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Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
Tobacco and oral cancer  cancer
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Tobacco and oral cancer cancer

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  • 1. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap Tobacco Oral cancer & Precancer
  • 2. 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
  • 3. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 4. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap  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
  • 5. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 6. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 7. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 8. Tobacco Oral Cancer & PreCancer 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.
  • 9. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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)
  • 10. Tobacco Oral Cancer & PreCancer 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
  • 11. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 12. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 13. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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.
  • 14. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 15. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 16. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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 -
  • 17. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 18. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 19. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 20. Tobacco Oral Cancer & PreCancer 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.
  • 21. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 22. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 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
  • 23. Tobacco Oral Cancer & PreCancer 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:
  • 24. Tobacco Oral Cancer & PreCancer 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:
  • 25. Tobacco Oral Cancer & PreCancer 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/exclusi on Criteria: Currently recruiting 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/exclusi on Criteria: Currently recruiting 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/exclusi on Histopatology/ blood chemistry Criteria: Currently recruiting
  • 26. Tobacco Oral Cancer & PreCancer 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/exclusi on Criteria: Histopatology/ blood chemistry Currently recruiting (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
  • 27. Tobacco Oral Cancer & PreCancer 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.
  • 28. Tobacco Oral Cancer & PreCancer 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
  • 29. Tobacco Oral Cancer & PreCancer 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.
  • 30. Tobacco Oral Cancer & PreCancer 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: goldfarb@inovio.com 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-
  • 31. Tobacco Oral Cancer & PreCancer 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
  • 32. Tobacco Oral Cancer & PreCancer 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).
  • 33. Tobacco Oral Cancer & PreCancer 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.
  • 34. Tobacco Oral Cancer & PreCancer 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
  • 35. Tobacco Oral Cancer & PreCancer 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.
  • 36. Tobacco Oral Cancer & PreCancer 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.
  • 37. Tobacco Oral Cancer & PreCancer 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
  • 38. Tobacco Oral Cancer & PreCancer 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,
  • 39. Tobacco Oral Cancer & PreCancer 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 NCT001549 73 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
  • 40. Tobacco Oral Cancer & PreCancer 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
  • 41. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap Bibliography 1. Community Dent Oral Epidemiol 2005; 33: 397–9) Poul Erik Petersen Chief, Oral Health Programme, World Health Organization, Geneva, Switzerland 2. CA Cancer J Clin 2002; 52:195-215.) 3. Axell T, Holmstrup P, Kramer I, Pindborg JJ, Shear M. International seminar on oral leucoplakia and associated lesions related to tobacco habits. Community Dent Oral Epidemiol 1984; 12:145-54. 4. Hampf BGC, Malmstrom M, Aalberg VA, Hannula JA, Vikkula J (1987). Psychiatric disturbance in patients with oral lichen planus. Oral Surg Oral Med 5. Neville BW, Damm DD, Allen CM, et al Oral Pathol 1996, 63:429-432. 6. Zhang ZF, Morgenstern H, Spitz MR, et al 7. Axell T, Holmstrup P, Kramer I, Pindborg JJ, Shear M1996 & Axell T, Pindborg JJ, Smith CJ, van der Waal I, 1984 8. Oral Pathol Med 1996; 25:49-54. 9. Fotos PG, Vincent SD, Hellstein JW. Oral candidosis. Clinical, historical, and therapeutic features of 100 cases. Oral Surg Oral Med Oral Pathol 1992;74:41-9 .
  • 42. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap 10 Epstein JB, Gorsky M, Caldwell J. Fluconazole mouth rinses for oral candidiasis in post irradiation, transplant, and other patients. Oral Surg. Oral Med Oral Pathol Oral Radiol Endod 2002; 93:671-5. 11 David A. Sirois, D.M.D., PH.D Oral Manifestations of HIV Disease. Oct/Nov 1998 # 5 & 6 Vol 65:322–332 12 Rivera-Hidalgo F, Shulman JD, Beach MM , Oral Dis 2004;10:335-45). 13 Assimakopoulos D, Patrikakos G, Fotika C, Elisaf M.Benign migratory glossitis or geographic tongue: anenigmatic oral lesion. Am J Med 2002; 113(9): 751-5 14 Neville BW. Herpes simplex virus. In: Oral and Maxillofacial Pathology. Philadelphia, Pa.: Saunders, 2002:213-20. 15 MMWR Morbidity Mortal Wkly Rep 1992 Dec 18; 41(RR-17):1-19. 16 Jesper Reibel (2003) International and American Associations for Dental Research 17 Butterworth CE Jr, Hatch KD, Soong SJ, et al, Am J Obstet Gynecol 992;166:803–809.CA Cancer J Clin 2004;54:150–180 18 S. Xi1 and J.R. GrandisGene Therapy for the Treatment of Oral Squamous Cell Carcinoma , J Dent Res 82(1):11-16, 2003 19 Schwartz GJ, Mehta RH, Wenig BL, Shaligram C, Portugal LG (2000). Salvage treatment for recurrent squamous cell carcinoma of the oral cavity. Head Neck 22:34-41. 20 Schrijvers D, Johnson J, Jiminez U, Gore M, Kosmidis P, Szpirglas H et al., 1998 J Clin Oncol 16:1054-1059.( Phase III trial of modulation of cisplatin / fluorouracil chemotherapy by interferon alfa-2b in patients with
  • 43. Tobacco Oral Cancer & PreCancer Dr.Rajeev Kashyap recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group) 21 Lancet Oncology in 2003.20 A. 22 Sporn MB. Approaches to prevention of epithelial cancer during the Pre- neoplastic period. Cancer Res.1976; 36:2699–2702. 23 AJCC Manual for Staging of Cancer, 1997, Ed: Fleming ID, et al. , Lippincott-Raven Publishers, Philadelphia, PA. 24 NCI's Web site 25 www.sagepublications.com, Keith I. Block, MD, and Charlotte Gyllenhaal, PhD 26 Clinical trials.gov 27 www.cancer.gov 28 National Cancer Institute 29 Biomed Opt, September 1, 2004; 9(5): 940-950 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)

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