Vitamin E and Selenium Biochemoprevention New Targets and Biomarkers... H-ras Gene Epidermal Growth Factor Receptor p53 Gene Cyclooxygenase-2 Inhibitors Conclusions References

 

1. Jemal A, Murray T, Samuels A et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26.[Abstract/Free Full Text]
2. Spitz MR. Epidemiology and risk factors for head and neck cancer. Semin Oncol 1994;21:281–288.[Medline]
3. Vokes EE, Weichselbaum RR, Lippman SM et al. Head and neck cancer. N Engl J Med 1993;328:184–194.[Free Full Text]
4. Sturgis EM, Miller RH. Second primary malignancies in the head and neck cancer patient. Ann Otol Rhinol Laryngol 1995;104:946–954.[Medline]
5. Cooper JS, Pajak TF, Rubin P et al. Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience. Int J Radiat Oncol Biol Phys 1989;17:449–456.[Medline]
6. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953;6:963–968.[CrossRef][Medline]
7. Huber MH, Hong WK. Biology and chemoprevention of head and neck cancer. Curr Probl Cancer 1994;18:81–140.[Medline]
8. Braakhuis BJ, Tabor MP, Kummer JA et al. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 2003;63:1727–1730.[Abstract/Free Full Text]
9. O’Shaughnessy JA, Kelloff GJ, Gordon GB et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 2002;8:314–346.[Abstract/Free Full Text]
10. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–1388.[Abstract/Free Full Text]
11. Thun MJ, Namboodiri MM, Heath CW Jr. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991;325:1593–1596.[Abstract]
12. Steinbach G, Lynch PM, Phillips RK et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342:1946–1952.[Abstract/Free Full Text]
13. Sudbo J, Kildal W, Risberg B et al. DNA content as a prognostic marker in patients with oral leukoplakia. N Engl J Med 2001;344:1270–1278.[Abstract/Free Full Text]
14. Schantz SP, Ostroff JS. Novel approaches to the prevention of head and neck cancer. Proc Soc Exp Biol Med 1997;216:275–282.[CrossRef][Medline]
15. Murr G, Kostelic F, Donkic-Pavicic I et al. [Comparison of the vitamin A blood serum level in patients with head-neck cancer and healthy persons.] HNO 1988;36:359–362. German.[Medline]
16. de Vries N, Snow GB. Relationships of vitamins A and E and beta-carotene serum levels to head and neck cancer patients with and without second primary tumors. Eur Arch Oto-Rhino-Laryngol 1990;247:368–370.[Medline]
17. Lotan R, Xu XC, Lippman SM et al. Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med 1995;332:1405–1410.[Abstract/Free Full Text]
18. Stich HF, Hornby AP, Mathew B et al. Response of oral leukoplakias to the administration of vitamin A. Cancer Lett 1988;40:93–101.[CrossRef][Medline]
19. van Zandwijk N, Dalesio O, Pastorino U et al. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 2000;92:977–986.[Abstract/Free Full Text]
20. Contreras Vidaurre EG, Bagan Sebastian JV, Gavalda C et al. Retinoids: application in premalignant lesions and oral cancer. Med Oral 2001;6:114–123.[Medline]
21. Smith MA, Parkinson DR, Cheson BD et al. Retinoids in cancer therapy. J Clin Oncol 1992;10:839–864.[Abstract/Free Full Text]
22. Koch HF. Biochemical treatment of precancerous oral lesions: the effectiveness of various analogues of retinoic acid. J Maxillofac Surg 1978;6:59–63.[CrossRef][Medline]
23. Schantz SP. Chemoprevention strategies: the relevance of premalignant and malignant lesions of the upper aerodigestive tract. J Cell Biochem Suppl 1993;17F:18–26.[Medline]
24. Hong WK, Endicott J, Itri LM et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986;315:1501–1505.[Abstract]
25. Lippman SM, Batsakis JG, Toth BB et al. Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med 1993;328:15–20.[Abstract/Free Full Text]
26. Chiesa F, Tradati N, Marazza M et al. Prevention of local relapses and new localisations of oral leukoplakias with the synthetic retinoid fenretinide (4-HPR). Preliminary results. Eur J Cancer B Oral Oncol 1992;28B:97–102.[Medline]
27. Chiesa F, Tradati N, Marazza M et al. Fenretinide (4-HPR) in chemoprevention of oral leukoplakia. J Cell Biochem Suppl 1993;17F:255–261.[Medline]
28. Gross EG, Helfgott MA. Retinoids and the eye. Dermatol Clin 1992;10:521–531.[Medline]
29. De Palo G, Veronesi U, Marubini E et al. Controlled clinical trials with fenretinide in breast cancer, basal cell carcinoma and oral leukoplakia. J Cell Biochem Suppl 1995;22:11–17.[Medline]
30. Hong WK, Lippman SM, Itri LM et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990;323:795–801.[Abstract]
31. Benner SE, Pajak TF, Lippman SM et al. Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: long-term follow-up. J Natl Cancer Inst 1994;86:140–141.[Free Full Text]
32. Bolla M, Lefur R, Ton Van J et al. Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study. Eur J Cancer 1994;30A:767–772.
33. Khuri FR, Kim ES, Lee JJ et al. The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial. Cancer Epidemiol Biomarkers Prev 2001;10:823–829.[Abstract/Free Full Text]
34. Khuri FR, Lee JJ, Lippman SM et al. Isotretinoin effects on head and neck cancer recurrence and second primary tumors. Proc Am Soc Clin Oncol 2003;22:359a.
35. Peto R, Doll R, Buckley JD et al. Can dietary beta-carotene materially reduce human cancer rates? Nature 1981;290:201–208.[CrossRef][Medline]
36. Suda D, Schwartz J, Shklar G. Inhibition of experimental oral carcinogenesis by topical beta carotene. Carcinogenesis 1986;7:711–715.[Abstract/Free Full Text]
37. Garewal HS, Meyskens FL Jr, Killen D et al. Response of oral leukoplakia to beta-carotene. J Clin Oncol 1990;8:1715–1720.[Abstract]
38. Toma S, Benso S, Albanese E et al. Treatment of oral leukoplakia with beta-carotene. Oncology 1992;49:77–81.[CrossRef][Medline]
39. Kaugars GE, Silverman S Jr, Lovas JG et al. A clinical trial of antioxidant supplements in the treatment of oral leukoplakia. Oral Surg Oral Med Oral Pathol 1994;78:462–468.[CrossRef][Medline]
40. Mayne ST, Cartmel B, Baum M et al. Randomized trial of supplemental beta-carotene to prevent second head and neck cancer. Cancer Res 2001;61:1457–1463.[Abstract/Free Full Text]
41. Hennekens CH, Buring JE, Manson JE et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145–1149.[Abstract/Free Full Text]
42. Omenn GS, Goodman GE, Thornquist MD et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150–1155.[Abstract/Free Full Text]
43. Knekt P, Aromaa A, Maatela J et al. Vitamin E and cancer prevention. Am J Clin Nutr 1991;53(suppl 1):283S–286S.[Abstract/Free Full Text]
44. Benner SE, Winn RJ, Lippman SM et al. Regression of oral leukoplakia with alpha-tocopherol: a community clinical oncology program chemoprevention study. J Natl Cancer Inst 1993;85:44–47.[Abstract/Free Full Text]
45. Goodwin WJ Jr, Lane HW, Bradford K et al. Selenium and glutathione peroxidase levels in patients with epidermoid carcinoma of the oral cavity and oropharynx. Cancer 1983;51:110–115.[CrossRef][Medline]
46. Kiremidjian-Schumacher L, Roy M. Effect of selenium on the immunocompetence of patients with head and neck cancer and on adoptive immunotherapy of early and established lesions. Biofactors 2001;14:161–168.[Medline]
47. Shin DM, Wang ZK, Feng C et al. Biochemopreventive combination (13-cis-retinoic acid, interferon-2a and -tocopherol) may have synergistic effects over single-agents or 2-drug combinations in vitro culture of squamous cell carcinoma of the head and neck cells. Proc Am Assoc Cancer Res 2002;43:311a.
48. Papadimitrakopoulou VA, Clayman GL, Shin DM et al. Biochemoprevention for dysplastic lesions of the upper aerodigestive tract. Arch Otolaryngol Head Neck Surg 1999;125:1083–1089.[Abstract/Free Full Text]
49. Shin DM, Mao L, Papadimitrakopoulou VM et al. Biochemopreventive therapy for patients with premalignant lesions of the head and neck and p53 gene expression. J Natl Cancer Inst 2000;92:69–73.[Free Full Text]
50. Shin DM, Khuri FR, Murphy B et al. Combined interferon-alfa, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial. J Clin Oncol 2001;19:3010–3017.[Abstract/Free Full Text]
51. Shin DM, Richards TJ, Seixas-Silva JA. Phase II trial of bioadjuvant therapy with interferon-alpha2a, 13-cis-retinoic acid, and alpha-tocopherol for locally advanced squamous cell carcinoma of the head and neck: long term follow-up. Proc Am Soc Clin Oncol 2003;22:1995a.
52. van der Riet P, Nawroz H, Hruban RH et al. Frequent loss of chromosome 9p21-22 early in head and neck cancer progression. Cancer Res 1994;54:1156–1158.[Abstract/Free Full Text]
53. Anderson JA, Irish JC, McLachlin CM et al. H-ras oncogene mutation and human papillomavirus infection in oral carcinomas. Arch Otolaryngol Head Neck Surg 1994;120:755–760.[Abstract/Free Full Text]
54. Oku N, Shimada K, Itoh H. Ha-ras oncogene product in human oral squamous cell carcinoma. Kobe J Med Sci 1989;35:277–286.[Medline]
55. Hahn SM, Bernhard EJ, Regine W et al. A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer. Clin Cancer Res 2002;8:1065–1072.[Abstract/Free Full Text]
56. Carpenter G. Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem 1987;56:881–914.[CrossRef][Medline]
57. Reiss M, Stash EB, Vellucci VF et al. Activation of the autocrine transforming growth factor alpha pathway in human squamous carcinoma cells. Cancer Res 1991;51:6254–6262. Erratum in: Cancer Res 1992;52:6137.[Abstract/Free Full Text]
58. Hofer DR, Sherwood ER, Bromberg WD et al. Autonomous growth of androgen-independent human prostatic carcinoma cells: role of transforming growth factor alpha. Cancer Res 1991;51:2780–2785.[Abstract/Free Full Text]
59. Neal DE, Marsh C, Bennett MK et al. Epidermal-growth-factor receptors in human bladder cancer: comparison of invasive and superficial tumours. Lancet 1985;1:366–368.[CrossRef][Medline]
60. Sainsbury JR, Malcolm AJ, Appleton DR et al. Presence of epidermal growth factor receptor as an indicator of poor prognosis in patients with breast cancer. J Clin Pathol 1985;38:1225–1228.[Abstract/Free Full Text]
61. Veale D, Ashcroft T, Marsh C et al. Epidermal growth factor receptors in non-small cell lung cancer. Br J Cancer 1987;55:513–516.[Medline]
62. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993;53:3579–3584.[Abstract/Free Full Text]
63. Grandis JR, Tweardy DJ, Melhem MF. Asynchronous modulation of transforming growth factor alpha and epidermal growth factor receptor protein expression in progression of premalignant lesions to head and neck squamous cell carcinoma. Clin Cancer Res 1998;4:13–20.[Abstract]
64. Shin DM, Ro JY, Hong WK et al. Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 1994;54:3153–3159.[Abstract/Free Full Text]
65. Ke LD, Adler-Storthz K, Clayman GL et al. Differential expression of epidermal growth factor receptor in human head and neck cancers. Head Neck 1998;20:320–327.[CrossRef][Medline]
66. Grandis JR, Melhem MF, Barnes EL et al. Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer 1996;78:1284–1292.[CrossRef][Medline]
67. Herbst RS, Maddox AM, Rothenberg ML et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 2002;20:3815–3825.[Abstract/Free Full Text]
68. Cohen EE, Rosen F, Stadler WM et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21:1980–1987.[Abstract/Free Full Text]
69. Inoue A, Saijo Y, Maemondo M et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003;361:137–139.[CrossRef][Medline]
70. Cohen E, Stenson K, Gustin DM et al. A phase II study of 250-mg gefitinib monotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 2003;22:502a.
71. Tominaga O, Hamelin R, Remvikos Y et al. p53 from basic research to clinical applications. Crit Rev Oncol 1992;3:257–282.
72. Shin DM, Lee JS, Lippman SM et al. p53 expressions: predicting recurrence and second primary tumors in head and neck squamous cell carcinoma. J Natl Cancer Inst 1996;88:519–529.[Abstract/Free Full Text]
73. Boyle JO, Hakim J, Koch W et al. The incidence of p53 mutations increases with progression of head and neck cancer. Cancer Res 1993;53:4477–4480.[Abstract/Free Full Text]
74. Cabelguenne A, Blons H, de Waziers I et al. p53 alterations predict tumor response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma: a prospective series. J Clin Oncol 2000;18:1465–1473.[Abstract/Free Full Text]
75. Rudin CM, Cohen EE, Papadimitrakopoulou VA et al. An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia. J Clin Oncol 2003;21:4546–4552.[Abstract/Free Full Text]
76. Lin DT, Subbaramaiah K, Shah JP et al. Cyclooxygenase-2: a novel molecular target for the prevention and treatment of head and neck cancer. Head Neck 2002;24:792–799.[CrossRef][Medline]
77. Masferrer JL, Leahy KM, Koki AT et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000;60:1306–1311.[Abstract/Free Full Text]
78. Mestre JR, Chan G, Zhang F et al. Inhibition of cyclooxygenase-2 expression. An approach to preventing head and neck cancer. Ann N Y Acad Sci 1999;889:62–71.[CrossRef][Medline]
79. Bresalier RS. Chemoprevention comes to clinical practice: COX-2 inhibition in familial adenomatous polyposis. Gastroenterology 2000;119:1797–1798.[CrossRef][Medline]
80. Reddy BS, Hirose Y, Lubet R et al. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res 2000;60:293–297.[Abstract/Free Full Text]
81. Reddy BS, Rao CV. Colon cancer: a role for cyclo-oxygenase-2-specific nonsteroidal anti-inflammatory drugs. Drugs Aging 2000;16:329–334.[CrossRef][Medline]
82. Davies G, Martin LA, Sacks N et al. Cyclooxygenase-2 (COX-2), aromatase and breast cancer: a possible role for COX-2 inhibitors in breast cancer chemoprevention. Ann Oncol 2002;13:669–678.[Abstract/Free Full Text]
83. Badawi AF, Badr MZ. Chemoprevention of breast cancer by targeting cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma (Review). Int J Oncol 2002;20:1109–1122.[Medline]
84. Hu KQ. Rationale and feasibility of chemoprevention of hepatocellular carcinoma by cyclooxygenase-2 inhibitors. J Lab Clin Med 2002;139:234–243.[CrossRef][Medline]
85. Patton SE, Hall MC, Ozen H. Bladder cancer. Curr Opin Oncol 2002;14:265–272.[CrossRef][Medline]
86. Wang Z, Fuentes CF, Shapshay SM. Antiangiogenic and chemopreventive activities of celecoxib in oral carcinoma cell. Laryngoscope 2002;112:839–843.[CrossRef][Medline]
87. Chen Z, Zhang X, Wang Z et al. A possible interaction between epidermal growth factor receptor and cyclooxygenase-2 mediated pathways in squamous cell carcinoma of the head and neck. Proc Am Assoc Cancer Res 2003;44:510a.
88. Shin DM, Wang ZQ, Zhang X et al. ZD1839, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), inhibits cell growth synergistically with a cyclooxygenase-2 (COX-2) inhibitor, celecoxib, in squamous cell carcinoma of the head and neck (SCCHN). Proc Am Assoc Cancer Res 2003;44:1084a.

This article has been cited by other articles:

				M. Sakaguchi, Y. Kuroda, and M. Hirose The antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor. Anesth. Analg., April 1, 2006; 102(4): 1103 - 1107. [Abstract] [Full Text] [PDF]

				J.-L. Lefebvre Current clinical outcomes demand new treatment options for SCCHN Ann. Onc., January 1, 2005; 16(suppl_6): vi7 - vi12. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rhee, J. C. Articles by Shin, D. M. Search for Related Content PubMed PubMed Citation Articles by Rhee, J. C. Articles by Shin, D. M.