FOCAL PHOTODYNAMIC THERAPY METHODS

Abstract

Improved methods of treating prostate cancer by vascular-targeted photodynamic therapy, and improved methods of planning treatment, are presented using a light density index to plan and guide effective treatment.

Claims

1-32. (canceled)

33. A computer program product comprising a computer usable medium having computer readable program code embodied therein, the computer readable program code adapted to be executed by a computer to implement a method for producing a patient-specific treatment plan for photodynamic therapy of prostate cancer, the method comprising: setting the total length of illuminating fibers needed for effective therapy based upon the planned treatment volume (PTV) and a prior-determined treatment-effective light density index, LDI, threshold, wherein the treatment-effective LDI threshold is prior-determined from historical data from use of the same photosensitizing agent, and wherein the total length of illuminating fibers is calculated as the product of PTV and said prior-determined treatment-effective light density index threshold, or scalar multiple thereof.

34-35. (canceled)

36. The computer program product of claim 33, wherein the treatment-effective LDI threshold is prior-determined from historical data from use of the same photosensitizing agent, administered at the same systemic dosage.

37. The computer program product of claim 36, wherein the treatment-effective LDI threshold is prior-determined from historical data from use of the same photosensitizing agent, administered at the same systemic dosage, and same wavelength of delivered light.

38. The computer program product of claim 37, wherein the treatment-effective LDI threshold is prior-determined from historical data from use of the same photosensitizing agent, administered at the same systemic dosage, same irradiating light wavelength, and same light density.

39. An assistance method, implemented by computer, for the planning of treatment of a patient by photodynamic therapy, in which a predefined photosensitizing agent must be administered to the patient, and then subjected to illumination at a predetermined wavelength through at least one illuminating fiber designed to be introduced over a length of insertion into the treatment area, characterized in that it includes the following steps: calculating the planned treatment volume, PTV, of the treatment area; determining a treatment-effective light density index, LDI, threshold, wherein the treatment-effective LDI threshold is prior-determined from historical data from use of the same photosensitizing agent; and then setting the total length of said at least one illuminating fiber to be used for treatment based upon the planned treatment volume, PTV, and said prior-determined treatment-effective light density index threshold, wherein the total length of illuminating fiber is calculated as the product of PTV and said prior-determined treatment-effective LDI threshold or scalar multiple thereof.

40-41. (canceled)

42. The assistance method of claim 39, wherein the treatment-effective LDI threshold is prior-determined from historical data from use of the same photosensitizing agent, administered at the same systemic dosage.

43. The assistance method of claim 42, wherein the treatment-effective LDI threshold is prior-determined from historical data from use of the same photosensitizing agent, administered at the same systemic dosage, and same wavelength of delivered light.

44. The assistance method of claim 43, wherein the treatment-effective LDI threshold is prior-determined from historical data from use of the same photosensitizing agent, administered at the same systemic dosage, same irradiating light wavelength, and same light density.

Description

4. DETAILED DESCRIPTION

[0018] Using the photosensitizing agent, Palladium 3.sup.1-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13.sup.1-(2-sulfoethyl) amide (WST11; TOOKAD Soluble), we have discovered that a Light Density Index (LDI) can be calculated that predicts the efficacy of photodynamic therapy of prostate tumors. The prediction of efficacy has been validated by MRI as early as 1 week post-treatment, and further confirmed by negative biopsy at 6 months post-treatment. The LDI can be used to define a treatment-effective threshold light dose from historical data, providing a readily-calculable dose parameter that can be used in prospective treatment planning to increase likelihood of successful treatment, without adding significantly, and potentially reducing, computational complexity, while concomitantly increasing likelihood of therapeutic success.

[0019] Accordingly, in a first aspect, a method of treating prostate cancer is provided. The method comprises systemically administering a photosensitizing agent to a patient having a prostate tumor, and then activating the photosensitizing agent by delivering light of appropriate wavelength through at least one optical fiber positioned proximal to the tumor, wherein the administered light dose is at or above a prior-determined treatment-effective light density index (LDI) threshold.

[0020] LDI

[0021] The Light Density Index (LDI) is calculated as

LDI=(n)L/PTV,

where (n)L is the total length of all illuminating fibers and PTV is the planned treatment volume. In typical embodiments, the length of all illuminating fibers is measured in centimeters, and the planned treatment volume is measured in milliliters.

[0022] The patient-specific PTV used in calculating the LDI is planned using known treatment planning approaches. In some embodiments, the PTV is derived by volume reconstruction from a series of MRI images of the patient's prostate, typically a transverse series, on a plurality of which, typically on all of which, the tumor margin has been outlined. The outline of the tumor margin on sectional images is typically performed by a radiologist or surgeon, although in certain embodiments discrimination of the tumor margin is performed by image recognition software, which is typically thereafter reviewed by a radiologist or surgeon. Volume reconstruction is performed using standard digital image processing techniques and algorithms. In typical embodiments, the PTV is planned to include an additional enveloping volume to ensure that treatment is sufficient to fully include the actual tumor margin. In such embodiments, the treatment planning software typically adds the user-chosen or software-predetermined margin to each two-dimensional sectional image in which the tumor margin has been circumscribed. In some embodiments, the margin can be added after the volume reconstruction, although this computationally more complex approach is presently not preferred. In some embodiments, the PTV is calculated according to the methods described in Davidson et al., Treatment planning and dose analysis for interstitial photodynamic therapy of prostate cancer, Phys. Med. Biol. 54:2293-2313 (2009).

[0023] Treatment-Effective LDI Threshold

[0024] The treatment-effective LDI threshold is determined prior to treatment. In typical embodiments, the treatment-effective LDI threshold is prior-determined from historical clinical data.

[0025] In typical embodiments, the treatment-effective LDI threshold is determined by first correlating the magnitude of the treatment LDI for each of a series of historical patients with one or more later-observed patient-specific outcomes. The later-observed outcomes are chosen from art-accepted outcomes, including clinical outcomes, such as post-treatment survival, change in tumor stage or grade, or more typically, from radiologic and/or pathologic outcomes that are art-recognized as useful surrogates, such as evidence of tissue necrosis on post-treatment MRI, or percentage of negative biopsies post-treatment.

[0026] In some embodiments, the treatment LDI is calculated from historical data using the actual treated volume (ATV) instead of the historical prospective PTV. The ATV is usefully calculated from the area of necrosis observed on post-treatment MRI images, such as MRI images taken at 1 week post-treatment, 1 month post-treatment, 2 months post-treatment, 3 months post-treatment, and/or 6 months post-treatment. In certain embodiments, the ATV is derived by volume reconstruction from a series of post-treatment MRI images of the patient's prostate, typically a transverse series, on a plurality of which, typically on all of which, the margins of the necrotic area, or hypoperfused area, has been outlined. The outline of the necrotic or hypoperfused area on sectional images is typically performed by a radiologist or surgeon, although in certain embodiments, discrimination of the margin is performed by image recognition software, which is typically thereafter reviewed by a radiologist or surgeon. Volume reconstruction is performed using standard digital image processing techniques and algorithms.

[0027] In typical embodiments, standard statistical approaches will be applied to the correlated treatment LDI and outcome data to determine a treatment-effective threshold that provides a desired degree of statistical confidence. For example, in Example I, below, we identify a treatment-effective LDI threshold having a P value of <0.01 with respect to predicting necrosis volume on MRI at 1 week post-treatment as a percentage of the PTV, and also having a P value <0.01 with respect to the percentage of negative biopsies at 6 months post-treatment. Any chosen treatment-effective LDI threshold may provide different magnitudes of statistical significance with respect to different outcomes.

[0028] Because the treatment-effective LDI threshold may differ depending on the choice of photosensitizing agent, its systemic dosage, and the irradiating wavelength delivered locally to the prostate, the treatment-effective LDI threshold is usefully derived from historical data drawn from prior clinical use of the same photosensitizing agent to be used in the subject patient. In some embodiments, the historical data are from use of the same photosensitizing agent, administered at the same systemic dosage, to be used in the subject patient. In some embodiments, the historical data are from use of the same photosensitizing agent, administered at the same systemic dosage, and irradiated with the same wavelength to be used in the subject patient. In addition, because the treatment-effective LDI threshold may differ depending on the light density (e.g., in Joules/cm) delivered through each fiber, the treatment-effective LDI threshold is usefully derived from historical data drawn from prior clinical use of the same light density to be used in the subject patient.

[0029] The prior-determined treatment-effective LDI threshold does not require recalculation from historical data for each patient to be treated. In typical embodiments, the treatment-effective LDI threshold will be treated as a constant, typically user-entered, by treatment planning algorithms. However, it is contemplated that the treatment-effective LDI threshold will be recalculated on a periodic basis as additional historical data become available, such as the data on additional patients, and/or additional outcome data on patients included in the prior calculation. Furthermore, in certain embodiments, the treatment-effective LDI threshold will be calculated separately for defined subpopulations of historical patients, and the treatment-effective LDI threshold used for administering treatment to a given patient will be chosen based on the patient's similarity to the historical subpopulation.

[0030] Photosensitizing Agents

[0031] The efficacy of the LDI parameter to predict treatment efficacy was demonstrated using the photosensitizing agent, Palladium 3.sup.1-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13.sup.1-(2-sulfoethyl) amide (WST11; TOOKAD Soluble) as the dipotassium salt.

[0032] Thus, in a preferred embodiment of the methods of this aspect of the present invention, the photosensitizing agent is Palladium 3.sup.1-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13.sup.1-(2-sulfoethyl) amide, or a pharmaceutically acceptable salt thereof. The WST11 compound in its un-ionized form has the structure given below, in formula (Ia), in which the tetrapyrrole carbons are numbered according to standard IUPAC nomenclature:

##STR00001##

[0033] In various embodiments, pharmaceutically acceptable WST11 salts usefully include a counterion selected from monovalent and divalent alkaline and alkaline earth metal cations, such as one or more of K.sup.+, Na.sup.+, Li.sup.+, and Ca.sup.2+. In an embodiment that is at present particularly preferred, the dipotassium salt is used, as shown in Formula Ib:

##STR00002##

[0034] The compounds of formulae Ia and Ib are prepared according to known procedures. See WO 2004/045492 and US pre-grant application publication no. US 2006/01422260 A1, the disclosures of which are incorporated herein by reference in their entireties.

[0035] In other embodiments, the photosensitizing agent is a compound of Formula II:

##STR00003##

wherein

[0036] M represents 2H or a metal atom selected from divalent Pd, Pt, Co, Sn, Ni, Cu, Zn and Mn, and trivalent Fe, Mn and Cr;

[0037] R.sub.1, R.sub.2, and R.sub.4 each independently is YR.sub.5;

[0038] Y is O, S or NR.sub.5R.sub.6;

[0039] R.sub.3 is selected from CHCH.sub.2, C(O)CH.sub.3, C(O)H, CHNR.sub.7, C(CH.sub.3)NR.sub.7, CH.sub.2OR.sub.7, CH.sub.2SR.sub.7, CH.sub.2NR.sub.7R.sub.7, CH(CH.sub.3)OR.sub.7, CH(CH.sub.3)SR.sub.7, CH(CH.sub.3)NR.sub.7R.sub.7, CH(CH.sub.3)Hal, CH.sub.2-Hal, CH.sub.2R.sub.7, CHCR.sub.7R.sub.7, C(CH.sub.3)CR.sub.7R.sub.7, CHCR.sub.7Hal, C(CH.sub.3)CR.sub.7Hal, and CCR.sub.7;

[0040] R.sub.5, R.sub.6, R.sub.7 and R.sub.7 each independently is H or is selected from the group consisting of: [0041] (a) C.sub.1-C.sub.25 hydrocarbyl optionally containing one or more heteroatoms, carbocyclic or heterocyclic moieties, and/or optionally substituted by one or more functional groups selected from the group consisting of halogen, oxo, OH, SH, CHO, NH.sub.2, CONH.sub.2, a negatively charged group, and an acidic group that is converted to a negatively charged group at the physiological pH; [0042] (b) a residue of an amino acid, a peptide or of a protein; and [0043] (c) when Y is O or S, R.sub.5 may further be R.sub.8.sup.+; [0044] m is 0 or 1; and [0045] R.sub.8.sup.+ is H.sup.+ or a cation; [0046] provided that: [0047] (i) at least one, preferably two, of R.sub.5, R.sub.6, R.sub.7 and R.sub.7 is a hydrocarbon chain as defined in (a) above substituted by a negatively charged group or by an acidic group that is converted to a negatively charged group at the physiological pH; or [0048] (ii) at least one, preferably two, of R.sub.1, R.sub.2, and R.sub.4 is OH, SH, O.sup.R.sub.8.sup.+ or S.sup.R.sub.8.sup.+; or [0049] (iii) at least one of R.sub.1, R.sub.2, and R.sub.4 is OH, SH, O.sup.R.sub.8.sup.+ or S.sup.R.sub.8.sup.+ and at least one of R.sub.5, R.sub.6, R.sub.7 and R.sub.7 is a hydrocarbon chain substituted by a negatively charged group or by an acidic group that is converted to a negatively charged group at the physiological pH; or [0050] (iv) at least one of R.sub.1, R.sub.2, and R.sub.4 is OH, SH, O.sup.R.sub.8.sup.+ or S.sup.R.sub.8.sup.+ and at least one of R.sub.5, R.sub.6, R.sub.7 and R.sub.7 is a residue of an amino acid, a peptide or of a protein; or [0051] (v) at least one of R.sub.5, R.sub.6, R.sub.7 and R.sub.7 is a hydrocarbon chain substituted by a negatively charged group or by an acidic group that is converted to a negatively charged group at the physiological pH and at least one of R.sub.5, R.sub.6, R.sub.7 and R.sub.7 is a residue of an amino acid, a peptide or of a protein; [0052] but excluding the compounds of formula I wherein M is as defined, R.sub.3 is C(O)CH.sub.3, R.sub.1 is OH or OR.sub.8.sup.+ and R.sub.2 is OCH.sub.3, and the compound of formula II wherein M is 2H, R.sub.3 is C(O)CH.sub.3, R.sub.1, R.sub.2 and R.sub.4 are OH, and m is 0 or 1.

[0053] In various embodiments of photosensitizing agents of formula II, the negatively charged groups are selected from the group consisting of COO.sup., COS.sup., SO.sub.3.sup., and/or PO.sub.3.sup.2. In various embodiments, the acidic groups that are converted to negatively charged groups at physiological pH are selected from the group consisting of COOH, COSH, SO.sub.3H, and/or PO.sub.3H.sub.2. In certain embodiments, R.sub.1 is YR.sub.5; Y is O, S or NH; and R.sub.5 is a hydrocarbon chain substituted by functional groups selected from OH, SH, SO.sub.3H, NH.sub.2, CONH.sub.2, COOH, COSH, PO.sub.3H.sub.2. In selected embodiments, R.sub.5 is the residue of an amino acid, a peptide or a protein. Usefully, M is a divalent palladium atom.

[0054] In certain embodiments of photosensitizing agents of formula II, [0055] M represents 2H, divalent Pd, Cu, or Zn or trivalent Mn; [0056] R.sub.1 is O.sup.R.sub.8.sup.+, NH(CH.sub.2).sub.nSO.sub.3.sup.R.sub.8.sup.+, NH(CH.sub.2).sub.nCOO.sup.R.sub.8.sup.+; NH(CH.sub.2).sub.nPO.sub.3.sup.2(R.sub.8.sup.+).sub.2; or YR.sub.5 wherein Y is O, S or NH and R.sub.5 is the residue of an amino acid, a peptide or a protein; [0057] R.sub.2 is C.sub.1-C.sub.6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, more preferably methoxy; [0058] R.sub.3 is C(O)CH.sub.3, CHN(CH.sub.2).sub.nSO.sub.3.sup.R.sub.8.sup.+; CHN(CH.sub.2).sub.nCOO.sup..sub.8.sup.+; CHN(CH.sub.2).sub.nPO.sub.3.sup.2(R.sub.8.sup.+).sub.2; CH.sub.2NH(CH.sub.2).sub.nSO.sub.3.sup.R.sub.8.sup.+; NH(CH.sub.2).sub.nCOO.sup.R.sub.8.sup.+; or NH(CH.sub.2).sub.nPO.sub.3.sup.2(R.sub.8.sup.+).sub.2; [0059] R.sub.4 is NH(CH.sub.2).sub.nSO.sub.3.sup.R.sub.8.sup.+; NH(CH.sub.2).sub.nCOO.sup.R.sub.8.sup.+; NH(CH.sub.2).sub.nPO.sub.3.sup.2(R.sub.8.sup.+).sub.2; R.sub.8.sup.+ is a monovalent cation such as K.sup.+, Na.sup.+, Li.sup.+, NH.sub.4.sup.+, more preferably K.sup.+; and [0060] m is 1, and n is an integer from 1 to 10, preferably 2 or 3.

[0061] In certain embodiments of photosensitizing agents of formula II, [0062] M is divalent Pd; [0063] R.sub.1 is O.sup.R.sub.8.sup.+, NH(CH.sub.2).sub.nSO.sub.3.sup.R.sub.8.sup.+, or YR.sub.5 wherein Y is O, S or NH and R.sub.5 is the residue of an amino acid, a peptide or a protein; [0064] R.sub.2 is C.sub.1-C.sub.6 alkoxy, preferably methoxy; [0065] R.sub.3 is C(O)CH.sub.3, CHN(CH.sub.2).sub.nSO.sub.3.sup.R.sub.8.sup.+; or CH.sub.2NH(CH.sub.2).sub.nSO.sub.3.sup.R.sub.8.sup.+; [0066] R.sub.4 is NH(CH.sub.2).sub.nSO.sub.3.sup.R.sub.8.sup.+; NH(CH.sub.2).sub.nCOO.sup.R.sub.8.sup.+; NH(CH.sub.2).sub.nPO.sub.3.sup.2(R.sub.8.sup.+).sub.2; R.sub.8.sup.+ is a monovalent cation, preferably K.sup.+; [0067] m is 1, and n is 2 or 3.

[0068] The compounds of Formula II may be synthesized according procedures described in WO 2004/045492 and US pre-grant application publication no. US 2006/01422260 A1, the disclosures of which are incorporated herein by reference in their entireties.

[0069] In typical embodiments, the photosensitizing agent is administered intravenously. In certain embodiments, the photosensitizing agent is administered by intravenous infusion. In other embodiments, the photosensitizing agent is administered as an intravenous bolus.

[0070] In certain embodiments in which the photosensitizing agent is WST11, or pharmaceutically acceptable salt thereof, the photosensitizing agent is administered intravenously at a dose of about 2-6 mg/kg. In certain embodiments, the WST11 or salt thereof is administered intravenously at a dose of about 2 mg/kg, 3 mg/kg, about 4 mg/kg, about 5 mg/kg, even about 6 mg/kg. In one series of embodiments, the photosensitizing agent is Palladium 3.sup.1-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13.sup.1-(2-sulfoethyl) amide dipotassium salt administered intravenously at 4 mg/kg.

[0071] Light Wavelength

[0072] The wavelength of light delivered will be appropriate for the chosen photosensitizing agent, and in typical embodiments will approximate an absorption maximum of the agent.

[0073] In embodiments in which the photosensitizing agent is WST11 or salt thereof, the wavelength will typically be between about 670 to about 780 nm. In various embodiments, the wavelength will be about 750 nm, including about 753 nm.

[0074] In another aspect, an improvement is provided to methods of photodynamic treatment planning. The improvement comprises setting the total length of illuminating fiber to be used for treatment based upon the planned treatment volume (PTV) and a prior-determined treatment-effective light density index threshold. As would be understood, the length of illuminating fiber refers to the length of optical fiber that is positioned in the prostate tissue and capable of delivering light to the tissue.

[0075] In typical embodiments, the total length of all illuminating fiber is calculated as the product of a prior-determined treatment-effective LDI threshold x PTV, or scalar transformation thereof. In typical embodiments, the LDI threshold and PTV are determined as above-described. In certain embodiments, the total length of all illuminating fiber is provided by a single fiber. More typically, the total length of all illuminating fiber is contributed by a plurality of fibers. In some embodiments, all fibers are of identical length. In other embodiments, the fibers differ in length.

[0076] The improvement can used in conjunction with existing methods of treatment planning that are designed to optimize the placement of optical fibers for photodynamic therapy of prostate cancer. In some embodiments, for example, the total length of all illuminating fiber calculated as above-described is used in conjunction with light diffusion-based treatment planning methods, such as that described in Davidson et al., Treatment planning and dose analysis for interstitial photodynamic therapy of prostate cancer, Phys. Med. Biol. 54:2293-2313 (2009). In other embodiments, the total length of all illuminating fiber calculated as above-described is used in conjunction with other treatment planning algorithms.

[0077] By establishing the total length of illuminating fiber, the improvement usefully reduces the number of variables to be considered, reducing computing complexity, while ensuring that the optimized fiber placement delivers a light dose that is above the therapeutic threshold. Thus, the improvement can usefully be incorporated into software used to plan photodynamic treatment.

[0078] Thus, in another aspect, a computer program product is provided, comprising a computer usable medium having computer readable program code embodied therein, the computer readable program code adapted to be executed by a computer to implement a method for producing a patient-specific treatment plan for photodynamic therapy of prostate cancer, the method comprising a step of setting the total length of illuminating fiber to be used for treatment based upon the planned treatment volume (PTV) and a prior-determined treatment-effective light density index threshold. In typical embodiments, the PTV and prior-determined treatment-effective light density index threshold are calculated as above-described, and the total length of illuminating fiber is calculated as the product of a prior-determined treatment-effective LDI threshold x PTV, or scalar transformation thereof.

[0079] Further advantages and features are shown in the following Example, which is presented by way of illustration and is not to be construed as limiting the scope of the present invention.

5. EXAMPLES

Example 1: Light Density Index Predicts Early Efficacy of Focal Vascular Targeted Photodynamic Treatment of Prostate Cancer

[0080] Materials and Methods

[0081] Palladium 3.sup.1-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13.sup.1-(2-sulfoethyl) amide dipotassium salt (TOOKAD Soluble) was prepared as described in WO 2004/045492 and US 2006/0142260, the disclosures of which are incorporated herein by reference in their entireties.

[0082] Men with low risk organ-confined prostate cancer (Gleason 3+3 on minimum 10 core TRUS biopsy) were recruited into two consecutive studies: PCM201 (a dose escalation study) or PCM203 (a confirmatory study). The vascular-targeted photodynamic therapy (VTP) procedure, carried out under general anesthesia, involved administration of TOOKAD Soluble intravenously at 4 mg/kg, which was then activated by low power laser light delivered locally to the prostate via a brachytherapy-style transperineal template with a light density of 200 J/cm. Planned treatment volume (PTV, in mls) was determined by the location of tumor on biopsy and by MRI, and varied in volume from less than one lobe, to the whole prostate.

[0083] The Light Density Index (LDI) was calculated as LDI=(n)L/PTV, where (n)L is the total length of all illuminating fibers (in cm), and PTV is the planned treatment volume, in mls.

[0084] Early treatment effect was determined as the proportion of the PTV which showed lack of uptake of gadolinium on 1 week MRI. This was also correlated with the result of 6 month transrectal ultrasound (TRUS)-guided biopsy (positive or negative for any cancer).

[0085] The correlation between LDI and the volume of tissue necrosis at day 7 and with the rate of negative biopsies at Month 6 was assessed in search of a threshold.

[0086] Results

[0087] 90 men were treated with a TOOKAD Soluble dose of 4 mg/kg and a light dose of 200 J/cm in the two studies. Of these 89 were analyzable for LDI. Results using an LDI threshold of 1 are presented below.

TABLE-US-00001 Treatment effect on 1 week MRI % of negative biopsies as % of PTV (n lobes) (6 months) (n lobes)) PCM201 PCM203 PCM201 PCM203 LDI < 1 59 (17) 60 (22) 31 (4/17) N/A LDI 1 95 (12) 94 (28) 83 (10/12) N/A P <0.01 <0.01 <0.01 (N/Anot yet available)

CONCLUSION

[0088] LDI is a reliable predictor of treatment effect using TOOKAD Soluble VTP, both in terms of effect seen on 1 week MRI, and 6 month biopsy.

[0089] While various specific embodiments have been illustrated and described, it will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s).