|Year : 2016 | Volume
| Issue : 1 | Page : 4-11
Chemoprevention in head and neck cancer
Joydeep Ghosh, Anant Ramamswamy, Vijay Patil, Amit Joshi, Vanita Noronha, Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||23-May-2016|
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Head and neck cancer comprises of a large section of our malignancies. The locations of the organs allows us to have an early diagnosis, and consequently, early treatment. However, even with the best possible treatment, the outcomes are quite dismal in many cases. So , newer strategies targeting prevention of the development of head and neck cancers are required. Epidemiological studies have given us a fair idea about the role of environmental factors as well as many precancerous lesions that predate the development of invasive cancers. There has been multiple efforts the decipher the pathways leading to the evolution of normal tissue to premalignant lesions to invasive carcinomas. Also, there have been many attempts to halt the process at various stages to prevent the development of the final step. This review focuses on the risk factors in brief, the pathways as well as biomarkers, and the agents that have been tested for prevention of head and neck malignancies.
Keywords: Chemoprevention, head and neck cancer, retinoic acid
|How to cite this article:|
Ghosh J, Ramamswamy A, Patil V, Joshi A, Noronha V, Prabhash K. Chemoprevention in head and neck cancer. J Head Neck Physicians Surg 2016;4:4-11
|How to cite this URL:|
Ghosh J, Ramamswamy A, Patil V, Joshi A, Noronha V, Prabhash K. Chemoprevention in head and neck cancer. J Head Neck Physicians Surg [serial online] 2016 [cited 2019 May 22];4:4-11. Available from: http://www.jhnps.org/text.asp?2016/4/1/4/182855
| Introduction|| |
Malignancies of the head and neck region are one of the most common malignancies in our country. It is the most common cancer of males in India and the fifth most common in females. They account for a significant amount of morbidity, treatment-related complications as well as mortality. In India, the age-adjusted rates among females are the highest. The majority of the malignancies in head and neck are squamous cell carcinomas (HNSCCs), which comprises of almost 90% of the tumors. Moreover, a significant number of these SCC are actually preceded by some premalignant lesions in the oral cavity, most commonly being leukoplakia. There have been many advances in the field of cancer chemoprevention, and most of the targets have been to reduce the incidence of premalignant lesions. However, many of these trials did have an impact on the incidence of premalignant lesions, hardly any of them had any clinically significant impact on the incidence or mortality of invasive cancers. Many scientists have also tried to target molecular pathways, but none of them yielded a clinically meaningful outcome. In this review, we discuss the various aspects of chemoprevention, the controversies as well as the recent updates.
| Risk Factors for Head and Neck Cancers|| |
Of the multitude of risk factors, the earliest and the most significant one has been smoking. Tobacco, in its various forms, has always been associated with increased incidence of SCC. A study showed that smoking increases the risk of HNSCC by 5–25 times. A population-based analysis by showed that the relative risk of current tobacco users in 6.5. Evidence also comes from a case-controlled study, which shows that patients who smoked more than one pack of cigarettes per day had a 13-fold increase in the risk of head and neck cancer. As far as HNSCC is specifically concerned, especially oral cancers, the role of smokeless tobacco is significant. Initially, there was a concern regarding the role of passive smoking, which has been shown to be a risk factor for women in a study by Tan et al. Second after smoking comes alcohol, which is another important risk factor. The relative risk for alcohol is dose-dependent. One study reported a five to six-fold increased risk for head and neck cancer with alcohol intake >50 g/day versus <10 g/day. Alcohol intake and tobacco smoking appear to have an interactive and multiplicative effect. Viruses have been found to contribute to the pathogenesis of many premalignant conditions as well as invasive cancers. Most notable among them are human papillomavirus (HPV). The most common serotype pf HPV is the p16 variant. It is usually associated with oral cancers like those involving the tonsillar fossa. The patients are usually nonsmoker young males, who otherwise do not have usual risk factors. They also are a risk factor for nasopharyngeal cancers. Epstein-Barr virus (EBV) has been associated with nasopharyngeal cancers. They express Epstein-Barr nuclear antigen, latent membrane protein1 and 2 which mediate the oncogenesis. Some studies have shown that there is a decline in the serological levels of EBV with effective treatment, although its prognostic relevance is yet to be determined. HIV has also been shown to increase the chances of HNSCC by 2–3 folds. The association with herpes simplex virus (HSV) is less strongly correlated. HSV-encoded peptide that increases mutagenicity of infected cells. A study found out that the serum antibody levels against HSV were significantly higher in patient compared to healthy controls. Another common behavior that can predispose to oral cancers is betel nut chewing. The effect of betel nut seems to be synergistic with tobacco and alcohol. Prior irradiation for either malignant or benign disease has been linked to thyroid cancer, salivary gland tumors, squamous cell cancers, and sarcomas, however, the overall risk is low. Genetic factors have also being studied in the pathogenesis, metabolic polymorphisms that influence the exposure to the carcinogens in tobacco smoke, DNA repair gene polymorphisms, as well as variations in other pathways, contribute to carcinogenesis. Moreover, Fanconi's anemia has been shown to increase the risk.
| Carcinogenesis|| |
It is high complex molecular disarray that involves multiple steps and multiple pathways. The use of several molecular biology techniques to diagnose oral precancerous lesions and cancer may markedly improve the early detection of alterations that are invisible under the microscope. This would identify patients at a high risk of developing oral cancer. The various approaches to identify the oral cancer pathogenesis are microarray technology, methylation microarrays, gene expression microarrays, array comparative genomic hybridization, proteomics, mitochondrial arrays, and micro-RNA arrays. High-throughput approaches are currently being used to search for oral cancer biomarkers in biofluids, such as saliva and serum.
Field cancerization is an important concept to understand the pathogenesis of head and neck cancers. This concept is also applicable for urothelial malignancy. The whole of the epithelium undergoes various mutations and molecular changes that ultimately lead to the development of invasive cancer. This is the reason of finding the second primary in the same epithelial site very commonly. It may also be defined by the expression of mutations in the exons of tumor suppressor genes. One such tumor suppressor gene is p53, and mutations of this gene have been observed in various sites of premalignant leukoplakia and carcinoma in the same oral cavity. A reduction in tumor suppressor activity by the gene and the development of mutations in p53 are associated with smoking and an increased risk for oral carcinoma development. The continual presence of mutations may also signify changes in DNA repair and apoptosis, thereby increasing the susceptibility to future transformation. Mutational adaptations that modify the survivability of particular clones of transforming cells may also further enhance the level of resistance to therapeutic control. Studies have shown that cancers arising at a different site have the same molecular clone.
| Biomarkers|| |
Biomarkers help in evaluating the preventive measures or therapies and the detection of the earliest stages of oral mucosal malignant transformation. Biomarkers reveal the genetic and molecular changes related to early, intermediate, and late end-points in the process of oral carcinogenesis. These biomarkers will refine the ability to enhance the prognosis, diagnosis, and treatment of oral carcinomas. The efficacy of genetic and molecular markers will determine the safety and efficacy of chemoprevention agents. Chemopreventive agents reduce the incidence of the premalignant disease before the signs symptoms appear. Biomarkers will also reduce the number of patients and the time for long-term follow-up required to define a significant clinical response to a chemopreventive agent., However, the use of biomarkers is yet to have its effect on clinical practice, as majority of them are not yet validated in large prospective trials. Till now, the markers that have been found to have some relationship to the pathogenesis are as follows [Table 1]:
| Chemoprevention|| |
Retinoids induce apoptosis, suppress carcinogenesis, decrease the growth rate of epithelial cells, and reduce free radicals., It is one of the most commonly studied agents for chemoprevention in HN cancers across the globe.,, In a study, 44 patients were randomly assigned to receive 13-cis-retinoic acid (13-cRA) (24 patients) or placebo, 1–2 mg/kg of body weight per day for 3 months, and followed them for 6 months. There were major decreases in the size of the lesions of those given the drug and of those given placebo (P = 0.0002); dysplasia was reversed in 54 percent of the drug group and in 10% of the placebo group (P = 0.01). The clinical response to the drug correlated with the histologic response in 56% (9 of 16) of the patients evaluated. Relapse occurred in 9 of 16 patients 2–3 months after treatment ended. They concluded that 13-cRA, even in short-term use, appears to be an effective treatment for oral leukoplakia and has an acceptable level of toxicity. Toxicity was a major issue for such high dose used in the previous trial. Hence, there was a randomized trial that had two phases. In the first phase, patients were given high-dose retinoids and assessed for response. Those who responded, they were randomized to maintenance therapy with either beta-carotene (30 mg/day) or a low dose of isotretinoin (0.5 mg/kg/day) for 9 months. A total of 55% patients responded. Of the 53 patients who could be evaluated, 22 in the low-dose isotretinoin group and 13 in the beta carotene group responded to maintenance therapy or continued to have stable lesions (92% vs. 45%, P < 0.001). In situ carcinoma developed in one patient in each group, and invasive SCC in five patients in the beta carotene group. Toxicity was generally mild, though greater in the group given low-dose isotretinoin therapy. Hence, it was concluded that when preceded by high-dose induction therapy, low-dose isotretinoin therapy was significantly more active against leukoplakia than beta carotene and was easily tolerated. In another study by Koch, 75 cases with homogeneous leukoplakia without or with minimal epithelial dysplasia were included. They tested different derivatives of retinoic acid. Over 60% of the cases treated showed positive early results. In follow-ups from 1 to 6 years, about 45% of cases showed complete or partial remission. The rest showed relapses or even progression. In cases with recurrence without changes in the morphological characteristics, positive effects were achieved with 1–4 repeated courses of therapy. Analysis of the efficacy of derivatives suggested that aromatic retinoid seems to have the best curative potential in homogenic leukoplakia. A study by Chiesa et al. concluded that 4-HPR is well-tolerated and appears to be effective in preventing relapses and new localizations during the treatment period.
Second primary tumor prevention trials
Research has also focused on the role of retinoic acid in the secondary chemoprevention after curative treatment of head and neck cancers. The first study was done by Hong et al., where 103 pts after curative treatment and disease-free status was included in the study. These patients were randomly assigned to receive either isotretinoin (13-cRA) (50-100 mg per square meter of body-surface area per day) or placebo, to be taken daily for 12 months. There were no significant differences between the two groups in the number of local, regional, or distant recurrences of the primary cancers. However, the isotretinoin group had significantly fewer second primary tumors (SPTs). After a median follow-up of 32 months, only two patients (4%) in the isotretinoin group had SPTs, as compared with 12 (24%) in the placebo group (P = 0.005). Multiple SPTs occurred in four patients, all of whom were in the placebo group. Of the 14 s cancers, 13 (93%) occurred in the head and neck, esophagus, or lung. Hence, they concluded that daily treatment with high doses of isotretinoin is effective in preventing SPTs in patients who have been treated for SCC of the head and neck, although it does not prevent recurrences of the original tumor. With longer follow-up, the retinoid-treated patients have continued to develop fewer SPTs 7 (14%) in the isotretinoin group, compared with 16 (31%) in the placebo group. These results suggest that the beneficial chemopreventive effect of isotretinoin persisted after the year of treatment. Since the high dose had toxicities, low dose was also tried in this setting by Bolla et al. Researchers randomly assigned 316 patients to treatment with etretinate (50 mg/day for 1 month, followed by 25 mg/day for 24 months) or placebo. The two treatment groups were equivalent for both the occurrence of SPTs and relapse of the initial cancer. Data from an intergroup large-scale Phase III trial of low-dose, long-term isotretinoin in Stage I or II HNSCC showed no difference in SPT development or overall survival. Researchers randomized 1190 patients in this study to receive either 30 mg/day of isotretinoin or placebo; after a 3-year follow-up, the SPT rate in both groups was 4.7%.,
Vitamin A is an important differentiating agent, and deficiency leads to various mucosal and dermatological changes that resemble and sometimes is a precursor for premalignant lesions. The association of Vitamin A deficiency has been proven in studies. The mechanism underlying the chemopreventative effects of Vitamin A and its derivatives is the restored expression of retinoic acid receptor-beta mRNA, which promotes normal tissue growth and differentiation. A study from India looked into the effects of short-term Vitamin A supplementation in patients who were tobacco/betel chewers and had developed oral leukoplakia. Participants were randomly distributed into two groups, one receiving 200,000 IU Vitamin A per week (0.14 mg/kg body weight per day) for 6 months, and the other receiving placebo capsules. The 6-month oral administration of Vitamin A caused complete remission in 57.1% of participants, and a total suppression of the development of new leukoplakias in all chewers receiving Vitamin A as compared to 3% and 21%, respectively, in the placebo group. Their results were confirmed with tissue examination at the beginning and end of the study. Another major study also studied the role of Vitamin A, the EUROSCAN study. This was an open-label multicenter trial of over 2592 patients with head and neck cancer or lung cancer. The endpoint was SPT prevention after treatment with curative intent of early-stage head and neck cancer or lung cancer. In the study, patients were randomized to receive Vitamin A (300,000 IU/day followed by 150,000 IU/day in the 2nd year), N-acetylcysteine (600 mg/day for 2 y), both compounds, or placebo. After a median follow-up of 49 months, there were no differences between the placebo group and the 3 active treatment groups for SPTs, event-free survival, or long-term survival rates.
| Beta Carotene|| |
Beta carotene is a naturally occurring, nontoxic carotenoid with biologic properties that may be suitable against oral leukoplakia. Beta carotene was found to inhibit the formation of oral SCC in animal models. Garewal et al. described a high response rate in a Phase II trial of beta carotene in leukoplakia. Twenty-four patients who could be evaluated were treated, 17 of whom had major responses (2 complete, 15 partial), for a response rate of 71%. In another Phase II study of beta carotene in oral leukoplakia, conducted by Suda et al. in 1989, the response rate was 44.4%. Sankaranarayanan et al. conducted a double-blind, placebo-controlled trial to evaluate the chemopreventive potential of either Vitamin A alone or beta carotene alone in patients with oral leukoplakia in India. In their study, 160 patients with oral precancerous lesions received either oral Vitamin A or beta carotene for 12 months. The complete regression rates were as follows: 10% in the placebo group, 52% in the Vitamin A group, and 33% in the beta-carotene group. In a study by Kaugars et al., 79 patients with oral leukoplakia received 30 mg/day of beta carotene, 1000 mg/day of ascorbic acid, and 800 IU/day of alpha-tocopherol for 9 months. Clinical improvement of the oral lesion was noted in 55.7% of the patients. In a randomized, placebo-controlled, double-blind clinical multicenter trial that included 264 patients who had been curatively treated for a recent early-stage SCC of the oral cavity, pharynx, or larynx patients were randomly assigned to receive either 50 mg/day of beta carotene or placebo; the patients were monitored for up to 90 months. After a median follow-up of 51 months, the two groups did not differ in the development of SPTs, local recurrences, and mortality. In a Physician's Health Study (a large randomized, double-blind, placebo-controlled trial that enrolled 22,071 male physicians from the United States), 12 years of supplementation with beta carotene showed virtually no early or late differences in the overall incidence of malignant neoplasms. Another large trial in the United States, the Beta Carotene and Retinol Efficacy Trial, involved more than 18,000 men and women who were smokers, worked with asbestos, or both. After 4 years of 50,000 IU/day of beta carotene, the lung cancer rate in this group increased by 28%, and the cancer mortality rate increased by 17%. The study was discontinued prematurely because of these findings. This study prompted beta carotene to be removed from chemoprevention trials for oral premalignancy in people who smoke.
Vitamin E is found to have antioxidant properties and was shown to inhibit cell lines of various malignancies as well asin vitro studies in prevention of head neck cancer in animals. As far as the human studies are concerned, a single-arm Phase II study showed that, among 43 patients with oral keratosis with atypia who took 400 IU of Vitamin E twice daily for 24 weeks, 20 (46%) had clinical responses and 9 (21%) had histologic responses. Treatment was extremely well tolerated, with excellent patient compliance. It was also tried in second primary cancer prevention, where a randomized, double-blind, placebo-controlled trial to assess whether supplementation with antioxidant vitamins could reduce the incidence of second primary cancers among patients with head and neck cancer. Contrary to the expectations, the patient in the intervention arm had a higher incidence of second primary cancer, so the trial was discontinued.
| Biochemoprevention|| |
The combination of different biologic agents such as interferon (IFN-α), 13-cRA, and α-tocopherol was evaluated in a Phase II study as an adjuvant approach to prevent recurrence or SPTs in patient with locally advanced SCC of the head and neck. Retinoids and IFNs have single-agent and synergistic combined effects in modulating cell proliferation, differentiation, and apoptosisin vitro and clinical activityin vivo in the head and neck and other sites. Alpha-tocopherol has chemopreventive activity in the head and neck and may decrease 13-cRA toxicity. After definitive local treatment with surgery, radiotherapy, or both, patients with locally advanced SCC of the HN (SCCHN) were treated with 13-cRA (50 mg/m 2/day, orally, daily), IFN - (3 × 106 IU/m 2, subcutaneous injection, 3 times a week), and α-tocopherol (1200 IU/day, orally, daily) for 12 months. The combination of IFN-α, 13-cRA, and α-tocopherol was generally well tolerated and toxicity was consistent with previous IFN and 13-cRA reports, 86% of patients completing the planned therapy. Median 1- and 2-year rates of overall survival were 98% and 91%, respectively, and of disease-free survival were 91% and 84%, respectively. These results have prompted for a Phase III randomized trial which is underway.
There is some low-grade evidence that low selenium levels may have increased the risk of cancers. A study conducted in India found that patients with low levels of selenium have significantly more head and neck cancers than patients with higher selenium levels. In a prospective study, supplementation with 200 µg/day of sodium selenite during therapy for SCC of the head and neck, for example, surgery, radiation, or surgery and radiation, resulted in a significantly enhanced cell-mediated immune responsiveness. The enhanced responsiveness was evident during therapy and following the conclusion of therapy. In contrast, patients in the placebo arm of the study showed a decline in immune responsiveness during therapy. The results from studies on mice inoculated with SCC cells expressing the receptor for interleukin-2 (IL-2) and supplemented with Se (2.00 ppm) indicated that Se significantly retards the clinical appearance of tumors; peritumoral injections of 2000 IU of IL-2 resulted in 50% reduction in the size of established tumors and 72% of early tumors. The combined data suggested that local immunotherapy with IL-2 in hosts supplemented with Se may represent an effective modality of treatment for the prevention of recurrences at the site of conventionally treated primary tumors.
| Cyclooxygenase 2 Inhibitors|| |
Many studies have proven that chronic inflammation can be a harbinger of metaplastic changes. Many malignancies have proven this fact. Hence, investigators were tempted to test cyclooxygenase (COX-2) inhibitors in the prevention of such inflammation. Celecoxib has been shown to be effective in colon cancer. Recently, COX-2 has been found to be associated with poor prognosis in HNSCC. The efficacy of COX-2 inhibition that was predicted on the basis of molecular biology results was confirmed in an oral cancer chemoprevention study in which dietary administration of a specific COX-2 inhibitor (celecoxib) and a nonspecific COX-2 inhibitor (piroxicam) reduced oral cancer incidence, the invasiveness of induced cancers, and cancer-associated mortality. The combination of COX-2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) leads to the inhibition of cell growth by simultaneously blocking EGFR and COX-2 pathways. This combination holds great potential for HNSCC prevention, treatment, or both.
| Aspirin|| |
Aspirin is a nonselective COX inhibitor that blocks the action of COX-1 and COX-2, in turn inhibiting prostaglandin (PG) synthesis, particularly PGE2. Thun et al. examined the relative risk of death from buccal cavity and pharyngeal cancers in aspirin users and found a 30% nonsignificant risk reduction in some categories of aspirin use. In another study by Bosetti et al., there was a 67% reduction in upper aerodigestive cancers in subjects who took aspirin for more than 5 years. One hospital-based case–control study showed that aspirin use was associated with a 25% reduction in the risk of head and neck cancer (adjusted odds ratio, 0.75; 95% confidence interval, 0.58–0.96). These effects were more pronounced in individuals with low-to-moderate exposure to cigarette smoke or alcohol consumption. Risk reduction was more significant in women and in patients with cancers of the oral cavity and oropharynx.
| Bowman-Birk Inhibitor|| |
Bowman-Birk inhibitor (BBI) is a PI that was identified in soybeans by Bowman in the 1940s and purified by Birk in the early 1960s. Interest in the use of soybean products as cancer-preventive agents emanated from epidemiologic studies that demonstrated low incidence rates of several cancers in populations with a high soy intake. BBI has been demonstrated to prevent development of malignancies in animal models. BBI demonstrated clinical activity after oral administration in patients with oral keratosis and atypia. Armstrong et al. conducted a 1-month Phase IIa clinical trial of BBI concentrate in 32 patients with oral keratosis and atypia; 31% of patients achieved a clinical response, and no detectable side effects were observed.
| Green Tea Extracts|| |
Green teas contain the following four major polyphenols: Epicatechin (EC), epigallocatechin (EGC), EC-3-gallate, and EGC-3-gallate (EGCG). The chemopreventive or antitumor effect of (−)-EGCG, the most abundant and most active phenolic constituent of green tea, has been extensively studied in chemically induced rodent carcinogenesis models and in several types of cancer cells in culture. Multiple biologic functions have been attributed primarily to EGCG, and it seems to work as an antioxidant and inhibit cell proliferation, invasiveness, and angiogenesis mediated by signaling transduction pathways involving EGFR, nuclear factor (NF) - B, tumor NF-alpha, AKT, mitogen-activated protein kinase, p53, and others. Prospective cohort data collected over 10 years suggest that consumption of more than ten cups of green tea a day results in decreased cancer incidence, with a hazard ratio of 0.59.
| Epidermal Growth Factor Receptor Inhibitors|| |
Overexpression of EGFR and its ligands transforming growth factor alpha or EGF has been observed in 80–90% of SCCHN specimens and correlates with poor disease-free and overall survival and increased risk of disease recurrence and metastasis. One approach to block the EGFR includes targeted agents that inhibit EGFR tyrosine kinase. These TKIs include gefitinib and erlotinib. Erlotinib, an EGFR TKI, has shown strong antitumor and chemopreventive efficacies in a variety of cancer types, including SCCHN, through blocking EGFR-related signal transduction pathways.
Several promising new compounds are being studied in clinical chemoprevention trials in head and neck cancer:
- EKB-569 - Family of drugs called EGFR inhibitors
- Pioglitazone - Peroxisome proliferator–activated receptor inhibitor
- Ad5CMV - Targets the TP53 gene
- Polyphenols of pomegranate juice
- Curcumin analogs
- Erlotinib, an EGFR TKI.
| Conclusion|| |
Although it is supposed to be the most exciting field of oncology, preventing the development of cancer itself, chemoprevention has failed the test of time as of now to prove its benefit in the context of invasive cancer. We are yet to see a trial that has actually shown a reduction in incidence of head and neck cancer and it goes without saying that such trial has to be large population-based trials and not just a Phase III randomized design. One possible explanation can be that none of the agents have intruded into the molecular pathogenesis of the invasive cancers. Hence, the trials are largely negative when we consider the incidence of head and neck cancer. Maybe with the advent of newer technologies and more widespread use and validation of molecular markers, we may stand a chance to actually have an impact of targeted agents for chemoprevention.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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