10.1245/ASO.2005.09.005
Annals of Surgical Oncology 12:808-816 (2005)
© 2005 Society of Surgical Oncology
Photodynamic Therapy With 5,10,15,20-Tetrakis(m-Hydroxyphenyl) Bacteriochlorin for Colorectal Liver Metastases Is Safe and Feasible: Results From a Phase I Study
Frederieke H. van Duijnhoven, MD, PhD1,
Jeroen P. Rovers, MD, PhD1,
Kerstin Engelmann, MD2,
Zdenko Krajina, MD, PhD3,
Shaun F. Purkiss, MS, FRCS4,
Frans A. N. Zoetmulder, MD, PhD5,
Thomas J. Vogl, MD, PhD2 and
Onno T. Terpstra, MD, PhD, FRCS1
1 Department of Surgery, K6-R, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands
2 Diagnostische und Interventionelle Radiologie, Zentrum der Radiologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
3 Department for Oncology and Radiotherapy, Clinical Hospital Osijek, Osijek, Croatia
4 Department of Surgery, The Royal London Hospital, London, United Kingdom
5 Department of Medical Oncology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands
Correspondence: Address correspondence and reprint requests to: Onno T. Terpstra, MD, PhD, FRCS; E-mail: o.t.terpstra{at}lumc.nl.
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ABSTRACT
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Background: The prognosis for patients with liver metastases from colorectal carcinoma is limited because of the low number of patients who are eligible for curative hepatic resection. In this phase I study, 31 liver metastases in 24 patients with nonresectable metastases from colorectal carcinoma were treated with photodynamic therapy (PDT).
Methods: The photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl)bacteriochlorin (mTHPBC) was intravenously administered in a dose of .6 mg/kg (n = 12) or .3 mg/kg (n = 12). After 120 hours (n = 18) or 48 hours (n = 6), tumors were illuminated for 300 to 600 seconds through percutaneously inserted optical fibers with a light dose of 60 J/cm of diffuser (740 nm).
Results: Tumor necrosis at 1 month after PDT was achieved in all treated lesions. Laser treatment was associated with mild pain (n = 8) and transient subclinical hepatotoxicity (n = 21). In one patient, PDT damage to the pancreas was inflicted, and in another patient, PDT damage of the skin occurred, but no serious clinical complications from PDT were reported. Administration of .6 mg/kg of mTHPBC led to transient phlebitis in 10 patients, and 3 patients experienced mild skin phototoxicity after excess light exposure.
Conclusions: Colorectal liver metastases that are ineligible for resection can be safely and effectively treated with interstitial mTHPBC-based PDT.
Key Words: Photodynamic therapy • Liver metastases • Colorectal cancer • Phase I
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INTRODUCTION
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Photodynamic therapy (PDT) is a method for local tumor treatment that is currently applied in several cancers. In PDT, a photosensitizing agent is administered systemically and will, with varying specificity, localize in tumor tissue.1,2 On subsequent tumor illumination by light of an appropriate wavelength, the photosensitizer is excited by photons to an unstable higher energy level. When returning to its ground-state energy level, the absorbed energy is transferred to oxygen, which leads to the formation of reactive oxygen species. These reactive oxygen species are cytotoxic and cause direct tumor cell damage, vascular damage,3 and possibly activation of the immune system.4 The efficacy of PDT is dependent on various parameters, such as the interval between sensitizer administration and tumor illumination, doses of photosensitizer and light, and pharmacological properties of the photosensitizer. Because exposure of photosensitizer to light is essential for activation, the pharmacological effect without illumination is absent. Unfortunately, the reverse is also true: because the photosensitizer is also present in skin tissue, patients remain photosensitive for several weeks after sensitizer administration and should avoid bright (sun)light in this period to avoid skin phototoxicity.5
The first and still most commonly used photosensitizers are porphyrin-based compounds, such as hematoporphyrin derivative and its purified version porfimer sodium (Photofrin, Axcan Pharma, Birmingham, AL). These sensitizers are activated by light of approximately a 630-nm wavelength, which penetrates tissue only for several millimeters. PDT with these sensitizers is very effective against superficial and luminal tumors such as cholangiocarcinoma and basal cell, bladder, and esophageal carcinoma.6–9 Porfimer sodium was also the photosensitizer used in the first study with PDT of experimental liver metastases in a rat model for adenocarcinoma.10 Along with tumor tissue, surrounding normal tissue was extensively damaged because of the poor tumor selectivity of porfimer sodium. Shortly after, Purkiss et al.11 further developed this technique by using multiple optical fibers interstitially. Application of this technique in hematoporphyrin derivative–based PDT of colorectal liver metastases in patients resulted in tumor destruction, which was, however, incomplete and did not affect patient survival.12 This was partly due to the limited depth of tissue penetration by light of a 630-nm wavelength and the poor tumor selectivity of porfimer sodium in liver tissue, which required a high drug and light dose to induce sufficient effect.13
Further pharmacological developments resulted in the production of second-generation sensitizers that are activated by wavelengths of >700 nm, thus allowing deeper tissue penetration of up to 1 cm. Consequently, these sensitizers are more suitable for interstitial treatment of solid tumors, in which light is delivered directly to the tumor by the insertion of optical fibers. One of these sensitizers is the hydrophobic tetrahydroporphyrin 5,10,15,20-tetra-kis (m-hydroxyphenyl) bacteriochlorin (mTHPBC), a bacteriochlorin of temoporfin (Foscan, Biolitec AG, Jena, Germany), which is used successfully in the clinical treatment of head and neck cancer.14 mTHPBC is activated by 740-nm light and has already been shown to be highly effective when compared with conventional photosensitizers in colon tumor cell lines and animal models.15,16 A study in white pigs showed that it was feasible to get clinically relevant lesions with mTHPBC-based PDT by using interstitial optical fibers. Preclinical work indicated that the effect of PDT with temoporfin increases with a shorter drug-light interval and with increased drug or light doses, with optimal antitumor effect of illumination at 24 to 48 hours after drug administration. For mTHPBC, similar results were found in rat studies.17–19
The combination of this effective sensitizer, activation by deeply penetrating light, and interstitial treatment should increase the efficacy of PDT for deeply seated, solid tumors such as liver metastases. Because PDT is a minimally invasive technique that can be applied under ultrasound and computed tomographic (CT) guidance, it could be a valuable addition to the range of treatment options available to patients with nonresectable colorectal liver metastases. In this study, we report the results of a multicenter phase I trial of the safety and technical feasibility of mTHPBC-based PDT for colorectal liver metastases.
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PATIENTS AND METHODS
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Study Objectives
The aim of this phase I study was to assess the feasibility and safety of PDT for nonresectable colorectal liver metastases with several treatment regimens.
Patient Characteristics
Between April 2000 and May 2001, 24 patients were included in this multicenter trial, with participating centers in Germany, Croatia, the United Kingdom, and The Netherlands. Only patients with nonresectable liver metastases of previously resected primary colorectal carcinoma without evidence of local disease or other distant metastases were included. Additional inclusion criteria were a Karnofsky status of at least 60%, age >18 years, and accessibility of the liver metastases for adequate percutaneous fiber placement. Exclusion criteria were metastases >7 cm in diameter; abnormal blood coagulation (prothrombin time >1.3 times normal and platelet count <100 x 109/L); grade 3 or 4 ala-nine aminotransferase (ALT) or total bilirubin toxicity (according to the Common Toxicity Criteria of the National Cancer Institute)20; chronic liver impairment; ascites; treatment with chemotherapy, radiotherapy, or other photosensitizing or experimental drugs 30 days before inclusion; and disease that is caused or exacerbated by light. Local medical ethics committees approved the trial, and written informed consent was obtained from all patients.
Study Design
The initial drug dose selection of .6 mg/kg of mTHPBC was based on safety data from general toxicology studies in mice, rats, and dogs. The results of these preclinical studies showed treatment to be safe and effective with drug-light intervals of 24 to 120 hours. To minimize the risk of damage to normally functioning liver tissue, the drug-light interval in the first group of patients was set at 120 hours, because the ratio of photosensitizer in tumor tissue versus normal liver tissue is high at this time point. The first 12 patients (group A) were therefore treated at 120 hours after the administration of .6 mg/kg of mTHPBC.
This drug dose proved to be highly effective but was associated with drug-related adverse events such as phlebitis and skin phototoxicity. In addition, pharmacokinetic data from this first set of patients showed higher concentrations of mTHPBC compared with those seen in animal studies. The drug dose was therefore decreased to .3 mg/kg for the next 6 patients (group B). Because no adverse events occurred with this drug dose and drug-light interval and to ensure maximum efficacy with this lower systemic drug dose, the drug-light interval was shortened to 48 hours in the last 6 patients (group C).
Administration of mTHPBC
The photosensitizer mTHPBC was administered by slow intravenous injection over a minimum of 15 minutes. After photosensitizer administration, patients were kept in a room with subdued lighting. They received a lux light meter with light-exposure instructions to avoid skin phototoxicity (Table 1
). To monitor the cardiovascular effects of drug administration, electrocardiograms were made directly before and 1 hour after drug administration. Vital signs (heart rate, temperature, blood pressure, and saturation) were assessed before and 4, 8, 12, and 24 hours after drug administration. To assess the pharmacokinetics of mTHPBC, blood samples were taken 1, 4, 6, 8, and 24 hours and 3, 4, 5, 7, 14, and 28 days after drug administration.
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TABLE 1. Summary of the guidelines regarding light exposure and corresponding maximum lux doses after the administration of 5,10,15,20-tetrakis(m-hydroxyphenyl)bacteriochlorin
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Tumor Illumination
For tumor illumination, 18-gauge needles were placed in the tumors with local or general anesthesia under CT guidance (Fig. 1). Optical fibers (CeramOptec, Bonn, Germany) with cylindrical diffuser lengths varying from 1 to 6 cm were inserted through the needles. Laser light of 740 nm was produced by continuous-wave diode lasers from CeramOptec. Tumors were illuminated with 60 J/cm of diffuser length per single fiber application. To shorten the treatment time during treatment of large tumors, a fiber beam splitter with a 1:4 ratio (ATI Optique, Courcouronnes, France) was used to ensure simultaneous illumination with four fibers. Control spiral CT scans were performed according to local protocol and assessed by both the local treating radiologist and an independent radiologist 4 days after tumor illumination (baseline CT scan) and 1 month after mTHPBC administration. Treated tumors were qualified as being locally progressive or stable, according to the reporting criteria proposed by the International Working Group on Image-Guided Tumor Ablation.21 The size of the induced necrotic lesion and the presence of tumor tissue was assessed on the baseline CT scan to determine whether complete necrosis of tumor tissue was achieved. On the 1-month control CT scan, lesion size was again assessed, and if it was increased compared with the lesion size at the baseline CT scan, this was qualified as lesion progression. If the lesion size was unchanged or decreased, the lesion was qualified as stable.
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FIG. 1. Simultaneous placement of optic fibers into the central tumor under computed tomographic guidance. (a) Second pass of fibers 1 to 3 centrally in the tumor (GB, gallbladder; IVC, inferior vena cava). (b) Fourth pass of needles 1 and 2 caudally in the tumor.
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Blood samples for hematological and biochemical parameters (total bilirubin, alkalic phosphatase, 
-glutamyltransferase, ALT, aspartate aminotransferase, and coagulation parameters) were obtained before drug administration and 1, 2, 3, 4, 5, 6, 7, and 8 days and 1 and 3 months after drug administration. The toxicity of serum enzyme levels was graded according to the Common Toxicity Criteria of the National Cancer Institute.22
Statistics
Hepatotoxicity, mTHPBC-related adverse events, and local tumor progression were compared between groups by using Pearson’s 
2 test. A P value 
.05 was considered statistically significant.
Role of the Funding Source
Scotia Pharmaceuticals Ltd. (Stirling, Scotland) provided centers with photosensitizer mTHPBC and laser equipment for tumor illumination and arranged for collection of study data. Serum levels of mTHPBC were measured by Huntington Life Sciences Ltd. (Huntington, UK). All data were analyzed by F.H.v.D. Scotia Pharmaceuticals Ltd. had no decisive role in data analysis, data interpretation, writing of the article, or the decision to submit the paper for publication.
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RESULTS
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Patient and Treatment Characteristics
Of 24 included patients, 23 were treated with laser illumination. Laser treatment was canceled in one patient because of the detection of extrahepatic disease after mTHPBC administration. The mean age of patients was 60 years (median, 61 years; range, 35–78 years), with 13 women and 11 men. The median interval between diagnosis of primary colorectal carcinoma and PDT was 14.5 months (range, 1.5–122 months).
A total of 31 liver metastases (1–4 lesions per patient), with an average diameter of 3.2 cm (median, 3.0 cm; range, 1.2–6.8 cm) were treated by PDT. Because a single optic fiber causes a cylinder of necrotic tissue measuring 2 cm in diameter and 1 to 6 cm in length (depending on diffuser length), multiple applications were generally necessary to adequately treat the entire tumor. A total of 124 fiber applications were used (median, 4 fiber applications per lesion; range, 1–12) to treat these 31 metastases. A light dose of 60 J/cm of diffuser length was delivered at an intensity of 143 to 200 mW/cm of diffuser length. Treatment time per application varied between 300 and 460 seconds (Table 2). According to varying local hospital protocols, 14 patients received prophylactic antibiotics. Twenty-one of 23 assessable patients completed 1-month follow-up for assessment of feasibility and safety. Two patients were lost to follow-up.
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TABLE 2. Average tumor size, treatment time, total delivered energy, and output power for tumors in groups A, B, and C
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Pharmacokinetics of mTHPBC
After the initial increase of the mTHPBC plasma concentration in the first 24 hours, mTHPBC levels in both dose groups decreased to 50% of the maximum value at 2 days after administration (Fig. 2a). At 14 days after administration, mTHPBC was hardly present in plasma anymore. Both in the .6 mg/kg and in the .3 mg/kg dose groups, the concentration of mTHPBC was highest at 6 to 8 hours after drug administration (Fig. 2b). The mTHPBC plasma concentration was higher in the .6 mg/kg dose group than in the .3 mg/kg dose group—a difference that was significant at all time points within 6 days after drug administration (P < .008). At 7, 14, and 28 days after administration, there was no significant difference between dose groups anymore.
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FIG. 2. The 5,10,15,20-tetrakis(m-hydroxyphenyl)bacteriochlorin (mTHPBC) concentration (ng/mL) in plasma from patients in group A (.6 mg/kg; n = 12) and in groups B and C (.3 mg/kg; n = 12). (a) From 0 to 28 days after mTHPBC administration; (b) from 0 to 24 hours after mTHPBC administration. *P < .008 for the .6 mg/kg mTHPBC group versus the .3 mg/kg mTHPBC group.
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Toxicity of mTHPBC
Intravenous administration of mTHPBC was accompanied by pain and tingling in seven patients (29%) that was independent of injection duration (Table 3). In the days after mTHPBC administration, 9 patients (38%) developed a transient phlebitis of the injection vein. Hyperpigmentation of the injection arm was seen in four patients, in two of whom residual hyperpigmentation remained (Fig. 3). Occurrence of these mild (n = 18) to moderate (n = 5) adverse events was related to the mTHPBC dose because they were observed significantly (P .05) more often in the .6 mg/kg group than in the .3 mg/kg groups (Table 3).
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FIG. 3. Hyperpigmentation of the arm after 5,10,15,20-tetrakis (m-hydroxyphenyl)bacteriochlorin administration.
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Because of skin photosensitivity, moderate hyperpigmentation, other than of the injection arm, occurred in two patients. Three patients experienced mild sunburn after excess light exposure in the first week (n = 2) or in the third week (n = 1) because of insufficient adherence to light instructions. One of these patients also experienced two mild oximeter burns during laser treatment. No hepatotoxicity occurred after mTHPBC administration, nor was there any effect on vital signs. Electrocardiogram readings remained stable after mTHPBC administration.
Safety and Feasibility of Tumor Illumination
In all patients, lesions could be treated with interstitial tumor illumination. A severe adverse event occurred in one patient: bleeding of the treated liver metastasis during treatment that recovered fully and without lasting effects. Two other patients experienced moderate adverse events from tumor illumination: one patient had a lesion of the skin surrounding the fiber insertion site (diameter 5 cm) after treatment that recovered over the course of several months, and another patient had damage of the pancreas caused during illumination of an adjacent tumor, without clinical symptoms or biochemical abnormalities.
Other adverse events related to tumor illumination were (1) abdominal pain (n = 8), (2) pain at the fiber-insertion site (n = 2), (3) appearance of pleural fluid (n = 2), and (4) pyrexia (n = 3; Table 4). All these events were graded as mild (n = 9) or moderate (n = 4). Pain during laser treatment was located at the fiber-insertion site and occurred during fiber insertion and subsequent relocation, but not during tumor illumination. Mild abdominal pain was present after surgery for several hours to 2 days. Karnofsky performance status remained stable throughout treatment except in one patient, who experienced pain, increased temperature, and a skin lesion at the fiber-insertion site after treatment.
Within 48 hours after tumor illumination, 1 or more liver enzymes were increased in 21 patients. Hepatotoxicity was transient and not clinically significant, because at 1 month all values had returned to pre-PDT levels. Hepatotoxicity was not related to the drug-light interval or the mTHPBC drug dose (Table 5), because there were no significant statistical differences between groups regarding hepatotoxic levels of -glutamyltransferase, bilirubin, alkalic phosphatase, aspartate aminotransferase, or ALT. Tumor illumination had no effect on coagulation parameters.
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TABLE 5. Hepatotoxicity graded according to Common Toxicity Criteria of the National Cancer Institute in groups A, B, and C within 48 hours of laser illumination
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Antitumor Efficacy
Adequate necrosis was induced in 30 of 31 treated lesions, as shown by the absence of contrast enhancement in treated lesions on CT scans performed 4 days after PDT (Fig. 4; Table 6). At 1 month after PDT, all lesions in group B were stable. In group A, 13 (87%) of 15 treated lesions were stable; 2 lesions in 2 different patients were locally progressive. In group C, four (66%) of six treated lesions were stable, and two lesions (33%) showed local tumor progression (Table 6). Although there was a trend indicating that lesions in group C did worse than those in groups A and B, these differences were not significant.
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FIG 4. Computed tomographic scans showing a large central tumor at 6 days before photodynamic therapy (PDT) (a), 5 days after PDT (b), 3 weeks after PDT (c), and 3 months after PDT (d). Initially, a large area of necrosis at the site of the tumor is induced that gradually decreases in time, with no viable tumor tissue left at 3 months after PDT.
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DISCUSSION
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Our study showed interstitial PDT with mTHPBC to be a safe and feasible treatment of deeply seated liver metastases. Adequate tumor necrosis was induced in 30 of 31 treated lesions: 84% of lesions showed no signs of local tumor progression at 1 month after PDT. No severe complications occurred. Two patients in our study inadvertently experienced PDT damage of the pancreas and fiber-insertion site. Visual confirmation of correct fiber placement and adequate control of laser treatment may help to avoid this damage to adjacent organs and tissues. Although skin photosensitivity reactions were reduced to a minimum by decreasing the sensitizer dose to .3 mg/kg, patients should be made well aware of the risk of light exposure, because skin remains photosensitive for several weeks after intravenous administration.5,23 The disadvantage of skin photosensitivity has a pronounced effect on patients’ daily routine, especially in sunny seasons.
A recent study by Lustig et al.24 also showed PDT for solid tumors to be feasible and safe. In this phase I study, talaporfin sodium was used for PDT of 21 solid tumors from various origins. Talaporfin sodium is activated by 664-nm wavelength light and therefore does not penetrate tissue quite as well as mTHPBC, but it has the advantage of a very short drug-light interval, because tumors can be treated at 1 hour after intravenous administration. Tumors were not illuminated by laser but by newly developed light-emitting diodes that can be percutaneously inserted in the tumor, thus enabling tumor illumination for a prolonged period (until 664 minutes in this study).25 Although these new sensitizers and techniques greatly facilitate the treatment of solid tumors, PDT should at present not be used for tumors >7 cm. Because the diameter of necrosis induced by one fiber does not extend beyond 2 cm, several fiber insertions are necessary to treat large tumors, with an increased risk of inadequate placement. An associated problem is the lack of real-time visualization during PDT, because the necrosis caused by PDT is not immediately present but develops until 48 hours after the maximum effect is reached.15 Because the efficacy of PDT is largely dependent on the induction of a necrotic lesion that exceeds the tumor in size, the correct placement of fibers is essential. To do so without real-time imaging requires skills and experience, and, because there is limited earlier experience with this technique, a learning curve element in this study must not be underestimated.
Other local ablative techniques used in treatment for colorectal liver metastases include radiofrequency ablation (RFA) and laser-induced thermotherapy (LITT). In RFA, needle electrodes deliver a high-frequency alternating current to the tissue. This causes hyperthermia of the tissue and, thus, induces coagulative necrosis. Currently, RFA is an established therapy and has resulted in complete response rates of 52% to 95%.26,27 It can offer palliation by prolongation of disease-free and overall survival to respectively 50% and 94% at 1 year28 and possibly even cure, although at present the limited follow-up time in most studies does not allow a meaningful determination of survival rates. In LITT, a laser applicator delivers light energy through optical fibers and results in coagulative necrosis. Studies have shown tumor responses up to 97% after 6 months, with median survival ranging from 32 to 39 months.29,30
The main advantage of PDT, RFA, and LITT is their feasibility in patients who are not eligible for resection, which is still considered the gold standard therapy for colorectal liver metastases. In addition, they can be applied percutaneously and may be repeated if necessary. PDT may, however, be specifically suitable for patients with liver metastases in the vicinity of large vessels. Blood flow in vessels near the treated tumor has a cooling effect on thermal energy–based treatments such as RFA and LITT; they prevent tissue from reaching a sufficiently high temperature (>60°C) to be irreversibly destroyed.31 PDT, however, is not compromised by this heat-sink effect, because the effectiveness of this minimally invasive local technique is not dependent on the generation of heat, but on the generation of reactive oxygen species. If an open procedure, in which a Pringle maneuver could be performed to prevent this effect, is contra-indicated or otherwise undesirable, percutaneous PDT could be a very useful therapeutic option.
Received for publication September 8, 2004.
Accepted for publication April 18, 2005.
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ABSTRACT
INTRODUCTION
