PN-II-ID-PCE-2012-4-0067 (closed)

Project coordinator: Marcu Loredana

Period: 1st octomber 2013 – 31st December 2016

Description of the project

The challenges: One of the main reasons for treatment failure among head and neck cancer patients is high levels of tumour hypoxia. Hypoxic tumours are poor responders to radiotherapy due to their ability to repair radiation-induced damage. Furthermore, acute hypoxia is highly unpredictable as there is no certainty regarding the appearance, location and duration of temporally hypoxic regions within the tumour.

The goals: The main goal of this project is to implement a framework in which to realistically model the growth and behaviour of a virtual head and neck tumour, from a spatial and temporal perspective. The semi-phenomenological model will be based on harvested PET/CT patient data on hypoxic regions and their change over time and location within the tumour. A correlation will be made between tumour hypoxia and radiotracer uptake (the PET component) and the extent/distribution of iodinated contrast uptake (the CT component) within the tumour. To validate this approach, the virtual tumour will be treated by simulating radiotherapy according to clinical protocols.

The outcome: The validated tumour growth model will allow unconventional treatment simulations in order to find the optimal schedule. Additionally, the flexibility of Monte Carlo modelling will consent to further simulation of other hypoxic tumour sites (brain, lung) and their corresponding radiotherapy schedules. The project will move us closer to the ultimate goal of modern oncology, individualised treatment.

Objectives

I. Model development and validation.

I.1. Grow a virtual head and neck tumour using computational techniques (Monte Carlo) based on biologically realistic parameters. The virtual tumour will be created using both spatial and temporal characteristics based on statistical data. A range of partial oxygen pressure values (pO2) will be allocated to tumour cells, depending on their hypoxia levels (spatial location). To allow for acute hypoxia modelling, the pO2 parameter will be randomly allocated to the percentage of cells which are predefined to be hypoxic.

I.2. Adjust spatial characteristics of virtual tumour to correlate with data obtained from PET/CT imaging of a particular patient. The oxygenation status of the tumour during tumour growth (after a few volume doublings) is defined using the partial oxygen pressure.

I.3. Simulate real treatment undergone by particular patient.

I.4. Compare simulation results with clinical results obtained by PET/CT imaging of particular patient after treatment.

I.5. Adjust model to correlate with clinical results. The virtual tumour is validated against a biological head and neck tumour using cell kinetic parameters characteristic for this type of tumour, tumour composition, extent and distribution of hypoxia.

I.6. Apply the above steps for a larger head and neck patient group until the clinical data correlates with the model outcome. Given that head and neck cancers account for around 5% of all solid tumours (www.cancer.net) and that the “PET Diagnosztika” centre currently images around 1000 patients a year, it is predicted that the number of patients required for statistical validation of the model will be accrued over 18 months. Once model validation is achieved, it can be applied for clinical outcome assessment and prediction. 

II. Model application for treatment optimisation.

II.1. Use the perfected model to simulate the response of various altered fractionation schedules. Novel treatment methods targeting tumour sub-volumes will be employed, based on the hypoxic regions indicated by the imaging methods.

II.2. Data analysis and interpretation of tumour response to various treatment simulations.

II.3. Design optimal treatment schedule based on previous data analysis.

II.4. Validate the resulted optimal treatment against international clinical trial data.

Results

Scientific-report-2016Download

II.1. Articles published in ISI journals (cumulative impact factor 24.45)

  1. L. Marcu, D. Marcu, In silico modelling of a cancer stem cell-targeting agent and its effects on tumour control during radiotherapy, Scientific Reports 6, 32332 (2016)
  1. L. Marcu, Future treatment directions for HPV-associated head and neck cancer based on radiobiological rationale and current clinical evidence, Critical Reviews in Oncology/Hematology 103:27-36 (2016)
  1. L. Marcu, D. Marcu, S. Filip. In silico study of the impact of cancer stem cell dynamics and radiobiological hypoxia on tumour response to hyperfractionated radiotherapy Cell Proliferation 49(3):304-314 (2016)
  1. R. Chirla, L. Marcu, PET-based quantification of statistical properties of hypoxic tumor subvolumes in head and neck cancer, Physica Medica 32:23-35 (2016)
  1. L. Marcu, The first Rs of radiotherapy – or standing on the shoulders of giants, Australasian Phys Eng Sci Med, 38(4) (2015) (IF = 0.882) (invited article)
  1. M. Jennings, L. Marcu, E. Bezak, PET-specific parameters and radiotracers in theoretical tumour modelling, Computational and Mathematical Methods in Medicine Article ID 415923 (2015) (IF = 1,08)
  1. L. Marcu, W. Harriss-Phillips, S. Filip, Hypoxia in head and neck cancer in theory and practice: a PET-based imaging approach, Computational and Mathematical Methods in Medicine, Article ID 624642 (2014) (IF = 1,08)
  1. L. Marcu, Tumour repopulation and the role of abortive division in squamous cell carcinomas during chemotherapy, Cell Proliferation 47(4):318-325 (2014) (IF = 3,28)
  1. L. Marcu, Improving therapeutic ratio in head and neck cancer with adjuvant and cisplatin-based treatments, Biomed Research International 2013: 817279 (2013) (IF = 2.880)

II.2. Publications indexed in International Databases

  1. L. Marcu, D. Marcu, S. Filip, In silico repopulation model of various tumour cells during treatment breaks in head and neck cancer radiotherapy, World Academy of Science, Engineering and Technology, International Science Index, Medicine and Health Sciences 9(3) (2015)

II.3. International conference presentations and invited seminars

  1. L. Marcu, Cancer stem cells – a new variable in the equation of tumour modelling? Karolinska Institutet, Stockholm, 18-24 Sept (2016) (Invited talk)
  1. L. Marcu, D. Marcu, Radiobiological effects of cancer stem cell-targeting therapy in a head and neck cancer model, Ist European Congress of Medical Physics (ECMP), Athens, 1-4 Sept (2016)
  1. E. Bezak, L. Marcu, Normal tissue complications in combined chemo-radiotherapy for head and neck cancer – a modelling approach, MASCC Congress, Adelaide, 23-25 June (2016) (Invited talk)
  1. L. Marcu, Promises and challenges of cancer stem cell-targeting agents in the management of head and neck cancer

Sansom Institute for Health Research, Division of Health Sciences, University of South Australia, Adelaide, 21 May – 3 June (2016) (Invited talk)

  1. A. Dinu, T. Flonta, V. Virag, L. Marcu, Comparative techniques of adaptive radiotherapy for locoregionally advanced oropharyngeal cancer, The 7th AAMP Meeting (Alpe-Adria Medical Physics), Zagreb, 19-21 May (2016) 
  1. L. Marcu, D. Marcu, S. Filip, The role of in silico modelling in radiotherapy optimisation and personalisation, International Conference on Sciences, Oradea, 13-14 May (2016)
  1. L. Marcu, D. Marcu, Hyper- versus hypofractionated radiotherapy in a radioresistant head and neck cancer model, ESTRO 35, Turin, Italy, 29 April – 3 May (2016) 
  1. L. Marcu, In silico research towards optimisation of personalised treatment in head and neck cancer, Conference of Diaspora in Scientific Research, Timisoara, Romania, 25-28 April (2016)
  1. L. Marcu, D. Marcu, E. Bezak, Monte Carlo simulation of cancer stem cell-targeting agents and their effect on tumour control, The 14th International Workshop on Radiation Damage to DNA, Melbourne, Australia, 20-24 March (2016)
  1. L. Marcu, D. Marcu, Modeling the effect of symmetrical division of cancer stem cells on tumour response to radiation, ICTR-PHE Conference, Geneva, Switzerland, 15-19 February (2016)
  1. L. Marcu, D. Marcu, In silico evaluation of radiobiological hypoxia and its effect on tumour control during radiotherapy, Proceedings of the 39th ARA Congress, Frascati, Rome, Italy, 28-31 July (2015)
  1. L. Marcu, D. Marcu, S. Filip, Cancer stem cells in a hierarchical model of tumour regrowth in five head and neck carcinomas, World Congress on Medical Physics & Biomedical Engineering, Toronto, Canada, 7-12 June (2015)
  1. L. Marcu, Medical physics – or how a change in career path becomes a passion, World Congress on Medical Physics & Biomedical Engineering, Toronto, Canada, 7-12 June (2015)
  1. L. Marcu, The impact of cancer stem cells (CSCs) on radiotherapy outcome: an in silico approach, ACPESM WA Branch Meeting, Perth, Australia, 17-22 May (2015) (Invited talk)
  1. L. Marcu, D. Marcu, Monte Carlo simulation of personalised radiotherapy for head and neck cancer driven by tumour growth kinetics, ICRR 2015, The 15th International Congress of Radiation Research, Kyoto, Japan, 25-29 May (2015)
  1. L. Marcu, D. Marcu, S. Filip, In silico repopulation model of various tumour cells during treatment breaks in head and neck cancer radiotherapy, IEEE, International Conference on Radiation Medicine, Dubai, UAE, 11-12 March (2015)
  1. D. Marcu, L. Marcu, In silico growth of a hypoxic head and neck tumour including angiogenic processes, The 60th Annual Meeting of the Radiation Research Society, Las Vegas, 21-24 Sept (2014)
  1. L. Marcu, The influence of repopulation mechanisms on treatment gap timing in head and neck cancer radiotherapy, Workshop: Biological basis of radiotherapy – where do we stand? Stockholm, 4-5 Sept (2014)
  1. L. Marcu, D. Marcu, In silico simulation of tumour radiobiology towards individualised treatment, The 3rd International Congress on Personalised Medicine (UPCP), Prague, 26-29 June (2014)
  1. L. Marcu, The effect of abortive division as a repopulation mechanism on head and neck cancer radiotherapy, ESTRO 33, Vienna, Austria, 4-8 April (2014)
  1. L. Marcu, D. Marcu, S. Filip, O. Straciuc, The implementation of tumour-specific radiobiological parameters in a head & neck tumour growth model, International Conference on Sciences, Băile Felix, 8-9 November (2013)
  1. O. Straciuc, C. Oncu, Zs. Lengyel, Modern diagnostic imaging of prostate cancer, International Conference on Urology, Gynaecology and Urogynaecology UroGyn, Oradea 14-17 November (2013) 

II.4. National conference presentations

  1. A. Dinu, O. Straciuc, FDG-PET as an imaging biomarker in head and neck carcinomas, The 2nd National Congress on Medical Oncology and Radiotherapy, Sinaia, 23-25 Oct (2014)
  • O. Straciuc, C. Oncu, The modern diagnostic imaging of cancer, Ar-Medica Conference, Arad, 2-4 November (2013)

II.5. Books/book chapters and special issue journals

  1. L. Marcu (editor), Contemporary Issues in Head and Neck Cancer Management, InTech Publishing, ISBN: 978-953-51-2135-0 (2015)
  1. L. Marcu, E. Bezak, I. Toma-Dasu, A. Dasu (editors), Predictive Models Of Tumour Response To Treatment Using Functional Imaging Techniques (Special issue journal), Computational and Mathematical Methods in Medicine, ISSN: 1748-670X (2015)
  1. L. Marcu, I. Toma-Dasu, A. Dasu, The 6 Rs of head and neck cancer radiotherapy (book chapter) In: ed. L. Marcu, Contemporary issues in head and neck cancer management, InTech Publ., ISBN 978-953-51-2135-0 (2015)