Patient Selection for Hypoxia Modifying Treatments Based on Functional Microregional Imaging of Tumor Vasculature, Oxygenation and Proliferation in Squamous Cell Carcinoma of the Larynx
Prognostic indicators discriminate patients with good and bad prognosis. Predictive assays
are tools that select patients for specific treatments or treatment modifications such that
outcome will be improved relative to conventional treatment. In oncology, many prognostic
indicators based on clinical or biological tumor characteristics have been described but
only very few have proven to be useful as predictive assays. We have developed an imaging
modality for coregistration of tumor oxygenation and proliferation at the microregional
level with preservation of the tumor anatomy and the microenvironmental structure. We have
strong indications that this functional imaging can be a powerful tool for identifying those
patients that will profit from hypoxia modifying treatments.
Tumor oxygenation and proliferation are recognized as important determinants of the outcome
of radiotherapy and possibly also of other treatment modalities in a number of tumor types
and in particular in squamous cell carcinomas. Various exogenous and endogenous markers for
hypoxia and proliferation are currently available which can be studied in relation to each
other, the tumor architecture and the tumor microenvironment using immunohistochemistry and
advanced image analysis techniques.
The purpose of this project is to identify microregional profiles of oxygenation and
proliferation based on exogenous and endogenous markers that:
1. Are predictive for outcome of radiotherapy in squamous cell carcinoma of the larynx.
2. Can identify the patients that are most likely to benefit from hypoxia modifying
3. Validate these marker profiles in a prospective manner and in a sufficiently large
group of patients.
Plan of investigation
In 2001 a multicenter randomized trial was initiated comparing accelerated radiotherapy with
carbogen and nicotinamide as hypoxic modifiers against accelerated radiotherapy alone in
patients with carcinoma of the larynx. This trial is approved and supported by the Dutch
Cancer Society and currently 6 Dutch and 1 British center are participating. This trial
provides a unique opportunity to prospectively test oxygenation and proliferation related
marker profiles in a large homogeneous patient population and to assess the predictive
capacity in a comparative setting with one group of patients receiving a hypoxia modifying
treatment and the other group not.
Paraffin-embedded biopsy specimens will be collected from all patients entered in this
trial. In part of the patients, biopsies will be taken after injection of the hypoxic marker
pimonidazole and the S-phase marker iododeoxyuridine (IdUrd). Sections will be
immunohistochemically processed and stained for various combinations of vascular markers,
endogenous hypoxia and proliferation markers and, if applicable, for pimonidazole and IdUrd.
The sections will be analyzed by computerized image processing. Apart from overall single
parameter values that will be obtained, the interrelationship of the various parameters will
be studied and the microregional phenotype of the tumors will be characterized by
quantification and integration of the marker profiles. The information thus obtained will be
related to treatment outcome in terms of both local control and survival and results from
the two treatment groups will be compared.
This investigation can identify oxygenation and proliferation related parameters and
profiles that are predictive for outcome of radiotherapy in squamous cell carcinoma of the
larynx and provide a selection tool for hypoxia modifying treatments. The principle of
characterization of the tumor phenotype at the microregional level using functional imaging
may also be applied to other tumor types and treatment strategies.
Observational Model: Cohort, Time Perspective: Prospective
Johannes HA Kaanders, M.D., Ph.D.
Radboud University Nijmegen Medical Centre, Dept Radiation Oncology
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)