Design of a rectal probe for diffuse optical spectroscopy imaging for chemotherapy and radiotherapy monitoring

Diffuse optical spectroscopy imaging (DOSI) has shown great potential for the early detection of non-responding tumors during neoadjuvant chemotherapy in breast cancer, already one day after therapy starts. Patients with rectal cancer receive similar chemotherapy treatment. The rectum geometry and tissue properties of healthy and tumor tissue in the rectum and the requirement of surface contact impose constraints on the probe design. In this work we present the design of a DOSI probe with the aim of early chemotherapy/radiotherapy effectiveness detection in rectal tumors. We show using Monte Carlo simulations and phantom measurements that the colon tissue can be characterized reliably using a source-detector separation in the order of 10 mm. We present a design and rapid prototype of a probe for DOSI measurements that can be mounted on a standard laparoscope and that fits through a standard rectoscope. Using predominantly clinically approved components we aim at fast clinical translation.


INTRODUCTION
Rectal cancer is characterized by a low 5-year survival rate, until recently even lower than 50% [1]. To increase survival, different therapies are combined, typically chemotherapy and radiation therapy, often followed by surgery. However, chemotherapy and radiation often (up to 30%) do not reach a pathologically complete response (no vital tumor cells left) or some patients do not respond at all, particularly to chemotherapy. These response variations require the monitoring of tumor response during therapy.
To measure the tumor response in early therapy stages, functional imaging, e.g. of tumor metabolism changes, is preferred over structural imaging which only measures secondary therapy effects. Apart from nuclear modalities, perfusion based magnetic resonance imaging (MRI) and computed X-ray tomography have been used for functional tumor imaging. All these methods, however, have drawbacks that prevent frequent monitoring, particularly injections of radiotracers or contrast agents and/or ionizing radiation.
Diffuse optical spectroscopy is a promising modality that does not suffer from these drawbacks. Here, inherent optical tissue contrast is used to, typically, measure blood content and oxygenation as well as water and lipid concentrations [2][3][4]. By measuring in the near-infrared (NIR), tissue optical properties can be determined up to a few centimeters deep. In chemotherapy monitoring of the breast this modality has shown promising results [3,5]. Particularly promising is Diffuse Optical Spectroscopy Imaging [4], which has shown in pilot studies to allow tumor response prediction already one day after the start of chemotherapy [6]. However, diffuse optical spectroscopy measurements require the measurement probe to touch the tissue under investigation to prevent light reflections at the air-tissue boundary. When measuring tumors close to the outside skin (as in breast), probe size and geometry are relatively unrestricted. Measuring in the rectum poses additional geometric and accessibility challenges:

1.
Measurements have to take place in a confined space. This limits the probe size and thereby also significantly changes measurement characteristics.

2.
The colon wall is relatively thin (~2.5 mm) compared to the penetration depth of NIR light. The properties of deeper tissue are uncertain and may vary, thereby increasing measurement uncertainty.

3.
No direct vision is available for the operator. This complicates measuring at the correct location and with good tissue contact.

4.
The probe should be safe for internal use and easy to clean.
These challenges have been partly addressed in [7], but the short distances between source and detector fibers (0-4 mm), restrict measurements to (close to) the tissue surface.
In this work we perform a feasibility study to the application of diffuse optical spectroscopy imaging (DOSI) in the rectum. We address the challenges above by designing a rectum probe that can be mounted on a standard 10 mm diameter laparoscope. Expected measurement results are simulated using Monte Carlo simulations and the feasibility of measuring using a small probe is validated with phantom measurements.

Diffuse optical spectroscopy imaging
Important parameters that influence the trajectories of photons in tissue are the refractive index of the tissue n, the reduced scattering coefficient μs' and the absorption coefficient μa. While n can be considered constant (typically in the order of n=1.4), large variations exist in μs' and μa between different biological tissues. The coefficients μs' and μa are wavelength dependent and provide intrinsic tissue contrast ( Figure 2). DOSI uses intensity modulated laser diodes and NIR broadband illumination to separate the μs' and μa in the complete NIR range, between 650 and 1000 nm [5,8] (Figure 1). Source and detector fibers are spatially separated, at a distance ρ. Depending on the modulation frequency, μs' and μa and ρ, the detected intensity signal is attenuated and phase-shifted with respect to the illumination source. As the modulation frequency is known, μ s ' and μ a can be solved for (See details in [8]). In strongly scattering media (μ s '>>μ a ) such as biological tissue and for large source-detector separations (ρ>>1/(μ s '+μ a )), the diffusion approximation can be used. In this work four intensity modulated laser diodes (660, 690, 785, 830 nm) are used which perform a frequency sweep between 0 and 500 MHz. The modulated signal is detected using an avalanche photo diode (APD). Wide near-infrared spectral measurements as in Figure 2 are obtained from a halogen lamp, which response is measured using a spectrometer. From this broadband signal, the scatter and absorption coefficients along the complete spectrum between 650 nm and 1000 nm are estimated by calibrating this signal using the scatter and absorption estimates at the 4 modulated wavelengths (See details in [8]).

Expected colon tissue optical properties
Healthy colon tissue consists of a layered structure with varying optical properties. As we are currently unable to measure these properties using DOSI, we have to rely on literature for scattering and absorption estimates. In the scarce literature available with in-vivo colon measurements, Zonios, et al. [9] mainly report measurements of the superficial epithelial layer. Hidović-Rowe and Claridge [10] use in-vitro measurements of absorber concentrations and wavelength independent scattering properties (scatter size, volume fraction) to determine the absorption and scattering measureme   inside sses of several centimeters. Little information about the optical properties of colon tumor tissue is available from literature. Most work has concentrated on polyp [9] or ex-vivo measurements [11]. Due to lack of in-vivo colon tumor measurements in the near-infrared we will use the optical properties as measured from breast tumor tissue [4], shown in Figure 2b,d.

Monte Carlo simulations
Frequency domain Monte Carlo simulations [12] were performed to estimate for which source-detector separation distances a sufficiently high phase shift of the modulated signal would be obtained for the separation of scattering and absorption (Section 2.1). To this end the reflectance amplitude and phase were simulated using the tissue properties for both healthy colon and tumor tissue using 10 5 photons.
To investigate which tissue layers in the healthy colon tissue mainly contribute to measured spectra, photon hitting densities (PHD) were estimated by multiplying the fluences of forward and adjoint Monte Carlo simulations [13]. Below the colon tissue layers a 20 mm inter-organ fat layer was added to prevent artifacts due to a tissue-air boundary. Histograms of PHD per tissue layer were computed to estimate the relative contribution of each tissue to the measured signal.
Monte Carlo simulations were performed for wavelengths covering the broadband spectrum: 660, 690, 780, 830, 880, 920, 960, 1000 nm. All layers were assumed to have a limited thickness, but having an infinite extent in the other two dimensions. All simulations were performed using the VirtualPhotonics toolbox (www.virtualphotonics.org).

Colon phantom
To validate the feasibility of measuring at short source-detector distances in tissues with the properties from Section 2.2, silicon phantoms were created with the properties in Table 1, where μa and μs' are the designed properties at 600 nm. The phantom mimicking healthy colon tissue was made as a homogeneous phantom. Its scatter and absorption coefficients approximated that of a (simulated) layered phantom when measured with a source-detector separation of 10 mm. The latter phantom also contained a 20 mm diameter hole to mimic the inside of the colon. The phantom optical properties were measured using DOSI with ρ∈{5,10,13} mm within the phantom cavity and with a multi-distance DOSI probe with source-detector separations at 15, 20, 28 and 35 mm at the phantom surface. The latter measurement counts as the optical properties ground truth.

Monte Carlo: phase shift
Simulated phase shifts at 500 MHz between source signal and detected signal are shown in Figure

Monte
Photon hit tumor tissu should not tissue, but separation. shown in F wavelength ρ<10 mm i the tumor f

Phanto
The optica cavity and phantom a same trend show that show that c ρ=5 mm a frequency estimates. A e Carlo: photo tting densities ue. A typical te that the visu also the auxi . Histograms t Figure 4b,c,d fo hs almost 50% is preferable in for each simula      Figure 6: (a) Colon phantom and (b) rapid prototyping fiber guide. Diagram of (c) side-and (d) front-view of rectal probe.

DISCUSSION
This feasibility study showed that DOSI measurements are possible within the constraints imposed by the rectum geometry and tissue properties. The Monte Carlo simulations showed that the required short source-detector separations are actually advantageous. Using these short distances, the unknown layer behind the colon muscularis (currently modeled as fat) has a limited contribution to the estimated tissue properties. The phantom experiments showed that measuring at these short distances (~10 mm) is very well feasible. The initial probe design showed that using a standard laparoscope a probe can be devised that fits through the channel of a standard rectum scope. The use of these standard components and the absence of any electric components inside the body significantly simplify clinical translation.
Although not shown explicitly, the used diffusion approximation for photon propagation holds for all of the source-detector distances in this work. However, the tissue properties for healthy colon are an average estimate (See also Section 3.2) that strongly depends on the user-specified source-detector separation.
A limitation of this study is the approximation of colon tumor tissue using breast tumor tissue, probably underestimating absorption. Phantom measurements showed that higher absorption can be measured reliably.
In the near future, the prototype in Figure 6b will be used for pre-clinical in-vivo colon tissue measurements in Yorkshire pigs. Subsequently, this probe will be developed into a clinically applicable device for the early detection of chemotherapy effectiveness and finally a flexible probe will be developed for measuring in the entire colon.