Copy Of Oral Precancer &Cancer

Prepared By Rajeev Kashyap 1

ORAL Precancer &CANCER

Clinical Research Program CLIN 213-50 –2007

Humber College

North Campus

Toronto


Oral Precancer & Cancer Introduction Common Sites of oral

cancer Incidence rate

(A) Asian countries

(B) Internationally Incidence and Mortality Established Risk Factors

Factors association Types of precancer and

cancer Available therapies Signs and symptoms Staging system Clinical trials Preventive measures


Oral CancerOne 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: Lips 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 cancershead 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 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.


Oral Cancer 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 StudiedC A C a n c e r J C l i n 1 9 9 9 ; 4 9 : 3 3 - 6 4Vol. 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.OrRisk 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 Smoking tobacco. Chewing tobacco/oral snuff. Chewing betel quid(pan) with tobacco. (Areca nut are known 4th 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)

Genetic disposition.Sun light( Lip cancer).Dental trauma.Viral infections.


Other factors Poor diet and nutrition. Immunological disorders. HIV infections. Fungal or viral infections. Jagged teeth or ill fitting

dentures. Poor oral hygiene.


Malignant Transformation

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%).


Oral Leukoplakia


Squamous cell carcinoma( Floor of mouth)


Geographic Tongue


Lichen Planus


Oral Leukoplakia 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

•Surgery•Radiotherapy•Chemo prevention•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)


Oncogenesis(Cancer genes) Considering vast size of the mammalian

genosome, which is approximately 3*109 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.(J Clin Oncol 18:3339-3345. © 2000 by American Society of Clinical Oncology).


The Effects of Tobacco Aesthetics. Dental caries. Dental implants. Healing of wounds. Heart disease. Oral mucosal disease Loss of taste And smell. Periodontal disease.


Other forms of Tobacco Nass or Naswar.( common in Pakistan) SMOKING OF BIDI( Indian population) Reverse smoking( Andhra Pradesh)


Oral cancer & Tobacco 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 Hoarseness. Ear pain. 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 neoplasm337 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 Screening Prevention( 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 Phase II Participants will visit the clinic at Baseline,

Week 6 and Week 12 Treatment Agents –Rosiglitazone One Avandia 8 mg tablet by mouth once daily

for 12 weeks. Medication may be taken at any time of the day.

Independent Multicenter


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 schedulesBiologically 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)


Stage 0 Tis No Mo

Stage I T1 No Mo

Stage II T2 No Mo

Stage III T3T1T2T3

NoN1N1N1

MoMoMoMo

Stage IV T4Any T

No or N1Any N

MoM1

T represent tumor size , T is = Carcinoma in situTi = <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.

The UICC 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 tumorTis Carcinoma in situ T1 Tumor 2 cm or less in greatest dimensionT2 Tumor more than 2 cm but not more than 4 cm in greatest dimensionT3 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 metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimensionN2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than6 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 dimensionN2a 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 dimensionN3 Metastasis in a lymph node more than 6 cm in greatest dimensionMX Presence of distant metastasis cannot be assessed M0 No distant metastasisM1 Distant metastasis ( Ref : J Biomed Opt, September 1, 2004; 9(5): 940-950 )

The TNM staging system


Efficacy Classical end points

survival non-inferiority or demonstrated equivalency Improved time to progression (TTP) improvement of symptoms and quality of life

Cytotoxic chemotherapy has been the focus of strategies


Measuring efficacy in oral cancer trials Efficacy or optimal care Effectiveness trials Phase II trials

screening tool for phase III Phase III studies

define drug efficacy utilise explicit endpoints


Safety Parameters Chemotherapy

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 Ionizing radiation Chemotherapy Surgery

Randomized discontinuation design


Inclusion and exclusion criteria

Treatment dependentHealth professionals

determine the final eligibility


Inclusion Criteria Presence of primary oral cavity lesion Lesion size will depend on the trial staging used

ECOG PERFORMANCE STATUS*Grade ECOG

0 Fully active, able to carry on all pre-disease performance without restriction1 Restricted in physically strenuous activity but ambulatory and able to carry out

work of a light or sedentary nature, e.g., light house work, office work2 Ambulatory and capable of all self-care but unable to carry out any work

activities. Up and about more than 50% of waking hours3 Capable of only limited self-care, confined to bed or chair more than 50% of

waking hours4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or

chair5 Dead

* As published in Am. J. Clin. Oncol.:Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity AndResponse Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.


Inclusion Criteria 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

approved contraception

Life expectancy of at least 6 months Informed Consent


Exclusion Criteria 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.


Patient recruitment

1. Identifying sources of patients2. Requesting referrals3. Contacting and screening patients4. Obtaining Informed Consent5. Training recruitment staff


Patient recruitment Good quality of advertising

clear message about enrollment criteria

message in contact with patients, dental community and medical community (tv,radio, newspaper,websites etc)


Patient Recruitment Medical community Scotland Survey 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


Medical community Lack of information for ongoing

clinical trials Standard therapy is the best

treatment Longer treatment for their patients


Patient Issues Education on oral cancers

Florida Study identified from 1773 responders 40-years and older15,5% had never heard about oral cancers

40,3% knew little or nothing about OCone-half of them did not think oral white or red patches or bleeding could indicate OC

27,6% identified correctly three risk factors


Patient education19,5% 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


Patient Issues Suspicious about clinical trials Afraid of abuses(syphilis study) Barriers ( site away from home,

insurance coverage, leaving work etc.)


Dental community 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

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.


Informed consent Initial meeting 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. Health education. Health promotion 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).


KEY MESSAGE. Don’t smoke. Don’t drink alcohol to excess. Reduce the use of betel quid / paan and

do not use tobacco in the quid. Eat more fresh fruit and vegetables. Ensure oral hygiene is improved.


THANK YOU

AvoidTobacco &Alcohol

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