Cancer of the oral cavity is the sixth most common malignancy worldwide, with over 400,000 new cases diagnosed annually, and its incidence is rising in many countries. It is more common in developing than in developed countries and is particularly prevalent in South and South-East Asia, where it has been associated with the common habit of chewing a stimulant known as betel quid. Although it can be fairly easily treated, death rates are higher than for many other cancer types, mainly because it is often detected late.

With the cancer burden rising in the developing world, there is an increased awareness of the need for regionally-targeted cancer research and development there. Most developing-world institutions are, not surprisingly, resource poor, but there, as elsewhere, partnerships between institutions and between disciplines may prove effective in optimising results from the resources available. In Malaysia, a "rapidly developing" South-East Asian country where oral cancer is perceived as a significant and growing health problem, the Oral Cancer Research and Coordination Centre (OCRCC), was established in 2005 as a resource centre for oral cancer. The OCRCC arose from a partnership between two universities, the University of Malaya (UM) and the University Sains Malaysia (USM); the Cancer Research Initiatives Foundation (CARIF); and the Ministry of Health Malaysia. Rosnah Zain, the Centre's director and professor of dentistry at the University Malaya in Kuala Lumpur, says "Before the OCRCC was set up, research into oral cancer in Malaysia was very patchy, with much based in centres seeing only a few patients a year. We have brought research together under one umbrella, we have set up a database to record cases diagnosed in selected centres in Malaysia and we store samples from as many tumours as possible."

Malaysia comprises fourteen states; twelve are in peninsular Malaysia and the other two, Sarawak and Sabah, form East Malaysia on the island of Borneo. Its population includes many ethnic groups, the largest being the Malays followed by the Chinese, the indigenous peoples of Borneo and the Indians. Current figures show that oral cancer incidence in the country varies both by gender and by ethnic group, with the highest prevalence among Indians and indigenous groups. The oral cavity is the sixth most common cancer site for Indian males and the third most common site for Indian females in Malaysia. Chewing betel quid – a traditional stimulant mixture of areca nut and/or tobacco with the betel leaf (Piper betle) – is common in Malaysia only in these ethnic groups. Even there it is now largely confined to the lower socio-economic groups, such as the Indians who work on palm oil estates. Among the Chinese and Malays, where mouth cancer is less prevalent, the major risk factors are the common ones of tobacco smoking and (among the Chinese) alcohol consumption. Researchers in Malaysia and elsewhere have established that further, perhaps less obvious risk factors for oral cancer can include dietary factors, the presence of syphilis or Candida infection, exposure to radiation and poor oral hygiene, and there is also a fairly small genetic component.

The OCRCC is the major coordinating partner developing the Malaysian Oral Cancer Database and Tissue Bank System. This coordinates the collection of data and samples from eight hospital-based centres that see patients with oral cancer and precancerous lesions based across the country. There are three centres in Kuala Lumpur, two close to the Thai border, one other in the north of the country and one in each of the East Malaysian states. The database also contains control samples obtained from volunteers. "Initially, we hoped to obtain all our control samples from patients attending the same hospitals for other conditions, but it proved difficult to persuade people to participate and we have had to look more widely", says Zain. Even now, the database holds data on over twice as many cases as controls, limiting the possible power of any statistical analysis carried out.

Patients are generally referred to oral cancer centres from general medical or dental practice, with typical signs and symptoms including white or red patches in the mouth, persistent sores, and bleeding. The main treatment modality is surgery, with or without post-operative radiotherapy. "If a patient is diagnosed with frank carcinoma, then it will be surgically removed, however small it is", says Zainal Ariff, a surgeon in the Faculty of Dentistry at University Malaya. "Patients diagnosed with precancerous oral lesions, such as white patches, will be followed up closely and, where appropriate, given advice on changing their diet and habits." Sadly, however, few patients are seen at such an early stage. More than seventy percent of cancer patients in the database had been diagnosed with Stage III and Stage IV disease, where the cancer has already spread at least to the lymph nodes. "About half the cases I see will be inoperable, and these patients' prognoses are very poor", says Ariff. Most of the patients diagnosed with early cancer are picked up through "watching and waiting" precancerous lesions. Over 90% of the cancers Ariff sees are squamous cell carcinoma, with the majority occurring in the cheek mucosa: this site is particularly closely associated with the habit of betel quid chewing, as this is the location in the mouth where the betel quid is stored. Cancer of the cheek mucosa is less common without betel quid as a risk factor.

Ariff is generally content with the facilities available in Kuala Lumpur for surgery, chemotherapy and radiotherapy: "we can get hold of most chemotherapy drugs, and our radiotherapy equipment is up to date", he says. The country is less well resourced in other areas. "There are only two PET scanners in the whole of Malaysia, with a population of over 28 million. Facilities for rehabilitation, helping patients who have had radical surgery to recover some ability to speak and to swallow, are also not optimal." And where surgery for advanced oral cancer is possible, it often has a devastating effect on a patient's quality of life; for instance, the whole of the tongue is often removed. In the UK, Times journalist John Diamond wrote graphically about his life after surgery for a similar cancer, unable to talk or eat normally, in his acclaimed book C: Because cowards get cancer too[1].

Quality of life is an important issue in cancer care, and numerous questionnaires have been derived to assess it. It is important, however, to see quality of life in a cultural context as the relative importance of different issues will differ between groups. Jennifer Doss of the Department of Community Dentistry at UM has cross-culturally adapted a questionnaire that is specific both for oral cancer and for the Malaysian context. She chose to base it on a US-based instrument, the Functional Assessment of Chronic Illness Therapy[2], made specific to head and neck cancer (FACIT-H&N). This asks patients to 

answer about forty questions covering areas covering their physical, functional, social and emotional well-being, how able they are to cope with and enjoy daily life, and how far they are troubled by symptoms associated with head and neck cancer and its treatment (such as difficulties with breathing, eating and talking). A supplementary list of eight issues were identified as being relevant to Malaysian oral cancer patients and appended. “One of the questions added to the Malaysian version concerned the effect of the disease on the patients’ spiritual life”, says Doss. “Many of those we interviewed found this to be important.” The questionnaire was initially validated with 78 patients at three time points; 1-2 weeks after diagnosis and one and three months after surgery. This cross-culturally adapted questionnaire is now in use with all new oral cancer patients registered in the OCRCC database.  “A number of patients failed to follow up during the study”, she says. “There were many reasons for this. Some had passed away or were too ill to participate; others were simply unable to come to the centres to be interviewed. Because of the sensitive nature of some of the questions, we have had to deliver it face-to-face rather than by phone.”

The OCRCC has been involved in several studies of the reasons for delay in diagnosing oral cancer. Dr. Nurulaida, an oral-maxillofacial surgery resident in the Department of Oral and Maxillofacial Surgery at UM, conducted a cross-sectional study of eighty-seven consecutive patients referred to six of the eight OCRCC-linked oral cancer centres in Malaysia, and divided delay in diagnosis into patient delay (between first symptoms and the patient being first seen by health care professionals) and professional delay (between the patient first seen by professionals and definitive pathological diagnosis). Patient delay was more common than professional delay; reasons given included the ‘asymptomatic’ nature of the disease and a ‘hope of healing’ without intervention. A small percentage of patients sought help from outside the Western medical tradition. “Indigenous people and Malays also use medicinal herbs, rather than see a doctor or dentist”, says Nurulaida. Socio-demographic factors can also be important. “People in the ethnic and socio-economic groups where mouth cancer is most prevalent often live in remote areas with few dentists, and cannot easily travel to see one”, adds Ariff. “In the most extreme case of patient delay in my sample, the patient waited four years between the first symptoms until seen by the health care professionals”, says Nurulaida. Worryingly, very similar numerical results were obtained in a study published in 1996 by Nurulaida’s supervisor, P. Shanmuhasuntharam, and the proportion of cancers diagnosed at Stages III and IV has also hardly changed since then. Since 2006, the OCRCC and its partners have set up a yearly Mouth Cancer Awareness project to educate the public about the symptoms of the disease and the importance of early diagnosis.

It is self-evident that not everyone who chews betel quid will go on to develop oral cancer. Like all cancers, it is caused by the interplay between genetic and environmental factors. Molecular biologist Cheong Sok Ching of the Cancer Research Initiatives Foundation has been making a study of genetic changes associated with mouth cancer in the Malaysian population, focusing particularly on genes involved in the p53 pathway. One gene in this pathway, MDM2, is often over-expressed in oral cancer. Cheong recently published a paper showing that one single nucleotide polymorphism in this gene could modulate the age of onset of disease[3], although it was not associated with an increase in overall risk. Working with Zain and the OCRCC partners, she analysed gene expression patterns in a number of oral cancer samples and found that patients who smoked produced a different gene expression pattern in their tumours from those who chewed betel quid⁴. “This clear result shows the value of using tissue samples from a relevant population, where risk factors can be stratified easily”, she says. “It is, however, not a surprising one, as the oral cavity of the two groups will have been exposed to different carcinogens.” She now plans to use these results to help develop targeted therapies for sub-groups of the disease. Cheong’s interests extend well beyond the basic science of cancer: she is working with the Mouth Cancer Awareness project with funding from the International Union against Cancer (UICC) to develop educational material about the signs and symptoms of the disease that is suitable both for dentists and for general TV viewers.

Oral cancer can be seen as something of a “Cinderella” disease compared to, for instance, breast, lung or colorectal cancer, partly at least because it is most prevalent in poorer countries and among poorer ethnic groups. The successful establishment of the OCRCC as a multidisciplinary research institute specific for this disease in a rapidly developing country must be bound to lead to improvements in its diagnosis and treatment, not only in Malaysia but throughout South-East Asia as a whole.