Copy Of Oral Precancer &Cancer Presentation Transcript
ORAL Precancer &CANCER Clinical Research Program CLIN 213-50 –2007 Humber College North Campus Toronto
Oral Precancer & Cancer
Common Sites of oral cancer
(A) Asian countries
Incidence and Mortality
Established Risk Factors
Types of precancer and cancer
Signs and symptoms
One of the 10 most common cancers in the world.
Oral cancer is a disease with high morbidity and mortality,
(A WHO Meeting)
Oral Precancer & Cancer
The oral cavity and oropharynx have many parts:
Lining of your cheeks
Salivary glands (glands that make saliva)
Roof of your mouth (hard palate)
Back of your mouth (soft palate and uvula)
Floor of your mouth (area under the tongue)
Gums and teeth ,Tongue &Tonsils
Oral Precancer & Cancer
Cancer begins in cells, the building blocks that make up tissues. Tissues make up the organs of the body
Precancerous lesion is defined by an international working group as “ a morphologically altered tissue” in which cancer is most likely to occur than its apparently normal counter part. ( Axell et al, 1984)
Sometimes this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should. These extra cells can form a mass of tissue called a growth or tumor
ORAL PRECANCER &CANCER
Oral cancer is part of a group of cancers called head and neck cancers
Oral cancer can develop in any part of the oral cavity or oropharynx.
all oral cancers begin in the flat cells (squamous cells) that cover the surfaces of the mouth, tongue, and lips. These cancers are called squamous cell carcinomas.
Oral cancer is one of the few conditions that Dental Professionals may encounter within their Dental Surgeries which can be fatal.
It is therefore essential that members of Dental Team understand the Epidemiology and natural history of conditions and possible options for prevention .
Oral Cancer Common Sites
Cancer of Lip
Cancer of Tongue
Cancer of mouth
Cancer of Pharynx
This picture shows the area under the tongue.
Facts about oral cancer
Disease is twice as common in men
Majority of malignancies are squamous cell carcinoma.
Incidence increases with age.
Regional variations occurs.
Socio-economic inequalities exist in oral cancer rates.
India, Bangladesh, Pakistan and Sri-Lanka - It is most common and accounts for a third of all cancers .
A high proportions of oral cancers in UK and USA appears to arise in mucosa , which clinically , does not show precancerous lesion.(Buquuot et al 1988)
Incidence of Oral Cancer- Internationally
Incidence varies considerably with very high rates in INDIA and SRI LANKA – oral malignancies are commonest type of cancer accounting 40% of all cancers.
In developed nation like UK oral cancer accounts for 1-2% of all new cases of cancer.
Incidence is higher in parts of Brazil,Canada,France and USSR
World Areas Studied C A C a n c e r J C l i n 1 9 9 9 ; 4 9 : 3 3 - 6 4 Vol. 49 No. 1 January/February 1999
Incidence rate in Asian countries
Accurate data are not yet available, where incidence rate is known to be high.
The population of the world is 6.3 billion and it is increasing by 78 million each year. China has the biggest population; 21% of the world total
Incidence and mortality
In recent years there are indications that incidence and mortality rates have started to increase.
(Boyle et al 1993., Hindle et al, 1994)
Factors influencing survival from oral cancer.
Site of lesion( the further back in the mouth, the poor the prognosis.)
Size of lesion.
Involvement of the regional lymph nodes.
Presences of distant metastases.
Cause of Oral cancer. Or Risk of oral cancer
People with various TOBACCO habits.
Frequency of those habits.
TOBACCO CHEWING HABITS
TOBACCO SMOKING HABITS
Inter Relationship of Factors Associated with Oral Pre cancer & Cancer
ESTABLISHED RISK FACTORS
Chewing tobacco/oral snuff.
Chewing betel quid(pan) with tobacco.
(Areca nut are known 4 th Addictive Substance cause sub mucous fibrosis )
Heavy consumption of alcohol.
Presence of potentially malignant lesion.
PREDISPOSING RISK FACTORS
Dietary deficiencies( Vit A,C ,E & Iron)
Sun light( Lip cancer).
Poor diet and nutrition.
Fungal or viral infections.
Jagged teeth or ill fitting dentures.
Poor oral hygiene.
Certain oral lesions such as LEUKOPLAKIA (White patches) & ERYTROPLAKIA (Red patches) can precede the development of malignancies.( However rate of transformation is low at 2-6%).
Squamous cell carcinoma ( Floor of mouth )
Oral leukoplakia is a relatively common oral lesion that, in a varying proportion of cases, undergoes malignant transformation.
Clinical examination and histological assessment of lesion mostly asymptomatic
The frequency of leukoplakia is highly variable among geographical areas and demographic groups .
The prevalence in the general population varies from < than 1 to > than 5 percent.
Leukoplakia is often associated with tobacco smoking although idiopathic forms are not rare.
Therapies For Oral Cancer
Gene Therapy for oral Squamous cell carcinoma ( currently under investigation in Clinical Trials)
Definition of Gene Therapy
Gene therapy can be defined as gene transfer for the purpose of treating human disease .This includes the transfer of new genetic material as well as the manipulation of existing genetic material.
Cusack and Tanabe, 1998
( J Dent Res 82(1):11-16, 2003 )
Considering vast size of the mammalian genosome, which is approximately 3*10 9 base pair of DNA location of particular genetic targets involved in cancer remained mystery for so long.
Study of oncogenic reterovirus led to discovery of oncogenes (Bishop & Vermus)
There are over 20 genes in the genosomes of different retrovirus, activity of one or more of which seems essential for cell transformation and development of neoplasm( Varmus)
Carcinogenesis ( Concluding Perspective)
Process of Multi-step carcinogenesis may be divided into the basic stages of initiation, promotion and progression.
Initiation – mutational event in unknown genes may be caused by chemical carcinogens, radiation or virus and is irreversible.
Promotion and Progression involves further genetic alterations , which leads to malignancy.
Oncogenes are responsible for different stages of multi-step Carcinogenesis in these diseases.
Radiotherapy for head and neck cancer
Phase III Randomized Trial of Amifostine as a Radio protector in Head and Neck Cancer
Amifositine and its active metabolite, WR-1065,accumulate with high concentrations in the salivary glands.
Patients with previously untreated head and neck squamous cell carcinoma were eligible.
Primary end points included the incidence of grade > 2 acute xerostomia, grade > 3 acute mucositis.
Amifostine was administered (200 mg/m2 intravenous) daily 15 to 30 minutes before irradiation.
grade > 2 late xerostomia and were based on the worst toxicity reported.
Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy.
Patients evaluated their symptoms through a questionnaire during and after treatment.
Conclusion: Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.
Evidence of carcinogenic effect of tobacco use are clear.
Virtually every case of oral cancer occurs in person who use tobacco.
People who chew tobacco have greatly elevated risk of developing oral cancer.
Tobacco & Alcohol- oral cancer
Alcohol appears to have synergistic effect on risk of oral cancer.
Areca nut +Tobacco and Oral Precancer & Cancer Alkaloids of areca nut cause Sub mucous fibrosis And the tobacco leached N’-Nitro -amines Po (polonium) And NNN= N’nitrosonornicotine, Are known carcinogen and Also addictive in behavior
Oral Cancer Signs & Symptoms
Swellings, lumps or bumps on the lips, gums or other areas inside the mouth
Velvety white, red, or speckled (red and white) patches in the mouth
Unexplained bleeding in the mouth.
Unexplained numbness, loss of feeling, or pain in any area of the face, mouth or neck.
Persistent sores on the face, neck, or mouth that do not heal within two weeks.
A lump or thickening in the oral soft tissues.
A soreness or feeling that something is caught in the back of the throat.
Difficulty chewing or swallowing.
Difficulty moving the jaw or tongue
Numbness of the tongue or other areas of the mouth.
A swelling of the jaw that causes dentures to fit poorly or become uncomfortable.
CLINICAL TRIALS Head and neck or oral neoplasm 337 studies found in this group 99 studies world wide in progress for oral neoplasm. And 5 Studies are in in progress in Canada
Clinical Trial Purpose
To test new treatments
New methods of diagnosis
( Harmful effects are not known before a trial is conducted)
Dose and Schedule modification are required for participants if they develop side effect from treatment or test.
PHASE IIA TRIAL OF ROSIGLITAZONE (AVANDIA) FOR ORAL LEUKOPLAKIA
Cancer Prevention Head And Neck
Participants will visit the clinic at Baseline, Week 6 and Week 12
Treatment A gents – Rosiglitazone
One Avandia 8 mg tablet by mouth once daily for 12 weeks. Medication may be taken at any time of the day.
PHASE IIA TRIAL OF ROSIGLITAZONE (AVANDIA) FOR ORAL LEUKOPLAKIA(Contd.)
A dysplastic measurable leukoplakia or erythroplakia in the oral cavity or accessible oropharynx or hyperplastic leukoplakia
Males or females with a suspected or histologically confirmed
two-stage registration process 1 completed informed consent. 2. histologically confirmed
life expectancy is > 12 weeks and Karnofsky performance score is 70-100%.
The subject is willing and able to fully participate for the duration of the study.
White blood cells >/= 3,000/mL, Platelets >/= 125,000/mL, Total bilirubin </= 1.5 x ULN, AST (SGOT)/ALT (SGPT) </= 1.5 x ULN, BUN and serum creatinine </= 1.5 x ULN, LDH </= 1.5 x ULN, Urinalysis < 100,000 bacteria
Radiotherapy and concurrent chemotherapy (CRT) is superior to radiotherapy alone for the treatment of locally advanced, nonmetastatic squamous carcinoma of the head and neck (HNC).
Choice between surgery and CRT for patients with resectable disease. Fluorodeoxyglucose–positron emission tomography scanning may identify patients who require adjuvant neck dissection.
Second issue is optimization of radiotherapy and chemotherapy schedules
Biologically targeted therapy into CRT treatment programs
Radiotherapy and Chemotherapy
Staging Systems of Cancer
AJC – American Joint committee for Cancer Staging (1977)
UICC – International union against Cancer ( 1988)TNM staging Technique
DOSAK – Examined 18 pre therapeutic factors to create a Treatment Dependent Prognosis Index (TPI)( Multicenter, German, Austrian, Swiss Association of Head and Neck Tumors)(Platz,Fries & Hudec., 1986)
( Risk Markers for oral disease – Edited by NWJohnson)
The UICC TNM staging System T represent tumor size , T is = Carcinoma in situ Ti = <2cms in greatest diameter., T 2= 2. - 4cm , T3 = 4 - -6 cm, t4 > 4cms and deeply penetrating underlying structures. No= no clinically detectable enlarged nodes. N1 = enlarged ipsilateral lymph nodes present < 3cms. N2 = ipsilateral single> 3-6 cm or ipsilateral multiple<6cm or bilateralor Or contra lateral < 6cm. N2 = any palpable node> 6cm. Mo and M1+ absent or distant blood born metastases. Stage 0 Tis No Mo Stage I T1 No Mo Stage II T2 No Mo Stage III T3 T1 T2 T3 No N1 N1 N1 Mo Mo Mo Mo Stage IV T4 Any T No or N1 Any N Mo M1
The TNM staging system Another method of staging oral carcinomas is referred to as the TNM method. In this method T describes the tumor, N describes the lymph nodes, and M describes distant metastasis . 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. (Lip) Tumor invades adjacent structures (e.g., through cortical bone, into deep [extrinsic] muscle of tongue, maxillary sinus, skin) T4 (Oral cavity) Tumor invades adjacent structures (e.g., through cortical bone, into deep [extrinsic] muscle of tongue, maxillary sinus, skin) 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; in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N2a Metastasis in 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 bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N3 Metastasis in a lymph node more than 6 cm in greatest dimension MX Presence of distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis ( Ref : J Biomed Opt, September 1, 2004; 9(5): 940-950 )
Classical end points
non-inferiority or demonstrated equivalency
Improved time to progression (TTP)
improvement of symptoms and quality of life
has been the focus of strategies
Measuring efficacy in oral cancer trials
Efficacy or optimal care
Phase II trials
screening tool for phase III
Phase III studies
define drug efficacy
utilise explicit endpoints
therapeutically tolerable dose
not a potentially life threatening dose
Liver functioning test
Adequate bone marrow function
white blood cells are above a predetermined level
Treatment design issues
When designing an oral cancer clinical trial a lot has to be considered
“ at present, there is no definitive clinical or microscopic reliable method to identify which lesion will undergo malignant transformation and which will not.”
Lodi.G, Sardella A, Bez C, Demarosi F, Carrassi A. Systemic Review of Randomized Trials for the Treatment of Oral Leukoplakia. Journal of Dental Education Volume 66; No 8: 896-902
Treatment design issues
Randomized discontinuation design
Inclusion and exclusion criteria
determine the final eligibility
Presence of primary oral cavity lesion
Lesion size will depend on the trial staging used
At least 18 years old
A protocol driven period of time where no treatment has been given
More than 6 months since surgery
If of childbearing potential
Life expectancy of at least 6 months
Patients with tumours suspected of involving a 50% or greater encasement of a blood vessel
Patients with tumours having bone invasion
Patients with hypersensitivity to treatment active ingredients
Women who are pregnant, or are nursing.
Identifying sources of patients
Contacting and screening patients
Obtaining Informed Consent
Training recruitment staff
Good quality of advertising
clear message about enrollment criteria
message in contact with patients, dental
community and medical community
(tv,radio, newspaper,websites etc)
70% of general practitioners identified lack of training on oral cancer examination
47% recognized lack of time during consultation
37% revealed they had never received any organized tuitition on the subject
Lack of information for ongoing clinical trials
Standard therapy is the best treatment
Longer treatment for their patients
Education on oral cancers
Florida Study identified from 1773 responders 40-years and older
15,5% had never heard about oral cancers
40,3% knew little or nothing about OC
one-half of them did not think oral white or red patches or bleeding could indicate OC
27,6% identified correctly three risk factors
19,5% received annual exam
Hispanic or persons with low level of education, or lacked a regular dentist were less likely to have a recent oral exam
“ The mortality rate for oral cancers has not improved in the past 40 years. Fighting this disease must begin with educating American public about risk factors,signs and symptoms” Dr. Marc Mintzer
Suspicious about clinical trials
Afraid of abuses(syphilis study)
Barriers ( site away from home, insurance coverage, leaving work etc.)
Key factor for examination and screening OC
“ A recent pivotal study in UK has determined for the first time that opportunistic screening in general dental practice is ideal. It showed that a three-minute examination of patients, who had completed a short survey for high risk factors, was effective.”
Compliance for serious disease such as oral cancer will provide adequate motivation for participating in clinical trial.
It may be affected by death, refusal on randomization or kind of therapy choices.
Time to assimilate the information
Provide opportunities to ask questions
High level of communication is important knowing the difficult psychological state of the patient.
Primary prevention Activities
Focused upon modifying habits on use of tobacco.
Encourage people never to adopt ant tobacco habit.
Encourage people who already have habit to STOP.
Encourage , who already have habit to decrease the use or modify behavior.
Oral cancer control priorities.
Programmes to educate school children against tobacco use.
Education programmes for current tobacco users.
( smoking cessation)
Community level early detection programme.
Continuation of current treatment programme.
Use of chemotherapy for late stage disease.
Improvement of quality of treatment.
Oral cancer control programmes
Focus on primary prevention.
Community based early detection programmes
Developing high standards of treatments.
Funding New Cancer Drugs in Ontario
issues have included dealing with evidence arising solely from phase II versus phase III trials. trials, using economic information, and involving community representatives. ( Evidence limited to phase II studies).
there is no obvious way to rank agents whose evaluation is restricted to such studies because the data supporting each agent are relatively weak.
Fund only those drugs for which there is phase III evidence (randomized trials) of effectiveness.
Fund all federally approved drugs, but only for their approved indications.
Develop a numeric rating system with a cutoff point for funding.
( By the American Society of Clinical Oncology).
Don’t drink alcohol to excess.
Reduce the use of betel quid / paan and do not use tobacco in the quid.