Monitoring Response to Treatment

Hormone ablation is the preferred treatment choice for patients with advanced disease, but is also used in patients before radiation therapy or prostatectomy. The response of patients to treatment can be assessed by digital rectal examination, by changes in serum PSA levels, TRUS and MRI (Pinault et al. 1992; SheareR et al. 1992; Chen et al. 1996; Nakashima et al. 1997; Padhani et al. 2001). Clinical evaluations and imaging studies all show significant reductions in both glandular size and tumour volume. Reductions of 10%-52% in prostate glandular volume and 20%-97% in tumour volume have been reported (Pinault et al. 1992; Shearer et al. 1992; Chen et al. 1996; Nakashima et al. 1997; Padhani et al. 2001). On MRI, the central gland decreased in signal and became more homogenous with treatment and seminal vesicle atrophy has also been noted (Secaf et al. 1991; Chen et al. 1996; Nakashima et al. 1997; Padhani et al. 2001). As a result, hormonal ablation also reduced the number of MR detectable tumours (Chen et al. 1996; Nakashima et al. 1997; Padhani et al. 2001). This occurs because the peripheral gland showed a decrease in signal intensity thus reducing tumour-peripheral gland contrast. These morphologic appearances are due to distinctive histological changes occurring in patients treated with luteinizing hormone releasing hormone analogues (LH-RHa) (Murphy et al. 1991; Smith and Murphy 1994; Civantos et al. 1996). The histological „LH-RHa effect" is characterised by a reduction in gland size and density, compression of glandular lumina and increased periglandular fibrous tissue.

Padhani et al. (2001) recently reported that decreases in transfer constant occurred in all prostatic tissues after 3-6 months of hormonal treatment; tumour, median 56%, central gland (40%) and peripheral gland (31%). A typical example is shown in Fig. 12.10. These changes may be explained by the fibrotic changes described histologically (Murphy et al. 1991; Smith and Murphy 1994; Civantos et al. 1996). Additionally, the reduction in transfer constant of prostatic tissues may be related to down-regulation of VEGF production and subsequent apoptosis of immature prostate vessels caused by androgen deprivation (see Sect. 12.2) (Bostwick 2000). However, a recent histological study by Matsushima et al. (1999) appears to contradict this view; their study showed that intratumoral microvessel density (MVD) does not appear to differ in patients treated with neoadjuvant hormonal deprivation compared to untreated patients, but they did show decreased proliferative activity and enhanced apoptosis of prostatic cancer cells.

There is poor documentation on the early vascular effects of radiotherapy as observed by DCE-MRI. Recently, Barke et al. (2003) have noted that hyper-aemia occurs soon after commencing radiotherapy evidenced by an increased permeability surface area product. This confirms the work of Harvey et al. (2001) who reported on 22 such patients evaluated by functional CT and showed that there was an acute hyperaemic response following radiotherapy to the prostate gland as early as 1-2 weeks following completion of treatment and this remained so after 6-12 weeks. We have recently evaluated 25 patients with DCE-MRI patients 2 years after completion of radiotherapy in whom there is no evidence of tumour recurrence (biochemical or histological). We observed that morphologically the gland has similar appearances to that seen after androgen deprivation, i.e. a small gland with poor zonal differentiation on T2 weighted images (Fig. 12.11). On DCE-MRI, central gland enhancement was greater than the peripheral gland and kinetic parameters were also statistically higher. A slow rising pattern of enhancement was seen in the majority in the peripheral gland but in only five patients within the central gland. Contrast medium washout was not observed in the peripheral gland and was seen in only one patient within the central gland.

New treatments for prostate cancer and obstructive BPH include pulsed high-energy focused ultrasound, cryosurgical ablation, laser ablation and transurethral thermal ablation using microwaves

Pre-treatment <- 123 days -► Post-treatment

Pre-treatment <- 123 days -► Post-treatment

Fig. 12.10. Transfer constant changes after androgen deprivation treatment. A 62-year-old man with prostate cancer (Gleason grade 3+4). Left images: Pre-treatment images (PSA=6 ng/ml), T2-weighted turbo spin-echo image and transfer constant map (maximum transfer constant=1 min-1). A low signal intensity mass in the right peripheral zone with invasion of the central gland is seen. The peripheral zone in the left side of the gland appears normal. Higher transfer constant levels are seen in the tumour and central gland (0.46 and 1.54 min-1) compared to the peripheral zone (0.17 min-1). Note that some pixels do not display colour because there was a poor fit of the multi-compartment model to the data observed. Right images: Following 123 days of androgen deprivation (PSA 1.2 ng/ml), the glandular volume has reduced by 46%. The tumour and normal peripheral zone are still visible. Transfer constant map shows a decrease in transfer constant both in the tumour and central gland (0.28 and 0.53 min-1). The peripheral zone transfer constant has also reduced to 0.07 min-1. [Images reproduced from Padhani et al. (2001) with kind permission]

Fig. 12.10. Transfer constant changes after androgen deprivation treatment. A 62-year-old man with prostate cancer (Gleason grade 3+4). Left images: Pre-treatment images (PSA=6 ng/ml), T2-weighted turbo spin-echo image and transfer constant map (maximum transfer constant=1 min-1). A low signal intensity mass in the right peripheral zone with invasion of the central gland is seen. The peripheral zone in the left side of the gland appears normal. Higher transfer constant levels are seen in the tumour and central gland (0.46 and 1.54 min-1) compared to the peripheral zone (0.17 min-1). Note that some pixels do not display colour because there was a poor fit of the multi-compartment model to the data observed. Right images: Following 123 days of androgen deprivation (PSA 1.2 ng/ml), the glandular volume has reduced by 46%. The tumour and normal peripheral zone are still visible. Transfer constant map shows a decrease in transfer constant both in the tumour and central gland (0.28 and 0.53 min-1). The peripheral zone transfer constant has also reduced to 0.07 min-1. [Images reproduced from Padhani et al. (2001) with kind permission]

(BeerlAge et al. 2000). Histopathology of prostatic xenografts has revealed intratumoral haemorrhage, disruption of tumour vasculature, and necrosis in the focus of the ultrasound field (Huber et al. 1999). Histological examination in humans has shown periurethral necrosis following laser treatments for obstructive benign prostatic hyperplasia (Boni et al. 1997). A number of studies have evaluated contrast enhanced MRI in evaluating the effectiveness of such treatments and early results indicate that reductions in enhancement (often called „perfusion defects") closely correlate with the treatment volume (Boni et al. 1997; Huber et al. 1999; Osman et al. 2000).

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