Interstitial photodynamic therapy (IPDT) provides a promising means to treat large cancerous tumors and solid organs inside the human body. The treatment outcome is dependent on the distributions of light, photosensitizer, and tissue oxygenation. We present a scheme for reconstructing the spatial distribution of a fluorescent photosensitizer. The reconstruction is based on measurements performed in the human prostate, acquired during an ongoing IPDT clinical trial, as well as in optical phantoms. We show that in an experimental setup we can quantitatively reconstruct a fluorescent inclusion in a fluorescent background. We also show reconstructions from a patient showing a heterogeneous distribution of the photosensitizer mTHPC in the human prostate. (C) 2009 Optical Society of Americ

Andersson-Engels, Stefan

Axelsson, Johan

Swartling, Johannes

English

Lund University Publications

LUND UNIVERSITYPO Box 117221 00 Lund+46 46-222 00 00In vivo photosensitizer tomography inside the human prostateAxelsson, Johan; Swartling, Johannes; Andersson-Engels, StefanPublished in:Optics Letters2009Link to publicationCitation for published version (APA):Axelsson, J., Swartling, J., & Andersson-Engels, S. (2009). In vivo photosensitizer tomography inside the humanprostate. Optics Letters, 34(3), 232-234.Total number of authors:3General rightsUnless other specific re-use rights are stated the following general rights apply:Copyright and moral rights for the publications made accessible in the public portal are retained by the authorsand/or other copyright owners and it is a condition of accessing publications that users recognise and abide by thelegal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private studyor research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portalRead more about Creative commons licenses: https://creativecommons.org/licenses/Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will removeaccess to the work immediately and investigate your claim.232 OPTICS LETTERS / Vol. 34, No. 3 / February 1, 2009In vivo photosensitizer tomography inside thehuman prostateJohan Axelsson,1,* Johannes Swartling,2 and Stefan Andersson-Engels11Department of Physics, Lund University, P.O. Box 118, SE-221 00 Lund, Sweden2SpectraCure AB, Ole Römers väg 16, SE-223 70 Lund, Sweden*Corresponding author: johan.axelsson@fysik.lth.seReceived October 7, 2008; revised November 28, 2008; accepted November 29, 2008;posted December 8, 2008 (Doc. ID 102292); published January 21, 2009Interstitial photodynamic therapy (IPDT) provides a promising means to treat large cancerous tumors andsolid organs inside the human body. The treatment outcome is dependent on the distributions of light,photosensitizer, and tissue oxygenation. We present a scheme for reconstructing the spatial distribution of afluorescent photosensitizer. The reconstruction is based on measurements performed in the human prostate,acquired during an ongoing IPDT clinical trial, as well as in optical phantoms. We show that in an experi-mental setup we can quantitatively reconstruct a fluorescent inclusion in a fluorescent background. We alsoshow reconstructions from a patient showing a heterogeneous distribution of the photosensitizer mTHPC inthe human prostate. © 2009 Optical Society of AmericaOCIS codes: 170.3880, 170.3660, 170.5180, 170.7230.Interstitital photodynamic therapy (IPDT) is a prom-ising treatment alternative or complement to radi-tion therapy of solid tumors. As of today several re-search groups have focused on treating prostatecancer using IPDT, where optical fibers are im-planted into the prostate gland [1–3]. The fibers de-liver therapeutic light, i.e., light that activates thephotosensitizing drug, resulting in the generation ofradicals. The radicals will then react with the tissueleading to necrosis. To target the entire prostategland, commonly the approach in prostate-photodynamic therapy (PDT), as well as localized re-gions, rigorous dosimetry is required.Current schemes adopt an explicit dosimetrymodel [4] and rely only on the light fluence as a mea-sure of the PDT dose [5,6]. It has been reported thatby adjusting the light dose based on pretreatmentmonitoring of the photosensitizer concentration, in-terpatient variation of the treatment outcome can bereduced [7]. The same should hold for intrapatientvariations. With knowledge also of the photosensi-tizer concentration further improvements may bepossible. Hence there is a need for methods that as-sess the spatial distribution of the photosensibledrug. Futhermore these methods form the foundationfor spatial reconstruction of the bleaching kineticsduring treatment. Potentially such methods couldrender an improved light-photosensitizer dosimetrymodel.In this Letter we present a scheme that is capableof reconstructing an estimate of the spatial distribu-tion of a photosensitizer within the human prostate.The reconstruction is based on data acquired duringour ongoing clinical trial of primary prostate cancer.The IPDT instrument operates along the scheme de-picted in Fig. 1. PDT treatment is governed by 18 op-tical fibers that are coupled through a fiber switch to18 diode lasers. The lasers emit at 652 nm matchingthe absorption peak for mTHPC, the photosensitizeremployed. During treatment the light irradiation ishalted, and a sequence of measurements is per-0146-9592/09/030232-3/$15.00 ©formed. Here each of the fibers emit light, while thesix neighboring fibers collect the transmitted andfluorescent light. Light detection is governed by a setof spectrometers. For this Letter the important mea-surable is the mTHPC fluorescence emitted as abroad peak between 710 and 730 nm following exci-tation at 652 nm. Further details about the predeces-sor to the system working along the same scheme canbe found in [8]. The main differences between thepresent system and the predecessor is the number ofavailable fibers and the operating wavelength nowoptimized for mTHPC. The currently employed do-simetry algorithm is explained in [5]. During a moni-toring sequence a total of 108 fluorescence recordingsare acquired between 54 source-detector pairs. Thefibers are positioned within the prostate gland withthe intention to maximize the light dose within theprostate while surrounding tissues are spared. Theoptimal positions are found using a random searchalgorithm [5]. The algorithm relies on the knowledgeof the three-dimensional anatomy of the prostate andsurrounding tissues, retrieved from a transrectal ul-trasound scan.The fluorophore distribution is represented by thefluorophore yield r=afr, where  is the quan-tum yield and afr is the absorption coefficient forthe fluorophore. The problem at hand is to find an es-timate of the fluorophore yield that minimizes the re-sidual between a forward model calculated for  andthe measurements. This minimization problem is ill-posed, thus regularization is incorporated. Here weemploy Tikhonov regularization so that the minimi-zation problem becomesFig. 1. (Color online) Schematic picture of the IPDTinstrument.2009 Optical Society of AmericaFebruary 1, 2009 / Vol. 34, No. 3 / OPTICS LETTERS 233 = arg min2 + L − 02. 1Here =−F, where F is the forward modelcalculated for parameter , while  denotes the mea-surable;  is the regularization parameter, and L is aregularization matrix, explained below, while 0 isthe initial estimate of the fluorophore distribution,here set to zero.The forward model employed is the diffusion equa-tion [9]. The measurable is the fluorescence measure-ment scaled with the excitation measurement, nor-mally referred to as the normalized Born ratio [10].Discretizing the geometry into elements, defined bynodes, the forward model is given byF =1Uxrs,rdn=1NNUm* rd,rnUxrs,rnVn, 2where rs,d,n denotes the coordinates for source, detec-tor, and internal node, respectively. Ux,m representsthe forward solution of the excitation light and fluo-rescent light, respectively, while Ux,m* is the adjointsolution to the forward fluorescent problem. FurtherNN is the total number of nodes, V is the elementvolume, and n is the fluorescence yield for node n. Inthis Letter the forward solutions Ux,m are retreivedusing homogeneous optical properties. The inverseproblem is solved using an iterative scheme. The pa-rameter estimate for iteration i is denoted as i. Tofind the parameter i that minimizes Eq. (1) the first-order derivative is set to zero, i.e.,  /=0. In ma-trix notation this leads to [11]= JTi − LTLi − 0 = 0. 3Here J denotes the Jacobian defined by J=F /. Us-ing a Taylor series to linearize the forward model inEq. (3), i.e., FiFi−1+Ji−i−1, the parameterupdate equation becomesi = i−1 + JTJ + LTL−1 	 JTi−1 − LTLi−1.4Calculations were performed using the NIRFAST pack-age implementing the finite element method [12].The regularization matrix follows the same schemeas presented in [11,12]. L is then a NN	NN matrixdefined by Li,j=1 if i= j, Li,j=0 if i and j are not withinthe same tissue region, and Li,j=−1/NR if i and j aredifferent but in the same region. Here NR is thenumber of nodes in this region. The specific regionsare defined through the sensitivity, i.e., Jacobian,where the sum of the Jacobian for all source-detectorpairs is first calculated through Sn=iNMJi,n. The firstregion is formed by all nodes satisfying the criterionSn /maxS0.05%, while the other region is formedby all the other nodes. The regularization parameteris chosen according to the L-curve method, where thesolution norm L is plotted versus the residualnorm F− for a wide range of regularization pa-rameters  [13]. This is effectively done using a gen-eralized singular-value decomposition of the matrixpair J ,L thoroughly described in [13].The ability of the reconstruction scheme to assess afluorophore distribution within a scattering volumewas verified employing data from an optical phantomexperiment. The phantom was made of a plastic tankfilled with Intralipid (Fresenius Kabi, 200 mg/ml)and ink (Pelican Fount India Ink, 1:100 stock solu-tion). In the plastic tank a smaller container wasplaced filled with the same bulk phantom solution de-picted in Fig. 2(d). Using a time-of-flight spectroscopysystem [14], the bulk optical properties were as-sessed to be a=0.058 mm−1 and s=0.95 mm−1 at660 nm. The laser dye Oxazine-1 was used as thefluorophore. The quantum yield for Oxazine-1 is 0.11[15]. The quantum yield was scaled to the wave-length range between 695 and 705 nm according toEq. (16) in [16]. In the larger tank the fluorophorewas mixed with the bulk solution in a concentrationretrieving a fluorophore absorption coefficient of af=3.9	10−3 mm−1. In the smaller compartment ahigher concentration was used, yielding an absorp-tion of af=6.1	10−3 mm−1. Fiber positions werebased on patient data from the clinical trial. The for-ward model was solved on a mesh made in COMSOLMULTIPHYSICS with a higher node density close to thefiber positions. The forward mesh consisted of 15,127nodes, while the inverse problem was solved on aregular grid made of 3375 nodes after interpolatingthe forward solution onto the grid.In Figs. 2(a)–2(c) the reconstructed fluorophore ab-sorption coefficient is seen. In Figs. 2(a) and 2(b) thesmaller compartment is reconstructed within 15% ofthe true absorption coefficient as seen in Fig. 2(d).The absorption coefficient in the container is lower,although it is overestimated by approximately 40%.This is an effect inherited by the region-based priorthat adds smoothing to the result, and hence the re-sult is effectively averaged within each region. Thisresults in a lower contrast between the smaller com-partment and the container. In Figs. 2(a)–2(c) it isalso seen that the fluorophore absorption is very lowoutside the prostate. This is also an effect of theFig. 2. (Color online) (a)–(c) Reconstruction results from aphantom experiment showing cross-sectional slices at z=15, 20, and 25 mm, respectively. (d) Schematic of thephantom fluorophore distribution. The fiber positions inthe xy plane are also shown.234 OPTICS LETTERS / Vol. 34, No. 3 / February 1, 2009region-based prior that is formed based on the sensi-tivity. Outside the prostate the sensitivity is low ow-ing to fiber positioning. Figure 2(c) shows a decreasedfluorescent contrast between the compartment andthe background. This is consistent with the low num-ber of optical fibers positioned deeper in the volume.Data acquired during a prostate-PDT sessionwithin the scope of our ongoing clinical trial of pri-mary localized prostate cancer were used to recon-struct the mTHPC distribution in the human pros-tate. Data were collected 96 h postdrug injection. Thereconstruction results are shown as cross-sectionalslices in Figs. 3(a)–3(c). Optical properties for the hu-man prostate were assessed using spatially resolvedmeasurements described in [5]. In Fig. 3(d) the differ-ent regions used in the region-based regularizationmatrix is seen in one cross-sectional slice. ThemTHPC distribution depicted in Figs. 3(a) and 3(b)has a slight heterogeneous appearance. The distribu-tion is smooth, which is expected owing to the region-based smoothing. The distribution is on the samescale as previously reported for another photosensi-tizer [17]. Figure 3(c) shows again a decreased con-trast owing to the limited number of fibers deeper inthe prostate, where the gland has a smaller diameter.The drug is administered 4 days prior to the treat-ment; hence it is expected that the drug has diffusedout from the blood stream yielding a smooth drug dis-tribution within the prostate.The results presented here are initial reconstruc-tions based on clinical as well as experimental data.It is seen that the fluorophore concentration isFig. 3. (Color online) (a)–(c) Reconstruction results from aclinical trial showing cross-sectional slices at z=15, 20, and25 mm, respectively. White curves mark the prostate andurethra boundaries. (d) One slice of the prostate showingthe tissue regions where 1 is normal, 2 is the prostate, andslightly overestimated. We believe that this effect is aresult of the regularization scheme adopted in thisLetter. Despite that the regularization smooths thesolution, it is still possible to demarcate a region withhigher fluorophore contrast in a three-dimensionalvolume. To improve the accuracy of the reconstruc-tion method we are investigating alternative regular-ization schemes. Currently we are adopting thisscheme to reconstruct changes in the fluorophoreconcentration in each voxel of the prostate tissue dur-ing a prostate-PDT treatment.This work was supported by SpectraCure AB.References1. K. L. Du, R. Mick, T. Busch, T. C. Zhu, J. C. Finlay, G.Yu, A. G. Yodh, S. B. Malkowicz, D. Smith, R.Whittington, D. Stripp, and S. M. Hahn, Lasers Surg.Med. 38, 427 (2006).2. C. M. Moore, T. R. Nathan, W. R. Lees, C. A. Mosse, A.Freeman, M. Emberton, and S. G. Bown, Lasers Surg.Med. 38, 356 (2006).3. R. A. Weersink, A. Bogaards, M. Gertner, S. R. H.Davidson, K. Zhang, G. Netchev, J. Trachtenberg, andB. C. Wilson, J. Photochem. Photobiol. B 79, 211(2005).4. B. C. Wilson, M. S. Patterson, and L. Lilge, LasersMed. Sci. 12, 182 (1997).5. A. Johansson, J. Axelsson, S. Andersson-Engels, and J.Swartling, Med. Phys. 34, 4309 (2007).6. M. D. Altschuler, T. C. Zhu, J. Li, and S. M. Hahn,Med. Phys. 32, 3524 (2005).7. X. D. Zhou, B. W. Pogue, B. Chen, E. Demidenko, R.Joshi, J. Hoopes, and T. Hasan, Int. J. Radiat. Oncol.Biol. Phys. 64, 1211 (2006).8. M. Soto-Thompson, A. Johansson, T. Johansson, S.Andersson-Engels, S. Svanberg, N. Bendsoe, and K.Svanberg, Appl. Opt. 44, 4023 (2005).9. S. R. Arridge, Inverse Probl. 15, R41 (1999).10. V. Ntziachristos and R. Weissleder, Opt. Lett. 26, 893(2001).11. P. K. Yalavarthy, B. W. Pogue, H. Dehghani, and K. D.Paulsen, Med. Phys. 34, 2085 (2007).12. B. A. Brooksby, “Combining near infrared tomographyand magnetic resonance imaging to improve breasttissue chromophore and scattering assessment,” Ph.D.dissertation (Dartmouth College, 2005).13. P. C. Hansen, Numer. Algorithms 6, 1 (1994).14. E. Alerstam, S. Andersson-Engels, and T. Svensson,Opt. Express 16, 10440 (2008).15. R. Sens and K. H. Drexhage, J. Lumin. 24, 709 (1981).16. J. Axelsson, J. Svensson, and S. Andersson-Engels,Opt. Express 15, 13574 (2007).17. J. C. Finlay, T. C. Zhu, A. Dimofte, D. Stripp, S. B.Malkowcz, T. M. Busch, and S. M. Hahn, Photochem.Photobiol. 82, 1270 (2006).3 is the urethra. The fiber positions in the xy plane are alsoshown.

In vivo photosensitizer tomography inside the human prostate

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In vivo photosensitizer tomography inside the human prostate

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