Anwar R. Padhani

Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy.

PURPOSE The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biology of hypoxia as it relates to cancer and cancer therapy, and to define clinical scenarios in which in vivo hypoxia imaging could prove valuable. RESULTS Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiology and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold standard for measuring hypoxia; Eppendorf measurement of pO(2) has been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques. CONCLUSIONS This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biology.

Dynamic contrast‐enhanced MRI in clinical oncology: Current status and future directions

Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) is performed after the administration of intravenous contrast medium to noninvasively access tumor vascular characteristics. DCE‐MRI techniques utilizing low‐molecular‐weight contrast media have successfully made the transition from methodological development to preclinical and clinical validation and are now rapidly becoming mainstream clinical tools. DCE‐MRI using macromolecular contrast medium (MMCM) can also assay microvascular characteristics of human tumor xenografts. MMCM approval for human use will occur soon. The success of both techniques depends on their ability to demonstrate quantitative differences of contrast medium behavior in a variety of tissues. Evidence is mounting that kinetic parameters correlate with immunohistochemical surrogates of tumor angiogenesis, including microvessel density, and with pathologic tumor grade. DCE‐MRI is being applied to monitor the clinical effectiveness of a variety of treatments, including antiangiogenic drugs. Kinetic parameter changes following treatment have correlated with histopathological outcome and patient survival. This article reviews the current clinical status of low‐molecular‐weight DCE‐MRI and reviews the potential of MMCM techniques for evaluating human tumors. Ongoing challenges faced by DCE‐MRI as clinical and research tools will be explored. J. Magn. Reson. Imaging 2002;16:407–422.

Combretastatin A4 Phosphate Has Tumor Antivascular Activity in Rat and Man as Demonstrated by Dynamic Magnetic Resonance Imaging

PURPOSE Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment. MATERIALS AND METHODS Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2. RESULTS A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor Ktrans in six of 16 patients treated at >or= 52 mg/m2, with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium-diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle Ktrans or in kidney AUC in group analysis of the clinical data. CONCLUSION CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

Technology insight: water diffusion MRI--a potential new biomarker of response to cancer therapy.

Diffusion-weighted MRI (DW-MRI) is a functional imaging technique that displays information about the extent and direction of random water motion in tissues. Water movement in tissues is modified by interactions with hydrophobic cellular membranes, intracellular organelles and macromolecules. DW-MRI provides information on extracellular-space tortuosity, tissue cellularity and the integrity of cellular membranes. Images can be sensitive to large or small displacements of water, therefore, macroscopic water flows and microscopic water displacements in the extracellular space can be depicted. Preclinical and clinical data indicate a number of potential roles of DW-MRI in the characterization of malignancy, including determination of lesion aggressiveness and monitoring response to therapy. This Review outlines the biological basis of observations made on DW-MRI and describes how measurements are acquired and quantified, and discusses the interpretation of images and limitations of the technique. The strength of evidence for adoption of DW-MRI as a biomarker for the assessment of tumor response is presented.

Imaging oxygenation of human tumours

Tumour hypoxia represents a significant challenge to the curability of human tumours leading to treatment resistance and enhanced tumour progression. Tumour hypoxia can be detected by non-invasive and invasive techniques but the inter-relationships between these remains largely undefined. 18F-MISO and Cu-ATSM-PET, and BOLD-MRI are the lead contenders for human application based on their non-invasive nature, ease of use and robustness, measurement of hypoxia status, validity, ability to demonstrate heterogeneity and general availability, these techniques are the primary focus of this review. We discuss where developments are required for hypoxia imaging to become clinically useful and explore potential new uses for hypoxia imaging techniques including biological conformal radiotherapy.

Evaluating the effect of rectal distension and rectal movement on prostate gland position using cine MRI

PURPOSE To evaluate the dynamic interrelationship between rectal distension and rectal movements, and to determine the effect of rectal movement on the position of the prostatic gland using cine magnetic resonance imaging (MRI). METHODS AND MATERIALS Fifty-five patients with biopsy-proven or suspected prostate cancer were examined in the axial plane using repeated spoiled gradient-echo sequences every 10 seconds for 7 minutes. Twenty-four patients received bowel relaxants before imaging. Images were analyzed for the degree of rectal distension, for the incidence, magnitude, and number of rectal and prostate movements. RESULTS Rectal movements were seen in 28 (51%) patients overall, in 10 (42%) of those receiving bowel relaxants and in 18 (58%) not receiving bowel relaxants. The incidence of rectal movements correlated with the degree of rectal distension (p = 0.0005), but the magnitude of rectal movements did not correlate with the degree of rectal distension. Eighty-six rectal movements resulting in 33 anterior-posterior (AP) prostate movements were seen. The magnitude of rectal movements correlated well with degree of prostate movements (p < 0.001). Prostate movements in the AP direction were seen in 16 (29%) patients, and in 9 (16%) patients the movement was greater than 5 mm. The median prostate AP displacement was anterior by 4.2 (-5 to +14 mm). CONCLUSIONS Cine MRI is able to demonstrate near real time rectal and associated prostate movements. Rectal movements are related to rectal distension and result in significant displacements of the prostate gland over a time period similar to that used for daily fractionated radiotherapy treatments. Delivery of radiotherapy needs to take into account these organ movements.

Magnetic resonance imaging (MRI): considerations and applications in radiotherapy treatment planning.

The emerging utilisation of conformal radiotherapy (RT) planning requires sophisticated imaging modalities. Magnetic resonance imaging (MRI) has introduced several added imaging benefits that may confer an advantage over the use of computed tomography (CT) in RT planning such as improved soft tissue definition, unrestricted multiplannar and volumetric imaging as well as physiological and biochemical information with magnetic resonance (MR) angiography and spectroscopy. However, MRI has not yet seriously challenged CT for RT planning in most sites. The reasons for this include: (1) the poor imaging of bone and the lack of electron density information from MRI required for dosimetry calculations; (2) the presence of intrinsic system-related and object-induced MR image distortions; (3) the paucity of widely available computer software to accurately and reliably integrate and manipulate MR images within existing RT planning systems. In this review, the basic principals of MRI with its present potential and limitations for RT planning as well as possible solutions will be examined. Methods of MRI data acquisition and processing including image segmentation and registration to allow its application in RT planning will be discussed. Despite the difficulties listed, MRI has complemented CT-based RT planning and in some regions of the body especially the brain, it has been used alone with some success. Recent work with doped gel compounds allow the MRI mapping of dose distributions thus potentially providing a quality assurance tool and in a manner analogous to CT, the production of dose-response information in the form of dose volume histograms. However, despite the promise of MRI, much development research remains before its full potential and cost-effectiveness can be assessed.

Reduction of small and large bowel irradiation using an optimized intensity-modulated pelvic radiotherapy technique in patients with prostate cancer.

PURPOSE To investigate the role of intensity-modulated radiation therapy (IMRT) to irradiate the prostate gland and pelvic lymph nodes while sparing critical pelvic organs, and to optimize the number of beams required. METHODS AND MATERIALS Target, small bowel, colon, rectum, and bladder were outlined on CT planning scans of 10 men with prostate cancer. Optimized conventional (RT) and 3-dimensional conformal radiotherapy (3D-CRT) plans were created and compared to inverse-planned IMRT dose distributions using dose-volume histograms. Optimization of beam number was undertaken for the IMRT plans. RESULTS With RT the mean percentage volume of small bowel and colon receiving >45 Gy was 21.4 +/- 5.4%. For 3D-CRT it was 18.3 +/- 7.7% (p = 0.0043) and for 9-field IMRT it was 5.3 +/- 1.8% (p < 0.001 compared to 3D-CRT). For 7, 5, and 3 IMRT fields, it was 6.4 +/- 2.9%, 7.2 +/- 2.8%, and 8.4 +/- 3.8% (all p < 0.001 compared to 3D-CRT). The rectal volume irradiated >45 Gy was reduced from 50.5 +/- 16.3% (3D-CRT) to 5.8 +/- 2.1% by 9-field IMRT (p < 0. 001) and bladder from 52.2 +/- 12.8% to 7 +/- 2.8% (p < 0.001). Similar benefits were maintained for 7, 5, and 3 IMRT fields. CONCLUSIONS The reduction in critical pelvic organ irradiation seen with IMRT may reduce side effects in patients, and allow modest dose escalation within acceptable complication rates. These reductions were maintained with 3-5 IMRT field plans which potentially allow less complex delivery techniques and shorter delivery times.

Early Changes in Functional Dynamic Magnetic Resonance Imaging Predict for Pathologic Response to Neoadjuvant Chemotherapy in Primary Breast Cancer

Purpose: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows noninvasive, in vivo measurements of tissue microvessel perfusion and permeability. We examined whether DCE-MRI done after two cycles of neoadjuvant chemotherapy could predict final clinical and pathologic response in primary breast cancers. Experimental Design: Thirty-seven patients with primary breast cancer, due to receive six cycles of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy, were examined using DCE-MRI before neoadjuvant chemotherapy and after two cycles of treatment. Changes in DCE-MRI kinetic parameters (Ktrans, kep, ve, MaxGd, rBV, rBF, MTT) were correlated with the final clinical and pathologic response to neoadjuvant chemotherapy. Test-retest variability was used to determine individual patient response. Results: Twenty-eight patients were evaluable for response (19 clinical responders and 9 nonresponders; 11 pathologic responders and 17 nonresponders). Changes in the DCE-MRI kinetic parameters Ktrans, kep, MaxGd, rBV, and rBF were significantly correlated with both final clinical and pathologic response (P < 0.01). Change in Ktrans was the best predictor of pathologic nonresponse (area under the receiver operating characteristic curve, 0.93; sensitivity, 94%; specificity, 82%), correctly identifying 94% of nonresponders and 73% of responders. Change in MRI-derived tumor size did not predict for pathologic response. Conclusion: Changes in breast tumor microvessel functionality as depicted by DCE-MRI early on after starting anthracycline-based neoadjuvant chemotherapy can predict final clinical and pathologic response. The ability to identify nonresponders early may allow the selection of patients who may benefit from a therapy change.

Whole-Body Diffusion-weighted MR Imaging in Cancer: Current Status and Research Directions

Diffusion-weighted (DW) magnetic resonance (MR) imaging is emerging as a powerful clinical tool for directing the care of patients with cancer. Whole-body DW imaging is almost at the stage where it can enter widespread clinical investigations, because the technology is stable and protocols can be implemented for the majority of modern MR imaging systems. There is a continued need for further improvements in data acquisition and analysis and in display technologies. Priority areas for clinical research include clarification of histologic relationships between tissues of interest and DW MR imaging biomarkers at diagnosis and during therapy response. Because whole-body DW imaging excels at bone marrow assessments at diagnosis and for therapy response, it can potentially address a number of unmet clinical and pharmaceutical requirements. There are compelling needs to document and understand how common and novel treatments affect whole-body DW imaging results and to establish response criteria that can be tested in prospective clinical studies that incorporate measures of patient benefit.