Clinical role of proton magnetic resonance spectroscopy in oncology: brain, breast, and prostate cancer

Review

Clinical role of proton magnetic resonance spectroscopy in oncology: brain, breast, and prostate cancer Lester Kwock, J Keith Smith, Mauricio Castillo, Matthew G Ewend, Frances Collichio, David E Morris, Thomas W Bouldin, Sharon Cush

Standardised proton magnetic resonance spectroscopic imaging (MRSI) was initially developed for routine in-situ clinical assessment of human brain tumours, and its use was later extended for examination of prostate and breast cancers. MRSI coupled with both routine and functional MRI techniques provides more detailed information about a tumour’s location and extent of its infiltration than any other modality alone. Information obtained by adding MRSI data to anatomical and functional MRI findings aid in clinical management decisions (such as watchful waiting vs immediate intervention). In this Review, we discuss the current status of proton MRSI, with emphasis on its clinical use to map the location and extent of tumour processes for spectroscopic image-guided biopsy procedures and to monitor treatment paradigms for brain, prostate, and breast cancer.

Introduction

Refining preoperative differential diagnosis

Since the 1980s, the medical application of two complementary techniques—namely MRI and magnetic resonance spectroscopy (MRS)—for examination of anatomical and metabolic processes of tumours has been realised.1 Over the past 25 years, use of MRI to investigate anatomical changes associated with malignant disease has matured much faster than MRS, which is used to look at biochemical alterations in cancers (figure 1). The main diagnostic procedure used to detect metabolic changes associated with tumour processes was PET. However, at a magnetic resonance workshop on translational research in cancer held in November, 2004, which was sponsored by the National Cancer Institute, an invited group of people working in the area of clinical MRS reached a consensus that proton MRS at that time had “reached a sufficient level of maturity to be ready for multi-center, multi-vendor clinical trials in brain, prostate and breast cancer”.2 The main objective of attendees of this workshop was to develop recommendations for the National Cancer Institute on standardised human MRS measurements and endpoints for use in multicentre trials of anticancer drugs.2 The major advantage of MRS over PET is that many serial studies can be undertaken without electromagnetic radiation exposure to the patient. PET requires an ionising radiation source, whereas MRS uses nonionising radiation, and thus the number of PET studies that can be done on an individual will be governed by their total radiation exposure. In this Review, the part that proton MRS can play in brain, breast, and prostate cancer will be discussed. The fundamental principles of this technique are described elsewhere.3–5 The importance of proton MRS for complementing and extending MRI findings in brain tumours has been discussed by Henson and colleagues,6 and we have furthered their work to include malignant disease of the prostate and breast. The crucial roles of proton MRS are: refinement of preoperative differential diagnosis data, which can be used to guide surgical biopsy procedures; and detection and monitoring of a tumour’s response to treatment or its progression.

Primary brain cancer

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For clinical management of primary brain cancers, histological grade is important, and tissue diagnosis is usually needed. To a large extent, the grade of the lesion defines a patient’s survival probability and course of treatment. People diagnosed with grade II astrocytomas have a median survival of 2–8 years, those with grade III tumours have a 2-year median survival, and survival is less than 1 year for those with grade IV cancers.7 Contrastenhanced MRI is the current gold standard used to guide the neurosurgeon when obtaining biopsy tissue for diagnosis of brain tumours. However, this technique can sometimes be ambiguous. Abnormal contrast enhancement in a diffuse astrocytoma generally implies the presence of a high-grade lesion, even if the biopsy

Lancet Oncol 2006; 7: 859–68 Department of Radiology (Prof L Kwock PhD, J K Smith MD, M Castillo MD), Division of Neurosurgery (M G Ewend MD, S Cush RN), Division of Hematology-Oncology (F Collichio MD), Department of Radiation Oncology (D E Morris MD), and Department of Pathology (T W Bouldin MD), University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA Correspondence to: Prof Lester Kwock, Department of Radiology, University of North Carolina School of Medicine, CB 7515, Chapel Hill, NC 275997515, USA [email protected]

Figure 1: Proton MRS image of tumour activity in high-grade glioma Bar refers to choline/creatine scale, in which red=maximum and blue=minimum.

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sample shows only low-grade components.6 Alternatively, the absence of enhancement does not mean that the cancer is pathologically a low-grade astrocytoma, since up to a third of non-enhancing gliomas in adults are high grade.8 Henson and colleagues suggest that a biopsy sample should be taken of all non-enhancing masses suspected of being gliomas.6 Furthermore, because of the intrinsic heterogeneity of gliomas, new imaging methods need to be developed to help neurosurgeons select tissue for biopsy that will most probably contain the high-grade tumour.6 Proton MRS shows great promise as an imaging technique for guidance of tumour biopsy procedures in the brain (figure 1). Proton magnetic resonance spectra are characterised by a reduction in N-acetyl-aspartate (a neuronal marker) and creatine (an indicator of cellular energy) and an increase in choline (a marker of proliferative rate) at MRS echo times (TE) of 135 ms and 270 ms, compared with healthy brain tissue. More comprehensive descriptions of the scientific and molecular basis for the noted biochemical changes in proton metabolites in tumours are available elsewhere.3–5 Various proton metabolite ratios have been used to differentiate and characterise astrocytomas empirically. For instance, choline/creatine ratios rise with increasing tumour grade (TE >135 ms) whereas myoinositol/creatine ratios fall (TE <30 ms; table).3,9,10 Generation of a spectroscopic map of the choline/creatine ratio registered onto an anatomical image can produce a distributional guide to cancer activity within the tissue (figure 1). This map—obtained by a chemical-shift imaging pointresolved spectroscopy sequence (TE=135 ms, repetition time [TR] 1500 ms)—can then be used to guide the surgeon to the most active portion of the tumour for biopsy. The peak area ratios of choline to creatine for every region (nominal volume 6·25×6·25×10·00 mm3) are calculated with the peak areas of every metabolite resonance and overlaid onto the anatomical magnetic resonance image used to plan the MRS study. In figure 1, a choline/creatine threshold of 1·5 (blue) was set for the lowest ratio, and the highest ratio was 3·14 (red). Empirically, choline/creatine ratios of more than 2·0 are classified as definite for the presence of malignant 860

disease whereas values between 1·5 and 2·0 are judged suspicious for tumour infiltration. In clinicopathological studies,11–13 proton MRS is a very sensitive technique that can differentiate high-grade gliomas from low-grade lesions. Preul and colleagues12 used linear discriminate analysis and proton metabolite/ creatine signal-intensity ratios of magnetic resonance spectral profiles to distinguish grade and type of primary cancer (ie, benign vs malignant and primary brain tumour vs metastatic) from biopsy-proven brain tumours and healthy contralateral tissue, with more than 90% accuracy. In 104 of 105 spectra, grade and type of malignant disease were classified correctly with MRS, whereas conventional preoperative clinical diagnosis misclassified 20 of 91 lesions. In a similar study,13 in which a single-voxel MRS technique was applied instead of the multivoxel spectroscopic imaging technique used by Preul and colleagues, researchers assessed 164 patients with suspected brain tumours. Compared with anatomical MRI data alone, addition of proton MRS to MRI led to a 15% rise in the number of correct diagnoses with respect to grade and type of lesion, 6·2% fewer incorrect diagnoses, and 16% fewer equivocal diagnoses. In a preliminary study14 of six patients by use of MRI and MRS, an intraoperative single-voxel MRS study was done before brain biopsy samples were taken to correlate results of magnetic resonance data with pathological findings. In every individual in whom recurrent malignant disease was suspected on the basis of the magnetic resonance spectroscopic pattern, viable active tumour was seen in the biopsy sample. Radiation necrosis was identified in one person in whom the choline concentration was diminished relative to normal values. In a larger study15 of 21 patients in which a multivoxel magnetic resonance spectroscopic imaging (MRSI) technique was used together with conventional MRI, the researchers also obtained 100% diagnostic success with histological findings—ie, 17 of 21 confirmed viable tumours showed raised choline concentrations, and the remaining four samples that showed reduced amounts of choline were areas of necrosis. Dowling and coworkers16 used a three-dimensional (3D) proton MRSI technique and MRI to assess 29 patients with brain tumours before they underwent surgery. When the pattern of MRS metabolites showed choline concentrations two SDs higher than normal values and N-acetyl-aspartate amounts two SDs below normal, the histological samples from these areas were noted invariably to be cancer (21 of 21). If the choline and N-acetyl-aspartate resonances were below the range recorded in healthy tissue, histological findings were variable, and included radiation necrosis, astrogliosis, macrophage infiltration, and tissues containing a mixture of tumour grades. These researchers showed that 3D MRSI could identify clearly regions of viable active malignant disease, which could be used to guide not only surgical biopsy procedures for tissue diagnosis but also http://oncology.thelancet.com Vol 7 October 2006

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focal treatments. Similar results were obtained in another biopsy study17 guided by MRS and MRI, in which either the single-voxel or multivoxel technique was used. In all the investigations described above, the researchers concluded that proton MRS is a highly effective technique to locate non-invasively representative tumour samples for accurate pathological diagnosis.14–17

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Clinical decision-making for treatment of prostate cancer is based on an abnormal digital rectal examination, raised amounts of prostate-specific antigen (PSA), and results of transrectal biopsy procedures. The biopsy samples, usually obtained in a sextant manner with three samples from each side of the gland, are analysed for malignant changes and a Gleason score is assigned—an important factor for predicting outcome. In general, patients with a Gleason score of 7 or less coupled with a PSA concentration of 10 μg/mL or less are candidates for surgical cure.18 Transrectal ultrasonography-guided symmetrical needle biopsy is the current standard for the detection, localisation, and staging of prostate tumours. However, biopsy procedures are currently being undertaken in a very non-directed way. In most individuals, cancer of the prostate is undetectable by routine ultrasound, CT, and MRI, which means that many cases of malignant disease are not identified at the time of the initial biopsy procedure, even when 10–20 needle-biopsy samples are obtained. Results of clinical studies19 have shown that the systematic sextant biopsy technique is not the best approach, with a positive predictive value of only 30% for detection of prostate cancer. Thus, a non-invasive procedure that could be used to detect, localise, and stage prostate tumours more accurately than present methods would make a substantial contribution to the clinical decision-making process for this malignant disease. Findings20–23 have shown that MRI combined with proton MRSI might be the non-invasive technique to provide information about location and spatial extent of cancer within the peripheral zone of the prostate gland. Proton MRS can detect changes in the amounts of some molecular markers in the prostate, such as citrate, creatine, and choline (figure 2). Variations in the concentrations of these substances can predict accurately the presence of tumour within the peripheral zone of the prostate.20 In a clinicopathological magnetic resonance study21 of the prostate, up to 91% specificity and 95% sensitivity was achieved when MRI was combined with 3D MRSI. Biopsy samples alone are not accurate for establishing the Gleason score, which is the measure of the malignant potential of prostate cancers: biopsy samples obtained before radical prostatectomy predicted the Gleason grade correctly in only 31% of 226 patients in one study18 and in 58% of 449 patients in another report.24 Since scores obtained before surgery are used to predict outcome and to make clinical treatment decisions for prostate cancer patients, there is clearly a compelling need to enhance

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Figure 2: Proton MRS patterns of healthy prostate (A) and prostate adenocarcinoma (B) Transverse (upper), coronal (middle), and saggital (lower) images obtained by T2-weighted turbo spin echo imaging (TE=114ms, TR=4900 ms). Spectra obtained by 3D chemical-shift imaging point resolved spectroscopy (TE=120 ms; TR=1000 ms) with 120 mm field of view. Data obtained as 12x12 matrix with 1-cm slice thickness and interpolated to 16x16 matrix to give nominal volume of 0·56 mm3.

our ability to accurately determine the malignant potential of tumours. Preliminary findings of studies23,25,26 of in-vivo and in-vitro MRS techniques for assessment of prostate cancer aggressiveness have shown that the ratios of choline+creatine/citrate in lesions correlates with Gleason grade. Relative augmentation of choline and reduction of citrate indicates a more aggressive and higher grade tumour. In human prostate cancer samples, progression of tumours to more aggressive lesions is 861

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Courtesy of Michael Garwood, University of Minnesota, Minneapolis, MN, USA

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accompanied by a substantial change in polyamine metabolism.27 To investigate whether polyamines are a valuable diagnostic and prognostic biomarker in prostate cancer, van der Graaf and colleagues28 used MRS and high-performance liquid chromatography techniques to study various samples of prostatic tissue for differences in amounts of polyamines. Findings of their highperformance liquid chromatography analysis showed that healthy and benign hyperplastic prostatic samples were characterised by a high content of spermine. In tumours, especially tissue from patients with metastatic lesions, lower spermine concentrations relative to healthy prostatic tissue were recorded. In a quantitative pathological analysis of MRI and 3D-MRSI-targeted postsurgical prostate cancers, Swanson and coworkers29 noted large significant increases in choline and reductions in citrate and polyamines in aggressive lesions. The Gleason grade is an important predictor of patients’ outcome, when assessed accurately. This fact provides a strong rationale for adding MRI and 3D MRSI to pretreatment assessment of patients with prostate cancer and targeting tissue areas within the prostate for tissue biopsy and analysis. For this reason, several large multicentre trials are underway to establish the clinical importance of these imaging techniques for detection and characterisation of prostate cancer. Two studies are multinational and are sponsored by MRI vendors. A third is being undertaken by the American College of Radiology (ACRIN-6659), which is sponsored by the Cancer Imaging Programme at the National Cancer Institute.

Breast cancer The main method of screening and diagnosis for breast cancer is conventional film-screen mammography. Although this technique has a high sensitivity (70–90%) for detection of abnormal breast tissue, especially in breasts 862

with low-density tissue, it has low specificity (32–64%).30 About 75% of breast tumours detected by mammography are benign on histopathological characterisation.31 The specificities of contrast-enhanced MRI (50%) and ultrasonography (30%) for classification of benign and malignant lesions are similar to that for mammography.31,32 Clearly, the high number of breast biopsy examinations that result in a benign diagnosis indicates that the specificity of the methods currently used needs to be increased or that new techniques need to be developed to establish whether a cancer is benign or malignant more accurately . In-vitro MRS assessment of fine-needle aspirate biopsy samples of primary tumours can show objectively whether a lesion is benign or malignant by measurement of the amount of choline present; this method has been shown to have 93% accuracy.33,34 These findings have been confirmed by further MRS work done in vivo; raised choline concentrations are generally recorded in malignant cancers whereas in healthy tissue and benign lesions, choline concentrations are generally low or undetectable (figure 3).35,36 Because of these and other investigations,37 proton MRS has been proposed as an adjunct to MRI examinations to enhance the specificity of distinguishing malignant from benign breast cancers. Katz-Brull and colleagues37 analysed data from five proton MRS clinical studies to ascertain factors that affect the diagnostic capabilities of this method to establish whether a breast lesion is malignant or benign. In this pooled analysis, 153 tumours were assessed: 100 were histologically proven to be malignant and 53 were benign. Cancers with detectable choline resonances in their proton spectrum were diagnosed as malignant and those with none were said to be benign. Sensitivity of identifying malignant disease was 83% (95% CI 73–89) and specificity was 85% (71–93). The major limiting factor that affected sensitivity was size of the tumour: exclusion of those less than 2 cm in diameter boosted sensitivity to 92%. The main issue affecting specificity was use of only MRS for identification of benign cancers. If MRI information was included in the analysis, only two of the six false-positive cases would have been shown as positive for cancer, and specificity would have risen to 92%. Addition of MRS information to MRI data has been shown to increase sensitivity, specificity, and accuracy in clinical studies38,39 to distinguish between malignant and benign breast processes. In a combined study of 1·5 T MRI and MRS done in 50 patients after positive findings at mammography but before biopsy, MRI alone had 100% sensitivity but only 62·5% specificity for detection of malignant disease. Addition of proton MRS data boosted specificity to 87·5%.38

Detection and monitoring of response to treatment and progression of tumour Primary brain cancer As described in the previous section on brain cancers, patients with WHO grade III and IV gliomas have a poor http://oncology.thelancet.com Vol 7 October 2006

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Figure 4: Proton MRS patterns of recurrent brain tumour 6 months (A), 15 months (B), and 27 months (C) after resection and radiotherapy Bars refer to choline/creatine scale, in which red=maximum and blue=minimum.

outlook. Consequently, much effort has been expended in the development of new drugs and techniques for treatment of these cancers. However, patients undergoing these new strategies sometimes have no clear signs about whether the procedure is effective, at which point to begin another course of treatment can be too late. Changes in tumour size are usually ascertained from contrast-enhanced MRI data by comparing the pretreatment image with that from the current posttreatment study to establish response. In most cases, size is assessed by measuring and multiplying two orthogonal diameters on the largest contrast-enhancing portion of the lesion taken from the same image on successive studies to obtain its area. However, increases in contrast enhancement are not only indicative of increasing tumour size or changes in the properties of blood—brain barrier, they could also be the result of reactive processes, tumour necrosis, or healing along the margin after surgery.40,41 Thus, measurement of contrast enhancement could give misleading conclusions about how the tumour is responding to the treatment. Additionally, several features of gliomas make reliance on tumour size difficult.6 Measurements of size from contrast enhancement assume that primary brain cancers are rectangular or circular, but in reality, gliomas—especially high-grade tumours—can are often irregular in shape, so cross-sectional dimensions do not indicate the true volume of the tumour. Many gliomas can have large cystic or necrotic regions, which are included in the calculation and will probably not respond to treatment. Additionally, disease can progress within a small region of the cancer, so successive linear measurements across the same portion of the tumour from study to study might not detect any evidence of early progression. Thus, use of a method to assess tumour size that is based solely on cross-sectional diameter measurements of contrasthttp://oncology.thelancet.com Vol 7 October 2006

enhanced MRI data alone is a suboptimum approach for assessment of response. Findings of clinical studies42–47 have shown that proton MRS can detect and differentiate between healthy, tumour, and necrotic brain tissue. Evidence from these studies—obtained by different magnetic resonance systems, techniques, and measurements—indicates clearly that proton MRSI coupled to MRI techniques can provide volumetric and metabolic information to assess new treatments for brain tumours. Nelson and colleagues have presented seminal work in this area,42,46 which can be used as a template for clinical studies of MRSI and MRI. These reports include the type of data acquisition and analysis procedures that are needed to undertake serial proton MRI and MRSI brain lesion examinations. Because of the anatomical and heterogeneous character of brain tumours, serial analysis of response of primary cancers to treatment should be done with a 3D MRSI technique.48,49 This approach allows complete delineation of the extent of the metabolic abnormality of the lesion (enhancing and non-enhancing areas) and co-registration with MRI studies for volumetric measurements. Data obtained by MRI and 3D MRSI allow for monitoring of either progression or recurrence of cancers in areas originally outside the noted morphological tumour region.46 Figure 4 shows the MRSI pattern recorded in a pathologically confirmed, recurrent, low-grade oligoastrocytoma in an adjacent slice inferior to the initially resected and irradiated tumour site. The highest choline/creatine ratio recorded 6 months after treatment was 1·49 (figure 4A). After a further 9 months (figure 4B), choline/creatine ratios greater than 2·0 and 1·5 were noted in three voxels each, and 1 year later (figure 4C), seven voxels had ratios of greater than 2·0. This region adjacent to the resection site never showed any gadolinium enhancement or 863

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increased blood perfusion, and analysis of a biopsy sample showed presence of a grade 3 oligoastrocytoma. The patient is now undergoing chemotherapy for this recurrence. A different spectral pattern is recorded for responding tumours. Generally, in such primary brain cancers treated with conformal radiotherapy, chemotherapy, or both, declines in signal intensity of choline resonances are noted first, followed by decreases in N-acetyl-aspartate and creatine and increases in lipid/lactate resonances.46,50 These changes can arise immediately or, more usually, within 6 months of completion of the therapeutic regimen.

Prostate cancer At present, measurement of PSA concentrations is used to monitor patients undergoing treatment for both primary prostate cancer and recurrent and metastatic tumours. People diagnosed with prostate cancer with Gleason scores of 6 or higher can be treated with either surgery or radiotherapy. Both methods are judged curative if the patient has no known metastatic disease. Individuals who have PSA-positive relapse are eligible for salvage radical prostatectomy51 or radiotherapy52 provided they have a biopsy-proven local recurrence, a pretreatment clinical stage of T1–T2, and no evidence of metastatic disease. Salvage radical prostatectomy is usually not undertaken in patients with prostate cancer who have been treated with external-beam radiotherapy. In this population, this surgical technique is much more demanding and leads to higher morbidity than primary radical prostatectomy.53 Thus, salvage surgery is usually undertaken only in individuals who have been shown conclusively to have local recurrence, with no evidence of distant metastasis.51,53 However, as with detection of untreated prostate cancer, diagnosis of local recurrence by digital rectal examination, transrectal ultrasonography, and ultrasound-guided sextant biopsy, are still difficult. Transrectal ultrasonography, with a sensitivity of 49% and a specificity of 57% for prediction of a positive biopsy sample, is the only imaging technique with reported diagnostic accuracy for local recurrence after radiotherapy. This method is no more accurate than digital rectal examination, which has 73% sensitivity and 66% specificity.54 In an ex-vivo study,55 Menard and colleagues analysed MRS spectral changes in prostatic tissue from patients who had undergone radiotherapy for prostate cancer to develop a multivariate analytical strategy that could be used to identify tumours. They recorded a sensitivity of 88·9% and a specificity of 92% for MRS, with overall accuracy of 91·4%. Likewise, in an in-vivo study56 of 21 patients who had undergone radiotherapy for their cancer, using the number of suspicious voxels to define diagnostic thresholds, Coakley and coworkers reported that MRSI had a sensitivity of 89% and a specificity of 82% for diagnosis 864

of biopsy-confirmed local recurrence when three or more voxels showed choline/creatine ratios of greater than 1·5. Pucar and colleagues57 used an MRSI technique to look at choline+creatine/citrate ratios in nine people post-radiotherapy. They reported a sensitivity of 77% and a specificity of 78% for detection of biopsy-proven local recurrence. In these MRSI studies, even though different proton metabolic ratios and criteria were used to define the threshold for detection of tumour, sensitivity and specificity of the procedure were still higher than those of transrectal ultrasonography or digital rectal examination for detection of local recurrence after external-beam radiotherapy of the prostate. In individuals who have undergone radical prostatectomy for treatment of prostate cancer and now have rising PSA concentrations, ascertainment of whether they have only localised recurrent disease at the resection site, recurrent and systemic disease, or both, is difficult to diagnose with present methods. As discussed in the previous section, conventional imaging methods such as transrectal ultrasonography, CT, and MRI sometimes cannot distinguish accurately between healthy and malignant tissue after resection or other treatments for prostate cancer because of induced tissue changes.20 The only way at present to identify definitively whether tissue is malignant is to undertake histological analyses of biopsy samples. In patients who have undergone radical prostatectomy, such samples are obtained in a random manner, and thus are subject to large sampling errors. In individuals who have undergone cryosurgery, MRI and MRSI have been shown to discriminate residual or recurrent prostate cancer from healthy and necrotic tissue.58 In this MRSI study, voxels that showed a loss of all observable prostatic metabolites were confirmed histologically as necrotic areas, those with choline+creatine/citrate ratios of 2·4 (SD 1·0) were malignant regions, and choline+creatine/citrate ratios of 0·61 (0·21) were either healthy or benign tissue. In patients who have had radical prostatectomy procedures, no citrate should be recorded since no prostate gland should be present. Figure 5 shows an MRI image of a region below the base of the bladder that seemed abnormal in a man who underwent radical prostatectomy and was found to have a rising PSA concentration 1 year later. The region was investigated with MRSI and several voxels containing highly increased choline/creatine ratios were noted (eight voxels, choline/creatine ratio of 4·5 [SD 2·4]). No citrate resonance (between 2·5 and 2·7 ppm) was recorded in any region, and in most voxels, only resonances at 2 ppm or less could be noted, which presumably corresponds to aminoacid and lipid resonances in proteins. With this information, the radiation oncologist decided to treat this area with conformal radiotherapy without confirmation by biopsy. On completion, the patient’s PSA concentration was zero. 6 months later he returned for his second http://oncology.thelancet.com Vol 7 October 2006

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follow-up assessment and the amount of PSA was still zero. The man was re-examined with MRI and 3D MRSI, and no voxels containing increased choline/creatine ratios could be detected. Post-treatment ratios were 1·2 (SD 0·2). More than 1 year after radiotherapy, the patient’s PSA concentration remains at zero.

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Neoadjuvant chemotherapy followed by surgery and radiotherapy is used to treat patients with large (≥3 cm) and locally advanced (T3, T4, or N2) breast cancers. Although neoadjuvant chemotherapy by itself does not offer any substantial increase in survival over a postoperative regimen, researchers have shown that how a tumour responds to a chemotherapeutic drug can be used to predict treatment outcome.59,60 People who obtain the greatest survival advantage from neoadjuvant chemotherapy are those whose cancer completely disappears before resection.59 MRI is a more reliable technique for assessment of the response of breast lesions to neoadjuvant chemotherapy and for detection of multifocal disease before surgery compared with physical examination, mammography, ultrasound, or a combination of these: use of MRI correctly measured the residual tumour size in 63% of patients (53 with invasive ductal breast cancer and seven with invasive lobular carcinomas given neoadjuvant chemotherapy) compared with 52% by physical examination, 38% by mammography, and 43% by ultrasound. Furthermore, in all cases, use of MRI correctly established the objective response to neoadjuvant chemotherapy in individuals who had either a complete response (five of 60), partial response (43 of 60), or no response (12 of 60). However, reliable ascertainment of response to chemotherapy is unknown until about 6 weeks after induction of the regimen.62 An ideal method would be able to detect an immediate response to a specific chemotherapeutic regimen, which would allow for optimisation of individualised treatment for patients, with the major objective of obtaining a complete pathological tumour response. A great deal of interest has arisen with respect to use of proton MRS techniques to monitor neoadjuvant chemotherapy of locally advanced breast cancer.63,64 Malignant breast lesions contain raised amounts of compounds containing total choline, which are detectable and quantifiable by proton MRS.34–38,40 Using the resonance for choline of 3·2 ppm, Jagannathan and colleagues63 showed that changes in the amount of total choline that were recorded in the tumours of women with breast cancer given neoadjuvant chemotherapy correlated with the clinical and histopathological response of the patient. However, as in the MRI studies, assessment of response by these researchers was made after completion of the chemotherapy regimen. In a single-voxel 4 T MRS study64 of 16 individuals with locally advanced breast cancer being treated with neoadjuvant chemotherapy, Meisamy and coworkers

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Figure 5: Proton MRS patterns of recurrent prostate adenocarcinoma before treatment (A) and 6 months after radiotherapy (B) Transverse (upper), saggital (middle), and coronal (lower) images of prostate obtained by T2-weighted turbo spin echo imaging (TE=114ms, TR=4900 ms). Spectra obtained by 3D chemical-shift imaging point resolved spectroscopy (TE=120 ms; TR=1000 ms) with 120 mm field of view. Data obtained as 12x12 matrix with 1-cm slice thickness and interpolated to 16x16 matrix to give nominal volume of 0·56 mm3.

showed that changes in concentration of total choline from baseline to within 24 h after the first dose correlated significantly with changes in tumour size (r=0·79, p=0·001). 865

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Figure 6: Monitoring of response to neoadjuvant paclitaxel Sagittal 3D gadolinium-enhanced fat-suppressed fast low-angle shot (13·5/4·1) MRI (left) and corresponding spectra (right) of right breast with invasive ductal carcinoma and positive lymph nodes. Measurements were taken 2 days before treatment (A); within 24 h of first dose (B); after second dose (C); and after fourth dose (D). Spectral peaks: 1=lipid; 2=total choline; 3=water. Lines above and below total choline peak are fitted and actual curves, respectively. Boxes around lesions are spectroscopy voxels.

Figure 6 shows magnetic resonance images and corresponding spectra of one of the 16 patients described above. The amount of total choline by 24 h fell by 20%, which predicts an objective response to neoadjuvant chemotherapy. The tumour was 58% smaller after the fourth dose, which also accords with an objective response. Additionally, changes in total choline concentration within 24 h after the first dose of chemotherapy differed significantly between patients with an objective response and those with no response (p=0·007). These preliminary 866

Although we have discussed use of proton MRS only in brain, breast, and prostate cancers, the technique is being used to investigate other malignant processes, such as lymph-node involvement65–67 and uterine cervical carcinomas.68 The studies we describe clearly indicate a role for proton MRS as a non-invasive diagnostic method for cancer assessment. A major observation in the data for in-vitro and in-vivo studies is the consistent increase in amount of choline in tumours compared with surrounding healthy tissue and the consistent decrease in choline concentrations in lesions responding to treatment versus non-responding cancers. These variations are independent of tumour type. Malignant and non-responsive cancers, whether from brain, prostate, or breast, show rises in the amounts of choline compared with concentrations in healthy tissue and lesions responding to treatment. This finding suggests that proton MRS, when combined with MRI techniques (ie, gadolinium enhancement, perfusion, and diffusion) can be used not only to ascertain the extent of an active tumour process in tissue but also as a strategy to monitor early response. Owing to physical issues associated with the anatomical location of cancers, proton MRS cannot be used to monitor all tumours. Breathing or peristaltic motion and large air-tissue interfaces lead to severe magnetic susceptibility difficulties, which affect the local magnetic field homogeneity, leading to severe line broadening and loss of signal. Thus, carcinomas located in the chest, abdomen, and gastrointestinal tract can be very difficult to monitor with MRS. Another physical issue that could restrict the usefulness of this technique for monitoring of tumour processes is the size of the voxel needed to obtain adequate signal/noise ratios to detect the presence of the cancer. In the case of breast carcinoma, lesions less than 2 cm in diameter diminish the sensitivity of MRS to distinguish benign from malignant cancers because of a reduced signal/noise ratio of the choline resonance due to decreased voxel size.37 Biochemical limitations of invivo proton MRS at 1·5 T and 3 T are intrinsic constraints for detection of metabolites other than choline as tumour biomarkers, because of the much lower concentrations of other compounds associated with specific cancer processes (0·01 mol/L for choline vs 0·00001 mol/L or lower for other biochemical compounds). Even with these limitations (which can be overcome), proton MRS in combination with MRI provides a very valuable diagnostic clinical strategy to investigate the metabolism, physiology, and anatomy of tumour processes in one clinical procedure. http://oncology.thelancet.com Vol 7 October 2006

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Search strategy and selection criteria References were identified by use of PubMed and from references cited in relevant articles using the keywords “primary brain tumors”, “breast cancer”, “prostate cancer”, and “proton magnetic resonance spectroscopy”. Our search was from January, 1990, to January, 2006. Only articles written in English and dealing with proton MRS were included. Conflicts of interest We declare no conflicts of interest. References 1 Evanochko WT, Ng TC, Glickson JD. Application of in vivo NMR spectroscopy to cancer. Magn Reson Med 1984; 1: 508–34. 2 Evelhoch J, Garwood M, Vigneron D, et al. Expanding the use of magnetic resonance in the assessment of tumor response to therapy: workshop report. Cancer Res 2005; 65: 7041–44. 3 Smith JK, Castillo M, Kwock L. MR spectroscopy of brain tumors. Magn Reson Imaging Clin N Am 2003; 11: 415–29. 4 Barker PB. Fundamentals of MR spectroscopy. In: Gillard JH, Waldman AD, Barker PB, eds. Clinical MR neuroimaging. Cambridge: Cambridge University Press, 2005: 7–26. 5 Salibi N, Brown MA. Clinical applications: hydrogen spectroscopy (chapter 6). In: Salibi N, Brown MA, eds. Clinical MR spectroscopy: first principles. New York: Wiley-Liss, 1998: 143–72. 6 Henson JW, Gaviani P, Gonzalez RG. MRI in treatment of adult gliomas. Lancet Oncol 2005; 6: 167–75. 7 Castillo M, Scatliff JH, Bouldin TW, Suzuki K. Radiologic-pathologic correlation: intracranial astrocytoma. AJNR Am J Neuroradiol 1992; 13: 1609–16. 8 Barker FG 2nd, Chang SM, Huhn SL, et al. Age and the risk of anaplasia in magnetic resonance-non-enhancing supratentorial cerebral tumors. Cancer 1997; 80: 936–41. 9 Castillo M, Smith JK, Kwock L. Correlation of myo-inositol levels and grading of cerebral astrocytomas. AJNR Am J Neuroradiol 2000; 21: 1645–49. 10 Shimizu H, Kumabe T, Shirane R, Yoshimoto T. Correlation between choline level measured by proton MR spectroscopy and Ki-67 labeling index in gliomas. AJNR Am J Neuroradiol 2000; 21: 659–65. 11 Magalhaes A, Godfrey W, Shen Y, et al. Proton magnetic resonance spectroscopy of brain tumors correlated with pathology. Acad Radiol 2005; 12: 51–57. 12 Preul MC, Caramanos Z, Collins DL, et al. Accurate, non-invasive diagnosis of human brain tumors by using proton magnetic resonance spectroscopy. Nat Med 1996; 2: 323–25. 13 Moller-Hartmann W, Herminghaus S, Krings T, et al. Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology 2002; 44: 371–81. 14 Hall WA, Martin AJ, Liu H, et al. Brain biopsy using high-field strength interventional magnetic resonance imaging. Neurosurgery 1999; 44: 807–13. 15 Martin AJ, Liu H, Hall WA, Truit CL. Preliminary assessment of turbo spectroscopic imaging for targeting in brain biopsy. AJNR Am J Neuroradiol 2001; 22: 959–68. 16 Dowling C, Bollen AW, Noworolski SM, et al. Preoperative proton MR spectroscopic imaging of brain tumors: correlation with histopathologic analysis of resection specimens. AJNR Am J Neuroradiol 2001; 22: 604–12. 17 Chen CY, Lirng JF, Chan WP, Fang CL. Proton magnetic resonance spectroscopy-guided biopsy for cerebral glial tumors. J Formos Med Assoc 2004; 103: 448–58. 18 Cookson MS, Fleshner NE, Soloway SM, Fair WR. Correlation between Gleason score of needle biopsy and radical prostatectomy specimen: accuracy and clinical implications. J Urol 1997; 157: 559–62. 19 Flanigan RC, Catalona WJ, Richie JP, et al. Accuracy of digital rectal examination and transrectal ultrasonography in localizing prostate cancer. J Urol 1994; 152: 1506–09.

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