February 2016

Journa C A L I F O R N I A

D E N TA L

February 2016 Intraoral Lesions Oropharyngeal Cancer Oral Cancer Chemoprevention

A S S O C I AT I O N

ORAL CANCER: NOVEL CONCEPTS FOR THE ORAL HEALTH CARE PRACTITIONER

Diana V. Messadi, DDS, MMSc, DMSc

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C D A J O U R N A L , V O L 4 4 , Nº 2

D E PA R T M E N T S

73 The Associate Editor/Stepping Outside the Operatory 75 Impressions 129 RM Matters/Getting the All-Clear Signal: Medical Clearance Forms and Follow-Up

135 Regulatory Compliance/Infection Control Q-and-A

75

139 Periscope 142 Tech Trends

F E AT U R E S

82 Oral Cancer: Novel Concepts for the Oral Health Care Practitioner An introduction to the issue. Diana V. Messadi, DDS, MMSc, DMSc

85 Managing Intraoral Lesions in Oral Cancer Patients in a General Dental Practice: An Overview Patients with active cancer or a history of cancer may present with multiple side effects that dental practitioners can manage or prevent. The authors discuss some of these concerns and provide management strategies. Reuben Han-Kyu Kim, DDS, PhD; Paul Yang, BS, MS; and Eric C. Sung, DDS

93 Current Trends in the Incidence and Presentation of Oropharyngeal Cancer This article reviews the current knowledge about oropharyngeal cancers for their epidemiology, pathogenesis, clinical behavior, treatment and prevention. Fariba S. Younai, DDS

101 Oral Cancer Chemoprevention: Current Status and Future Direction The aim of this study is to review the current status of cancer chemoprevention and its effectiveness in treatment of oral premalignant lesions and prevention of their progression to oral cancer. Diana V. Messadi, DDS, MMSc, DMSc, and Kazumichi Sato, DDS, PhD

112 Targeting Cancer Stem Cells in Oral Cancer This article reviews the current knowledge of the cancer stem cells (CSCs) hypothesis in oral cancer and the traits displayed by CSCs. Qilin Xu, MD, PhD, and Anh D. Le, DDS, PhD

121 A Chemopreventive Nanodiamond Platform for Oral Cancer Treatment In this paper, the authors propose a chemopreventive nanodiamond platform for the delivery of celecoxib to oral cancer lesions. Albert Yen, BS; Kangyi Zhang, PhD; Giulia Daneshgaran, BS; Ho-Joong Kim, PhD; and Dean Ho, PhD

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Assoc. Editor Editor


Stepping Outside the Operatory Ruchi K. Sahota, DDS, CDE

W

hen was the last time someone asked you, “How can I make your life easier?” It was incredibly reassuring to hear this from a member of our CDA Executive Committee. She asked me what CDA could do to ensure that parents of young children, like me, felt supported and able to serve in leadership positions at our association. Long emails in paragraph form ensued. We discussed challenges, including difficulty attending face-toface meetings while nursing a baby. We re-examined processes that were already in place. We reviewed other options. At the same time, she brought a few other young mothers into the conversation. We swapped stories. We strengthened connections. We confirmed that one thing that always makes a person feel better — we confirmed that we were not alone. There were other young mother CDA volunteers out there. In that moment, I realized organized dentistry’s sincere intentions to help. Here was another tangible member benefit. This isn’t anything new. Time and time again, organized dentistry has helped me be a better leader — and a better person. It continues to renew its special place in my heart. CDA has become like family. When organized dentistry connected me to other young mother leaders, I was filled with emotions. I felt relief — there were others out there trying to balance work, family, volunteerism, friends and all things life. I felt pride — there were others out there trying to set an example of strength, poise and diligence for their little ones. And I felt support — there were other dentists from around the state willing to lend me their time, experience and encouragement. After almost 15 years of volunteering, I can value how much it has given back to my life. So it is natural to wonder: Why are there not more young parents involved? Of course, it may be simpler to stay within the confines of the office walls and

Time and time again, organized dentistry has helped me be a better leader — and a better person.

9-to-5 schedule. At times, involvement in organized dentistry takes us away from our normal day-to-day lives. Arthur A. Dugoni, DDS, MSD, dean emeritus of the University of the Pacific, Arthur A. Dugoni School of Dentistry, recently spoke at CDA Presents in San Francisco. He encouraged attendees to step out of their comfort zone, saying, “You have to live beyond the nine-by-nine operatory and your high-speed handpiece.” The volunteer life cycle starts off as we apply for positions in our dental society or maybe a CDA council. We may aim to represent our personal demographic, voice our opinions and share our experiences. Slowly … leadership in organized dentistry enhances our ability to see. Within a short period of time, volunteering starts giving back. Motivation seeps into the consciousness. It makes us want to do better in our own offices. We are inspired to find ways to give back to our communities at home. And we become more productive in our overall lives. What started as a mission to serve transforms itself into a generous gift. Many may not apply for volunteer positions because of the lack of monetary compensation. Napoleon Hill said, “The [wo]man who does more than [s]he is paid for will soon be paid for more than [s]he does.” Volunteer leadership gives us the opportunity to be a part of something bigger than ourselves. Volunteering involves us in the movement to bring positive change to the oral health of the general public — isn’t that a part of the Hippocratic Oath we take?

Dr. Dugoni alluded to the many benefits of getting involved in his speech. But he repeatedly went back to the same piece of advice. Dr. Dugoni reminded us to smile. He reminded us to laugh as much as possible. More often than not, we smile and laugh when we are amongst friends and family — when we are with those who wish us joy and happiness. We belong to a magnificent profession with some pretty amazing colleagues — many of whom are kind, virtuous and ultimately inspirational. We will never know them — unless we step outside the comfort zone and get involved. We will have more of a chance to follow Dr. Dugoni’s advice if we leave our nine-bynine operatories. We will have more of a chance to laugh and smile when we connect with other dentists in organized dentistry. They will restore our sense of purpose in our profession. They will connect with us, share their experiences and inevitably remind us that we are not alone. There are others out there — going through many of the same challenges. And there are others out there who we will meet through organized dentistry who will offer to “make your life easier.” ■ Ruchi K. Sahota, DDS, CDE, practices family dentistry in Fremont, Calif., and serves as faculty at the University of the Pacific, Arthur A. Dugoni School of Dentistry. She is also a certified dental editor, a consumer advisor for the American Dental Association, past president of the Southern Alameda County Dental Society and a fellow of the American College of Dentists, International College of Dentists and the Pierre Fauchard Academy. F E B R U A R Y 2 0 1 6 73

You are the protector of the smile. You enable people to laugh without shame, eat their favorite foods and experience the dignity of aging with grace. That’s why this association tirelessly advocates for the profession and stands up for those in need of care. Because the world is a better place when people are smiling, and that’s thanks to you.

Renew today.

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Impressions


A Cry for Help David W. Chambers, EdM, MBA, PhD

The nub: 1. Social fatigue is damaging our willingness to help others. 2. Help is more likely to come from one who shares your problems than from experts. 3. No one cares how much you know until he or she knows how much you care.

David W. Chambers, EdM, MBA, PhD, is professor of dental education at the University of the Pacific, Arthur A. Dugoni School of Dentistry, San Francisco, and editor of the Journal of the American College of Dentists.

I am one of those very peculiar men who regularly asks for directions when driving. I believe in the African saying, “If you want to go fast, go alone. If you want to go far, go together.” But my system is failing. I find it harder these days to get help. As a country, we prefer to sell solutions instead of answer questions. It seems it is becoming unfashionable in America to help others. Part of the reason was obvious when I signed onto my computer this morning. Several minutes of protecting myself against unwanted spam put me in such a negative mood I had to pump myself up to be civil to those who were asking for my help. Of course, I do need help from time to time with my computer. Very occasionally, I will go to the IT department at the school where I teach. They are knowledgeable when my number eventually comes up in the cue. I am much more inclined to chat informally with one of my colleagues. There is a person in HR who is a wizard with Word. A new faculty member in the basic sciences is a master of graphics. I prefer the users to the experts for several reasons. First, they are almost always able to help immediately, e.g., when I need the help. Second, they know the context of the problem I am trying to solve and help me with the problem I should be working on instead of the one I asked about. Third, they make certain I understand the answer rather than taking my computer and changing something so it no longer misbehaves in exactly the same way. I believe the same is true for dentists who recognize that they face ethical issues: they would prefer to get help from a colleague rather than from an academic expert. And for the same reasons. In an article in the February 2015 issue of the Academy of Management Journal, I read about helping behavior in a software engineering firm that uses teams to develop projects. Among colleagues who were expected to help each other, 26 percent of the email requests for assistance and 28 percent of the phone calls for help were ignored. OK, I have a better record than that. However, the computer has become an all-purpose labor saving device. Just ignore inconvenient requests. Calls for help are more successful when begun by establishing or reaffirming existing social relationships. Another way to boost success is to explain why it matters to the person from whom help is sought. Acknowledging the status of the helper is useful. Finally, only a tiny fraction of requests for help that are made in person are refused. ■ F E B R U A R Y 2 0 1 6 75

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IMPRESSIONS C D A J O U R N A L , V O L 4 4 , Nº 2

Image: Oregon State University

New Patent on Synthetic Biochemical Compound for Gum Disease Treatment

Bioactive Glass May Be the Future of Fillings Bioactive glass can be used in tooth fillings to help reduce the ability of bacteria to attack composite tooth fillings and perhaps even provide some of the minerals needed to replace those lost to tooth decay, according to new research from engineers at Oregon State University. “Bioactive glass, which is a type of crushed glass that is able to interact with the body, has been used in some types of bone healing for decades,” said Jamie Kruzic, a professor and expert in advanced structural and biomaterials in the OSU College of Engineering, in a news release. “This type of glass is only beginning to see use in dentistry, and our research shows it may be very promising for tooth fillings,” he said. “The bacteria in the mouth that help cause cavities don’t seem to like this type of glass and are less likely to colonize on fillings that incorporate it. This could have a significant impact on the future of dentistry.” Bioactive glass is made with compounds such as silicon oxide, calcium oxide and phosphorus oxide, and looks like powdered glass. It is referred to as “bioactive” because the body notices it is there and can react to it, as opposed to other biomedical products that are inert. Bioactive glass is very hard and stiff and can replace some of the inert glass fillers that are currently mixed with polymers to make modern composite tooth fillings. 76 F E B R U A R Y 2 01 6

University of Louisville researchers recently received a patent on a synthetic biochemical compound and its variants, moving science closer to a treatment for gum disease. This discovery could lead to the formulation of a mouth rinse or tooth varnish to prevent the pathogen, P. gingivalis, from colonizing in the mouth and establishing itself orally. The researchers developed and tested 40 different molecular compounds, and the three most potent compounds are being developed further. This patent builds on previous work of researchers who developed a series of peptides, the building blocks of protein in a cell, that prevent interaction between P. gingivalis and S. gordonii. “When P. gingivalis enters the oral environment, it initially interacts with the bacterium S. gordonii — an otherwise benign organism — in order to lay the ground work to propagate and ultimately gain a foothold below the gum line, leading to periodontal disease,” said Donald Demuth, PhD, associate dean for research and enterprise at the UofL School of Dentistry. Demuth found that administering the peptide in an animal model prevented P. gingivalis-related bone loss and prevented the spread of the bacterium in the mouth. Creating peptides is expensive, Demuth said, but synthetic compounds that mimic the active peptides are easier to formulate and less costly to produce on a large scale. Bacterial biofilm in the presence of the inhibitory compounds.

Bacterial biofilm in the absence of the inhibitory compounds. (Images courtesy of University of Louisville.)

“New tooth decay often begins at the interface of a filling and the tooth, and is called secondary tooth decay. The tooth is literally being eroded and demineralized at that interface,” Kruzic said. Bioactive glass may help prolong the life of fillings because, according to researchers, the new study showed that the depth of bacterial penetration into the interface with bioactive glasscontaining fillings was significantly

smaller than for composites lacking the glass. Fillings made with bioactive glass should slow secondary tooth decay and provide minerals that could help replace those being lost. The combination of these two forces should result in a tooth filling that works just as well, but lasts longer, according to the authors. For more, see the study in the journal Dental Materials, January 2016, vol. 32, issue 1, pp. 73-81.


How Teeth Find Their Way to the Right Spot in the Jaw Led by scientists at the University of California, San Francisco, researchers recently showed in mice that molar progenitor cells migrate to their final locations during development, rather than forming the teeth in place, as researchers had previously thought. According to a news release from the university, this is the first time researchers have captured on video how teeth find their way to the right spot in the jaw.

The authors report that by combining lineage tracing, genetic cell ablation and confocal live imaging, they were able to identify a migratory population of Fgf8-expressing epithelial cells in the embryonic mandible. These findings are published in the journal Developmental Cell and suggest that the progenitor cells that produce other organs could also exhibit asyet unrecognized wanderlust, and

Osteoporosis and Marginal Bone Loss in Osseointegrated Implants Researchers from the University of Seville recently conducted a study to evaluate the possibility of a correlation between osteoporosis, as measured by the mandibular cortical index (MCI), and marginal bone loss (MBL) and to assess how various systemic diseases, periodontitis and placement of implants in regenerated bone are correlated with MBL and MCI. MBL and MCI were assessed from panoramic radiographs and the retrospective study, which examined 212 implants inserted in 67 patients, found that when the total sample implant was evaluated, a significant association was found between the presence of osteoporosis and MCI and between the presence of diabetes mellitus and MCI. According to the authors, significant associations were also found between MBL and placement of implants in regenerated sites and between MBL and a previous history of periodontitis. “When the sample is evaluated only in selected implants (one per patient), significant differences appear to relate only to the MBL with the placement of implants in regenerated bone sites,” the authors wrote. “Osteoporosis (as evaluated by MCI) does not pose a risk for the development of greater MBL,” the study concluded, noting that “parameters adversely affecting the development of increased MBL are a previous history of periodontitis and especially the placement of implants at sites of bone regeneration.” For more, see the study in the Journal of Periodontology, January 2016, vol. 87, no. 1, pp. 14-20.

could help explain how teeth and other organs ended up in such diverse configurations in different species over the course of evolution. The insights may even have implications for understanding how cancerous cells migrate to invade other tissues. “It’s a crucial part of development,” said Ophir Klein, MD, PhD, chair of the divisions of craniofacial anomalies and orthodontics at UCSF, and senior author of the new study. “For example, you need to get the eyes in the right part of the face. The limb positioning needs to be perfectly balanced. For each particular species, the teeth need to be at the right place in the jaw for the animal to be able to eat or to defend itself. But we knew little to nothing about how they get there, at least in mammals.” For more, see the study published in the journal Developmental Cell, vol. 35, issue 6, pp. 713-724. CORREC TION . In the January 2016 issue of the Journal, the conflict of interest disclosure for Dr. Peter M. Milgrom was inadvertently omitted. His disclosure should have read “Dr. Milgrom is a principal in ADP Silver Dental Arrest LLC, which licenses permission to market Advantage Arrest to Elevate Oral Care LLC.” The online version of the article has been corrected. We apologize for the error. F E B R U A R Y 2 0 1 6 77

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Reconstructing the Jaw With Free-Flap Fibula Graft

Sound of Bristles Impacts Tooth Brushing Satisfaction How effectively we clean our teeth and how satisfied we are with the brushing job depends a lot on the sound of the bristles scrubbing against the enamel, according to new research from scientists in Japan. In trials with volunteer teeth cleaners, the researchers used a tiny microphone in a modified toothbrush to “sample” the sound being made in the mouth during brushing and to modulate it and then feed that sound back to the volunteer. The study, which is published in the International Journal of Arts and Technology, explains how modulating the brush sound affects brushing efficacy and satisfaction. The authors found that if they manipulated the pitch, or frequency and loudness, of the brushing sound, they could alter the volunteers’ perception of comfort and accomplishment. They also found that if they gradually increased the frequency as teeth cleaning progressed, the volunteers felt like the process was more comfortable and that their teeth were cleaner at the end of the process. “Tooth brushing provides a ‘negative reward’ for users as they brush their teeth to avoid developing caries,” the research team explains. “Subsequently, users do not consider the impact of omitting the action until suffering from caries or other dental diseases,” the team adds. 80 F E B R U A R Y 2 01 6

In an article published in the Journal of Oral Implantology, researchers describe a step-by-step process to completely reconstruct the jaw using a bone graft and an implant-supported denture. Their case report is one of only a few studies that focus on the final, prosthetic phase of the process and a technique known as a free-flap fibula graft. Free-flap reconstruction is the standard technique used after part or all of a patient’s jaw has been removed. Surgeons prefer to use bone from the patient’s fibula to rebuild the jaw. The case report focuses on a 24-year-old woman who had undergone surgery to remove a tumor in her jaw three years earlier with a fibular graft to rebuild her jawbone, but the graft was not successful. A second surgery was performed using the free fibular vascular flap of her other leg, and four implants and a denture were inserted. Over the next two years, the patient reported great comfort and ability to function with the prosthesis. She could wear the denture easily and eat a mostly normal diet, except for nuts and meats. Her speech was clear and her facial proportions and symmetry were closer to normal. For this patient, the plastic attachments had to be replaced once due to routine wear and tear. She had no problems in the leg that had been used as the donor site. The patient felt good about her rehabilitation, which made her confident in her appearance and daily activities. The authors concluded that their method is safe and reliable, stating that it resulted in a functional and esthetically acceptable jaw that greatly enhanced the patient’s quality of life. For details, see the study published in the Journal of Oral Implantology, vol. 41, no. 6, pp. 740-745.

Study results show that it is possible to motivate users by interactively manipulating the frequency of brushing sounds, so that the task becomes more satisfying. Importantly, the system can tell, through a built-in force sensor, whether a person is brushing too hard, which can damage the gum line, and give them aural feedback to encourage them to clean their teeth more gently.

The prototype system requires the teeth cleaner to wear headphones, which is impractical in real life. However, there are bone conduction speaker systems that might be incorporated into the smart toothbrush so that the amplified feedback loop is created in the mouth. For more, see the study in the International Journal of Arts and Technology, vol. 8, no. 4, pp. 307-324.


Adults With Diabetes Lose Twice the Number of Teeth Adults with diabetes lose approximately twice the number of teeth as those without diabetes, according to a recent study from the U.S. Centers for Disease Control and Prevention. Published in the CDC’s Preventing Chronic Disease, the study aimed to assess the trends in tooth loss among adults with and

without diabetes mellitus in the United States as well as racial/ethnic disparities in tooth loss patterns. “Research shows a bidirectional relationship between diabetes and periodontal disease. Periodontal disease is considered the sixth complication of diabetes and has been identified as a risk factor for poor metabolic control in

Multiplying Teeth Working with colleagues from the Tokyo Medical and Dental University, researchers have found a way to, literally, multiply teeth. In mice, the researchers were able to extract teeth germs — the groups of cells formed early in life that later develop into teeth — split them into two and then implant the teeth into the mice’s jaws where they developed into two fully functional teeth, according to a new study in Scientific Reports, an online journal of the publishers of Nature. To manipulate the teeth development process, the researchers removed teeth germs from mice and grew them in culture. At an appropriate point in the development process, which according to the authors turned out to be 14.5 days, they nearly sliced the germs in two with nylon thread, leaving just a small portion attached, and continued to culture them. The hope was that signaling centers, which control the wave of molecules that regulate the development of the tooth, would arise in each part — and this, in fact, was the case. The ligated germs developed naturally into two teeth, which the team transplanted into holes drilled into the jaws of the mice. Though they were only half the size of normal teeth, the split teeth erupted into the oral cavity and restored physiological tooth functions, including mastication, periodontal ligament function and responsiveness to noxious stimuli. Significantly, the researchers also report that they were able to manipulate the teeth using orthodontic methods, equivalent to braces, and the bone properly remodeled to accommodate the movement of the teeth. For details on this research, see the Dec. 17, 2015, edition of Scientific Reports. Photo of a tooth germ with a nylon noose (left) and the noose tightened (right).

people with diabetes,” the authors explained in their report. The study used data from nine waves of the National Health and Nutrition Examination Survey (NHANES) from 1971 through 2012 and included an analytical sample of 37,609 dentate (i.e., with at least one permanent tooth) adults aged 25 years or older. Because of insufficient sample size, the study excluded those with complete tooth loss and other racial/ ethnic groups (Asians, Native Americans and Hispanics whose country of origin was not Mexico). The researchers found that the estimated number of teeth lost among non-Hispanic blacks with diabetes increased more with age than that among non-Hispanic whites with diabetes or Mexican Americans with diabetes. The researchers also evaluated trends in tooth loss by age, birth cohorts and survey periods and, according to the report, found that non-Hispanic blacks with diabetes lost the largest number of teeth, and they had the greatest increase in tooth loss as they aged. The importance of necessary dental care and tooth retention needs to be further promoted among patients and clinical providers, the authors wrote. For more details from this research, see the study published in the CDC’s Preventing Chronic Disease, Dec. 3, 2015, vol. 12:150309. F E B R U A R Y 2 0 1 6 81

introduction C D A J O U R N A L , V O L 4 4 , Nº 2

Oral Cancer: Novel Concepts for the Oral Health Care Practitioner Diana V. Messadi, DDS, MMSc, DMSc

GUEST EDITOR Diana V. Messadi, DDS, MMSc, DMSc, is a professor and chair of the section of oral medicine and orofacial pain and the associate dean for education and faculty development at the University of California, Los Angeles, School of Dentistry. Conflict of Interest Disclosure: None reported.

O

ral cancer is a significant global health concern, responsible for more than 600,000 new cases per year worldwide and approximately 42,000 annual incident cases in the U.S. Most cases are diagnosed at a late stage, resulting in poor fiveyear survival rates between 30 and 60 percent.1,2 Hence, the need is high for early detection and development of new management strategies to reduce the mortality and morbidity of late-stage diagnosis.3 The disease burden of oral cancer is significant; patients require intensive multimodality treatments and prolonged rehabilitation with longterm support to achieve an adequate recovery. General dental practitioners frequently encounter cancer survivors for their routine dental care and these patients are likely to present with

oral side effects that are associated with multiple cancer therapies.4 This issue includes insightful articles related to oral cancer emerging technologies in early intervention, potential therapies and dental management of cancer survivors. The first article by Reuben Kim, DDS, PhD, Paul Yang, BS, MS, and Eric Sung, DDS, describes the most common oral effects of associated cancer therapies and discusses how general dental practitioners can manage and treat these conditions. The increasing incidence of human papillomavirus-positive head and neck cancers highlights the need to better understand the role of HPV in the development of these cancers. Fariba Younai, DDS, focuses on the role of HPV in head and neck cancer development especially among HIV-seropositive individuals. More specifically, she F E B R U A R Y 2 0 1 6 83

introduction C D A J O U R N A L , V O L 4 4 , Nº 2

describes the epidemiologic trends for HPV-related oropharyngeal squamous cell carcinoma and provides an update on the HPV life cycle, oncogenic properties and prognostic role in carcinogenesis. Furthermore, she emphasizes the role of dental health care providers in prevention, early detection and expert referral for this category of head and neck cancers. Cancer chemoprevention is defined as the use of a systemic agent to halt the carcinogenesis process. This has been an attractive topic in head and neck squamous cell carcinoma (HNSCC) for the past three decades.

Progress toward identifying an effective chemopreventive agent to reduce the incidence of oral cancer has been limited by poor efficacy and intolerable toxicity profiles. Kazumichi Sato, DDS, PhD, and I review the current status of cancer chemoprevention and its effectiveness in treatment of oral premalignant lesions (OPL) and prevention of their progression to oral cancer. Unfortunately, despite the significant efforts over the past decades and the substantial gain in knowledge of the biology of oral premalignant lesions, no tangible indications for chemoprevention have emerged for this disease.

Cancer stem cells (CSCs) may be involved in oral cancer progression, metastasis, treatment resistance, and recurrence. In their article, Anh Le, DDS, and Qilin Xu, MD, PhD, discuss the biological properties of CSCs and their implication in oral carcinogenesis, which could lead to the development of novel antitumor drugs that specifically target oral cancer stem cells. Nanodiamonds are promising biomedical agents that have markedly enhanced the efficacy and safety of drug delivery and imaging. They combine several properties that include uniquely faceted surfaces, biocompatibility, and scalable manufacturing parameters, making them applicable toward oncology and dentistry. Dean Ho, PhD, et al. explore the potential use of nanodiamondchemotherapeutic agents to increase intratumoral retention while markedly reducing dose-limiting toxicity in an experimental cancer mouse model. These advancements have opened the doors to developing nanodiamond-based therapies for oral health indications. I would like to extend my deepest appreciation to all the authors for sharing their expertise and knowledge on the topic of oral cancer. I hope that you, the readers, find this issue educational and useful in your dental practice in regard to the current roles of HPV, stem cells, nanodiamonds and chemoprevention in oral cancer detection and management. ■ RESOURCES

1. American Cancer Society. Cancer Facts and Figures 2014. Atlanta: American Cancer Society, 2014. 2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-8. 3. Messadi DV. Diagnostic aids for detection of oral precancerous conditions. Int J Oral Sci 2013; 5:59-65. 4. Jawad H, Hodson NA, Nixon PJ. A review of dental treatment of head and neck cancer patients, before, during and after radiotherapy: Part 1. Br Dent J 2015; 218, 65-68.

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intraoral lesions C D A J O U R N A L , V O L 4 4 , Nº 2

Managing Intraoral Lesions in Oral Cancer Patients in a General Dental Practice: An Overview Reuben Han-Kyu Kim, DDS, PhD; Paul Yang, BS, MS; and Eric C. Sung, DDS

A B S T R A C T As medical technology advances in the area of cancer therapeutics,

dental practitioners will encounter patients with active cancer or a history of cancer. Typically, these patients may have had or are undergoing therapies such as surgery, radiation, chemotherapy or a combination of therapies. These patients may present with multiple side effects that dental practitioners can manage or prevent. We discuss some of these concerns and provide management strategies.

AUTHORS Reuben Han-Kyu Kim, DDS, PhD, is an associate professor, vice chair in the section of restorative dentistry and the course chair for direct restorations for predoctoral students at the University of California, Los Angeles, School of Dentistry. He is actively engaged in research related to oral diseases including wound healing and oral cancers. Conflict of Interest Disclosure: None reported. Paul Yang, BS, MS, is a first-year student in the DDS/ PhD combined program at the University of California, Los Angeles, School of Dentistry. Mr. Yang earned his bachelor’s and master’s degrees in biology from UCLA. He is interested in

pursuing oral maxillofacial and facial surgery training and oral medicine after his DDS/PhD training. Conflict of Interest Disclosure: None reported. Eric C. Sung, DDS, is a professor of clinical dentistry, chair in the section of special needs patients and the program director of the general practice residency program at the University of California, Los Angeles, School of Dentistry. His background is in training and providing comprehensive treatment for medically, physically and psychologically complex individuals. Conflict of Interest Disclosure: None reported.

A

recent study showed that nearly 14.5 million Americans had experiences with cancers as of 2014, and almost 1.7 million new cancer cases were expected to be diagnosed in 2015.1 Among them, 2 percent is attributed to oral and oropharyngeal cancers, ranking them as the sixth most commonly occurring cancer in the U.S. with 63 percent and 51 percent of overall five- and 10-year survival rates, respectively. A similar trend can also be seen worldwide,2 suggesting that oral and oropharyngeal cancers in the oral cavity impose significant health issues not only in the U.S., but also throughout the world. Approximately 45,780 new diagnoses of oral and oropharyngeal cancers alone were expected in 2015

in the U.S.1 While some of these patients may seek a large cancer center where their dental needs can be addressed in a hospital-based setting before, during or after cancer therapy, significant numbers of these patients are being referred to local general dental practitioners for their dental care.3 With progressive increase in life expectancy due to the advancement in medical technology, these cancer patients seeking general dentists to address their dental needs will only escalate. Therefore, as a general dental practitioner it is important to know about, and to be better prepared for, any disease or pathology that may specifically develop in the oral cavity in patients who are undergoing or who have undergone therapy for their cancer. Depending on the treatment modality, the side effects commonly F E B R U A R Y 2 0 1 6 85


found in the oral cavity are diverse, ranging from xerostomia, oral mucositis, opportunistic infection and trismus to osteoradionecrosis (ORN). These side effects may be overlooked because some of them are asymptomatic in nature, but can be severe such that normal functioning in daily life may be significantly compromised. Detailed descriptions of screening and examining oral cancers in patients can be found on the Foundation for Oral-Facial Rehabilitation’s website (ffofr.org) and in other reviews.4 We primarily focus on the etiology, clinical presentation, treatment and management of these oral lesions in patients who are undergoing or underwent therapy for their cancers. The use of adjuvant cancer therapeutic agents such as antiresorptive (e.g., bisphosphonates and denosumab) or anti-angiogenic (e.g., sunitinib or bevacizumab) drugs is increasingly common to treat metastatic cancers. These patients are at risk of developing oral-specific lesions called medication-related osteonecrosis of the jaw (MRONJ). We also discuss the management of MRONJ lesions.

cancers. However, this approach is often limited due to compromised functions and esthetics.5 Surgical removal of a cancer mass in the oral cavity often creates large structural defects, and the outcomes may be disfiguring. In addition, intraoral surgical removal may result in significantly altered oral functions for speech and mastication. Therefore, patients may opt out of this therapeutic modality because of these functional and esthetic concerns.

Radiation therapy has the advantage of inducing DNA damage in highly proliferating cancer cells by ionizing radiation via generating reactive oxygen species (ROS).6 Because cancer cells constantly replicate DNA for their continual proliferation, DNA damage by ionizing radiation through radiation therapy leads to cell death. Radiation is delivered to the tumor sites by fractionating the doses with different radiation paths in multiple visits. Typically, an average of 2 gray (Gy) per fraction is delivered over a course of six to seven weeks, resulting in a total dose of 60-72 Gy.

Although these treatment modalities are specifically formulated to reduce the cancer burden by inducing cancer cell death, normal cells responsible for maintaining body homeostasis by continually proliferating, differentiating and replenishing tissue structures and functions are also affected. As such, there are multiple complications associated with cancer therapy, such as nausea, vomiting, hair loss, myelosuppression and stomatotoxicity. Among them, several side effects are observed in the oral-specific manner and compromise the quality of patients’ lives. These complications include oral mucositis, xerostomia, ORN, trismus and secondary infection.

Cancer Therapy Options

Chemotherapy

Oral Mucositis

To better manage oral-specific side effects that are induced during or after cancer therapy, it is helpful to understand the nature of each therapeutic modality. These treatment modalities include surgical therapy, radiation therapy, chemotherapy or a combination of therapies.

Chemotherapy is usually treated on an outpatient basis, but hospitalization may be required if serious sequelae develop. The modality of chemotherapy is largely dependent on the cytotoxicity of the drug and the patient’s body defense condition. Combinations of different drugs (e.g., alkylating agents, antimetabolites, antitumor antibiotics, antineoplastics and monoclonal antibody such as cetuximab) are preferred to avoid the development of single-agent resistance in cancer cells. In addition, combination chemotherapy as well as radiation therapy can lower the drug doses and result in better remission and cure rate.7

General description: Oral mucositis, the breakdown of oral epithelial tissues leading to painful ulcerative lesions, is one of the most common side effects in patients undergoing radiotherapy and/or chemotherapy. The degree of mucositis severity varies depending on fields, doses and fractionation of radiation. Ulcerative mucositis lesions are more severe in patients receiving adjunctive or concurrent chemotherapy. The etiology of oral mucositis is primarily due to the generation of reactive oxygen species (ROS) by radiation and/or chemotherapy, which cause direct DNA damage to actively proliferating stem cells that are responsible

Surgical Therapy Surgical therapy for cancer is a treatment choice, as it allows for the physical removal of the entire tumor mass. Following surgical removal, patients may undergo adjuvant radiation or chemotherapy for complete eradication of 86 F E B R U A R Y 2 01 6

Radiation Therapy

FIGURE 1. Mucositis covered by a pseudomembranous layer with areas of erythema and ulceration.

Oral Complications Associated With Cancer Therapy


Xerostomia FIGURE 2A . Xerostomia causing gross decay

FIGURE 2B . Gross decay leading to fracture at the

(arrows).

gumline (arrow).

FIGURES 2 . Rampant caries secondary to xerostomia.

for replenishing the tissues, leading to oral mucosal damages.8,9 Ironically, this is also the basic principle behind the use of radiation and/or chemotherapy to target cancer cells. The severity of mucosal reaction is more evident in the less keratinized oral mucosa, such as under the tongue. The ulceration escalates in patients with chronic alcoholism, liver cirrhosis and insulin-dependent diabetes. Clinical manifestation: Mucositis initially presents as an erythematous lesion as early as seven to 10 days after the initial treatment dose. These initial erythematous mucositis will soon develop into ulcerative mucositis that is typically covered by pseudomembranes (FIGURE 1 , arrows). These lesions are usually confined to the tissues associated with the initial tumor site. Ulcerative mucositis lasts throughout the treatment period, but the lesions are usually self-limiting after two to four weeks following the completion of therapy during which they are re-epithelialized and covered by normal-appearing oral mucosa. Caution should be taken when managing the irradiated oral mucosal tissues as they can be easily perforated by trauma, resulting in secondary ulceration that could take months to heal. The practitioner should carefully examine the localized ulcerative mucositis in oral mucosal tissues particularly around the metallic crown that is in the path of the radiation beam due to backscatter effects of radiation. Management: As these lesions are often self-limiting, the primary goal of managing patients with oral mucositis should be focused on alleviating pain.

Topical anesthetics in the form of sprays, ointments, gels or rinses, such as lidocaine, benzocaine, dyclonine or capsaicin, can be used. The practitioner should examine loss of oral function, weight loss and secondary infection.10 It should be noted that patients with severe mucositis may require hospitalization. Patients should be instructed to avoid hot, spicy or acidic foods or beverages. Any sharp or hard food intake should be curtailed, as they can be traumatic to the oral mucosal tissues. If oral mucositis is generalized throughout the oral cavity, analgesics can be administered systemically, which may require hospitalization. Emphasizing good oral hygiene practices to patients is important to reduce the chances of developing infection secondary to mucositis. Fungal and bacterial infections are common with these lesions and antifungal and/or antibacterial medications may be prescribed as needed. Some of these patients may have already undergone preventive therapeutic treatment, such as cryotherapy, palifermin or amifostine, so practitioners should be aware of these methods. Palifermin, a truncated human keratinocyte growth factor (KGF) recombinant protein, is FDA approved and currently available to use in the clinic; however, recent clinical trials demonstrated the modest effects of palifermin.11,12 Amifostine, a radioprotectant, can be administered intravenously or subcutaneously before therapy to reduce the severity of oral mucositis, but it may induce several side effects such as headaches, nausea or hypotension.

General description: Xerostomia is another commonly occurring side effect in cancer patients undergoing radiation therapy or concomitant chemotherapy. Xerostomia occurs because of partial or complete damages, which may be either recoverable or irreversible to the salivary glands (e.g., parotid, submandibular and sublingual glands) especially when these glands are in the radiation path. Histologically, early changes at the tissue level include interstitial fibrosis, progressive loss of the fine vasculature and vacuolization of serous acinar cells. Of note, serous acinar cells seem to be more readily affected by radiation when compared to the mucous cells, presumably because of the relatively rapid turnover rate and profuse vasculature of serous cells. As such, saliva is more acidic and viscous with less buffering capacity. During the late stages of radiation therapy, glands become progressively fibrotic, leading to almost complete loss of acinar elements and the striated duct system. Ultimately, no saliva may be present. Because such environmental alterations make the oral cavity more susceptible to rampant caries, acute and chronic fungal infections and compromised tolerance to prosthesis such as dentures, early detection and management of xerostomia in these patients are critical to alleviate discomforts and possible permanent structural damage in the oral cavity. Clinical manifestation: Practitioners should actively look for signs and symptoms related to salivary hypofunction including fissures at the lip commissures, difficulties in swallowing or chewing as well as with speech. Salivary reduction up to 80 percent of its original flow13 and xerostomia can be specifically noted in cancer patients two weeks after initial radiation therapy or at a cumulative dose of 20 Gy. The diminished salivary flows bring changes to the oral flora, increasing the chances F E B R U A R Y 2 0 1 6 87


FIGURE 3A . Custom trays for maxillary and mandibular dentition.

FIGURE 3B . Custom trays on the maxillary and

mandibular dentition.

FIGURES 3 . Stannous fluoride gel application with custom tray.

of bacterial and/or fungal infection. These changes predispose the patient to radiation caries, which is typically located at the incisal edge and cervical third of the teeth. Rampant caries progress rapidly and extensively such that teeth become nonrestorable (FIGURE 2A ) or fractured at the gingival margin (FIGURE 2B ); therefore, early detection and immediate restorations are highly recommended. Management: Early symptoms of xerostomia include thick or ropey saliva in the oral cavity. Carboxymethylcellulose-, mucin-, water- or glycerin-based saliva substitutes may be used, although the effectiveness of these agents is somewhat questionable. In mild cases, a simple increase in the frequency of water intake is helpful. If salivary glands are spared from complete eradication by radiation therapy, salivary stimulants such as pilocarpine or cevimeline may be used. Xylitol-based chewing gum that has a nonfermentable sugar alcohol may also be used to increase salivary flow. The early use of stannous fluoride gel applied with custom carriers (FIGURE 3A ) and five-minute daily applications is highly recommended to reduce caries risk (FIGURE 3B ). If significant numbers of rampant caries are noted, dental treatment should be performed without any delay. Due to the high caries risk, fluoride-releasing glass ionomers and/or amalgam restorations are more predictable when compared to composite restorations. Patients should be counseled about eliminating sucrose from their diet and reducing the frequency of meals. 88 F E B R U A R Y 2 01 6

Osteoradionecrosis (ORN) General description: Osteoradionecrosis (ORN), as the name implies, means bone death because of radiation. The incidence of ORN ranges from 8 percent to 35 percent, largely depending on observational periods that range from months to years.14,15 Most of ORN (about 75 percent) occurs within the first three years of radiation therapy treatment.16 ORN is more prevalent in the mandible than the maxilla, owning to the poor vascularization and increased density that allows for absorbing more radiation in the mandible. The cause of ORN is still unclear although there are several hypotheses, such as bacterial infection, hypoxia and fibroatrophy.17-19 Risk factors include location of primary tumor, cancer staging, dose of radiation (> 60 Gy), poor oral hygiene, alcohol and tobacco use and invasive dental procedures such as tooth extraction.20 It is noteworthy that, once radiation therapy is delivered, cancer patients have the risk of developing ORN that is lifelong and does not decrease over time. Therefore, thorough examination at each visit for periodic examination is essential. Clinical manifestation: ORN is clinically defined as an area of exposed bone that persists for more than three months (FIGURE 4 ). However, radiographic findings of irregular radio-opacity that is indicative of sequestrum formation without breached overlaying mucosal closure is also common (FIGURE 5 ). Ulcerative or necrotic soft tissues can also be seen frequently around the exposed area. Long-term exposure without proper oral

FIGURE 4 . Osteoradionecrosis lesion with exposed bone in the lower right mandibular arch. Note plaque accumulation around the exposed bone.

care may lead to the accumulation of plaque that covers the exposed bone. Management: In one study, tooth extractions were found to be responsible for 50 percent of all ORN cases.14 Therefore, invasive dental procedures should be reserved. Periodontal procedures such as deep scaling and flap surgery are also contraindicated particularly in heavily irradiated patients. Instead, more conservative treatment approaches, such as endodontic therapy with or without coronal restorations, are preferable (FIGURE 6 ). When bone exposure is evident, a patient’s chief complaint is typically pain associated with bacterial infection secondary to exposed bone. Prescribing antibiotics may help resolve the pain. Regular checkups and dental prophylaxis every four months are highly recommended to maintain optimal conditions in the oral cavity along with giving the clinician ample opportunity to catch dental disease at the early stages. Hyperbaric oxygen (HBO) therapy that provides high contents of oxygen has been used to manage ORN conditions but without drastic improvement.21 If possible, it is highly encouraged to remove any sources of dental diseases including advanced caries, periapical infection and pathologic periodontal bone loss before a patient undergoes radiation therapy. New alternatives to HBO treatments have been introduced, such as the use of pentoxifylline and/or tocopherol,22,23 and the use of these medications may hold promising results in reducing the risk of and managing patients with ORN.


FIGURE 5A . Sclerotic changes around No. 31 area (arrows) after radiation therapy.

FIGURE 5B . After two years, sequestrum was

pushed out spontaneously.

FIGURE 6 . Endodontically treated Nos. 18 and 19 that are domed with amalgam restoration.

FIGURES 5 . Radiographic findings of irregular radio-opacity.

FIGURE 7. Trismus. Note the limited mouth opening.

FIGURE 8 . Candida albicans.

Trismus

worse and are often irreversible, early identification of trismus and immediate initiation of an exercise program using devices such as Therabite are critical to improving the condition significantly.27,28

General description: Trismus refers to limited mouth opening caused by any etiological reason related to sustained contraction of one or more mastication muscles.24 The most common etiological factors involve radiation-induced fibrosis and postsurgical scar formation.25 Trismus occurs most commonly when radiation is combined with a surgical procedure (e.g., radical maxillectomy) that affects the temporal mandibular joint (TMJ) and the muscles of mastication. Clinical manifestation: Clinically, mouth opening less than 35 mm is considered to be trismus, although the degree of limited mouth opening may be subjective.26 In severe cases, the maximum opening may be reduced to less than 10 mm (F I G U R E 7 ). The severity of trismus depends on age and concomitant chemotherapy. Management: The treatment consists of exercise and the use of dynamic bite openers. Because fibrosis and scar formation become progressively

Oral Candidiasis General description: Oral candidiasis is fungal lesions predominantly mediated by the yeast Candida albicans. C. albicans occurs naturally in the body including the oral cavity. In a normal setting, it does not give rise to any lesions, but candidiasis occurs when there is a drastic change within the oral environment (e.g., immunosuppression) that favors its reproduction. As such, it is often called an opportunistic infection. Brown, et al. reported that irradiation caused up to a hundredfold increases in fungal populations.29 This increase in fungal populations has significant clinical implications and is often overlooked. During the administration of radiation therapy, acute candidiasis is likely to occur due to altered immunity and xerostomia secondary to hyposalivary functions in the oral cavity.30

Upon completion of radiation, progressive fibrosis of the salivary glands will continue, which increases the risk of xerostomia. As this continues, the increase in the fungal population will continue. Much of this will be determined by the amount of xerostomia the patient experiences. Clinical manifestation: Candidiasis is one of the most frequent lesions experienced by patients undergoing cancer therapy. It presents as pseudomembranous (thrush), erythematous and angular cheilitis (FIGURE 8 ). Severe oral infections can result in discomfort and morbidity during and after radiation therapy.31 Postradiationtherapy chronic candidiasis is known to occur in up to 27 percent of patients.32 These patients may complain of a burning sensation in the oral mucosa and cracked lips along the commissure; however, these symptoms are often overlooked. Management: Nystatin is a drug of choice, which can be dispensed in a number of configurations, such as lozenges, powder, creams or oral suspension. Oral suppositories may be the best route of drug delivery to treat acute oral fungal infections. Many nystatin lozenges contain large of amounts of sucrose and should be used with caution in edentulous patients. In this population, vaginal/ rectal suppositories can be considered because they have no sucrose. However, taste or difficulty in use may affect compliance. Systemic administration of ketoconazole or fluorconozole is favored by many clinicians 33 and is preferred for potentially noncompliant patients. F E B R U A R Y 2 0 1 6 89


FIGURE 9. MRONJ

A

B

C

Prolonged use of antifungal medications is discouraged because of the risk of developing fungal resistance to these drugs.

Altered Taste Buds Alterations in taste acuity are first noticed as early as the second week of radiation therapy (approximately 30 Gy of radiation). Perception of bitter and acid flavors is more susceptible to impairment than salt and sweet. The architecture of the taste buds is almost completely eliminated at 50 Gy. However, taste generally returns to normal two to four weeks after the completion of therapy as long as salivary flow is reasonable. In the case of severe xerostomia following radiation therapy, the number of buds are significantly decreased and their morphology is altered. The perception of taste may be permanently altered.

Oral Complications Associated With Adjuvant Chemotherapy Cancers in advanced stages typically metastasize to other parts of the body. In particular, some cancers, including breast, prostate, lung, thyroid and kidney, are more prone to metastasize to other areas including bone. These lesions may also lead to high calcium levels in the blood stream called hypercalcemia. Medications commonly prescribed for the management of metastasis include 90 F E B R U A R Y 2 01 6

lesions induced by longterm bisphosphonate use. (A) Note radiolucency around the affected area (arrows), which is an indicative of nonviable bone. (B) A typical MRONJ lesion with plaque formation induced by the long-term use of bisphosphonates on the lower left mandibular arch. (C) Bony sequelae that fell out spontaneously from the upper right maxillary arch (A, arrowhead) that the patient brought to the clinic.

antiresorptive (e.g., bisphosphonates or denosumab) or anti-angiogenic (e.g., sunitinib or bevacizumab) drugs. The use of these medications is associated with MRONJ that specifically occurs in the oral cavity. Therefore, general practitioners should be aware of these MRONJ lesions when managing patients who are receiving such adjuvant chemotherapy.

MRONJ General description: The first formal report on osteonecrosis of the jaw (ONJ) by bisphosphonates was published in 2003,34 but the etiology is still unknown. Multiple hypotheses have been suggested, including suppression of bone remodeling, inflammation, inhibition of angiogenesis and soft tissue toxicity.35 The terminology of bisphosphonate-related osteonecrosis of the jaw, or simply BRONJ, was recently updated to MRONJ in order to be more inclusive of medications other than bisphosphonates, such as denosumab or bevacizumab.36 MRONJ is clinically defined as patients with a history of treatment with antiresportive or anti-angiogenic agents, exposed bone for more than eight weeks and no history of radiation therapy to the head and neck regions.36 A detailed classification of MRONJ can be found elsewhere.36 Individuals with advancedstage cancers that invade bone may take these medications, usually intravenously or

subcutaneously, to prevent the cancer from spreading to bone. As such, practitioners should keep in mind that osteoporosis patients also take these drugs orally, and that although the incidence of MRONJ occurring by this route is relatively less, these patients may still develop MRONJ lesions when they have been on these medications for more than four years.37 Practitioners should also be aware of the risk factors associated with MRONJ, such as high (e.g., IV or subcutaneous administration) and long duration (e.g., > four years) of doses, pre-existing inflammatory dental diseases (e.g., periodontal disease or periapical lesions), dentoalveolar surgery (e.g., tooth extraction), age and corticosteroids,37-43 all of which may exacerbate ONJ lesions. Clinical manifestation: A typical clinical presentation is very similar to that of ORN. Long-term exposure of bone is almost inevitably accompanied by plaque accumulation (FIGURE 9B ). Practitioners should consider this for patients who have pain with unidentifiable origin as it may indicate stage 0 MRONJ. Abnormal findings (e.g., sclerosis) from radiography and computed tomography (CT) should also be noted, but interpreted with caution, as it may be suggestive of MRONJ.44,45 Bone exposure is likely to be seen in previously extracted areas but can also occur spontaneously in thin oral mucosal areas such as tori. Spontaneous bone exposure may be associated with chronic inflammation (e.g., periodontal or periapical diseases) and previously traumatized areas. Radiographically, nonviable bone can be predicted based on radiolucent periphery around the affected area (FIGURE 9A ). A periodontal probe instrument can be used to detect bony surface through mucosal fistulas, which is indicative of MRONJ at the stage 1, 2 or 3. Management: Similar to ORN, invasive dental procedures should be refrained from, but conservative approaches are


TABLE

Summary of Oral-Specific Side Effects and Management in Cancer Patients Types of side effects

Types of cancer therapy

Common sites in the oral cavity

Patients’ chief complaints

Clinical manifestation

Goals of management

Management

Oral mucositis

Radio/chemo

All

Pain

Erythematous Ulcerative

To alleviate pain

Self-limiting after cancer therapy Topical anesthetics (lidocaine, benzocaine, dyclonine, capsaicin) Avoid irritating food

Xerostomia

Radio/chemo

All

Thick or ropey saliva

Rampant caries, decalcification

To increase salivary flow or substitutes To prevent secondary pathological events (e.g., rampant caries, infections)

Saliva substitutes (carboxymethylcellulose, mucin, water, glycin) Salivary stimulants (pilocarpine, cevimeline)

Osteoradionecrosis

Radio

Mandible

Nonhealing and/or pain at the exposed bony sites Unpleasant mouth smell

Exposed bone, plaque accumulation

To prevent further bone exposure To refer to specialist for surgical intervention for stage 3 patients

Analgesics Antibiotics Antimicrobial rinse (0.12% chlorhexidine) Avoid invasive dental procedures HBO chamber Pentoxifylline/tocopherol

Trismus

Surgical/radio/ chemo

Mastication muscles

Cannot open mouth

Limited mouth opening

To identify limited mouth opening early

Mouth opening exercise (Therabite)

Oral candidiasis

Radio/chemo

All

Burning sensation

White patches that can rub off

To eradicate candidiasis lesions

Nystatin (lozenges, powder, creams, oral suspension)

Altered taste

Radio/chemo

All

Cannot taste

None

None

Self-limiting after cancer therapy

MRONJ

Chemo (for advanced cancer)

Maxilla/ mandible

Nonhealing and/or pain at the exposed bony sites Unpleasant mouth smell

Exposed bone, plaque accumulation

To prevent further bone exposure To refer to specialist for surgical intervention for stage 3 patients

Analgesics Antimicrobial rinse (0.12% chlorhexidine) Good oral hygiene Avoid invasive dental procedures

recommended. It is important to know whether cancer patients are taking the aforementioned medications, as dental treatment options are significantly limited due to increased risk of MRONJ after invasive dental treatment. Once identified, patients with MRONJ should be managed according to the MRONJ staging. As a general practitioner, the primary goals of managing these patients are to maintain good oral hygiene in a nonsurgical manner in patients with stage 2 or less and to monitor progression of lesions such that, when the lesions meet the stage 3 criteria, the patients can be referred to oral surgeons for possible surgical interventions. For patients who are taking these mediations

without signs/symptoms of MRONJ, routine oral hygiene including scaling and root planning should be continued. For stage 0 patients with the chief complaint of pain with unidentifiable origins, the use of medication to control pain is helpful. In stage 1 or 2 patients with exposed bone, the use of oral antimicrobial rinses (e.g., 0.12% chlorhexidine) is recommended. Although infection as a primary etiological factor in causing MRONJ is still controversial, the use of antibiotics is also recommended in order to reduce bacterial colonization particularly at the area with exposed bone. It is not uncommon to observe a tooth with class 3 mobility. In such cases, extraction should be avoided; instead,

the occlusal plane can be reduced as needed to eliminate occlusal contacts and contact-associated pain until the tooth falls out spontaneously. In certain instance, patients may present with bony sequelae that naturally sequester out (FIGURE 9C ), and such a sign is usually accompanied by reepithelialization at the healing site. These sites should be continuously monitored.

Conclusion Once established, the relationship between dentists and patients can last for many years. As life expectancy increases and advancement of medical technology continues to grow, these relations may potentially be lifelong. During that time, F E B R U A R Y 2 0 1 6 91


dentists are likely to encounter patients who are undergoing or who have a history of cancer therapy. As general dental practitioners, knowing different cancer therapeutic modalities (e.g., surgical, radiation, chemo, or combination therapies) is essential for assessing and managing these cancer patients. Many side effects from cancer therapy, including oral mucositis, xerostomia, ORN, trismus and secondary infection, are inevitable but manageable, and to a certain degree, treatable (TABLE ). This holds true for MRONJ lesions in cancer patients undergoing adjuvant therapy with bisphosphonates and denosumab. As such, it is of paramount importance for the general dental practitioner to know how cancer therapy can affect oral health and to manage these patients accordingly in order to provide the full spectrum of dental services. Because managing cancer patients successfully in the general dental practice is a team effort, it is equally important for general practitioners to communicate not only with the patients but also with medical practitioners to determine the optimal management plan for each patient. ■ ACKNOWLEDGMENT

This study was supported by grants R01DE023874 and R01DE023348 from the National Institute of Dental and Craniofacial Research/National Institutes of Health. REFERENCES

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Acta Oncol 2014;53(4):502-9. 29. Brown LR, Dreizen S, Handler S, Johnston DA. Effect of radiation-induced xerostomia on human oral microflora. J Dent Res 1975;54(4):740-50. 30. Bensadoun RJ, Patton LL, Lalla RV, Epstein JB. Oropharyngeal candidiasis in head and neck cancer patients treated with radiation: Update 2011. Support Care Cancer 2011;19(6):737-44. 31. Ramirez-Amador V, Silverman Jr. S, Mayer P, Tyler M, Quivey J. Candidal colonization and oral candidiasis in patients undergoing oral and pharyngeal radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84(2):149-53. 32. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: A comprehensive review of agents in clinical use, current investigational compounds and putative targets for antifungal drug development. Adv Pharmacol 1998;44:343-500. 33. Haveman CW. Xerostomia management in the head and neck radiation patient. Tex Dent J 2004;121(6):483-97. 34. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 2003;61(9):1115-7. 35. Reid IR, Cornish J. Epidemiology and pathogenesis of osteonecrosis of the jaw. Nat Rev Rheumatol 2012;8(2):90-6. 36. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons position paper on medicationrelated osteonecrosis of the jaw — 2014 update. J Oral Maxillofac Surg 2014;72(10):1938-56. 37. Lo JC, O’Ryan FS, Gordon NP, et al. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 2010;68(2):243-53. 38. Thumbigere-Math V, Michalowicz BS, Hodges JS, et al. Periodontal disease as a risk factor for bisphosphonate-related osteonecrosis of the jaw. J Periodontol 2014;85(2):226-33. 39. Malden N, Lopes V. An epidemiological study of alendronaterelated osteonecrosis of the jaws. A case series from the southeast of Scotland with attention given to case definition and prevalence. J Bone Miner Metab 2012;30(2):171-82. 40. Henry D, et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: An analysis of data from patients with solid tumors. Support Care Cancer 2014;22(3):679-87. 41. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors and outcomes of osteonecrosis of the jaw: Integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012;23(5):1341-7. 42. Vahtsevanos K, Kyrgidis A, Verrou E, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009;27(32):5356-62. 43. Fehm T, Beck V, Banys M, et al. Bisphosphonate-induced osteonecrosis of the jaw (ONJ): Incidence and risk factors in patients with breast cancer and gynecological malignancies. Gynecol Oncol 2009;112(3):605-9. 44. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: A systematic review and international consensus. J Bone Miner Res 2015;30(1):3-23. 45. Bedogni A, Fedele S, Bedogni G, et al. Staging of osteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease. Br J Oral Maxillofac Surg 2014;52(7):603-8. THE CORRESPONDING AUTHORS,

Reuben Han-Kyu Kim, DDS, PhD, and Eric C. Sung, DDS, can be reached at [email protected] and [email protected].

oropharyngeal cancer C D A J O U R N A L , V O L 4 4 , Nº 2

Current Trends in the Incidence and Presentation of Oropharyngeal Cancer Fariba S. Younai, DDS

A B S T R A C T The prevalence and behavior of oropharyngeal cancers have

dramatically changed over the past 30 years. It is now clear that human papillomavirus (HPV) plays a major role in the incidence of head and neck cancers in the general population and among patients with HIV infection. This article reviews the current knowledge about oropharyngeal cancers for their epidemiology, pathogenesis, clinical behavior, treatment and prevention. This review further examines the subset of oropharyngeal cancers among the HIV-seropositive patients.

AUTHOR Fariba S. Younai, DDS, is a professor of clinical dentistry in the section of oral medicine and orofacial pain in the division of oral biology and medicine at the University of California, Los Angeles, School of Dentistry, where she currently serves as the vice chair of the division of oral biology and medicine. Dr. Younai earned her dental degree from the School of Dental Medicine at the State University of New York at Stony Brook and completed her training in hospital dentistry at Long Island Jewish Medical Center in New York. Conflict of Interest Disclosure: None reported.

A

new global pattern of oropharyngeal cancer epidemiology started to emerge in the 1990s. An increased incidence of malignant lesions, specifically squamous cell carcinomas, was being noted to occur mostly in the posterior region of the oropharynx and among younger individuals who did not have the traditional oral cancer risks such as smoking and excess alcohol use.1 Since then, the scientific evidence has increasingly shown that this subset of head and neck cancers is a distinct entity connected to an infection with human papillomavirus (HPV) and, in fact, exhibits better overall survival rates and response to treatment.2-6 This association between HPV and oral malignancy is even more pronounced among individuals seropositive for the human immunodeficiency virus

(HIV) who, in recent years, have also started to present with an increased incidence of head and neck and oropharyngeal squamous cell carcinomas.3

Oropharyngeal Cancer Epidemiology Every year, more than 600,000 new cases of head and neck cancer (HNC) are reported worldwide.7 As the sixth most common type of cancer, the incidence rates of HNC have great variations across the globe — it is the most common form of cancer in India while its incidence rates in the United States and in northern Europe are lower than in countries in Latin America.8 The majority of head and neck cancers are of the squamous cell carcinoma (SCC) type involving the oral cavity, oropharynx, hypopharynx, larynx, sinonasal tract and nasopharynx.7 The term “oral cavity cancer” (OCC) typically refers to a malignant lesion in the anterior part of the oral cavity, F E B R U A R Y 2 0 1 6 93


including gingivae, floor of the mouth, buccal mucosa, retromolar trigone, hard palate and the anterior two-thirds of the tongue, while the “oropharyngeal cancer” (OPC) designation is for those lesions located in any of four distinct subsites: the posterior pharyngeal wall, the soft palate, the tonsillar complex and the base of the tongue.9,10 Several studies have provided overwhelming evidence for the increasing incidence of oropharyngeal cancer worldwide. In the U.S., an assessment of the incidence data from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI) showed that between 1973 and 1995, the incidence of tonsillar SCC among men younger than 60 years of age increased by about 2 to 3 percent per year.11 Another analysis of the data from the SEER Program and the mortality data from the National Center for Health Statistics (NCHS) further revealed that from the late 1980s to 2001, the risk for tonsillar SCC increased for males age 40-64 years while the incidence for this type of cancer and progression to death decreased for those age 65 years and older.12 A parallel pattern was reported from Sweden and Finland during the same approximate time period.13,14 Looking at the global statistics, one study using data from the Cancer Incidence in Five Continents database, maintained by the International Agency for Research on Cancer (IARC), constructed age-period-cohort models to examine the incidence trends for OPC and OCC across 23 countries around the world.15 This comprehensive analysis showed that between 1983 and 2002, significant increases in OPC incidence were observed among both men and women, predominantly among individuals younger than 60 years and in economically developed countries such as the U.S., Australia, Canada, Japan 94 F E B R U A R Y 2 01 6

and Slovakia.15 The striking finding in this analysis was that the increased OPC incidence among men corresponded with a reduction in the incidence of both OCC and lung cancer, but among women, a reverse pattern was observed where the increased OPC incidence occurred with concomitant increases in the incidence of OCC and lung cancer. These findings suggested significant differences between the OPC risk factors and those of OCC and lung cancer, differences that may be more influential in cancer development among men than women.

Several studies have provided overwhelming evidence for the increasing incidence of oropharyngeal cancer worldwide.

After the introduction of effective combination antiretroviral therapies (ART or cART) in the mid-1990s, the incident rates for the AIDS-defining cancers, such as Kaposi’s sarcoma, was dramatically reduced, while a trend toward increased incidence of other types of cancer, like lung cancer, invasive anal SCC, head/neck cancers and Hodgkin lymphoma, started to emerge.16-18 Pooled data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) studies between 1996 and 2009 showed that the HIVinfected individuals’ risk of development of HNC, specifically SCC, was threefold higher than that of the general U.S. population.19 This report also showed a modest role for immunosuppression (low CD4 count) prior to cancer diagnosis.

It is not entirely clear if the increase in the incidence of head and neck cancers among HIV-infected individuals is related to behavioral factors such as tobacco and alcohol use, immune suppression, long-term use of cART, other infectious agents or results from a combination of all these factors.

HPV Infection and Oropharyngeal Cancer Globally, smoking, alcohol consumption and betel nut chewing are traditional risk factors for the SCC type of HNC and OCC.20 In fact, aside from cases of oral dysplasia seen related to betel nut chewing that is common in Asia and the tropical Pacific region, traditional patients with OCC have been older men with a significant smoking and drinking history. As noted before, there has been a significant reduction in the rates of OCC among older male smokers, mostly due to reductions in the global smoking and alcohol consumption rates.21,22 At the same time, there has been a dramatic increase in incidence rates of oropharyngeal cancer among middle-aged white men who are often nonsmokers or former/light smokers, a phenomenon now attributed to infection with HPV.23-26 In the U.S., by 2010, the rate of OPC among men became higher than the rate of cervical cancer in women and if this trend continues, by the year 2020 the annual number of HPV-positive OPC will surpass the annual number of cervical cancers.27 An analysis of the SEER data from three regions (Hawaii, Iowa and Los Angeles) showed that while the incidence rate for HPV-negative OPC dropped from 2.0 per 100,000 in 1988 to 1.0 per 100,000 in 2004, the rates for HPV-positive tumors increased by more than threefold, from 0.8 per 100,000 in 1988 to 2.6 per 100,000 in 2004 (F I G U R E 1 ).27


4 3.5

Rates per 100,000

3 2.5 2 1.5 1

Oropharynx (overall) HPV-negative oropharynx HPV-positive oropharynx

.5 0

1988–1990

1991–1992

1995–1996

1999–2000

2003–2004

Surveillance Period FIGURE 1. Incidence rates for overall HPV-positive and HPV-negative OPC (SEER data from Hawaii, Iowa and

Los Angeles 1988-2004). Adopted from J Clinical Oncology 2011;29(32):4294-4301.

HPV-positive squamous cell carcinoma is a genetically, clinically and epidemiologically distinct subtype of HNC with a predilection for the oropharyngeal tissues, referred to by many as HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).28 The first reports of a potential role for HPV in the HNC development were published almost 35 years ago.29-31 However, it was not until the surge in the HNC incidence that the role of HPV in OPC carcinogenesis became subject to intense scientific research for its natural history, transmission patterns and primary and secondary prevention approaches. Human papillomavirus has more than 320 different subtypes found in many vertebrae, of which more than 200 genotypes have been fully sequenced in humans.32 HPV has five different genera (alpha, beta, gamma, mu and nu) and although each group has a specific anatomic site predilection, they all share great epithelial tropism and are found in either skin, mucosa or both, even when nonpathogenic.33 In their pathogenic form in the skin, the anogenital tissues and the tracheobronchial and oral mucosa, several HPV subtypes lead to benign hyperproliferative epithelial lesions that

include cutaneous and genital warts and recurrent respiratory papillomatosis.34 In the anogenital tissues specifically, a number of HPV genotypes are connected to premalignant and malignant lesions such as squamous intraepithelial lesions (SILs) and anal, vaginal and cervical cancers. Of more than 15 high-risk HPV subtypes, HPV 16 and 18 are best known for their role in anogenital cancers and were initially targeted for vaccine development.35

The HPV Life Cycle Human papillomavirus is a small, nonencapsulated virus consisting of a core with an 8,000 base pair long circular DNA and an outer capsid that contains two main proteins, L1 and L2.34 The L1 protein is the highly conserved main capsid component, and because of an ability to elicit virusneutralizing antibodies in humans, it has been the basis for the currently available HPV vaccines; the L2 protein along with L1 interacts with a number of cellular proteins during the viral entry process into the host cell.35 The virus has six main nonstructural regulatory proteins, E1, E2, E4, E5, E6 and E7, each with a specific function related to viral replication and/ or oncogenesis.34 The E and L designations are based on the order of expression of

these viral gene products, early or late in the transcription process during viral replication. The HPV genome contains segments referred to as open reading frames (ORF — codons or sequence of nucleotides with the potential to be transcribed into RNA) that encode early proteins E1 through E8 and late proteins L1 and L2.34 Of all the regulatory proteins, E1 and E2 are necessary for viral replication and, therefore, the genes encoding for these as well as the capsid proteins L1 and L2 are called the “core” genes, while the genes encoding for the other proteins that mainly affect the cellular environment of the virus are called “accessory” genes.34,35 The viral infection of the epithelial basal cells and HPV entry into the cell’s nucleus is thought to ensue a series of steps that include: a) microtrauma to the epithelium, b) an interaction between the viral L1 capsid protein and the extracellular matrix (ECM) or the cell surface of basal layer keratinocytes and c) an interaction between the L2 capsid protein and the host lysosomal membrane for viral endocytosis.34-37 After entry into the host cell, papillomaviruses replicate and assemble exclusively in the nucleus in a fashion that is regulated by the patterns of keratinocyte maturation and differentiation across the epithelial cell layers. For instance, the expression of the early regulatory proteins occurs in the lower undifferentiated or intermediately differentiated keratinocytes while the transcription of the late capsid proteins takes place in the upper layer of keratinocytes undergoing terminal differentiation.36 Of all the viral proteins, E1 and E2 actively function in viral DNA replication,36 E4 facilitates virion release into the environment,38 and E5, E6 and E7 facilitate the transformation of regularly maturing keratinocytes into malignant cells. More specifically, E5 protein activates the cell growth-promoting signaling of F E B R U A R Y 2 0 1 6 95


TABLE

TNM Staging for Tumors of the Oropharynx

factors such as platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). The other viral proteins E6 and E7 interfere with epithelial cell cycle regulatory mechanisms. E6 promotes uncontrolled cell growth by mainly mediating the degradation of p53, the protein product of the tumor suppressor gene TP53; in humans, this gene has a gatekeeper function, conserving genetic stability, preventing genome mutations and inducing death (apoptosis) in cells that have damaged DNA. E7 inactivates members of the retinoblastoma protein (pRb) family of tumor suppressor proteins produced by tumor suppressor gene RB; normally, these proteins prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide.39,40 Taken together, these viral proteins and the genes that encode for them (referred to as oncogenes) serve to prevent apoptosis and promote cell cycle progression with enhanced uncontrolled viral DNA replication. Because the expression of E6 and E7 oncogenes occurs in the malignant phenotype in HPV-induced cancers, their transcription products are currently targeted for therapeutic HPV vaccine development.41 After viral DNA replication is complete, the new infectious progeny virus accumulates in the keratinocytes in the outermost layers of the skin or mucosal surface. The assembled viruses may remain dormant in the tissues and not produce a clinical disease. In these chronic infections, the release of the new virions occurs through normal epithelial desquamation process from the surface and therefore is not associated with host cell lysis and an inflammatory response. This is one mechanism that HPV uses to evade the host immune response, others include a life cycle that is exclusively intraepithelial and without viremia, a lack of any 96 F E B R U A R Y 2 01 6

TNM

Definitions

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor 2 cm or less in greatest dimension

T2

Tumor more than 2 cm but not more than 4 cm in greatest dimension

T3

Tumor more than 4 cm in greatest dimension •T4a

Tumor invades the larynx, deep/extrinsic muscle of tongue, medial pterygoid, hard palate or mandible

•T4b

Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx or skull base or encases carotid artery

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension

N2

Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension •N2a

Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension

•N2b

Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension

•N2c

Metastasis in a lymph more than 6 cm in greatest dimension

N3 Mx

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

Adopted from CA Cancer J Clin 2005;55;242-258. American Cancer Society.

proinflammatory cytokine production and no activation of Langerhans or dendritic cell signaling.34 The HPV infection can be immunologically cleared or remain dormant and not produce a high number of viral copies until immunologic suppression.34 It should be noted that much of the HPV life cycle mechanisms described are based on studies of anogenital infections as the natural history of oral and oropharyngeal HPV is still under investigation. Preliminary studies suggest that like anogenital infections, oral HPV clears within one or two years, mostly because of oral mucosal immune responses, but the rate of clearance is dependent upon

the oral viral load.42 It is estimated that about 7 percent of the U.S. population (men and women aged 14 to 69 years) have oral HPV, 1 percent carrying the HPV type 16, with peak prevalence among individuals aged 30 to 34 years,43 while among HIV-seropositive patients this rate may be as high as 12.3 percent.44 In one study, the rate of HPV carriage among HIV-negative men who have sex with men (MSM) attending a sexually transmitted disease (STD) clinic was 13.7 percent, 5.9 percent for high-risk HPV, not correlating with the rate in the anogenital samples, suggesting a different natural history of the virus in the oropharyngeal tissues.45 Interestingly, the level of oral HPV carriage


FIGURE 2 . A ginigival SCC in an HIV-seropositive

patient.

seems to correlate with sexual behaviors. Indeed, having a higher number of oral sex and “rimming” partners, recently or over a lifetime, is associated with increased odds of oral HPV prevalence.43,46-50 As data support a lower rate of oral HPV clearance among HIV-seropositive individuals, especially those with lower CD4 counts,50 a higher risk of oral cancer development,51 higher mortality rates for oral cancer than many other cancers,52 and considering the high rate of HPV (and high-risk-HPV) carriage in the oral tissues of both HIV-seropositive and HIV-negative high-risk individuals, especially correlated with sexual behaviors as described above, cancer prevention strategies must therefore include targeted patient education as well as clinical vigilance, especially by oral health care providers.

Clinical Considerations As previously described, the great majority of oropharyngeal cancers are squamous cell carcinomas that are found, for the most part, in the tonsillar complex as well as the base of the tongue, the soft palate and the posterior pharyngeal wall. In clinical dental practice, a careful visual assessment of the oral/pharyngeal structures and the regional lymph nodes with digital palpation is critical to detecting cancerous lesions. In addition, alarm symptoms such as trismus, dysphagia, changes in tongue mobility and otalgia should be further investigated for lesions that may have penetrated deeper tissues in

the region.53 Other diagnostic modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) or positron emission tomography are helpful in more accurate assessment of the extent of OPC. Traditionally, the TNM staging, based on the tumor size (T), regional nodal involvement (N) and level of distant metastasis (M), has been used to classify cancers into stages 1 to 4 in order to guide treatment decisions and to predict the treatment outcomes. The TABLE shows the definitions for the TNM staging of oropharyngeal cancers according to the Fourth Collaborative Staging between the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC).54 Currently, the major clinical outcome of oropharyngeal cancer treatment is to preserve patients’ function; therefore, nonsurgical treatment options using chemotherapy and radiation therapy are preferred whenever possible.54 However, organ preservation therapy may not be possible for all patients and surgical resection may be the only option. In patients who require surgical excision, the pathologic stage of the tumor (pTNM) derived from histopathologic examination of the tumor and/or regional lymph nodes is useful in selecting postoperative adjuvant therapy and for estimating prognosis.54 The histologic classification of OPSCC consists of well-differentiated, moderately differentiated and poorly differentiated squamous cell carcinomas.53 The significance of this classification is that when the level of maturation of the cells and their organization in the tumor tissue are close to normal cells, referred to as “well-differentiated,” the rate of growth and spread of the tumor is slower than when tumors are “poorly” or even “moderately differentiated.” For advanced stage disease where tumor resection is not an option, induction chemotherapy with cisplatin in combination with

5-fluorouracil and/or docetaxel has shown improved patient survival.55-58 Other possible agents under investigation for use in induction chemotherapy include the biological agents, among which anti-epidermal growth factor receptor-targeted (EGFR) monoclonal antibody may provide additional benefits to standard chemotherapy.59 It has not been determined if the treatment outcomes for the HIVseropositive patients are any different from the outcomes for patients without HIV infection. FIGURE 2 shows a gingival SCC in an HIV-positive patient who was also diagnosed with anal intraepithelial neoplasia and SCC for the preceding four years; both cancers were positive for HPV 16. The initial treatment of this gingival lesion consisted of only surgical resection with no radiation therapy and the lesion recurred in less than three months, requiring a marginal resection of the jaw. One retrospective study of 73 HIV patients with HNSCC suggested that HIV infection may negatively impact patients’ locoregional control (presence or absence of recurrence or second primary tumors) and overall survival.60 This study had certain limitations though, it included a variety of cancer types and locations and the patients had varying degrees of immune suppression and cART use and received a combination of treatment approaches including radiation and/or chemotherapy. Clearly, more robust studies with adequate patient stratification and longer periods of followup are necessary to truly demonstrate the impact of HIV infection in HNC survival.

Molecular Studies As mentioned earlier, HPV-associated OPSCC has better clinical prognosis, both in terms of progression rate and response to treatment. Although the exact reasons for this phenomenon remain elusive, among the proposed mechanisms are the F E B R U A R Y 2 0 1 6 97


younger age of individuals at diagnosis, lower rates of smoking and alcoholrelated morbidities and more sensitivity to treatment because of HPV-induced P53 dysfunction and better apoptotic response of cancer cells to radiation and chemotherapy.61 In addition to these factors, HPV-positive OPSCC has a more indolent clinical behavior with a clinical staging that is in an earlier T-category and a more advanced N-category but lymph node metastasis that is often cystic in nature.62 Based on these properties inferred by HPV infection, HPV testing of the cancer tissues is becoming the standard of care at many cancer treatment centers. Molecular detection of HPV DNA, the gold standard for the identification of HPV in tissues, can be accomplished by methods such as Southern transfer hybridization, dot blot hybridization, in situ hybridization (ISH), hybrid capture and polymerase chain reaction (PCR).63,64 Although identifying the presence of HPV in the cancer tissue samples is important to predicting its prognosis, it has become exceedingly clear that even among HPV-positive OPSCC lesions, there is a great degree of heterogeneity that is driven by the level of HPV biological activity, offering an opportunity for specific prognostic molecular markers that may further enhance outcomes of these cancers in the future.59 For instance, the level of expression of p16INK4a (a cyclin-dependent kinase inhibitor that promotes cell cycle arrest) in the HPV-positive SCC tissues may be a good molecular proxy for this level of activity. It turns out that the suppressive effect of HPV E7 protein on pRb leads to an over expression of the INK4a, a tumor suppressor gene and its protein product p16INK4A and hence improves the overall cancer prognosis. Therefore, immunostaining for p16INK4A in conjunction with HPV DNA testing 98 F E B R U A R Y 2 01 6

of the tissue can be a good prognostic marker for the level of HPV biological activity.65 The clinical relevance of this was shown in one study that compared the prognostic value of HPV-16 DNA viral load with p16 protein expression, showing the most favorable prognosis for patients whose tumors were HPV16-positive/p16 expressive.66 It should be noted that continuous smoking and alcohol use can change the behavior of HPV-positive tumors, as both smoking and alcohol can induce mutational loss of p53 and p16INK4A.59 Currently,

Based on these properties inferred by HPV infection, HPV testing of the cancer tissues is becoming the standard of care at many cancer treatment centers.

several other molecular mechanisms are being investigated for their possible contributions to the overall prognosis of HPV-positive tumors. Some of these include the role of HPV in the Wnt and Notch signaling pathways involved in keratinocyte differentiation, the role of epigenetic factors such as the differences in the methylation profile of HPV-positive and HPV-negative tumors and the contribution of angiogenesis factors such as vascular endothelial growth factor (VEGF) and endothelin-1 in tumor progression.67-69

Prevention Strategies With an estimated life-long risk of cervical HPV infection up to 80 percent among sexually active women, HPV is considered the most

common sexually transmitted infection worldwide.70Although HPV is known to be transmitted through direct skin or mucosa contact, its transmission patterns and the exact determinants of susceptibility and infectivity are less established. In one recent study, a perperson transmission probability of about 20 percent during a six-month period was shown among discordant couples.71 In this study, the transmission rates from women to men and men to women were the same, varied little with the circumcision status of the men and showed a trend toward higher rates for HPV 16. Because of its relationship with cancer development in cervical tissues, HPV malignant subtypes have been targeted for vaccine development. In the U.S., a quadrivalent HPV vaccine (4vHPV) that targets HPV 6, 11, 16 and 18 has been available since 2006 and a 9-valent vaccine (9vHPV) targeting additional HPV subtypes 31, 33, 45, 52 and 58 was licensed for use in females and males in December 2014.72 In addition, a bivalent HPV vaccine against HPV subtypes 16 and 18 has also been available since 2009.73 According to the U.S. Advisory Committee on Immunization Practices (ACIP), the HPV vaccines are recommended to be used routinely for females and males at age 11 or 12 years (can be started beginning at age 9) up to age 26 years.74 Each HPV vaccine is delivered through a series of three intramuscular injections over a six-month period and is not recommended for pregnant women; if the vaccine schedule is interrupted, the vaccination series does not need to be restarted and there are no booster doses recommended.74 These vaccines are now available in most countries in the world and are recommended by the World Health Organization to be used in young women after age 9 and in two doses six months apart.75


There is no doubt that vaccination of females, despite low vaccine coverage, has contributed to a reduction in the prevalence of cervical infections of the targeted HPV subtypes. One U.S. study showed an HPV positivity rate of 5.1 percent of cervicovaginal specimens from 2007 to 2010 compared to 11.5 percent of the specimen in 2003-2006.76 What is not clear is the extent to which HPV vaccination has impacted the incidence of cervical cancer, and even less is known about its impact on other types of HPV-related cancers. A recent Centers for Disease Control and Prevention study used about 2,700 cancer archival tissues collected from 1993 to 2005 from seven U.S. cancer registries and, after HPV DNA testing of the samples, provided estimates for the impact of HPV vaccines in reducing the HPV-related cancers.77 The study estimated that the quadrivalent vaccine can potentially prevent the majority of invasive cervical, anal, oropharyngeal and vaginal cancers, almost 25,000 cases annually, and the 9-valent vaccine has the potential to prevent an additional 4,000 cases.77 These estimates are very encouraging and call for improved vaccination coverage for both young men and women, before they become sexually active.

Conclusion HPV-related oropharyngeal cancers are increasing, and while HPV vaccination can reduce the incidence of these cancers, early clinical detection and lower cancer staging is key to patient survival after diagnosis. Focused scientific research has started to produce reliable prognostic molecular markers and novel treatment approaches that, once clinically validated and adopted in everyday practice, can forever transform the landscape of oropharyngeal cancer detection, staging and treatment. ■

REFERENCES

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Head and Neck Squamous Cell Carcinoma in HIV-infected individuals. North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA. Oral Oncol 2014;50(12):1169-76. 20. Licitra L, Bernier J, Grandi C, et al. Cancer of the oropharynx. Crit Rev Oncol Hematol 2002;41:107-122. 21. Ng M, Freeman MK, Fleming TD, et al. Smoking Prevalence and Cigarette Consumption in 187 Countries, 1980-2012. JAMA 2014;311(2):183-192. 22. Pytynia KB, Dahlstrom KR, Sturgis EM. Epidemiology of HPV-associated oropharyngeal cancer. Oral Oncol 2014; 50(5):380-386. 23. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709-720. 24. Dahlstrand HM, Dalianis T. Presence and influence of human papillomaviruses (HPV) in tonsillar cancer. Adv Cancer Res 2005;93:59-89. 25. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review. Cancer Epidemiol Biomarkers Prev 2005;14(2):467-75. 26. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29(32):4294-4301. 27. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence Trends for Human Papillomavirus–Related and –Unrelated Oral Squamous Cell Carcinomas in the United States. J Clin Oncol 2008;26:612-619. 28. Edwards BK, Noone AM, Mariotto AB, et al. Annual Report to the Nation on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast or prostate cancer. Cancer 2014;120(9):1290-314. 29. Syrjänen KJ, Surjänen SM. Histological evidence for the presence of condylomatous epithelial lesions in association with laryngeal squamous cell carcinoma. J Otorhinolaryngol Relat Spec 1981;43(4):181-94. 30. Syrjänen K, Syrjänen S, Pyrhönen S. Human papilloma virus (HPV) antigens in lesions of laryngeal squamous cell carcinomas. J Otorhinolaryngol Relat Spec 1982;44(6):32334. 31. Syrjänen K, Syrjänen S, Lamberg M, et al. Morphological and immunohistochemical evidence suggesting human papillomavirus (HPV) involvement in oral squamous cell carcinogenesis. Int J Oral Surg 1983;12(6):418-24. 32. PaVE: The papillomavirus knowledge source. Papillomavirus Episteme. pave.niaid.nih.gov. Accessed Aug. 9, 2015. 33. de Villiers EM. Crossroads in the classification of papillomaviruses. Virology 2013;445(1-2):2-10. 34. Egawa N, Egawa K, Griffin H, Doorbar J. Human Papillomaviruses; Epithelial Tropisms and the Development of Neoplasia. Viruses 2015;7(7):3863-90. 35. June 8, 2006 Approval Letter — Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant. www.fda.gov/BiologicsBloodVaccines/Vaccines/ ApprovedProducts/ucm111283.htm. Accessed Aug. 8, 2015. 36. Zheng ZM, Baker CC. Papillomavirus genome structure, expression and post-transcriptional regulation. Front Biosci 2006;11:2286-2302. F E B R U A R Y 2 0 1 6 99


37. Richards KF, Mukherjee S, Bienkowska-Haba M, et al. Human papillomavirus species-specific interaction with the basement membrane-resident non-heparan sulfate receptor. Viruses 2014;6(12):4856-79. 38. Doorbar J. The E4 protein; structure, function and patterns of expression. Virology 2013;445(1-2):80-98. 39. Ramakrishnan S, Partricia S, Mathan G. Overview of highrisk HPV’s 16 and 18 infected cervical cancer: Pathogenesis to prevention. Biomed Pharmacother 2015;70:103-10. 40. Rampias T, Sasaki C, Psyrri A. Molecular mechanisms of HPV induced carcinogenesis in head and neck. Oral Oncol 2014;50(5):356-63. 41. Goodwin EC, DiMaio D. Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Nat Acad Sci USA 2000;97(23):12513-8. 42. Beachler DC, Guo Y, Xiao W, et al. High Oral Human Papillomavirus Type 16 Load Predicts Long-Term Persistence in Individuals With or at Risk for HIV Infection. J Infect Dis 2015 Nov 15;212(10):1588-91. 43. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of Oral HPV Infection in the United States, 2009-2010. JAMA 2012;307(7):693-703. 44. Kreimer AR, Pierce CM, Lin HY, et al. Incidence and clearance of oral human papillomavirus infection in men: The HIM cohort study. Lancet 2013;382(9895):877-87. 45. King EM, Gilson R, Beddows S, et al. Oral human papillomavirus (HPV) infection in men who have sex with men: Prevalence and lack of anogenital concordance. Sex Transm Infect 2015;91(4):284-6. 46. D’Souza G, Agrawal Y, Halpern J, et al. Oral sexual behaviors associated with prevalent oral human papillomavirus infection. J Infect Dis 2009;199(9):1263-9. 47. Kreimer AR, Alberg AJ, Daniel R, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 2004;189(4):686-98. 48. Heck JE, Berthiller J, Vaccarella S, et al. Sexual behaviours and the risk of head and neck cancers: A pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol 2010;39(1):166-81. 49. Beachler DC, Weber KM, Margolick JB, et al. Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults. Cancer Epidemiol Biomarkers Prev 2012;21(1):122-33. 50. Beachler DC, Sugar EA, Margolick JB, et al. Risk factors for acquisition and clearance of oral human papillomavirus infection among HIV-infected and HIV-uninfected adults. Am J Epidemiol 2015;181(1):40-53. 51. Chen CH, Chung CY, Wang LH, et al. Risk of cancer among HIV-infected patients from a population-based nested case-control study: Implications for cancer prevention. BMC Cancer 2015;15:133. 52. Castel AD, Young H, Akiwumi AM, et al. Trends in cancer diagnoses and survival among persons with AIDS in a high HIV prevalence urban area. AIDS Care 2015;27(7):860-9. 53. Cohan DM, Popat S, Kaplan SE, et al. Oropharyngeal cancer: Current understanding and management. Curr Opin Otolaryngol Head Neck Surg 2009;17(2):88-94. 54. Patel SG, Shah JP. TNM Staging of Cancers of the Head and Neck: Striving for Uniformity Among Diversity. CA Cancer J Clin 2005;55;242-258. American Cancer Society. www. oralcancerfoundation.org/discovery-diagnosis/pdf/TNM-

100 F E B R U A R Y 2 01 6

staging.pdf. Accessed Aug. 12, 2015. 55. Osborne RF, Brown JJ. Carcinoma of the oral pharynx: An analysis of subsite treatment heterogeneity. Surg Oncol Clin N Am 2004;13(1):71-80. 56. Stupp R, Weichselbaum RR, Vokes EE. Combined modality therapy of head neck cancer. Semin Oncol 1994;21:349-58. 57. Adelstein D, Sharan V, Earle AS, et al. Long-term results after chemoradiation for locally confined squamous cell head and neck cancer. Am J Clin Oncol 1990;13:440-7. 58. Vermorken JB, Remenar E, van Herpen C, et al., EORTC 24971/TAX 323 Study Group. Cisplatin, fluorouracil and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357(17):1695-704. 59. Wirth LJ, Allen AM, Posner MR, et al. Phase I dosefinding study of paclitaxel with panitumumab, carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck. Ann Oncol 2010;21(2):342-7. 60. Mourad WF, Hu KS, Shasha D, et al. Long-term outcome of seropositive HIV patients with head and neck squamous cell carcinoma treated with radiation therapy and chemotherapy. Anticancer Res 2013;33(12):5511-6. 61. Guihard S, Ramolu L, Macabre C, et al. The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation. Int J Oncol 2012 Oct;41(4):1531-40. 62. Goldenberg D, Begum S, Westra WH, et al. Cystic lymph node metastasis in patients with head and neck cancer: An HPV-associated phenomenon. Head Neck 2008 Jul;30(7):898-903. 63. Zaravinos A. An updated overview of HPV-associated head and neck carcinomas. Oncotarget 2014;5(12):3956-69. 64. Zaravinos A, Mammas IN, Sourvinos G, Spandidos DA. Molecular detection methods of human papillomavirus (HPV). Int J Biol Markers 2009;24(4):215-22. 65. Liang C, Marsit CJ, McClean MD, et al. Biomarkers of HPV in head and neck squamous cell carcinoma. Cancer Res 2012;72(19):5004-13. 66. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus — associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006;24(5):736-47. 67. Rampias T, Sasaki C, Psyrri A. Oral Oncol 2014;50(5):356-63. 68. van Kempen PM, Noorlag R, Braunius WW, et al. Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma: A systematic review. Epigenetics 2014;9(2):194-203. 69. Baruah P, Lee M, Wilson PO, et al. Impact of p16 status on pro- and anti-angiogenesis factors in head and neck cancers. Br J Cancer 2015;113(4):653-659. 70. Veldhuijzen NJ, Snijders PJ, Reiss P, et al. Factors affecting transmission of mucosal human papillomavirus. Lancet Infect Dis 2010 Dec;10(12):862-74. 71. Burchell AN, Coutlée F, Tellier PP, et al. Genital transmission of human papillomavirus in recently formed heterosexual couples. J Infect Dis 2011;204:1723. 72. Food and Drug Administration. Highlights of prescribing information. Gardasil 9 (human papillomavirus 9-valent vaccine, recombinant). Silver Spring, Md.: U.S. Department of Health and Human Services, Food and Drug Administration; 2014. www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ ApprovedProducts/UCM426457.pdf. Accessed Aug. 12, 2015.

73. FDA Licensure of Bivalent Human Papillomavirus Vaccine (HPV2, Cervarix) for Use in Females and Updated HPV Vaccination Recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(20):626-629. 74. Petrosky E, Bocchini Jr. JA, Hariri S, et al. Use of 9-Valent Human Papillomavirus (HPV) Vaccine: Updated HPV Vaccination Recommendations of the Advisory Committee on Immunization Practices. MMWR 2015;64(11):300-304. 75. World Health Organization. Weekly epidemiological record. Human papillomavirus vaccines. WHO position paper 2014;89:465-492. 76. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 20032010. J Infect Dis 2013;208(3):385-93. 77. Saraiya M, Unger ER, Thompson TD, et al. HPV Typing of Cancers Workgroup. U.S. assessment of HPV types in cancers: Implications for current and 9-valent HPV vaccines. J Natl Cancer Inst 2015;107(6):djv086. THE AUTHOR,

Fariba S. Younai, DDS, can be reached at [email protected].

chemoprevention C D A J O U R N A L , V O L 4 4 , Nº 2

Oral Cancer Chemoprevention: Current Status and Future Direction Diana V. Messadi, DDS, MMSc, DMSc, and Kazumichi Sato, DDS, PhD

A B S T R A C T The aim of this study is to review the current status of cancer

chemoprevention and its effectiveness in treatment of oral premalignant lesions and prevention of their progression to oral cancer. The challenges encountered in the different oral cancer chemoprevention clinical trials, including lack of surrogate endpoints, reversal of histologic premalignant changes as study endpoints, tobacco use, human papillomavirus, delivery system, adverse effects and risk of bias in clinical studies, are presented.

AUTHORS Diana V. Messadi, DDS, MMSc, DMSc, is a professor and chair of the section of oral medicine and orofacial pain and the associate dean for education and faculty development at the University of California, Los Angeles, School of Dentistry. Conflict of Interest Disclosure: None reported.

Kazumichi Sato, DDS, PhD, is an associate professor in the department of oral medicine and oral and maxillofacial surgery at Tokyo Dental College in Sugano, Ichikawa, Chiba, Japan. During the preparation of this manuscript he was a research scholar in the section of oral medicine and orofacial pain at the University of California, Los Angeles, School of Dentistry. Conflict of Interest Disclosure: None reported.

C

ancer chemoprevention is defined as the use of natural, synthetic or biological chemical agents to suppress, reduce or prevent the progression of carcinogenesis. The term was first coined by Sporn et al.1 It is defined as drugs that have an effect of slowing or stopping cancer development and preventing malignant transformation of premalignant lesions. Clinicians have considered that the best target populations for oral cancer chemoprevention are patients with oral premalignant lesions (OPLs) and/ or postoperative oral cancer patients without tumor bearing for prevention of secondary primary tumors.2-4 One of the major obstacles in chemoprevention studies to date has been the inability to identify oral lesions with a high risk of malignant

transformation and the difficulty in patient recruitment. The most common OPLs are leukoplakia, erythroplakia and erosive lichen planus. These lesions are very heterogeneous, varying in color, size, texture and anatomic site, with studies showing a wide percentage progressing to malignancy ranging from 1.1 to 25 percent. This variability arises partly because of the differences in study populations (i.e., clinic-based versus population-based), tobacco history and durations of follow-up after leukoplakia diagnosis.5-6 Oral leukoplakia, the most common OPL, 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. Biopsy and histopathologic analysis is required to definitively diagnose as leukoplakia and erythroplakia lesions. Under the microscope, these lesions F E B R U A R Y 2 0 1 6 101


FIGURE . A 54-year-old male with a leukoplakia lesion on the right lateral border of the tongue measured by an intraoral ruler for size documentation before administering the chemopreventive agent.

demonstrate a spectrum of possible histopathological features ranging from hyperkeratosis to hyperplasia and various grades of dysplasia including mild, moderate and severe dysplasia to carcinoma in situ (CIS) and squamous cell carcinoma (SCC).7-9 These lesions are considered the perfect model to study the effect of chemopreventive agents on cancer progression due to their easy accessibility for both direct visualization (F I G U R E 1 ), sample acquisitions and monitoring of clinical, histologic and molecular responses to any given preventive intervention. Most chemopreventive trials use a combination of clinical change and histology to identify eligible patients and to monitor the impact of drugs. In most studies, the inclusion criteria for patients with OPL include histologic diagnosis of dysplasia, mainly mild, moderate or severe, and severe hyperkeratosis in a high-risk location (i.e., soft palate, floor of mouth, ventral tongue and alveolar ridge). If a diagnosis of CIS or SCC is rendered, then patients undergo the routine treatment of surgical excision and are excluded from the studies.9-13 Although numerous clinical trials have been performed based on objective scientific data, most reviews indicate that these studies need larger cohort groups to be successfully validated. The Cochrane Collaboration states that there are no significant studies that demonstrated prevention of malignant transformation 102 F E B R U A R Y 2 01 6

of OPL.13-14 Needless to say, promising chemopreventive agents are needed as a treatment option for OPL, especially in lesions that are diffuse, with multiple occurrences such as proliferative verrucous leukoplakia (PVL) or in elderly people who may have difficulties undergoing extensive surgeries.

Methods: Search Strategy and Data Collection The following databases were searched: Medline, PubMed and Clinicaltrials.gov. The search was restricted to randomized clinical trials for chemoprevention of OPL and development of secondary primary tumors after head and neck cancer therapy. The data of each clinical trial, such as study design, administration method, effects of each endpoint, side effects and risk of bias evaluated as a reference of assessment tools, were extracted and are summarized in TABLES 1–3 .15-24

Current Status of Chemopreventive Agents for Oral Precancer Lesions Vitamin A (retinol), 13-cis-retinoic Acid (isotretinoin) and Beta-Carotene Vitamin A (retinol) and retinoic acid (teretinoin, alitretinoin, isotretinoin, etc.), also known as retinoids, as well as betacarotene of provitamin A, have been used in several clinical trials because of their effect on specific biological processes such as epithelial development, differentiation, proliferation and apoptosis (TA BLE 1 ).1519 Extensive studies of retinoids and beta-carotene have shown that their administration period and evaluation points are characteristically longer than in other chemopreventive agents such as cyclooxygenase-2 inhibitor, epidermal growth factor receptor-targeted therapy and some natural compounds.25 Lippman et al. conducted a phase I controlled study where leukoplakia patients were randomly

selected and underwent induction therapy with a high-dose (1.5mg/kg/day) of isotretinoin for three months; in the second phase, patients were randomly assigned to maintenance therapy with either beta-carotene (30mg/day) or low-dose (0.5mg/kg/day) isotretinoin for nine months.26 The authors reported that the rate of clinical disease progression (increase of lesion size or appearance of any new lesion) in the isotretinoin group was significantly lower than the rate in the beta-carotene group. Side effects included dry skin, cheilitis and conjunctivitis, which were minimal during the administration of low-doses of isotretinoin compared to high-doses of isotretinoin. Long-term follow-up (66 months) was reported and showed no significant differences regarding malignant tumor transformation.26 In addition, studies of vitamin A and betacarotene treatments were found to have no effect after several years following the end of a one-year treatment period (TA BLE 2 ).15,19 Another study by Lippman et al., with a long-term intervention period of low-dose isotretinoin in a large sample group of patients with history of oral cancer, showed that isotretinoin did not reduce the rate of second primary tumors or increase survival compared with a placebo.16 Studies by Papadimitrakopoulou et al. on a small cohort of patients with OPL defined these precancerous lesions as “clinical and histologic evidence of measurable or assessable OPLs (leukoplakia and/or erythroplakia), histologic examination showing dysplasia or extensive leukoplakia with hyperplasia and symptoms (e.g., pain), cosmetic cases (e.g., leukoplakia of the lips) or high-risk location (i.e., soft palate, floor of mouth, ventral tongue and alveolar ridge).”17 Their results showed no effect (clinical and histological response) in long-term


intervention periods when administrating low-dose isotretinoin.17,19 In general, the balance of dose and side effects has been important for retinoids and betacarotene when studying their potential use as chemopreventive agents for oral cancer (TA BLE 3 ). Although clinical or histological regression were seen in short-term periods of observation, the response was reversed when the treatment was terminated and this resulted in posttreatment lesional recurrences.17,27

Green Tea Similar to retinoids and betacarotene, green tea has been studied as a chemopreventive agent for an extensive period. The background for its use stems from the idea that drinking green tea reduces cancer risk.28 In Japan, with its large population of tobacco users (around 20 percent of adults) and drinking green tea as part of its culture, reports show that oral cancer patients are about 1 percent of all cancer patients and the prevalence of OPL is 2.5 percent, which is lower than other countries.25,30 The leading compound in the mechanism of green tea cancer chemoprevention is a type of polyphenol, specifically, epigallocatechin-3-gallate (EGCG). Studies showed that multiple signal pathways are involved in the inhibitory effect of polyphenols on cancer cell growth.29-32 A phase II study reported by Tsao et al. used three green tea dosages including a 1,000 mg/m2 of green tea extract based on a previous phase I study.20 The clinical response in this phase II study did not reach statistical significance in all green tea extract arms versus placebo. However, the two higher-dose green tea extract arms had higher responses (clinical response), confirming dose-response effect (TA BLE 1 ). Although some side effects were observed, the therapy was well tolerated and safe. They concluded that these promising results supported longer-

term clinical testing of green tea extract for oral cancer prevention. On the other hand, a cross over clinical trial of green tea was reported with a focus on dropout cases. The study showed that the rates of drop out were significantly higher among smokers than nonsmokers.31 Only a few of the dropout cases were interviewed, with bitter taste and teeth staining as the main reasons for their drop out. Green tea extract does not cause bitter taste and teeth staining, but absorption of caffeine should be considered according to patient preference. Studies are being conducted

This potential benefit is still not strong enough for a universal recommendation to drink green tea in order to prevent oral cancer.

to enhance the bioavailability and potency of green tea by manufacturing a prodrug formulation of EGCG. Another promising approach is to formulate nanoparticles for effective delivery.32-33 Despite the promising evidence on the benefits of green tea in preventing oral and other cancers in animal models and cell cultures, this potential benefit is still not strong enough for a universal recommendation to drink green tea in order to prevent oral cancer.33

Cyclooxygenase-2 (COX-2) Inhibitor The anticarcinogenic properties of COX-2 inhibitor have been thoroughly investigated in multiple experimental and clinical studies.34-37 In case of OPL, Mulshine et al. reported the use of the cyclooxygenase inhibitor ketorolac as an

oral rinse in oropharyngeal leukoplakia, unfortunately, their study demonstrated that ketorolac did not cause leukoplakia regression as compared to placebo.37 Similarly, Papadimitrakopoulou et al. also reported no effective results of COX-2 inhibitor as a chemopreventive agents in OPL (TABLES 1 and 2 ).21 They also reported some adverse reactions observed by patients such as dizziness and oral pain, including one patient with a grade three cerebrovascular accident (cerebral infarction) (TABLE 3 ). They concluded that these results discouraged their pursuit of this agent as an oral cancer chemopreventive agent. These studies confirm that using COX-2 inhibitor solely as a chemopreventive agent for oral cancer will unlikely be available in clinical practice.

Bowman-Birk Inhibitor Concentrate Bowman-Birk inhibitor concentrate (BBIC) is defined as a serine protease inhibitor isolated from soybeans possessing domains with trypsin and chymotrypsin inhibitory activity.38 Although BBIC has been shown in some cell culture and animal studies to inhibit oral carcinogenesis, the specific inhibitory mechanism is still unknown.39-42 It is considered that BBIC may be acting as a tumor suppressor similar to the serine protease inhibitors. It also has anti-inflammatory properties, inhibiting free radical production and altering the levels of several oncogenes (TABLES 1 and 2 ).22 BBIC has few side effects because it is prepared from natural food and is a common ingredient in Japanese foods (soybean-based foods such as miso and tofu). Therefore, BBIC, just like green tea, was expected to be an effective chemopreventive agent for oral cancer. Recently, Armstrong et al. performed a phase IIb double-blinded placebo controlled study that showed no difference between the placebo and the BBIC arm in oral cancer prevention.22, 42-43 F E B R U A R Y 2 0 1 6 103


TABLE 1

Summary of the Nine Studies (eligible participants, study design, control, location of study, sample size, registration period) 15–24 Summary of the study Author Year

Agents

Eligible participants

Study design (RCT: randomized control trial)

Control

Location

Jyothirmayi 1996

Vitamin A

Head and neck cancer treated with surgery and/or radiation therapy (disease free)

RCT two-arm

Placebo

India

Khuri 2006

Isotretinoin (13-cis retinoic acid)

Head and neck cancer treated with surgery and/or radiation therapy (stage 1 or 2)

RCT (pilot phase III) two-arm multicenter

Placebo

USA

Papadimitrakopoulou 2009

Isotretinoin (13-cis retinoic acid)

Premalignant lesions

two-arm (open-label trial) single-center

Beta-carotene + retinyl palmitate or retinyl palmitate alone

USA

Nagao 2014

Beta-carotene

Leukoplakia (never smoked or ex-smokers)

RCT two-arm multicenter

Placebo (50mg/day vitamin c)

Japan

Tsao 2009

Green tea extract


RCT (phase II) four-arm single-center

Placebo

USA


Cyclooxygenase-2 (COX-2)


RCT (pilot phase II) three-arm multicenter

Placebo

USA

Armstrong 2013

Bowman-Birk inhibitor concentrate

Leukoplakia, erythroplakia

RCT (phase IIb) two-arm Placebo multicenter

USA

Mallery 2014

Freeze-dried black raspberry (black raspberry: BRB)

Premalignant lesions (no tobacco use)

RCT two-arm multicenter

Placebo

USA

Sun 2010

ZengShengPing (a mixture of medicinal herbs)

Leukoplakia

RCT two-arm single-center

Placebo

China

Freeze-Dried Black Raspberry and ZengShengPing Freeze-dried black raspberry (BRB) contains natural ingredients such as vitamin A, vitamin E, beta-carotene, multiple anthocyanins and phytosterols. These ingredients have been shown to exhibit a chemopreventive effect both in an in vitro model using oral cancer cell lines and in vivo in a pilot study with oral leukoplakia patients.44-47 BRB has many functions, including the suppression of redox-mediated intracellular signaling, reducing production of pro-angiogenic cytokines and stimulating an apoptotic 104 F E B R U A R Y 2 01 6

pathway.46 A clinical study using a topical 10% BRB gel applied daily for a three-month period demonstrated statistical significant regression of OPL, where 41 percent of participants achieved a decrease in lesional dysplastic grade when compared to patients using placebo23 (TABLE 1 ). The authors attributed the BRB’s chemopreventive effect to its primary phenolic compounds, anthocyanins. In addition, the comparison of the histological grade and loss of heterozygosity (LOH) in the pretreatment versus posttreatment tissues demonstrated that application of BRB resulted in a

statistical decrease of histologic grading, whereas placebo gel application did not have a significant impact.23 ZengShengPing (ZSP) is a registered trademark and herbal mixture composed of six herbs (Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictamnus dasycarpus and Dioscorea bulbifera). Although the effective compounds of ZSP have not yet been identified, individual herbs of ZSP are known to contain bioactive chemicals with anti-inflammatory and anticancer activities.48 Preclinical studies have shown that ZSP inhibited


Sample size

Registration period (enrolled period)

106 [agents 56, control 50] (oral cancer patients: 77.4%)

1992

1190 [agents 590, control 600] (oral cancer patients: 30.1%)

1991–1999

162 [Isotretinoin 81, beta-carotene + retinyl palmitate 45, retinyl

1992 – 2001

regressing leukoplakia lesions was still present after three months following cessation of ZSP treatment (TA B L E 3 ). These two compounds were investigated in small pilot projects; larger cohort groups need to be studied in order to successfully validate these products as chemopreventive agents for oral precancerous conditions.

Epidermal Growth Factor ReceptorTargeted Therapy

palmitate alone 36] (167: randomized patients) 46 [agents 23, control 23]

no mention

39 patients completed [agents 28, control 11] (41: randomized patients)

2002–2008


2000–2004


1999–2009

40 patients [agents 22, control 18]

no mention

112 patients completed) [agents 59, control 53] (120: randomized patients)

1998–2001

inflammation and inflammationassociated carcinogenesis in animal models.24 Clinical trials in China from the late 1970s to early 1990s confirmed that oral intake of ZSP had reduced the progression of histopathologically confirmed precancerous esophageal squamous dysplasia to carcinoma by 48 to 52 percent compared to placebo.48 Sun et al. used ZSP in a short-term randomized placebo-controlled clinical trial on patients with leukoplakia lesions after demonstrating its preventive effect in two animal models.24 Their study showed that clinical responses in

Oral premalignant lesions have increased epidermal growth factor receptor-targeted (EGFR) protein expression and increased EGRF gene copy number compared to normal mucosa. Oral premalignant lesions with overexpression of EGFR or EGFR gene copy number gain are at higher risk for malignant transformation.49 EGFR–targeted therapy has already been FDA approved and widely used as a chemotherapeutic drug for several types of solid tumors including oral, lung and breast cancer. Several studies have demonstrated the role of EGFR dysregulation as a molecular marker of cancer risk and a key player in the process of malignant transformation.49 Clinical trials with EGFR targeted agents, including cetuximab, erlotinib and vandetanib, are currently underway to evaluate the efficacy of EGFR inhibitors for oral cancer chemoprevention. The major one is the multi-institutional study known as the Erlotinib Prevention of Oral Cancer (EPOC) study (NCT00402779).49

Curcumin and Other Chemopreventive Agents Curcumin is the primary component in the spice turmeric. The anticancer effects of curcumin mainly result from multiple biochemical mechanisms that are involved in the regulation of programmed cell death and survival signals. The curcumin

targets that are involved in signaling pathways include transcription factors, growth factors, inflammatory cytokines and reactive oxidative stress.50-51 Its role as a promising new chemopreventive agent for oral cancer has been widely received. Cheng et al. reported in their phase I clinical trial of curcumin in patients with systemic high-risk conditions, including oral leukoplakia, that curcumin is nontoxic for human use when taken by mouth for three months for up to 8,000 mg/day.52 Additionally, histologic regression was observed in two out of seven patients with oral leukoplakia, where dysplasia regressed to hyperkeratosis. Unfortunately, one patient with oral leukoplakia developed oral cancer in spite of curcumin treatment. Another pilot study was conducted with head and neck cancer patients. These patients were given chewable 1 gram (gm) of curcumin gelatin capsules for 18 months, and then their saliva was collected and incubated with oral cancer cells in culture. The authors found that saliva containing curcumin inhibited IKKb (a transcription factor) kinase activity in these cells. IKKb is a known transcription factor involved in the carcinogenesis process, thus indicating that IKKb kinase could be a useful biomarker for detecting the effect of curcumin in head and neck cancer patients.53 Curcumin has unfavorable characteristics such as its hydrophobicity and rapid metabolic rate. Therefore, drug delivery systems such as nanoparticles, liposomes, microemulsions and polymeric implantable devices have been examined as one of the viable alternatives to deliver therapeutic concentrations of curcumin.54 Other chemopreventive agents that have recently been investigated as new potential chemopreventive agents for oral precancer conditions include Pioglitazone, Akt pathway inhibitor (SR13668) and lyophilized strawberries.55-59 F E B R U A R Y 2 0 1 6 105


TABLE 2

Administration Method (period, route of administration); Effects (evaluation point, endpoints, results of endpoints) in Nine Studies 15–24 Administration method

Effects

Author Year

Period

Route of administration

Evaluation point

Endpoints

Jyothirmayi 1996

1 year

Oral administration 200,000 IU/week

3 years

#0 Recurrence: including regional recurrence #1 Second primary tumors

Khuri 2006

3 years

Oral administration 30mg/day (3x daily)

7 years

#0 Rate of second primary tumors (primary endpoint) #1 Rate of smoking-associated cancers #2 Primary tumor recurrence #3 Smoking-associated disease–free survival #4 Overall survival


3 years

Oral administration 0.5mg/kg/day (1 year) 0.25mg/kg/day (2 years)

5 years

#0 Clinical response at 3 months (primary endpoint) #1 Toxicity #2 Improvement in histology #3 Oral cancer free survival

Nagao 2014

1 year

Oral administration 10mg/day with 500mg/day vitamin C

5 years

#0 Role in clinical remission (primary endpoint) #1 Malignant transformation

Tsao 2009

12 weeks

Oral administration 500mg/m2, 750mg/m2, 1000mg/m2 (3x daily)

12 weeks

#0 Clinical and histological response (primary endpoint) #1 Qualitative and quantitative toxicities of GTE #2 Effects of treatment on the expression of biomarkers (VEGF, p53, Ki-67, Cyclin D1, The p16 promoter methylation) #3 Any potential correlation between treatment efficacy and/ or toxicity with plasma concentrations of EGCG or caffeine


12 weeks

Oral administration 100mg or 200mg

12 weeks

#0 Clinical response rate (primary endpoint) #1 Histological improvement rate

Armstrong 2013

6 months (PR,CR ) add 12 months

Oral administration (powder + water) 600 C.I. units of BBIC/day (2x daily)

6 months

#0 Percent change in total lesion area (primary endpoint) #1 Change in clinical impression #2 Central pathology review #3 Change in buccal-cell Neu protein #4 Change in serum Neu protein #5 Change in buccal cell protease activity

Mallery 2014

3 months

Application (4x daily)

3 months

#0 Change in lesional size #1 Change in histological grade #2 Change in LOH events #3 Cumulative responsiveness score

Sun 2010

8–12 months

Oral administration 3.6mg (3x daily)

3 months (after cessation of treatment)

#0 clinical response (primary endpoint) #1 AgNOR and PCNA - labeling index

vit A: Vitamin A; N.S: not statistically significant; GTE: Green tea extract; EGCG: epigallocatechin 3-gallate; PR: partial response; CR: complete response; BBIC: Bowman-Birk inhibitor concentrate; LOH: loss of heterozygosity; BRB: black raspberry

106 F E B R U A R Y 2 01 6


Results of endpoints #0 vit A 11/56, placebo 5/50 #1 vit A 0/56, placebo 2/50 #0 N.S (Isotretinoin 130/590, placebo 131/600) #1 N.S (Isotretinoin 84/590, placebo 98/600) #2 N.S (recurrence-free survival P=0.21) #3 N.S (P=0.15) #4 N.S (P=0.73) #0 N.S (P=0.29) #1 refer to Table 2 side effects and adverse effects section #2 N.S #3 N.S #0 N.S (P=0.346: 1 year observation period) #1 Cases of malignant transformation: experimental 2/23, placebo 3/23 (60 months of the median duration of follow-up) #0 Clinical response: versus placebo (P=0.09), histological response: versus placebo (P=0.65) #1 The incidence of insomnia and nervousness was higher in patients receiving GTE at 750 and 1,000 mg/m2 #2 No mention of treatment side effects #3 1,000 mg/m2 dosing was most likely the reason for the increased insomnia and nervousness #0 N.S (P=1.0) #1 N.S (P=0.71) #0 N.S (P>0.94) #1 No mention #2 N.S (n=88) #3 N.S (n=45) #4 N.S (n=45) #5 N.S (n=41) #0 BRB versus Control P>ztKKͲŝŐŝƚĂůŐĞŶĞƌĂůƉƌĂĐƚŝĐĞůŽĐĂƚĞĚŝŶ ƐŝŶŐůĞƐƚŽƌǇďůĚŐǁͬϱĞƋŽƉƐ͘ZĞĂƐŽŶĂďůĞůĞĂƐĞ͘&ĞĞ ĨŽƌƐĞƌǀŝĐĞ͘ϱϬǇĞĂƌƐŽĨŐŽŽĚǁŝůů͘WƌŽũĞĐƚŝŶŐĂƉƉƌŽǆ͘ ΨϰϲϰĞĂƐĞŚŽůĚ/ŵƉƌŽǀĞŵĞŶƚĂŶĚƋƵŝƉͲ ŵĞŶƚKŶůǇ͊ĞĂƵƚŝĨƵůŽĨĨŝĐĞǁŝƚŚϯƐƉĂĐŝŽƵƐŽƉƐŝŶ Ăϭ͕ϱϱϮƐƋĨƚƐƵŝƚĞ͘>ŽŶŐƚĞƌŵůĞĂƐĞ͘WƌŽƉĞƌƚǇ/ ηϱϬϲϱ͘

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