Tobacco and oral cancer cancer

Tobacco Oral Cancer & PreCancer

Dr.Rajeev Kashyap

Tobacco Oral cancer

& Precancer


Dr.Rajeev Kashyap

CONTENT INTRODUCTION EPIDEMIOLOGY RISK FACTORS

Marijuana

Snuff

Tobacco

Alcohol

Betel quid

Dietary factors, PREMALIGNANT LESIONS AND CONDITIONS COMMON ORAL LESSIONS

Oral leukoplakia

Erythroplakia

Lichen planus

Oral Candidiasis

Xerostomia

SUBLINGUAL KERATOSIS

ORAL SUBMUCOUS FIBROSIS

Recurrent Apthous Stomatitis

Hairy Tongue

Herpes Labialis

Neoplasms ( Kopasi‘s Sarcoma) CANCER DEVELOPMENT IN ORAL MUCOSA CAUSATIVE FACTORS ORAL PRECANCER AND CANCER MANAGEMENT OF DYSPLASTIC LESIONS AVAILABLE TREATMENTS

Surgical excision

Chemo prevention Trials

Topical Retinoids DEFINITION OF GENE THERAPY STRATEGIES FOR GENE THERAPY CURRENT GENE THREAPY APPROACHES FOR CANCER CLINICAL STUDIES AND CONTINUING CONTROVERSIES STRUCTURAL CHANGE IN CELL ON CARCINOGENSIS WHAT WOULD BE REQUIRED IN CLINICAL TRIALS What is a Clinical Trial WHAT IS INFORMED CONSENT WHAT IS RANDOMIZATION STAGING

Staging for Tumors ELIGIBILITY CRITERIA

Inclusion Criteria

Exclusion Criteria Current Clinical Trials Funded by NIH, US at different Phase level of Studies


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CLINICAL TRIALS

1. Study Using the Medpulser Electroporation System With Bleomycin to Treat Head and Neck Cancer

Basic Trial Information

Trial Description

Summary

Study Information

Clinical Application

Trial Lead Organizations/Sponsors

Trial Sites 2. Oral Cancer Adjuvant Therapy (OCAT) Trial

Purpose

Study Type

Study Design

Primary Outcomes

Expected Total Enrollment:

Aims Of Study

Eligibility criteria

Trial Design 1. Surgery 2. Radiotherapy: 3. Chemotherapy

Stratification

End points 1. Primary end point 2. Secondary end point

Quality of life:

Sample size

Duration of accrual

Eligibility

Ages Eligible for Study

Genders Eligible for Study

Criteria

Inclusion Criteria

Exclusion Criteria

Contact Location

3. Study of Proxinium for Treating Patients With Squamous Cell Head and Neck Cancer. Study of Proxinium for Treating Patients With Squamous Cell Head and Neck Cancer

Verified by Viventia Biotech February 2007

Purpose


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Study Type

Study Design

Eligibility

Genders Eligible for Study

Criteria

Inclusion Criteria:

Patient Characteristics:

Exclusion Criteria:

Location and Contact Information Verified by Viventia Biotech February 2007

4. Fruit and Vegetable Extracts in Treating Patients With Stage I, Stage II, Stage III, Stage IVA, or Stage IVB Head and Neck Cancer.

Background

Objective

Design

Trial Description

Purpose:

Chemo prevention therapy.

Eligibility

Treatment/Intervention

Results

Conclusion

Investigator

5. Expression of Hypoxia-Inducible Factor- a in Oral Precancers and Cancers

Further Study Information

Eligibility Criteria

Inclusion Criteria:

Exclusion Criteria:

Trial Site:

6. The Pharmacological Antioxidant Amifostine—Implications of Recent Research for Integrative Cancer Care

7. History of Amifostine

BIBLOGRAPHY

http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45487&version=Patient&language=English


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Tobacco use is a primary cause of many oral diseases and adverse oral

conditions. Tobacco-induced diseases include particularly cancer of the oral

cavity (mostly of the tongue, but also lips), periodontal disease, tooth loss and

congenital defects (Reibel, 2003).

These oral diseases contribute significantly to the global disease burden. Oral

cancer is the eleventh most common cancer worldwide tobacco use is estimated

to account for about 41% of oral/pharyngeal cancer cases in men, and 11% in

women (Stewart and Kleihues, 2003)

Epidemiological studies from the USA, India, Pakistan, and Sweden provide

sound evidence that smokeless tobacco causes oral cancer in humans (Cogliano

et al., 2004). Many types of smokeless tobacco are marketed for oral or nasal

use. All contain nicotine and nitrosamines.

The incidence of oral cancer shows extensive variation. Incidence and mortality

rates are higher in men than woman. Differences across countries particularly

relate to distinct risk profiles and availability and accessibility of health services.

The 10th International Congress on Oral Cancer took place during 19–24 April

2005 in Crete, Greece, and was attended by nearly 1000 researchers, health

professionals, and public health administrators. Biologic, clinical and public

health aspects of oral cancer and precancer was analyzed by participants and

the congress programme focused on international disease trends and risk

factors; tools for early diagnosis of oral cancer; prevention and screening;

treatment, care and services; quality of life of patients suffering from oral cancer,

(Community Dent Oral Epidemiol 2005; 33: 397–9) Poul Erik Petersen Chief,

Oral Health Programme,World Health Organization, Geneva, Switzerland

In the United States, cancers of the oral cavity and oropharynx represent

approximately three percent of all malignancies in men and two percent of all

malignancies in women. Over 90 percent of these tumors are squamous cell


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carcinomas, which arise from the oral mucosal lining. In spite of the ready

accessibility of the oral cavity to direct examination, these malignancies still are

often not detected until a late stage, and the survival rate for oral cancer has

remained essentially unchanged over the past three decades. (CA Cancer J Clin

2002; 52:195-215.)

INTRODUCTION

Cancers of the oral cavity and oropharynx represent approximately three percent

of all malignancies in men and two percent of all malignancies in women in the

United States. Squamous cell carcinoma, which arises from the oral mucosal

lining, accounts for over 90 percent of these tumors.

EPIDEMIOLOGY

Oral cancer most commonly occurs in middle-aged and older individuals,

although a disturbing number of these malignancies is also being documented in

younger adults in recent years. From an epidemiological and clinicopathological

perspective, ―oral cancer‖ can be divided into three categories: carcinomas of the

oral cavity proper, carcinomas of the lip vermilion, and carcinomas arising in the

oropharynx. Intraoral and oropharyngeal tumors are more common among men

than women, with a male / female ratio of over 2:1.( Neville BW, Damm DD, Allen

CM, et al) When compared with intraoral carcinoma, the prognosis for lip cancer

is quite good, with a five-year survival rate of 95 percent

RISK FACTORS

Epidemiological studies show that the risk of developing oral cancer is five to

nine times greater for smokers than for nonsmokers, and this risk may increase

to as much as 17 times greater for extremely heavy smokers of 80 or more

cigarettes per day. The strong association between cancers of the oral cavity and

pharynx with tobacco use is well established.treated oral cancer patients who


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continue to smoke have a two to six times greater risk of developing a second

malignancy of the upper aerodigestive tract than those who stop smoking

Marijuana use is also considered to be a potential risk factor and may be partly

responsible for the rise in oral cancers seen among young adults (Zhang ZF,

Morgenstern H, Spitz MR, et al)

Snuff and chewing tobacco have also been associated with an increased risk for

oral cancer. In addition, a significant number of oral cancers in smokeless

tobacco users develop at the site of tobacco placement. However, the use of

smokeless tobacco appears to be associated with a much lower cancer risk than

that associated with smoked tobacco.

Alcohol use has been identified as a major risk factor for cancers of the upper

aerodigestive tract. In studies controlled for smoking, moderate-to-heavy drinkers

have been shown to have a three to nine times greater risk of developing oral

cancer.

In India and Southeast Asia, the chronic use of betel quid (paan) in the mouth

has been strongly associated with an increased risk for oral cancer The quid

typically consists of betel leaf that is wrapped around a mixture of areca nut and

slaked lime, usually with tobacco and sometimes with sweeteners and

condiments. The slaked lime results in the release of an alkaloid from the areca

nut, which produces a feeling of euphoria and well being in the user.

Betel quid chewing often results in a progressive, scarring precancerous

condition of the mouth known as oral sub mucous fibrosis. In India, one study

showed a malignant transformation rate of 7.6 percent for oral submucous

fibrosis.Recent evidence suggests that human papillomavirus (HPV) may be

associated with some oral and oropharyngeal cancers. HPV-16 has been

detected in up to 22 percent of oral cancers, and HPV-18 has been found in up to

14 percent of cases.28


Dr.Rajeev Kashyap

Dietary factors, such as a low intake of fruits and vegetables, may also be

related to an increased cancer risk.

Carcinomas of the lip have been reported in a number of kidney transplant

patients receiving immunosuppressive medications, and oral carcinomas have

been documented in young AIDS patient

PREMALIGNANT LESIONS AND CONDITIONS

Premalignant lesions are those lesions in which carcinoma may develop.

Premalignant conditions are associated with a risk of carcinoma at some site

within the mouth, not necessarily marked by a pre-existing lesion.

Common Oral Lesions:

Oral leukoplakia is a predominantly white lesion of the oral mucosa that cannot

be characterized as any other definable lesion.‖ Such a definition, also adopted

by the World Health Organization, is the result of the effort of an international

group of experts who met in Uppsala in 1994 to review leukoplakia definitions

and classifications on the basis of previously published work and new scientific

acquisitions. Thus, leukoplakia is a clinical term used when any other white oral

lesion has been excluded by means of clinical examination and histological

assessment. (Axell T, Pindborg JJ, Smith CJ, van der Waal I.)

Oral white lesions with special reference to precancerous and tobacco-related

lesions: conclusions of an international symposium held in Uppsala, Sweden,

May 18-21, 1994. International Collaborative Group on Oral White Lesions (Oral

Pathol Med 1996;25:49-54.)

Homogeneous leukoplakia. There is a bright, white, sharplydefined patch

extending from the gingiva on to the labial mucosa. The surface has a slightly

rippled appearance and no red areas are associated.An innocent-looking, poorly-

defined inconspicuous white patch which showed dysplasia on biopsy. Despite

excision, malignant transformation followed several months later.


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White patch with dysplasia. This postcommissural lesion is poorly defined and

comprises both red and white areas. Lesions at this site are frequently due to

candidosis.abnormal dysplastic cells is often present in the underlying onnective

tissue.

Erythroplasia (‘erythroplakia’) Erythroplakia are red patches. The surface is

frequently velvety in texture and the margin may be sharply defined. Lesions of

this type typically do not from plaques (hence the term ‗erythroplakia‘ is

misleading) but, instead, they are flat or depressed below the level of the

surrounding mucosa Erythroplakia is common in the mouth but carries the

highest risk of malignant transformation and lesions are often already malignant

on first biopsy.

Lichen planus is most probably a precancerous condition. It may have a tissue

reaction pattern similar to a contact hypersensitivity reaction. Another important

component of etiological or pathogeneses importance may be mental stress, and

there is now some evidence that psychogenic stress may be a pathogenetic

factor for lichen planus (Hampf et al., 1987).

Oral Candidiasis Oral candidiasis typically is a localized infection; however,

rarely it may progress to or occur in patients with systemic candidiasis.

Clinical patterns of oral candidiasis are variable and include pseudo-

membranous candidiasis, or thrush median rhomboid glossitis and other forms of

erythematous candidiasis.As many as 60 percent of healthy adults carry Candida

species as a component of their normal oral flora. However, certain local and

systemic factors may favor overgrowth.

These include use of dentures, use of a steroid inhaler, xerostomia, endocrine

disorders,human immunodeficiency virus (HIV) infection, leukemia, malnutrition,

reduced immunity based on age, radiation therapy, systemic chemotherapy, and

use of broad-spectrum antibiotics or corticosteroids.( Fotos PG, Vincent SD,

Hellstein JW. 1992;& Epstein JB, Gorsky M, Caldwell J. 2002)


Dr.Rajeev Kashyap

Xerostomia is common in HIV disease, most often as a side effect of antiviral

medications or of the other antihypertensive, antidepressant, anxiolytic or

analgesic medications commonly prescribed for patients with HIV infection. The

oral dryness presents a significant risk factor for caries and can lead to rapid

dental deterioration. Xerostomia also contributes to oral candidiasis, mucosal

injury and dysphagia, and is often associated with pain and reduced oral intake

of food. (DAVID A. SIROIS, D.M.D., PH.D, 1998)

SUBLINGUAL KERATOSIS The term sublingual Keratosis is applied to

white lesions on the floor of mouth and ventral tongue. Whether this lesion is a

different entity from other leukoplakia is unclear. Malignant change was reported

in an unusually high proportion of cases (30%) in one series but this has not

been widely confirmed. Probably the risk of malignant transformation is less than

10%and possibly much lower.

ORAL SUBMUCOUS FIBROSIS: Oral submucous fibrosis affected areas

of the oral mucosa such as the palate or buccal mucosa appear almost white.

The pallor is due to the underlying fibrosis and ischaemia rather than a superficial

plaque, and the mucosa is typically smooth, thin and atrophic erythroplakia and

leukoplakia may be associated and the epithelium may show dysplasia.

Recognition and diagnosis require taking a thorough history and performing a

complete oral examination Common superficial oral lesions include candidiasis,

recurrent herpes labialis, recurrent aphthous stomatitis, erythema migrans, hairy

tongue, and lichen planus.

Knowledge of clinical characteristics such as size, location, surface morphology,

color, pain, and duration is helpful in establishing a diagnosis

Recurrent Apthous Stomatitis

Recurrent Apthous Stomatitis, or ―canker sores,‖ is an oral ulcerative condition

with a prevalence ranging from 5 to 21 percent. (Rivera-Hidalgo F, Shulman JD,

Beach MM. 2004) Although a variety of host and environmental factors have


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been implicated, the precise pathogenesis remains unknown. Smoking is

associated with a lower prevalence

Hairy Tongue :Hairy tongue is characterized by elongation and hypertrophy of

the filiform papillae on the dorsal tongue, causing a hair-like appearance) This

condition results from inadequate desquamation or increased keratinization of

the papillae. These papillae, which normally are about 1 mm in length, may

become as long as 12 mm. It occurs most often in persons who smoke heavily

and it also may be associated with poor oral hygiene, oxidizing mouthwashes,

Candida albicans. (Assimakopoulos D, Patrikakos G, Fotika C, Elisaf M , 2002)

Benign migratory glossitis or geographic tongue: anenigmatic oral lesion..and

certain medications(Am J Med 2002;113(9):751-5)

Herpes Labialis : Primary oral infection with the herpes simplex virus (HSV)

typically occurs at a young age, is asymptomatic, and is not associated with

significant morbidity. (Neville BW)

A minority of persons develop a symptomatic primary infection, presenting with an

acute outbreak of oral vesicles that rapidly collapse to form zones of erythema

and ulceration. In all cases, the gingiva is involved; in addition, other oral

mucosal sites and the perioral skin may be affected. Concomitant cervical lymph

adenopathy, fever, chills, anorexia, and irritability are common findings.

Neoplasms ( Kopasi’s Sarcoma): Kaposi‘s sarcoma is the most common

intraoral malignancy associated with HIV infection Recognition of the lesion is

essential, since oral KS is often the first manifestation of the disease and is a

diagnostic criterion for AIDS.

(MMWR Morbidity Mortal Wkly Rep 1992

The lesion may appear as a red-purple macule, an ulcer, or as a nodule or mass.

Intraoral KS occurs on the heavily keratinized mucosa, the palate being the site

in more than 90% of reported cases


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Centers for Disease Control and Prevention. 1993 revised classification system

for HIV infection and expanded surveillance case definition for AIDS among

adolescents and adults.

MMWR Morbidity Mortal Wkly Rep 1992 Dec 18; 41(RR-17):1-19.

Cancer development in the oral mucosa

The concept of a two-step process of cancer development in the oral mucosa,

i.e., the initial presence of a precursor subsequently developing into cancer, is

well-established.

Oral leukoplakia is the best-known precursor lesion. The evidence that oral

leukoplakia are pre-malignant is mainly derived from follow-up studies showing

that between < 1 and 18% of oral pre-malignant lesions will develop into oral

cancer; it has been shown that certain clinical sub-types of leukoplakia are at a

higher risk for malignant transformation than others. The presence of epithelial

dysplasia may be even more important in predicting malignant development than

the clinical characteristics.

Three major problems, however, are attached to the importance of epithelial

dysplasia in predicting malignant development:

(1) The diagnosis is essentially subjective,

(2) It seems that not all lesions exhibiting dysplasia will eventually become

malignant and some may even regress, and

(3) Carcinoma can develop from lesions in which epithelial dysplasia was not

diagnosed in previous biopsies.

There is, therefore, a substantial need to improve the histological assessment of

epithelial dysplasia or, since epithelial dysplasia does not seem to be invariably

associated with or even a necessary prerequisite for malignant development, it

may be necessary to develop other methods for predicting the malignant potential

of pre-malignant lesions. As a consequence of these problems, numerous


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attempts have been made to relate biological characteristics to the malignant

potential of leukoplakia.

Molecular biological markers have been suggested to be of value in the diagnosis

and prognostic evaluation of leukoplakia. Markers of epithelial differentiation and,

more recently, genomic markers could potentially be good candidates for

improving the prognostic evaluation of precursors of oral cancer. As yet, one or a

panel of molecular markers has not been determined that allows for a prognostic

prediction of oral pre-cancer which is any more reliable than dysplasia recording.

However, these new markers could be considered complementary to

conventional prognostic evaluation.

By Jesper Reibel (2003) International and American Associations for Dental

Research

Causative factors Oral Pre cancer and Cancer Modified By Rajeev Kashyap

MANAGEMENT OF DYSPLASTIC LESIONS

The prognosis in oral carcinoma is good only when the diagnosis is made early

and the tumor is small. Accurate assessment of the risk of malignant change in

red and white patches is therefore desirable, but assessment is highly subjective.

The level of risk cannot be reliably assessed from the Histopatology alone and

the clinical features.

http://crobm.iadrjournals.org/misc/terms.shtml



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The best predictor of malignant potential is the presence of dysplasia on biopsy.

However, even this is rather poorly correlated with behavior for such reasons

such as inadequate sampling at biopsy and the subjective nature of assessment

The effectiveness of other treatments has not yet been assessed on any

adequate scale. After Cryotherapy ablation, the area heals rapidly to leave an

apparently normal mucosa. However, there is some uncertainty about the risk of

invasive carcinomas subsequently arising in these sites---- experimentally.

Treatment with systemic or topical Retinoids has also been tried.

.

Available Treatments

● Observation for early detection of carcinoma

● Surgical excision with grafting, if required

● Cryotherapy

● Laser excision or vaporization

● Topical chemotherapy

● Retinoids

Surgical excision is the most common approach. It provides an excision

biopsy specimen which can be examined for the extent of the dysplasia and for

possible carcinoma. Unfortunately, lesions in the highest risk areas in the

posterior floor of mouth are technically difficult to excise and large lesions may

require grafting.

Chemo prevention Trials

Beta carotene, folic acid, and systemic retinoid supplementation have been

studied in several cervical cancer chemoprevention trials, (Butterworth CE Jr,

Hatch KD, Soong SJ, et al 2004) but no benefit has been seen. Despite


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promising results in earlier Phase I/Iia trials, almost all large Phase IIb/III trials

showed no benefit in systemic chemoprevention for this cancer type

Topical Retinoids are largely ineffective and though a proportion of white

lesions resolve with systemic treatment, toxic effects are usually unacceptable.

Further, lesions, which resolve with treatment, recur on withdrawal of the drugs.

With all such treatments the lesion is not available for histological examination

and multiple biopsy before treatment is required to ensure that malignant change

is not already present. They may be of value in those for whom surgery is not

practical because of, for instance, unfitness for anesthesia. In summary, frequent

clinical observation, preferably with photographic records, and immediate biopsy

of any areas that are suspicious or change in appearance, is generally the best

option. Selected lesions with clinical features of high-risk or severe dysplasia on

biopsy are probably best excised

DEFINITION OF GENE THERAPY

Gene therapy can be defined as gene transfer for the purpose of treating human

disease (Cusack and Tanabe, 1998). This includes the transfer of new genetic

material as well as the manipulation of existing genetic material. This holds true

especially for cancer

STRATEGIES FOR GENE THERAPY

Potential uses of gene therapy in oral cancer include the treatment of recurrent

disease and adjuvant treatment—for example, at surgically resected margins.

Localized distant metastatic disease is another potential target of gene therapy in

patients with oral cancer.

Most of the traditional cancer therapies, including surgery, radiotherapy, and

chemotherapy, have not improved the survival rates of patients with mucosal

squamous cell carcinoma. Local and/or regional tumor recurrence develops in


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approximately one-third of patients, despite definitive treatment (Schwartz et al.,

2000). The patient with recurrent or metastastic cancer is often considered

incurable.

A variety of chemotherapeutic agents has been used alone, and in combination,

for the treatment of recurrent oral squamous cell carcinoma.

However, chemotherapy is associated with well-known toxicities and has

demonstrated no clear impact on survival in patients with recurrent oral cancer

(Schrijvers D, Johnson J, Jiminez U, Gore M, Kosmidis P, Szpirglas H et al.,

1998).

Current Gene Therapy Approaches for Cancer

Gene Therapy Development Stage Goal

Tumor cell- killing viruses

Pre-clinical

Kill tumor cell

Immunotherapy Clinical trial Enhance immunogenicity of cell

Gene addition therapy

Clinical trial

Suicide gene therapy Clinical trial Kill tumor cell and enhance chemotherapy

Anti-angiogenesis therapy

Pre-clinical

Inhibit tumor progression

Drug resistance genethreapy

Clinical trial Decrease toxicity of chemotherapy

Anti-angiogenesis therapy

Clinical trial Inhibit tumor progression

Antisense RNA Clinical trial Inhibit tumor cell growth

-


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There are several general strategies utilized in a gene therapy approach to

cancer, including:

(1) addition of a tumor-suppressor gene (gene addition therapy);

(2) deletion of a defective tumor gene (gene excision therapy);

(3) down-regulation of the expression of genes that stimulate tumor growth

(antisense RNA);

(4) enhancement of immune surveillance (immunotherapy);

(5) activation of prodrugs that have a chemotherapeutic effect ("suicide" gene

therapy);

(6) introduction of viruses that destroy tumor cells as part of the replication cycle;

(7) delivery of drug resistance gene(s) to normal tissue for protection from

chemotherapy; and

(8) introduction of genes to inhibit tumor angiogenesis.

(S. Xi1 and J.R. 2003)

Clinical Studies and Continuing Controversies

Despite the initial problems with toxicities and logistical drawbacks of amifostine

administration, research proceeded. Most clinical studies showed no evidence

of tumor protection. The development of treatment regimens with very serious

side effects, such as chemo radiation and high-dose conditioning with

chemotherapy or radiation prior to bone marrow transplant, spurred researchers

to extend their areas of

interest to these settings. Based on large randomized studies, FDA approval was

granted in 1995 for an important reduction of renal damage related to cisplatin

at standard chemotherapeutic doses for ovarian and non-small-cell lung cancer

(NSCLC). Approval was granted in 1999 for reducing Xerostomia in

postoperative chemo radiotherapy for head and neck cancer.

The study on which the latter approval was granted fueled the controversy about

amifostine and tumor protection. (Brizel et al) used amifostine with 303 patients


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receiving radiation for previously untreated head and neck cancer, with loco

regional control a primary antitumor end point, along with toxicity reduction.

Amifostine significantly reduced grades 2 to 4 acute xerostomia from 78% to 51%

and chronic Xerostomia grades 2 to 4 from 57% to 34%. Median saliva

production was also greater with amifostine, although there was not a reduction

in mucositis. With and without amifostine, 2-year loco regional control was 58%

versus 63%, and overall survival was 71% versus 66%. Controversy about

reliance on this study for FDA approval for the indication of radiation-induced

Xerostomia led to a head-to-head debate between (Brizel and respected Danish

radiation oncologist Jens) Overgaard on the role of amifostine in chemo radiation

in the pages of Lancet Oncology in 2003.20 A key point in this debate was the

ability of randomized trials to detect tumor protection. A single randomized trial,

even a fairly large one, such as that of Brizel, lacks the ability to detect small

degrees of tumor protection. Even a small percentage of tumor protection by a

cytoprotectant such as amifostine could negate the curative potential of cancer

therapy for thousands of patients, if the cytoprotectant was widely used. Brizel

summarized the debate, noting that to detect a survival reduction from 45% to

40% in the head and neck, cancer scenario, with 80% statistical power, a study

that would require 1246 patients per arm would be needed—a waste of funding

and patient resources.

(Lancet Oncology in 2003.20 A)

Structural Change in Cell on Carcinogenesis

● Drop-shaped rete ridges

● Nuclear hyperchromatism

● Nuclear pleomorphism and altered nuclear/cytoplasmic ratio

● Excess mitotic activity

● Loss of polarity of cells

● Deep cell keratinization

● Disordered or loss of differentiation

● Loss of intercellular adherence


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Multistep Carcinogenesis Model. Adapted from Soria JC, Kim ES, Fayette J, et al (CA Cancer J Clin 2004;54:150–180) Epithelial carcinogenesis is a multi-step process in which an accumulation of

genetic events within a single cell line leads to a progressively dysplastic cellular

appearance, deregulated cell growth, and, finally, carcinoma. Cancer chemon

prevention, as first defined by (Sporn in 1976), uses natural, synthetic, or biologic

chemical agents to reverse, suppress, or prevent carcinogenic progression

(Sporn MB, 1976).

What would be required in clinical trials?

Every clinical trial has a clearly defined objective

Clearly defined entry criteria

Clearly defined period of follow-up.

You would first have to meet a certain profile, outlined by the inclusion and

exclusion criteria. You would then have to be able to comply with the scheduled

treatment and follow-up visits. If you appeared to be eligible and could follow the


Dr.Rajeev Kashyap

treatment and follow-up schedule, you would be presented with an Informed

Consent Form to review and sign.

After you sign the Informed Consent Form, you will be given a copy. At that point

you are considered in the study, and you will be expected to follow the treatment

regimen as outlined to you.

You may be assigned to a particular treatment by a system called randomization.

You would not have any choice in the treatment you received. In a randomized

trial the treatment options are called treatment "arms". Treatment arms may

represent different doses of a drug, or may represent standard care

What is a Clinical Trial?

Clinical Trials, also called Research Studies or just Studies, are conducted over

several years for all new medical treatments before they can be approved by the

Food and Drug Administration for general use. There are typically different

phases of the studies that have to be conducted.

Phase I studies involve a small number of participants and focus on safety

issues. They may involve healthy volunteers or they may involve patients with a

specified disease or condition. Participants are given the investigational

treatment and monitored closely (often in hospital settings). Individual

participants may be involved in a Phase I study for a month or less.

Phase II studies are somewhat larger than Phase I studies, and the focus is

broadened from safety only to safety plus dose toleration and/or whether the

investigational product indicates that it is actually effective. Phase II studies

generally involve a year or less follow-up.

Phase III studies may be very large, because they focus on both safety of the

product and efficacy. Because of this, participants are often followed for over a

year.


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At each Phase, data is collected to document the participant's baseline condition,

what treatment they received, whether they experienced any adverse events

from the treatment, and how they responded to the treatment. The data is

analyzed at the end of each study and a decision is made regarding whether

there are safety issues that would make going forward unethical. Companies

sponsoring Clinical Trials consult regularly with the Food and Drug Administration

to determine how to design Clinical Trials to minimize risk to participants while

collecting sufficient data to support a final submission to the FDA.nvestigational

treatment, or a combination.

What is Informed Consent?

An Informed Consent Form provides you with a written summary of the research

being conducted, what your part in it would be if you participated, what your other

options for treatment are, how your private medical information will be protected,

and who would have access to your medical information during the course of the

study, and who to contact with questions or in case of emergency. It also tells

you what your rights are in case you are injured during the course of study

participation, and advises that you do not have to participate in order to receive

medical care.

However, Informed Consent is more than a form that you sign before you can

participate in a clinical trial. Informed Consent is also a process that occurs

throughout the study. You have the right to ask your doctor questions about your

treatment, and your participation in the study, and if the doctor becomes aware of

any information, which could have an effect on your continued participation, you

will be informed

What is randomization?

Randomization is a process - like flipping a coin - which randomly assigns you to

a treatment group. The randomization assignments are developed by


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statisticians to assure that patients are assigned to treatment arms in the

proportion outlined in the protocol.

Staging

Staging of oral cancer is important for establishing proper treatment and

determining prognosis. Tumors are staged using the TNM system, where T

represents the size of the primary tumor, N indicates the status of the regional

lymph nodes, and M indicates the presence or absence of TNM Staging of Oral

Cancer. (J Biomed Opt, September 1, 2004; 9(5): 940-950)

Staging for Tumors

T Staging for Tumors of the Lip and Oral Cavity

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 Lip Tumor invades through cortical bone, inferior alveolar

nerve, floor of mouth, or skin of face (ie, chin or nose)* , Oral , Cavity

Tumor invades through cortical bone, into deep _extrinsic_muscle of tongue

(genioglossus, hyoglossus, palatoglossus, and styloglossus), maxillary sinus, or

skin of face

T4b Tumor involves masticator space, pterygoid plates, or skull base and/or

encases internal carotid artery

N Staging for All Head and Neck Sites Except the Nasopharynx and Thyroid

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


Dr.Rajeev Kashyap

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 contra lateral 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 bilateral or contra lateral lymph nodes, none more than 6 cm in

greatest dimension

N3 Metastasis in a lymph more than 6 cm in greatest dimension

M Staging for Head and Neck Tumors

Mx Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

TNM Staging of Cancers of the Head and Neck(CA Cancer J Clin 2005;55:242–

258 , Volume 55 Y Number 4 Y July/August 2005)

Modified from AJCC Manual for Staging of Cancer, 1997, Ed: Fleming ID, et al. ,

Lippincott-Raven Publishers, Philadelphia, PA.

Eligibility criteria

In clinical trials, requirements that must be met for an individual to be included in

a study. These requirements help make sure that patients in a trial are similar to

each other in terms of specific factors such as age, type and stage of cancer,

general health, and previous treatment. When all participants meet the same

eligibility criteria, it gives researchers greater confidence that results of the study

are caused by the intervention being tested and not by other factors.

Inclusion Criteria:


Dr.Rajeev Kashyap

The presence of primary oral cavity, primary pharyngeal, primary

laryngeal, salivary gland, limited recurrent and second primary tumors

must be confirmed by histological examination of a tissue sample

(e.g., biopsy) obtained within 2 months of the subject receiving the study

treatment.

The length of the longest diameter of the study lesion must be < 5 cm and

the calculated treatment volume (tumor volume plus a 0.5 cm margin

around the tumor) for the study lesion [where treatment volume = 0.5

(a+1) (b+1)2 and where a = length of the longest diameter (cm), b = the

next longest diameter perpendicular to ―a‖ (cm)] must be < 60.0 cm3.

Age: 18 years or older.

Male or female.

Men and women of childbearing potential must be using Investigator

prescribed contraceptive methods while undergoing protocol related

therapy.

Baseline performance status: ECOG 0-2:

1. Grade 0: Fully active, able to carry on all pre-disease performance

without restriction.

2. Grade 1: 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 work.

3. Grade 2: Ambulatory and capable of all self-care, but unable to

carry out any work activities. Up and about more than 50% of

waking hours.

Life expectancy of at least 6 months.

Subjects must sign a written Informed Consent prior to receiving any

study procedures or treatments.

Exclusion Criteria:


Dr.Rajeev Kashyap

1.Subjects with tumors suspected of involving a 50% or greater encasement of a

blood vessel as measured by magnetic resonance imaging (MRI) or computed

tomography (CT) scan.

2.Subjects with tumors having bone invasion. Subjects with hypersensitivity

3.Subjects deemed unsuitable for general anesthesia.

4.Subjects with a significant history of emphysema or pulmonary fibrosis.

5.Subjects with indwelling cardiac pacemakers who cannot tolerate a period with

pacemaker turned off.

6.Subjects with a history of uncontrolled cardiac arrhythmia.

7.Women who are pregnant, or are nursing. Women must have a negative

pregnancy test (urine pregnancy tests are acceptable) within 7 days of study

treatment.

Some of the Current Clinical Trials Funded by NIH, US at different Phase level of Studies: STUDY PURPOSE TYPE ELIGIBILITY STATUS Expression of VEGF-C and VEGF-CR in Oral Cancers and Premalignant Lesions

role of vascular endothelial growth factor-C (VEGF-C) and its receptors

Observational Screening, Longitudinal, Defined Population, Retrospective Study

18 Years -85 Years, Genders =: Both Histopatology/ blood chemistry

Currently recruiting

Erlotinib Prevention of Oral Cancer (EPOC)

To learn if erlotinib hydrochloride (Tarceva (OSI-774 ) can prevent cancer in the mouth

Interventional , phase III trial :Prevention, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

18 Years and above , Gender eligible both, Histopatology/ blood chemistry Inclusion/exclusion Criteria:


Rosiglitazone in Preventing Oral Cancer in Patients With Oral Leukoplakia

How well rosiglitazone works in preventing oral cancer in patients with oral leukoplakia

Interventional Prevention, Non-Randomized, Open Label , Phase II a Trial

18 Years and above , Gender eligible both, Histopatology/ blood chemistry Inclusion/exclusion Criteria:


Oral Cancer Adjuvant Therapy (OCAT) Trial

Concurrent chemotherapy to post-operative adjuvant radiotherapy OR shortening of duration of post-operative radiotherapy

Interventional Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study, phase III

18 Years and above , Gender eligible both, Inclusion/exclusion Histopatology/ blood chemistry Criteria:



Dr.Rajeev Kashyap

Diagnosis of Oral Precancers and Cancers Using Optic Coherence Tomography

Diagnosis of oral precancers and cancers using optic coherence tomography

:Observational :Screening, Cross-Sectional, Defined Population, Prospective Study, phase IV

18 Years and above , Gender eligible both, Inclusion/exclusion Criteria: Histopatology/ blood chemistry


(Compiled from NIH web site Clinical trials.gov)

Study Using the Medpulser Electroporation System With Bleomycin to Treat Head and Neck Cancer Basic Trial Information Note: Information about this trial is from the ClinicalTrials.gov database.

Phase Type Status Age Sponsor protocolID

PHASE iv

Treatment Active 18years and above

Pharmaceutical industry

EU-HNBE- 2003 NCI00198263

Trial Description Summary

The purpose of the trial is to study the safety and efficacy of the Medpulser

Electroporation System with bleomycin in the treatment of head and neck cancer

.

Study Information

Electroporation therapy is a tumor-specific ablative treatment modality with the

potential to manage local tumors without the potentially undesirable side effects

of systemic chemotherapy agents or radiotherapy. Surgical resection of solid

tumors often leaves subjects with significant organ dysfunction and/or permanent

disfigurement requiring reconstructive surgery. In contrast, electroporation

therapy may offer equivalent disease control to conventional surgery with

lessened need for reconstructive surgery. Electroporation therapy may also

provide economic benefits over conventional surgical and or radiation procedures

through reduced operating theatre costs, hospital stays and post treatment

interventions. The ability to shrink or eliminate local tumors with the MedPulser®

System when used in conjunction with intralesional Bleomycin is an important


Dr.Rajeev Kashyap

new possible treatment for the conservative local management of SCCHN and

provides a possible alternative treatment option to surgical excision in the

management of cancer.

The use of the MedPulser Electroporation Therapy System is quite simply

understood and easy to apply:

The physician selects and connects the sterile applicator appropriate for

the nature and location of the tumor.

The patient is given general anesthesia in a hospital operating room

setting. Certain future applications may require only local anesthesia.

The drug is injected into the selected tissue, followed by a brief interval

lasting only a few minutes.

The applicator needles are then inserted into the tumor.

The physician activates the electrical pulse using a foot pedal or hand

switch.

For a larger tumor or area, the applicator is reinserted in an overlapping

pattern to cover the entire tissue area requiring treatment.

After treatment, the needle array applicator is discarded. The entire procedure

can be completed within 20 minutes or less and typically needs to be done only

once. The dosage of drug used is based on tumor volume and is typically a small

fraction of the dosage that would be used if injected systemically into the patient's

blood during chemotherapy. As a result of the lower dosage administered locally,

side effects have been minimal. No episodes of injury to normal (non-tumor)

tissue adjacent to the tumors have been observed in the patients treated to date.

The MedPulser® Tumor Ablation System delivers electric pulses of

specified voltage, duration and frequency through the generator.

The second component of the system is a sterile, single patient electrode

needle applicator.

There are three applicator designs: one stationary 3 cm adjustable length

unit and two with articulated ends 1-2 cm in length.


Dr.Rajeev Kashyap

Clinical Application: The MedPulser Electroporation Therapy System is

designed for use by qualified clinicians and may be used in an out-patient

surgical setting, for example, with cutaneous tumors. The MedPulser Instrument

is preprogrammed for the electrical parameters set for each applicator model.

After injection of oncolytic agent, the applicator needles are inserted into

the tumor and margins repeatedly, overlapping the treatment fields, to

ensure coverage of the entire tumor, including the margins.

Each electroporation sequence is activated by the MedPulser Instrument

Foot Switch.

The MedPulser Electroporation Therapy System incorporates safety

features that help to ensure the delivery of electrical pulses has been

correctly completed.

In the event of a fault condition, the MedPulser Electroporation Therapy

System aborts the treatment sequence and immediately alerts the user.

Bleomycin is injected into

an area affected by cancer. A probe from the MedPulser, which contains a ring of six electrodes. needles, is inserted into the site, delivering a small electrical charge


Dr.Rajeev Kashyap

The electrical charge creates temporary openings in the cell membrane,

allowing drugs to enter. The openings seal, trapping the drug inside. The drug kills the cancer cells

(Adopted from Inovio Biomedical Corporation web site)

Trial Lead Organizations/Sponsors :Inovio Biomedical Corporation

Trial Contact Information: Paul M. Goldfarb, MD, Study Chair Paul

Goldfarb, MD,

Eligibility Criteria Inclusion Criteria:

1. The presence of primary oral cavity, primary pharyngeal, primary laryngeal,

salivary gland, limited recurrent and second primary tumors must be confirmed

by histological examination of a tissue sample (e.g., biopsy) obtained within 2

months of the subject receiving the study treatment.

2. The length of the longest diameter of the study lesion must be < 5 cm and the

calculated treatment volume (tumor volume plus a 0.5 cm margin around the

tumor) for the study lesion [where treatment volume = 0.5 (a+1) (b+1)2 and

where a = length of the longest diameter (cm), b = the next longest diameter

perpendicular to ―a‖ (cm)] must be < 60.0 cm3.

3. Age: 18 years or older.

4. Male or female.

5. Men and women of childbearing potential must be using Investigator

prescribed contraceptive methods while undergoing protocol related therapy.

6. Baseline performance status: ECOG 0-2:

* Grade 0: Fully active, able to carry on all pre-disease performance without

restriction.

* Grade 1: Restricted in physically strenuous activity but ambulatory and able to

carry out work of a light or sedentary nature, e.g., lighthouse work, office work.


Dr.Rajeev Kashyap

* Grade 2: Ambulatory and capable of all self-care, but unable to carry out any

work activities. Up and about more than 50% of waking hours.

7. Life expectancy of at least 6 months.

8. Subjects must sign a written Informed Consent prior to receiving any study

procedures or treatments.

Exclusion Criteria:

1. Subjects with tumors suspected of involving a 50% or greater encasement of a

blood vessel as measured by magnetic resonance imaging (MRI) or computed

tomography (CT) scan.

2. Subjects with tumors having bone invasion.

3. Subjects with hypersensitivity to bleomycin.

4. Subjects who have received or will exceed a total lifetime dose of bleomycin

greater than 400 units.

5. Subjects deemed unsuitable for general anesthesia.

6. Subjects with a significant history of emphysema or pulmonary fibrosis.

7. Subjects with indwelling cardiac pacemakers who cannot tolerate a period with

pacemaker turned off.

8. Subjects with a history of uncontrolled cardiac arrhythmia.

9. Women who are pregnant, or are nursing. Women must have a negative

pregnancy test (urine pregnancy tests are acceptable) within 7 days of study

treatment.

Trial Sites : U.S.A.. California , San Diego , Inovio Biomedical Corporation, Paul

Goldfarb, MD , Email: [email protected] Ph: 858-410-3158

Oral Cancer Adjuvant Therapy (OCAT) Trial

Purpose

To demonstrate whether addition of Concurrent chemotherapy to post-operative

adjuvant radiotherapy OR shortening of duration of post-operative radiotherapy,

by administering 6 fractions / week instead of 5 fractions / week improves local-


Dr.Rajeev Kashyap

regional control and / or overall survival in high risk, locally advanced, resectable,

squamous cell carcinoma of oral cavity

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel

Assignment, and Efficacy Study

Primary Outcomes: Local-regional failure

Secondary Outcomes: Overall survival; Treatment related toxicity; Protocol

compliance; Overall treatment time; Quality of life: assessment by EORTC-QLQ-

C30 and EORTC-H&N-35

Expected Total Enrollment: 900

Aims Of Study: To demonstrate whether addition of Concurrent

chemotherapy to post-operative adjuvant radiotherapy OR shortening of duration

of post-operative radiotherapy, by administering 6 fractions / week instead of 5

fractions / week improves local-regional control and / or overall survival in high

risk, locally advanced, resectable, squamous cell carcinoma of oral cavity.

Eligibility criteria: Locally advanced, stage III and IVA, resectable, squamous

cell carcinomas of oral cavity with one of the following poor prognostic factors

extra capsular nodal extension, involvement of > 2 regional lymph nodes, margin

of resection with invasive cancer Extensive soft tissue and / or skin infiltration

requiring major reconstructive procedure.

Peri-neural invasion with positive lymph node. Lympho-vascular embolisation

with positive lymph node.

Trial Design The eligible patients will be randomly allocated to one of the three

arms


Dr.Rajeev Kashyap

1. Arm 1 (Control arm): Surgery followed by conventional radiotherapy

2. Arm 2: Surgery followed by Concurrent chemo-radiotherapy

3. Arm 3: Surgery followed by Accelerated radiotherapy

Surgery: Surgery will be same in all three arms. Wide excision tumour with

appropriate nodal dissection and reconstruction utilizing accepted criteria for the

region involved will be done.

Radiotherapy: Total dose of radiotherapy will be 56 – 60 Gy. Patients in Arms

1 and 2, five fractions per week for six weeks. Patients in Arm 3, six fractions a

week for five weeks.

Chemotherapy: Patients in Arm 2 will get weekly chemotherapy (Inj Cisplatin

30 mg / m2)

Stratification: Patients will be stratified according to following factors Site:

Gingivo-buccal complex cancers Vs Tongue and Floor of mouth cancers. T

stage. N stage. Extra-capsular spread (Peri-nodal extension) Surgical margin

Extensive soft tissue infiltration

End points

Primary end point: Local-regional failure.

Secondary end point: Overall survival. Other parameters to be assessed are

Treatment related toxicity Protocol compliance Overall treatment time

Quality of life: assessment by EORTC-QLQ-C30 and EORTC-H&N-35

Sample size: 900 pts (300 pts in each arm).


Dr.Rajeev Kashyap

Duration of accrual: 7 years. Duration of follow up: 5 years. With minimum

follow up of 2 years. Analysis: Intent to treat analysis will be done. Interim

analysis will be done after 450 patients (150 pts in each arm)

Eligibility

Ages Eligible for Study: 18 Years - 65 Years,

Genders Eligible for Study: Both

Criteria

Inclusion Criteria:

Previously untreated, resectable, loco-regionally advanced, stage III & IV, biopsy-

proven squamous cell carcinoma of the oral cavity. (Clinically lower stage

patients will also be included if upstaged to pathological stage III or IV after

Surgery)

One or more of the following must be present: extra capsular nodal

extension, involvement of > 2 regional lymph nodes, margin of resection with

invasive cancer (on Histopatology) Extensive soft tissue and / or skin infiltration

requiring major reconstructive procedure.

Peri-neural invasion with positive lymph node(s).

Lymph vascular embolisation with positive lymph node(s).

Age > 18. Karnofsky performance status of > 60.

WBC > 3500, platelets > 100,000

Serum creatinine < 1.2 mg / m2

Signed study-specific informed consent form.


Dr.Rajeev Kashyap

Protocol treatment must begin within 8 weeks surgery.

Exclusion Criteria:

Gross (visible or palpable) residual disease left after surgery. Prior chemotherapy

or radiation therapy to the head and neck region.

Evidence of distant metastasis. Any post-operative complication which will delay

starting of adjuvant treatment for more than 8 weeks.

Presence of synchronous or concurrent head and neck primary tumors. Prior

malignancy within the previous 5 years. Patients who because of their medical

status are not candidates for the proposed treatment.

KPS < 60. Age > 65 years.

Poor expected follow up

Contact Location: India, Maharashtra

Dr. Mandar. S. Deshpande, Tata Memorial Hospital,

Parel, Mumbai, Maharashtra, 400012, India;

Status: Recruiting

Study of Proxinium for Treating Patients With Squamous Cell Head and Neck Cancer Verified by Viventia Biotech February 2007

Purpose The purpose of this study is to determine the safety, effectiveness, and recommended dose of Proxinium in North American patients with Squamous Cell


Dr.Rajeev Kashyap

Head and Neck Cancer

Condition Intervention Phase

Recurrent Squamous Cell Carcinoma of the Head and Neck Carcinoma, Squamous Cell Neoplasms, Squamous Cell Head and Neck Neoplasms Mouth Neoplasms Head and Neck Cancer

Drug: Proxinium Phase II

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled,

Single Group Assignment, Safety/Efficacy Study

Official Title: A Phase II, Open-Label Study to Evaluate the Safety, Tolerability,

and Pharmacokinetic Profile of Proxinium in Patients With Recurrent Squamous

Cell Carcinoma of the Head and Neck Who Have Received at Least One Prior

Anti-Cancer Treatment Regimen for Recurrent Disease

Eligibility

Ages Eligible for Study: 18 Years and above,

Genders Eligible for Study: Both

Criteria

Inclusion Criteria:

Disease Characteristics:

Histologically confirmed recurrent squamous cell carcinoma of the head and

neck. Immunohistochemically confirmed epithelial cell adhesion molecule (Ep-

CAM)–positive SCCHN.

Must have progressed on or after receiving at least 1 prior anti-cancer treatment

regimen containing 1 or more anti-cancer agents (eg, chemotherapy, biologic

therapy, or photodynamic therapy) for their recurrent disease.

Must have at least 1 accessible target tumor that is amenable to adequate direct

injection.


Dr.Rajeev Kashyap

The patient must have at least 1 accessible target tumor without direct carotid

artery involvement.

Prior/Concurrent Therapy:

Minimum period of 4 weeks between the last dose of anti-cancer therapy (eg,

chemotherapy, biological therapy, or photodynamic therapy) or any

investigational therapy and the first dose of the study drug.

Minimum period of 8 weeks following the last dose of radiotherapy and the first

dose of the study drug.

Recovered or reached a stable state of symptomatology from any previous

treatment-related toxicity.

Patient Characteristics:

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

Life expectancy of at least 12 weeks.

Adequate hepatic function ALT and AST and total bilirubin levels ≤1.5 times ULN.

Adequate renal function (serum creatinine <2.0 mg/dL).

Hematologic values consisting of granulocytes ≥1500/μL, platelets ≥100 000/μL,

and hemoglobin >8 g/dL.

Prothrombin time and partial thromboplastin time within normal limits Other:

The patient must provide written informed consent.

Fertile patients must use effective contraception

Exclusion Criteria:

Brain tumor or brain metastases.

Nasopharyngeal SCCHN.

Human immunodeficiency virus, hepatitis C virus, or hepatitis B surface antigen.

Uncontrolled bleeding from any target tumor(s) that are being considered for

treatment or a history of tumor hemorrhage that has required medical

intervention (other than direct compression).

The patient is a candidate for surgical tumor resection of their target tumor(s).

Pregnant or lactating.


Dr.Rajeev Kashyap

Clinically significant renal or hepatic disease.

Requires regular use of aspirin, full-dose warfarin, or heparin.

Location and Contact Information: Verified by Viventia Biotech

February 2007

United States, Alabama, United States, Arkansas, United States, Colorado

United States, California, United States, Florida, United States, Illinois

United States, Louisiana, United States, Minnesota, United

states, Massachusetts, United States, Missouri, United States, New Hampshire,

United States, Oklahoma, United States, Pennsylvania

United States, South Carolina, United States, Texas

Canada, Ontario, Canada, Quebec

Fruit and Vegetable Extracts in Treating Patients With Stage I, Stage II, Stage III, Stage IVA, or Stage IVB Head and Neck Cancer.

Association between fruit and vegetable consumption and oral cancer: a meta-

analysis of observational studies

Background: Oral cancer ranks as the seventh most common form of cancer

worldwide. Recent reports have examined the effect of fruit and vegetable intake

on the risk of oral cancer, but results are controversial.

Objective: A meta-analysis was performed to arrive at quantitative conclusions

about the contribution of fruit and vegetable intakes to the occurrence of oral

cancer.

Design: A comprehensive, systematic bibliographic search of medical literature

published up to September 2005 was conducted to identify relevant studies.

Separate meta-analyses were conducted for fruit and vegetable consumption.

The effect of portion or daily intake of fruit or vegetables on the risk of oral cancer

was calculated. A multivariate meta-regression analysis was performed to


Dr.Rajeev Kashyap

explore heterogeneity. This multivariate meta-regression analysis examined the

effect of quality score, the type of cancers included, citrus fruit and green

vegetable consumption, and the time interval for dietary recall of the studies on

the role of fruit or vegetable consumption in the risk of oral cancer. The presence

of publication bias was assessed with a funnel plot for asymmetry.

The multivariate meta-regression showed that the lower risk of oral cancer

associated with fruit consumption was significantly influenced by the type of fruit

consumed and by the time interval of dietary recall.

Phase II Randomized Study of Fruit and Vegetable Extracts in Patients With

Stage I-IVB Head and Neck Cancer

Trial Description

Purpose:

Chemo prevention therapy is the use of certain substances to try to prevent the

development of cancer. Fruit and vegetable extracts may be effective in

preventing the recurrence or further development of Head & neck cancer.

This randomized phase II trials studying how well fruit and vegetable extracts

work in preventing the recurrence of stage I, stage II, stage III, stage IVA, or

stage IVB head and neck cancer.

Eligibility: Eligibility criteria include the following:

At least 18 years old

No cancer for at least 6 months

More than 6 months but less than 3 years since chemotherapy , hormone

therapy and / or radiation therapy

More than 6 months since surgery

Final eligibility for a clinical trial is determined by the health professionals

conducting the trial. For more details about the eligibility requirements for

this trial and the treatment or intervention,



Dr.Rajeev Kashyap

Treatment/Intervention: Patients will be randomly assigned to one of two

groups. Patient‘s in-group one will receive fruit and vegetable extracts by mouth

twice a day. Patient‘s in-group two will receive a placebo by mouth twice a day.

Treatment in both groups may continue for up to 12 weeks. Patients will be

evaluated once a year for 5 years.Patients will be evaluated once a year for 5

years.

Results: Sixteen studies (15 case-control studies and 1 cohort study) met the

inclusion criteria and were included in the meta-analysis. The combined adjusted

odds ratio (OR) estimates showed that each portion of fruit consumed per day

significantly reduced the risk of oral cancer by 49% (OR: 0.51; 95% CI: 0.40,

0.65). For vegetable consumption, the meta-analysis showed a significant

reduction in the overall risk of oral cancer of 50% (OR: 0.50; 95% CI: 0.38, 0. 65).

Conclusion: The consumption of fruit and vegetables is associated with a

reduced risk of oral cancer

Investigator: Maria Pavia, Claudia Pileggi, Carmelo GA Nobile and Italo F

Angelillo Expression of Hypoxia-Inducible Factor- a in Oral Precancers and Cancers Basic Trial Information

Phase Type Status Age Sponsor Protocol ID

No phase

specified

Natural

History

Epidemiolog

y

Active 18 to 85 National

University

Hospital

9261701447 NCT00154973

Trial Description

Summary

Expression of hypoxia-inducible factor-α in oral precancers and cancers

Further Study Information

Expression of hypoxia-inducible factor-α in oral precancers and cancers



Dr.Rajeev Kashyap

Eligibility Criteria

Inclusion Criteria:

oral cancer specimens

Exclusion Criteria:

not oral cancer specimens

Trial Lead Organizations/Sponsors

National Taiwan University Hospital

Trial Contact Information

Chun-Pin Chiang, DMSc

Principal Investigator

Ph: 886-2-23123456 Ext.6855

Trial Site: Taipei, National Taiwan University Hospital

Information obtained from ClinicalTrials.gov on July 20, 2007

The Pharmacological Antioxidant Amifostine—Implications of Recent Research for Integrative Cancer Care Keith I. Block, MD, and Charlotte Gyllenhaal, PhD

History of Amifostine Amifostine (Ethyol, WR-2721; Medimmune,Gaithersburg, Md) is a by-product of

the cold war. Initially developed in attempts to protect persons exposed to

nuclear fallout, it was later found to offer relative radioprotection to normal cells at

the expense of tumor cells and then developed as an intravenous cytoprotectant

for use in radiation therapy and chemotherapy. Amifostine is a phosphorylated of

Pro drug: its active metabolite WR-1065 is dephosphorylated by membrane

bound alkaline phosphatase.

Source: NCI's Web site


Dr.Rajeev Kashyap

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cisplatin / fluorouracil chemotherapy by interferon alfa-2b in patients with




Dr.Rajeev Kashyap

recurrent or metastatic head and neck cancer. Head and Neck Interferon

Cooperative Study Group)

21 Lancet Oncology in 2003.20 A.

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Health & Medicine

Tobacco and oral cancer cancer