Methods for photodynamic therapy (PDT) of bladder cancer

Abstract

The present invention relates to methods for photodynamic therapy (PDT) of bladder cancer and their use as adjuvant or neoadjuvant therapy in the treatment of bladder cancer. The present invention provides a composition comprising hexyl 5-ALA ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of photodynamic therapy of bladder cancer wherein the composition is dripped into the bladder of a patient in need of such treatment and the interior of the bladder is exposed to blue light having an energy flow rate of 1.5 to 12.5 mW / cm2.

Description

[0001] This application is a divisional application of the invention patent application with application number 201680079638.6, application date December 19, 2016, and invention name “Method for photodynamic therapy (PDT) for bladder cancer”.

[0002] The present invention relates to methods for photodynamic therapy (PDT) of bladder cancer and its use as adjuvant or neoadjuvant therapy in the treatment of bladder cancer.

[0003] Bladder cancer is the ninth most common cancer worldwide, with more than 330,000 new cases and more than 130,000 deaths each year. At any given time, 2.7 million people have a history of urinary bladder cancer.

[0004] The diagnosis of bladder cancer ultimately depends on cystoscopy (cystoscopy) and histologic evaluation of the excised tissue. Generally, cystoscopy is initially performed in the office using flexible instruments. At the time of the initial diagnosis of bladder cancer, 70% of cases are diagnosed as non-muscle invasive bladder cancer (NMIBC) and approximately 30% are diagnosed as muscle invasive bladder cancer (MIBC).

[0005] If a bladder tumor has been detected during cystoscopy, the patient will undergo a transurethral resection (TUR), a procedure that visualizes the bladder through the urethra and removes the tumor and lesions. In the case of NMIBC, such a resection is a complete removal of the tumor. In the case of MIBC, such a resection is palliative. In addition to tumor resection, a TUR is performed so that the pathologist can make a correct histological diagnosis of bladder cancer based on the examination of the removed tumor / tumor biopsy.

[0006] As standard procedures, cystoscopy and TUR are performed using white light. However, since the use of white light can lead to the omission of lesions that are present but not visible, photodynamic diagnosis (PDD) is often used in this surgery. Typically, PDD involves the application of a photosensitizer or its precursor (i.e., a "photosensitizer") to the target area. The photosensitizer or its precursor is absorbed into the cell, where the precursor of the photosensitizer is converted into an active photosensitizer. When the target area is exposed to light of a suitable wavelength, the photosensitizer is excited, and when relaxed to its ground state, fluorescence occurs, which is detected.

[0007] 5-ALA hexyl ester (hexaminolevulinate, HAL) and its salts are such photosensitizers. HAL preferably penetrates rapidly proliferating cells, such as tumor cells, where it is converted into porphyrins, such as protoporphyrin IX (PpIX), which is a photosensitizer and fluorescent compound. Under subsequent irradiation with blue light, the porphyrin emits red light, thereby enabling specific and accurate visualization of tumors. In the United States and Canada (PhotocureASA / Photocure Inc / Ipsen SA) is a commercially available approved diagnostic agent including HAL. As an adjunct to white light, Used with blue light for photodynamic detection of bladder cancer during cystoscopy and TUR procedures, see e.g. Highlights of Prescribing Information, 2011). Such photodynamic testing has become an important part of the overall treatment of bladder cancer, ie, diagnosis and treatment of this condition (see, for example, Thomas et al., Urology 68, Supplement, 2006, 206).

[0008] In NMIBC patients, cystoscopy and TUR guided by HAL have increased the detection of papillary tumors and flat carcinoma in situ (CIS) lesions, which are difficult to detect with white light alone. In NMIBC patients, compared with white light TUR alone, the bladder cancer TUR guided by HAL has also reduced the residual tumor rate after such surgery, and has led to a better recurrence-free survival (RFS) rate and an extended RFS interval (see Rink et al., Eur Urol 4 (64), 2013, 624). It is believed that in patients undergoing TUR guided by HAL for bladder cancer, the RFS rate is higher due to improved detection rate and removal of other undetected tumors (Burger et al., Eur Urol 5 (64), 2013, 846-854). Existing European NMIBC guidelines and consensus statements of several expert groups recommend the use of HAL-guided TUR in various settings of NMIBC treatment, with some even recommending its use in all NMIBC patients at the time of initial TUR (Witjes et al., Eur Urol 1(66), 2014, 863).

[0009] In patients with MIBC, the detection of the ratio of all tumor lesions and residual tumor in the bladder during TUR is not an issue, and in short, the bladder is removed en bloc. Therefore, TUR in patients with MIBC is usually performed with white light alone, and there is no guideline recommendation to use HAL guidance in this TUR. However, HAL-guided TUR also seems to have an impact on recurrence-free survival in patients undergoing cystectomy: in 268 consecutive patients undergoing cystectomy for bladder cancer, it was retrospectively investigated whether the patients underwent HAL-guided TUR before cystectomy or whether TUR was performed only under white light. Kaplan-Meier analysis was used to evaluate recurrence-free survival (RFS) and overall survival (OS). The 3-year RFS was 69.8% in patients with HAL-guided TUR and 58.2% in patients with white light TUR alone. The 3-year OS was 65.0% and 56.6% in patients with HAL-guided TUR. These results suggest that HAL-guided TUR is associated with improved RFS after cystectomy in patients with MIBC (Gakis et al., Urology Vol. 82, Issue 3, Supplement, 2013, Unmoderated Posters, UP. 046).

[0010] PDT - like PDD - involves the administration of a photosensitizer or its precursor (i.e., a "photosensitizer") to a target area. The therapeutic effect of PDT is based on a phototoxic reaction: the photosensitizer or its precursor is absorbed into cells, where the precursor of the photosensitizer is converted into an active photosensitizer. When the target area is exposed to light of the appropriate wavelength, the photosensitizer is excited from the ground singlet state to an excited singlet state. It then undergoes intersystem crossing to enter a long-lived excited triplet state. One of the few chemicals present in tissue that is in the ground triplet state is molecular oxygen. When the photosensitizer and the oxygen molecule are in proximity, energy transfer can occur, causing the photosensitizer to relax to its ground singlet state and produce an excited singlet oxygen molecule. Singlet oxygen is a very aggressive chemical that will react rapidly with any biomolecules in the vicinity. Ultimately, these reactions will kill the cell, i.e., the cancer cell.

[0011] PDT has been suggested previously for the treatment of bladder cancer, and clinical studies have been conducted to investigate the efficacy and safety of this treatment.

[0012] Berger et al., Urol 2003, 61(2), 338-341 have used PDT as a first-line treatment for patients with bladder cancer. The precursor 5-aminolevulinic acid (5-ALA) is instilled into the bladder as a solution. PDT is performed with red light (633 nm), and the laser system and probe are located in the center of the bladder to ensure that the entire interior of the bladder receives the same light dose. 30 J / cm was provided over a period of 16 to 32 minutes (average exposure time 21 minutes). 2and 50J / cm 2 For the above light doses, the average fluence rate (light dose divided by time [s]) is therefore 23.8 and 39.7 mW / cm 2 Side effects in the form of irritant urinary symptoms occurred in all patients and in 13% of patients, which did not subside before 2 weeks.

[0013] Waidelich et al., Urol 2003, 61(2), 332-337 also used 5-ALA, but chose white light irradiation from a xenon bulb. The light is transmitted to the bladder via a glass fiber inserted into the working channel of the cystoscope. Centralization of the fiber tip is accomplished with the aid of a balloon catheter designed specifically for the procedure based on a transurethral irrigation catheter. The position of the fiber tip is monitored by ultrasound. PDT is performed under general anesthesia and 100 J / cm is delivered over a period of 60 to 150 minutes. 2 The light dose (i.e., the energy flux rate is 11.1-27.7 mW / cm 2 ). Of the 12 patients treated, all complained of frequent and urgent urination, which were treated medically. Symptoms resolved within 1 week in 7 patients, while in 5 patients symptoms persisted for 3 weeks.

[0014] Skyrme et al., BJU Int 2005, 95(5), 1206-1210, used PDT as an adjunct to intravesical chemotherapy with mitomycin for bladder cancer. Following mitomycin treatment, 5-ALAPDT was performed under general or spinal anesthesia, with red laser irradiation (635 nm) delivered intravesically via a diffusor-tipped laser fiber inserted through the working channel of a cystoscope. However, focalization was a challenge, ultrasound visualization proved difficult, and treatment required interruptions every 5 minutes to ensure that there was neither decompression nor contact between the fiber tip and the bladder wall. Treatments of 10, 15, and 25 J / cm were provided for this purpose. 2 The light dose is 18mW / cm 2 In terms of side effects, 25J / cm 2 The light dose of 100 mg / dL is considered to be the tolerable upper limit of this therapy.

[0015] HAL has also been used for PDT of bladder cancer. Bader et al., Urol. Oncol. Seminars and Original Investigations 31, 2013, 1178-1183, have used HAL solutions (8mM and 16mM) and irradiated with white light from a xenon bulb, transmitted to the bladder through a glass fiber inserted into the working channel of a cystoscope. Patients received 3 HAL PDTs at 6-week intervals under general anesthesia. 100J / cm 2 However, a subgroup of patients received 25 J / cm during the first treatment. 2 , received 50J / cm during the second treatment 2 , received 100J / cm during the third treatment 2 These patients also received local anesthesia instead of general anesthesia. Irradiation was performed for a period of 52-100 minutes, i.e., the fluence range was 4 mW / cm based on the light dose and irradiation time. 2 (25J / cm 2 100 min) to 32 mW / cm 2 (100J / cm 2 100 min). Standard HAL TUR was performed before each PDT procedure, and any papillary tumor seen at this point was resected before the PDT procedure. After PDT, the bladder was examined again with blue light. 128 side effects were reported in 17 patients (about 88%), and 7 serious side effects were reported in 4 patients (23.5%), 2 of which were considered to be related to PDT. Of the 17 patients included, 9 were tumor-free at 6 months (52.9%), 4 were tumor-free at 9 months (23.5%), and 2 were tumor-free at 21 months (11.8%).

[0016] The above methods have the disadvantage of requiring specially designed equipment to perform PDT, which is not commercially available. Furthermore, the use of an optical fiber and the placement of the tip of said optical fiber in the center of the bladder is complicated and cumbersome, and the position of the fiber tip needs to be verified by ultrasound, or the PDT procedure needs to be interrupted to ensure that the fiber tip remains in the center and does not touch the bladder wall, which may cause damage. Furthermore, side effects are common and, depending on the PDT parameters used, may take a long time to resolve.

[0017] Therefore, there is a need for new and improved methods for photodynamic therapy of bladder cancer.

[0018] In a first embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of such treatment, and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 In a first preferred embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising dripping a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of such treatment, and exposing the interior of the bladder to a blue light having a flux of 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.2 to 15 J / cm 2 The light dose provided.

[0019] In an alternative first embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of photodynamic therapy of bladder cancer, wherein the composition is instilled into the bladder of a patient in need of such treatment and the interior of the bladder is exposed to a radiation having a power of 1.5 to 12.5 mW / cm 2 In a preferred alternative first embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of photodynamic therapy of bladder cancer, wherein the composition is instilled into the bladder of a patient in need of such treatment, and the interior of the bladder is exposed to a blue light having a flux of 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.2 to 15 J / cm 2 The light dose provided.

[0020] Without wishing to be bound by this theory, the photodynamic therapy according to the invention seems to affect bladder cancer to different extents: if the method of the invention is performed together with TUR, residual tumor cells are killed due to the phototoxic reaction as described above, i.e. tumor cells that were not removed during TUR, and / or reattached tumor cells, i.e. tumor cells that were detached during TUR but remained in the bladder due to insufficient flushing. On the other hand, the photodynamic therapy according to the invention seems to stimulate the patient's immune system to fight bladder cancer, see Example 3 in the present application. The photodynamic therapy according to the invention can be performed with commercially available equipment, see below, and is very well tolerated with only minor and transient adverse reactions (see Fradet et al., J. Urol. 2007, 178, 68-73).

[0021] Bladder cancer in the context of the present invention is muscle invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer (NMIBC). In the context of the first embodiment described above, bladder cancer is preferably NMIBC, which presents as papillary tumors and flat lesions (carcinoma in situ, CIS).

[0022] The term "5-ALA hexyl ester" (HAL) means n-hexyl aminolevulinate, ie n-hexyl 5-amino-4-oxo-pentanoate.

[0023] The term "pharmaceutically acceptable salts" denotes salts which are suitable and meet requirements relating to, for example, safety, bioavailability and tolerability (see, for example, PH Stahl et al. (eds.) Handbook of Pharmaceutical Salts, Publisher Helvetica Chimica Acta, Zurich, 2002).

[0024] The synthesis of 5-ALA hexyl ester is known in the art. It can be prepared, for example, as described in WO 96 / 28412, the entire contents of which are incorporated herein by reference. Briefly, 5-ALA hexyl ester can be prepared by reacting 5-ALA with hexanol in the presence of a catalyst, such as an acid. In addition, 5-ALA hexyl ester hydrochloride is commercially available, for example as (e.g. Photocure ASA) or (e.g. Photocure).

[0025] The 5-ALA hexyl ester used in the present invention is preferably in the form of a pharmaceutically acceptable salt. Such salts are preferably acid addition salts of pharmaceutically acceptable organic or inorganic acids. Suitable acids include, for example, hydrochloric acid, nitric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfonic acid and sulfonic acid derivatives, and ALA-esters and salts of the latter acids are described in WO 2005 / 092838, the entire contents of which are incorporated herein by reference. The preferred acid is hydrochloric acid, HCl. Synthetic processes for salt formation are conventional in the art, for example as described in WO2005 / 092838.

[0026] The concentration of HAL in the composition for use in the invention is suitably 0.1 to 5% by weight of the total weight of the composition or an equivalent concentration of a pharmaceutically acceptable salt of HAL, preferably 0.15 to 3.5%, and most preferably 0.17%, which corresponds to, for example, 0.2% HAL hydrochloride (8 mM).

[0027] The composition used in the present invention may include a pharmaceutically acceptable carrier, excipient or stabilizer. The composition used in the present invention is preferably a liquid composition, more preferably a suspension or even more preferably a solution of HAL in a liquid carrier. The preferred liquid carrier is water or an aqueous solution, and the most preferred liquid carrier is an aqueous buffer.

[0028] In a preferred embodiment, the composition used in the present invention is an aqueous solution of HAL, and most preferably a solution of HAL in an aqueous buffer, preferably a phosphate buffer. In a particularly preferred embodiment, the composition used in the present invention comprises an aqueous phosphate buffer as a liquid carrier, the buffer comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0029] In a preferred embodiment, HAL or a pharmaceutically acceptable salt thereof is provided in lyophilized form and reconstituted in a liquid carrier, preferably water or an aqueous solution, most preferably an aqueous buffer, prior to use.

[0030] If the composition used in the present invention is a liquid composition comprising water, the pH of the composition is preferably in the range of 4.5 to 7.5, more preferably in the range of 5.7 to 7.2.

[0031] In a particularly preferred embodiment, the composition for use in the present invention is That is, a solution of HAL hydrochloride (2 mg / ml; 8 mM) in an aqueous buffer comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0032] The amount of composition instilled into the bladder may vary depending on the volume and size of the bladder. As observed, a composition comprising 0.2% HAL hydrochloride (8 mM) in a volume of about 50 ml is suitable and sufficient.

[0033] The composition used in the present invention is preferably instilled into an empty bladder through a catheter and retained in the bladder for about 20 minutes to about 3 hours, more preferably about 30 minutes to about 2 hours, and most preferably not less than about 1 hour. Before exposing the interior of the bladder to light, the bladder is emptied. If the patient is unable to retain the composition for about 1 hour, at least about 1 hour should be allowed to pass from the instillation of the composition into the bladder to the start of exposing the interior of the bladder to light.

[0034] In a preferred embodiment, the Instill into the bladder and leave in the bladder for about 1 hour. The bladder is then emptied before the interior of the bladder is exposed to light. If the patient is unable to retain the composition for about 1 hour, At least about 1 hour should be allowed to elapse from the time the instillation is continued until the interior of the bladder begins to be exposed to light.

[0035] In the method of the present invention, the interior of the bladder is exposed to a radiation having a power of 1.5 to 12.5 mW / cm 2 In a preferred embodiment, the interior of the bladder is exposed to blue light with a fluence of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 , or 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 The energy flow rate of blue light.

[0036] In a preferred method of the invention, the interior of the bladder is exposed to a radiation having a power of 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.2 to 15 J / cm 2 In a more preferred embodiment, the interior of the bladder is exposed to a light having a light dose of 1.5 to 12.5 mW / cm 2 The energy flux of blue light is 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 The light dose provided.

[0037] In yet another preferred embodiment, the interior of the bladder is exposed to a radiation having a power of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 Fluence rate of blue light, or 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 The blue light has a fluence rate of 0.2 to 15 J / cm 2 In a more preferred embodiment, the interior of the bladder is exposed to a light having a light dose of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 Fluence rate of blue light, or 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 The blue light has an energy flux of 0.7 to 10.2 J / cm 2 In another more preferred embodiment, the interior of the bladder is exposed to a light having a dose of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 Fluence rate of blue light, or 5.5 to 8.5 mW / cm 2, for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 The blue light has an energy flux of 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 The light dose provided.

[0038] In yet another preferred embodiment, the interior of the bladder is exposed to a radiation having a power of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 The blue light has an energy flux of 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 In yet another preferred embodiment, the interior of the bladder is exposed to a light having a light dose of 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 The blue light has an energy flux of 0.7 to 10.2.0 J / cm 2 The light dose provided.

[0039] In another preferred embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of such treatment, exposing the interior of the bladder to a radiation having a power of 3.0 to 22.0 mW / cm 2 White light with a fluence of 1.5 to 12.5 mW / cm 2 In a preferred embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of such treatment, exposing the interior of the bladder to a blue light having a flux of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15 J / cm 2 The light dose provided.

[0040] In an alternative embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of photodynamic therapy of bladder cancer, wherein the composition is instilled into the bladder of a patient in need of such treatment and the interior of the bladder is exposed to a radiation having a power of 3.0 to 22.0 mW / cm2 White light with a fluence of 1.5 to 12.5 mW / cm 2 In a preferred alternative embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of photodynamic therapy of bladder cancer, wherein the composition is instilled into the bladder of a patient in need of such treatment, and the interior of the bladder is exposed to a blue light having a flux of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15 J / cm 2 The light dose provided.

[0041] In a preferred embodiment, the interior of the bladder is exposed to a radiation having a power of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 White light with an energy flux of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 The energy flow rate of blue light.

[0042] In another preferred embodiment, the interior of the bladder is exposed to a radiation having a power of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 The energy flux of white light is 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 The blue light has an energy flux of 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 The light dose is provided, and the white light is 0.6 to 15.0 J / cm 2 , for example 10.0, 11.5 or 13.0 J / cm 2 The light dose provided.

[0043] Generally, irradiation, ie, exposure of the interior of the bladder to blue light or white and blue light, is performed for a period of 2 to 20 minutes.

[0044] To expose the interior of the bladder to light, blue light is used, i.e., a wavelength of about 360 nm to about 450 nm. In another embodiment, white light, i.e., visible light with a wavelength of about 350 to about 700 nm, and blue light, i.e., a wavelength of about 360 nm to about 450 nm, are used. For exposure to both blue and white light, the interior of the bladder can be first exposed to white light and then to blue light, or vice versa. In a preferred embodiment, the interior of the bladder is first exposed to white light and then to blue light.

[0045] The light source can be a lamp or a laser. In a preferred embodiment, a commercially available rigid or flexible blue light cystoscope (e.g., from Karl Storz, Olympus, Richard Wolf) is used as a light source in the method of photodynamic therapy of the present invention. This blue light cystoscope allows both white light and blue light to be irradiated, and the use of this cystoscope in the method of the present invention does not require modifications such as optical fibers or diffuse tips. Commercially available cystoscopes are equipped with a lamp, such as a xenon arc lamp that emits white light and a device that provides blue light, such as a filtering system that blocks all other wavelengths except blue light.

[0046] In a second embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising dripping a solution of HAL hydrochloride in an aqueous buffer into the bladder of a patient and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 In a preferred second embodiment, the blue light has an energy flux of 0.2 to 15.0 J / cm 2 In another preferred second embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 In yet another preferred second embodiment, the interior of the bladder is exposed to blue light having a fluence of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0047] In the second embodiment and all preferred second embodiments, the solution includes 2 mg / ml HAL hydrochloride. The preferred fluence rate and / or light dose of blue light have been disclosed before and are preferably used in this second embodiment. In addition, the preferred fluence rate and / or light dose of white light have been disclosed before and are preferably used in this second embodiment. In addition, the preferred combination of the fluence rate and / or light dose of blue light and the fluence rate and / or light dose of white light have been disclosed before and are preferably used in this second embodiment.

[0048] In a third embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising dripping a solution of HAL hydrochloride in an aqueous buffer into the bladder of a patient and exposing the interior of the bladder to a radiation having a power of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 , or 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 In a preferred third embodiment, the blue light has an energy flux of 0.7 to 10.2 J / cm 2 or 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 In another preferred third embodiment, the interior of the bladder is exposed to a light having a light dose of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 White light with an energy flux of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 In yet another preferred third embodiment, the interior of the bladder is exposed to blue light having a fluence of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 The energy flux of white light is 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 The blue light has an energy flux of 0.6 to 15.0 J / cm 2 , for example 10.0, 11.5 or 13.5 J / cm 2 The light dose is provided, and the blue light is 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 The light dose provided.

[0049] In the third embodiment and all preferred third embodiments, the solution includes 2 mg / ml HAL hydrochloride. The preferred fluence rate and / or light dose of blue light has been disclosed before and is preferably used in this third embodiment. In addition, the preferred fluence rate and / or light dose of white light has been disclosed before and is preferably used in this third embodiment. In addition, the preferred combination of the fluence rate and / or light dose of blue light and the fluence rate and / or light dose of white light has been disclosed before and is preferably used in this third embodiment.

[0050] In a fourth embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising dripping a solution of HAL hydrochloride in an aqueous buffer solution into a patient's bladder, the aqueous buffer solution comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water, and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 In a preferred fourth embodiment, the blue light has an energy flux of 0.2 to 15.0 J / cm 2 In another preferred fourth embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 In yet another preferred fourth embodiment, the interior of the bladder is exposed to blue light having a fluence of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0051] In the fourth embodiment and all preferred fourth embodiments, the solution includes 2 mg / ml HAL hydrochloride. The preferred fluence rate and / or light dose of blue light has been previously disclosed and is preferably used in this fourth embodiment. In addition, the preferred fluence rate and / or light dose of white light has been previously disclosed and is preferably used in this fourth embodiment. In addition, the preferred combination of the fluence rate and / or light dose of blue light and the fluence rate and / or light dose of white light has been previously disclosed and is preferably used in this fourth embodiment.

[0052] In a fifth embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising dripping a solution of HAL hydrochloride in an aqueous buffer solution into a patient's bladder, the aqueous buffer solution comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water, and exposing the interior of the bladder to a radiation having a power of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 , or 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 In a preferred fifth embodiment, the blue light has an energy flux of 0.7 to 10.2 J / cm 2 or 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 In another preferred fifth embodiment, the interior of the bladder is exposed to a light having a light dose of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 White light with an energy flux of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 In yet another preferred fifth embodiment, the interior of the bladder is exposed to a blue light having a fluence of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 The energy flux of white light is 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 The blue light has an energy flux of 0.6 to 15.0 J / cm 2 , for example 10.0, 11.5 or 13.5 J / cm 2 The light dose is provided, and the blue light is 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 The light dose provided.

[0053] In the fifth embodiment and all preferred fifth embodiments, the solution includes 2 mg / ml HAL hydrochloride. Preferred fluence rates and / or light doses of blue light have been disclosed before and are preferably used in this fifth embodiment. In addition, preferred fluence rates and / or light doses of white light have been disclosed before and are preferably used in this fifth embodiment. In addition, preferred combinations of fluence rates and / or light doses of blue light and fluence rates and / or light doses of white light have been disclosed before and are preferably used in this fifth embodiment.

[0054] In a sixth embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising dripping a solution of HAL hydrochloride in an aqueous buffer into the bladder of a patient, and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.2 to 15.0 J / cm 2 In a preferred sixth embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0055] In a sixth embodiment and a preferred sixth embodiment, the solution includes 2 mg / ml HAL hydrochloride. Preferred fluence rates and / or light doses of blue light have been disclosed before and are preferably used in this sixth embodiment. In addition, preferred fluence rates and / or light doses of white light have been disclosed before and are preferably used in this sixth embodiment. In addition, preferred combinations of fluence rates and / or light doses of blue light and fluence rates and / or light doses of white light have been disclosed before and are preferably used in this sixth embodiment.

[0056] In a seventh embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising dripping a solution of HAL hydrochloride in an aqueous buffer into the bladder of a patient, and exposing the interior of the bladder to a radiation having a power of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 , or 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 The blue light has an energy flux of 0.7 to 10.2 J / cm 2 or 0.3 to 8.0 J / cm2 , for example 6.5, 7.0 or 7.5 J / cm 2 In a preferred seventh embodiment, the interior of the bladder is exposed to a light having a light dose of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 The energy flux of white light is 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 The blue light has an energy flux of 0.6 to 15.0 J / cm 2 , for example 10.0, 11.5 or 13.5 J / cm 2 The light dose is provided, and the blue light is 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 The light dose provided.

[0057] In the seventh embodiment and the preferred seventh embodiment, the solution includes 2mg / ml HAL hydrochloride. The preferred fluence rate and / or light dose of blue light has been disclosed before and is preferably used in this seventh embodiment. In addition, the preferred fluence rate and / or light dose of white light has been disclosed before and is preferably used in this seventh embodiment. In addition, the preferred combination of the fluence rate and / or light dose of blue light and the fluence rate and / or light dose of white light has been disclosed before and is preferably used in this seventh embodiment.

[0058] In an eighth embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising dripping a solution of HAL hydrochloride in an aqueous buffer solution into a patient's bladder, the aqueous buffer solution comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water, and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.2 to 15.0 J / cm 2 In a preferred eighth embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0059] In an eighth embodiment and a preferred eighth embodiment, the solution includes 2 mg / ml HAL hydrochloride. Preferred fluence rates and / or light doses of blue light have been disclosed before and are preferably used in this eighth embodiment. In addition, preferred fluence rates and / or light doses of white light have been disclosed before and are preferably used in this eighth embodiment. In addition, preferred combinations of fluence rates and / or light doses of blue light and fluence rates and / or light doses of white light have been disclosed before and are preferably used in this eighth embodiment.

[0060] In a ninth embodiment, the present invention provides a method for photodynamic therapy of bladder cancer, comprising dripping a solution of HAL hydrochloride in an aqueous buffer solution into a patient's bladder, the aqueous buffer solution comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water, and exposing the interior of the bladder to a radiation having a power of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 , or 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 The blue light has an energy flux of 0.7 to 10.2 J / cm 2 or 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 In a preferred ninth embodiment, the interior of the bladder is exposed to a light having a light dose of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 The energy flux of white light is 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 The blue light has an energy flux of 0.6 to 15.0 J / cm 2 , for example 10.0, 11.5 or 13.5 J / cm 2 The light dose is provided, and the blue light is 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 The light dose provided.

[0061] In the ninth embodiment and the preferred ninth embodiment, the solution includes 2mg / ml HAL hydrochloride. The preferred fluence rate and / or light dose of blue light has been disclosed before and is preferably used in this ninth embodiment. In addition, the preferred fluence rate and / or light dose of white light has been disclosed before and is preferably used in this ninth embodiment. In addition, the preferred combination of the fluence rate and / or light dose of blue light and the fluence rate and / or light dose of white light has been disclosed before and is preferably used in this ninth embodiment.

[0062] In the second to ninth embodiments, the light source is preferably a commercially available blue light cystoscope that allows blue light irradiation or is used for blue light and white light irradiation.

[0063] In the second to ninth embodiments, the HAL hydrochloride solution is instilled into the bladder through a catheter and preferably remains in the bladder for about 1 hour. In preferred second to ninth embodiments, the bladder is emptied before the interior of the bladder is exposed to light. If the patient is unable to retain the solution for about 1 hour, at least about 1 hour should be allowed to pass from the instillation of the solution into the bladder to the start of exposure of the interior of the bladder to light.

[0064] The method for photodynamic therapy of bladder cancer according to the present invention can be used as a stand-alone bladder cancer treatment. Alternatively, it can be used as an adjunctive therapy in the treatment of bladder cancer, ie in addition to the primary / main therapy for bladder cancer.

[0065] Thus, in a tenth embodiment, the present invention provides a method for treating bladder cancer, wherein photodynamic therapy is used as an adjuvant therapy, the method of photodynamic therapy comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into a patient's bladder, and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 In a preferred tenth embodiment, the blue light has an energy flux of 0.2 to 15.0 J / cm 2 In another preferred tenth embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 In yet another preferred tenth embodiment, the interior of the bladder is exposed to blue light having a fluence of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0066] In an eleventh embodiment, the present invention provides a method for treating bladder cancer, wherein a photodynamic therapy method is used as an adjuvant therapy, the photodynamic therapy method comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into a patient's bladder, and exposing the interior of the bladder to a radiation having a power of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 , or 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 In a preferred eleventh embodiment, the blue light has an energy flux of 0.7 to 10.2 J / cm 2 or 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 In another preferred eleventh embodiment, the interior of the bladder is exposed to a light having a light dose of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 White light with an energy flux of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 In yet another preferred eleventh embodiment, the interior of the bladder is exposed to blue light having a fluence of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 The energy flux of white light is 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 The blue light has an energy flux of 0.6 to 15.0 J / cm 2 , for example 10.0, 11.5 or 13.5 J / cm 2 The light dose is provided, and the blue light is 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 The light dose provided.

[0067] In an alternative tenth embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of treating bladder cancer, wherein a method of photodynamic therapy is used as an adjunct therapy, the method of photodynamic therapy comprising instilling the composition into the bladder of a patient in need of such treatment and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm2 In a preferred alternative tenth embodiment, the blue light has an energy flux of 0.2 to 15.0 J / cm 2 In another preferred alternative tenth embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 In yet another preferred alternative tenth embodiment, the interior of the bladder is exposed to blue light having a fluence rate of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0068] In an alternative eleventh embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of treating bladder cancer, wherein a method of photodynamic therapy is used as an adjunct therapy, the method of photodynamic therapy comprising instilling the composition into the bladder of a patient in need of such treatment and exposing the interior of the bladder to a radiation having a radiation intensity of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 , or 5.5 to 8.5 mW / cm 2 , for example 6.0, 6.5, 7.0, 7.5 or 8.0 mW / cm 2 In a preferred alternative eleventh embodiment, the blue light has an energy flux of 0.7 to 10.2 J / cm 2 or 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 In another preferred alternative eleventh embodiment, the interior of the bladder is exposed to a light having a light dose of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2 White light with an energy flux of 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 In yet another preferred alternative eleventh embodiment, the interior of the bladder is exposed to blue light having a fluence of 5.0 to 12.5 mW / cm 2 , such as 7.0, 9.0 or 11.0 mW / cm 2The energy flux of white light is 2.5 to 7.0 mW / cm 2 , such as 5.5, 6.0 or 6.5 mW / cm 2 The blue light has an energy flux of 0.6 to 15.0 J / cm 2 , for example 10.0, 11.5 or 13.5 J / cm 2 The light dose is provided, and the blue light is 0.3 to 8.0 J / cm 2 , for example 6.5, 7.0 or 7.5 J / cm 2 The light dose provided.

[0069] In a preferred tenth or eleventh embodiment, or in a preferred alternative tenth or eleventh embodiment, the composition for use in the method is an aqueous solution of HAL, most preferably a solution of HAL in an aqueous buffer, preferably a phosphate buffer. In a particularly preferred embodiment, the composition for use in the method comprises an aqueous phosphate buffer as a liquid carrier, the buffer comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0070] In said tenth or eleventh embodiment, or in said preferred alternative tenth or eleventh embodiment, the bladder cancer may be NMIBC or MIBC.

[0071] Typically, for NMIBC, the primary treatment is TUR, which is surgery to visualize the bladder through the urethra and remove the tumor and lesions. TUR is often followed by immunotherapy and / or chemotherapy.

[0072] The method of photodynamic therapy of the present invention is preferably performed as an adjunct to TUR in patients in need of such treatment, ie, patients who have been diagnosed with NMIBC or patients suspected of having NMIBC.

[0073] The adjuvant therapy of the present invention can be performed simultaneously with TUR or after TUR.

[0074] Thus, when performed simultaneously, a method for treating NMIBC may begin by instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of such treatment, and exposing the interior of the bladder to white light for visual inspection, then switching to blue light for fluorescence detection and lesion treatment. The lesion is then excised, for example, under white light. The completeness of the excision can be monitored by using blue light. In the method, the interior of the bladder is exposed to a light having a wavelength of 1.5 to 12.5 mW / cm 2 In a preferred embodiment, the above white light has an energy flux of 3.0 to 22.0 mW / cm 2In a preferred embodiment, the blue light is emitted at a flux of 0.2 to 15.0 J / cm 2 In another preferred embodiment, the white light is provided at a light dose of 0.4 to 26.5 J / cm 2 The irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0075] Thus, in a twelfth embodiment, the present invention provides a method for treating NMIBC by concurrent adjuvant therapy and transurethral resection of NMIBC, the method comprising a) instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of such NMIBC treatment, b) exposing the interior of the bladder to white light for visual inspection, followed by exposing the interior to blue light for fluorescent detection and treatment of lesions; c) resecting the lesions; and d) optionally monitoring the completeness of the resection by exposing the interior to blue light for fluorescent detection of residual NMIBC, wherein the blue light has a wavelength of 1.5 to 12.5 mW / cm 2 Energy flow rate.

[0076] In a preferred twelfth embodiment, the blue light is emitted at a rate of 0.2 to 15.0 J / cm 2 Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0077] In another preferred twelfth embodiment, the present invention provides a method for treating NMIBC by concurrent adjuvant therapy and transurethral resection of NMIBC, the method comprising a) instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of such NMIBC treatment, b) exposing the interior of the bladder to white light for visual inspection, followed by exposing the interior to blue light for fluorescent detection and treatment of lesions; c) resecting the lesions; and d) optionally monitoring the completeness of the resection by exposing the interior to blue light for fluorescent detection of residual NMIBC, wherein the white light has a wavelength of 3.0 to 22.0 W / cm 2 The energy flux of blue light is 1.5 to 12.5 mW / cm 2 Energy flow rate.

[0078] In yet another preferred twelfth embodiment, the white light is emitted at a rate of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0079] Various embodiments and preferred embodiments of the method of treating NMIBC, ie, embodiments 1-11, are described above and may be used in this twelfth embodiment.

[0080] In an alternative twelfth embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of treating NMIBC by concurrent adjunctive therapy and transurethral resection of NMIBC, wherein a) the composition is instilled into the bladder of a patient in need of such NMIBC treatment, b) the interior of the bladder is exposed to white light for visual inspection and then to blue light for fluorescence detection and lesion treatment; c) the lesion is resected; and d) optionally, the completeness of the resection is monitored by exposing the interior to blue light for fluorescence detection of residual NMIBC, wherein the blue light has a wavelength of 1.5 to 12.5 mW / cm 2 Energy flow rate.

[0081] In a preferred alternative twelfth embodiment, the blue light is emitted at a rate of 0.2 to 15.0 J / cm 2 Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0082] In another preferred alternative twelfth embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of treating NMIBC, a method of treating NMIBC by concurrent adjuvant therapy and transurethral resection of NMIBC, wherein a) the composition is instilled into the bladder of a patient in need of such NMIBC treatment, b) the interior of the bladder is exposed to white light for visual inspection and then to blue light for fluorescence detection and lesion treatment; c) the lesion is removed; and d) optionally, the completeness of the resection is monitored by exposing the interior to blue light for fluorescence detection of residual NMIBC, wherein the white light has a wavelength of 3.0 to 22.0 mW / cm 2 The energy flux of blue light is 1.5 to 12.5 mW / cm 2 Energy flow rate.

[0083] In yet another preferred twelfth embodiment, the white light is emitted at a rate of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0084] Various embodiments and preferred embodiments, ie, embodiments 1-11, of compositions comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in methods of treating NMIBC are described above and may be used in this alternative twelfth embodiment.

[0085] When performed after TUR, adjunctive therapy for the treatment of NMIBC may begin with instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient who has undergone TUR and exposing the interior of the bladder to a 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0086] Thus, in a thirteenth embodiment, the present invention provides an adjuvant therapy for treating NMIBC, comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient who has undergone TUR, and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0087] In a preferred thirteenth embodiment, the blue light is emitted at a rate of 0.2 to 15.0 J / cm 2 Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0088] In another preferred thirteenth embodiment, the present invention provides an adjuvant therapy for treating NMIBC, comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient who has undergone TUR, and exposing the interior of the bladder to a radiation having a power of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0089] In yet another preferred thirteenth embodiment, the white light is emitted at a rate of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0090] Various embodiments and preferred embodiments of the method of treating NMIBC, ie, embodiments 1-11, are described above and may be used in this thirteenth embodiment.

[0091] In an alternative thirteenth embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in adjunctive therapy for treating NMIBC, wherein the composition is instilled into the bladder of a patient who has undergone TUR and the interior of the bladder is exposed to a radiation having a power of 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0092] In a preferred alternative thirteenth embodiment, the blue light is emitted at 0.2 to 15.0 J / cm 2 Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0093] In another preferred alternative thirteenth embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in adjunctive therapy for treating NMIBC, wherein the composition is instilled into the bladder of a patient who has undergone TUR, and the interior of the bladder is exposed to a radiation having a radiation intensity of 3.0 to 22.0 mW / cm 2 White light with a fluence of 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0094] In yet another preferred alternative thirteenth embodiment, the white light is 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0095] Various embodiments and preferred embodiments, ie, embodiments 1-11, of the composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for the adjunct therapy of NMIBC are described above and may be used in the alternative thirteenth embodiment.

[0096] The method of treating NMIBC according to the invention may be performed once or repeatedly, such as two or more times, such as 3, 4, 5 or 6 times, with a period of time between treatments of, for example, 4 days to 4 weeks, such as 1, 2 or 3 weeks.

[0097] Adjuvant therapy for NMIBC according to the present invention may be performed once or repeatedly, such as two or more times, such as 3, 4, 5 or 6 times, with a period between treatments of, for example, 4 days to 4 weeks, such as 1, 2 or 3 weeks, or together with TUR, such as after TUR, or alone.

[0098] The adjuvant therapy for treating NMIBC of the present invention can be combined with chemotherapy, such as systemic or intravesical administration of a suitable chemotherapeutic agent for NMIBC, such as cisplatin, methotrexate, vinblastine, valrubicin, doxorubicin or mitomycin C, and / or with a suitable immunotherapeutic agent for NMIBC, such as systemic administration of an anti-cancer vaccine or intravesical administration of Bacillus Calmette-Guérin (BCG).

[0099] Alternatively, the adjuvant therapy for treating NMIBC according to the present invention can replace or partially replace other adjuvant therapies, such as chemotherapy and / or immunotherapy. In a preferred embodiment, the adjuvant therapy according to the present invention replaces or partially replaces other adjuvant therapies such as mitomycin and / or BCG administered intravesically. In a particularly preferred embodiment, the adjuvant therapy for treating NMIBC according to the present invention partially or completely replaces BCG. BCG treatment usually starts a few weeks after transurethral resection of NMIBC, once a week, for 6 weeks. The adjuvant therapy according to the present invention can replace 1, 2, 3, 4, 5 or all 6 times of this BCG treatment.

[0100] Up to 40% of NMIBC patients will fail intravesical BCG therapy. The vast majority of low-grade NMIBC are prone to recurrence, but rarely evolve. Failure after intravesical BCG in these patients is usually superficial and low-grade, and such patients can be treated with intravesical regimens, including repeated BCG, BCG plus cytokines, intravesical chemotherapy, thermochemotherapy or new immunotherapy methods. On the other hand, in high-risk T1 bladder cancer and / or carcinoma in situ, failure to respond to BCG is more problematic because these tumors are often likely to evolve into muscle-invasive. In these cases, after BCG failure, radical cystectomy remains the main means. Therefore, it is necessary to find new treatment alternatives for BCG-refractory bladder cancer patients, and the adjuvant therapy for treating NMIBC according to the present invention meets this need.

[0101] Complete replacement of BCG with adjuvant therapy according to the invention is preferred for BCG-refractory NMIBC patients, ie patients in whom BCG therapy does not lead to the desired therapeutic success.

[0102] Thus, in a fourteenth embodiment, the present invention provides an adjuvant therapy for treating NMIBC in BCG-refractory patients, comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a BCG-refractory patient, and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0103] In a preferred fourteenth embodiment, the blue light is emitted at a rate of 0.2 to 15.0 J / cm 2 Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0104] In another preferred fourteenth embodiment, the present invention provides an adjuvant therapy for treating NMIBC in BCG-refractory patients, comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a BCG-refractory patient, and exposing the interior of the bladder to a radiation having a power of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0105] In yet another preferred fourteenth embodiment, the white light is emitted at a rate of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0106] Various embodiments and preferred embodiments, ie, embodiments 1-11, of adjuvant therapy for treating NMIBC in BCG-refractory patients are described above and may be used in this fourteenth embodiment.

[0107] In an alternative fourteenth embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in adjunctive therapy for treating NMIBC in BCG-refractory patients, wherein the composition is instilled into the bladder of the BCG-refractory patient and the interior of the bladder is exposed to a radiation having a radiation intensity of 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0108] In a preferred alternative fourteenth embodiment, the blue light is emitted at 0.2 to 15.0 J / cm 2Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0109] In another preferred alternative fourteenth embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in adjunctive therapy for treating NMIBC in BCG-refractory patients, wherein the composition is instilled into the bladder of the BCG-refractory patient and the interior of the bladder is exposed to a radiation having a radiation intensity of 3.0 to 22.0 mW / cm 2 White light with a fluence of 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0110] In yet another preferred alternative fourteenth embodiment, the white light is 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 Preferably, the irradiation / exposure is performed for a period of 2 minutes (for small and / or few lesions) to 20 minutes (for large and / or multiple lesions).

[0111] Various embodiments and preferred embodiments, namely, embodiments 1-11, of compositions comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in this adjunctive therapy for treating NMIBC in BCG-refractory patients are described above and may be used in this preferred alternative fourteenth embodiment.

[0112] For patients with MIBC, the main treatment is radical cystectomy, which is the removal of the bladder and adjacent organs, i.e., the prostate and seminal vesicles in men, and the uterus and adnexa in women, including the removal of regional lymph nodes. Cystectomy is also advocated for patients with NMIBC who are at high risk for progression, i.e., patients with multiple recurrent high-grade tumors or high-grade T1 tumors or high-grade tumors with carcinoma in situ (CIS). In addition, cystectomy is advocated for NMIBC patients who have received BCG immunotherapy but have failed this treatment.

[0113] The method of photodynamic therapy of the present invention is preferably performed as neoadjuvant therapy to cystectomy, ie prior to such cystectomy, in patients in need of such treatment (ie patients already diagnosed with MIBC).

[0114] Thus, in a fifteenth embodiment, the present invention provides a method for neoadjuvant therapy for treating MIBC prior to cystectomy, the method comprising a) instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of said treatment, and b) exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0115] In a preferred fifteenth embodiment, the blue light is emitted at a rate of 0.2 to 15.0 J / cm 2 In another preferred fifteenth embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 In yet another preferred fifteenth embodiment, the interior of the bladder is exposed to blue light having a fluence of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0116] Various embodiments and preferred embodiments of the method of neoadjuvant therapy for treating MIBC, ie, embodiments 1-11, are described above and may be used in this fifteenth embodiment.

[0117] In an alternative fourteenth embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of neoadjuvant therapy for treating MIBC, the method comprising a) instilling the composition into the bladder of a patient in need of said treatment; and b) exposing the interior of said bladder to a radiation having a radiation intensity of 1.5 to 12.5 mW / cm 2 The energy flux of blue light;

[0118] In a preferred alternative fifteenth embodiment, the blue light is emitted at a rate of 0.2 to 15.0 J / cm 2 In another preferred alternative fifteenth embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 In yet another preferred alternative fifteenth embodiment, the interior of the bladder is exposed to blue light having a fluence rate of 3.0 to 22.0 mW / cm 2The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0119] Various embodiments and preferred embodiments, ie, embodiments 1-11, of a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of neoadjuvant therapy for treating MIBC are described above and may be used in this alternative fifteenth embodiment.

[0120] In a sixteenth embodiment, the present invention provides a method for treating MIBC, the method comprising a) neoadjuvant therapy and b) subsequent cystectomy, the method for treating MIBC comprising a) instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of said treatment, and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 blue light with a fluence rate of 100 nm; and b) performing a cystectomy.

[0121] In a preferred sixteenth embodiment, the blue light is emitted at a rate of 0.2 to 15.0 J / cm 2 In another preferred sixteenth embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 In yet another preferred fifteenth embodiment, the interior of the bladder is exposed to blue light having a fluence of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0122] Various embodiments and preferred embodiments of this method of treating MIBC, ie, embodiments 1-11, are described above and may be used in this sixteenth embodiment.

[0123] In an alternative sixteenth embodiment, the present invention provides a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of treating MIBC comprising a) neoadjuvant therapy and b) subsequent cystectomy, the method of treating MIBC comprising a) instilling the composition into the bladder of a patient in need of said treatment, and exposing the interior of said bladder to a radiation having a strength of 1.5 to 12.5 mW / cm 2 and b) performing cystectomy under blue light with a fluence rate of 100 nm.

[0124] In a preferred alternative sixteenth embodiment, the blue light is emitted at 0.2 to 15.0 J / cm 2 In another preferred sixteenth embodiment, the interior of the bladder is exposed to a light having a light dose of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 In yet another preferred fifteenth embodiment, the interior of the bladder is exposed to blue light having a fluence of 3.0 to 22.0 mW / cm 2 The energy flux of white light is 1.5 to 12.5 mW / cm 2 The blue light has an energy flux of 0.4 to 26.5 J / cm 2 The light dose is provided, and the blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

[0125] Various embodiments and preferred embodiments, ie, embodiments 1-11, of the composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in the method of treating MIBC are described above and may be used in this alternative sixteenth embodiment.

[0126] The time period between the neoadjuvant therapy and cystectomy of the present invention described above can vary, but is preferably zero to 6 weeks, such as zero to 4 weeks, 3 weeks, 2 weeks or 1 week. "Zero" means that the cystectomy is performed directly after the neoadjuvant therapy, i.e., after the light irradiation / exposure of the inside of the bladder is completed.

[0127] Neoadjuvant therapy may be repeated prior to cystectomy, for example two or more times, for example 3, 4, 5 or 6 times, with a time period between treatments of, for example 4 days to 4 weeks, for example 1, 2 or 3 weeks.

[0128] Neoadjuvant therapy can be combined with neoadjuvant radiation therapy and / or neoadjuvant chemotherapy.

[0129] Despite being the gold standard for treatment of MIBC and advocated in certain types of NMIBC patients, radical cystectomy provides 5-year survival in only about 50% of patients. To improve these unsatisfactory outcomes, the use of neoadjuvant therapy has been explored since the 1980s.

[0130] Neoadjuvant radiotherapy has been used, and downgrading of the tumor after radiotherapy takes approximately 4–6 weeks. However, delaying surgery for patients with locally advanced bladder cancer for more than 90 days has been shown to result in a significant increase in extravesical disease (81 vs. 52%). According to current European guidelines for MIBC, neoadjuvant radiotherapy is not recommended because there are no data to support increased survival with neoadjuvant radiotherapy in operable MIBC.

[0131] Neoadjuvant chemotherapy has many advantages, including administration of chemotherapy at the earliest possible time point when the burden of micrometastatic disease is expected to be low; chemotherapy is expected to be better tolerated before cystectomy than after cystectomy; and it is hypothesized that patients with micrometastatic disease may respond to neoadjuvant therapy and show favorable pathologic status as determined primarily by negative nodal status and negative surgical margins. Neoadjuvant cisplatin-containing chemotherapy has been shown to significantly improve survival (5% absolute improvement in 5-year survival). However, as noted above, delayed cystectomy may affect outcomes in patients who are chemotherapy-insensitive, and in general, preoperative anemia and neuropathy are more common in patients who receive neoadjuvant chemotherapy before cystectomy. Current European guidelines for MIBC state that “….neoadjuvant chemotherapy has its limitations in terms of patient selection, current developments in surgical techniques, and current combination chemotherapy regimens.” Therefore, there is room for improvement in the neoadjuvant treatment of patients with bladder cancer who require cystectomy.

[0132] Compared to neoadjuvant radiotherapy, (neo)adjuvant chemotherapy and (neo)adjuvant immunotherapy, adjuvant or neoadjuvant therapy according to the method of the invention has several advantages, among which nausea, vomiting, fatigue, anemia, epithelial surface damage, intestinal discomfort / gastrointestinal irritation, nephrotoxicity, neurotoxicity, swelling, immune system suppression and infertility are well-known and common side effects. In contrast, the most reported adverse reactions of HAL (in terms of The effects are short-lived and range from mild to moderate in intensity. The most common adverse reactions were bladder spasm, reported by 2.4% of patients, dysuria by 1.8%, bladder pain by 1.7%, and hematuria by 1.7%.

[0133] In addition, HAL has a very favorable metabolic profile compared to chemotherapy drugs such as cisplatin. HAL interferes with the body's own heme biosynthesis pathway and leads to the accumulation of photoactive porphyrins, especially protoporphyrin IX (PpIX), the final intermediate of heme synthesis. Since this photoactive porphyrin is a naturally occurring compound in the body, there is a "natural process" in the body to degrade (metabolize) and secrete the degraded heme. Example

[0134] Example 1

[0135] Orthotopic Rat Bladder Tumor Model

[0136] Rat bladder cancer cell lines were used in these experiments to establish superficial bladder tumors in female Fischer rats weighing 150-175 g as described by Francois et al., J. Urol. 190(2), 2013, 731-736. Animals were used for experiments 5 days after tumor cell inoculation.

[0137] Intravesical PDT in rats

[0138] Lyophilized HAL ( The HAL solution was emptied and 0.5 ml of PBS was dripped into the bladder of the rats and retained in the bladder for about 1 hour. After the HAL solution was emptied, 0.5 ml of PBS was dripped into the bladder and the 170 mW Modulight laser model ML 6500-405 transmitting light at a wavelength of 401 nm was used to illuminate the bladder at 3.5 or 7.0 mW / cm 2 The whole bladder was irradiated with blue light at a fluence of 4.0 J / cm2 using a laser model RD05 / 500 / 800 (Medlight, Ecublens, Switzerland) coupled to a cylindrical diffuser (1 × 5 mm) placed in the center of the bladder. 2 (Energy flux 3.5mW / cm 2 ) or 7.5 J / cm 2 (Energy flux 7.0mW / cm 2 ) of blue light dose

[0139] For control, Hexvix was not instilled, and only blue light irradiation was performed at the above-mentioned irradiation fluence / light dose.

[0140] Post-PDT regimen

[0141] 48 hours after irradiation, rats were killed with an overdose of pentobarbital. The bladder was filled with formaldehyde (4%), removed from the animal and transferred to a vial with formaldehyde (4%) for at least 4 hours. The bladder was then cut into 4 parts under macroscopic conditions and fixed for 48 hours. After different cycles of gradient dehydration in ethanol and xylene, the bladder tissue was included in paraffin. Paraffin-embedded sections of 5 μm were cut and stained with hematoxylin / eosin for histological examination.

[0142] result

[0143] Bladders of control animals (n=2 for each fluence rate / light dose) showed no inflammation (a sign of PDT effect) but showed persistent and chorioinvasive tumors for both fluence rates / light doses.

[0144] 3.5mW / cm 2 / 4J / cm 2 The bladder of one animal (50%) in the group (n=2) showed no inflammation, persistent and chorioinvasive tumor, while the bladder tumor of another animal (50%) looked less compact and the superficial layers of the tumor were destroyed.

[0145] 7.0mW / cm 2 / 7.5J / cm 2 The bladders of group (n=2) animals showed increased tissue thickness / inflammation (two signs of PDT effect) and disintegrated / less compact tumor tissue.

[0146] Example 2

[0147] HAL / Blu-ray Group:

[0148] HAL is placed through a catheter The solution is instilled into the patient's bladder and retained in the bladder for about 1 hour. If the patient is unable to retain the composition for about 1 hour, Allow at least about 1 hour to elapse from the time the instillation begins to expose the interior of the bladder to light. Afterwards, a commercially available blue light cystoscope was inserted into the bladder, and TUR was performed by exposing the interior of the bladder to white light for visual inspection, followed by blue light exposure for fluorescent detection of bladder cancer lesions, resection of the detected lesions under white light, and monitoring of the completeness of the resection by using blue light. Blue light was emitted at a power of 1.5 to 12.5 mW / cm 2 Fluence rate and 0.2 to 15.0 J / cm 2 The light dose is provided at 3.0 to 22.0 mW / cm 2 Fluence rate and 0.4 to 26.5 J / cm 2 The light dose provided.

[0149] The resected bladder tumor is processed according to methods known in the art and a primary cell culture is established from the patient-derived bladder tumor in culture under appropriate conditions. In vitro primary cell cultures cannot be established from the resected bladder tumor.

[0150] Without HAL / white light group:

[0151] A commercially available white light cystoscope is inserted into the patient's bladder and TUR is performed by exposing the interior of the bladder to white light for visual inspection, detection of bladder cancer lesions, resection of said lesions, and monitoring of resection completeness.

[0152] The excised bladder tumors were treated the same as the HAL / blue light group. In vitro primary cell cultures of such excised bladder tumors can be established.

[0153] The fact that in vitro primary cell cultures could not be established from bladder tumors resected in the HAL / blue light patient group points to a phototoxic effect, i.e., tumor cells being killed during the TUR procedure performed.

[0154] Example 3

[0155] A prospective, randomized, comparative, controlled phase III multicenter study was conducted in patients with non-muscle invasive papillary bladder cancer (NMIBC). The study population included 551 patients who were randomized into two groups (see below). The two groups were similar in age, sex, race, history of bladder cancer, and previous intravesical treatment.

[0156] HAL Group : 271 patients. The method of the present invention is performed as follows: HAL is inserted into the The solution is instilled into the patient's bladder and retained in the bladder for about 1 hour. If the patient is unable to retain the composition for about 1 hour, At least about 1 hour should be allowed to elapse from the time the instillation is continued until the interior of the bladder begins to be exposed to light.

[0157] In emptying Afterwards, cystoscopy was performed with a commercially available cystoscope (blue light and white light). The interior of the bladder was first exposed to white light and visually assessed, and then exposed to blue light to detect cancerous lesions in the bladder. Transurethral resection (TUR) of the detected lesions was performed under white light, and the completeness of the resection was assessed under blue light.

[0158] White light group : 280 patients. Cystoscopy and TUR for bladder cancer were performed under white light only, without HAL.

[0159] Patients in both groups with histologically confirmed Ta or T1 lesions underwent white-light cystoscopy after 3, 6, and 9 months. During the 9-month follow-up, all tumor recurrences were histologically confirmed.

[0160] Comparison of tumor recurrence in patients in the white light group and the HAL group according to the present invention

[0161] During the 9-month follow-up, tumor recurrence was observed in 157 of 280 patients (56.1%) in the white light group and in 128 of 271 patients (42.7%) in the HAL group. This difference in tumor recurrence rate was statistically significant and has been explained by improved tumor detection and more complete resection in the HAL group (Stenzl et al., J Urol 184, 2010, 1907-1914).

[0162] Comparison of tumor recurrence in patients treated with or without intravesical BCG therapy

[0163] Fifty patients (18.5%) in the HAL group and 55 patients (19.6%) in the white light group received BCG treatment during the 9-month follow-up period. BCG (bacillus Calmette-Guérin) is an immunotherapy agent for the treatment of bladder cancer. It is usually instilled repeatedly into the bladder. The tumor recurrence rate in both patient groups was determined and the results are shown in Table 1

[0164] Table 1: Tumor recurrence rates by group and BCG treatment

[0165]

[0166] As mentioned above, during the 9-month follow-up, 157 of 280 patients in the white light group (56.1%) and 128 of 271 patients in the HAL group (42.7%) demonstrated tumor recurrence (Table 1, right column). This difference was mainly influenced by patients who did not receive BCG (61.8% in the white light group vs. 49.3% in the HAL group). The difference in tumor recurrence was less significant in patients who received BCG (32.7% in the white light group vs. 38.0% in the HAL group).

[0167] In the white light group, the difference in recurrence rate between patients treated with and without BCG was statistically significant with a p-value < 0.001 (32.7% vs. 61.8%), demonstrating the efficacy of BCG in preventing bladder cancer recurrence.

[0168] However, in the HAL group, the efficacy of BCG treatment could not be demonstrated because the difference in recurrence rate between patients who received and did not receive BCG was not statistically significant (p value = 0.148, 38.0% vs. 49.3%). This absence of a significant BCG effect was mainly due to a significant reduction in tumor recurrence rate in patients who did not receive BCG (49.3% vs. 61.8%), and this reduction in tumor recurrence rate may be explained by the therapeutic effect of HAL (HAL PDT effect) leading to the prevention of bladder cancer recurrence.

[0169] Comparison of tumor recurrence rates in patients treated with or without intravesical BCG and / or mitomycin

[0170] Mitomycin is a chemotherapeutic agent used to treat bladder cancer. It can be instilled after TUR (single instillation) to, for example, prevent tumor cell seeding, i.e., reattachment of tumor cells detached during resection to the bladder wall. Mitomycin was administered to 16 patients (5.9%) in the HAL group and 20 patients (7.1%) in the white light group after TUR.

[0171] The tumor recurrence rates of both patient groups were determined and the results are shown in Table 2

[0172] Table 2: Tumor recurrence rate by group and BCG and / or mitomycin treatment

[0173]

[0174] In the white light group, the difference in recurrence rate between patients who did and did not receive BCG and / or mitomycin treatment was statistically significant with a p-value < 0.001 (36.5% vs. 63.1%), demonstrating the efficacy of BCG and / or mitomycin in preventing bladder cancer recurrence.

[0175] However, in the HAL group, the efficacy of these treatments could not be demonstrated because the difference in recurrence rates between patients who received and did not receive BCG and / or mitomycin was not statistically significant (p value = 0.291, 41.5% vs. 49.0%). This absence of a significant BCG and / or mitomycin effect was mainly due to a significant reduction in tumor recurrence rates in patients who did not receive BCG and / or mitomycin (49.3% vs. 63.1%), and this reduction in tumor recurrence rates may be explained by the therapeutic effect of HAL leading to the prevention of bladder cancer recurrence (HALPDT effect).

[0176] Various embodiments of the present invention are as follows:

[0177] Embodiment 1: A method for photodynamic therapy of bladder cancer comprising a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof, wherein the composition is instilled into the bladder of a patient in need of such treatment and the interior of the bladder is exposed to a radiation having a power of 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

[0178] Embodiment 2: The composition used according to embodiment 1, wherein the blue light is emitted at 0.2 to 15.0 J / cm 2 The light dose provided.

[0179] Embodiment 3: The composition for use according to embodiment 1 or 2, wherein the interior of the bladder is exposed to an energy flux of 2.5 to 7.0 mW / cm 2 of blue light.

[0180] Embodiment 4: The composition used according to embodiment 3, wherein the blue light is emitted at 0.3 to 8.0 J / cm 2 The light dose provided.

[0181] Embodiment 5: The composition for use according to any one of embodiments 1 to 4, wherein the interior of the bladder is also exposed to an energy flux of 3.0 to 22.0 mW / cm 2 of white light.

[0182] Embodiment 6: The composition used according to embodiment 5, wherein the white light is 0.4 to 26.5 J / cm 2 The light dose provided.

[0183] Embodiment 7: A composition for use according to embodiment 5, wherein the interior of the bladder is exposed to an energy flux rate of 5.0 to 12.5 mW / cm 2 of white light.

[0184] Embodiment 8: The composition used according to embodiment 7, wherein the white light is 0.6 to 15.0 J / cm 2 The light dose provided.

[0185] Embodiment 9: The composition for use according to any one of embodiments 1 to 8, wherein the composition is an aqueous solution of HAL, preferably a solution of HAL in an aqueous buffer, more preferably a solution of HAL in a phosphate buffer.

[0186] Embodiment 10: The composition for use according to embodiment 9, wherein the pH of the composition is in the range of 4.5 to 7.5, preferably in the range of 5.7 to 7.2.

[0187] Embodiment 11: A composition for use according to any one of embodiments 1 to 10, wherein the composition is a solution of 2 mg / ml HAL hydrochloride in an aqueous buffer comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0188] Embodiment 12: A composition for use according to any one of embodiments 5 to 11, wherein the interior of the bladder is first exposed to white light and then to blue light.

[0189] Embodiment 13: The composition for use according to any one of embodiments 1 to 12, wherein a blue light cystoscope is used as the light source to provide blue light or said blue light and white light.

[0190] Embodiment 14: The composition for use according to embodiment 13, wherein the blue light cystoscope is a commercially available blue light cystoscope.

[0191] Embodiment 15: A composition for use according to any one of embodiments 1 to 14, wherein the interior of the bladder is exposed to blue light or blue and white light for a period of 2 to 20 minutes.

[0192] Embodiment 16: Use of the composition according to any one of embodiments 1 to 15 in a method of treating bladder cancer, wherein the method of photodynamic therapy is used as an adjuvant therapy.

[0193] Embodiment 17: The composition for use according to embodiment 16, wherein the bladder cancer is NMIBC, and the method of photodynamic therapy is performed concurrently with transurethral resection of NMIBC.

[0194] Embodiment 18: The composition for use according to embodiment 16, wherein the bladder cancer is NMIBC and the method of photodynamic therapy is performed in a patient who has undergone transurethral resection of NMIBC.

[0195] Embodiment 19: The composition for use according to embodiments 16-18, wherein the photodynamic therapy method replaces or partially replaces other auxiliary therapies.

[0196] Embodiment 20: The composition for use according to embodiment 19, wherein the other adjuvant therapy is chemotherapy and / or immunotherapy, preferably BCG treatment.

[0197] Embodiment 21: A composition for use according to embodiment 19, wherein the method of photodynamic therapy is performed in BCG-refractory patients.

[0198] Embodiment 22: The composition for use according to any one of embodiments 1 to 15, for use in a method of treating bladder cancer, wherein the method of photodynamic therapy is used as a neoadjuvant therapy.

[0199] Embodiment 23: A composition for use according to embodiment 22, wherein the bladder cancer is MIBC. Embodiment 24: A composition for use according to embodiment 23, wherein the method of photodynamic therapy is performed prior to cystectomy.

[0200] Embodiment 25: The composition for use according to embodiment 24, wherein the cystectomy is performed directly after the method of photodynamic therapy.

[0201] Embodiment 26: A method for photodynamic therapy of bladder cancer comprising instilling a composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof into the bladder of a patient in need of such treatment and exposing the interior of the bladder to a radiation having a power of 1.5 to 12.5 mW / cm 2 Embodiment 27: The method according to embodiment 26, wherein the blue light has an energy flux of 0.2 to 15.0 J / cm 2 The light dose provided.

[0202] Embodiment 28: The method of embodiment 26 or 27, wherein the interior of the bladder is exposed to an energy flux of 2.5 to 7.0 mW / cm 2 of blue light.

[0203] Embodiment 29: The method of embodiment 28, wherein the blue light is emitted at 0.3 to 8.0 J / cm 2 The light dose provided.

[0204] Embodiment 30: The method according to any one of embodiments 26 to 29, wherein the interior of the bladder is further exposed to an energy flux rate of 3.0 to 22.0 mW / cm 2 of white light.

[0205] Embodiment 31: The method of embodiment 30, wherein the white light is at 0.4 to 26.5 J / cm 2 The light dose provided.

[0206] Embodiment 32: The method of embodiment 30, wherein the interior of the bladder is exposed to an energy flux rate of 5.0 to 12.5 mW / cm 2 of white light.

[0207] Embodiment 33: A composition for use according to embodiment 32, wherein the white light is at 0.6 to 15.0 J / cm 2 The light dose provided.

[0208] Embodiment 34: The method according to any one of embodiments 26 to 33, wherein the composition is an aqueous solution of HAL, preferably a solution of HAL in an aqueous buffer, more preferably a solution of HAL in a phosphate buffer.

[0209] Embodiment 35: The method according to embodiment 34, wherein the pH of the composition is in the range of 4.5 to 7.5, preferably in the range of 5.7 to 7.2.

[0210] Embodiment 36: A method according to any one of embodiments 26 to 35, wherein the composition is a solution of 2 mg / ml HAL hydrochloride in an aqueous buffer comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

[0211] Embodiment 37: The method of any one of Embodiments 30 to 36, wherein the interior of the bladder is first exposed to white light and then to blue light.

[0212] Embodiment 38: The method according to any one of embodiments 26 to 37, wherein a blue light cystoscope is used as the light source to provide blue light or said blue light and white light.

[0213] Embodiment 39: The method according to embodiment 38, wherein the blue light cystoscope is a commercially available blue light cystoscope.

[0214] Embodiment 40: The method of any one of Embodiments 26 to 39, wherein the interior of the bladder is exposed to blue light or blue and white light for a period of 2 to 20 minutes.

[0215] Embodiment 41: The method according to any one of embodiments 26 to 40, for use in a method of treating bladder cancer, wherein the method of photodynamic therapy is used as an adjuvant therapy.

[0216] Embodiment 42: The method according to embodiment 41, wherein the bladder cancer is NMIBC, and the method of photodynamic therapy is performed concurrently with transurethral resection of NMIBC.

[0217] Embodiment 43: The method according to embodiment 41, wherein the bladder cancer is NMIBC, and the method of photodynamic therapy is performed in a patient who has undergone transurethral resection of NMIBC.

[0218] Embodiment 44: The method according to embodiments 41 to 43, wherein the photodynamic therapy method replaces or partially replaces other auxiliary therapies.

[0219] Embodiment 45: The method according to embodiment 44, wherein said other adjuvant therapy is chemotherapy and / or immunotherapy, preferably BCG treatment.

[0220] Embodiment 46: A method according to embodiment 44, wherein the method of photodynamic therapy is performed in BCG-refractory patients.

[0221] Embodiment 47: The method according to any one of embodiments 26 to 40, for use in a method of treating bladder cancer, wherein the method of photodynamic therapy is used as a neoadjuvant therapy.

[0222] Embodiment 48: The method according to embodiment 47, wherein the bladder cancer is MIBC.

[0223] Embodiment 49: The method of embodiment 48, wherein the method of photodynamic therapy is performed prior to cystectomy.

[0224] Embodiment 50: The method of embodiment 49, wherein the cystectomy is performed directly after the method of photodynamic therapy.

Claims

1. A composition comprising 5-ALA hexyl ester (HAL) or a pharmaceutically acceptable salt thereof for use in a method of photodynamic therapy of bladder cancer, wherein the composition is instilled into the bladder of a patient in need of such treatment and the interior of the bladder is exposed to a radiation having a power of 1.5 to 12.5 mW / cm 2 The energy flow rate of blue light.

2. The composition for use according to claim 1, wherein The blue light is 0.2 to 15.0 J / cm 2 The light dose provided.

3. The composition for use according to claim 1 or 2, wherein The interior of the bladder is exposed to an energy flux rate of 2.5 to 7.0 mW / cm 2 of blue light.

4. The composition for use according to claim 3, wherein The blue light is 0.3 to 8.0 J / cm 2 The light dose provided.

5. The composition for use according to any one of claims 1 to 4, wherein The interior of the bladder is also exposed to energy at a flux rate of 3.0 to 22.0 mW / cm 2 of white light.

6. The composition for use according to claim 5, wherein The white light is 0.4 to 26.5 J / cm 2 The light dose provided.

7. The composition for use according to claim 5, wherein The interior of the bladder is exposed to an energy flux rate of 5.0 to 12.5 mW / cm 2 of white light.

8. The composition for use according to claim 7, wherein The white light is 0.6 to 15.0 J / cm 2 The light dose provided.

9. The composition for use according to any one of claims 1 to 8, wherein The composition is an aqueous solution of HAL, preferably a solution of HAL in an aqueous buffer, more preferably a solution of HAL in a phosphate buffer.

10. The composition for use according to claim 9, wherein The pH of the composition is in the range of 4.5 to 7.5, preferably in the range of 5.7 to 7.

2.

11. The composition for use according to any one of claims 1 to 10, wherein The composition is a solution of 2 mg / ml HAL hydrochloride in an aqueous buffer comprising dehydrated disodium phosphate, monopotassium phosphate, sodium chloride, hydrochloric acid, sodium hydroxide and water.

12. The composition for use according to any one of claims 5 to 11, wherein The interior of the bladder is first exposed to white light and then to blue light.

13. The composition for use according to any one of claims 1 to 12, wherein A blue light cystoscope is used as a light source to provide blue light or the blue light and white light.

14. The composition for use according to claim 13, wherein The blue light cystoscope is a commercially available blue light cystoscope.

15. The composition for use according to any one of claims 1 to 14, wherein The interior of the bladder is exposed to blue light or blue and white light for a period of 2 to 20 minutes.

16. Composition for use according to any one of claims 1 to 15, for use in a method of treating bladder cancer, wherein the method of photodynamic therapy is used as an adjuvant therapy.

17. The composition for use according to claim 16, wherein The bladder cancer is NMIBC, and the method of photodynamic therapy is performed concurrently with transurethral resection of NMIBC.

18. The composition for use according to claim 16, wherein The bladder cancer is NMIBC, and the method of photodynamic therapy is performed in a patient who has undergone transurethral resection of NMIBC.

19. The composition for use according to claims 16-18, wherein The photodynamic therapy method replaces or partially replaces other auxiliary therapies.

20. The composition for use according to claim 19, wherein The other adjuvant therapy is chemotherapy and / or immunotherapy, preferably BCG treatment.

21. The composition for use according to claim 19, wherein The method of photodynamic therapy was performed in BCG-refractory patients.

22. A composition for use according to any one of claims 1 to 15, for use in a method for treating bladder cancer, wherein: The method of photodynamic therapy is used as a neoadjuvant therapy.

23. The composition for use according to claim 22, wherein The bladder cancer is MIBC.

24. The composition for use according to claim 23, wherein The method of photodynamic therapy is performed before cystectomy.

25. The composition for use according to claim 24, wherein The cystectomy was performed directly after the photodynamic therapy method.

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