1.1.

Patients and Methods

The study was submitted to and approved by the Joint University College London, University College London Hospitals Foundation Trust (UCLH) Committee on the Ethics of Human Research. Patients having high dose rate brachytherapy under the care of Dr. Heather Payne at University College London Hospitals Trust were approached to take part in the study.

4.1.

Validation of the optical technique

This technique was validated using an intralipid and dye phantom, which was designed to have similar properties to previously published values for prostate tissue (based on Lees’ data). [One liter of phantom was composed of 50 ml 20% intralipid, 0.5 ml dye (ICI 5109564, 5% solution) with the balance being water, giving an effective attenuation coefficient (μ_eff) of 0.173 mm⁻¹ at 763 nm. We gratefully acknowledge the help of Professor Hebden, Department of Medical Physics, UCL in undertaking this validation.]

The setup was validated using a container filled with the phantom, over which a custom-made template with 5-mm spaced holes was fitted (Fig. 3). The delivery needle was inserted into the phantom via a template hole, and the detector needles were positioned at various distances from the delivery needle. The cylindrical diffuser was positioned in a mid position in the phantom, and the detector was then withdrawn along the detector needle in 6 mm steps, which would correspond with a reading at every second CT slice in the clinical part of the study. Readings were taken of light intensity at each position.

5.1.

Validation of the technique using an optical phantom

Figure 4 shows the variation in fluence as the detector is moved in relation to the light delivery needle. Each line corresponds to the fluence readings along one nearby needle; the radial distance of the detector needle from the diffuser needle is shown in the legend. The fluence reduces with an increasing distance from the source, and the maximum fluence is recorded at the midpoint of the diffuser, for all needles except one (that at a 7 mm radial distance from the diffuser).

Fig. 4

Graph showing variation of light intensity with distance for a 2-cm cylindrical diffuser within a lipid phantom.

The graph shown in Fig. 5 is plotted from fluence measurements taken at the midpoint of the diffuser at four different radial distances, corresponding to the maximum fluence in four different needles. The position of the measurements is 33 mm from the bottom of the glass container, where the midpoint of the diffuser is expected to be.

Fig. 5

Plot of ln (fluence x √distance) versus radial distance from the midpoint of the diffuser (at midpoint of diffuser on Fig. 4).

The slope of this graph gives a value for μ_eff of 0.154. The expected value from the phantom recipe was 0.173. An experimental value within 11% of the predicted value is an acceptable experimental error for this kind of phantom. In the next section it can be seen that this discrepancy is small compared to the patient to patient or even the intra-prostatic variation in optical properties in individual patients.

6.1.

Fluence readings along the detector needles

The figures in this section show the variation in fluence along each detector needle for patient F, who had the most readings taken. Figure 6 shows the variation in fluence along four different needles at different distances from source at template position c1 (shown as a red bar underneath the plots). This graph looks similar to those obtained in the phantom study, with peak fluence detected by all detectors at the mid point of the source and greater fluence recorded in needles closer to the delivery fiber. However, not all of the sources showed fluence curves which were as predictable as those seen for the phantom.

Fig. 6

Fluence readings along 4 different detectors as the detector is pulled back along needle (Patient F, source c1).

Jumps in readings were quite common, and, as mentioned earlier, we immediately repeated these measurements whenever this was observed. Nevertheless, it can be seen that jumps were still visible, suggesting that it is not an experimental artifact.

For source d1 (Fig. 7) it can be seen that the maximum fluence is seen at different points along the diffuser, for two of the detector needles. This could be due to movement of the light delivery fibre between measurements made along one needle and measurements made along the next; also, however, it could be due to movement of the needle in which the light detector was placed, between the CT scan and the optical study. Another explanation would be that there was something (e.g., calcification) which deflected the light in one direction, giving a true higher reading at one position compared to another.

Fig. 7

Fluence readings as detector is pulled back along needle (Patient F, source d1).

In addition, the needles were not always exactly parallel. This is reflected in the range of distances given in the legend for some light detector needles, such as source B1.5 (Fig. 8).

Fig. 8

Fluence readings as detector pulled back along needle (Patient F, source B1.5).

As the readings were recorded manually we were able to check them at the time, and those that are seen here are those that, if they did not follow an expected pattern, were rechecked and found to be the same on repeat testing. Therefore, the variation in light intensity seen here is a true reflection of that in the prostate at the time, within the limitations imposed by the needle positions, which were chosen for brachytherapy rather than for the optical study. This means that sometimes a fiber further away from the light delivery fiber will have higher fluence readings than one close to the needle.

6.1.1.

Effective attenuation coefficient and penetration depth

The set of the plots used to calculate the μ_eff, and hence the penetration depth (pd) for patient F is shown in Fig. 9. Each graph corresponds to one source position. The data points on the graph represent readings taken from needles at different radial distances from the source, using the readings taken closest to the midpoint of the diffuser fiber.

Fig. 9

Effective attenuation coefficient graphs for patient F.

The gradient of each graph is the effective attenuation coefficient. The letters refer to the template position of the source. The penetration depth is the inverse of the effective attenuation coefficient.

Figure 10 shows the penetration depth schematically, for patients A, B, E, and F. The drawing shows the brachytherapy template, with letter coordinates on the x axis and number coordinates on the y axis. Each template position can be identified by its letter and number coordinate, e.g. F1.5. An idealized prostate and urethra outline is drawn onto the template, for reference.

Fig. 10

i: Patient A penetration depth range 0.27 –1.21 cm (variability factor 4.45); ii: patient B penetration depth 0.18 – 0.72 cm; variability factor 3.96; iii: patient E penetration depth 0.28 – 3.43 cm; variability factor 12.3; iv: patient F enetration depth 0.14 – 0.38 cm; variability factor 2.81.

Each circle corresponds to one source. The centre of the circle is positioned at the template position for the source. The radius of the circle corresponds to the penetration depth, which is the inverse of the gradient of one of the graphs for that source.

Table 1 shows the μ_eff and pd (mean and range) for all patients. The variability factor was calculated for each patient as the ratio of the maximum to minimum pd. As can be seen from the table this variability factor ranged from 1.3 to 12.3 with a mean variability within an individual patient of 4.3. It seems likely that this value of 12.3 fold variation in penetration depth in 1 patient (patient E) was due to readings along one needle, and it is possible that these outlying values were artifactual error.

Fig. 11

Effect of fiber separation on absolute fluence levels.

Table 1

Effective attenuation coefficient (μeff) and penetration depth (pd) for each patient.

	No. of	No. of	No of	Mean μeff	Minimum μeff	Maximum μeff	Minimum	Maximum	Mean	Variability factor
Patient	readings	needle pairs	sources	(cm−1)	(cm−1)	(cm−1)	pd (cm)	pd (cm)	pd (cm)	(max/min pd)
A	31	31	10	1.51	0.83	3.69	0.27	1.21	0.66	4.45
B	312	54	13	2.34	1.38	5.46	0.18	0.724	0.43	3.96
C	90	10	2	1.75	1.53	2.03	0.49	0.655	0.57	1.33
D	116	21	5	1.81	1.20	3.38	0.30	0.835	0.55	2.82
E	87	11	4	0.78	0.29	3.57	0.28	0.343	1.28	12.3
F	286	29	7	4.36	2.63	7.41	0.14	0.379	0.23	2.81
G	68	9	3	2.96	1.68	5.43	0.18	0.596	0.34	3.24
H	87	14	4	2.06	0.95	4.65	0.22	1.05	0.49	4.87
Mean	134	22.3	6	1.76	0.91	3.89	0.26	1.11	0.57	4.32

7.1.

Methodological Limitations

It can be seen from Fig. 4 which shows data from the phantom work that one of the detectors in the series (that at a 7 mm radial distance from the diffuser) showed an apparent peak of light intensity away from the midpoint of the diffuser. Although this may have been due to a difference in detected intensity at that point it is also possible that this was due to movement of the diffuser or detector from their intended positions. As this happened in the phantom it is also possible that this could have happened in the patient work, giving rise to error in our calculations.

Accurate measurement of the distances between the needles is required to give accurate estimates of the optical properties of the prostate. Zhu and colleagues presume a distance between needles based on perfect alignment of the needles with the template.⁵ Thus, measurement of the actual distances using CT slices at 6 mm intervals, as done in our study, should represent an improvement on the technique used by Zhu. However, the situation is complicated as the prostate swells following needle insertion, and the light fluence measurements were made 1–2 h after the CT scan, which was itself 1–2 h after the needles were inserted.

In order to overcome this problem, the light measurements could be made in the CT scanning room (which would be impractical as another patient would require the CT scanner), or measurements could be taken whilst the patient was under general anaesthetic, with needle separation measurements made on ultrasound. However, the idea of doing the study under anaesthetic was rejected on ethical grounds, as it would increase the total anaesthetic time, without benefit to the patient.

All the patients studied had had treatment with hormone therapy prior to brachytherapy. The effect of hormone treatment on the optical properties of the prostate in a human prostate cancer patient group is not known. However, as the prostate reduces in size, and, on needle insertion often feels tough in comparison to nonhormone treated prostate, it is certainly possible that the optical properties may change. Although the effect of hormone treatment limits the relevance of this study to the patients we have treated with PDT, it is possible that neoadjuvant hormone therapy may be considered in the PDT setting as well as the radiotherapy setting, and so we deemed it worthwhile to study this patient group. Because all men had had hormone therapy for at least 4 months prior to brachytherapy, it was not possible to assess for a difference between treatments of different duration.

The aim of our study was not to develop an optimal model of light fluence in tissues but to see whether dosimetry planning using optical measurements made intra-operatively could be used as the basis for dose planning. We therefore used a simple method for calculation of penetration depth, the same technique has been used by a number of other investigators however, Zhu used a more complex method of calculating penetration depth and noted similar variation to that seen in this study.⁵

Zhu also describes the use of a motorised probe to withdraw the detector within the needle, and software to record the optical readings, allowing many more readings to be taken than with our manual method. The similarity of our results would suggest that there may be little difference between the two methods.

Human prostate is composed of a number of different tissue types, including malignant and benign tissue, calcification, cysts and adenomas. The heterogeneity of prostate tissue is well demonstrated on dynamic contrast enhanced MRI. As this study used CT rather than MRI, it was not possible to determine whether the variation could be correlated with the different tissue types. Also, as we measured the penetration depth over relatively large prostate volumes, which overlapped, it would have been difficult to correlate the results with a particular tissue type. If both delivery and detector fibre were contained within the same open ended needle (in a technique similar to that used by Pantelides, Whitehurst, and Lee) and these needle positions were captured on MRI, then it may have been possible to correlate the tissue type and penetration depth. We could not have done this, however, as the patients already had closed ended needles in situ.

It is thought that bleeding around the needles could interfere with light distribution in the prostate. It is likely that his is a greater problem when using a shorter wavelength, such as the 630 nm used in other studies, where the specific extinction coefficient is 4.2 cm⁻¹ mmole⁻¹. At the longer wavelength of 763 nm used in this work, haemoglobin has a specific extinction coefficient of 1.6 cm⁻¹ mmole⁻¹ (Ref. 15) so the possible attenuating effect of blood pooling around the plastic needles should be less than that seen at 630 nm. As we used CT images to assess the prostate difference it was not possible to detect bleeding, and hence to assess whether this directly affected the variability that we recorded. However, if the study was carried out using MRI, where blood is seen clearly on T1 weighted images, it would be possible to directly measure this.

In this study we have not determined conclusively whether the variability that we have shown is due to the prostate tissue itself, or bleeding around the needles, or indeed the equipment used. However, as can be seen from the discussion of the equipment the known variability of emission is around ±3% over the central position of the diffuser where the optical properties were calculated from, and that the detector variability is within the order of ±10%. The variability in calculated optical properties that we recorded was much greater than this, and so it is likely that this is either due to prostate variability or bleeding around the needles. However, the object of this study was to see if it would be useful to calculate optical properties using data which could be collected during clinical prostate PDT; in this situation it would not be possible to eliminate, or assess, bleeding around the needles. So, whatever the cause of the variability we postulate that this would also occur in the clinical prostate PDT setting. It may be that the way to overcome this is to give light doses well above the threshold required, so that the variability can be compensated for.

7.2.

Comparison of Data to Other Studies

The closest results to those of this study are those reported by Zhu using multiple measurements prior to light delivery for PDT using motexafin lutetium.⁵ Zhu used the wavelength (732 nm) closest to that which we used, and, like us, also took multiple measurements throughout the prostate. He reports a similar range of values for penetration depth, with similar variability to our data. The large variability, in comparison to work done by Lee and colleagues may well be due to intrinsic variability in the optical properties of prostate tissue, which is detected by the larger number of measurements taken. The mean values for a range of studies are shown in Table 2, with data from this study also included.

Table 2

Comparison of μeff and pd in different studies.

Svensson and colleagues from Lund report variation between values derived using the diffusion approximation, and the novel White Monte Carlo approach that they use ^{7, 16, 17} The fibre separation distances used in this work were much greater than those that we used, and would not be expected to be able to detect a variation in optical properties at smaller distances.