Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix

doi:10.1016/S0167-8140(00)00259-0

Radiotherapy and Oncology

Volume 57, Issue 1, 1 October 2000, Pages 53-59

https://doi.org/10.1016/S0167-8140(00)00259-0 Get rights and content

Abstract

Background and purpose: The Eppendorf pO₂ histograph is the ‘gold standard’ method for measuring tumour oxygenation. The method is not suitable for widespread application because its use is limited to accessible tumours. A non-invasive imaging technique would be an attractive alternative. Therefore, the relationships between tumour oxygenation and dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters were investigated.

Materials and methods: The study comprised 30 patients with carcinoma of the cervix. Tumour oxygenation was measured pre-treatment as median pO₂ and the proportion of values less than 5 mmHg (HP5) using a pO₂ histograph. Repeat measurements were obtained for nine patients following 40–45 Gy external beam radiotherapy giving a total of 39 measurements. Dynamic contrast-enhanced MRI using gadolinium was performed prior to obtaining the oxygenation data. Time/signal intensity curves were generated to obtain two standard parameters: maximum enhancement over baseline (SI−I) and the rate of enhancement (SI−I/s).

Results: Using the 39 measurements, there was a significant correlation between SI−I and both median pO₂ (r=0.59; P<0.001) and HP5 (r=−0.49; P=0.002). There was a weak, borderline significant correlation between SI−I/s and both median pO₂ (r=0.29; P=0.071) and HP5 (r=−0.34; P=0.037). There was a significant relationship between tumour size and SI−I (r=0.54; P<0.001), but not SI−I/s. In 29 tumours, where data were available, there was no relationship between histological assessment of tumour angiogenesis (intra-tumour microvessel density; IMD) and either MRI parameter.

Conclusions: Tumour oxygenation levels measured using a pO₂ histograph correlate with dynamic contrast-enhanced MRI parameters. Therefore, non-invasive dynamic MRI may be a method for measuring hypoxia in human tumours.

Introduction

Increasing evidence suggests that tumour hypoxia is important in determining cancer treatment outcome [7], [15], [23]. Currently, the Eppendorf pO₂ histograph system is regarded as the ‘gold standard’ for measuring tumour oxygenation [26]. However, the method has limitations that make widespread application in many tumour sites difficult. In particular, the technique is not widely available, is limited to accessible tumours and invasive. It is recognized that there is a need to develop reliable methods to determine tumour oxygenation with a wider clinical application, thus enabling the selection of patients who might benefit most from hypoxia-modifying treatments. A non-invasive method is attractive for measuring tumour oxygenation and there are a number of possibilities based on cross-sectional imaging. These include contrast-enhanced dynamic computed tomography (CT) [14], blood oxygen level dependent imaging with magnetic resonance (MR) [24] and dynamic contrast-enhanced magnetic resonance imaging (MRI) [11]. Using a MRI-based method is particularly attractive in carcinoma of the cervix where it is regarded as the imaging technique of choice to delineate the extent and volume of the primary tumour [13], [20].

Recently, there has been increased interest in using dynamic contrast-enhanced MRI to assess tumour microcirculation [2], [6], [10]. The technique is based on the temporal and spatial change in signal intensity following the rapid injection of a paramagnetic contrast medium (such as gadolinium–diethylentriaminepenta-acetatic acid; Gd-DTPA). The enhancement seen following injection is related to several factors, including tumour perfusion and vascular density [1], [2], [6], [12]. As tumour oxygenation is dependent on the microcirculation [27], the technique may be useful to define patients with poor blood flow, and therefore, hypoxic tumours [20]. In support of this, a relationship between hypoxia and perfusion has been demonstrated in both animal and human tumours [8], [9].

The purpose of the work reported here, therefore, was to perform dynamic contrast-enhanced MRI in a series of patients with locally advanced carcinoma of the cervix pre- and post-external beam radiotherapy, and compare the findings with the level of tumour oxygenation measured using polarographic needle electrodes. As a relationship has been reported between MRI parameters and histologically assessed angiogenesis [10], [11], the level of tumour angiogenesis was measured also.

Section snippets

Patients

Between May 1996 and November 1999, 30 patients with locally advanced carcinoma of the cervix underwent both pre-treatment oxygenation measurement using the Eppendorf pO₂ histograph system and dynamic contrast-enhanced MRI. In nine patients, repeat oxygenation measurements and imaging were performed following 40–45 Gy of external beam radiotherapy given in 20 fractions over 28 days. In all cases, MRI data were obtained prior to oxygen electrode measurements. Imaging was performed at a maximum

Results

Fig. 1 illustrates time–intensity curves for two tumours. Two curves were obtained for every tumour (representing the two ROI studied), and these illustrate the level of intra- compared with inter-tumour heterogeneity. Two standard MRI parameters were measured based on time–intensity curves to quantify the degree of tumour enhancement. Reproducibility MRI measurements were examined using a phantom made from a dilution series of contrast agent. Over a typical range of T1 values, the standard

Discussion

Our values for SI−I and SI−I/s are in accordance with those reported in the literature[11], [19]. Generally, two methods have been proposed to analyze the signal intensity curves generated by dynamic contrast-enhanced MRI, a standard method [2], [5] and a pharmacokinetic method [1]. In the standard analysis, the slope of the time–intensity curve (SI−I/s) and the increase in signal intensity over baseline (SI−I) can be calculated directly from the curves. The pharmacokinetic method is based on a

Acknowledgements

This work was supported by the Cancer Research Campaign and a European Commission Concerted Action (BMH4-98-3006).

References (27)

R.A. Cooper et al.
Changes in oxygenation during radiotherapy in carcinoma of the cervix
Int J Radiat Oncol Biol. Phys
(1999)
A.W. Fyles et al.
Oxygenation predicts radiation response and survival in patients with cervix cancer
Radiother Oncol
(1998)
R. Hermans et al.
Tumoural perfusion as measured by dynamic computed tomography in head and neck carcinoma
Radiother Oncol
(1999)
N.A. Mayr et al.
Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: a new non-invasive predictive assay
Int J Radiat Oncol Biol Phys
(1996)
N.A. Mayr et al.
Tumor size evaluated by pelvic examination compared with 3-D quantitative analysis in the prediction of outcome for cervical cancer
Int J Radiat Oncol Biol Phys
(1997)
M. Nordsmark et al.
Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck
Radiother Oncol
(1996)
P. Stadler et al.
Influence of the hypoxic subvolume on the survival of patients with head and neck cancer
Int J Radiat Oncol Biol Phys
(1999)
G. Brix et al.
Quantitative assessment of tissue microcirculation by dynamic contrast-enhanced MR imaging
Adv MRI Contrast
(1994)
L.D. Buadu et al.
Breast lesions: correlation of contrast medium enhancement patterns on MR images with histopathologic findings and tumor angiogenesis
Radiology
(1996)
R.A. Cooper et al.
High tumor angiogenesis is associated with poorer survival in carcinoma of the cervix treated with radiotherapy
Clin Cancer Res
(1998)

H. Degani et al.

Mapping pathophysiological features of breast tumors by MRI at high spatial resolution

Nat Med

(1997)

C. Frouge et al.

Correlation between contrast enhancement in dynamic magnetic resonance imaging of the breast and tumor angiogenesis

Invest Radiol

(1994)

F. Goda et al.

The relationship between partial pressure of oxygen and perfusion in two murine tumors after X-ray irradiation: a combined gadopentetate dimeglumine dynamic magnetic resonance imaging and in vivo electron paramagnetic resonance oximetry study

Cancer Res

(1996)

Cited by (197)

A Phase 2 Trial of Primary Tumor Stereotactic Body Radiation Therapy Boost Before Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer
2024, International Journal of Radiation Oncology Biology Physics
Primary tumor failure is common in patients treated with chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control (PTC) in early-stage NSCLC. This trial tested an SBRT boost to the primary tumor before the start of CRT to improve PTC.
Patients with LA-NSCLC received an SBRT boost in 2 fractions (central location 12 Gy, peripheral location 16 Gy) to the primary tumor, followed by standard CRT (60 Gy in 30 fractions). The primary objective was PTC rate at 1 year, and the hypothesis was that the 1-year PTC rate would be ≥90%. Secondary objectives included objective response rate, regional and distant control, disease-free survival (DFS), and overall survival (OS). Correlative studies included functional magnetic resonance imaging and blood-based miRNA analysis.
The study enrolled 21 patients (10 men and 11 women); the median age was 62 years (range, 52-78). The median pretreatment primary tumor size was 5.0 cm (range, 1.0-8.3). The most common nonhematologic toxicities were pneumonitis, fatigue, esophagitis/dysphagia, dyspnea, and cough. Only 1 treatment-related grade 4 nonhematologic toxicity occurred (respiratory failure/radiation pneumonitis), and no grade 5 toxicities occurred. The objective response rate at 3 and 6 months was 72.7% and 80.0%, respectively, and PTC at 1 and 2 years was 100% and 92.3%, respectively. The 2-year regional and distant control rates were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 years were 46.1% and 50.3%, respectively, and median survival was 37.8 months. Functional magnetic resonance imaging detected a mean relative decrease in blood oxygenation level–dependent signal of –87.1% (P = .05), and miR.142.3p was correlated with increased risk of grade ≥3 pulmonary toxicity (P = .01).
Dose escalation to the primary tumor using upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably to standard treatment. Functional magnetic resonance imaging suggested changes in oxygenation with the first SBRT boost dose, and miR.142.3p was correlated with pulmonary toxicity.
An International Consensus on the Design of Prospective Clinical–Translational Trials in Spatially Fractionated Radiation Therapy
2022, Advances in Radiation Oncology
Spatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials.
Primary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development.
Clinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each (a total of 163 criteria) was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed.
This consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community.
Imaging Hypoxia
2021, Molecular Imaging: Principles and Practice
Hypoxia is a well-established pathophysiologic feature of solid tumors that has demonstrated links to poor prognosis. It is a direct cause of radioresistance and also contributes to chemoresistance. In addition, it is immunosuppressive. Given these pleiotropic effects, there is strong rationale for developing strategies to image hypoxia. This chapter reviews the characteristics of hypoxia that enable it to be imaged. A critical review of the three major methods for imaging hypoxia (Optics, PET/SPECT, and Magnetic Resonance Imaging) is presented; the strengths and weaknesses of each method for preclinical and clinical uses are described.
Patient-Centric Head and Neck Cancer Radiation Therapy: Role of Advanced Imaging
2020, Neuroimaging Clinics of North America
Fundamentals of functional imaging II: emerging MR techniques and new methods of analysis
2018, Radiologia
La resonancia magnética (RM) integra en los protocolos multiparamétricos clínicos actuales información estructural, fisiológica y metabólica del cáncer. Existen técnicas emergentes, como ASL, BOLD, RM elastografía, CEST e hiperpolarización, que aportan un nuevo tipo de información y que están cerca de su integración en la clínica diaria. Además, existe un gran interés en el estudio de la heterogeneidad tumoral con imagen como factor pronóstico y de resistencia al tratamiento. Para ello, se están aplicando nuevos métodos de análisis de los protocolos multiparamétricos, y a su vez se están desarrollando nuevos biomarcadores oncológicos integrando la información de la RM con los datos clínicos, analíticos, genéticos e histológicos, gracias a la aplicación del big data y la inteligencia artificial. En esta revisión se analizan varias técnicas emergentes de RM que permiten evaluar las características fisiológicas, metabólicas y mecánicas del cáncer, así como sus principales aplicaciones clínicas. Además, se resumen los métodos de análisis más novedosos de la información radiológica funcional en oncología.
Current multiparameter MRI protocols integrate structural, physiological, and metabolic information about cancer. Emerging techniques such as arterial spin-labeling (ASL), blood oxygen level dependent (BOLD), MR elastography, chemical exchange saturation transfer (CEST), and hyperpolarization provide new information and will likely be integrated into daily clinical practice in the near future. Furthermore, there is great interest in the study of tumor heterogeneity as a prognostic factor and in relation to resistance to treatment, and this interest is leading to the application of new methods of analysis of multiparametric protocols. In parallel, new oncologic biomarkers that integrate the information from MR with clinical, laboratory, genetic, and histologic findings are being developed, thanks to the application of big data and artificial intelligence. This review analyzes different emerging MR techniques that are able to evaluate the physiological, metabolic, and mechanical characteristics of cancer, as well as the main clinical applications of these techniques. In addition, it summarizes the most novel methods of analysis of functional radiologic information in oncology.
Advances in PET and MRI imaging of tumor hypoxia
2023, Frontiers in Medicine

View all citing articles on Scopus

View full text

Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix

Abstract

Introduction

Section snippets

Patients

Results

Discussion

Acknowledgements

Int J Radiat Oncol Biol. Phys

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Quantitative assessment of tissue microcirculation by dynamic contrast-enhanced MR imaging

Adv MRI Contrast

Breast lesions: correlation of contrast medium enhancement patterns on MR images with histopathologic findings and tumor angiogenesis

Radiology

High tumor angiogenesis is associated with poorer survival in carcinoma of the cervix treated with radiotherapy

Clin Cancer Res

Mapping pathophysiological features of breast tumors by MRI at high spatial resolution

Nat Med

Correlation between contrast enhancement in dynamic magnetic resonance imaging of the breast and tumor angiogenesis

Invest Radiol

The relationship between partial pressure of oxygen and perfusion in two murine tumors after X-ray irradiation: a combined gadopentetate dimeglumine dynamic magnetic resonance imaging and in vivo electron paramagnetic resonance oximetry study

Cancer Res