Open Access, Peer-reviewed
pISSN 2093-582X
eISSN 2093-5641
    J Gastric Cancer. 2020 Dec;20(4):355-375. English.
    Published online Dec 28, 2020.
    https://doi.org/10.5230/jgc.2020.20.e39
    Copyright © 2020. Korean Gastric Cancer Association
    Review

    Photodynamic Diagnosis and Therapy for Peritoneal Carcinomatosis from Gastrointestinal Cancers: Status, Opportunities, and Challenges

    Hyoung-Il Kim,1,2,3,4 and Brian C. Wilson4,5
      • 1Department of Surgery, Yonsei University College of Medicine, Seoul, Korea..
      • 2Gastric Cancer Center, Yonsei Cancer Center, Seoul, Korea.
      • 3Open NBI Convergence Technology Research Laboratory, Severance Hospital, Seoul, Korea.
      • 4Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
      • 5Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
    • Correspondence to Brian C. Wilson. Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, Canada. Email: brian.wilson@uhnresearch.ca
    Received November 15, 2020; Accepted December 15, 2020.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Selective accumulation of a photosensitizer and the subsequent response in only the light-irradiated target are advantages of photodynamic diagnosis and therapy. The limited depth of the therapeutic effect is a positive characteristic when treating surface malignancies, such as peritoneal carcinomatosis. For photodynamic diagnosis (PDD), adjunctive use of aminolevulinic acid- protoporphyrin IX-guided fluorescence imaging detects cancer nodules, which would have been missed during assessment using white light visualization only. Furthermore, since few side effects have been reported, this has the potential to become a vital component of diagnostic laparoscopy. A variety of photosensitizers have been examined for photodynamic therapy (PDT), and treatment protocols are heterogeneous in terms of photosensitizer type and dose, photosensitizer-light time interval, and light source wavelength, dose, and dose rate. Although several studies have suggested that PDT has favorable effects in peritoneal carcinomatosis, clinical trials in more homogenous patient groups are required to identify the true benefits. In addition, major complications, such as bowel perforation and capillary leak syndrome, need to be reduced. In the long term, PDD and PDT are likely to be successful therapeutic options for patients with peritoneal carcinomatosis, with several options to optimize the photosensitizer and light delivery parameters to improve safety and efficacy.

    Keywords
    Surgical guidance; Photodynamic diagnosis; Photodynamic therapy; Photosensitizer; Carcinomatosis

    INTRODUCTION

    Fluorescence-guided surgical resection is emerging as a valuable clinical approach to improve tumor margin identification and enable maximal safe reductive surgery [1]. Several fluorescent agents are currently used routinely in clinical practice for surgical guidance, such as indocyanine green (ICG) [2] and fluorescein [3]. Additionally, various novel fluorophores are in development, including molecules or nanoparticles that are specifically targeted to tumors through conjugation to antibodies or peptides [4, 5]. A further option is to use fluorophores that are also photodynamic sensitizers, and in this case, the term “photodynamic diagnosis (PDD)” is often used. Photodynamic therapy (PDT) utilizes high doses of photosensitizer and light to destroy malignant tissue, often via the generation of cytotoxic reactive oxygen species (ROS), such as singlet oxygen. Tumor cell death may occur directly via necrotic and/or apoptotic pathways or by shutting down the tumor microvasculature via endothelial cell death when light is applied while the photosensitizer remains in circulation [6]. Historically, many developments in PDD and PDT have been closely linked, although not all fluorophores (materials that emit longer-wavelength light upon photoexcitation) are photosensitizers (molecules producing biochemical changes through photophysical and photochemical processes) and vice versa. Indeed, fluorescence and ROS generation are competing processes, as illustrated in Fig. 1. Singlet oxygen-mediated PDT occurs only when a photosensitizer, oxygen, and light are present in sufficient amounts (Fig. 2). Ideally, the photosensitizer should also have a degree of selectivity for tumor tissue over normal tissue selectivity, either through higher uptake in malignant cells/tissues and/or through differential sensitivity to ROS-mediated damage. The advantages of PDT as a clinical modality include its low systemic toxicity (apart from skin photosensitivity, reported with some earlier photosensitizers) and excellent tissue healing, since the lack of heat means that collagen is not destroyed during PDT and the normal tissue architecture is preserved. More recently, preclinical and clinical evidence have shown that immune upregulation contributes to the tumor response [7, 8].

    Fig. 1
    Photophysical pathways (energy-level diagram) in PDD and PDT.
    PDD = photodynamic diagnosis; PDT = photodynamic therapy; PS = photosensitizer; ROS = reactive oxygen species.

    Fig. 2
    Schematic showing the interactions between the main elements required in PDT.

    While many potential PDD/PDT agents can be used in the management of peritoneal carcinomatosis (PC), 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) is of special interest. 5-ALA is a small agent that is administered orally and is involved in the regulation of heme biosynthesis. Exogenous ALA increases heme synthesis; during the penultimate step, the fluorescent photosensitizer PpIX preferentially accumulates in tumor cells [9], most likely due to the low levels of ferrochelatase needed to convert PpIX into heme.

    A variety of visible and near-infrared light sources (diode lasers, light-emitting diodes [LEDs]) and light delivery technologies, including fiberoptics and specialized light diffusers, are used [10, 11, 12] depending on the treatment site and clinical requirements. Both surface application and interstitial light delivery may be applied externally, intraoperatively, or endoscopically. PDT is particularly well suited for the treatment of surface malignancies, such as basal cell carcinomas and early-stage intraluminal lesions [13, 14], where selective photosensitizer uptake in the tumor cells, targeted light irradiation, and, depending on the wavelength, limited light penetration in tissue can selectively destroy tumor or pre-malignant lesions (dysplasia) with minimal damage to underlying normal tissue. Combining PDD with laparoscopic guidance PDT treatment delivery using a minimally invasive approach is facilitated by the widespread use of endoscopic and laparoscopic tools.

    Historically, PC was considered an incurable condition in patients with gastric, pancreatic, colorectal, or ovarian cancers. The discovery of one or more metastatic nodules during surgery changes the surgical plan from curative to palliative resection, or to no resection. Thus, early diagnosis of metastatic nodules has significant clinical implications. Despite improvements in computed tomography (CT) and magnetic resonance imaging (MRI), tumor nodules less than 5 mm are rarely detectable before surgery, and some are overlooked during surgery [15]. PDD addresses the latter; used as an adjunct to diagnostic laparoscopy, PDD with ALA-PpIX fluorescence contrast increases the rate of PC diagnosis by as much as 30% [16].

    Aggressive treatments for peritoneal metastasis, such as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy [17], intraperitoneal chemotherapy [18], or pressurized intraperitoneal aerosol chemotherapy [19], have shown positive outcomes in some patients. PDT has also been investigated as an adjunct to cytoreductive surgery [20, 21, 22, 23, 24]. In principle, PDT is an attractive option, since the treatment effect is confined to the irradiated area and to a few millimeters below the tissue surface, while high accumulation of photosensitizer in cancer cells may provide a further level of selectivity. However, clinical experience to date is limited, and serious treatment-related complications have been reported [25], as discussed below.

    The aims of this paper are: 1) to briefly review the current status and limitations of PDD and PDT for the treatment of PC originating from gastrointestinal or gynecological cancers, and 2) to consider potential approaches to overcome these limitations so that the advantages of PDT can be achieved with an improved safety profile in clinical practice.

    STATUS OF PDD IN PC

    Preclinical studies

    Ovarian, colorectal, and gastric cancer cell lines have been used in mouse and rat models of PC with induced metastatic nodules (Table 1). ALA-PpIX is the most widely studied agent under blue light (405 nm) excitation, with detection of red (≥600 nm) fluorescence. Considering that clinical laparoscopy systems were used for these studies, the smallest detectable tumor size of approximately 0.5 mm should be comparable between patients [35]. The sensitivity and specificity for in situ tumor detection were derived from examining of hundreds of metastatic nodules (e.g., 555 [27], 171 [28], and 105 [33]) and were within the range 21%–100% and 53%–100%, respectively. The diagnostic accuracy has been validated in experiments using tumor cells expressing red [27] or green [16, 26] fluorescent proteins. Selective localization of photosensitizer in tumor versus normal tissue was measured by fluorescence spectroscopy and expressed as the tumor-to-normal ratio (TNR), and the reported values varied from 1.17 to 6.27. Time series measurements indicated that the maximum fluorescence intensity differed in tissues in different anatomical regions (small bowel, peritoneum, and liver) [37, 40]. This has clinical implications, since PC nodules in a patient may have different fluorescence readings during PDD depending on the anatomical site and time between ALA administration and fluorescence detection. This requires further investigation.

    Table 1
    PDD: preclinical studies

    Clinical trials

    5-ALA is the only photosensitizer used to date for PDD of PC arising from gastric, ovarian, and pancreatic cancers (Table 2). In most studies, 20 mg 5-ALA was administered orally 3–4 hours before PDD. Unlike in animal models, not all patients had metastatic cancer nodules; therefore, the sensitivity and specificity could not be determined. However, the accuracy of PDD has been compared with that of white light tumor visualization: the detection rate under white-light (range, 11.7%–100%) [16, 42, 43, 45, 49, 50, 54, 55] increased by an average of 10% (range, 0–33%) [26, 43, 45, 49, 53, 54, 55, 56] when 5-ALA PDD was also used. In addition, fluorescence imaging identified patients with metastatic nodules that were missed under white-light investigation [43, 45, 49, 55, 56]. The prognostic impact of these additionally detected nodules was not determined. A study of 113 patients with metastatic nodules revealed by PDD, and subsequently resected, had survival times similar to those in 51 patients with no metastatic nodules [43]. However, this important finding needs to be confirmed using larger sample sizes. Regarding the size of peritoneal nodules that can currently be detected by PDD, Menon et al. [57] found that nodules as small as 1 mm in diameter contained measurable levels of PpIX. Interestingly, another study revealed no detectable fluorescence, even in primary tumors, in patients who underwent neoadjuvant chemotherapy prior to PDD [16]. Although the regimen and mechanism were not described in the report, this finding should be investigated in patients receiving neoadjuvant chemotherapy.

    Table 2
    PDD: clinical trials

    Complications associated with the diagnostic use of ALA-PpIX for fluorescence detection are rare. Since the PpIX concentration in skin peaks around 3–4 hours after ALA administration, and is undetectable by 24 hours [58], patients are advised to avoid direct sunlight and bright artificial lights for 1 day, and few complications have been reported. Self-limiting nausea and vomiting were the only morbidities reported following oral ALA administration at diagnostic doses (<30 mg/kg body weight); however, the possibility of adverse events should be considered during the procedure [46, 54].

    STATUS OF PDT IN PC

    Preclinical studies

    Ovarian cancer is the most common primary tumor that has been investigated in preclinical studies of PDT for PC, followed by gastric cancer (Table 3). A variety of photosensitizers and corresponding treatment wavelengths have been used in mouse and rat models. Thus, the treatment protocols have varied in terms of the photosensitizer-light time interval and light doses. Unlike human trials, repeat treatment schedules have been used often. Molpus et al. (benzoporphyrin derivative monoacid [BPD-MA], 690 nm activation) [79] and Kishi et al. (talaporfin, 664 nm) [68] reported details of phototoxicity, photosensitizer biodistribution, tumor response, and survival following treatment. Kishi et al. [68] used (laser) light doses of 2, 5, or 10 J/cm2 at 2 or 4 hours after talaporfin injection in mice. Animals treated with 2 J/cm2 at 2 hours drug-light interval died of intestinal perforation within 2 or 3 days, whereas there were no complications in the group treated with 2 J/cm2 at 4 hours [79]. The efficacy of different treatment wavelengths has also been investigated. For example, Hino et al. [65] used 5-ALA and 4.5 J/cm2 of violet (405 nm), green (532 nm), or red (635 nm) light delivered at laparotomy. Furthermore, Mroz et al. [66] used fullerene nanoparticles as the photosensitizer, with white (400–700 nm), green (540 nm), or red (635 nm) external-beam irradiation at a light dose of 100 J/cm2. Overall, red light demonstrated an inferior therapeutic effect despite its common use in ALA-PpIX PDT for other indications, such as interstitial PDT for pancreatic [83] and brain tumors [84]. Several studies have used other photosensitizers activated by near-infrared light following external application [5, 59, 60, 61, 63, 64]. This approach was effective, because the small body size of mice allowed the light to penetrate the abdominal wall into the peritoneal cavity; however, it would be ineffective in patients. Indeed, as discussed below, a major technical challenge in PDT for PC is how to deliver the treatment light so that all tissue surfaces within the complex anatomy of the peritoneal cavity receive an adequate light dose to optimize the efficacy and safety.

    Table 3
    PDT: preclinical studies

    Clinical trials

    Data from limited clinical trials of PDT in PC have been published (Table 4). In all cases, PDT was applied in a single session as an adjunct to cytoreductive or debulking surgery. Multiple factors need to be considered to optimize the efficacy versus safety profile of intraperitoneal PDT, including the choice of photosensitizer, the photosensitizer-light time interval, the irradiation wavelength, and the light dose and dose rate.

    Table 4
    PDT: clinical trials

    Photosensitizer

    Each photosensitizer has unique pharmacokinetic and optical absorption (activation) characteristics. Patients in clinical trials on the first-generation photosensitizer, Photofrin® (Pinnacle Biologics, Inc., Bannockburn, IL, USA) [20, 22, 24, 85], were instructed to avoid direct sunlight for 6 weeks after PDT. Second-generation photosensitizers (e.g., meta-tetrakis[3-hydroxyphenyl]chlorin [mTHPC] and 5-ALA) are more convenient because they require the avoidance of direct sunlight or bright artificial light exposure for only 24 hours and are associated with lower systemic toxicity [21].

    Photosensitizer-light time interval

    The optimum time for PDT following photosensitizer administration depends primarily on the rates of uptake and clearance in tumor and normal host tissue. In addition, using a short drug-light interval ensures the photosensitizer is still in circulation, meaning that the primary anti-tumor effect is mediated by microvascular damage, primarily thrombosis; this strategy has been employed in the PDT of solid tumors [93]. However, since PC usually involves small and superficial targets following surgical debulking, and considering that oxygen diffusion can reach approximately 200 μm in tissue [94], using a longer interval to allow photosensitizer uptake by the tumor cells is preferred for direct photodynamic killing.

    Treatment light wavelength

    The optimum treatment wavelength for relatively superficial disease as in PC may differ from that for interstitial PDT of bulk tumors. For example, in the PDT of prostate cancer, in which a minimum light dose is required throughout a significant tissue volume [95], red or near-infrared light (up to 630–800 nm) is advantageous because of its deeper penetration, mainly due to reduced absorption of light by hemoglobin. Conversely, in PC, the risk of bowel perforation is less at shorter (e.g., blue or green) wavelengths. The light penetration depth in tissue generally increases with wavelength, and clinical trials have assumed that red and green light provide effective treatment depths of up to 5–10 mm and <3 mm, respectively [89, 91, 96]. Even with red light, the response of bulky tumors may be poor, as reported for rectal cancer [22]. An alternative is to perform cytoreductive debulking surgery followed by PDT with green light, with the option of adding a selective boost dose with red light in cases of gross tumor involvement [20, 24]. If the photosensitizer has significant absorption at shorter wavelengths, as with porphyrin-based compounds, it may also be possible to reduce the total light energy dose while generating sufficient singlet oxygen for effective treatment, assuming that the full depth of the tumor can be adequately treated.

    Light dose and rate

    Tissues, including tumors, generally display a threshold behavior to PDT; that is, a minimum photosensitizer-light dose product needs to be reached to induce necrosis (or other endpoint) [97]. For a given tissue concentration of photosensitizer, the effective treatment depth is logarithmically proportional to the applied light dose (J/cm2); thus, to double the treatment depth, an approximately four-fold increase in light is required. This is a purely biophysical effect. However, a light dose that is high enough to induce significant tumor necrosis may also generate damage-associated molecular patterns (DAMPs), initiating an inflammatory response that triggers immune upregulation, which contributes to the overall tumor response [98]. At lower doses, PDT-induced apoptosis may still occur, but rarely stimulate an immune response, while at very low doses there may be increased tumor cell growth [99]. Conversely, delivering too high a light dose risks causing damage to normal tissue within the light field, unless there is a high tumor-to-normal tissue photosensitizer concentration. In general, the rate of light delivery in clinical PDT is selected to avoid significant tissue heating, typically being below approximately 200 mW/cm2 for well-perfused tissues. This has been reported for all clinical trials in PC to date [20, 85]. Dose rates as low as 10 mW/cm2 demonstrated efficacy in a preclinical study [81], since this avoids the tissue oxygen being photochemically depleted faster than it can be replenished by blood perfusion, at least in relatively hypoxic (e.g., tumor) tissue.

    CONSIDERATIONS FOR THE CLINICAL APPLICATION OF PDT IN PC

    In this section, we will consider the factors that contribute to the efficacy and safety of PDT for PC in clinical practice. As summarized above, intraperitoneal PDT has demonstrated favorable outcomes in terms of tumor responses [24, 85, 90]. However, because the patient cohorts have been heterogeneous within and between studies, and have included patients with various primary tumors (colorectal, ovarian, and sarcoma), the clinical benefits of PDT remain unclear. Interestingly, one study performed a recurrence-pattern analysis to assess the treatment response [87], which suggested the value of PDT for local control, based on recurrence being rarely observed at sites treated by a PDT boost dose.

    Regarding safety, the high rates of adverse events, primarily perforation of the stomach, small intestine, and colon, as well as capillary leak syndrome, currently limit the clinical application of PDT. Some studies have also reported ureteral injury, but it is unclear whether this was related directly to the PDT [22, 91]. One report described bilateral ureteral leaks that required bilateral nephrostomies for urinary diversion [22]. Capillary leak syndrome is the most serious toxicity reported, manifesting as tachycardia and hypotension requiring massive fluid resuscitation and prolonged mechanical ventilation, with a high incidence of pulmonary complications and significant whole-body edema [20, 25, 89]. The effects occurred during the first 4–5 days post-PDT, peaking at 1–3 days. Patients typically received a net positive fluid balance of 20 L in the first 24 hours [20]. A retrospective analysis of a phase II trial [25] found that this syndrome was significantly associated with surgical duration and nodule number. However, the analysis did not include the light irradiation dose. Thus, we assume that more extensive light irradiation follows more extensive surgery. The degree of systemic inflammatory response following cytoreductive surgery with PDT is more severe than in other major gastrointestinal surgeries, such as hepatectomy, pancreaticoduodenectomy, and esophagectomy. Thus, one can infer indirectly that trauma associated with intra-peritoneal PDT significantly contributes to capillary-leak syndrome.

    Using conventional PDT treatment protocols comprising single doses of photosensitizer and light, the greatest challenge for improving the clinical efficacy is to increase the tumor specificity of the photosensitizer, such that greater tumor control can be achieved using higher light doses while limiting off-target toxicity. A technical challenge for light delivery is ensuring that a minimum (threshold) light dose is delivered throughout the peritoneal cavity. Here, we will consider other novel approaches that may alter the equation for optimizing the photosensitizer and light parameters.

    Route of photosensitizer administration

    The pharmacokinetics and biodistribution of photosensitizers depend on the route of administration, as well as on their intrinsic properties. Perry et al. [80] evaluated the efficiency and toxicity of Photofrin2 following intraperitoneal (ip) injection versus intravenous (iv) administration in a mouse model [80]. The results suggested that ip injection is a safer and more effective route than iv administration. Kishi et al. [68] reported similar preclinical findings with talaporfin, leading to a switch from iv to ip administration. In clinical trials, Loning et al. [53, 55] delivered 5-ALA ip without complications. Considering that ip photosensitizers can be absorbed on the surface of the peritoneal organ, which is analogous to topical treatments for skin tumors, direct uptake into tumor nodules may improve the tumor-to-normal tissue profile if the photosensitizer is distributed throughout the peritoneal cavity. Depending on the formulation, a fraction of the total photosensitizer dose will enter the circulation and be delivered through the systemic route. Optimizing the formulation and dispersal of photosensitizers for ip administration to achieve the highest tumor uptake and TNR should be elaborated in future studies.

    Irradiation schedule

    During the early development of X-ray therapy, large single doses of radiation were found to be less effective and caused greater damage to normal tissue than multiple small doses (fractionation), which is now standard clinical practice. PDT has generally been delivered in a single session, partly because it is necessary to reach a minimum threshold dose. This approach has been successful in a variety of tumors and stages [12, 13, 95] and has the added advantages of patient/clinician convenience and of avoiding the need for multiple photosensitizer administrations. However, there are exceptions to this. For example, Kato et al. [59] used two irradiation sessions, on days 0 and 7, to kill disseminated pancreatic cancer cells following ip administration of Mal3-Chlorin (maltotriose-conjugated chlorin) in a mouse model. Harada et al. [60] delivered light irradiation daily for up to 3 days using a near-infrared photosensitizer (GSA-IR700) in an ovarian cancer mouse model. Furthermore, Sato et al. [64] delivered 50 J/cm2 on day 1 and 100 J/cm2 on day 2, and repeated these conditions every week for up to 3 weeks with the photosensitizer TRA-IR700 in a gastric cancer mouse model. Using BPD-MA, Molpus et al. [79] delivered 20 J light irradiation in three to five treatments at 3–7-day intervals in a murine tumor model. The rationale for this approach was to exert the maximum therapeutic effect and reduce complications. Other preclinical studies have demonstrated that fractionized PDT using a relatively low light dose performed better than conventional single high-dose PDT [67, 71].

    A more radical approach, termed metronomic PDT (mPDT), has been proposed by Wilson and colleagues [11, 84, 100, 101], in which both the photosensitizer and light are delivered continuously or in many small fractions at very low rates over an extended period. This is analogous to metronomic chemotherapy using low doses over an extended duration [102], although the mechanisms of action differ. Thus, in an intracranial glioma model, ALA was administered without toxicity in drinking water at a low rate of 100 mg/kg per day over several days. An optical fiber implanted in the tumor delivered light at 23 μW/cm2 over 5 days, for a total energy dose of 10 J/cm2, which was comparable to the total dose used in conventional “acute” single-fraction PDT [84]. Importantly, tumor cells underwent apoptosis with no evidence of necrosis. Additionally, there was no evidence of either necrotic or apoptotic damage to the adjacent normal brain, and post-PDT edema was reduced. This concept has been used clinically, at least in multiple-fraction rather than full continuous metronomic mode, for treating chest wall recurrences in patients with breast cancer [103, 104]. We suggest that this strategy could be used for intraperitoneal PDT of PC, with treatment extending over several days, which would also allow treatment to be terminated if side effects are observed. The limitations of mPDT include the potential for increased tumor growth if the tumor is very aggressive [99] and the risk that apoptotic cell death may not trigger an immune response that contributes to the anti-tumor efficacy of PDT [98, 105]. The main technical challenge will be how to safely deliver light at a low-dose rate throughout the peritoneal cavity. We are currently addressing this; at least in principle, one could envisage metronomic treatment being delivered even in an ambulatory setting following intraoperative source implantation.

    Uneven bowel contours

    The small bowel, large bowel, and omentum are packed tightly into the peritoneal cavity; therefore, irradiating the entire peritoneal surface with a uniform dose is technically challenging during PDT light delivery. Historically, light-scattering media [106] have been used to distribute light more uniformly in order to improve treatment efficacy. A National Cancer Institute report described protocols for irradiating and monitoring light energy in the peritoneal space [24, 91]. Thus, diluted (0.2%) Intralipid™ (Sigma-Aldrich, St. Louis, MO, USA), a liquid fat-protein suspension used for intraparental feeding, served as the light-scattering medium to distribute light into deep-seated bowel surfaces. A diffusing “wand” connected to a laser source was used for light delivery, protecting the tissues from thermal or mechanical injury due to direct contact [91]. In a subsequent study, 1.5% dextrose peritoneal dialysis solution was used instead of Intralipid, which caused hypocalcemia and hypomagnesemia. In turn, this was then changed to Ringer's solution with 1.7 mEq/L additional magnesium [24]. The visceral peritoneal surfaces (diaphragm, omentum, retroperitoneal gutters, pelvis, and abdominal wall) were illuminated by manually moving the wand, which comprised an optical fiber placed within a cuffed endotracheal tube, capped and filled with 0.1% lipid emulsion, with 0.02% emulsion used to inflate the cuff.

    The delivered light intensity (fluence rate, mW/cm2) was continuously monitored during irradiation by a photodiode sutured to the tissue surface in the right upper quadrant, left upper quadrant, and pelvis, with an additional, untethered diode placed in the target region. The wand was moved manually to achieve the highest uniformity in light delivery by equalizing the cumulative light dose received by the photodetectors. Depending in the organ, the target light dose was 5–10 J/cm2, and was calculated (according to the power of light delivered by the wand), based on the surface of each region as a percentage of the total peritoneal surface, and assuming that the body surface area was the same as the peritoneal surface area [107]. Measuring the delivered light dose in this complex setting is challenging [108], and the use of an anatomical phantom to simulate, and thereby optimize, intraoperative PDT has been proposed [109]. There is significant room for improvement in the process of light-delivery and monitoring. For example, there could be more extensive use of multiple distributed light sources for the simultaneous illumination of different intraperitoneal surfaces, and by continuous imaging and multiple point measurements of the light distribution, with automatic feedback control to dynamically adjust the power from each light source. This type of on-line monitoring and control system has been used for other complex anatomical sites, such as whole-prostate PDT [110], guided by pre-treatment planning based on volumetric CT or MRI.

    Surgical procedure

    Several minor surgical issues could result in large differences in the efficacy of PDT. First, since blood on a tissue surface strongly absorbs the activating light (to a greater or lesser extent, depending on the wavelength), complete hemostasis should be ensured [23]. Likewise, when the peritoneal cavity is filled with a light-scattering fluid, it is important to avoid blood contamination, since the increased path length of the light amplifies the effect of hemoglobin absorption, such that continuous or frequent fluid exchange during light irradiation may be required. Second, bowel edema, ascitic fluid collection, and subsequent ileus are common after PDT of PC. One clinical trial reported a high incidence of perforations at the anastomosis sites [24], although there was no histological evidence of injury except at the enterotomy. Thus, the PDT-induced edema was thought to cause traction on the staple line or focal ischemia and subsequent perforation. Transient thrombocytopenia is also commonly observed in PC patients receiving PDT [24, 89]. Although this was self-limiting, it could increase surgical morbidity.

    CONCLUSIONS

    Photodynamic diagnosis, that is, fluorescence imaging or point spectroscopy of the photosensitizer, could be used as an adjunct to improve the detection of otherwise unidentified peritoneal metastasis during diagnostic laparoscopy. Except for some self-limiting skin photosensitivity, the photosensitizer is associated with minimal side effects, given that low (sub-therapeutic) doses and light exposures are used. Since diagnosis of peritoneal metastasis is critical for clinical decision making, PDD is likely to become standard clinical practice. The main issue is which fluorescent agent to use (which may or may not be photodynamically active), while issues around the additional costs for the equipment and the photosensitizer, as well as the increased procedural time, are also important practical factors.

    Regarding photodynamic treatment, the limited thickness of intraperitoneal nodules, especially after surgical debulking, makes PDT a suitable modality, given that the limited light penetration protects underlying organs from injury. The effective treatment depth depends on the photosensitizer, its concentration in the target tumor, the tumor-to-normal tissue selectivity, as well as the treatment wavelength, tissue optical properties at this wavelength, and tissue oxygenation. To date, clinical trials of PDT in PC have demonstrated moderate anti-tumor efficacy, but high complication rates. Therefore, the various treatment parameters, particularly the photosensitizer selectivity and light delivery, require further development and optimization to translate this modality into routine clinical practice with safe and reliable outcomes. Given i) the diverse range of photosensitizers available (including, in the future, active tumor targeting), ii) the increasing sophistication of PDT treatment planning, delivery, and monitoring technologies that have been demonstrated in the PDT of other cancers, iii) the use of novel photobiological strategies such as mPDT, and iv) the full exploitation of the immune effects of PDT, clinical translation and adoption are likely to be feasible in the foreseeable future. Current research in our laboratory on mPDT and specialized light delivery systems will hopefully advance this field.

    Notes

    Funding:This work was supported by a faculty research grant from Yonsei University College of Medicine (6-2020-0088) and by the Princess Margaret Cancer Foundation, Toronto, Canada.

    Author Contributions:

    • Conceptualization: K.H.I., B.C.W.

    • Data curation: K.H.I.

    • Writing - original draft: K.H.I.

    • Writing - review & editing: B.C.W.

    Conflict of Interest:No potential conflict of interest relevant to this article was reported.

    References

      1. Valdés PA, Jacobs V, Harris BT, Wilson BC, Leblond F, Paulsen KD, et al. Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin IX biomarker as a surgical adjunct in low-grade glioma surgery. J Neurosurg 2015;123:771–780.
      1. Kwon IG, Son T, Kim HI, Hyung WJ. Fluorescent lymphography-guided lymphadenectomy during robotic radical gastrectomy for gastric cancer. JAMA Surg 2019;154:150–158.
      1. Hansen RW, Pedersen CB, Halle B, Korshoej AR, Schulz MK, Kristensen BW, et al. Comparison of 5-aminolevulinic acid and sodium fluorescein for intraoperative tumor visualization in patients with high-grade gliomas: a single-center retrospective study. J Neurosurg 2020;133:1324–1331.
      1. Li Z, Sun L, Lu Z, Su X, Yang Q, Qu X, et al. Enhanced effect of photodynamic therapy in ovarian cancer using a nanoparticle drug delivery system. Int J Oncol 2015;47:1070–1076.
      1. Tsujimoto H, Morimoto Y, Takahata R, Nomura S, Yoshida K, Horiguchi H, et al. Photodynamic therapy using nanoparticle loaded with indocyanine green for experimental peritoneal dissemination of gastric cancer. Cancer Sci 2014;105:1626–1630.
      1. Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol 1992;55:145–157.
      1. Beltrán Hernández I, Yu Y, Ossendorp F, Korbelik M, Oliveira S. Preclinical and clinical evidence of immune responses triggered in oncologic photodynamic therapy: clinical recommendations. J Clin Med 2020;9:333.
      1. Theodoraki MN, Lorenz K, Lotfi R, Fürst D, Tsamadou C, Jaekle S, et al. Influence of photodynamic therapy on peripheral immune cell populations and cytokine concentrations in head and neck cancer. Photodiagnosis Photodyn Ther 2017;19:194–201.
      1. Valdés PA, Leblond F, Kim A, Harris BT, Wilson BC, Fan X, et al. Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker. J Neurosurg 2011;115:11–17.
      1. Wong Kee Song LM, Wilson BC. Endoscopic detection of early upper GI cancers. Best Pract Res Clin Gastroenterol 2005;19:833–856.
      1. Davies N, Wilson BC. Tetherless fiber-coupled optical sources for extended metronomic photodynamic therapy. Photodiagnosis Photodyn Ther 2007;4:184–189.
      1. Pinthus JH, Bogaards A, Weersink R, Wilson BC, Trachtenberg J. Photodynamic therapy for urological malignancies: past to current approaches. J Urol 2006;175:1201–1207.
      1. Moghissi K, Dixon K, Stringer M, Thorpe JA. Photofrin PDT for early stage oesophageal cancer: long term results in 40 patients and literature review. Photodiagnosis Photodyn Ther 2009;6:159–166.
      1. de Albuquerque IO, Nunes J, Figueiró Longo JP, Muehlmann LA, Azevedo RB. Photodynamic therapy in superficial basal cell carcinoma treatment. Photodiagnosis Photodyn Ther 2019;27:428–432.
      1. Patel CM, Sahdev A, Reznek RH. CT, MRI and PET imaging in peritoneal malignancy. Cancer Imaging 2011;11:123–139.
      1. Kishi K, Fujiwara Y, Yano M, Inoue M, Miyashiro I, Motoori M, et al. Staging laparoscopy using ALA-mediated photodynamic diagnosis improves the detection of peritoneal metastases in advanced gastric cancer. J Surg Oncol 2012;106:294–298.
      1. Yoshida K, Yamaguchi K, Okumura N, Tanahashi T, Kodera Y. Is conversion therapy possible in stage IV gastric cancer: the proposal of new biological categories of classification. Gastric Cancer 2016;19:329–338.
      1. Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, et al. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol 2018;36:1922–1929.
      1. Dakwar GR, Shariati M, Willaert W, Ceelen W, De Smedt SC, Remaut K. Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal carcinomatosis - Mission possible? Adv Drug Deliv Rev 2017;108:13–24.
      1. Hahn SM, Fraker DL, Mick R, Metz J, Busch TM, Smith D, et al. A phase II trial of intraperitoneal photodynamic therapy for patients with peritoneal carcinomatosis and sarcomatosis. Clin Cancer Res 2006;12:2517–2525.
      1. Wierrani F, Fiedler D, Grin W, Henry M, Krammer B, Grunberger W. Intraoperative meso-tetrahydroxyphenylchlorin-based photodynamic therapy in metastatic gynecologic cancer tissue: initial results. J Gynecol Surg 1997;13:23–29.
      1. Harlow SP, Rodriguez-Bigas M, Mang T, Petrelli NJ. Intraoperative photodynamic therapy as an adjunct to surgery for recurrent rectal cancer. Ann Surg Oncol 1995;2:228–232.
      1. Allardice JT, Abulafi AM, Grahn MF, Williams NS. Adjuvant intraoperative photodynamic therapy for colorectal carcinoma: a clinical study. Surg Oncol 1994;3:1–10.
      1. DeLaney TF, Sindelar WF, Tochner Z, Smith PD, Friauf WS, Thomas G, et al. Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. Int J Radiat Oncol Biol Phys 1993;25:445–457.
      1. Canter RJ, Mick R, Kesmodel SB, Raz DJ, Spitz FR, Metz JM, et al. Intraperitoneal photodynamic therapy causes a capillary-leak syndrome. Ann Surg Oncol 2003;10:514–524.
      1. Kondo Y, Murayama Y, Konishi H, Morimura R, Komatsu S, Shiozaki A, et al. Fluorescent detection of peritoneal metastasis in human colorectal cancer using 5-aminolevulinic acid. Int J Oncol 2014;45:41–46.
      1. Alexander VM, Sano K, Yu Z, Nakajima T, Choyke PL, Ptaszek M, et al. Galactosyl human serum albumin-NMP1 conjugate: a near infrared (NIR)-activatable fluorescence imaging agent to detect peritoneal ovarian cancer metastases. Bioconjug Chem 2012;23:1671–1679.
      1. Zhong W, Celli JP, Rizvi I, Mai Z, Spring BQ, Yun SH, et al. In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring. Br J Cancer 2009;101:2015–2022.
      1. Collinet P, Sabban F, Cosson M, Farine MO, Villet R, Vinatier D, et al. Laparoscopic photodynamic diagnosis of ovarian cancer peritoneal micro metastasis: an experimental study. Photochem Photobiol 2007;83:647–651.
      1. Regis C, Collinet P, Farine MO, Mordon S. Comparison of aminolevulinic acid- and hexylester aminolevulinate-induced protoporphyrin IX fluorescence for the detection of ovarian cancer in a rat model. Photomed Laser Surg 2007;25:304–311.
      1. Till H, Bergmann F, Metzger R, Haeberle B, Schaeffer K, von Schweinitz D, et al. Videoscopic fluorescence diagnosis of peritoneal and thoracic metastases from human hepatoblastoma in nude rats. Surg Endosc 2005;19:1483–1486.
      1. Lüdicke F, Gabrecht T, Lange N, Wagnières G, Van Den Bergh H, Berclaz L, et al. Photodynamic diagnosis of ovarian cancer using hexaminolaevulinate: a preclinical study. Br J Cancer 2003;88:1780–1784.
      1. Chan JK, Monk BJ, Cuccia D, Pham H, Kimel S, Gu M, et al. Laparoscopic photodynamic diagnosis of ovarian cancer using 5-aminolevulinic acid in a rat model. Gynecol Oncol 2002;87:64–70.
      1. Gahlen J, Prosst RL, Pietschmann M, Haase T, Rheinwald M, Skopp G, et al. Laparoscopic fluorescence diagnosis for intraabdominal fluorescence targeting of peritoneal carcinosis experimental studies. Ann Surg 2002;235:252–260.
      1. Canis M, Botchorishvili R, Berreni N, Manhes H, Wattiez A, Mage G, et al. 5-aminolevulinic acid-induced (ALA) fluorescence for the laparoscopic diagnosis of peritoneal metastasis. AST an experimental study. Surg Endosc 2001;15:1184–1186.
      1. Gahlen J, Pietschmann M, Prosst RL, Herfarth C. Systemic vs local administration of delta-aminolevulinic acid for laparoscopic fluorescence diagnosis of malignant intra-abdominal tumors. Experimental study. Surg Endosc 2001;15:196–199.
      1. Aalders MC, Sterenborg HJ, Stewart FA, van der Vange N. Photodetection with 5-aminolevulinic acid-induced protoporphyrin IX in the rat abdominal cavity: drug-dose-dependent fluorescence kinetics. Photochem Photobiol 2000;72:521–525.
      1. Gahlen J, Prosst RL, Pietschmann M, Rheinwald M, Haase T, Herfarth C. Spectrometry supports fluorescence staging laparoscopy after intraperitoneal aminolaevulinic acid lavage for gastrointestinal tumours. J Photochem Photobiol B 1999;52:131–135.
      1. Gahlen J, Stern J, Laubach HH, Pietschmann M, Herfarth C. Improving diagnostic staging laparoscopy using intraperitoneal lavage of delta-aminolevulinic acid (ALA) for laparoscopic fluorescence diagnosis. Surgery 1999;126:469–473.
      1. Hornung R, Major AL, McHale M, Liaw LH, Sabiniano LA, Tromberg BJ, et al. In vivo detection of metastatic ovarian cancer by means of 5-aminolevulinic acid-induced fluorescence in a rat model. J Am Assoc Gynecol Laparosc 1998;5:141–148.
      1. Major AL, Rose GS, Chapman CF, Hiserodt JC, Tromberg BJ, Krasieva TB, et al. In vivo fluorescence detection of ovarian cancer in the NuTu-19 epithelial ovarian cancer animal model using 5-aminolevulinic acid (ALA). Gynecol Oncol 1997;66:122–132.
      1. Harada K, Murayama Y, Kubo H, Matsuo H, Morimura R, Ikoma H, et al. Photodynamic diagnosis of peritoneal metastasis in human pancreatic cancer using 5-aminolevulinic acid during staging laparoscopy. Oncol Lett 2018;16:821–828.
      1. Ushimaru Y, Fujiwara Y, Kishi K, Sugimura K, Omori T, Moon JH, et al. Prognostic significance of basing treatment strategy on the results of photodynamic diagnosis in advanced gastric cancer. Ann Surg Oncol 2017;24:983–989.
      1. Hillemanns P, Wimberger P, Reif J, Stepp H, Klapdor R. Photodynamic diagnosis with 5-aminolevulinic acid for intraoperative detection of peritoneal metastases of ovarian cancer: a feasibility and dose finding study. Lasers Surg Med 2017;49:169–176.
      1. Kishi K, Fujiwara Y, Yano M, Motoori M, Sugimura K, Takahashi H, et al. Usefulness of diagnostic laparoscopy with 5-aminolevulinic acid (ALA)-mediated photodynamic diagnosis for the detection of peritoneal micrometastasis in advanced gastric cancer after chemotherapy. Surg Today 2016;46:1427–1434.
      1. Yonemura Y, Canbay E, Ishibashi H, Nishino E, Endou Y, Sako S, et al. 5-aminolevulinic acid fluorescence in detection of peritoneal metastases. Asian Pac J Cancer Prev 2016;17:2271–2275.
      1. Yonemura Y, Endo Y, Canbay E, Liu Y, Ishibashi H, Takeshita K, et al. Selection of patients by membrane transporter expressions for aminolevulinic acid (ALA)-guided photodynamic detection of peritoneal metastases. Int J Sci 2015;4:66–77.
      1. Namikawa T, Inoue K, Uemura S, Shiga M, Maeda H, Kitagawa H, et al. Photodynamic diagnosis using 5-aminolevulinic acid during gastrectomy for gastric cancer. J Surg Oncol 2014;109:213–217.
      1. Kishi K, Fujiwara Y, Yano M, Motoori M, Sugimura K, Ohue M, et al. Diagnostic laparoscopy with 5-aminolevulinic-acid-mediated photodynamic diagnosis enhances the detection of peritoneal micrometastases in advanced gastric cancer. Oncology 2014;87:257–265.
      1. Liu Y, Endo Y, Fujita T, Ishibashi H, Nishioka T, Canbay E, et al. Cytoreductive surgery under aminolevulinic acid-mediated photodynamic diagnosis plus hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis from ovarian cancer and primary peritoneal carcinoma: results of a phase I trial. Ann Surg Oncol 2014;21:4256–4262.
      1. Canbay E, Ishibashi H, Sako S, Kitai T, Nishino E, Hirano M, et al. Photodynamic detection and management of intraperitoneal spreading of primary peritoneal papillary serous carcinoma in a man: report of a case. Surg Today 2014;44:373–377.
      1. Murayama Y, Ichikawa D, Koizumi N, Komatsu S, Shiozaki A, Kuriu Y, et al. Staging fluorescence laparoscopy for gastric cancer by using 5-aminolevulinic acid. Anticancer Res 2012;32:5421–5427.
      1. Löning MC, Diddens HC, Holl-Ulrich K, Löning U, Küpker W, Diedrich K, et al. Fluorescence staining of human ovarian cancer tissue following application of 5-aminolevulinic acid: fluorescence microscopy studies. Lasers Surg Med 2006;38:549–554.
      1. Zöpf T, Schneider AR, Weickert U, Riemann JF, Arnold JC. Improved preoperative tumor staging by 5-aminolevulinic acid induced fluorescence laparoscopy. Gastrointest Endosc 2005;62:763–767.
      1. Löning M, Diddens H, Küpker W, Diedrich K, Hüttmann G. Laparoscopic fluorescence detection of ovarian carcinoma metastases using 5-aminolevulinic acid-induced protoporphyrin IX. Cancer 2004;100:1650–1656.
      1. Orth K, Russ D, Steiner R, Beger HG. Fluorescence detection of small gastrointestinal tumours: principles, technique, first clinical experience. Langenbecks Arch Surg 2000;385:488–494.
      1. Menon C, Kutney SN, Lehr SC, Hendren SK, Busch TM, Hahn SM, et al. Vascularity and uptake of photosensitizer in small human tumor nodules: implications for intraperitoneal photodynamic therapy. Clin Cancer Res 2001;7:3904–3911.
      1. Mĺkvy P, Messmann H, Regula J, Conio M, Pauer M, Millson CE, et al. Sensitization and photodynamic therapy (PDT) of gastrointestinal tumors with 5-aminolaevulinic acid (ALA) induced protoporphyrin IX (PPIX). A pilot study. Neoplasma 1995;42:109–113.
      1. Kato A, Kataoka H, Yano S, Hayashi K, Hayashi N, Tanaka M, et al. Maltotriose conjugation to a chlorin derivative enhances the antitumor effects of photodynamic therapy in peritoneal dissemination of pancreatic cancer. Mol Cancer Ther 2017;16:1124–1132.
      1. Harada T, Nakamura Y, Sato K, Nagaya T, Okuyama S, Ogata F, et al. Near-infrared photoimmunotherapy with galactosyl serum albumin in a model of diffuse peritoneal disseminated ovarian cancer. Oncotarget 2016;7:79408–79416.
      1. Ishida M, Kagawa S, Shimoyama K, Takehara K, Noma K, Tanabe S, et al. Trastuzumab-based photoimmunotherapy integrated with viral HER2 transduction inhibits peritoneally disseminated HER2-negative cancer. Mol Cancer Ther 2016;15:402–411.
      1. Yokoyama Y, Shigeto T, Miura R, Kobayashi A, Mizunuma M, Yamauchi A, et al. A strategy using photodynamic therapy and clofibric acid to treat peritoneal dissemination of ovarian cancer. Asian Pac J Cancer Prev 2016;17:775–779.
      1. Sato K, Hanaoka H, Watanabe R, Nakajima T, Choyke PL, Kobayashi H. Near infrared photoimmunotherapy in the treatment of disseminated peritoneal ovarian cancer. Mol Cancer Ther 2015;14:141–150.
      1. Sato K, Choyke PL, Kobayashi H. Photoimmunotherapy of gastric cancer peritoneal carcinomatosis in a mouse model. PLoS One 2014;9:e113276
      1. Hino H, Murayama Y, Nakanishi M, Inoue K, Nakajima M, Otsuji E. 5-Aminolevulinic acid-mediated photodynamic therapy using light-emitting diodes of different wavelengths in a mouse model of peritoneally disseminated gastric cancer. J Surg Res 2013;185:119–126.
      1. Mroz P, Xia Y, Asanuma D, Konopko A, Zhiyentayev T, Huang YY, et al. Intraperitoneal photodynamic therapy mediated by a fullerene in a mouse model of abdominal dissemination of colon adenocarcinoma. Nanomedicine (Lond) 2011;7:965–974.
      1. Estevez JP, Ascencio M, Colin P, Farine MO, Collinet P, Mordon S. Continuous or fractionated photodynamic therapy? Comparison of three PDT schemes for ovarian peritoneal micrometastasis treatment in a rat model. Photodiagnosis Photodyn Ther 2010;7:251–257.
      1. Kishi K, Yano M, Inoue M, Miyashiro I, Motoori M, Tanaka K, et al. Talaporfin-mediated photodynamic therapy for peritoneal metastasis of gastric cancer in an in vivo mouse model: drug distribution and efficacy studies. Int J Oncol 2010;36:313–320.
      1. Piatrouskaya NA, Kharuzhyk SA, Vozmitel MA, Mazurenko AN, Istomin YP. Experimental study of antiangiogenic and photodynamic therapies combination for treatment of peritoneal carcinomatosis: preliminary results. Exp Oncol 2010;32:100–103.
      1. Raue W, Kilian M, Braumann C, Atanassow V, Makareinis A, Caldenas S, et al. Multimodal approach for treatment of peritoneal surface malignancies in a tumour-bearing rat model. Int J Colorectal Dis 2010;25:245–250.
      1. Ascencio M, Estevez JP, Delemer M, Farine MO, Collinet P, Mordon S. Comparison of continuous and fractionated illumination during hexaminolaevulinate-photodynamic therapy. Photodiagnosis Photodyn Ther 2008;5:210–216.
      1. Ascencio M, Collinet P, Farine MO, Mordon S. Protoporphyrin IX fluorescence photobleaching is a useful tool to predict the response of rat ovarian cancer following hexaminolevulinate photodynamic therapy. Lasers Surg Med 2008;40:332–341.
      1. Ascencio M, Delemer M, Farine MO, Jouve E, Collinet P, Mordon S. Evaluation of ALA-PDT of ovarian cancer in the Fisher 344 rat tumor model. Photodiagnosis Photodyn Ther 2007;4:254–260.
      1. Song K, Kong B, Li L, Yang Q, Wei Y, Qu X. Intraperitoneal photodynamic therapy for an ovarian cancer ascite model in Fischer 344 rat using hematoporphyrin monomethyl ether. Cancer Sci 2007;98:1959–1964.
      1. del Carmen MG, Rizvi I, Chang Y, Moor AC, Oliva E, Sherwood M, et al. Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivo. J Natl Cancer Inst 2005;97:1516–1524.
      1. Molpus KL, Hamblin MR, Rizvi I, Hasan T. Intraperitoneal photoimmunotherapy of ovarian carcinoma xenografts in nude mice using charged photoimmunoconjugates. Gynecol Oncol 2000;76:397–404.
      1. Lilge L, Molpus K, Hasan T, Wilson BC. Light dosimetry for intraperitoneal photodynamic therapy in a murine xenograft model of human epithelial ovarian carcinoma. Photochem Photobiol 1998;68:281–288.
      1. Goff BA, Blake J, Bamberg MP, Hasan T. Treatment of ovarian cancer with photodynamic therapy and immunoconjugates in a murine ovarian cancer model. Br J Cancer 1996;74:1194–1198.
      1. Molpus KL, Kato D, Hamblin MR, Lilge L, Bamberg M, Hasan T. Intraperitoneal photodynamic therapy of human epithelial ovarian carcinomatosis in a xenograft murine model. Cancer Res 1996;56:1075–1082.
      1. Perry RR, Smith PD, Evans S, Pass HI. Intravenous vs intraperitoneal sensitizer: implications for intraperitoneal photodynamic therapy. Photochem Photobiol 1991;53:335–340.
      1. Tochner Z, Mitchell JB, Smith P, Harrington F, Glatstein E, Russo D, et al. Photodynamic therapy of ascites tumours within the peritoneal cavity. Br J Cancer 1986;53:733–736.
      1. Tochner Z, Mitchell JB, Harrington FS, Smith P, Russo DT, Russo A. Treatment of murine intraperitoneal ovarian ascitic tumor with hematoporphyrin derivative and laser light. Cancer Res 1985;45:2983–2987.
      1. Huggett MT, Jermyn M, Gillams A, Illing R, Mosse S, Novelli M, et al. Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer. Br J Cancer 2014;110:1698–1704.
      1. Bisland SK, Lilge L, Lin A, Rusnov R, Wilson BC. Metronomic photodynamic therapy as a new paradigm for photodynamic therapy: rationale and preclinical evaluation of technical feasibility for treating malignant brain tumors. Photochem Photobiol 2004;80:22–30.
      1. Herrera-Ornelas L, Petrelli NJ, Mittelman A, Dougherty TJ, Boyle DG. Photodynamic therapy in patients with colorectal cancer. Cancer 1986;57:677–684.
      1. Hahn SM, Putt ME, Metz J, Shin DB, Rickter E, Menon C, et al. Photofrin uptake in the tumor and normal tissues of patients receiving intraperitoneal photodynamic therapy. Clin Cancer Res 2006;12:5464–5470.
      1. Wilson JJ, Jones H, Burock M, Smith D, Fraker DL, Metz J, et al. Patterns of recurrence in patients treated with photodynamic therapy for intraperitoneal carcinomatosis and sarcomatosis. Int J Oncol 2004;24:711–717.
      1. Hendren SK, Hahn SM, Spitz FR, Bauer TW, Rubin SC, Zhu T, et al. Phase II trial of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. Ann Surg Oncol 2001;8:65–71.
      1. Bauer TW, Hahn SM, Spitz FR, Kachur A, Glatstein E, Fraker DL. Preliminary report of photodynamic therapy for intraperitoneal sarcomatosis. Ann Surg Oncol 2001;8:254–259.
      1. Wierrani F, Fiedler D, Grin W, Henry M, Dienes E, Gharehbaghi K, et al. Clinical effect of meso-tetrahydroxyphenylchlorine based photodynamic therapy in recurrent carcinoma of the ovary: preliminary results. Br J Obstet Gynaecol 1997;104:376–378.
      1. Sindelar WF, DeLaney TF, Tochner Z, Thomas GF, Dachoswki LJ, Smith PD, et al. Technique of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. Phase I study. Arch Surg 1991;126:318–324.
      1. Garza OT, Abati A, Sindelar WF, Pass HI, Hijazi YM. Cytologic effects of photodynamic therapy in body fluids. Diagn Cytopathol 1996;14:356–361.
      1. Huang Z, Chen Q, Luck D, Beckers J, Wilson BC, Trncic N, et al. Studies of a vascular-acting photosensitizer, Pd-bacteriopheophorbide (Tookad), in normal canine prostate and spontaneous canine prostate cancer. Lasers Surg Med 2005;36:390–397.
      1. Krogh A, editor. The Anatomy and Physiology of Capillaries. New Haven (CT): Yale University Press; 1922.
      1. Shafirstein G, Bellnier D, Oakley E, Hamilton S, Potasek M, Beeson K, et al. Interstitial photodynamic therapy-a focused review. Cancers (Basel) 2017;9:12.
      1. Wilson BC, Jeeves WP, Lowe DM. In vivo and post mortem measurements of the attenuation spectra of light in mammalian tissues. Photochem Photobiol 1985;42:153–162.
      1. Lee LK, Whitehurst C, Chen Q, Pantelides ML, Hetzel FW, Moore JV. Interstitial photodynamic therapy in the canine prostate. Br J Urol 1997;80:898–902.
      1. Mroz P, Hashmi JT, Huang YY, Lange N, Hamblin MR. Stimulation of anti-tumor immunity by photodynamic therapy. Expert Rev Clin Immunol 2011;7:75–91.
      1. Piette J. Signalling pathway activation by photodynamic therapy: NF-κB at the crossroad between oncology and immunology. Photochem Photobiol Sci 2015;14:1510–1517.
      1. Davies N, Wilson BC. Interstitial in vivo ALA-PpIX mediated metronomic photodynamic therapy (mPDT) using the CNS-1 astrocytoma with bioluminescence monitoring. Photodiagnosis Photodyn Ther 2007;4:202–212.
      1. Bogaards A, Varma A, Zhang K, Zach D, Bisland SK, Moriyama EH, et al. Fluorescence image-guided brain tumour resection with adjuvant metronomic photodynamic therapy: pre-clinical model and technology development. Photochem Photobiol Sci 2005;4:438–442.
      1. Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105:1045–1047.
      1. Liu Y, Hou G, Zhang X, Liu JJ, Zhang S, Zhang J. A pilot randomized clinical study of the additive treatment effect of photodynamic therapy in breast cancer patients with chest wall recurrence. J Breast Cancer 2014;17:161–166.
      1. Morrison SA, Hill SL, Rogers GS, Graham RA. Efficacy and safety of continuous low-irradiance photodynamic therapy in the treatment of chest wall progression of breast cancer. J Surg Res 2014;192:235–241.
      1. Fujino M, Nishio Y, Ito H, Tanaka T, Li XK. 5-Aminolevulinic acid regulates the inflammatory response and alloimmune reaction. Int Immunopharmacol 2016;37:71–78.
      1. Perry RR, Evans S, Matthews W, Rizzoni W, Russo A, Pass HI. Potentiation of phototherapy cytotoxicity with light scattering media. J Surg Res 1989;46:386–390.
      1. Dedrick RL. Theoretical and experimental bases of intraperitoneal chemotherapy. Semin Oncol 1985;12:1–6.
      1. Vulcan TG, Zhu TC, Rodriguez CE, Hsi A, Fraker DL, Baas P, et al. Comparison between isotropic and nonisotropic dosimetry systems during intraperitoneal photodynamic therapy. Lasers Surg Med 2000;26:292–301.
      1. Azaïs H, Rebahi C, Baydoun M, Serouart B, Ziane L, Moralès O, et al. A global approach for the development of photodynamic therapy of peritoneal metastases regardless of their origin. Photodiagnosis Photodyn Ther 2020;30:101683
      1. Swartling J, Höglund OV, Hansson K, Södersten F, Axelsson J, Lagerstedt AS. Online dosimetry for temoporfin-mediated interstitial photodynamic therapy using the canine prostate as model. J Biomed Opt 2016;21:28002.
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    MeSH Terms
    Capillary Leak Syndrome
    Carcinoma
    Clinical Protocols
    Diagnosis*
    Gastrointestinal Neoplasms*
    Humans
    Laparoscopy
    Neoplasms
    Optical Imaging
    Peritoneal Neoplasms*
    Photochemotherapy
    Photosensitizing Agents
    Therapeutic Uses
    Metrics
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