Premalignancy and chemoprevention studies in head and neck cancer typically focus on the oral cavity. Avoiding or cessation of alcohol and smoking, early detection of potentially malignant disorders or cancer, and early detection of recurrent and/or second primary tumor form the basis of prevention of oral cancer. Analysis of tissue prospectively collected in evaluation of retinoids for chemoprevention trials allowed identification of molecular biomarkers of risk to develop oral cancer, loss of heterozygosity being the most validated one. Improving risk assessment and identification of new targets for chemoprevention represent the main challenges in this field.
| COX2 | Cyclooxygenase-2 |
| EGCG | Epigallocatevhin-3-gallate |
| EPOC | Erlotinib for Prevention of Oral Cancer |
| EUROSCAN | The European Study on Chemoprevention with Vitamin A and N-Acetylcysteine |
| GWAS | Genome-wide association studies |
| HNSCC | Head and neck squamous cell carcinoma |
| LOH | Loss of heterozygocity |
| NSND | Non-smoker non-drinker |
| OL | Oral leukoplakia |
| OSCC | Oral squamous cell carcinoma |
| PMDs | Potentially malignant disorders |
| SNPs | Single nucleotide polymorphisms |
| SPTs | Second primary tumors |
| TKI | Tyrosine kinase inhibitor |
Key points
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Premalignancy and chemoprevention studies in head and neck cancer typically focus on the oral cavity.
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Avoiding or cessation of alcohol and smoking, early detection of potentially malignant disorders (PMD) or cancer, and early detection of recurrent and/or second primary tumor form the basis of prevention of oral cancer.
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Oral leukoplakia represents the most frequent PMD.
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Clinical and pathologic parameters are poor predictors of oral cancer development.
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Despite disappointing results of extensive evaluation of retinoids for chemoprevention in the secondary or tertiary prevention setting, analysis of the tissue prospectively collected in those trials allowed identification of molecular biomarkers of risk to develop oral cancer, loss of heterozygosity being the most validated one.
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Improving risk assessment and identification of new targets for chemoprevention represent the main challenges in this field.
Introduction
Head and neck cancer is the fifth most common cancer worldwide. Males are more affected than females. The incidence is high in some regions of Europe, Hong Kong, India, and Brazil and among African Americans in the Unites States. In the United States, 52,000 Americans develop head and neck cancer annually and 11,500 die from the disease. Most premalignancy and chemoprevention studies have focused on head and neck squamous cell carcinoma (HNSCC) of the oral cavity. The primary risk factors associated with HNSCC cancer include tobacco use and alcohol consumption, with a dose-response relationship and synergistic effect. Betel nut chewing in Asia is an independent risk factor. A subgroup of nonsmoker-nondrinker (NSND) patients has been identified: (1) young to middle-aged men with oropharyngeal cancer associated with human papilloma virus infection, and (2) young women with oral tongue cancer, or elderly women with gingival/buccal cancer with no clear etiologic factor.
Field cancerization and multistep carcinogenesis form the biologic basis of chemoprevention. The concept of field cancerization refers to the effects of chronic exposure to tobacco and alcohol in patients with or without cancer, with progressive onset of molecular alterations in initially histologically and clinically normal epithelia. It is supported by the identification of similar genetic alterations in matched dysplastic and malignant lesions from the oral cavity. The lateral migration of genetically altered cells through the oral mucosa can form multiple lesions, a phenomenon called clonal cancerization. In other cases, genetic alterations found in dysplastic lesions were not found in matched cancer, providing some evidence that multifocal disease can arise from the development of several genetically altered clones from different initiating events. Finally, the frequent development of synchronous or metachronous second or multiple primaries in the head and neck and/or the lung also supports the concept of field cancerization. The use of molecular markers, such as DNA methylation of individual genes or global gene expression changes, has validated the concept of field cancerization.
Califano and colleagues proposed a “Vogelgram” for HNSCC, which linked histologic changes to specific molecular alterations. They proposed that the accumulation of genetic events drives the transformation of squamous mucosa of the head and neck. Histologically, changes occur from normal to hyperkeratosis; hyperplasia; mild, moderate, and severe dysplasia; and carcinoma in situ before becoming invasive carcinoma. Molecular alterations in epithelial cells precede histologic changes. Clinically, the mucosa may appear normal, or appear grossly abnormal with the findings of leukoplakia, erythroplakia, leukoerythroplakia, or lichen planus. Lesions appearing with these characteristics or submucous fibrosis, palatal lesions in reverse smokers, or other less common findings are referred to as potentially malignant disorders (PMDs).
Introduction
Head and neck cancer is the fifth most common cancer worldwide. Males are more affected than females. The incidence is high in some regions of Europe, Hong Kong, India, and Brazil and among African Americans in the Unites States. In the United States, 52,000 Americans develop head and neck cancer annually and 11,500 die from the disease. Most premalignancy and chemoprevention studies have focused on head and neck squamous cell carcinoma (HNSCC) of the oral cavity. The primary risk factors associated with HNSCC cancer include tobacco use and alcohol consumption, with a dose-response relationship and synergistic effect. Betel nut chewing in Asia is an independent risk factor. A subgroup of nonsmoker-nondrinker (NSND) patients has been identified: (1) young to middle-aged men with oropharyngeal cancer associated with human papilloma virus infection, and (2) young women with oral tongue cancer, or elderly women with gingival/buccal cancer with no clear etiologic factor.
Field cancerization and multistep carcinogenesis form the biologic basis of chemoprevention. The concept of field cancerization refers to the effects of chronic exposure to tobacco and alcohol in patients with or without cancer, with progressive onset of molecular alterations in initially histologically and clinically normal epithelia. It is supported by the identification of similar genetic alterations in matched dysplastic and malignant lesions from the oral cavity. The lateral migration of genetically altered cells through the oral mucosa can form multiple lesions, a phenomenon called clonal cancerization. In other cases, genetic alterations found in dysplastic lesions were not found in matched cancer, providing some evidence that multifocal disease can arise from the development of several genetically altered clones from different initiating events. Finally, the frequent development of synchronous or metachronous second or multiple primaries in the head and neck and/or the lung also supports the concept of field cancerization. The use of molecular markers, such as DNA methylation of individual genes or global gene expression changes, has validated the concept of field cancerization.
Califano and colleagues proposed a “Vogelgram” for HNSCC, which linked histologic changes to specific molecular alterations. They proposed that the accumulation of genetic events drives the transformation of squamous mucosa of the head and neck. Histologically, changes occur from normal to hyperkeratosis; hyperplasia; mild, moderate, and severe dysplasia; and carcinoma in situ before becoming invasive carcinoma. Molecular alterations in epithelial cells precede histologic changes. Clinically, the mucosa may appear normal, or appear grossly abnormal with the findings of leukoplakia, erythroplakia, leukoerythroplakia, or lichen planus. Lesions appearing with these characteristics or submucous fibrosis, palatal lesions in reverse smokers, or other less common findings are referred to as potentially malignant disorders (PMDs).
Primary, secondary, and tertiary prevention for oral squamous cell carcinoma
Primary prevention of HNSCC refers to the prevention of cancer by avoiding known carcinogens ( Table 1 ). Secondary cancer prevention includes early detection of cancer through screening programs in a population at risk and asymptomatic, as well as prevention of the transformation of PMDs. Tertiary cancer prevention refers to the prevention and early detection of second primary tumors (SPTs) in individuals who have been treated for cancer. Individuals with tobacco and/or smoking history and normal-appearing mucosa, patients with PMDs, and patients who have been treated for HNSCC and at risk for recurrent disease and SPT have increasing risks of developing HNSCC.
| Definition | |
|---|---|
| Primary prevention | Avoiding known carcinogens |
| Secondary prevention | Early detection of cancer Prevention of the transformation of potentially malignant disorders |
| Tertiary prevention | Prevention of second primary tumors or recurrence Early detection of second primary tumors or recurrence |
Primary Cancer Prevention
Quitting tobacco smoking and alcohol reduces the risk of developing HNSCC. It has been reported that the benefit of smoking cessation is great and can be realized in a relatively short period of time. For example, those who have stopped smoking for 1 to 4 years have a 30% lower risk for developing HNSCC than those who continue smoking. The risk of HNSCC decreases to that of never smokers for those who have quit smoking for 20 years or more. Cessation of alcohol is also associated with a reversal of HNSCC risk after quitting for 20 years or more.
Secondary Cancer Prevention
Diagnostic delay is a recognized challenge in the population of patients diagnosed with oral squamous cell carcinoma (OSCC) and includes patient delay, limited accessibility to the health care system, and health care provider delay. Diagnostic delay has been shown as a risk factor for tumor growth. Diagnostic delays have been associated with decreased survival in some recent studies. Therefore, increased public awareness of early symptoms of PMDs, as well as education of health care providers about these lesions should improve early detection, increase cure rates, and decrease treatment-related morbidity.
Screening for OSCC
Recommendations regarding screening for OSCC have been recently published. Screening by means of examination can detect PMDs and malignant lesions ; however, clinical features alone cannot reliably distinguish between malignant and benign or premalignant lesions and the clinician cannot always accurately predict the risk of malignant transformation on the basis of routine biopsy. Only one randomized clinical trial has evaluated the effect of screening by means of visual and tactile examination on oral cancer mortality in India.
Between 1996 and 2004, of the 96,517 eligible participants in the intervention group, 87,655 (91%) were screened at least once, 53,312 (55%) were screened twice, and 29,102 (30%) were screened 3 times. Of the 5145 individuals who screened positive, 3218 (63%) complied only with referral; 95,356 eligible participants in the control group received standard care. The mortality rate was not significantly different in the intervention group compared with the control group when considering the overall population. Interestingly, men who used tobacco and/or alcohol who underwent screening had a significant mortality rate decrease (hazard ratio 0.57, 95% confidence interval [CI]: 0.35–0.93). This suggests that visual and tactile examination in a high-risk population may improve survival; however, this observation came from a subgroup analysis and needs further validation in a prospective study. Also, the applicability of these findings in Western countries remains to be demonstrated.
Commercially available visualization devices based on tissue reflectance (ViziLite and ViziLite Plus Aila Inc, Colins, CO) and autofluorescence (VELscope, DenMat Holdings LLC, Santa Maria, CA) have been evaluated but there is insufficient evidence that they improve the detection of PMDs beyond that of a conventional visual and tactile examination, and their use can be associated with an increased risk of false-positive findings. In patients with clinically suspicious lesions, the Oral CDx Brush Test (CDx Diagnostics, Suffern, NY) can detect transepithelial cytology of disaggregated cells; however, in these cases, immediate biopsy is indicated, which makes the relevance of this test questionable. The American Dental Association Council on Scientific Affairs recommends that clinicians remain alert for signs of potential malignancy when performing a routine visual and tactile examination in dental patients, especially those with a history of smoking and heavy alcohol use. The expert review panel also recommended that further research is needed to develop reliable, cost-effective screening tests.
Tertiary Prevention
Regular posttreatment follow-up is highly recommended in patients after curative treatment of HNSCC by the National Comprehensive Cancer Network in order to detect the following:
- 1.
Recurrence
- 2.
A second primary cancer in the head and neck or lung
- 3.
Complications of treatment
Another major goal should also include smoking and alcohol cessation. In patients with a smoking history of 20 pack-years or more, the use of low-dose helical computed tomography scanning of the lung can be discussed for screening of a second primary tumor in the lung.
Natural history and treatment of oral leukoplakia, the most frequent premalignancy disease
Oral leukoplakia (OL) is clinically defined as a white patch or plaque on the oral mucosa that cannot be removed by scraping and cannot be classified clinically or microscopically as another disease entity. It encompasses a wide variety of histologic findings from hyperkeratosis to hyperplasia and various grades of dysplasia. Three classifications have been proposed to describe the degree of dysplasia. To increase the likelihood of agreement between pathologists, a 2-class classification has been recently proposed that will need to be evaluated prospectively :
- 1.
No/questionable/mild: low risk
- 2.
Moderate/severe: high risk
Liu and colleagues studied the usefulness of the binary system of grading dysplasia by reviewing retrospectively 218 Chinese cases of OL with a median follow-up period of 5.3 years. High-risk OL had a hazard ratio of 4.6 (95% CI: 2.36–8.84) to develop OSCC and was an independent risk factor of transformation. The risk was particularly high during the first 2 to 3 years of follow-up.
The natural history of OL remains poorly understood. OL can remain for many years without changing, can regress spontaneously or after cessation of tobacco or alcohol use, and can transform to invasive SCC. The reported rate of malignant transformation has been low in community-based studies in developing countries (0.06% per year) and higher in observational studies in Western countries involving patients followed in hospital-based academic centers (1%–5% per year). Most the studies in the United States found a rate of malignant transformation between 17% and 24% during periods of up to 30 years.
No consensus is available for the treatment of OL. Various surgical techniques, including scalpel excision, cryosurgery, and laser surgery, have been reported; however, no prospective studies are available to compare the efficacy and morbidities of treatments, or to test whether excision versus observation decreases the risk of recurrence or the risk of malignant transformation. Kuribayashi and colleagues reported an OL recurrence rate of 15.1% with 2.0% of the patients developing OSCC after scalpel excision. Recurrence occurs more often in patients with positive or close resection margins, and in patients with gingival leukoplakia. When a complete excision of OL is not feasible, cryosurgery is an option. Laser obliteration has been proposed as an alternative to scalpel excision of premalignant lesions. The duration of the interval that the lesion has been present and the size of the lesion are 2 additional factors associated with recurrence and transformation. Recurrence and malignant transformation rates of 29.3% and 1.2%, respectively, have been reported after laser surgery. Laser treatment provides good hemostasis, preservation of oral function, satisfactory wound healing, and can be done repeatedly under local anesthesia, but is associated with delayed epithelial healing. It is important to note that the main disadvantage of cryosurgery and laser surgery is that obliteration of the lesion by these means precludes histologic evaluation of the entire specimen as opposed to a true excision. Therefore, in the case of laser obliteration, the pretreatment biopsy provides only a representative sample of the entire lesion.
The main challenge of surgical excision remains the multifocal nature of “field cancerization” and the notion that normal-appearing mucosa may also have the potential for malignant transformation. To reduce the rate of margins positive for dysplasia and the risk of recurrence and malignant transformation, the use of vital tissue staining is suggested by some investigators. In patients with multiple malignant and premalignant lesions, the use of photodynamic therapy has also been proposed. Grant and colleagues pioneered the method in a small series of patients. In a large series of patients with oral dysplasia from the United Kingdom, a complete response was observed in 81.0% of patients, a partial response or stable disease was observed in 8.0% and 3.4% of patients, respectively, and malignant transformation was observed in 7.5%, with a mean follow-up of 7.3 years. Zhang and colleagues suggested the use of biomarkers (loss of heterozygosity [LOH]) to guide surgical resection of low-grade dysplasia and reduce the risk of transformation, and some investigators propose an association of resection and chemoprevention.
Several studies have shown tobacco cessation was associated with decreased incidence and resolution of OLs. Although it is tempting to believe that alcohol and/or tobacco cessation is associated with a decreased risk of malignant transformation, no evidence is available. Patient follow-up strategies are discussed elsewhere but have not been prospectively evaluated. A clinician survey has indicated follow-up regimens of 6 monthly for lesions without dysplasia, 3 monthly for mild/moderate dysplasia, and monthly for severe dysplasia/carcinoma in situ. The degree of dysplasia and the anatomic site were the 2 factors influencing the follow-up schema.
Clinical, pathologic, and molecular markers for risk assessment
Most of the work in predictive biomarkers has been done in patients with PMDs of the oral cavity, the most frequent being OL ( Table 2 ). Clinical factors associated with malignant transformation of OL are the following :
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Female gender
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Long duration of leukoplakia
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Patient age
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Never smokers
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Size greater than 200 mm 2
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Nonhomogeneous type
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Location on the lateral and ventral tongue, floor of mouth, and retromolar trigone and soft palate sites
| Clinical | Pathologic | Biomarkers |
|---|---|---|
| Female gender Long duration of leukoplakia Older patients Never smokers Size >200 mm 2 Nonhomogeneous type Lateral and ventral tongue Floor of mouth, and retromolar/soft palate sites | Degree of dysplasia | LOH Chromosomal instability or aneuploidy DeltaNp63 expression Podoplanin EGFR expression and gene copy number Gene expression profiles Constitutional genetic variations |
However, the presence of dysplasia is often the criterion that influences clinical management of OLs. The challenges are that OL without dysplasia may still progress to cancer, that a high interobserver- and intraobserver discordance rate has been reported in the evaluation of dysplasia, that the degree of dysplasia has not always been associated with increased cancer risk, and that OL may be reversible even when dysplasia is identified, irrespective of environmental factors.
Inconsistencies in the value of clinical and pathologic factors to predict the risk of malignant transformation of OL led to the development of biomarkers. However there have been several challenges to biomarker development, including the low prevalence of OL in Western countries, the fact that many lesions are not biopsied, and the rate of malignant transformation per year is generally low, which requires long follow-up periods to be able to derive any conclusion. Chemoprevention studies with retinoids allowed unique prospective collections of biospecimens that led to biomarker development.
Biomarkers: LOH
The most robust and validated biomarkers were described in LOH studies performed by Mao and colleagues in 1996. OL harboring LOH at 3p14 and/or 9p21 were associated with a risk of developing invasive cancer in 37%, compared with only 6% in lesions without LOH at 3p14 and/or 9p21. These findings were subsequently validated by larger retrospective studies from 2 independent groups. OLs at former cancer sites with LOH at 3p and/or 9p were associated with a higher risk of development of invasive cancer (72% at 5 years) compared with leukoplakias without LOH (6% at 5 years).
The presence of LOH at the histologically negative margins of resection in patients with surgically treated HNSCC was a marker of risk of recurrence. Lee and colleagues have shown that the most predictive factors of risk of cancer are the following:
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Degree of dysplasia
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Previous cancer history
- •
Three of the 5 biomarkers assessed:
- 1.
Chromosomal polysomy
- 2.
p53 protein expression
- 3.
LOH at 3p or 9p
- 1.
A recent study prospectively validated LOH profiles as risk predictors of progression in a prospective cohort of 296 patients with primary mild/moderate oral dysplasia. High-risk lesions (3p and/or 9p LOH) had a 22.6-fold increase in risk compared with low-risk lesions (3p and/or 9p retention). Addition of another 2 markers (loci on 4q/17p) further improved risk prediction, with 5-year progression rates of 3.1%, 16.3%, and 63.1% for the low-risk, intermediate-risk, and high-risk lesions, respectively.
Biomarkers Beyond LOH
TP63 is involved in the stem cell biology of stratified squamous epithelium, and is a marker of SCC commonly used in clinical practice; the deltaNp63 isoform has oncogenic properties. Podoplanin was shown to promote invasion in different cancer types, and was shown to be associated with poor prognosis in OSCC. We reported that overexpression of podoplanin and deltaNp63 were prevalent in OL and associated with a higher risk to develop OSCC. We also reported increased epidermal growth factor receptor ( EGFR ) gene copy number in 41% of OLs, and showed a strong association with the risk of developing OSCC in patients with OLs overexpressing EGFR. In the same cohort of patients, we showed that the vast majority of the genes associated with a high risk or low risk to develop OSCC are upregulated or downregulated in HNSCC versus normal mucosa, respectively. A 25-gene signature improved our prediction of OSCC development over clinical and pathologic biomarkers, including the degree of dysplasia and the expression of deltaNp63 and podoplanin. Validation of those biomarkers in other cohorts of patients is pending. Other markers, such as DNA content and DNA instability, have shown some potential for risk assessment as well, and are reviewed elsewhere.
Molecular Epidemiology: Genetic Polymorphisms
Molecular epidemiologic studies have identified genetic polymorphisms associated with the risk of HNSCC. Most of studied genes are related to single nucleotide polymorphisms (SNPs) in genes involved in cell cycle control and alcohol and more general metabolism. Recent genome-wide association studies (GWAS) have identified variants in the nicotinic acetylcholine receptor associated with nicotine dependence and lung cancer risk. Interestingly, one variant was shown to be associated with the risk of HNSCC and esophagus cancer in women but not in men. This finding was replicated in the International Head and Neck Cancer Epidemiology (INHANCE) consortium cohorts. A particular situation is Fanconi anemia, which represents a population at higher risk of developing HNSCC in the absence of other risk factors. Wu and colleagues identified 6 chromosomal SNPs and 7 mitochondrial SNPs significantly associated with risk of SPT/recurrence from a panel of 9645 SNPs representing 998 cancer-related genes with risk of SPT/recurrence. These studies underscore the potential of incorporating germ-line genetic variation data with clinical and risk factor data in constructing prediction models for clinical outcomes, but will require further validation in independent cohort of patients.
Chemoprevention: rationale and results
Chemoprevention refers to the use of natural or synthetic products to arrest or reverse the process of malignant transformation. The rationale that led to the development of chemoprevention is the failure of conventional therapies, including surgery, radiation, and chemotherapy, to prevent recurrence in a significant number of patients, and the risk of SPT. Systemic administration of chemopreventive agents aims to address the challenge associated with the field cancerization. Different classes of agents have been evaluated so far, including natural products that may act through various mechanisms (green tea), and more targeted agents, such as retinoid receptors ligands, selective cyclooxygenase inhibitors, p53-targeted agents, peroxisome activator receptor gamma (PPARγ) agonists, and EGFR inhibitors.
Retinoids
Retinoids are naturally occurring and synthetic vitamin A (retinol) metabolites and analogues that bind to retinoid receptors of the RAR and RXR types, and promote cell differentiation and decrease proliferation and apoptosis. The loss of nuclear RARβ has been described as an early event observed in premalignant dysplastic lesions, which suggested that targeting the retinoid signaling pathway could have merit as a chemopreventive strategy. This led to the extensive evaluation of retinoids in chemoprevention that helped to prove the principle of chemoprevention of oral cancer. However, the toxicity of the retinoids and the rapid reversal of their beneficial effects after stopping these agents prevented them from being considered as a standard of care. However, significant advances in cancer risk assessment were achieved from correlative studies of clinical specimens obtained through these efforts.
Retinoids for OL (Secondary Prevention)
Limitations of most of the studies of retinoids for OL is that the primary end point focused on OL clinical and/or histologic response, which only marginally correlates with long-term oral cancer-free survival, and molecular abnormalities may still persist despite disappearance of the lesion with the chemopreventive agent.
In 1986, Hong and colleagues reported the first double-blind, placebo-controlled trial of high-dose 13-cis retinoic acid (13cRA) (1–2 mg/kg per day for 3 months) in this setting. The clinical response rate and rate of histologic improvement were 67% and 54%, respectively, in the retinoid arm and 10% in the placebo arm. However, mucocutaneous adverse events and hypertriglyceridemia were frequent and severe, requiring dose reductions in half of patients, and more than half of the patients experienced a relapse within 3 months of treatment cessation.
Lippman and colleagues conducted a phase IIb maintenance trial following induction retinoid therapy. In this study, patients with OL were treated with 13cRA 1.5 mg/kg per day for 3 months (induction phase), followed by either low-dose 13cRA (0.5 mg/kg per day) or beta-carotene for 9 months in individuals not experiencing progression of the lesion (maintenance phase). Consistent with the previous trials, 55% and 43% of the patients had a clinical and pathologic response, respectively, to the induction therapy. After the maintenance phase, further clinical response was observed. Severity of adverse events was lower during the maintenance phase, with a more favorable toxicity profile in the beta-carotene arm. However, on long-term follow-up, the incidence of in situ or invasive carcinoma was not different between the 13cRA and beta-carotene groups.
The follow-up trial consisted of 13cRA (0.5 mg/kg per day for 1 year followed by 0.25 mg/kg per day orally for 2 years) versus vitamin A (retinyl palmitate 25,000 IU per day) plus beta-carotene (50 mg per day) for 3 years. During the conduct of the study, data became available with regards to the increased lung cancer incidence and mortality associated with beta-carotene in other ongoing chemoprevention studies. As a result, the experimental arm was modified to vitamin A single agent. Vitamin A single agent was associated with a lower 3-month clinical response rate (20%) compared with beta-carotene plus vitamin A (32.5%) and 13cRA (48.1%). The 5-year oral cancer-free survival was similar across the treatment groups (78%–84%), and clinical response at 3 months was only marginally correlated with long-term oral cancer-free survival. This was one of the largest and longest-term studies in OL ever conducted, and it brought into question whether the use of clinical response is a valid end point in trials of PMD oral premalignant lesions. Prevention of OSCC development has been recently considered as a more meaningful end point than clinical or histologic response of the oral premalignant lesions.
Fenretinide is a synthetic retinoid with a more favorable toxicity profile. In a randomized study including 170 patients with resected oral premalignant lesions, Chiesa and colleagues demonstrated that, compared with observation, treatment with fenretinide for 12 months was associated with a significant reduction in the risk of relapse 19 months after randomization. The drug was well tolerated. Unfortunately, the trial had to be stopped prematurely because of slow accrual.
Retinoids to Prevent SPTs (Tertiary Prevention)
In 1990, Hong and colleagues reported the results of a randomized trial of 13cRA (50–100 mg/m 2 per day) versus placebo for 12 months in patients with stage I to IV HNSCC who completed definitive therapy showing a lower incidence of SPT compared with placebo. Unfortunately, a large, multicenter, phase III, placebo-controlled trial of 13cRA for 3 years that enrolled 1190 patients with stage I or II HNSCC who completed definitive treatment failed to confirm the results originally reported by Khuri and colleagues. Subsequent analysis of SNPs in the RXRA gene in 450 patients from this trial revealed that more than 70% of patients had the rs3118570 allele and this SNP was associated a 3.33-fold increased risk of developing a second primary. Interestingly, this locus also identified individuals who received benefit from chemoprevention with a significant 38% reduced risk (95% CI, 0.43–0.90), suggesting that a pharmacogenetic approach could help select patients for 13-cRA chemoprevention.
The European Study on Chemoprevention with Vitamin A and N-Acetylcysteine (EUROSCAN) randomized 2592 patients with treated lung (40%) or head and neck (60%) malignancies to receive no intervention, retinyl palmitate, N-acetylcysteine, or both in a 2 × 2 factorial design. Unfortunately, the EUROSCAN failed to show a benefit from either N-acetylcysteine or retinyl palmitate in terms of survival, event-free survival, or second primary tumor rates. Bairati and colleagues randomized 540 patients with stage I or II HNSCC treated with radiation therapy to receive alpha-tocopherol plus beta-carotene versus placebo for 3 years. After enrollment of 156 patients, beta-carotene supplementation was discontinued, given the increased risk of lung cancers observed in other ongoing chemoprevention studies. The remaining patients received alpha-tocopherol or placebo. After a median follow-up of 52 months, there was a higher rate of SPTs during the alpha-tocopherol supplementation period, but a lower rate after supplementation was discontinued. After 8 years of follow-up, the proportion of patients free of SPTs was similar between the groups.
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