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					         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?

				
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