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Keywords:

  • spectroscopy;
  • prostate cancer;
  • radiation therapy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Objective

To correlate 3-T magnetic resonance spectroscopic imaging (MRSI) with prostate-specific antigen (PSA) levels in patients with prostate cancer treated with external beam radiation therapy to assess the potential advantages of MRSI.

Materials and Methods

A total of 50 patients (age range 65–83 years) underwent PSA and MRSI surveillance before and at 3, 6, 12, 18 and 24 months after radiotherapy.

Results

Of the 50 patients examined, 13 patients completely responded to therapy showing metabolic atrophy (MA), defined as a choline-plus-creatine/citrate (CC/C) ratio <0.2, at 3 months; in this group none had biochemical relapse (PSA nadir + 2 ng/mL) by the end of the follow-up.

Of the 50 patients, 35 showed a partial response to therapy (CC/C ratio between 0.2 and 0.8) at 3 and 6 months and, of these 35 patients, 30 reached MA at 12 months, while five developed a recurrence (CC/C ratio >0.8).

Three of those patients with recurrence had a biochemical relapse at 18 months and the other two at 24 months.

Two of the 50 patients did not respond to the treatment, showing persistent disease from the 3rd month (CC/C ratio >0.8); one patient had biochemical relapse at 6 and the other at 12 months.

Conclusions

MRSI was shown to have a greater potential than PSA level in monitoring patients after radiotherapy, because it anticipates PSA nadir, and biochemical relapse in particular.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Multiparametric MRI of the prostate gland has become a valid tool in the diagnosis and evaluation of tumour biology for assessing its aggressiveness [1], for tumour staging so as to schedule an appropriate treatment plan and for follow-up to monitor treatment response [2]. Multiparametric MRI can make a diagnosis of prostate cancer (PCa) by highlighting a low signal intensity in T2-weighted images, neoangiogenesis in perfusion sequences, movement restriction of water molecules in diffusion sequences (diffusion-weighted imaging) and altered metabolites detected by magnetic resonance spectroscopic imaging (MRSI) [3, 4].

The main metabolites in the prostate gland are citrate (a marker of benign tissue), creatinine (insignificant for diagnosis, but difficult to resolve from choline), and choline (a marker of malignant tissue). Within a normal prostate gland, citrate levels are typically higher than other metabolites because the high concentration of intracellular zinc inhibits the citric acid cycle, leading to accumulation of citric acid in the normal prostate cells. Because of the change in this metabolic pathway, citric acid does not accumulate in the PCa cells; instead, citrate levels are drastically reduced in favour of an abnormal increase in choline [5].

In qualitative MRSI analysis, the peak heights of citrate and choline are visually compared, while in the quantitative analysis the peak integrals of all metabolites are estimated by means of the choline-plus-creatine/citrate ratio (CC/C). Cancer in the peripheral and transitional zones should show, in at least two adjacent voxels, a CC/C ratio >2 and 3 standard deviations above the mean ratio, respectively [6-10].

Among the imaging techniques used during the follow-up of patients undergoing hormone deprivation therapy and/or external beam radiation therapy (EBRT), T2-weighted MRI is of limited diagnostic value because the diffuse reduction of signal intensity on T2-weighted images (caused by glandular atrophy and fibrosis secondary to treatment) makes it difficult to differentiate the tumour from the normal surrounding parenchyma, as both of which appear hypointense on T2-weighted images [11]. 1H-MRSI improves the ability of MRI to monitor PCa remission or recurrence after treatment [11-13]. MRSI may verify successful radiation treatment by documenting the achievement of metabolic atrophy (MA), defined as a spectrum that does not contain significant peaks of metabolites.

Radiation therapy, both EBRT and brachytherapy, is a valid alternative to surgery (radical retropubic prostatectomy) in patients with low- to intermediate-risk PCa and a long life expectancy [14]. Currently, in assessing the effectiveness of treatment, the most widely used method is measurement of serum PSA, which is considered to be quite reliable and economical for evaluating disease progression [15]. Nevertheless, it is true that in patients who have undergone radical prostatectomy, PSA values reach their nadir quite soon, becoming undetectable within 3 or 4 weeks, but this is not the case if radiation therapy is chosen as a therapeutic tool. In fact, from the end of radiotherapy, PSA values fluctuate over time and nadir may be reached even after 12–18 months [16, 17].

The aim of the present study was to correlate the results of three-dimensional MRSI at 3 T with PSA levels in patients with localized low- to intermediate-risk PCa treated with EBRT to determine whether MRSI follow-up has advantages compared with serum PSA level.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Patient Population

This prospective study was approved by our institutional ethics committee, and all patients gave written informed consent.

From January 2010 to April 2012, 50 male patients (age range 65–83 years) with localized low- to intermediate-risk PCa of the peripheral zone were referred to our institution for follow-up diagnostic imaging before and after EBRT. Patients were included if they had: a histological diagnosis of PCa; PSA ≤20 ng/mL; clinical stage < T3; absence of detectable abdomino-pelvic disease at CT examination; and negative bone scintigraphy for secondary disease. Exclusion criteria were: patient history of radical prostatectomy and/or cryoablation and/or systemic chemotherapy; previous radiation therapy in the pelvic region; previous hormone deprivation therapy; and contraindications to endocoil (which is required to attain optimum MRSI execution).

Of the selected patients in the present study, 14 out of 50 (28%) had a clinical stage of cT2a, 18 (36%) had cT2b, and 18 (36%) had cT2c. Gleason scores were as follows: four patients (8%) had a score of 5 (2 + 3), 18 patients (36%) a score of 6 (3 + 3), 19 patients (38%) a score of 7 (4 + 3) and nine (18%) a score of 7 (3 + 4).

A blood sample was taken from all patients for the measurement of PSA before the radiation treatment (baseline) and subsequently after EBRT treatment at 3, 6, 12, 18 and 24 months; at baseline the mean (range) PSA was 8.05 (4.7–20) ng/mL. At baseline they also underwent an MRI examination, assessing the entire prostate gland. Evaluation of response to therapy was carried out using three-dimensional MRSI in which the metabolic modification in the lesion diagnosed before treatment was assessed, taking into account the CC/C ratio in at least four consecutive voxels.

Radiation Therapy Protocol

All patients underwent EBRT targeted to the prostate gland and to the seminal vesicles, with an intensity-modulated radiation therapy step-and-shoot technique, using an Oncor Siemens linear accelerator (Siemens Medical Solutions, Erlangen, Germany). The radiation dose delivered was 76 Gy, 2 Gy per daily fraction, five times per week.

MRI Equipment and Image Acquisition Protocol

All examinations were performed on a high-field 3-T MRI Magnetom Verio (Siemens Medical Solutions), equipped with a phased array surface coil (Body Matrix; Siemens Medical Solutions) and an endorectal coil (e-Coil; Medrad, Pittsburgh, PA, USA), filled with 70–90 mL of air on the basis of patient tolerance. For each examination, morphological T2-weighted images and spectroscopic images were acquired.

Morphological images of the prostate gland were obtained using T2-weighted turbo spin-echo sequences on sagittal, axial and coronal plans with the following parameters: echo time = 110 ms, ASSET Factor (array spatial sensitivity encoding technique) = 4, repetition time = 8500 ms, flip angle = 130°, field of view = 180, true matrix 512 × 512, averages = 3, slice thickness 3 mm).

Spectroscopic study was performed with a three-dimensional multivoxel CSI sequence with a spectral/spatial pulse optimized for quantitative metabolites detection and in particular choline, creatine and citrate (field of view: 60 × 60 × 60 mm; repetition time: 550 ms, echo time: 145 ms, flip angle: 65°; interpolation: 16; vector size: 512, acquisition time 7.32 min, delta frequency: −1.80 ppm; average 5; isotropic voxel 0. 25 × 0.25 × 0.25 cm).

Post-Processing MRI and Image Interpretation

The images were evaluated on an off-line dedicated workstation (Leonardo; Siemens Medical Solutions). Two radiologists, specialized in genitourinary imaging (V.P and F.B., with 15 and 4 years' experience, respectively), blinded to the serum PSA levels before and after radiation therapy, evaluated the images independently and blindly. Disagreement between readers was resolved by consensus.

The radiologists evaluated the spectra after baseline correction and automated frequency shifting to optimize the alignment of statistically significant peaks (signal-to-noise ratio >5:1) in the spectrum with the expected locations of choline, creatine, citrate and residual water resonances. Subsequently, a zero-order phase was applied to generate an upright and symmetric water resonance, and metabolite resonances were baseline-corrected using local nonlinear fitting to the non-peak regions of the spectra. After the evaluation of each MRSI study quality, spectra were analysed with a quantification algorithm that provides an estimate of metabolite concentrations in arbitrary units. The algorithm fits model resonances, based on a combination of Gaussians and Lorentzians, to the preprocessed spectrum. Model resonances are built with a set of a priori parameters, chosen to reproduce the resonances of interest. Choline, creatine and citrate were included in the fit, modelled respectively as a single resonance at 3.2 ppm, a single resonance at 3.0 ppm, and a multiplet around 2.6 ppm. Metabolite resonance areas were obtained as the area subtended by the line shape fitted to each metabolite.

Spectra were superimposed on the axial high-resolution T2-weighted fast spin echo images and the corresponding spectral arrays were plotted. Voxel data analysis was always performed at the apex, middle gland and basal region of the peripheral zone in both prostate lobes, with special attention to the site of original tumour. When necessary, the position of the spectral grid was retrospectively changed to better include the region of interest. In qualitative analysis, the peak heights of citrate and choline were visually compared. In quantitative analysis, the peak integrals of all metabolites were estimated by means of the CC/C ratio using dedicated software which provided maps of CC/C ratio overlapped with T2-weighted images. The greatest concern when assessing superimposed axial T2-weighted images with the grid of CC/C maps was to be sure to analyse the voxels in the right site because the overlap of the grid makes the identification of the hypointense tumour focus difficult.

A threshold of 0.8 to distinguish between residual/recurrence disease (CC/C >0.8) and tissue responsive to therapy (CC/C < of 0.8) was selected. In the latter case, if the value was between 0.8 and 0.2 it was considered to be a partial response, if it was <0.2 it was considered to be a complete response to therapy (MA).

According to the literature [2], the threshold for definitely benign and malignant tissues in the peripheral zone is a CC/C ratio of <0.44 and >0.86, respectively. The post-processed CC/C maps provided by our dedicated software calculated automatically up to the first decimal number, therefore 0.8 was set as the threshold above which to consider the tissue residual disease/recurrence. After radiation therapy, the metabolite levels are dramatically reduced on MRSI and successful treatment is characterized by a lack of metabolic activity (i.e. MA); therefore, MA is reached when the CC/C ratio tends to zero. In the present study, we arbitrarily chose a threshold of 0.2, below which we considered the response to radiation treatment to be complete and therefore MA to have been achieved.

Approximately 15% of voxels were discarded because they were partially outside the prostatic capsule. Such voxels could be affected by a contamination of spectra by lipid signal surrounding the prostate from periprostatic fat tissue or rectal wall. The suspicious pathological areas detected on MRI before radiation treatment were considered to be tumour zones if they corresponded to the sites of positive biopsies. In the 50 patients examined, 75 suspicious areas were depicted for a total of 61 ascertained tumour foci. Tumour size before EBRT was estimated on T2-weighted imaging, taking into account the voxels with an altered metabolic ratio within the hypointense zone: the parts of the hypointense area with no altered voxels were not considered to have tumour involvement.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

At the end of the follow-up period, the patients were divided into four groups according to different MRSI patterns which represented disease response to radiation treatment. A total of 13 patients (27%) completely responded to therapy, reaching MA (CC/C ratio <0.2) at the beginning of the follow-up (Group 1). In all patients in this group, MA was achieved before reaching PSA nadir (reached in every case within 6 months). At the subsequent follow-ups (12, 18 and 24 months) all the patients maintained MA and none had a biochemical relapse (PSA nadir + 2 ng/mL) by the end of the follow-up.

In the early stages of the follow-up (3 and 6 months), 35 patients (70%) had a fluctuating PSA over time and a partial response to therapy, as shown by voxels in the regions of interest with a CC/C ratio never <0.2 but always <0.8 (values compatible with a tendency to response to therapy). Of these, 30 patients (Group 2) reached MA at 12 months and maintained this at 18 and 24 months (Figs 1, 2); none of these patients had a biochemical relapse.

figure

Figure 1. A 75-year-old man with cT2b PCa of the peripheral zone. (A) Axial T2-weighted images before EBRT showing a hypointense focus on the right peri-apical zone corresponding to cancerous lesion. MRSI showed a peak of choline, with a CC/C ratio >1; PSA = 9.7 ng/mL. (B) Axial T2-weighted images performed 3 months after EBRT, where the hypointense focus is no longer recognizable. The MRSI showed a lower choline peak with a CC/C ratio of 0.6, indicative of tendency of response to therapy; PSA = 1.8 ng/mL. (C) 12 months after radiation treatment MRSI showed no peak in choline with a CC/C ratio <0.1 (MA), indicative of response to treatment; PSA = 2.1 ng/mL. (D) 24 months after EBRT, MRSI continued to show MA; PSA = 2.5 ng/mL. Ci, citrate; Cho, choline; Cr, creatinine.

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figure

Figure 2. A 69-year-old patient with cT2a PCa of the peripheral zone. (A) Axial T2-weighted images before EBRT highlight an hypointense focus on the right basal zone (arrow). MRSI shows a peak in choline, with a CC/C ratio >1; PSA = 13.7 ng/mL. (B) Axial T2-weighted images performed 3 months after EBRT, where the hypointense zone is no longer recognizable. The MRSI shows a lower choline peak with a CC/C ratio of 0.6, indicative of tendency of response to therapy; PSA = 3.3 ng/mL. (C) 12 months after radiation treatment, MRSI patterns consistent with MA were found (CC/C ratio <0.2); PSA = 3.1 ng/mL. Ci, citrate; Cho, choline; Cr, creatinine.

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Five patients (Group 3) developed a recurrence according to MRSI patterns, as shown by voxels in the zones of interest with a CC/C ratio >0.8 at 12 months (Figs 3, 4). Three of these patients had a biochemical relapse at 18 months, and the other two at 24 months.

figure

Figure 3. A 72-year-old man with cT2c PCa of the peripheral zone. (A) Axial T2-weighted images before EBRT showing a hypointense focus on the right posterior zone at the third middle gland. MRSI shows a peak of choline, with a CC/C ratio >of 1; PSA = 12.4 ng/mL. (B) Axial T2-weighted images performed 6 months after EBRT, where the hypointense focus is no longer recognizable. The MRSI shows a lower choline peak with a CC/C ratio of 0.5, indicative of tendency of response to therapy; PSA = 2.5 ng/mL. (C) 12 months after radiation treatment, T2-weighted images show a little gradient hypointense focus in the same zone of cancerous lesion detected before EBRT, and MRSI shows a peak of choline, with a CC/C ratio of >1. These patterns were suggestive of a recurrence; PSA = 4.1 ng/mL. Ci, citrate; Cho, choline; Cr, creatinine.

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figure

Figure 4. A 76-year-old man with cT2c PCa of the peripheral zone. (A) Axial T2-weighted images before EBRT show a hypointense zone on the right posterior zone at the third middle gland. MRSI shows a peak of choline, with a CC/C ratio >0.9; PSA = 15.2 ng/mL. (B) Axial T2-weighted images performed 6 months after EBRT, where the hypointense focus is not well depicted. The MRSI shows a lower choline peak with a CC/C ratio of ∼0.3, indicative of tendency of response to therapy; PSA = 2.9 ng/mL. (C) 12 months after radiation treatment, T2-weighted images show a little hypointense focus in the same zone of cancerous lesion detected before EBRT (arrowhead), and MRSI shows a peak of choline, with a CC/C >1. These patterns were suggestive of a recurrence; PSA = 3.8 ng/mL. Ci, citrate; Cho, choline; Cr, creatinine.

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Two patients (3%) were non-responders (Group 4). These patients did not respond to the treatment, showing metabolic patterns of persistent disease from 3 months (voxels in the lesion showing a CC/C ratio >0.8); one patient had biochemical relapse at 6 months and the other at 12 months.

The patients who experienced a biochemical relapse were treated with hormone deprivation therapy and were excluded from the MRI follow-up study. To ensure that the location of the MRSI abnormality was the only site of persistent disease/recurrence, a choline positron emission tomography/CT examination was performed. No distant metastases were found.

After 24 months all the patients enrolled in the study continued to be followed up with measurement of PSA serum level (median follow-up: 3 years and 4 months; range: 3 years and 3 months to 3 years and 6 months) and no biochemical relapse was found.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Evaluation of PSA serum level after radiotherapy has a less defined role than it does after surgery, because prostate tissue remains in place during and after radiation treatment. PSA variations are linked to irradiated tissue vitality and functionality. The current standard definition of recurrent and/or persistent disease after radiotherapy is a PSA level >2.0 ng/mL above the nadir value [14]; however, no pattern of PSA kinetics after radiation therapy has conclusively differentiated between local and distant failure [18]. There is therefore a need for new techniques that can provide morphological and functional information for monitoring patients with PCa after radiotherapy.

At present, multiparametric MRI plays a major role in the study of both PCa [19] and recurrences [20, 21], having been shown to be superior to positron emission tomography/CT with [18F]-choline [22].

Cellular changes in PCa resulting from radiotherapy can be non-invasively detected by diffusion-weighted imaging. Changes in the apparent diffusion coefficient (ADC) values after radiotherapy result from an effective treatment, which causes both cell lysis and an increase in the proportion of total extracellular fluid because of a corresponding decrease in cell size or number; this leads to an increase in ADC values [23]. By contrast, a decrease in ADC values reflects decreased free water movement caused by an increase in total cell size or number [24, 25]. After radiation therapy, a decrease in ADC values may occur because of fibrosis as well as cancer progression caused by increased number of cancer cells. Thus diffusion-weighted imaging has great potential for the measurement of treatment response in PCa, but it is not so reliable in detecting residual tumour or recurrence [23, 26, 27]. MRSI refines and enriches MRI of the prostate gland, allowing a more complete assessment of the damage that can be found in this organ [28, 29]. MRSI patterns in genitourinary radiology could be used as biomarkers that could indicate a need to change the treatment plan and assess the response to therapy [30, 31]. 1H-MRSI allows the analysis of the prostate in a three-dimensional way, thanks to the placement of grids which divide the gland into 0.25-mm cubic voxels. Within each voxel it is possible to calculate the peak value of different metabolites (choline, creatine, citrate and polyamines). According to the literature, the ratio between various metabolites must be altered for assessing pathological tissue in a given voxel. The peak area CC/C ratio is the considered ratio, and its reference values in the peripheral zones are: definitely malignant tissue >0.86; probably malignant tissue 0.72–0.86; possible malignant tissue 0.58–0.72; probably benign tissue 0.44–0.58; and definitely benign tissue <0.44 [2]. Radiotherapy induces a decrease in the peak values of all metabolites, starting from citrate, which is produced by healthy cells which go first into apoptosis, followed by a decrease in choline and creatine values, which are tumour markers; the final step is MA, where metabolite values are almost undetectable (CC/C ratio tending to 0).

The aim of the present study was to correlate the results of three-dimensional MRSI at 3 T with PSA levels in patients with localized low- to intermediate-risk PCa treated with EBRT to assess if MRSI follow-up has advantages compared with PSA serum level.

The effect of radiation treatment was evaluated according to a quantitative approach by calculating the CC/C ratio in the voxels of tumour zones; this assessment was achieved by means of dedicated software which provided maps of CC/C ratios overlapped with T2-weighted images. Two radiologists evaluated independently and blindly MR images with an agreement in 59/61 lesions (concordance rate 97%). Agreement was reached between the two readers after discussion in the remaining two cases.

Although MRSI is highly specific and reasonably sensitive in detecting tumour areas, false-negatives can occur. In the present study, the target lesions selected to be monitored after radiation treatment were the parts of the hypointense zones, corresponding to the sites of positive biopsies, where there were voxels of altered metabolic ratio; the parts of the hypointense areas with no altered voxels were not considered to have tumour involvement.

During the follow-up we found that none of the patients who reached so-called MA (86%) ever had a biochemical relapse, and the patients who had an MRSI pattern compatible with recurrence or persistent disease (14%) subsequently had PSA serum levels suggestive of relapse.

Patients can have ‘bounces’ in PSA values after EBRT, usually during the first 2 years after treatment, and a transient rise in serum PSA level could be misdiagnosed as biochemical relapse. In the present study, all the patients who had a MRSI pattern compatible with recurrence or persistent disease and subsequently experienced a biochemical relapse, had a PSA rising persistently over time, which makes the possibility of a bounce less likely.

We believe that the follow-up methods used for the patients with PCa treated with radiotherapy included in the present study are reproducible, and that the results are very promising. Nevertheless, it would be appropriate to compare the results with those of other prospective studies to confirm the potential of MRSI in monitoring PCa treated by radiation treatment.

The presence of reduced metabolic activity that is detectable even before the reaching of the minimum and stable PSA value can be a reliable indicator of response to therapy. In addition, the finding of areas within the prostate characterized by a pathological metabolism may be indicative of a partial response to therapy and can aid in the choice of salvage therapies.

The most important benefit could be the possibility to recognize well in advance patients who initially show a partial response to therapy and then develop a disease recurrence.

The present data showed that, during a 2-year follow-up, all patients with MRSI patterns indicative of progressive disease subsequently developed biochemical relapse. According to our experience MRSI can demonstrate PCa recurrence or residual disease before the biochemical relapse occurs. This may lead to the possibility of early salvage local therapy, and the chance for cure.

In conclusion, 1H-MRSI has proved to be a useful tool in monitoring patients treated with EBRT. The outcomes of the present study show that the predictive ability of MRSI has a greater potential than PSA serum level in the monitoring of patients after EBRT, because MRSI anticipates the PSA nadir and especially the biochemical relapse; however, the present data require confirmation in a larger number of patients with longer follow-up.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
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Abbreviations
MRSI

magnetic resonance spectroscopic imaging

PCa

prostate cancer

MA

metabolic atrophy

CC/C

choline-plus-creatine/citrate

EBRT

external beam radiation therapy

ADC

apparent diffusion coefficient