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    Tobacco and oral cancer  cancer Tobacco and oral cancer cancer Document Transcript

    • Tobacco Oral Cancer & PreCancer Tobacco Oral cancer & PrecancerDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerCONTENTINTRODUCTIONEPIDEMIOLOGYRISK FACTORS  Marijuana  Snuff  Tobacco  Alcohol  Betel quid  Dietary factors,PREMALIGNANT LESIONS AND CONDITIONSCOMMON 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 MUCOSACAUSATIVE FACTORS ORAL PRECANCER AND CANCERMANAGEMENT OF DYSPLASTIC LESIONSAVAILABLE TREATMENTS  Surgical excision  Chemo prevention Trials  Topical RetinoidsDEFINITION OF GENE THERAPYSTRATEGIES FOR GENE THERAPYCURRENT GENE THREAPY APPROACHES FOR CANCERCLINICAL STUDIES AND CONTINUING CONTROVERSIESSTRUCTURAL CHANGE IN CELL ON CARCINOGENSISWHAT WOULD BE REQUIRED IN CLINICAL TRIALS What is a Clinical TrialWHAT IS INFORMED CONSENTWHAT IS RANDOMIZATIONSTAGING  Staging for TumorsELIGIBILITY CRITERIA  Inclusion Criteria  Exclusion CriteriaCurrent Clinical Trials Funded by NIH, US at different Phase level of StudiesDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerCLINICAL 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  PurposeDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancer  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 CancersFurther 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 AmifostineBIBLOGRAPHYDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerTobacco use is a primary cause of many oral diseases and adverse oralconditions. Tobacco-induced diseases include particularly cancer of the oralcavity (mostly of the tongue, but also lips), periodontal disease, tooth loss andcongenital defects (Reibel, 2003).These oral diseases contribute significantly to the global disease burden. Oralcancer is the eleventh most common cancer worldwide tobacco use is estimatedto account for about 41% of oral/pharyngeal cancer cases in men, and 11% inwomen (Stewart and Kleihues, 2003)Epidemiological studies from the USA, India, Pakistan, and Sweden providesound evidence that smokeless tobacco causes oral cancer in humans (Coglianoet al., 2004). Many types of smokeless tobacco are marketed for oral or nasaluse. All contain nicotine and nitrosamines.The incidence of oral cancer shows extensive variation. Incidence and mortalityrates are higher in men than woman. Differences across countries particularlyrelate to distinct risk profiles and availability and accessibility of health services.The 10th International Congress on Oral Cancer took place during 19–24 April2005 in Crete, Greece, and was attended by nearly 1000 researchers, healthprofessionals, and public health administrators. Biologic, clinical and publichealth aspects of oral cancer and precancer was analyzed by participants andthe congress programme focused on international disease trends and riskfactors; 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, SwitzerlandIn the United States, cancers of the oral cavity and oropharynx representapproximately three percent of all malignancies in men and two percent of allmalignancies in women. Over 90 percent of these tumors are squamous cellDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancercarcinomas, which arise from the oral mucosal lining. In spite of the readyaccessibility of the oral cavity to direct examination, these malignancies still areoften not detected until a late stage, and the survival rate for oral cancer hasremained essentially unchanged over the past three decades. (CA Cancer J Clin2002; 52:195-215.)INTRODUCTIONCancers of the oral cavity and oropharynx represent approximately three percentof all malignancies in men and two percent of all malignancies in women in theUnited States. Squamous cell carcinoma, which arises from the oral mucosallining, accounts for over 90 percent of these tumors.EPIDEMIOLOGYOral cancer most commonly occurs in middle-aged and older individuals,although a disturbing number of these malignancies is also being documented inyounger adults in recent years. From an epidemiological and clinicopathologicalperspective, ―oral cancer‖ can be divided into three categories: carcinomas of theoral cavity proper, carcinomas of the lip vermilion, and carcinomas arising in theoropharynx. Intraoral and oropharyngeal tumors are more common among menthan women, with a male / female ratio of over 2:1.( Neville BW, Damm DD, AllenCM, et al) When compared with intraoral carcinoma, the prognosis for lip canceris quite good, with a five-year survival rate of 95 percentRISK FACTORSEpidemiological studies show that the risk of developing oral cancer is five tonine times greater for smokers than for nonsmokers, and this risk may increaseto as much as 17 times greater for extremely heavy smokers of 80 or morecigarettes per day. The strong association between cancers of the oral cavity andpharynx with tobacco use is well established.treated oral cancer patients whoDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancercontinue to smoke have a two to six times greater risk of developing a secondmalignancy of the upper aerodigestive tract than those who stop smokingMarijuana use is also considered to be a potential risk factor and may be partlyresponsible 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 fororal cancer. In addition, a significant number of oral cancers in smokelesstobacco users develop at the site of tobacco placement. However, the use ofsmokeless tobacco appears to be associated with a much lower cancer risk thanthat associated with smoked tobacco.Alcohol use has been identified as a major risk factor for cancers of the upperaerodigestive tract. In studies controlled for smoking, moderate-to-heavy drinkershave been shown to have a three to nine times greater risk of developing oralcancer.In India and Southeast Asia, the chronic use of betel quid (paan) in the mouthhas been strongly associated with an increased risk for oral cancer The quidtypically consists of betel leaf that is wrapped around a mixture of areca nut andslaked lime, usually with tobacco and sometimes with sweeteners andcondiments. The slaked lime results in the release of an alkaloid from the arecanut, which produces a feeling of euphoria and well being in the user.Betel quid chewing often results in a progressive, scarring precancerouscondition of the mouth known as oral sub mucous fibrosis. In India, one studyshowed a malignant transformation rate of 7.6 percent for oral submucousfibrosis.Recent evidence suggests that human papillomavirus (HPV) may beassociated with some oral and oropharyngeal cancers. HPV-16 has beendetected in up to 22 percent of oral cancers, and HPV-18 has been found in up to14 percent of cases.28Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerDietary factors, such as a low intake of fruits and vegetables, may also berelated to an increased cancer risk.Carcinomas of the lip have been reported in a number of kidney transplantpatients receiving immunosuppressive medications, and oral carcinomas havebeen documented in young AIDS patientPREMALIGNANT LESIONS AND CONDITIONSPremalignant lesions are those lesions in which carcinoma may develop.Premalignant conditions are associated with a risk of carcinoma at some sitewithin 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 cannotbe characterized as any other definable lesion.‖ Such a definition, also adoptedby the World Health Organization, is the result of the effort of an internationalgroup of experts who met in Uppsala in 1994 to review leukoplakia definitionsand classifications on the basis of previously published work and new scientificacquisitions. Thus, leukoplakia is a clinical term used when any other white orallesion has been excluded by means of clinical examination and histologicalassessment. (Axell T, Pindborg JJ, Smith CJ, van der Waal I.)Oral white lesions with special reference to precancerous and tobacco-relatedlesions: conclusions of an international symposium held in Uppsala, Sweden,May 18-21, 1994. International Collaborative Group on Oral White Lesions (OralPathol Med 1996;25:49-54.)Homogeneous leukoplakia. There is a bright, white, sharplydefined patchextending from the gingiva on to the labial mucosa. The surface has a slightlyrippled appearance and no red areas are associated.An innocent-looking, poorly-defined inconspicuous white patch which showed dysplasia on biopsy. Despiteexcision, malignant transformation followed several months later.Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerWhite patch with dysplasia. This postcommissural lesion is poorly defined andcomprises both red and white areas. Lesions at this site are frequently due tocandidosis.abnormal dysplastic cells is often present in the underlying onnectivetissue.Erythroplasia (‘erythroplakia’) Erythroplakia are red patches. The surface isfrequently velvety in texture and the margin may be sharply defined. Lesions ofthis type typically do not from plaques (hence the term ‗erythroplakia‘ ismisleading) but, instead, they are flat or depressed below the level of thesurrounding mucosa Erythroplakia is common in the mouth but carries thehighest risk of malignant transformation and lesions are often already malignanton first biopsy.Lichen planus is most probably a precancerous condition. It may have a tissuereaction pattern similar to a contact hypersensitivity reaction. Another importantcomponent of etiological or pathogeneses importance may be mental stress, andthere is now some evidence that psychogenic stress may be a pathogeneticfactor 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 oferythematous candidiasis.As many as 60 percent of healthy adults carry Candidaspecies as a component of their normal oral flora. However, certain local andsystemic factors may favor overgrowth.These include use of dentures, use of a steroid inhaler, xerostomia, endocrinedisorders,human immunodeficiency virus (HIV) infection, leukemia, malnutrition,reduced immunity based on age, radiation therapy, systemic chemotherapy, anduse of broad-spectrum antibiotics or corticosteroids.( Fotos PG, Vincent SD,Hellstein JW. 1992;& Epstein JB, Gorsky M, Caldwell J. 2002)Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerXerostomia is common in HIV disease, most often as a side effect of antiviralmedications or of the other antihypertensive, antidepressant, anxiolytic oranalgesic medications commonly prescribed for patients with HIV infection. Theoral dryness presents a significant risk factor for caries and can lead to rapiddental deterioration. Xerostomia also contributes to oral candidiasis, mucosalinjury and dysphagia, and is often associated with pain and reduced oral intakeof food. (DAVID A. SIROIS, D.M.D., PH.D, 1998)SUBLINGUAL KERATOSIS The term sublingual Keratosis is applied towhite lesions on the floor of mouth and ventral tongue. Whether this lesion is adifferent entity from other leukoplakia is unclear. Malignant change was reportedin an unusually high proportion of cases (30%) in one series but this has notbeen widely confirmed. Probably the risk of malignant transformation is less than10%and possibly much lower.ORAL SUBMUCOUS FIBROSIS: Oral submucous fibrosis affected areasof 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 superficialplaque, and the mucosa is typically smooth, thin and atrophic erythroplakia andleukoplakia may be associated and the epithelium may show dysplasia.Recognition and diagnosis require taking a thorough history and performing acomplete oral examination Common superficial oral lesions include candidiasis,recurrent herpes labialis, recurrent aphthous stomatitis, erythema migrans, hairytongue, and lichen planus.Knowledge of clinical characteristics such as size, location, surface morphology,color, pain, and duration is helpful in establishing a diagnosisRecurrent Apthous StomatitisRecurrent Apthous Stomatitis, or ―canker sores,‖ is an oral ulcerative conditionwith a prevalence ranging from 5 to 21 percent. (Rivera-Hidalgo F, Shulman JD,Beach MM. 2004) Although a variety of host and environmental factors haveDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerbeen implicated, the precise pathogenesis remains unknown. Smoking isassociated with a lower prevalenceHairy Tongue :Hairy tongue is characterized by elongation and hypertrophy ofthe filiform papillae on the dorsal tongue, causing a hair-like appearance) Thiscondition results from inadequate desquamation or increased keratinization ofthe papillae. These papillae, which normally are about 1 mm in length, maybecome as long as 12 mm. It occurs most often in persons who smoke heavilyand 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..andcertain 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 withsignificant morbidity. (Neville BW)A minority of persons develop a symptomatic primary infection, presenting with anacute outbreak of oral vesicles that rapidly collapse to form zones of erythemaand ulceration. In all cases, the gingiva is involved; in addition, other oralmucosal sites and the perioral skin may be affected. Concomitant cervical lymphadenopathy, fever, chills, anorexia, and irritability are common findings.Neoplasms ( Kopasi’s Sarcoma): Kaposi‘s sarcoma is the most commonintraoral malignancy associated with HIV infection Recognition of the lesion isessential, since oral KS is often the first manifestation of the disease and is adiagnostic criterion for AIDS.(MMWR Morbidity Mortal Wkly Rep 1992The 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 sitein more than 90% of reported casesDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerCenters for Disease Control and Prevention. 1993 revised classification systemfor HIV infection and expanded surveillance case definition for AIDS amongadolescents and adults.MMWR Morbidity Mortal Wkly Rep 1992 Dec 18; 41(RR-17):1-19.Cancer development in the oral mucosaThe 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, iswell-established.Oral leukoplakia is the best-known precursor lesion. The evidence that oralleukoplakia are pre-malignant is mainly derived from follow-up studies showingthat between < 1 and 18% of oral pre-malignant lesions will develop into oralcancer; it has been shown that certain clinical sub-types of leukoplakia are at ahigher risk for malignant transformation than others. The presence of epithelialdysplasia may be even more important in predicting malignant development thanthe clinical characteristics.Three major problems, however, are attached to the importance of epithelialdysplasia 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 ofepithelial dysplasia or, since epithelial dysplasia does not seem to be invariablyassociated with or even a necessary prerequisite for malignant development, itmay be necessary to develop other methods for predicting the malignant potentialof pre-malignant lesions. As a consequence of these problems, numerousDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerattempts have been made to relate biological characteristics to the malignantpotential of leukoplakia.Molecular biological markers have been suggested to be of value in the diagnosisand prognostic evaluation of leukoplakia. Markers of epithelial differentiation and,more recently, genomic markers could potentially be good candidates forimproving the prognostic evaluation of precursors of oral cancer. As yet, one or apanel of molecular markers has not been determined that allows for a prognosticprediction of oral pre-cancer which is any more reliable than dysplasia recording.However, these new markers could be considered complementary toconventional prognostic evaluation.By Jesper Reibel (2003) International and American Associations for DentalResearch Causative factors Oral Pre cancer and Cancer Modified By Rajeev KashyapMANAGEMENT OF DYSPLASTIC LESIONSThe prognosis in oral carcinoma is good only when the diagnosis is made earlyand the tumor is small. Accurate assessment of the risk of malignant change inred and white patches is therefore desirable, but assessment is highly subjective.The level of risk cannot be reliably assessed from the Histopatology alone andthe clinical features.Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerThe best predictor of malignant potential is the presence of dysplasia on biopsy.However, even this is rather poorly correlated with behavior for such reasonssuch as inadequate sampling at biopsy and the subjective nature of assessmentThe effectiveness of other treatments has not yet been assessed on anyadequate scale. After Cryotherapy ablation, the area heals rapidly to leave anapparently normal mucosa. However, there is some uncertainty about the risk ofinvasive 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● RetinoidsSurgical excision is the most common approach. It provides an excisionbiopsy specimen which can be examined for the extent of the dysplasia and forpossible carcinoma. Unfortunately, lesions in the highest risk areas in theposterior floor of mouth are technically difficult to excise and large lesions mayrequire grafting.Chemo prevention TrialsBeta carotene, folic acid, and systemic retinoid supplementation have beenstudied in several cervical cancer chemoprevention trials, (Butterworth CE Jr,Hatch KD, Soong SJ, et al 2004) but no benefit has been seen. DespiteDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerpromising results in earlier Phase I/Iia trials, almost all large Phase IIb/III trialsshowed no benefit in systemic chemoprevention for this cancer typeTopical Retinoids are largely ineffective and though a proportion of whitelesions 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 examinationand multiple biopsy before treatment is required to ensure that malignant changeis not already present. They may be of value in those for whom surgery is notpractical because of, for instance, unfitness for anesthesia. In summary, frequentclinical observation, preferably with photographic records, and immediate biopsyof any areas that are suspicious or change in appearance, is generally the bestoption. Selected lesions with clinical features of high-risk or severe dysplasia onbiopsy are probably best excisedDEFINITION OF GENE THERAPYGene therapy can be defined as gene transfer for the purpose of treating humandisease (Cusack and Tanabe, 1998). This includes the transfer of new geneticmaterial as well as the manipulation of existing genetic material. This holds trueespecially for cancerSTRATEGIES FOR GENE THERAPYPotential uses of gene therapy in oral cancer include the treatment of recurrentdisease and adjuvant treatment—for example, at surgically resected margins.Localized distant metastatic disease is another potential target of gene therapy inpatients with oral cancer.Most of the traditional cancer therapies, including surgery, radiotherapy, andchemotherapy, have not improved the survival rates of patients with mucosalsquamous cell carcinoma. Local and/or regional tumor recurrence develops inDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerapproximately one-third of patients, despite definitive treatment (Schwartz et al.,2000). The patient with recurrent or metastastic cancer is often consideredincurable.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 hasdemonstrated 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 Pre-clinical Kill tumor cell viruses Immunotherapy Clinical trial Enhance immunogenicity of cell Gene addition Clinical trial therapy Suicide gene therapy Clinical trial Kill tumor cell and enhance chemotherapy Anti-angiogenesis Pre-clinical Inhibit tumor therapy progression Drug resistance Clinical trial Decrease toxicity genethreapy of chemotherapy Anti-angiogenesis Clinical trial Inhibit tumor therapy progression Antisense RNA Clinical trial Inhibit tumor cell growth -Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerThere are several general strategies utilized in a gene therapy approach tocancer, 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" genetherapy);(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 fromchemotherapy; and(8) introduction of genes to inhibit tumor angiogenesis.(S. Xi1 and J.R. 2003)Clinical Studies and Continuing ControversiesDespite the initial problems with toxicities and logistical drawbacks of amifostineadministration, research proceeded. Most clinical studies showed no evidenceof tumor protection. The development of treatment regimens with very seriousside effects, such as chemo radiation and high-dose conditioning withchemotherapy or radiation prior to bone marrow transplant, spurred researchersto extend their areas ofinterest to these settings. Based on large randomized studies, FDA approval wasgranted in 1995 for an important reduction of renal damage related to cisplatinat standard chemotherapeutic doses for ovarian and non-small-cell lung cancer(NSCLC). Approval was granted in 1999 for reducing Xerostomia inpostoperative chemo radiotherapy for head and neck cancer.The study on which the latter approval was granted fueled the controversy aboutamifostine and tumor protection. (Brizel et al) used amifostine with 303 patientsDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerreceiving radiation for previously untreated head and neck cancer, with locoregional 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 salivaproduction was also greater with amifostine, although there was not a reductionin mucositis. With and without amifostine, 2-year loco regional control was 58%versus 63%, and overall survival was 71% versus 66%. Controversy aboutreliance on this study for FDA approval for the indication of radiation-inducedXerostomia led to a head-to-head debate between (Brizel and respected Danishradiation oncologist Jens) Overgaard on the role of amifostine in chemo radiationin the pages of Lancet Oncology in 2003.20 A key point in this debate was theability 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 smalldegrees of tumor protection. Even a small percentage of tumor protection by acytoprotectant such as amifostine could negate the curative potential of cancertherapy for thousands of patients, if the cytoprotectant was widely used. Brizelsummarized the debate, noting that to detect a survival reduction from 45% to40% in the head and neck, cancer scenario, with 80% statistical power, a studythat would require 1246 patients per arm would be needed—a waste of fundingand 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 adherenceDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancer 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 ofgenetic events within a single cell line leads to a progressively dysplastic cellularappearance, deregulated cell growth, and, finally, carcinoma. Cancer chemonprevention, as first defined by (Sporn in 1976), uses natural, synthetic, or biologicchemical 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 andexclusion criteria. You would then have to be able to comply with the scheduledtreatment and follow-up visits. If you appeared to be eligible and could follow theDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancertreatment and follow-up schedule, you would be presented with an InformedConsent Form to review and sign.After you sign the Informed Consent Form, you will be given a copy. At that pointyou are considered in the study, and you will be expected to follow the treatmentregimen 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 randomizedtrial the treatment options are called treatment "arms". Treatment arms mayrepresent different doses of a drug, or may represent standard careWhat is a Clinical Trial?Clinical Trials, also called Research Studies or just Studies, are conducted overseveral years for all new medical treatments before they can be approved by theFood and Drug Administration for general use. There are typically differentphases of the studies that have to be conducted.Phase I studies involve a small number of participants and focus on safetyissues. They may involve healthy volunteers or they may involve patients with aspecified disease or condition. Participants are given the investigationaltreatment and monitored closely (often in hospital settings). Individualparticipants 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 isbroadened from safety only to safety plus dose toleration and/or whether theinvestigational product indicates that it is actually effective. Phase II studiesgenerally involve a year or less follow-up.Phase III studies may be very large, because they focus on both safety of theproduct and efficacy. Because of this, participants are often followed for over ayear.Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerAt each Phase, data is collected to document the participants baseline condition,what treatment they received, whether they experienced any adverse eventsfrom the treatment, and how they responded to the treatment. The data isanalyzed at the end of each study and a decision is made regarding whetherthere are safety issues that would make going forward unethical. Companiessponsoring Clinical Trials consult regularly with the Food and Drug Administrationto determine how to design Clinical Trials to minimize risk to participants whilecollecting sufficient data to support a final submission to the FDA.nvestigationaltreatment, or a combination.What is Informed Consent?An Informed Consent Form provides you with a written summary of the researchbeing conducted, what your part in it would be if you participated, what your otheroptions for treatment are, how your private medical information will be protected,and who would have access to your medical information during the course of thestudy, and who to contact with questions or in case of emergency. It also tellsyou what your rights are in case you are injured during the course of studyparticipation, and advises that you do not have to participate in order to receivemedical care.However, Informed Consent is more than a form that you sign before you canparticipate in a clinical trial. Informed Consent is also a process that occursthroughout the study. You have the right to ask your doctor questions about yourtreatment, and your participation in the study, and if the doctor becomes aware ofany information, which could have an effect on your continued participation, youwill be informedWhat is randomization?Randomization is a process - like flipping a coin - which randomly assigns you toa treatment group. The randomization assignments are developed byDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerstatisticians to assure that patients are assigned to treatment arms in theproportion outlined in the protocol.StagingStaging of oral cancer is important for establishing proper treatment anddetermining prognosis. Tumors are staged using the TNM system, where Trepresents the size of the primary tumor, N indicates the status of the regionallymph nodes, and M indicates the presence or absence of TNM Staging of OralCancer. (J Biomed Opt, September 1, 2004; 9(5): 940-950)Staging for TumorsT Staging for Tumors of the Lip and Oral CavityTX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor 2 cm or less in greatest dimensionT2 Tumor more than 2 cm but not more than 4 cm in greatest dimensionT3 Tumor more than 4 cm in greatest dimensionT4a Lip Tumor invades through cortical bone, inferior alveolarnerve, floor of mouth, or skin of face (ie, chin or nose)* , Oral , CavityTumor invades through cortical bone, into deep _extrinsic_muscle of tongue(genioglossus, hyoglossus, palatoglossus, and styloglossus), maxillary sinus, orskin of faceT4b Tumor involves masticator space, pterygoid plates, or skull base and/orencases internal carotid arteryN Staging for All Head and Neck Sites Except the Nasopharynx and ThyroidNx Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatestdimensionDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerN2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not morethan 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, nonemore than 6 cm in greatest dimension; or in bilateral or contra lateral lymphnodes, none more than 6 cm in greatest dimensionN2a Metastasis in a single ipsilateral lymph node more than 3 cm but not morethan 6 cm in greatest dimensionN2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm ingreatest dimensionN2c Metastasis in bilateral or contra lateral lymph nodes, none more than 6 cm ingreatest dimensionN3 Metastasis in a lymph more than 6 cm in greatest dimensionM Staging for Head and Neck TumorsMx Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasisTNM 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 criteriaIn clinical trials, requirements that must be met for an individual to be included ina study. These requirements help make sure that patients in a trial are similar toeach other in terms of specific factors such as age, type and stage of cancer,general health, and previous treatment. When all participants meet the sameeligibility criteria, it gives researchers greater confidence that results of the studyare caused by the intervention being tested and not by other factors.Inclusion Criteria:Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancer  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
    • Tobacco Oral Cancer & PreCancer1.Subjects with tumors suspected of involving a 50% or greater encasement of ablood vessel as measured by magnetic resonance imaging (MRI) or computedtomography (CT) scan.2.Subjects with tumors having bone invasion. Subjects with hypersensitivity3.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 withpacemaker turned off.6.Subjects with a history of uncontrolled cardiac arrhythmia.7.Women who are pregnant, or are nursing. Women must have a negativepregnancy test (urine pregnancy tests are acceptable) within 7 days of studytreatment.Some of the Current Clinical Trials Funded by NIH, US at different Phaselevel of Studies: STUDY PURPOSE TYPE ELIGIBILITY STATUS Expression of role of vascular Observational 18 Years -85 Currently VEGF-C and endothelial growth Screening, Longitudinal, Years, recruiting VEGF-CR in factor-C (VEGF-C) Defined Population, Genders =: Both Oral Cancers and its receptors Retrospective Study Histopatology/ and blood chemistry Premalignant Lesions Erlotinib To learn if erlotinib Interventional , phase III 18 Years and Currently Prevention of hydrochloride trial above , Gender recruiting Oral Cancer (Tarceva (OSI-774 ) :Prevention, Randomized, eligible both, (EPOC) can prevent cancer Double-Blind, Histopatology/ in the mouth Placebo Control, blood chemistry Parallel Assignment, Inclusion/exclusi Safety/Efficacy Study on Criteria: Rosiglitazone in How well Interventional 18 Years and Currently Preventing Oral rosiglitazone works Prevention, Non- above , Gender recruiting Cancer in in preventing oral Randomized, Open Label eligible both, Patients With cancer in patients , Histopatology/ Oral with oral leukoplakia Phase II a Trial blood chemistry Leukoplakia Inclusion/exclusi on Criteria: Oral Cancer Concurrent Interventional 18 Years and Currently Adjuvant chemotherapy to Treatment, Randomized, above , Gender recruiting Therapy (OCAT) post-operative Open Label, eligible both, Trial adjuvant Active Control, Inclusion/exclusi radiotherapy OR Parallel Assignment, on Histopatology/ shortening of Efficacy Study, blood chemistry duration of post- phase III Criteria: operative radiotherapyDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancer Diagnosis of Diagnosis of oral :Observational 18 Years and Currently Oral Precancers precancers and :Screening, Cross- above , Gender recruiting and Cancers cancers using optic Sectional, eligible both, Using Optic coherence Defined Population, Inclusion/exclusi Coherence tomography Prospective Study, on Criteria: Tomography phase IV Histopatology/ blood chemistry(Compiled from NIH web site Clinical trials.gov)Study Using the Medpulser Electroporation System WithBleomycin to Treat Head and Neck CancerBasic Trial InformationNote: Information about this trial is from the ClinicalTrials.gov database. Phase Type Status Age Sponsor protocolID PHASE Treatment Active 18years Pharmaceutical EU-HNBE- iv and industry 2003 above NCI00198263Trial DescriptionSummaryThe purpose of the trial is to study the safety and efficacy of the MedpulserElectroporation System with bleomycin in the treatment of head and neck cancer.Study InformationElectroporation therapy is a tumor-specific ablative treatment modality with thepotential to manage local tumors without the potentially undesirable side effectsof systemic chemotherapy agents or radiotherapy. Surgical resection of solidtumors often leaves subjects with significant organ dysfunction and/or permanentdisfigurement requiring reconstructive surgery. In contrast, electroporationtherapy may offer equivalent disease control to conventional surgery withlessened need for reconstructive surgery. Electroporation therapy may alsoprovide economic benefits over conventional surgical and or radiation proceduresthrough reduced operating theatre costs, hospital stays and post treatmentinterventions. The ability to shrink or eliminate local tumors with the MedPulser®System when used in conjunction with intralesional Bleomycin is an importantDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancernew possible treatment for the conservative local management of SCCHN andprovides a possible alternative treatment option to surgical excision in themanagement of cancer.The use of the MedPulser Electroporation Therapy System is quite simplyunderstood 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 procedurecan be completed within 20 minutes or less and typically needs to be done onlyonce. The dosage of drug used is based on tumor volume and is typically a smallfraction of the dosage that would be used if injected systemically into the patientsblood 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
    • Tobacco Oral Cancer & PreCancerClinical Application: The MedPulser Electroporation Therapy System isdesigned for use by qualified clinicians and may be used in an out-patientsurgical setting, for example, with cutaneous tumors. The MedPulser Instrumentis 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 chargeDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancer 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 CorporationTrial Contact Information: Paul M. Goldfarb, MD, Study Chair PaulGoldfarb, MD,Eligibility CriteriaInclusion Criteria:1. The presence of primary oral cavity, primary pharyngeal, primary laryngeal,salivary gland, limited recurrent and second primary tumors must be confirmedby histological examination of a tissue sample (e.g., biopsy) obtained within 2months of the subject receiving the study treatment.2. The length of the longest diameter of the study lesion must be < 5 cm and thecalculated treatment volume (tumor volume plus a 0.5 cm margin around thetumor) for the study lesion [where treatment volume = 0.5 (a+1) (b+1)2 andwhere a = length of the longest diameter (cm), b = the next longest diameterperpendicular 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 Investigatorprescribed 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 withoutrestriction.* Grade 1: Restricted in physically strenuous activity but ambulatory and able tocarry out work of a light or sedentary nature, e.g., lighthouse work, office work.Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancer* Grade 2: Ambulatory and capable of all self-care, but unable to carry out anywork 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 studyprocedures or treatments.Exclusion Criteria:1. Subjects with tumors suspected of involving a 50% or greater encasement of ablood vessel as measured by magnetic resonance imaging (MRI) or computedtomography (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 bleomycingreater 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 withpacemaker turned off.8. Subjects with a history of uncontrolled cardiac arrhythmia.9. Women who are pregnant, or are nursing. Women must have a negativepregnancy test (urine pregnancy tests are acceptable) within 7 days of studytreatment.Trial Sites : U.S.A.. California , San Diego , Inovio Biomedical Corporation, PaulGoldfarb, MD , Email: goldfarb@inovio.com Ph: 858-410-3158Oral Cancer Adjuvant Therapy (OCAT) TrialPurposeTo demonstrate whether addition of Concurrent chemotherapy to post-operativeadjuvant radiotherapy OR shortening of duration of post-operative radiotherapy,by administering 6 fractions / week instead of 5 fractions / week improves local-Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerregional control and / or overall survival in high risk, locally advanced, resectable,squamous cell carcinoma of oral cavityStudy Type: InterventionalStudy Design: Treatment, Randomized, Open Label, Active Control, ParallelAssignment, and Efficacy StudyPrimary Outcomes: Local-regional failureSecondary Outcomes: Overall survival; Treatment related toxicity; Protocolcompliance; Overall treatment time; Quality of life: assessment by EORTC-QLQ-C30 and EORTC-H&N-35Expected Total Enrollment: 900Aims Of Study: To demonstrate whether addition of Concurrentchemotherapy to post-operative adjuvant radiotherapy OR shortening of durationof post-operative radiotherapy, by administering 6 fractions / week instead of 5fractions / week improves local-regional control and / or overall survival in highrisk, locally advanced, resectable, squamous cell carcinoma of oral cavity.Eligibility criteria: Locally advanced, stage III and IVA, resectable, squamouscell carcinomas of oral cavity with one of the following poor prognostic factorsextra capsular nodal extension, involvement of > 2 regional lymph nodes, marginof resection with invasive cancer Extensive soft tissue and / or skin infiltrationrequiring major reconstructive procedure.Peri-neural invasion with positive lymph node. Lympho-vascular embolisationwith positive lymph node.Trial Design The eligible patients will be randomly allocated to one of the threearmsDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancer1. Arm 1 (Control arm): Surgery followed by conventional radiotherapy2. Arm 2: Surgery followed by Concurrent chemo-radiotherapy3. Arm 3: Surgery followed by Accelerated radiotherapySurgery: Surgery will be same in all three arms. Wide excision tumour withappropriate nodal dissection and reconstruction utilizing accepted criteria for theregion involved will be done.Radiotherapy: Total dose of radiotherapy will be 56 – 60 Gy. Patients in Arms1 and 2, five fractions per week for six weeks. Patients in Arm 3, six fractions aweek for five weeks.Chemotherapy: Patients in Arm 2 will get weekly chemotherapy (Inj Cisplatin30 mg / m2)Stratification: Patients will be stratified according to following factors Site:Gingivo-buccal complex cancers Vs Tongue and Floor of mouth cancers. Tstage. N stage. Extra-capsular spread (Peri-nodal extension) Surgical marginExtensive soft tissue infiltrationEnd pointsPrimary end point: Local-regional failure.Secondary end point: Overall survival. Other parameters to be assessed areTreatment related toxicity Protocol compliance Overall treatment timeQuality of life: assessment by EORTC-QLQ-C30 and EORTC-H&N-35Sample size: 900 pts (300 pts in each arm).Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerDuration of accrual: 7 years. Duration of follow up: 5 years. With minimumfollow up of 2 years. Analysis: Intent to treat analysis will be done. Interimanalysis will be done after 450 patients (150 pts in each arm)EligibilityAges Eligible for Study: 18 Years - 65 Years,Genders Eligible for Study: BothCriteriaInclusion Criteria:Previously untreated, resectable, loco-regionally advanced, stage III & IV, biopsy-proven squamous cell carcinoma of the oral cavity. (Clinically lower stagepatients will also be included if upstaged to pathological stage III or IV afterSurgery)One or more of the following must be present: extra capsular nodalextension, involvement of > 2 regional lymph nodes, margin of resection withinvasive cancer (on Histopatology) Extensive soft tissue and / or skin infiltrationrequiring 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
    • Tobacco Oral Cancer & PreCancerProtocol treatment must begin within 8 weeks surgery.Exclusion Criteria:Gross (visible or palpable) residual disease left after surgery. Prior chemotherapyor radiation therapy to the head and neck region.Evidence of distant metastasis. Any post-operative complication which will delaystarting of adjuvant treatment for more than 8 weeks.Presence of synchronous or concurrent head and neck primary tumors. Priormalignancy within the previous 5 years. Patients who because of their medicalstatus are not candidates for the proposed treatment.KPS < 60. Age > 65 years.Poor expected follow upContact Location: India, MaharashtraDr. Mandar. S. Deshpande, Tata Memorial Hospital,Parel, Mumbai, Maharashtra, 400012, India;Status: RecruitingStudy of Proxinium for Treating Patients With Squamous CellHead and Neck CancerVerified by Viventia Biotech February 2007PurposeThe purpose of this study is to determine the safety, effectiveness, andrecommended dose of Proxinium in North American patients with Squamous CellDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerHead and Neck Cancer Condition Intervention Phase Recurrent Squamous Cell Drug: Proxinium Phase II Carcinoma of the Head and Neck Carcinoma, Squamous Cell Neoplasms, Squamous Cell Head and Neck Neoplasms Mouth Neoplasms Head and Neck CancerStudy Type: InterventionalStudy Design: Treatment, Non-Randomized, Open Label, Uncontrolled,Single Group Assignment, Safety/Efficacy StudyOfficial Title: A Phase II, Open-Label Study to Evaluate the Safety, Tolerability,and Pharmacokinetic Profile of Proxinium in Patients With Recurrent SquamousCell Carcinoma of the Head and Neck Who Have Received at Least One PriorAnti-Cancer Treatment Regimen for Recurrent DiseaseEligibilityAges Eligible for Study: 18 Years and above,Genders Eligible for Study: BothCriteriaInclusion Criteria:Disease Characteristics:Histologically confirmed recurrent squamous cell carcinoma of the head andneck. Immunohistochemically confirmed epithelial cell adhesion molecule (Ep-CAM)–positive SCCHN.Must have progressed on or after receiving at least 1 prior anti-cancer treatmentregimen containing 1 or more anti-cancer agents (eg, chemotherapy, biologictherapy, or photodynamic therapy) for their recurrent disease.Must have at least 1 accessible target tumor that is amenable to adequate directinjection.Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerThe patient must have at least 1 accessible target tumor without direct carotidartery 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 anyinvestigational therapy and the first dose of the study drug.Minimum period of 8 weeks following the last dose of radiotherapy and the firstdose of the study drug.Recovered or reached a stable state of symptomatology from any previoustreatment-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 contraceptionExclusion 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 fortreatment or a history of tumor hemorrhage that has required medicalintervention (other than direct compression).The patient is a candidate for surgical tumor resection of their target tumor(s).Pregnant or lactating.Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerClinically significant renal or hepatic disease.Requires regular use of aspirin, full-dose warfarin, or heparin.Location and Contact Information: Verified by Viventia BiotechFebruary 2007United States, Alabama, United States, Arkansas, United States, ColoradoUnited States, California, United States, Florida, United States, IllinoisUnited States, Louisiana, United States, Minnesota, Unitedstates, Massachusetts, United States, Missouri, United States, New Hampshire,United States, Oklahoma, United States, PennsylvaniaUnited States, South Carolina, United States, TexasCanada, Ontario, Canada, QuebecFruit and Vegetable Extracts in Treating Patients With Stage I,Stage II, Stage III, Stage IVA, or Stage IVB Head and NeckCancer.Association between fruit and vegetable consumption and oral cancer: a meta-analysis of observational studiesBackground: Oral cancer ranks as the seventh most common form of cancerworldwide. Recent reports have examined the effect of fruit and vegetable intakeon the risk of oral cancer, but results are controversial.Objective: A meta-analysis was performed to arrive at quantitative conclusionsabout the contribution of fruit and vegetable intakes to the occurrence of oralcancer.Design: A comprehensive, systematic bibliographic search of medical literaturepublished 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 cancerwas calculated. A multivariate meta-regression analysis was performed toDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerexplore heterogeneity. This multivariate meta-regression analysis examined theeffect of quality score, the type of cancers included, citrus fruit and greenvegetable consumption, and the time interval for dietary recall of the studies onthe role of fruit or vegetable consumption in the risk of oral cancer. The presenceof publication bias was assessed with a funnel plot for asymmetry.The multivariate meta-regression showed that the lower risk of oral cancerassociated with fruit consumption was significantly influenced by the type of fruitconsumed and by the time interval of dietary recall.Phase II Randomized Study of Fruit and Vegetable Extracts in Patients WithStage I-IVB Head and Neck CancerTrial DescriptionPurpose:Chemo prevention therapy is the use of certain substances to try to prevent thedevelopment of cancer. Fruit and vegetable extracts may be effective inpreventing the recurrence or further development of Head & neck cancer.This randomized phase II trials studying how well fruit and vegetable extractswork in preventing the recurrence of stage I, stage II, stage III, stage IVA, orstage 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
    • Tobacco Oral Cancer & PreCancerTreatment/Intervention: Patients will be randomly assigned to one of twogroups. Patient‘s in-group one will receive fruit and vegetable extracts by mouthtwice 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 beevaluated once a year for 5 years.Patients will be evaluated once a year for 5years.Results: Sixteen studies (15 case-control studies and 1 cohort study) met theinclusion criteria and were included in the meta-analysis. The combined adjustedodds ratio (OR) estimates showed that each portion of fruit consumed per daysignificantly 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 significantreduction 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 areduced risk of oral cancerInvestigator: Maria Pavia, Claudia Pileggi, Carmelo GA Nobile and Italo FAngelilloExpression of Hypoxia-Inducible Factor- a in Oral Precancersand CancersBasic Trial Information Phase Type Status Age Sponsor Protocol ID No phase Natural Active 18 to 85 National 9261701447 specified History University NCT001549 Epidemiolog Hospital 73 yTrial DescriptionSummaryExpression of hypoxia-inducible factor-α in oral precancers and cancersFurther Study InformationExpression of hypoxia-inducible factor-α in oral precancers and cancersDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerEligibility CriteriaInclusion Criteria:  oral cancer specimensExclusion Criteria:  not oral cancer specimensTrial Lead Organizations/SponsorsNational Taiwan University HospitalTrial Contact InformationChun-Pin Chiang, DMScPrincipal InvestigatorPh: 886-2-23123456 Ext.6855Trial Site: Taipei, National Taiwan University HospitalInformation obtained from ClinicalTrials.gov on July 20, 2007The Pharmacological Antioxidant Amifostine—Implications ofRecent Research for Integrative Cancer CareKeith I. Block, MD, and Charlotte Gyllenhaal, PhDHistory of AmifostineAmifostine (Ethyol, WR-2721; Medimmune,Gaithersburg, Md) is a by-product ofthe cold war. Initially developed in attempts to protect persons exposed tonuclear fallout, it was later found to offer relative radioprotection to normal cells atthe expense of tumor cells and then developed as an intravenous cytoprotectantfor use in radiation therapy and chemotherapy. Amifostine is a phosphorylated ofPro drug: its active metabolite WR-1065 is dephosphorylated by membranebound alkaline phosphatase.Source: NCIs Web siteDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancerBibliography 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.Dr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancer 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 withDr.Rajeev Kashyap
    • Tobacco Oral Cancer & PreCancer 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 NCIs 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)Dr.Rajeev Kashyap