Abstract
There is an increasing awareness that anatomical approaches based on measurements of tumor size have significant limitations for assessing therapy response. Functional imaging techniques are increasing being used to monitor response to therapies with novel mechanisms of action, often predicting the success of therapy before conventional measurements have changed. Dynamic contrast-enhanced and diffusion magnetic resonance imaging (MRI) are the most advanced in their evidence base, and in this manuscript we focus on them as response parameters. Technology, data gathering methods, and current limitations for these techniques are addressed. With few exceptions, most studies shows that successful treatment is reflected by increases in tumor water diffusion values visible as increased apparent diffusion coefficient values. Most response assessment studies also show that successful treatment results in decreases in tumor vascularization and microvessel permeability.
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Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Husband JE, Schwartz LH, Spencer J et al (2004) Evaluation of the response to treatment of solid tumours—a consensus statement of the International Cancer Imaging Society. Br J Cancer 90:2256–2260
Benjamin RS, Choi H, Macapinlac HA et al (2007) We should desist using RECIST, at least in GIST. J Clin Oncol 25:1760–1764
Nathan P, Judson I, Padhani A et al (2008) A phase I study of combretastatin A4 phosphate (CA4P) and bevacizumab in subjects with advanced solid tumors. J Clin Oncol 26:3550
Saltz LB, Clarke S, Diaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019
Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676
Miller KD, Chap LI, Holmes FA et al (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792–799
Workman P, Aboagye EO, Chung Y-L et al (2006) Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst 98:580–598
Weber WA, Czernin J, Phelps ME et al (2008) Technology insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs. Nat Clin Pract Oncol 5:44–54
Schaefer NG, Taverna C, Strobel K et al (2007) Hodgkin disease: diagnostic value of FDG PET/CT after first-line therapy—is biopsy of FDG-avid lesions still needed? Radiology 244:257–262
Bahri S, Chen JH, Mehta RS et al (2009) Residual breast cancer diagnosed by MRI in patients receiving neoadjuvant chemotherapy with and without bevacizumab. Ann Surg Oncol 16:1619–1628
Al-Ibraheem A, Buck A, Krause BJ et al (2009) Clinical applications of FDG PET and PET/CT in head and neck cancer. J Oncol 2009:208725. doi:10.1155/2009/208725
Hu LS, Baxter LC, Smith KA et al (2008) Relative cerebral blood volume values to differentiate high-grade glioma recurrence from posttreatment radiation effect: direct correlation between image-guided tissue histopathology and localized dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging measurements. Am J Neuroradiol. doi:10.3174/ajnr.A1377
Dewhirst MW, Cao Y, Moeller B (2008) Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8:425–437
Gillies RJ, Robey I, Gatenby RA (2008) Causes and consequences of increased glucose metabolism of cancers. J Nucl Med 49(Suppl 2):24S–42S
Nakanishi K, Kobayashi M, Nakaguchi K et al (2007) Whole-body MRI for detecting metastatic bone tumor: diagnostic value of diffusion-weighted images. Magn Reson Med Sci 6:147–155
Koh DM, Collins DJ (2007) Diffusion-weighted MRI in the body: applications and challenges in oncology. AJR Am J Roentgenol 188:1622–1635
Patterson DM, Padhani AR, Collins DJ (2008) Technology Insight: water diffusion MRI-a potential new biomarker of response to cancer therapy. Nat Clin Pract Oncol 5(4):220–233
Padhani AR, Liu G, Koh DM et al (2009) Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia 11:102–125
Stejskal EO, Tanner J (1965) Spin diffusion measurements: spin echoes in the presence of a time-dependent field gradient. J Chem Phys 42:288–292
Le Bihan D, Breton E, Lallemand D et al (1988) Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology 168:497–505
Niendorf T, Dijkhuizen RM, Norris DG et al (1996) Biexponential diffusion attenuation in various states of brain tissue: implications for diffusion-weighted imaging. Magn Reson Med 36:847–857
Taouli B, Vilgrain V, Dumont E et al (2003) Evaluation of liver diffusion isotropy and characterization of focal hepatic lesions with two single-shot echo-planar MR imaging sequences: prospective study in 66 patients. Radiology 226:71–78
Koh DM, Brown G, Riddell AM et al (2008) Detection of colorectal hepatic metastases using MnDPDP MR imaging and diffusion-weighted imaging (DWI) alone and in combination. Eur Radiol 18:903–910
Parikh T, Drew SJ, Lee VS et al (2008) Focal liver lesion detection and characterization with diffusion-weighted MR imaging: comparison with standard breath-hold T2-weighted imaging. Radiology 246:812–822
Sumi M, Sakihama N, Sumi T (2003) Discrimination of metastatic cervical lymph nodes with diffusion-weighted MR imaging in patients with head and neck cancer. AJNR Am J Neuroradiol 24:1627–1634
Yoshikawa MI, Ohsumi S, Sugata S et al (2008) Relation between cancer cellularity and apparent diffusion coefficient values using diffusion-weighted magnetic resonance imaging in breast cancer. Radiat Med 26:222–226
Manenti G, Di Roma M, Mancino S et al (2008) Malignant renal neoplasms: correlation between ADC values and cellularity in diffusion weighted magnetic resonance imaging at 3 T. Radiol Med (Torino) 113:199–213
Hayashida Y, Hirai T, Morishita S et al (2006) Diffusion-weighted imaging of metastatic brain tumors: comparison with histologic type and tumor cellularity. AJNR Am J Neuroradiol 27:1419–1425
Humphries PD, Sebire NJ, Siegel MJ et al (2007) Tumors in pediatric patients at diffusion-weighted MR imaging: apparent diffusion coefficient and tumor cellularity. Radiology 245:848–854
Zelhof B, Pickles M, Liney G et al (2009) Correlation of diffusion-weighted magnetic resonance data with cellularity in prostate cancer. BJU Int 103:883–888
Liu Y, Bai R, Sun H et al (2009) Diffusion-weighted magnetic resonance imaging of uterine cervical cancer. J Comput Assist Tomogr 33:858–862
Sugahara T, Korogi Y, Kochi M et al (1999) Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas. J Magn Reson Imaging 9:53–60
Lyng H, Haraldseth O, Rofstad EK (2000) Measurement of cell density and necrotic fraction in human melanoma xenografts by diffusion weighted magnetic resonance imaging. Magn Reson Med 43:828–836
Wang XZ, Wang B, Gao ZQ et al (2009) Diffusion-weighted imaging of prostate cancer: correlation between apparent diffusion coefficient values and tumor proliferation. J Magn Reson Imaging 29:1360–1366
Calvar JA, Meli FJ, Romero C et al (2005) Characterization of brain tumors by MRS, DWI and Ki-67 labeling index. J Neurooncol 72:273–280
Arvinda HR, Kesavadas C, Sarma PS et al (2009) Glioma grading: sensitivity, specificity, positive and negative predictive values of diffusion and perfusion imaging. J Neurooncol 94:87–96
Geschwind JF, Artemov D, Abraham S et al (2000) Chemoembolization of liver tumor in a rabbit model: assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis. J Vasc Interv Radiol 11:1245–1255
Kim H, Morgan DE, Zeng H et al (2008) Breast tumor xenografts: diffusion-weighted MR imaging to assess early therapy with novel apoptosis-inducing anti-DR5 antibody. Radiology 248:844–851
Liimatainen T, Hakumaki JM, Kauppinen RA et al (2009) Monitoring of gliomas in vivo by diffusion MRI and (1)H MRS during gene therapy-induced apoptosis: interrelationships between water diffusion and mobile lipids. NMR Biomed 22:272–279
Hamstra DA, Rehemtulla A, Ross BD (2007) Diffusion magnetic resonance imaging: a biomarker for treatment response in oncology. J Clin Oncol 25:4104–4109
Hamstra D, Rehemtulla A, BD R (2007) Diffusion magnetic resonance imaging: a biomarker for treatment response in oncology. J Clin Oncol 25:4104–4109
Pickles MD, Gibbs P, Lowry M et al (2006) Diffusion changes precede size reduction in neoadjuvant treatment of breast cancer. Magn Reson Imaging 24:843–847
Yankeelov TE, Lepage M, Chakravarthy A et al (2007) Integration of quantitative DCE-MRI and ADC mapping to monitor treatment response in human breast cancer: initial results. Magn Reson Imaging 25:1–13
Theilmann RJ, Borders R, Trouard TP et al (2004) Changes in water mobility measured by diffusion MRI predict response of metastatic breast cancer to chemotherapy. Neoplasia 6:831–837
Kamel IR, Rayes DK, Liapi E et al (2007) Functional MR imaging assessment of tumor response after 90Y microsphere treatment in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol 18:49–56
Cui Y, Zhang XP, Sun YS et al (2008) Apparent diffusion coefficient: potential imaging biomarker for prediction and early detection of response to chemotherapy in hepatic metastases. Radiology 248:894–900
Hayashida Y, Yakushiji T, Awai K et al (2006) Monitoring therapeutic responses of primary bone tumors by diffusion-weighted image: Initial results. Eur Radiol 16:2637–2643
Uhl M, Saueressig U, van Buiren M et al (2006) Osteosarcoma: preliminary results of in vivo assessment of tumor necrosis after chemotherapy with diffusion- and perfusion-weighted magnetic resonance imaging. Invest Radiol 41:618–623
Moffat BA, Chenevert TL, Lawrence TS et al (2005) Functional diffusion map: a noninvasive MRI biomarker for early stratification of clinical brain tumor response. Proc Natl Acad Sci USA 102:5524–5529
Mardor Y, Pfeffer R, Spiegelmann R et al (2003) Early detection of response to radiation therapy in patients with brain malignancies using conventional and high b-value diffusion-weighted magnetic resonance imaging. J Clin Oncol 21:1094–1100
Hamstra DA, Galban CJ, Meyer CR et al (2008) Functional diffusion map as an early imaging biomarker for high-grade glioma: correlation with conventional radiologic response and overall survival. J Clin Oncol 26:3387–3394
Batchelor TT, Sorensen AG, di Tomaso E et al (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95
Schaefer PW, Grant PE, Gonzalez RG (2000) Diffusion-weighted MR imaging of the brain. Radiology 217:331–345
Ries M, Jones RA, Basseau F et al (2001) Diffusion tensor MRI of the human kidney. J Magn Reson Imaging 14:42–49
Parker GJ (2004) Analysis of MR diffusion weighted images. Br J Radiol 77:S176–S185
Oostendorp M, Post MJ, Backes WH (2009) Vessel growth and function: depiction with contrast-enhanced MR imaging. Radiology 251:317–335
Kety S (1960) Measurement of local blood flow by the exchange of an inert, diffusible substance. Methods Med Res 8:228–236
Kety S (1960) Blood-tissue exchange methods. Theory of blood-tissue exchange and its application to measurement of blood flow. Meth Med Res 8:223–227
Tofts P, Brix G, Buckley D et al (1999) Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J Magn Reson Imaging 10:223–232
Wilkinson ID, Jellineck DA, Levy D et al (2006) Dexamethasone and enhancing solitary cerebral mass lesions: alterations in perfusion and blood-tumor barrier kinetics shown by magnetic resonance imaging. Neurosurgery 58:640–646, discussion 640–646
O’Connor JP, Carano RA, Clamp AR et al (2009) Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging. Clin Cancer Res 15:6674–6682
Lankester KJ, Maxwell RJ, Pedley RB et al (2007) Combretastatin A-4-phosphate effectively increases tumor retention of the therapeutic antibody, 131I-A5B7, even at doses that are sub-optimal for vascular shut-down. Int J Oncol 30:453–460
Lankester KJ, Taylor JN, Stirling JJ et al (2007) Dynamic MRI for imaging tumor microvasculature: comparison of susceptibility and relaxivity techniques in pelvic tumors. J Magn Reson Imaging 25:796–805
Leach MO, Brindle KM, Evelhoch JL et al (2005) The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer 92:1599–1610
Lankester KJ, Taylor NJ, Stirling JJ et al (2005) Effects of platinum/taxane based chemotherapy on acute perfusion in human pelvic tumours measured by dynamic MRI. Br J Cancer 93:979–985
Thukral A, Thomasson DM, Chow CK et al (2007) Inflammatory breast cancer: dynamic contrast-enhanced MR in patients receiving bevacizumab–initial experience. Radiology 244:727–735
Walker-Samuel S, Parker CC, Leach MO et al (2007) Reproducibility of reference tissue quantification of dynamic contrast-enhanced data: comparison with a fixed vascular input function. Phys Med Biol 52:75–89
Taylor NJ, Tunariu N, Stirling JJ et al (2009) Non-enhancing pixels: a specific additional DCE-MRI kinetic parameter for assessing antivascular effects of anti-angiogenic and vascular disruptive agents. Proceedings of the joint meeting of International Society of Magnetic Resonance in Medicine, 16th Scientific Meeting and Exhibition, Honolulu:2262
Dyke JP, Panicek DM, Healey JH et al (2003) Osteogenic and Ewing sarcomas: estimation of necrotic fraction = induction chemotherapy with dynamic contrast-enhanced MR imaging. Radiology 228:271–278
Schlemmer HP, Merkle J, Grobholz R et al (2004) Can pre-operative contrast-enhanced dynamic MR imaging for prostate cancer predict microvessel density in prostatectomy specimens? Eur Radiol 14:309–317
Padhani AR, Dzik-Jurasz A (2004) Perfusion MR imaging of extracranial tumor angiogenesis. Top Magn Reson Imaging 15:41–57
Ferrier MC, Sarin H, Fung SH et al (2007) Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography in the RG2 rat brain tumor model. Neoplasia 9:546–555
Eby PR, Partridge SC, White SW et al (2008) Metabolic and vascular features of dynamic contrast-enhanced breast magnetic resonance imaging and (15)O-water positron emission tomography blood flow in breast cancer. Acad Radiol 15:1246–1254
Niermann KJ, Fleischer AC, Huamani J et al (2007) Measuring tumor perfusion in control and treated murine tumors: correlation of microbubble contrast-enhanced sonography to dynamic contrast-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. J Ultrasound Med 26:749–756
Galban CJ, Chenevert TL, Meyer CR et al (2009) The parametric response map is an imaging biomarker for early cancer treatment outcome. Nat Med 15:572–576
Barentsz JO, Berger-Hartog O, Witjes JA et al (1998) Evaluation of chemotherapy in advanced urinary bladder cancer with fast dynamic contrast-enhanced MR imaging. Radiology 207:791–797
Ah-See ML, Makris A, Taylor NJ et al (2008) Early changes in functional dynamic magnetic resonance imaging predict for pathologic response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res 14:6580–6589
Padhani AR, Hayes C, Assersohn L et al (2006) Prediction of clinicopathologic response of breast cancer to primary chemotherapy at contrast-enhanced MR imaging: initial clinical results. Radiology 239:361–374
Reddick WE, Taylor JS, Fletcher BD (1999) Dynamic MR imaging (DEMRI) of microcirculation in bone sarcoma. J Magn Reson Imaging 10:277–285
de Lussanet QG, Backes WH, Griffioen AW et al (2005) Dynamic contrast-enhanced magnetic resonance imaging of radiation therapy-induced microcirculation changes in rectal cancer. Int J Radiat Oncol Biol Phys 63:1309–1315
Zahra MA, Tan LT, Priest AN et al (2009) Semiquantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging measurements predict radiation response in cervix cancer. Int J Radiat Oncol Biol Phys 74:766–773
Padhani AR, MacVicar AD, Gapinski CJ et al (2001) Effects of androgen deprivation on prostatic morphology and vascular permeability evaluated with mr imaging. Radiology 218:365–374
Li W, Brophy DP, Chen Q et al (2000) Semiquantitative assessment of uterine perfusion using first pass dynamic contrast-enhanced MR imaging for patients treated with uterine fibroid embolization. J Magn Reson Imaging 12:1004–1008
O’Connor JP, Jackson A, Parker GJ et al (2007) DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer 96:189–195
Zweifel M, Padhani AR (2010) Perfusion imaging in the early clinical development of antivascular drugs: decorations or decision making tools? Eur J Nucl Med Mol Imaging. In press
Morgan B, Thomas AL, Drevs J et al (2003) Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 21:3955–3964
Galbraith SM, Maxwell RJ, Lodge MA et al (2003) Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. J Clin Oncol 21:2831–2842
Liu G, Rugo HS, Wilding G et al (2005) Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol 23:5464–5473
Hahn OM, Yang C, Medved M et al (2008) Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J Clin Oncol 26:4572–4578
Flaherty KT, Rosen MA, Heitjan DF et al (2008) Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma. Cancer Biol Ther 7:496–501
Baar J, Silverman P, Lyons J et al (2009) A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: impact on angiogenic biomarkers. Clin Cancer Res 15:3583–3590
Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989
Kamoun WS, Ley CD, Farrar CT et al (2009) Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol 27:2542–2552
Weinmann HJ, Laniado M, Mutzel W (1984) Pharmacokinetics of GdDTPA/dimeglumine after intravenous injection into healthy volunteers. Physiol Chem Phys Med NMR 16:167–172
Tofts PS (1997) Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging 7:91–101
Buckley DL (2002) Uncertainty in the analysis of tracer kinetics using dynamic contrast-enhanced T1-weighted MRI. Magn Reson Med 47:601–606
Landis CS, Li X, Telang FW et al (2000) Determination of the MRI contrast agent concentration time course in vivo following bolus injection: effect of equilibrium transcytolemmal water exchange. Magn Reson Med 44:563–574
Buckley DL (2002) Transcytolemmal water exchange and its affect on the determination of contrast agent concentration in vivo. Magn Reson Med 47:420–424
Galbraith SM, Lodge MA, Taylor NJ et al (2002) Reproducibility of dynamic contrast-enhanced MRI in human muscle and tumours: comparison of quantitative and semi-quantitative analysis. NMR Biomed 15:132–142
Koh DM, Blackledge M, Collins DJ et al (2009) Reproducibility and changes in the apparent diffusion coefficients of solid tumours treated with combretastatin A4 phosphate and bevacizumab in a two-centre phase I clinical trial. Eur Radiol 19:2728–2738
Ashton E, Raunig D, Ng C et al (2008) Scan-rescan variability in perfusion assessment of tumors in MRI using both model and data-derived arterial input functions. J Magn Reson Imaging 28:791–796
Jackson A, O’Connor JP, Parker GJ et al (2007) Imaging tumor vascular heterogeneity and angiogenesis using dynamic contrast-enhanced magnetic resonance imaging. Clin Cancer Res 13:3449–3459
Rose CJ, Mills SJ, O’Connor JP et al (2009) Quantifying spatial heterogeneity in dynamic contrast-enhanced MRI parameter maps. Magn Reson Med 62:488–499
Lee KC, Bradley DA, Hussain M et al (2007) A feasibility study evaluating the functional diffusion map as a predictive imaging biomarker for detection of treatment response in a patient with metastatic prostate cancer to the bone. Neoplasia 9:1003–1011
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Padhani, A.R., Khan, A.A. Diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for monitoring anticancer therapy. Targ Oncol 5, 39–52 (2010). https://doi.org/10.1007/s11523-010-0135-8
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DOI: https://doi.org/10.1007/s11523-010-0135-8