INT

Translational research Translational research in head and neck cancer: in head and neck cancer:

preoperative chemotherapy in oral cavity preoperative chemotherapy in oral cavity cancer based on disease molecular cancer based on disease molecular

profiling.profiling.

Paolo Bossi

MSO young investigator and Salvatore Venuta Prize

Medical OncologyHead and Neck UnitFondazione IRCCS

Istituto Nazionale Tumori MilanoINT

INT

Head and Neck Cancer: a challenging field

- Most “visible” cancers

- They affect social functions

- More frequent in socially-deprived people

INT

Multidisciplinary work

RADIOTHERAPY

MEDICALONCOLOGY

SURGERY

RADIOLOGYNUTRITION

MOLECULAR BIOLOGY

MULTIDISCIPLINARY

ASCO-ESMO Consensus on Quality Cancer Care

INT

- 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

Ongoing studies on Translational Research…

INT

- The sixth most common cancer worldwide

- Visible? Parallel with colon cancer: 36% rate of early stage detection

- Overall Survivaldepending on stage:

Oral Cavity Squamous Cell Cancer–OCSCC-

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

Aim of the study:

to improve survival of OCSCC through a molecular profiled selected treatment

Phase II study of preoperative TPF chemotherapy in locally advanced

resectable OCSCC

INT

Journal of Clinical Oncology 2003Journal of Clinical Oncology 2003

BACKGROUND –Induction PF study

INT

198 patients enrolled

2 treatment arms: 1) CT (CDDP-5FU) surgery+/- RT2) surgery+/- RT

no different postoperative morbidity

no difference in survival

BACKGROUND - Induction PF study

INT

Global Overall Survival

Months

0 12 24 36 48 60 72 84 96 108 120

Pro

babi

lity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

INT

Overall Survival, by treatment arm

Months

0 12 24 36 48 60 72 84 96 108 120

Pro

babi

lity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

TreatmentControl

0.3402P

INT

Less mandibulectomy and postoperative RTin chemotherapy treated arm

BACKGROUND - Induction PF study

INT

- Pathologic Response Rate similar to Radiological-Clinical one

- Pathologic Complete Response (pCR) obtained in 27% of the patients treated with induction CT

BACKGROUND - Induction PF study

INT

Overall Survival

according to response to chemotherapy

p = 0.03p = 0.03p = 0.03p = 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

NEXT STEP

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

pCRnon pCR

pts

p53 protein "functional"

status

p53 nonfunctional

2/14(14%)

18/37(49%)

20

p53 functional

12/14(86%)

19/37(51%)

31

P = 0.02

NEXT STEP: predictive factors

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-TubPatient 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

capillary permeability.

INT

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