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British Journal of Radiology 75 (2002),959-966 © 2002 The British Institute of Radiology

Full Paper

Early in vivo detection of metabolic response: a pilot study of 1H MR spectroscopy in extracranial lymphoma and germ cell tumours

A J Schwarz, PhD, MInstP 1 N R Maisey, MBBS, MRCP 1,2 D J Collins, BA, MInstP 1 D Cunningham, MD, MRCP 2 R Huddart, MA, MRCP, FRCR 3 and M O Leach, PhD, FInstP, FMedSci 1

1 Cancer Research UK Clinical Magnetic Resonance Research Group, 2 Department of Medicine and 3 Academic Department of Radiotherapy, Institute of Cancer Research and Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK

Correspondence: Professor Martin O Leach


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Monitoring therapeutic efficacy is essential in oncological practice. We have investigated the feasibility of using proton 1H MR spectroscopy (MRS), localized to malignant lymphoma and germ cell lesions outside the cranial cavity, to monitor tumour metabolism in vivo during chemotherapy treatment. 1H single voxel MRS, (stimulated echo acquisition mode, repetition time/echo time=2000/20 ms) was performed prior to treatment in patients with lymphoma or germ cell tumours, and during the first cycle of chemotherapy. Patient response was assessed by independent clinical follow-up at a median of 57 days (range 44–93 days) post-treatment. All 12 non-cystic lesions scanned showed a signal assigned to choline-containing metabolites (tCho); 9 were scanned both pre- and post-treatment. Changes in the tCho:water ratio following treatment were found to predict subsequent patient response. In seven of these nine patients, the tCho:water ratio decreased in the first post-treatment scan, and all subsequently achieved a partial response to treatment. In the remaining two patients, both of whom progressed on treatment, the tCho:water ratio did not change significantly. Normalized to pre-treatment values, the non-responder group values (1.07 and 0.97) were clearly distinct from the responder group, whose values ranged from 0.43 to below detection level. To our knowledge, this is the first report of 1H MR spectra from these tumour types and sites. These preliminary results indicate that metabolite signals can be detected using 1H MRS in these tumour types and locations, as has already been established in the brain, breast and prostate. Moreover, the differential changes observed in the tCho region of the spectrum suggest that 1H MRS could provide an early and sensitive indicator of metabolic response to chemotherapy.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Monitoring therapeutic efficacy is essential in the management of cancer patients. Clinical response assessment is generally based on bi-directional measurements of tumour size using conventional radiological techniques, such as CT. Anatomical information, however, may not always be an accurate or complete measure of response. Additional functional information about the effect of a particular treatment could allow early treatment modification and avoid unnecessary toxicity.

Malignant lesions exhibit altered metabolism compared with normal tissues. This has led to the investigation of functional medical imaging modalities such as MR spectroscopy (MRS) as methods of monitoring tumour metabolism. This provides a non-invasive window on mobile metabolite moieties in vivo that may be used to investigate changes in response to therapy. To date, MRS studies of tumour response in extracranial human cancer have primarily employed phosphorus (31P) spectroscopy to study changes in phosphorylated metabolites, in particular the cell membrane precursors phoshphoethanolamine (PE) and phosphocholine (PC). Differential spectral changes as a function of subsequent chemotherapeutic response have been reported for a range of cancers, including non-Hodgkin's lymphoma (NHL), sarcoma and breast carcinoma [1–3]. However, proton (1H) MRS is intrinsically more sensitive than 31P (by a factor of 2.47) owing to the higher gyromagnetic ratio of the proton. In contrast to 31P, almost all human in vivo 1H MRS studies to date have focused on the brain, including intracranial tumours, and in this context 1H MRS has begun to find routine clinical use. It has been established that the 1H spectral characteristics of brain tumours differ significantly from those of normal grey and white matter and, moreover, can differentiate between tumour type and grade [4]. Recent human studies in prostate and breast cancer have observed elevated choline levels and suggest that 1H MRS may also supply useful information in tumours outside the cranial cavity at a scanner field strength of 1.5 T [5–9]. Pre-clinical 1H studies have shown significant decreases in choline and lactate resonances in radiation insensitive fibrosarcoma-1 tumours treated with radiation and 5-fluorouracil chemotherapy [10–12]. However, extracranial in vivo 1H studies are often subject to strong contaminating lipid signals from fatty tissues near the lesion of interest.

The aim of this pilot study was to assess the metabolic information available from 1H MRS spectra of extracranial lymphoma and germ cell malignancies, and to examine the potential utility of any metabolic changes occurring with chemotherapy treatment.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients
Patients were eligible for this study if they had a radiologically detectable extracranial lymphoma or germ cell tumour, measuring at least 3 cm x 3 cm if superficial or 5 cm x 5 cm if deeper lying, and were about to commence systemic chemotherapy. All patients underwent a 1H MRS examination prior to commencement of chemotherapy and, where possible, at least once during the first 5 weeks following commencement of treatment. 13 patients with a median age of 41 years (range 17–72 years) were studied. Five patients had non-Hodgkin's lymphoma, three had Hodgkin's disease, one had metastatic neuroendocrine carcinoma, three had metastatic seminoma and one had metastatic testicular teratoma. Of these, 10 patients were willing to return for post-treatment MRS.

Patient response was the primary end point, and was assessed at the first independent routine clinical follow-up, based on bi-directional measurements of lesion size from CT scans (World Health Organization criteria of response [13] or clinical evidence of disease progression on treatment. CT scans were performed at a median of 57 days (range 44–93 days) following commencement of chemotherapy.

In cases where MR anatomical images provided complete coverage of the lesion, the tumour volume was determined from freehand regions of interest drawn around the lesion periphery in each slice containing the tumour, for each of the three orthogonal imaging series obtained. The average of the volumes determined from each series was used as the MRI-derived tumour volume. However this was not used in the clinical response assessment.

All patients gave fully informed consent in agreement with internal ethics procedures.

MR measurements
All measurements were performed using a Siemens Magnetom Vision 1.5T whole body clinical MR system (Siemens, Erlangen, Germany). Patients were positioned supine in the magnet with the 1H surface coil placed adjacent to the target lesion. Tumours in the pelvic, abdominal or mediastinal regions were studied using a Siemens flexible 1H receive surface coil: (proprietary circularly polarized coil comprising three elements, one 12 cm wide x 14.1 cm long single loop, and two 15.4 cm wide x 14.7 cm long elements, forming a butterfly design (widths and lengths from a common axis). For neck nodes a circular, 10 cm diameter, receive coil was used.

The MR measurement protocol comprised sets of localizer T1 and T2 weighted images in three orthogonal planes followed by automated shimming to optimize local magnetic field homogeneity. We found a true-fast imaging with steady-state precession sequence (repetition time/echo time =6.32/3.0 ms, flip angle <=le;70°, slice thickness 6–8 mm) particularly useful for clear localization of the target lesion. Subsequently, spectra localized to a volume of interest (VOI) of 2–46 ml (mean 18 ml) positioned within the tumour were acquired using the manufacturer's single voxel stimulated echo acquisition mode (STEAM) spectroscopy sequences. VOIs were chosen to inscribe the largest contiguous portion of the lesion, and typically decreased with tumour shrinkage following treatment. With larger tumours a large VOI was selected in a region of the tumour closest to the coil. Short echo time (TE), 20 ms, spectra were obtained with a repetition time of 2 s, a mixing time of 30 ms and 128 averages each, giving a measurement time of approximately 4.5 min per spectrum. The water signal was suppressed using chemical shift selective pulses prior to each STEAM repetition, permitting the metabolite signals to be measured with maximum sensitivity. An unsuppressed water signal with 8–16 averages was also acquired at each TE as a normalization reference. The total measurement time for this protocol was typically 35 min. In subsequent scans, care was taken to reposition the coil and VOI in accordance with previous measurements.

A standard sequence was chosen for this pilot study to assess the feasibility of obtaining metabolite signals using 1H MRS in these cancers and tumour sites. Potential for methodological improvements in this area is discussed later.

Data analysis
Spectra were processed offline using the MR user interface (MRUI)/variable projection (VARPRO) time domain processing algorithm [14]. Gaussian model functions were fitted to the unsuppressed water signal and to identifiable metabolite and lipid peaks. Since the signals are fitted in the time domain, the fitted signal values reported correspond to the amplitudes of each signal's free induction decay (FID) at time t=0 (being the start of the signal acquisition). These values are directly proportional to the peak area of the equivalent frequency-domain resonance. The noise standard deviation ({sigma}N) is also calculated by MRUI for each metabolite spectrum from the residual time domain signal. As such, this provides a useful noise baseline for the values obtained for the individual metabolite signal amplitudes.

Metabolite signal values were expressed as percentages of the water signal at the same echo time, following correction for the differential receiver gains. The tumour volume was measured from its area in each of the contiguous image slices intersecting the tumour using all three orthogonal image sets. Post-treatment choline-containing metabolite (tCho):water signal amplitude ratios were expressed as fractions of the pre-treatment baseline value.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Patient diagnosis, tumour site and MRS results are summarized in Table 1Go.


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  		Table 1. Patient clinical details, and changes in the choline-containing metabolite tCho:water ratio observed via proton (1H) MR spectroscopy (MRS)

 
Spectra
In the pre-treatment spectra, metabolite signals, not including the main mobile lipid resonances at 0.9 ppm and 1.3 ppm were observed in 12 of the 13 patients studied at TE=20 ms. In one of these 12, the metabolite signal was ambiguous, and when quantified its time domain signal amplitude was lower than the time domain FID noise standard deviation. In patient 7, in whose spectrum no metabolite signals were identifiable, independent interpretation of CT scans indicated that the target lesion was cystic. All the other spectra featured a peak at approximately 3.2 ppm.

Based upon published 1H MRS observations in other human cancers, we tentatively assign the 3.2 ppm resonance to the trimethyl ammonium N-(CH3)3 moiety of tCho. Signals due to mobile lipids ([CH2]n at 1.3 ppm, CH3 at 0.9 ppm) were also observed in most spectra. However, given that many of the tumours studied were surrounded by fatty tissues (Figure 1Go), and that the MRS voxel was selected to be as large as possible within the tumour, it is likely that these signals contain substantial contributions from lipids external to the tumour, owing to residual sidelobes in the volume selection profiles and respiratory motion. Optimization of the acquisition methodology is required in order to reliably exclude lipid signals from outside the tumour.



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  		Figure 1. Sagittal T1 weighted localizer image from patient 8, showing para-aortic lesion in the lower middle of the image, with surrounding fatty tissue visible. The surface receive coil was placed over the patient's anterior abdominal wall (left).

 
Figure 2Go shows pre-treatment TE=20 ms spectra from a B-cell lymphoma (low grade), a large B-cell non-Hodgkin's lymphoma (high grade), a Hodgkin's disease lesion and a seminoma metastasis. The spectra in Figure 2b–dGo show additional metabolite peaks at chemical shifts of approximately 2.7 ppm and in the 3.6–3.8 ppm region in addition to lipid and tCho peaks. Interestingly, these are observed in tumours of different histopathology. In all, six of the pre-treatment spectra showed signals in these spectral regions.



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  		Figure 2. Pre-treatment echo time =20 ms spectra from (a) a B-cell lymphoma (low grade), (b) a large B-cell non-Hodgkin's lymphoma mass with sclerosis (high grade), (c) a Stage IIE nodular sclerosing Hodgkin's disease mass in the anterior chest wall, and (d) a para-aortal seminoma stage IIC metastasis. tCho, choline-containing metabolite.

 
Metabolic changes
Nine patients with a quantifiable pre-treatment tCho signal in the TE=20 ms spectra were scanned both pre- and post-treatment. The spectral changes observed following chemotherapy fell into two clearly distinct patterns that correlated with subsequent clinical response, as shown in Figure 3Go. In seven patients the tCho:water ratio had reduced substantially in the first post-treatment MRS scan (median 6 days, range 3–35 days); all seven of these patients were subsequently clinically assessed as showing a partial response to treatment at a median 87 days (range 54–93 days). In the remaining two patients the tCho:water ratio remained unchanged (5 days and 37 days), and in each case the patient was clinically assessed as having progressive disease (44 days and 57 days).



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  		Figure 3. Differential changes in choline-containing metabolite (tCho):water ratio between (a) subsequent responders and (b) non-responders. "Early" post-treatment scan corresponds to 3–7 days, "late" post-treatment to 14-35 days following commencement of chemotherapy. Values of zero reflect a tCho signal undetectable below the noise level.

 
Of the seven responders, four had a scan between day 3 and day 7 post-treatment. In two of these the tCho signal had already decreased to below the noise standard deviation. The remaining three responders had no detectable tCho signal in the first post-treatment scan at day 14–35.

If, in spectra with no discernible tCho, {sigma}N is interpreted as an upper limit to the tCho signal amplitude, the distinction between the two responder groups is retained for the five patients who had an early (3–7 days) post-treatment MRS examination (Figure 4Go). The standard error of the mean (SEM) for the four responders in this subgroup includes correction by the inverse t-distribution coefficient for 3 degrees of freedom at significance level 0.05. The non-responder value lies greater than twice the SEM above the mean responder value. In the three responders who had a later post-treatment MRS examination (14–35 days) and showed no discernible tCho, the {sigma}N:water ratio was greater than the pre-treatment tCho:water ratio value, implying that the absence of signal in these later measurements may be due, in part, to the substantially reduced tumour volumes. The post-:pre-volume ratios in these three patients, patients 3, 8 and 9, were 0.12, 0.37 and 0.13, respectively.



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  		Figure 4. Post-treatment choline-containing metabolite (tCho):water ratios, normalized to pre-treatment baseline values. The five patients scanned 3–7 days post-treatment are shown with the noise standard deviation taken as an upper limit on the tCho signal for those with no discernible tCho. SEM, standard error of the mean.

 
Independent of the CT scan used for clinical assessment, all seven responders showed a measurable decrease in tumour size as measured from the MRI images. In five of these a tumour volume could be calculated, and in the final MR examination the target lesion measured between 9% and 20% of its pre-treatment volume. However, the reduction in the tCho:water ratio was observed to be more rapid than volume changes after commencement of chemotherapy; in all four patients scanned 3–7 days post-treatment, the tCho:water ratio had decreased by a greater amount, relative to the pre-treatment baseline, than the tumour volume (Table 1Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
These results demonstrate the feasibility of obtaining signals from MR-visible, 1H-containing moieties in mobile metabolites in malignant lymphoma and germ cell neoplasms in the abdomen and extremities at an MR field strength of 1.5 T. Even relatively deep tumours, e.g. para-aortic, yielded useable spectra in most cases. The acquisition methodology used in this pilot study was not optimized, but we believe the results presented here provide motivation for development in this respect. The presence of residual sidelobes in the volume localization pulses leads to outer-volume contamination, particularly from surrounding fatty tissues. Further, respiratory motion can degrade single volume spectra owing to incoherent averaging and frequency shifts, as well as exacerbating outer volume contamination. However, a recent study into the effects of respiratory motion on 1H CSI studies of tumours in these locations showed that these lesions are generally well fixated and move much less than the diaphragm during the respiratory cycle [15].

1H MRS signatures appeared broadly similar across the different tumour types and histopathology, although differences may become apparent as data from larger groups of patients are acquired and the aquisition methodology is optimized for improved detection of metabolite signals. In 1H MRS of brain tumours, subtle differences in metabolite signal profiles have been shown to correlate with tumour type [16].

The presence of a tCho resonance in lymphoma and germ cell tumours, as well as in prostate and breast tumours, may reflect an increased cell proliferation, with a decrease in this peak after treatment reflecting a diminished number of viable cells in the neoplasm owing to the action of drugs. Studies of human glioma have shown that the MR-visible choline resonance correlates with tumour cell density [17] and with the Ki-67 proliferative index [18]. It has also been shown in ex vivo studies in man and rat [19, 20] that 1H MR spectra from malignant lymph nodes exhibit, relative to healthy controls, pronounced choline resonances as well as increased metabolite peaks at 2.1 ppm, 2.4 ppm, and 3.5–4.1 ppm; signals in the latter range were assigned to amino acids. In vivo 1H nuclear MR studies of brain exhibit resonances at ~2.1 ppm and ~2.4 ppm to glutamine and glutamate.

In the data presented here, any metabolite signals in the 2–2.5 ppm region of the spectrum are likely to be confounded by co-resonant lipid signals. The resonances observed in the 3.6–4.0 ppm region are intriguing, however, their identities remain to be elucidated. Since the methodology used for MRS acquisition in this study was not optimized to minimize outer volume contributions, no conclusions are drawn regarding lipid signals in the data reported here in terms of characterizing pathology or response. Nevertheless, reliable detection of mobile lipids within such tumours is potentially of much interest. In vivo MRS studies of brain tumours have shown 1H MRS-visible lipid profiles dependent on tumour type [21]. Ex vivo studies in astrocytomas have indicated a similar pathology dependence [22], and that lipid resonances correlate with increasing necrotic content within high grade tumours [23]. The main lipid resonances observed in 1H MR spectra are those at 1.3 ppm owing to the {-CH2-}n acyl chain "backbone", and 0.9 ppm owing to the terminating –CH3 group. Depending on the saturation profile, lipid resonances due to unsaturated bonds may be observed at 2.1 ppm and 5.3 ppm, and polyunsaturated lipids will also contribute a resonance at ~2.7 ppm. If the acquisition methodology can be optimized to robustly exclude outer volume contamination in the presence of respiratory motion and intense contaminating signals from adipose tissue, the lipid resonances may be used to determine a lipid saturation profile of the tumour itself from the resonances observed, which may provide another means of characterizing the disease. However, resonances at 2.1 ppm and 2.7 ppm may coincide with signals from other metabolites, complicating interpretation of the spectra. In this respect, in vivo two-dimensional MRS techniques may eventually provide a means of removing these ambiguities and improving metabolite assignments in the acquired data.

Based on the differential changes in signal intensities in the tCho region of the spectrum following chemotherapy, we hypothesize that metabolic changes observable by 1H MRS may be predictive of subsequent clinical response. In this respect, changes are consistent with those observed in the phosphomonoester region of 31P spectra, which consists primarily of PE and PC. In combination with other prognostic factors, such as the International Prognostic Index for lymphoma, biochemical information from MRS may find a role in individual patient management.

The results reported here were obtained from a small heterogeneous patient group and although promising, require substantiation in larger prospective patient series and focus on specific pathologies. In many of the observed spectra, the 3.2 ppm signal was broad, possibly owing to field inhomogeneity and motion due to the respiratory cycle. However, the observed peak may contain contributions from glycerophosphocholine (GPC), as well as PC and unphosphorylated choline (Cho). Although GPC, PC and Cho have discrete resonances over a range of 0.3 ppm [24], these are not distinguishable in vivo. Contributions from metabolites other than tCho to this signal also cannot be discounted. PE is known from 31P studies to be elevated in many extracranial tumours; in the proton spectrum PE has a coupled resonance at approximately 3.2 ppm, which may also be contributing to the observed peak in that region at TE=20 ms.

31P MRS requires specialized hardware beyond that routinely provided by MRI equipment manufacturers, which is optimized for MRI. In contrast, 1H MRS may be performed using the same equipment as MRI, and offers potential gains in sensitivity and spatial resolution. However, as discussed above, there is scope for optimization of the acquisition methodology. In the treatment of rapidly growing tumours, such as high grade NHL, this method may allow early optimization of therapy by detection of chemoresistance soon after treatment has commenced. As well as permitting MRS to be performed in a far wider range of MR centres, the development of 1H MRS for a greater range of pathologies and anatomical locations, as reported here, will facilitate the incorporation of MRS into multifunctional MR examinations, providing complementary metabolic and functional information. MRS methods may prove informative in monitoring Phase I hypothesis-based clinical trials of new anti-cancer treatments that target specific biological end points but are not expected to provide dramatic changes in tumour size.

To the best of our knowledge, this work is the first report of in vivo metabolite signals visible by 1H MRS in human lymphoma and germ cell cancers located outside the head/neck, prostate or breast. The observation of different trends in responders and non-responders suggests that further development of this method may provide a sensitive early indicator of metabolic response to treatment.


   Acknowledgments
 
We are grateful to F L Kinnaird for assistance with patient recruitment.


   Footnotes
 
Funding for this work was provided by Cancer Research UK (SP1780/0103) and the National Cancer Institute (UO1 CA62557-02). Back

Current address for A J Schwarz: Department of Neuroimaging (Biology), GlaxoSmithKline S.p.A., Via Fleming 4, 37135 Verona, Italy. Back

Received for publication January 24, 2002. Revision received July 31, 2002. Accepted for publication August 16, 2002.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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