MSO young investigator and Salvatore Venuta Prize Translational research in head and neck cancer: preoperative chemotherapy in oral cavity cancer based on disease molecular profiling. Paolo Bossi Medical Oncology Head and Neck Unit Fondazione IRCCS Istituto Nazionale Tumori Milano INT Head and Neck Cancer: a challenging field - Most “visible” cancers - They affect social functions - More frequent in socially-deprived people INT Multidisciplinary work MEDICAL SURGERY ONCOLOGY MULTIDISCIPLINARY NUTRITION RADIOLOGY MOLECULAR RADIOTHERAPY BIOLOGY ASCO-ESMO Consensus on Quality Cancer Care INT Ongoing studies on Translational Research… - Microarray analysis of preTx Nasopharyngeal Cancer Radioresistance Profile? - HPV negative oropharyngeal cancer: biomolecular prognostic factors - Role of cytokine profile and growth factors in serum and drainage fluids INT Oral Cavity Squamous Cell Cancer –OCSCC- - The sixth most common cancer worldwide - Visible? Parallel with colon cancer: 36% rate of early stage detection - Overall Survival depending on stage: INT State of the art Treatment “The ultimate goal of treatment is to eradicate the cancer, preserve or restore form and function, minimize the sequelae of treatment and finally prevent any subsequent new primary cancers” STAGE III-IV: optimal surgery, followed by radio(chemo)therapy INT Phase II study of preoperative TPF chemotherapy in locally advanced resectable OCSCC Aim of the study: to improve survival of OCSCC through a molecular profiled selected treatment INT BACKGROUND –Induction PF study Journal of Clinical Oncology 2003 INT BACKGROUND - Induction PF study 198 patients enrolled 2 treatment arms: 1) CT (CDDP-5FU) surgery+/- RT 2) surgery+/- RT no different postoperative morbidity no difference in survival INT Global Overall Survival 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0.0 0 12 24 36 48 60 72 84 96 108 120 Months INT Overall Survival, by treatment arm 1.0 0.9 Treatment Control 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 P 0.3402 0.0 0 12 24 36 48 60 72 84 96 108 120 Months INT BACKGROUND - Induction PF study Less mandibulectomy and postoperative RT in chemotherapy treated arm INT BACKGROUND - Induction PF study - Pathologic Response Rate similar to Radiological-Clinical one - Pathologic Complete Response (pCR) obtained in 27% of the patients treated with induction CT INT Overall Survival according to response to chemotherapy p = 0.03 INT NEXT STEP need for effective antiblastic treatment with a biological tumor selection To spare toxic treatment to whom is not expected to optimally respond INT NEXT STEP: TPF better than PF INT NEXT STEP: predictive factors p53 in Head and Neck Cancer - TP53 mutations recognized prognostic factor (disruptive mut and non functional protein in particular) - Predictive role of p53 in response to chemotherapy INT INT NEXT STEP: predictive factors non pCR pts pCR p53 2/14 18/37 p53 protein 20 nonfunctional (14%) (49%) "functional" p53 status 12/14 19/37 functional 31 (86%) (51%) P= 0.02 INT p53 translational research INT NEXT STEP: predictive factors Beta-Tubulin in Head and Neck Cancer - INT INT INT Ongoing phase II study of preoperative TPF INCLUSION CRITERIA - Hystologically proved primary OCSCC - Stage T2 (> 3 cm)-T3, N1-N3 and T4a any N -WHO performance status < 1 - Availability of Formalin Fixed Paraffin Embedded biopsy of the tumour - Radiological imaging with MRI pre-therapy INT Ongoing phase II study of preoperative TPF EXCLUSION CRITERIA - Prior antitumor therapy for head & neck cancer - Previous OCSCC to less than 2 cm from primary - Screening laboratory values - Weight loss > 20% in previous 3 months - Technical unresectability defined as: T4b staging or N ulcerating the skin or encasing internal carotid INT Ongoing phase II study of preoperative TPF STUDY DESIGN Patient Selection and Informed Consent Diagnostic Biopsy and Molecular Analysis non functional p53 and high B-Tub Patient non eligible functional p53 or high B-Tub 3 cycles of TPF chemotherapy Surgery Postoperative (chemo)radiation INT Ongoing phase II study of preoperative TPF PRIMARY ENDPOINT To increase rate of pCR to 50% of the patients treated with induction chemotherapy Sample Size: type I error of 10% for a mono-lateral test, power of 95% (beta=5%), plus 10% drop-out rate = 64 patients to be enrolled INT Ongoing phase II study of preoperative TPF SECONDARY ENDPOINT - Early functional response evaluation by DWI and DCE MRI - Comparison between (DWI - DCE) MRI response and pathological response Functional Imaging as possible predictor of early response and for the measurement of drug effects on tumour (micro)vascularity and INT capillary permeability. Ongoing phase II study of preoperative TPF SECONDARY ENDPOINT - Percentage of patient receiving postop radiotherapy and chemotherapy - Progression free survival and overall survival - Second primary tumour incidence INT Ongoing phase II study of preoperative TPF STRENGHT - Molecular profiled driven treatment - Prospective trial in specialized Centers - Centralized pathologic, molecular and radiologic evaluation - Trial potentially opening new scenarios in personalized treatment INT Ongoing phase II study of preoperative TPF WEAKNESS - Only 2 molecular alteration as predictor of response - Trial based on adding therapy, not on “removing” part of it (need for larger trial) INT Ongoing phase II study of preoperative TPF CONCLUSIONS - Results foreseen within 2012 - Looking for increase in OS, through new therapeutic strategy - Towards an individualized treatment approach - The importance of multidisciplinary work and translational research INT on-pathological Hypnagogic (going off to sleep) Hypnopompic (waking up) When it‟s NOT a hallucination Illusion = misperception of a REAL stimulus Daydream = imagery Pseudohallucination Occurs in inner subjective space eg voices INSIDE your head May have quality of your own thoughts Distressed patients not interested in this distinction! Thought Disorder in Schizophrenia Circumstantiality (goal eventually reached but tortuously indirect and over-inclusive) Knight‟s Move Thinking Illogical jumping between ideas. Listener can‟t follow train of thought. “I can‟t go to the zoo, no money. Oh... I have a hat - these members make no sense, man… What‟s the problem?” NOT the same as Flight Of Ideas, which you CAN follow Derailment (just losing the plot – goal of speech not reached) Fusion (themes recur but in odd order, hard to follow) Thought Block („snapping off‟ train of thought. No thoughts left) Case Vignette - 2 Brian began to be a worry to his parents at the age of 17. After doing quite well in his GCSEs, he seemed to lose interest and his ability to concentrate on his studies. He began to spend more time alone in his room listening to music and when he went out with his friends, he appeared dazed and distant on returning home. His parents suspected he was taking drugs but he denied this. When his mother went into his bedroom to tidy up one day, she found that he had draped a cloth over the mirror. He explained this by saying that he avoided looking at his face because he had a strange look in his eyes, as though he had become hypnotised. His parents tried to persuade him to visit their GP, but he refused to go. He became very quarrelsome and one day he punched one of his friends without warning. That evening, he removed all the light bulbs from their sockets after complaining that they were emitting dangerous radiation. His parents took him to hospital and he was admitted. Negative Symptoms Develop over time May not be detected (masked by positive symptoms Negative symptoms include: poverty of speech content, thought blocking, anergia, anhedonia, affective blunting, and lack of volition. Where can I find out more? “Symptoms in the Mind” Andrew Simms (the „bible‟ for descriptive psychopathology) NICE guidelines www.abpi.org.uk/publications/publication_details/targetSchizophrenia- 2003/section2.asp Bryan L. Roth, rothlab, (ppt presentation) Melinda Hermanns (ppt presentation) Douglas Ziedonis (ppt presentation) Quiz 2) Can you diagnose Sz in a patient who has been hearing voices for 2 weeks? No. Need >= 1 month of symptoms 3) do drugs cause Sz? Cannabis use in susceptible individuals increases risk X 6 Amphetamine, cocaine/crack cause identical syndromes 4) do pts with Sz smoke more than other people? 70-90% are addicted to smoking Neuropsychological basis for this – startle response Lack of other activities in hospital & outside 5) Are pts with Sz more violent than the rest of the population? Essentially not. Paranoia & hallucinations make pts frightened. Restraining people ditto. Sz pts have higher rates of drug & alcohol problems, lower IQ in general 6) „Psychotic‟ nowadays refers to the bizarre phenomena described above (eg hallucinations, delusions), the perplexed state and being out of touch with reality. Not about being violent or cruel as per Hollywood usage. 1) still have other questions?