Clinical Practice of Photodynamic Therapy Using Talaporfin Sodium

Journal of Clinical Medicine

Review Clinical Practice of Photodynamic Therapy Using Talaporﬁn Sodium for Esophageal Cancer

Tomonori Yano *, Tatsunori Minamide, Kenji Takashima, Keiichiro Nakajo , Tomohiro Kadota and Yusuke Yoda

Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa 277-8577, Japan; [email protected] (T.M.); [email protected] (K.T.); [email protected] (K.N.); [email protected] (T.K.); [email protected] (Y.Y.) * Correspondence: [email protected]; Tel.: +81-4-7133-1111; Fax: +81-4-7134-6928

Abstract: Photodynamic therapy (PDT) using a conventional photosensitizer was approved for esophageal cancer in the early 1990s; however, it was replaced by other conventional treatment modalities in clinical practice because of the high frequency of cutaneous phototoxicity and esophageal stricture after the procedure. The second-generation photosensitizer, talaporfin sodium, which features more rapid clearance from the body, was developed to reduce skin phototoxicity, and talaporfin sodium can be excited at longer-wavelength lights comparing with a conventional photosensitizer. Endoscopic PDT using talaporfin sodium was initially developed for the curative treatment of central- type early lung cancer in Japan, and was approved in the early 2000s. After preclinical experiments, PDT using talaporfin sodium was investigated for patients with local failure after chemoradiotherapy, which was the most serious unmet need in the practice of esophageal cancer. According to the favor-

able results of a multi-institutional clinical trial, PDT using talaporﬁn sodium was approved as an endoscopic salvage treatment for patients with local failure after chemoradiotherapy for esophageal

Citation: Yano, T.; Minamide, T.; cancer. While PDT using talaporfin sodium is gradually spreading in clinical practice, further evalua- Takashima, K.; Nakajo, K.; Kadota, T.; tion at the point of clinical benefit is necessary to determine the importance of PDT in the treatment Yoda, Y. Clinical Practice of of esophageal cancer. Photodynamic Therapy Using Talaporfin Sodium for Esophageal Keywords: photodynamic therapy; esophageal cancer; talaporfin sodium Cancer. J. Clin. Med. 2021, 10, 2785. https://doi.org/10.3390/jcm10132785

Academic Editors: Waseem Jerjes and 1. Introduction Jiro Akimoto Photodynamic therapy (PDT) is a unique cancer treatment that involves a photosensitizer (PS), which is incorporated into cancer cells and activates light of a speciﬁc Received: 15 May 2021 wavelength. The main mechanism of action of PDT for cancer tissue is known to be direct Accepted: 21 June 2021 Published: 24 June 2021 cytotoxicity due to reactive oxygen species, which occurs as a result of photochemical and photophysical reactions between PS and the speciﬁc light [1]. Esophageal cancer was, in

Publisher’s Note: MDPI stays neutral the early 1990s, one of the first approved clinical indications of PDT using conventional with regard to jurisdictional claims in porphyrin-based PS both in the United States and Japan [2]. In the United States, PDT has published maps and institutional affil- been approved as a palliative treatment for symptomatic obstructive advanced esophageal iations. cancer, and eradicative ablation of high-grade dysplasia of the esophagus, which is a premalignant disease of esophageal adenocarcinoma. Contrarily, PDT was approved as a curative treatment for superficial esophageal cancer that was deemed difficult to remove with conventional endoscopic resection (ER) in Japan. However, PDT was replaced in clinical practice by other effective and conventional treatment modalities for esophageal Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. cancer patients in both countries at the beginning of the 2000s. Radio-frequency ablation This article is an open access article was established as the standard of care for the eradication of dysplastic Barret’s esophagus distributed under the terms and based on a large volume of evidence, including a randomized control trial [3]. The use conditions of the Creative Commons of endoscopic submucosal dissection (ESD), an evolved technique of ER that can remove Attribution (CC BY) license (https:// large superficial esophageal cancer, has dramatically increased worldwide [4]. The most creativecommons.org/licenses/by/ significant reasons that PDT using porfimer sodium lost the opportunity to become a 4.0/). treatment for esophageal cancer patients were phototoxicity due to the PS and esophageal

J. Clin. Med. 2021, 10, 2785. https://doi.org/10.3390/jcm10132785 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 2785 2 of 9

stricture after PDT. Therefore, the development of a PS that clears more rapidly from the body, targeted at clinical applications so that PDT can take advantage of its strength, was necessary in order for this to become a clinical practice for esophageal cancer patients. In this article, we review the history of PDT using talaporﬁn sodium, a second-generation photosensitizer, and its progression into clinical practice for use in esophageal cancer cases.

2. The Characteristics of Talaporfin Sodium As mentioned above, a disadvantage of PDT using conventional PS, including porfimer sodium, is phototoxicity, which requires more than one month of sunshade. The second-generation PS, talaporfin sodium (Laserphyrin for Injection, Meiji Seika Pharma; Meiji Seika Pharma, Tokyo, Japan), which features a more rapid clearance from the body, was developed to reduce skin phototoxicity in Japan. Talaporfin sodium was developed as a mono-L-aspartyl chlorin e6 (NPe6), a chlorin-based pure plant-origin agent (Figure1 )[5,6]. Talaporfin sodium can absorb light at longer wavelengths (664 nm) compared to light absorbed by conventional porfimer sodium (630 nm); therefore, it is expected to affect deeper tissues. In a comparative experimental study between PDT using NPe6 and hematoporphyrin derivative (HpD) in a mouse model, PDT using NPe6 demonstrated the disap- pearance of palpable tumors with extremely low normal skin photosensitivity compared to HpD [6]. The depth of tumor tissue injury was significantly increased in PDT using Npe6 in a cholangiocarcinoma cell line-mounted mouse model compared with PDT using HpD [7]. Furthermore, considering the unique mechanism of blood flow stasis due to a significant reduction in the diameter of the lumen of arterioles, as well as direct cytotoxicity in rat models, the best tumor response was produced when the maximum effect of both vascular stasis and direct cytotoxicity was achieved in PDT using NPe6 [8]. A phase-I trial of PDT for patients with a variety of cutaneous cancerous lesions was investigated to assess the optimal dose of NPe6, as well as the safety and efficacy of PDT [9]. Twelve patients who refused or failed conventional treatment for metastatic or primary superficial cutaneous carcinoma, including head and neck squamous cell carcinoma or ductal adenocarcinoma of the breast, were enrolled in the study. A dose of 0.5–3.5 mg/kg of NPe6 was administered 4 h before laser illumination, and an argon-ion laser was used to activate PS at 664 nm. Flat tumors less than 1.5 cm in thickness were illuminated superficially using a microlens frontal fiber, and tumors with a thickness between 1.5 and 2.0 cm were illuminated interstitially using a cylindrical diffuser, while tumors more than 2.0 cm thick were not indicated. In this study, skin photosensitivity and phototoxicity were precisely assessed using a solar simulator. Phototoxicity was scored at frequent intervals within one week, and then every week until six weeks after drug administration. The NPe6 dose of 2.5 to 3.5 mg/kg combined with 100 J/cm2 light resulted in a 66% complete response (CR) and patients remained tumor-free for 12 weeks after treatment. Furthermore, apparent selectivity for destruction or necrosis was not shown between tumors and normal skin at the aforementioned doses of NPe6. PDT using NPe6 demonstrated a reduced degree and duration of cutaneous phototoxicity compared with conventional PS, even at a dose of 3.5 mg/kg, while patients treated with 3.5 mg/kg NPe6 showed only minimal erythema within 96 h after injection [9]. This phase-I trial demonstrated the potential of NPe6 as an effective and less cutaneous phototoxic PS in cancer patients. In Japan, Dr. Kato and Dr. Furukawa, along with their team members, developed a strategy for endoscopic application of PDT using talaporfin sodium as a curative treatment for central-type superficial lung cancer. They introduced a diode laser of 664 nm as a light source and performed a phase-I trial for patients with bronchogenic early squamous cell carcinoma [10]. An excellent CR rate (87.5%, 7/8) was achieved without serious adverse events in the phase-I trial; therefore, they conducted a multicenter phase-II trial to evaluate the safety and efficacy of PDT for patients with lung cancer [11]. Patients who were not candidates for surgery or refused surgery for lesions of 2 cm or less in size with histologically confirmed squamous cell carcinoma were eligible. They set the treatment dose of talaporfin sodium as 40 mg/m2 and laser illumination at a power density of J. Clin. Med. 2021, 10, 2785 3 of 9

J. Clin. Med. 2021, 10, 2785 3 of 9 150 mW/cm2 and energy level of 100 J/cm2 at 4 h after administration, according to the results of their phase-I trial. Forty-one patients with 46 lesions were enrolled in the study, and the CR rate was 84.6% of the evaluable lesions. Skin photosensitivity disappeared within two weeks of drug administration in 84.8% of patients. Based on the excellent results of this phase-II study, PDT using talaporﬁn sodium and a diode laser was approved for lung cancer in Japan in 2004. The endoscopic application of PDT using talaporﬁn sodium is expected to expand gastrointestinal cancer including esophageal cancer.

Figure 1. Structural formula of talaporfin sodium. 3. Innovation of PDT for Local Failure after Radiotherapy for Esophageal Cancer Figure 1. Structural formula of talaporfin sodium Among the esophageal cancers treated with PDT using porfimer sodium in the past, local failure was the first target for the development of PDT using talaporfin sodium. In Japan,Chemoradiotherapy Dr. Kato and (CRT) Dr. has demonstratedFurukawa, favorable along results with in patientstheir team with locally members, developed a advanced-stage esophageal cancer or in those who declined to be treated with an esophagec- strategy fortomy endoscopic at the operable stage. application However, more of than PDT half ofus theing patients talaporfin in this study sodium developed as a curative treatment for central-typelocal failure at the primarysuperficial site of the lung esophagus, cancer. and the They survival introduced outcome of these a patients diode laser of 664 nm as was extremely poor [12]. Therefore, the improvement of local control was an unmet issue a light sourcein the non-surgicaland performed intervention a for phase-I patients with trial esophageal for patients cancer. We with introduced bronchogenic PDT early squa- using porfimer sodium (Photofrin, Pfizer Japan Inc., Tokyo, Japan) and a 633 nm excimer mous cell dyecarcinoma laser (EDL-1; [10]. Hamamatsu An excellent Photonics, Hamamatsu,CR rate (87.5%, Japan) as a 7/8) treatment was option achieved for without serious adverse eventspatients within the local phase-I failure within trial; the T2 therefor stage withoute, they any metastasis, conducted and we carrieda multicenter out phase-II trial a single-center phase-II study to evaluate the efficacy and safety of PDT [13]. PDT was to evaluateperformed the safety with the and intravenous efficacy administration of PDT for of 2 mg/kgpatients of porfimer with sodiumlung 48–72cancer h [11]. Patients who were not candidatesafter excimer dye for laser surgery illumination or withrefused a fluence surger of 75 J/cmy for2. Twenty-fivelesions of patients 2 cm or less in size with were enrolled in the study, and 19 patients achieved CR resulting in a CR rate of 76% histologically(95% CI;confirmed 55–91%). All patientssquamous were instructed cell carcinoma to avoid sunlight were or strong eligible. artificial lightThey set the treatment dose of talaporfinfor one month sodium after porfimer as sodium40 mg/m administration;2 and laser however, illumination cutaneous phototoxicity at a power density of 150 was observed in eight patients (32%). We experienced a case of treatment-related death 2 2 mW/cm anddue to energy gastrointestinal level hemorrhage of 100 J/cm at the treated at 4 siteh after 33 days administration, after PDT. We also reported according to the results of their phase-Ifavorable trial. long-term Forty-on survival outcomese patients of patients with treated 46 with lesions PDT using were porfimer enrolled sodium in the study, and for local failure after CRT for esophageal squamous cell carcinoma in a retrospective study the CR rateat awas single 84.6% institution of [14 the]. evaluable lesions. Skin photosensitivity disappeared within two weeks of drug administration in 84.8% of patients. Based on the excellent results of this phase-II study, PDT using talaporfin sodium and a diode laser was approved for lung cancer in Japan in 2004. The endoscopic application of PDT using talaporfin sodium is expected to expand gastrointestinal cancer including esophageal cancer.

3. Innovation of PDT for Local Failure after Radiotherapy for Esophageal Cancer Among the esophageal cancers treated with PDT using porfimer sodium in the past, local failure was the first target for the development of PDT using talaporfin sodium. Chemoradiotherapy (CRT) has demonstrated favorable results in patients with locally advanced-stage esophageal cancer or in those who declined to be treated with an esophagectomy at the operable stage. However, more than half of the patients in this study developed local failure at the primary site of the esophagus, and the survival outcome of these patients was extremely poor [12]. Therefore, the improvement of local control was an unmet issue in the non-surgical intervention for patients with esophageal cancer. We introduced PDT using porfimer sodium (Photofrin, Pfizer Japan Inc., Tokyo, Japan) and a 633 nm excimer dye laser (EDL-1; Hamamatsu Photonics, Hamamatsu, Japan) as a treatment option for patients with local failure within the T2 stage without any metastasis, and we carried out a single-center phase-II study to evaluate the efficacy and safety of PDT [13]. PDT was performed with the intravenous administration of 2 mg/kg of porfimer sodium 48–72 h after excimer dye laser illumination with a fluence of 75 J/cm2. Twenty-five patients were enrolled in the study, and 19 patients achieved CR resulting in a CR rate of

J. Clin. Med. 2021, 10, 2785 4 of 9

76% (95% CI; 55–91%). All patients were instructed to avoid sunlight or strong artificial light for one month after porfimer sodium administration; however, cutaneous phototoxicity was observed in eight patients (32%). We experienced a case of treatment-related death due to gastrointestinal hemorrhage at the treated site 33 days after PDT. We also reported favorable long-term survival outcomes of patients treated with PDT using porfimer sodium for local failure after CRT for esophageal squamous cell carcinoma in a retrospective study at a single institution [14]. PDT using talaporfin sodium as a salvage treatment for local failure after CRT for esophageal cancer To resolve the cutaneous phototoxicity of PDT using porfimer sodium, we would like to introduce talaporfin sodium to patients with esophageal cancer. The excimer dye laser, which excites the porfimer sodium, was extremely large and expensive, and its release was canceled due to the lower popularity of PDT using porfimer sodium in the early 2000s in Japan. A diode laser with a wavelength of 664 nm, which can excite talaporfin sodium, was portable and cheaper than the conventional system (Figure 2). Therefore, we attempted to introduce PDT using talaporfin sodium for esophageal cancer in a preclinical J. Clin. Med. 2021, 10, 2785 study. Tissue damage to the esophagus due to PDT using4 of 9talaporfin sodium followed by 640 nm diode laser illumination through gastrointestinal endoscopy was evaluated in a living canine model, and tissue damage to the normal esophagus was deeper and larger PDT using talaporfin sodium as a salvage treatment for local failure after CRT for esophagealas the illuminated cancer. amount of laser increased [15]. Preclinical study results suggested it To resolve the cutaneous phototoxicity of PDT using porfimer sodium, we would like towould introduce be talaporfin desirable sodium to to patientsinvestigate with esophageal the optimal cancer. The la excimerser dose dye laser, by initiating the minimal dose to whichincrease excites thestep-by-step porfimer sodium, in was human extremely application. large and expensive, As andsuch, its release a phase-I study to determine the was canceled due to the lower popularity of PDT using porfimer sodium in the early 2000soptimum in Japan. Alaser diode fluence laser with arate wavelength commenced of 664 nm, which [16]. can Th exciteis laser talaporfin dose-escalation study used a 40 sodium,mg/m was2 fixed portable dose and cheaper of talaporfin than the conventional sodium, system and (Figure the2 ).starting Therefore, fluence we of the 664 nm diode laser attempted to introduce2 PDT using talaporfin sodium for esophageal cancer2 in a preclinical 2 study.was Tissue 50 J/cm damage, with to the esophagusan escalation due to PDT plan using to talaporfin 75 J/cm sodium and followed 100 byJ/cm with three patients at each 640level. nm diode In this laser illuminationphase-I trial, through there gastrointestinal were no endoscopy cases wasof evaluateddose-limiting in a toxicity at any level of the living canine model, and tissue damage to the normal esophagus was deeper and larger aslaser the illuminated dose. Furthermore, amount of laser increased five of [15 ].the Preclinical nine pati studyents results with suggested local it failure after CRT for esopha- wouldgeal becancer desirable achieved to investigate CR the optimal after laser PDT dose [16]. by initiating A multi-institutional the minimal dose phase II study was con- to increase step-by-step in human application. As such, a phase-I study to determine theducted optimum to laser evaluate fluence rate the commenced efficacy [16]. and This laser safety dose-escalation of PDT study using used atalaporfin sodium followed by 40diode mg/m2 fixedlaser dose illumination of talaporfin sodium, for andpatients the starting with fluence local of the 664failure nm diode after radiotherapy or CRT for laser was 50 J/cm2, with an escalation plan to 75 J/cm2 and 100 J/cm2 with three patients atesophageal each level. In this cancer phase-I [17]. trial, therePatients were no with cases histologically of dose-limiting toxicity confirmed at any residual or recurrent esoph- levelageal of the squamous laser dose. Furthermore, cell carcinoma five of the (ESCC) nine patients at the with primary local failure site, after limited to the T2 stage by en- CRT for esophageal cancer achieved CR after PDT [16]. A multi-institutional phase II studydoscopic was conducted ultrasound, to evaluate thewere efficacy eligible. and safety Twenty-six of PDT using talaporfin patients sodium with 28 histologically confirmed followedlesions by (T1b: diode laser 21 illuminationand T2: 7) for were patients enrolled, with local failure and after all radiotherapywere treated or with PDT. Of these patients, CRT for esophageal cancer [17]. Patients with histologically confirmed residual or recurrent esophageal23 with squamous 25 lesions cell carcinoma achieved (ESCC) CR at the (CR primary rate: site, limited88.5%). to the There T2 stage were by no cases of cutaneous skin endoscopic ultrasound, were eligible. Twenty-six patients with 28 histologically confirmed lesionstoxicity (T1b: 21even and T2: with 7) were a enrolled,two-week and all weresunshade treated with peri PDT.od Of theseand patients, no cases of severe adverse events, 23including with 25 lesions treatment-related achieved CR (CR rate: 88.5%). death There [17]. were Accordin no cases of cutaneousg to the skin results of this trial, PDT using toxicity even with a two-week sunshade period and no cases of severe adverse events, includingtalaporfin treatment-related sodium deathand [a17 diode]. According laser to thewas results approved of this trial, as PDT an using endoscopic salvage treatment for talaporfinpatients sodium with and esophageal a diode laser was cancer approved with as an endoscopiclocal failure salvage after treatment radiotherapy or CRT in Japan in for patients with esophageal cancer with local failure after radiotherapy or CRT in Japan in2015. 2015.

FigureFigure 2. The 2. system The ofsystem a diode laser of whicha diode can excite laser talaporﬁn which sodium. can excite talaporfin sodium.

J. Clin. Med. 2021, 10, 2785 5 of 9

J. Clin. Med. 2021, 10, 2785 5 of 9 4. Indication of PDT for Local Failure after Radiotherapy for Esophageal Cancer The approved indication of PDT using talaporfin sodium for esophageal cancer is 4.limited Indication to patients of PDT with for Locallocal failure Failure after after radiotherapy Radiotherapy or for CRT. Esophageal A clinical Cancer flowchart for the indication of PDT using talaporfin sodium is presented in Figure 3. First, lymph node The approved indication of PDT using talaporfin sodium for esophageal cancer is or distant metastasis should be evaluated using computed tomography; PDT is not indi- limited to patients with local failure after radiotherapy or CRT. A clinical flowchart for thecated indication if the patients of PDT have using metastases. talaporfin The sodium contraindication is presented of PDT in Figure using3 talaporfin. First, lymph sodium nodewas a or history distant of metastasis hypersensitivity should to be talaporf evaluatedin sodium using computed or concomitant tomography; porphyria. PDT Because is not indicatedof our experience if the patients of treatment-related have metastases. death The with contraindication gastrointestinal of hemorrhage PDT using talaporfin due to aor- sodiumtic rupture was in a historypatients of treated hypersensitivity with PDT tous talaporfining porfimer sodium sodium or concomitant [13,14], patients porphyria. whose Becauselesions before of our CRT experience were judged of treatment-related to involve the aorta death were with set gastrointestinal as contraindications hemorrhage for PDT dueusing to talaporfin aortic rupture sodium. in patients When treatedpatients with do not PDT have using metastasis, porfimer sodiumthe indication [13,14], for patients ER, in- whosecluding lesions ESD, should before CRTbe evaluated were judged because to involve ER is the the least aorta invasive were set treatment as contraindications for local fail- forure PDTlesions using [18,19]. talaporfin ER, including sodium. WhenESD, is patients generally do notindicated have metastasis, for lesions the within indication T1a in fordepth ER, without including ulceration ESD, should or severe be evaluated fibrosis; th becauseerefore, ER the is indication the least invasiveof ER is treatmentlimited and formust local be judged failure based lesions on [18 the,19 operator’s]. ER, including skill. While ESD, salvage is generally surgery indicated is the most for lesionsinvasive withintreatment T1a method in depth for without patients ulceration with local or failur severee after fibrosis; CRT therefore, for esophageal the indication cancer, it of can ER be isa curative limited andintent must treatment be judged when based complete on the re operator’ssection is skill.achieved While without salvage any surgery fetal compli- is the mostcations invasive [20,21]. treatment Therefore, method a patient’s for patientsphysical with tolerability local failure for surgery after CRT should for esophagealbe discussed cancer,with surgeons it can be at a the curative conference, intent treatmentpresenting when the advantages complete resection and disadvantages is achieved of without salvage anysurgery fetal for complications patients. After [20 these,21]. Therefore,steps, if the a pa patient’stient is judged physical to tolerability be intolerant for to surgery surgery shouldor the patient be discussed refuses withsurgery, surgeons PDT using at the tala conference,porfin sodium presenting can be the an advantages alternative andtreat- disadvantagesment option. The of salvagedefinitive surgery indication for patients. criteria After of PDT these in practice steps, if thefollow patient the iseligibility judged tocri- beteria intolerant of a phase-II to surgery study or[16], the as patient follows: refuses (1) local surgery, failure PDT lesion using that talaporfin is suspected sodium to be can lim- beited an to alternative within the treatment muscularis option. propria The (T2) definitive depth of indication the esophageal criteria wall; of PDT (2) inlongitudinal practice follow the eligibility criteria of a phase-II study [16], as follows: (1) local failure lesion that lesion length of 3 cm or less; (3) half circumference of the lumen or less; and (4) no invasion is suspected to be limited to within the muscularis propria (T2) depth of the esophageal of the cervical esophagus. The depth of invasion was carefully evaluated using endoscopic wall; (2) longitudinal lesion length of 3 cm or less; (3) half circumference of the lumen or ultrasonography and computed tomography. The limitation of the size of the criteria was less; and (4) no invasion of the cervical esophagus. The depth of invasion was carefully determined to prevent esophageal stricture, which is the most significant major complica- evaluated using endoscopic ultrasonography and computed tomography. The limitation of tion of PDT using porfimer sodium for esophageal cancer in previous reports [22,23]. Be- the size of the criteria was determined to prevent esophageal stricture, which is the most significantcause of the major anatomical complication stricture of at PDT the using cervical porfimer esophagus sodium or gag for esophagealreflux, it is cancerdifficult in to previouskeep the reportsper-oral [ 22endoscopy,23]. Because in the of theappropriate anatomical position stricture that at enables the cervical adequate esophagus laser illu- or gagmination reflux, to it the is difficulttarget lesions. to keep PDT the is per-oral not advocated endoscopy if the in lesions the appropriate have invaded position the thatcervi- enablescal esophagus. adequate laser illumination to the target lesions. PDT is not advocated if the lesions have invaded the cervical esophagus.

Figure 3.3. A clinicalclinical flowchart flowchart for for the the indication indication of PDTof PDT using using talaporfin talaporfin sodium sodium for esophageal for esophageal cancer. cancer

J. Clin. Med. 2021, 10, 2785 6 of 9

J. Clin. Med. 2021, 10, 2785 5. Clinical Practice of PDT Using Talaporfin Sodium for Esophageal6 ofCancer 9 In PDT using talaporfin sodium for esophageal cancer, we can only use the frontal diffuser; therefore, delivering an adequate dose of laser illumination while maintaining 5.the Clinical direct Practice light viewing of PDT Using angle Talaporfin of endoscopy Sodium and for Esophageal the appropriate Cancer distance between the tip of theIn PDTdiffuser using and talaporfin the lesion sodium is forimportant. esophageal At cancer, the appropriate we can only use angle the frontaland distance, a plastic diffuser; therefore, delivering an adequate dose of laser illumination while maintaining the directhood light was viewing attached angle to of the endoscopy tip of andthe theendoscope, appropriate and distance the betweenedge of the the tip hood of the was fixed to the diffusersurface and of thethe lesion esophageal is important. mucosa At the during appropriate illumination. angle and distance, Target a plasticillumination hood and a reduc- wastion attached in the toinfluence the tip of theof normal endoscope, mucosa and the should edge of thebe hoodspecifically was fixed focused to the surface on in order to avoid ofesophageal the esophageal stricture mucosa after during PDT. illumination. The illumination Target illumination was initiated and a reduction at the in distal the end of the le- influence of normal mucosa should be specifically focused on in order to avoid esophageal stricturesion; the after spot PDT. was The moved illumination to the was oral initiated side atof thethe distal lesion end step-by-step, of the lesion; the and spot the fluence of the wasdiode moved laser to thewas oral set side at of100 the J/cm lesion2 with step-by-step, a fluence and therate fluence of 150 of mW/cm the diode2 laser. If the was lesion was larger setthan at 1001 cm J/cm2, 2multiplewith a fluence treatment rate of 150 fields mW/cm were2. If overla the lesionpped was to larger cover than the1 cm 2entire, lesion. An multipleopaque treatment hood is fields attached were overlappedat the tip to of cover the theendoscope entire lesion. to Anshield opaque the hood surrounding is normal attached at the tip of the endoscope to shield the surrounding normal mucosa from the illuminatedmucosa from laser the in order illuminated to prevent laser esophageal in order stricture to prevent (Figure4). esophageal stricture (Figure 4).

FigureFigure 4. 4.Endoscopic Endoscopic images images of PDT of procedurePDT procedure for local for failure loca lesionl failure after lesion chemoradiotherapy after chemoradiotherapy for foresophageal esophageal cancer. cancer. ( a()a The) The local local failure failure lesion; lesion; we planned we planned to illuminate to illuminate laser the for laser two spots the for two spots (yel- (yellowlow circles) circles) to to covercover whole whole the the lesion lesion (identified (identified with green with arrows). green ( barrows).) An opaque (b) hood An wasopaque hood was at- attachedtached at thetip tip of of the the endoscope endoscope to shield to shield the surrounding the surrounding mucosa duringmucosa the during illumination the illumination in in order 2 orderto avoid to avoid esophageal esophageal stricture. (c )( Thec) The fluence fluence of the diodeof the laser diode at 100 laser J/cm atwith 100 a fluenceJ/cm2 with rate a fluence rate of 2 of150 150 mW/cm mW/cm2 waswas delivereddelivered through through endoscopy, endosco keepingpy, keeping a distance a ofdistance less than of 2 cmless from than the 2 cm from the sur- surface of the mucosa. (d) Endoscopic image a day after PDT showing the ischemic change at the face of the mucosa. (d) Endoscopic image a day after PDT showing the ischemic change at the laser- laser-illuminated mucosa (identified with blue arrows). illuminated mucosa (identified with blue arrows). After approval for clinical usage in Japan, PDT using talaporfin sodium followed by diode laserAfter illumination approval for for local clinical failure usage after CRT in orJapan, radiotherapy PDT using for esophageal talaporfin cancer sodium is followed by graduallydiode laser spreading, illumination and there for are local several failure reports afte of ther single-centerCRT or radiotherapy experiences [ 24for–27 esophageal]. cancer Minamide et al. reported a retrospective comparative study between PDT using talaporfin sodiumis gradually and porfimer spreading, sodium and in patients there withare several local failure reports after CRTof the [26 ].single-center The local com- experiences [24– 27]. Minamide et al. reported a retrospective comparative study between PDT using talaporfin sodium and porfimer sodium in patients with local failure after CRT [26]. The local complete response was better in patients treated with PDT using talaporfin sodium compared with PDT using porfimer sodium (69.0% vs. 58.1%), although the difference was not statistically significant. Regarding the safety of PDT, both skin phototoxicity (4.5% vs. 18.2%, p < 0.049) and esophageal stricture (4.5% vs. 36.4%, p < 0.001) after PDT were significantly lower in patients treated with talaporfin sodium compared with those treated

J. Clin. Med. 2021, 10, 2785 7 of 9

plete response was better in patients treated with PDT using talaporfin sodium compared with PDT using porfimer sodium (69.0% vs. 58.1%), although the difference was not statistically significant. Regarding the safety of PDT, both skin phototoxicity (4.5% vs. 18.2%, p < 0.049) and esophageal stricture (4.5% vs. 36.4%, p < 0.001) after PDT were significantly lower in patients treated with talaporfin sodium compared with those treated with porfimer sodium. PDT using talaporfin sodium was introduced to clinical practice later than that of porfimer sodium; therefore, the improvement of patients’ selection or technical tips could overestimate the clinical results of PDT. However, the study demonstrated a more favorable outcome following treatment with PDT using talaporfin sodium compared with conventional PDT. Amanuma et al. reported that a local complete response with PDT using talaporfin sodium was associated with good prognoses in patients with local failure after CRT for esophageal squamous cell carcinoma [27]. The local complete response was reported as 68% (23/34) in all patients (81% for T1 lesions and 46% for T2 lesions), and the median progression-free survival was 21.2 months in patients who achieved CR with PDT and 1.9 months in patients who did not achieve CR. Furthermore, the overall survival at two years was significantly better in patients who achieved CR with PDT than in patients who did not achieve CR (79%, 95% CI: 54–92% vs. 40%, 95% CI: 11–68%, p = 0.0389). These results highlight the importance of good local control in clinical oncology for esophageal cancer, and that PDT using talaporfin sodium could contribute to the survival benefit of patients with esophageal cancer.

6. Future Perspective and Conclusions PDT could allow for the opportunity to treat esophageal cancer patients through the introduction of more rapid clearance of talaporfin sodium and the determination of appropriate targets for PDT. With an aging society, PDT will play a more valuable role in the non-surgical treatment of patients with local failure after radiotherapy for esophageal cancer. In order to encourage the clinical application of PDT in practice, several develop- ments or clarifications in the practice of gastrointestinal oncology are necessary. First, the long-term survival benefit or treatment efficacy of PDT using talaporfin sodium, and the efficacy and safety of multiple sessions of PDT, have not yet been clarified. The long-term outcomes of the enrolled patients in phase-II trials will open soon, and other studies of sequential PDT for local failure after initial PDT are warranted in the future. Next, PDT is known to cause acute inflammation, leading to immune stimulation and increasing the presentation of tumor-derived antigens to T-cells [28]. PDT using third-generation PS of glucose-conjugated chlorin demonstrated a stronger antitumor effect and induced immunogenic cell death compared with talaporfin sodium in a preclinical study [29]. Sev- eral immune checkpoint inhibitors have shown more favorable survival outcomes for esophageal cancer patients compared with conventional systemic chemotherapy in phase- III trials, and these have been introduced into the clinical practice for advanced esophageal cancer patients in recent years [30,31]. The synergistic effect of PDT and immune checkpoint inhibitors has been investigated in preclinical studies for several cancers [32]. The combination of PDT and immune checkpoint inhibitors is an alternative treatment that should be evaluated in clinical practice for esophageal cancer patients. Third, there are several reports on the clinical application of PDT using talaporfin sodium for gastrointestinal cancer out of esophageal cancer [33]. A case series of PDT using talaporfin sodium for patients with gastric cancer or cholangiocarcinoma has been reported [34,35], and these studies represented the favorable outcome of PDT for patients. Further exploration is necessary to determine the appropriate target for PDT in clinical practice for these types of gastrointestinal cancers. In conclusion, PDT using talaporfin sodium showed favorable outcomes for esophageal cancer patients; further evaluation of PDT for esophageal cancer at the point of clinical benefit is necessary to determine the importance of PDT in the treatment of esophageal cancer.

Author Contributions: T.Y., writing—original draft preparation; T.M., K.T., K.N., T.K. and Y.Y., writing— review and editing. All authors have read and agreed to the published version of the manuscript. J. Clin. Med. 2021, 10, 2785 8 of 9

Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The study did not report any data. Conﬂicts of Interest: T.Y. received lecture fees from Meiji Seika Pharma. Other authors have no conﬂict of interest to be declared.

References 1. Dolmans, D.E.; Fukumura, D.; Jain, R.K. Photodynamic therapy for cancer. Nat. Rev. Cancer 2003, 3, 380–387. [CrossRef][PubMed] 2. Wu, H.; Minamide, T.; Yano, T. Role of photodynamic therapy in the treatment of esophageal cancer. Dig. Endosc. 2019, 31, 508–516. [CrossRef][PubMed] 3. Shaheen, N.J.; Sharma, P.; Overholt, B.F.; Wolfsen, H.C.; Sampliner, R.E.; Wang, K.K.; Lightdale, C.J. Radiofrequency ablation in Barrett's esophagus with dysplasia. N. Engl. J. Med. 2009, 360, 2277–2288. [CrossRef][PubMed] 4. Oyama, T.; Tomori, A.; Hotta, K.; Morita, S.; Kominato, K.; Tanaka, M.; Miyata, Y. Endoscopic submucosal dissection of early esophageal cancer. Clin. Gastroenterol. Hepatol. 2005, 3, S67–S70. [CrossRef] 5. Aizawa, K.; Okunaka, T.; Ohtani, T.; Kawabe, H.; Yasunaka, Y.; O'Hata, S.; Saito, T. Localization of mono-L-aspartyl chlorin e6 (NPe6) in mouse tissue. Photochem. Photobiol. 1987, 46, 789–793. [CrossRef] 6. Nelson, J.S.; Roberts, W.G.; Berns, M.W. In vivo studies on the utilization of mono-L-aspartyl chlorin (NPe6) for photodynamic therapy. Cancer Res. 1987, 47, 4681–4685. 7. Wong Kee Song, L.M.; Wang, K.K.; Zinsmeister, A.R. Mono-L-aspartyl chlorin e6 (NPe6) and hematoporphyrin derivative (HpD) in photodynamic therapy administered to a human cholangiocarcinoma mode. Cancer 1998, 82, 421–427. [CrossRef] 8. McMahon, K.S.; Wieman, T.J.; Moore, P.H.; Fingar, V.H. Effects of photodynamic therapy using mono-L-aspartyl chlorin e6 on vessel constriction, vessel leakage, and tumor response. Cancer Res. 1994, 54, 5374–5379. 9. Taber, S.W.; Fingar, V.H.; Coots, C.T.; Wieman, T.J. Photodynamic therapy using mono-L-aspartyl chlorin e6 (Npe6) for the treatment of cutaneous disease: A Phase I clinical study. Clin. Cancer Res. 1998, 4, 2741–2746. 10. Furukawa, K.; Okunaka, T.; Tsuchida, T. A phase I clinical study of photodynamic therapy for early-stage lung carcinoma using ME2906 and a diode laser system. Porphyrins 1998, 7, 199–206. 11. Kato, H.; Furukawa, K.; Sato, M.; Okunaka, T.; Kusunoki, Y.; Kawahara, M.; Horinouchi, H. Phase II clinical study of photodynamic therapy using mono-L-aspartyl chlorin e6 and diode laser for early superficial squamous cell carcinoma of the lung. Lung Cancer 2003, 42, 103–111. [CrossRef] 12. Zenda, S.; Hironaka, S.; Taku, K.; Sato, H.; Hashimoto, T.; Hasuike, N.; Nishimura, T. Optimal timing of endoscopic evaluation of the primary site of esophageal cancer after chemoradiotherapy or radiotherapy: A retrospective analysis. Dig. Endosc. 2009, 21, 245–251. [CrossRef] 13. Yano, T.; Muto, M.; Minashi, K.; Iwasaki, J.; Kojima, T.; Fuse, N.; Ohtsu, A. Photodynamic therapy as salvage treatment for local failure after chemoradiotherapy in patients with esophageal squamous cell carcinoma: A phase II study. Int. J. Cancer 2012, 131, 1228–1234. [CrossRef] 14. Hatogai, K.; Yano, T.; Kojima, T.; Onozawa, M.; Daiko, H.; Nomura, S.; Yoda, Y.; Doi, T.; Kaneko, K.; Ohtsu, A. Salvage photodynamic therapy for local failure after chemoradiotherapy for esophageal squamous cell carcinoma. Gastrointest. Endosc. 2016, 83, 1130–1139. [CrossRef] 15. Horimatsu, T.; Muto, M.; Yoda, Y.; Yano, T.; Ezoe, Y.; Miyamoto, S.; Chiba, T. Tissue damage in the canine normal esophagus by photoactivation with talaporfin sodium (laserphyrin): A preclinical study. PLoS ONE 2012, 7, e38308. [CrossRef] 16. Yano, T.; Muto, M.; Yoshimura, K.; Niimi, M.; Ezoe, Y.; Yoda, Y.; Yamamoto, Y.; Nishisaki, H.; Higashino, K.; Iishi, H. Phase I study of photodynamic therapy using talaporfin sodium and diode laser for local failure after chemoradiotherapy for esophageal cancer. Radiat. Oncol. 2012, 7, 113. [CrossRef] 17. Yano, T.; Kasai, T.; Horimatsu, K.; Yoshimura, S.; Teramukai, S.; Morita, H.; Tada, Y.; Yamamoto, H.; Kataoka, N.; Kakushima, R.; et al. Isomoto and M. Muto A multicenter phase II study of salvage photodynamic therapy using talaporfin sodium (ME2906) and a diode laser (PNL6405EPG) for local failure after chemoradiotherapy or radiotherapy for esophageal cancer. Oncotarget 2017, 8, 22135–22144. [CrossRef] 18. Yano, T.; Muto, M.; Hattori, S.; Minashi, K.; Onozawa, M.; Nihei, K.; Ishikura, S.; Ohtsu, A.; Yoshida, S. Long-term results of salvage endoscopic mucosal resection in patients with local failure after definitive chemoradiotherapy for esophageal squamous cell carcinoma. Endoscopy 2008, 40, 717–721. [CrossRef] 19. Nakajo, K.; Yoda, Y.; Hori, K.; Takashima, K.; Sinmura, K.; Oono, Y.; Ikematsu, H.; Yano, T. Technical feasibility of endoscopic submucosal dissection for local failure after chemoradiotherapy or radiotherapy for esophageal squamous cell carcinoma. Gastrointest. Endosc. 2018, 88, 637–646. [CrossRef] 20. Mitchell, K.G.; Nelson, D.B.; Corsini, E.M.; Vaporciyan, A.A.; Antonoff, M.B.; Mehran, R.J.; Rice, D.C.; Roth, J.A.; Sepesi, B.; Walsh, G.L.; et al. Morbidity following salvage esophagectomy for squamous cell carcinoma: The MD Anderson experience. Dis. Esophagus 2020, 33, doz067. [CrossRef] J. Clin. Med. 2021, 10, 2785 9 of 9

21. Cohen, C.; Tessier, W.; Gronnier, C.; Renaud, F.; Pasquer, A.; Théreaux, J.; Gagnière, J.; Meunier, B.; Collet, D.; Piessen, G.; et al. FREGAT (French Eso-Gastric Tumors working group)—FRENCH (Fédération de Recherche en Chirurgie)—AFC (Association Française de Chirurgie). Salvage Surgery for Esophageal Cancer: How to Improve Outcomes? Ann. Surg. Oncol. 2018, 25, 1277–1286. [CrossRef] 22. Mitchell, K.G.; Nelson, D.B.; Corsini, E.; Vaporciyan, A.A.; Antonoff, M.B.; Mehran, R.J.; Rice, D.C.; Roth, J.A.; Sepesi, B.; Walsh, G.L.; et al. Predictors of stricture formation after photodynamic therapy for high-grade dysplasia in Barrett’s esophagus. Gastrointest. Endosc. 2007, 65, 60–66. 23. Yano, T.; Muto, M.; Minashi, K.; Onozawa, M.; Nihei, K.; Ishikura, S.; Kaneko, K.; Ohtsu, A. Long-term results of salvage photodynamic therapy for patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma. Endoscopy 2011, 43, 657–663. [CrossRef] 24. Ishida, N.; Osawa, S.; Miyazu, T.; Kaneko, M.; Tamura, S.; Tani, S.; Yamade, M.; Iwaizumi, M.; Hamaya, Y.; Furuta, T.; et al. Photodynamic therapy Using Talaporfin Sodium for Local Failure after Chemoradiotherapy or Radiotherapy for Esophageal Cancer: A Single Center Experience. J. Clin. Med. 2020, 9, 1509. [CrossRef] 25. Hayashi, T.; Asahina, Y.; Nakanishi, H.; Terashima, T.; Okamoto, K.; Yamada, S.; Takatori, H.; Kitamura, K.; Mizukoshi, E.; Ninomiya, I.; et al. Evaluation of the efficacy and safety of salvage photodynamic therapy by talaporfin sodium for cervical esophageal cancers and lesions larger than 3 cm. Esophagus 2020.[CrossRef] 26. Minamide, T.; Yoda, Y.; Hori, K.; Shinmura, K.; Oono, Y.; Ikematsu, H.; Yano, T. Advantages of salvage photodynamic therapy using talaporfin sodium for local failure after chemoradiotherapy or radiotherapy for esophageal cancer. Surg. Endosc. 2020, 34, 899–906. [CrossRef] 27. Amanuma, Y.; Horimatsu, T.; Ohashi, S.; Tamaoki, M.; Muto, M. Association of local complete response with prognosis after salvage photodynamic therapy for esophageal squamous cell carcinoma. Dig. Endosc. 2021, 33, 355–363. [CrossRef] 28. Castano, A.P.; Mroz, P.; Hamblin, M.R. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer 2006, 6, 535–545. [CrossRef] 29. Minamide, T.; Yoda, Y.; Hori, K.; Shinmura, K.; Oono, Y.; Ikematsu, H.; Yano, T. Potential of Photodynamic Therapy Based on Sugar-Conjugated Photosensitizers. J. Clin. Med. 2021, 10, 841. [CrossRef] 30. Kato, K.; Cho, B.C.; Takahashi, M.; Okada, M.; Lin, C.Y.; Chin, K.; Kitagawa, Y. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019, 20, 1506–1517. [CrossRef] 31. Kojima, T.; Shah, M.A.; Muro, K.; Francois, E.; Adenis, A.; Hsu, C. HRandomized Phase III KEYNOTE-181 Study of Pem- brolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J. Clin. Oncol. 2020, 38, 4138–4148. [CrossRef][PubMed] 32. Cramer, G.M.; Moon, E.K.; Cengel, K.A.; Busch, T.M. Photodynamic Therapy and Immune Checkpoint Blockade. Photochem. Photobiol. 2020, 96, 954–961. [CrossRef][PubMed] 33. Yano, T.; Wang, K.K. Photodynamic Therapy for Gastrointestinal Cancer. Photochem. Photobiol. 2020, 96, 517–523. [CrossRef] [PubMed] 34. Nanashima, A.; Abo, T.; Nonaka, T.; Nonaka, Y.; Morisaki, T.; Uehara, R.; Nagayasu, T. Photodynamic therapy using talaporfin sodium (Laserphyrin®) for bile duct carcinoma: A preliminary clinical trial. Anticancer Res. 2012, 32, 4931–4938. [CrossRef] 35. Nakamura, T.; Oinuma, T. Usefulness of Photodynamic Diagnosis and Therapy using Talaporfin Sodium for an Advanced-aged Patient with Inoperable Gastric Cancer. Laser Ther. 2014, 23, 201–210. [CrossRef]