Photodynamic Therapy Indications and Limits in Malignant Tumors Treatment

Photodynamic Therapy – Indications and Limits in Malignant Tumors Treatment ADRIANA GABRIELA FILIP1, SIMONA CLICHICI1, DOINA DAICOVICIU1, DIANA OLTEAN...
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Photodynamic Therapy – Indications and Limits in Malignant Tumors Treatment ADRIANA GABRIELA FILIP1, SIMONA CLICHICI1, DOINA DAICOVICIU1, DIANA OLTEANU1, ADRIANA MUREŞAN1, SIMINA DREVE2 1

Physiology Department, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca 2 National R&D Institute of Isotopic and Molecular Technologies, Cluj-Napoca, Romania

Photodynamic therapy (PDT) is a very promising technique used for the treatment of a variety of solid neoplasms, based on the formation of singlet oxygen induced by a photosenstizer after irradiation with visible light. The mechanism of interaction of the photosensitizers and light is discussed, along with the effects produced in the target tissue. PDT has been approved in many countries for the treatment of lung, esophageal, bladder, skin and head and neck cancers. The antitumor effects of this treatment result from the combination of direct tumor cell photodamage, destruction of tumor vasculature and activation of an immune response. The present status of clinical PDT is discussed along with the newer photosensitizers being used and their clinical roles. Despite the promising results from earlier clinical trials of PDT considerable additional work is needed to bring this new modality of treatment into modern clinical practice. Key words: photodynamic therapy, photosensitizers, cancers, side effects.

Despite the latest advances in oncology, the problem of treating malignant diseases has not been resolved yet. In most cases, the treatment is beneficial at early stages of cancer. However, two thirds of patients reveal advanced cancer and only half of them undergo special treatment. Surgery, radiotherapy, and combined treatment have limited capabilities for advanced cancer, most of the patients die of relapses and metastases. Moreover, many patients (up to 25 percent) have operable cancer, but cannot have surgical treatment. This is because of serious associated diseases and agerelated disorders. These patients often undergo organ-saving surgical treatment with a high rate of local relapses. Until the last decade, there was no adequate treatment for these patients either. The advent of photodynamic therapy (PDT) has considerably extended oncologic capabilities. PDT is a relatively new therapeutic modality for neoplastic diseases, which involves light activation of certain photosensitizers (PS) that have been somewhat selectively taken up by the target tissue in the presence of molecular oxygen. PS are compounds that absorb energy from light of specific wavelengths and are capable of using that energy to induce reactions in other non-absorbing molecules [1]. PDT offers a number of advantages over traditional therapies for malignant tumors. First, PDT is highly selective and targeted in action. Second, it is free of surgical risks, serious damages, and systemic ROM. J. INTERN. MED., 2008, 46, 4, 285–293

complications. Third, PDT sessions can be repeated as many times as needed. Fourth, a single PDT procedure enables both the treatment and fluorescent diagnosis. Finally, most patients exhibit tumor resolution after a single PDT session, which can be performed under outpatient conditions [2]. HISTORY OF PDT

The studies regarding PDT have a long history, which dates back more than a century. The first clinical application of PDT was mentioned in 1903, when two researchers, Von Tappeiner H. and Jasionek A., observed that basal cell tumors would heal when exposed to eosine and light for a few weeks [3]. In 1942 Auler and Banzer injected hematoporphirin in tumor carrying animals and found that after exposing them to a halogen lamp, fluorescence and tumor necrosis appears. The purification of hematoporphirin, the use of its derivatives, and especially the introduction of laser as a light source by Maiman in 1960 lead to an improvement of the effects of this therapy [4]. The development of endoscopy offered new opportunities for the treatment of tumors located in less accessible areas such as the esophagus, the lung, the bladder, Hayata et al. being the first to utilize laser in the treatment of bronchial tumors [4]. In the USA Photofrin is the only PS approved by


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the Food and Drug Administration (FDA) for clinical use in palliation of “patients with completely obstructing esophageal cancer and for treatment of microinvasive endobronchial nonsmall cell lung cancer in patients for whom surgery and radiotherapy are not indicated” (National Cancer Institute Because of the long lasting skin phototoxicity of Photofrin, several new PS have recently been introduced in clinical trials: 5 amino-levulinic acid (5–ALA, Levulan; DUSA Pharmaceuticals Inc. Wilmington, MA), the methyl ester of ALA (Metvix, Photocure ASA, Oslo, Norway), Visudyne (verteporfin, benzoporphyrin derivative monoacid ring A, BPD-MA) and mesotetra-hydroxylphenyl-chlorin (mTHPC, Foscan, Biolitec Pharma Ltd., Dublin, Ireland) [2]. PRINCIPLE OF PDT

PDT involves the administration of a PS followed by local illumination of the tumor with light to activate the specific drug so that PS would pass from the base state to the excited state of singlet, with higher energy and very short life [2]. From this state the substance can follow two paths: it either passes back to the unexcited, base form and emits fluorescence which allows the detection of the photosensitiser in the tissue and the visualization of the tumor [5], or it passes in a triplet state with low energy and longer life span than the singlet form. In a triplet state, the molecule transfers its own energy either to the molecular oxygen present in the tissues and generates 1O2 (reaction type II) [4], or to the biomolecules from the tissue and it generates hydroxyl radicals, hydrogen peroxide, and anion superoxide (reaction type I) [5]. Radicals can also be formed after the reaction of 1O2 with the proteins and the unsaturated lipids from the cells resulting hydroperoxides, which in their turn react as secondary reactive oxygen species (ROS). The radicals and the peroxides having a long life can diffuse in the cell and can determine distant oxidative lesions, even in the DNA or proteins [6–8]. In fact, the results of the in vivo application of PDT depend on the effects that it has on tumor cells, on tumor vascularization as well as on the host’s immune cells, a combination of these effects contributing to the long-term control of the tumor [9]. The vascular modifications depend on PS, but in most of the cases lesions of the vascular


endothelium appear and thrombi form through the activation of the platelets and through the release of thromboxane. Also, vasoconstriction can occur due to the inhibition of formation/release of endothelial nitric oxide (NO) [10][11]. The inflammation is considered an important event in the development of the specific antitumor immunity; this type of therapy induces the expression of some cytokines and pro-inflammatory chemokines: interleukine (IL1ß, IL6), tumor necrosis alpha (TNFα), of inflammatory proteins of the macrophages (MIP-1, MIP-2) but also of the cellular adhesion molecules: Selectin E and intercellular adhesion molecule (ICAM). These modifications are accompanied by a massive infiltration of the treated tumor with leucocytes, most of them being neutrophils, mast cells and macrophages [9]. PHOTOSENSITIZERS

The ideal PS would be a chemically pure drug with preferential uptake in tumor, rapid clearance, and a strong absorption peak at light wavelengths >630 nm [2]. There are a few mechanisms which increase the retention of the PS in the tumors: tumor cells proliferate rapidly, have reduced lymphatic drainage, express more receptors for low density lipo-proteins, have low pH, have increased vascular permeability, have increased porphyrin binding collagen production, the macrophages in the tumor favor the captation of hydrophobic PS in cells [5]. FIRST GENERATION

The first generation of PS comprises hematoporphyrin (HpD), hematoporphyrin derivatives, and the purified commercial compound, Sodium Porfimer or Photofrin [2]. Photofrin, a mixture of porphyrin oligomers, has maximum absorption at 630 nm, a depth of action of 0.5 cm, has not specificity for tumor tissue, does not present systemic toxicity, and determines prolonged photosensitivity (4 to 8 weeks) [5]. It requires large dosages and a high fluence rate in order to obtain the same effects as the second generation of photosensitizing substances. SECOND GENERATION

The most utilized compound of the second generation is the 5-aminolevulinic acid (5-ALA)



Photodynamic therapy in malignant treatment

(Levulan), an intermediary product of the porphyrin biosynthesis, which, applied locally, increases the concentration of protoporphyrin IX (PpIX) in the tumor cells. The 5-ALA accumulation in the target cells is higher comparatively to the healthy tissue because these cells have an intense metabolic activity; they rapidly release the precursor, and because of a weak specificity of the ferrochelatase determine increased concentrations of the Pp IX [12]. Levulan only acts to a depth of 1.5 mm that is why it is used in the treatment of superficial cutaneous carcinoma, especially in the basocellular carcinoma and in the oral cavity dysplasias [13]. It does have advantages when compared to Sodium Porfimer because it persists less in the organism and the photosensitivity is reduced (1–2 days) [2]. Because of its hydrophylicity it enters the cells with difficulty. A few ALA alkyl esters with increased penetration in tissues were tried. The methyl ester ALA (Metvix) was approved by the European Union (EU) in 2001 for the treatment of the actinic keratoses and of the basal cells carcinoma [14]. Other porphyrins were also tested such as meso-tetrahydroxy tetraphenyl chlorin (m–THPC) or Foscan, which was approved by the EU in 2001 for the palliative treatment of head and neck cancers. It is more potent than Sodium Porfimer and ALA, it requires a small dosage for the control of the tumors (0.1mg/kg) and a fluence rate of 10–20J/cm2 and the photosensitivity persists for 2–4 weeks. It can penetrate deeper in the tissues because it has maximum absorption at 652mm. THIRD GENERATION

The new, 3rd generation PS are still in study, especially those activated by the long wavelength light which cause short photosensitivity and have broad tumor specificity. Although new classes of PS have entered in clinical trials few results have been published. These are: ethyletiopurpurin (SnET2), mono-L-aspartyl-chlorin e6 (Npe6), benzoporphyrin derivatives (BPD–Verteporfin), lutetium texaphyrin (Lu-Tex), phthalocyanines, anthracenes, rostaporfin (Photrex), purpurines, hypocrelines and hyperricin [5]. LIGHT SOURCES

The light sources used can be conventional, incoherent, cheap (halogen lamps, tungsten lamps, xenon lamps, fluorescent lamps), as well as unconventional, i.e. LASER. The conventional ones

have the advantage of being simple, cost effective, and can be applied both in vitro studies as well as in preclinical studies, in vivo. The disadvantages of this type of illumination are: significant thermal discomfort, low light intensity, and difficulties controlling the light dosage. Light emitting diodes (LED) represent a new light source for PDT. They can generate high luminous energy at the wished wavelength, and can be assembled in different shapes and sizes. The optimal illumination is obtained from LASERs because they are monochrome, have high intensity, and they can be easily coupled with fiber optics for endoscopic utilization or interstitial implants. The LASERs emit light with precise wavelengths but are expensive and require high-grade technical assistance [2]. PDT AS A CLINICAL APPLICATION FOR CANCER

For PDT, as for any new cancer therapy, it is important to identify the specific indications for the treatment and to evaluate its benefits and disadvantages relative to standard therapies. Before discussing in detail the possibilities of usage for the PDT in different types of carcinoma it is worth noting a few general aspects regarding this therapy. PDT is a treatment that usually requires only one administration of the photosensitizing substance followed by a single irradiation at a certain time interval, unlike radiotherapy and chemotherapy, which require more sessions for 6–7 weeks. The surgical treatment, although comprised of a single procedure, requires anesthesia and hospitalization for a period of time. The cost/effectiveness ratio suggests that PDT is an efficient treatment method, rather cheap and which increases the life expectancy when compared to other palliative treatments in head, neck and esophagus cancers [2]. Another argument for this type of therapy is that it is applied locally, the necrosis seldom passes 10mm and because the low penetrability of light, the healthy tissue around the tumor is not affected. The local side effects are minor; the functionality is kept with good tissue regeneration because the subepithelial collagen and elastin are kept intact. In the case of recurrence the treatment can be applied on exactly the same area that was previously irradiated which offers a real advantage compared to radiotherapy or surgery.


Adriana Gabriela Filip et al. GENERAL INDICATIONS TO PDT

In the case of early primary cancer and early relapses, PDT is indicated to patients with serious associated diseases and age-related disorders. It is performed according to a radical program when traditional therapeutic techniques (such as surgery and radiotherapy) are contraindicated. In the case of advanced tumors of tubular organs (such as the esophagus, cardiac portion of the stomach, trachea, rectum, as well as the main, intermediate, and lobe bronchi), PDT is performed to rechannel these organs. It is employed as a palliative therapeutic technique.


et al. have published extensively studies regarding their experience of using PDT in 103 patients, most of whom had high-grade dysplasia (HGD). The mean follow-up in this group was over 4 years. Of the 65 patients with HGD 78% had their HGD eliminated. On the basis of an intention-to-treat analysis, 54% had no residual BE [20]. The overall stricture rate for patients treated with PDT was 30%, but for those who required more than one PDT treatment it was 50%. Subsquamous, nondysplastic specialized intestinal metaplasia occurred in 4.9% of patients, but more importantly 3 patients (4.6%) developed subsquamous adenocarcinoma. CHOLANGIOCARCINOMA


Due to very low survival rates at 5 years (12.5%) and also because the standard treatment, esophagectomy has a very high mortality, new treatments were employed, that are less invasive: endoscopic mucosal resection, coagulation and PDT [15]. For PDT, illumination is given using flexible cylindrical diffusers that are placed via an endoscope, near the tumor. The first studies with PDT in the esophagus were done as palliative treatment for obstructive tumors [16]. In 1995 Lightdale et al. published the result of a prospective randomized multicenter trial that compared Photofrin-PDT with Nd:YAG thermal ablation for the palliation of partially obstructing esophageal tumors. In this trial PDT proved its efficiency leading to the relief of dysphasia for a longer period of time compared to thermal ablation. Moreover, there were less treatment sessions needed and 9 out of 236 had a complete response (CR) after PDT, there was only one patient with esophageal perforation compared to 7% registered using thermal ablation [17]. PDT is efficient as a curative treatment for small, superficial tumors. A CR of 87% after 6 months and of 25% after 5 years was obtained in a group of 123 patients treated with sodium Porfimer [18]. PDT has also been proposed for the treatment of Barrett’s esophagus (BE) with high-grade dysplasias to destroy an area of thin tissues spread eventually over a wide area instead of a mass of tissues [19]. Only PDT using Photofrin® is approved by the FDA for the treatment of precancerous lesions in BE. Overholt

PDT can be used in the endoscopic palliative treatment of cholangiocarcinoma. Two smallrandomized studies have reported both palliative effects and an increase in median survival. For example, Ortner et al. conducted a trial of 39 patients with nonresecable cholangiocarcinoma who were randomized to receive either endoscopic stenting alone or in conjunction with PDT. The median survival of the 20 patients in the PDT group was 493 days compared to 98 days in the 19 patients who underwent stenting alone. The trial was terminated prematurely due to the favorable results [21]. Preliminary studies suggest that operative PDT might also improve survival for those patients undergoing surgical resection [22]. Currently the National Comprehensive Cancer practice guidelines for the treatment of hepatobiliary cancer do not list photodynamic therapy as one of the treatment options. STOMACH CANCER

Most of the reports of PDT for gastric cancer are included in large reports of PDT for various upper gastrointestinal cancers such as esophageal, cardia region and gastric [23]. The data currently available for gastric cancer are very similar to those for early esophageal cancer in that they involve small series of patients with short follow-up, a variety of tumor stages, different light dosimetry, and different means of evaluating tumor response [23][24]. If light delivery can be improved and if gastric tumors can be detected early enough, then PDT may play a role in their treatment.


Photodynamic therapy in malignant treatment COLORECTAL CANCER

Only a handful of papers describe PDT for colon and rectal cancer; this is surprising when one considers the incidence of this disease [25][26]. PDT has been performed on smaller lesions, namely adenomas. The first study included eight patients with nine sessile villous adenomas, all but one of which recurred after Nd:YAG thermal ablation. After a follow-up period of 9 to 56 months, a biopsy was performed, and it was found that seven of the nine adenomas had been completely eradicated [27]. Use of the Nd: YAG laser to ablate adenomas is an alternative in nonoperative candidates. Although it successfully removes the lesion in 84% to 93% of cases with low morbidity and mortality rates (1% to 5% and 0%, respectively), the progression to invasive cancer after treatment is 5.7% to 9.1% [23]. Another study involved the treatment of large recurrent intestinal polyps in six patients with familial adenomatous polyposis. Of the two patients with colonic polyps, one was found to show a CR to treatment and no complications were reported [27]. HEAD AND NECK CANCER

Early-stage carcinomas in the head and neck area are normally treated with surgery and/or radiotherapy, while, for advanced disease, chemoradiation is standard treatment. Cure rates are good, especially for early disease, but can be associated with high morbidity (functional damage, swallowing, speech difficulties, xerostomia, trismus, and even osteonecrosis). PDT is effective for small superficial tumors or palliative treatment of recurrent disease but has the advantage of sparing tissue beneath the tumor, giving excellent long-term functional and cosmetic results [28]. Foscan is so far the most potent licensed photosensitizer for PDT. A large-scale multi-center study using Foscan-PDT for early stage (T1 and early T2) oral cancers has been done. The CR at 2 years was 75% after one PDT treatment but if re-PDT, surgery or radiotherapy were used a CR could be achieved in 8/13 patients [29]. PDT with mTHPC of second and multiple primary cancers resulted in CR rates of 67% for all tumors and 85% for T1 tumors [2]. For superficial tumors of the larynx and oropharynx similar results were obtained with a single treatment [30]. Of


19 patients treated had a histological CR over a follow-up period of 13–71 months. Because the action of PDT is limited to small superficial tumors to treat deep-seated, bulky tumors, Lou et al. implemented interstitial PDT. The overall median survival of the patients was 14 months while 72% overall palliative benefit was achieved. The local control rate at 12 months was 41% [31]. BASAL CELL CARCINOMA (BCC)

Skin cancers are ideal for the study of the effects of PDT [2]. Dougherty was the first to treat three BCC of face with PDT in a 72 years old patient with PDT with a CR of over 85% [9]. Feyh et al. [30] in a study conducted on 57 patients using hematoporfirin 2 mg/kg and laser argon light at a fluence of 100 J/cm2 evaluated the results using skin biopsies after 2 months and saw a complete response in 51 patients. The patients that did not have a complete response after the first treatment were treated again with PDT and a CR was registered in all the patients. For the patients with only few localized lesions is used topical ALA or an ester of ALA called Metvix. ALA can be applied topical a few hours before irradiation with excellent results in the treatment of basal cell carcinoma. Soler et al. [32] studied the long-term effects of methyl 5-aminolaevulinate (MAL)-PDT in 59 patients with 350 BCC. Nodular tumors were curetted before PDT and MAL (160 mg/g) was applied to all tumors for 24 h or 3h prior to irradiation with a broadband halogen light source (50–200 J/cm2). Patients were followed for 2–4 years (mean 35 months). Overall cure rate was 79%, cosmetic outcome was excellent or good in 98% of the completely responding lesions. Svanberg et al. [33] showed an improved response after PDT in nodular BCC (from 64% up to 100%) if prior to the treatment drugs that enhance the penetration into the tissue are applied (dimethyl sulfoxide 20% and EDTA 4% added to ALA 20%). In a recent European multicenter, open, randomized trial, MAL-PDT for nodular BCC was compared with surgery. A total of 101 patients were included and received either PDT twice, 7 days apart (75 J/cm2 red light) or surgical excision. The primary end point of this trial was the clinically assessed lesion clearance at 3 months after treatment, besides cosmesis. The 3-month cure rate was similar with MAL-PDT or surgery (915 vs. 98%), the 24 month recurrence rate was


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10% with MAL-PDT and 25 with surgery. The cosmetic result was rated good/excellent in 85% of the patients receiving PDT vs. 33% with surgery [34]. A recent prospective phase III trial that compared the effects of ALA-PDT with cryotherapy in the treatment of superficial and nodular BCC did not find any difference between the two, only superior results for PDT regarding cosmetical results and quicker healing [35]. Complete resolution of 96% after 12 months for BCC is possible if the treatment is repeated after 7 days [36]. The guideline issued by the British Association of Dermatologists in 1999 regarding the treatment of BCC advises the use of PDT as the primary treatment for superficial BCC in spread forms or in those with multiple localizations. BOWEN’S DISEASE

Bowen’s disease is the affection with the best response to PDT. Topical PDT using 20% ALA has been extensively assessed in Bowen’s disease with more than 14 open and three randomized comparison studies [36]. In a recent study by Salim et al. ALA-PDT was compared to topical 5-fluorouracil (5-FU). In this bi-center, randomized, phase III trial, 40 patients with one to three lesions of previously untreated, histologically proven Bowen’s disease received either PDT (20% ALA in an o/w emulsion 4h prior to illumination) or 5-FU (once daily in week one and then twice daily during weeks 2–4). Twenty-nine of 33 lesions (88%) treated with pDT showed CR vs. 67% after 5-FU [37]. The data in the literature are controversial, though, as to the antitumor response to ALA-PDT. Some researchers give results of 90–100% while others only 50% [38]. BLADDER CANCER

The first license for Photofrin was granted in Canada in 1993 for use following transurethral resection for papillary tumors [14]. In clinical trials with HpD or Porfimer sodium PDT it was observed that PDT is more efficient in the treatment of superficial recurrent bladder carcinoma, with very high initial response rates (70–100% at 3 months) and long term response rates of 30–60%, compared to the responses after transurethral resection or treatment with bacillus Calmette-Guerin [39]. For whole–bladder PDT there was, however, a very high incidence of side effects: urinary frequency,


pain, and persistent reduction in bladder capacity. These complications were associated with excessive light doses and no uniform light delivery. Because of severe and long lasting side effects, Nseyo et al. suggested multiple treatments at lower drug dose [40]. Whole bladder PDT with green light and proper dosimetry remains an attractive treatment option for carcinoma in situ although this has not been fully evaluated. Recently, it was shown that ALA PDT, used solely or in association with mitomycin C, determines a complete response in 40%–52% of the cases at 18–24 months, without any significant side effects [41]. Kreigmair et al. used intravesical ALA in 10 patients with refractory superficial transitional cell carcinoma and obtained a complete remission in 4 patients after 10–12 weeks and a partial one in 2 patients. Fifty percent of patients had progressive disease that required cystectomy after a mean follow-up of 15 months. It has been shown that with repeated PDT treatments, it is possible to limit or inhibit progression of disease and cures a proportion of patients [42]. PROSTATE CANCER

Since the beginning of the 90’s there were attempts to use Foscan and ALA PDT to treat patients with prostate cancer that do not respond to radiotherapy. In studies using canine models it was shown that PDT leads to necrosis of the prostatic tissue and does not affect the collagen. This suggests that using a proper dosage of light and PS you can destroy the whole prostatic tissue and not affect the perineal anatomy [43]. There are first phase trials using mTHPC in the treatment of recurrent forms of cancer [2]. Also Motexafin lutetium and Tookad were used for the complete ablation of the gland. This therapy involves the implantation of multiple diffuser fibers into the prostate gland through a transperineal brachytherapy template. Because there is a difference in the optical properties of the different tissues in the prostate we ought to measure in real time the concentration of PS and light fluence. Protection of the pelvic nerve also becomes an inevitable challenge during total ablation because we need to minimize the adverse effects on sexual and urinary functions [22]. Using Pd-bacteriopheophorbide or Tookad, also known as WST09 (NegmaLerads/Steba Biotech), has some advantages: rapid clearance,



Photodynamic therapy in malignant treatment

profound penetration of the light leading to important destructions in the glandular tissue; it affects primarily the blood vessels that feed the tumor. This supports the approach being used in current Phase I/II clinical trials of Tookad-PDT for recurrent prostate cancer [22]. LUNG CANCER

Many publications have shown the therapeutic usefulness of PDT in different stages of endobronchial disease. Palliative treatment of obstructive cancer with HpD or Porfimer sodium PDT was safe and resulted in symptom relief in almost all patients [44]. The effects are similar to those obtained with Nd:YAG laser but they last longer [14]. The results of a multicentric trial which compares the two modalities reported, but not published, shows a more durable response with PDT and the superiority of PDT comparatively to Nd: YAG for relief of dyspnea, cough and haemoptysis. PDT has also been used as a curative treatment in early lung cancer. Overall, 5-year survival rates were in the range of 56%–70% with a disease specific 5-years survival rate of 90% for carcinoma in situ. The optimum response appeared to be in patients with small tumors less than 1 cm

in length (97% versus 42.9% for tumors larger than 1 cm) [46]. Another indication for endobronchial PDT is field cancerization or recurrence of tumors after resection or irradiation. Malignant pleural mesothelioma, often related to asbestos exposure, responds poorly to conventional therapies and it is very aggressive. Photofrin-PDT has been tested as an adjuvant intraoperative modality in several countries and proved to be safe and efficient in stages II mesothelioma and I. To improve its efficiency it should be tried in combination with hyperbaric oxygenation [22].


In conclusion, future research will undoubtedly be directed toward the development of improved photosensitizers increased tumor normal selectivity and fewer side effects. The research is also focusing on more efficient light delivery and increased understanding of the optical properties of tissues in addition to the effects of drug and light fractionation. Only when all these issues have been addressed will PDT fully realize its potential role as a major form of cancer treatment.

Terapia fotodinamică (PDT) este o tehnică nouă utilizată în tratamentul neoplaziilor solide şi se bazează pe formarea de singlet oxigen indusă de fotosensibilizatori după iradierea cu lumină vizibilă. În articol se discută mecanismul interacţiunii fotosensibilizant – lumina precum şi efectele produse în tesutul ţintă. PDT a fost aprobată în multe ţări în tratamentul cancerelor din sfera ORL, a celor de esofag, plămân, vezică urinară, piele. Efectele antitumorale ale PDT se datorează atât actiunii citotoxice directe asupra celulelor tumorale cât şi leziunilor vasculare care apar şi activării imunităţii gazdei. Se discută în articol indicaţiile clinice ale PDT şi se trec în revistă principalele clase de fotosensibilizanţi. În ciuda rezultatelor promiţătoare obţinute în primele trialuri clinice sunt necesare în continuare studii pentru a transforma această modalitate de tratament într-o tehnică modernă. Corresponding author: Adriana Filip, MD Physiology Depart., “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca E-mail:[email protected]


SIBATA C.H., COLUSSI V.C., OLEINIK N.T., Photodynamic therapy: a new concept in medical treatment, Braz. J. Med. Biol. Res., 2000, 33(8): 869–880. TRIESSCHEIJN M., BAAS P., SCHELLENS J.H.M., Photodynamic therapy in oncology, The Oncologist, 2006, 11, 9: 1034–1044.

292 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.


Adriana Gabriela Filip et al.


VON TAPPEINER H., JESIONEK H., Therapeutische versuche mit fluoreszierenden stiffens. Munch Med. Wochenschr., 1903, 47: 2042–2044. KOMERIC N., A novel approach to cancer treatment: Photodynamic therapy, Turkish Journal of Cancer, 2002, 32, 3: 83–91. NOWIS D., MAKOWSKI M., STOKLOSA T., Direct tumor damage mechanisms of photodynamic therapy, Acta Biochimica Polonica, 2005, 52, 2: 339–352. BERLETT B.S., STADTMAN E.H., Protein oxidation in ageing, disease and oxidative stress. J. Biol. Chem., 1997, 33: 20313– 20316. SAKHAROV D.W., BUNSCHOTEN A., VAN WEELDEN H. et al., Photodynamic treatment and H2O2-induced oxidative stress result in different patterns of cellular protein oxidation. Eur. J. Biochem., 2003, 270: 4859–4865. MAGI B., ETTORE A., LIBERATORI S. et al., Selectivity of protein carbonylation in the apoptic response to oxidative stress associated with photodynamic therapy: a cell biochemical and proteomic investigation. Cell Death Differ., 2004, 11: 842–852. DOUGHERTY T., GOMER C., HENDERSON B., Photodynamic therapy. J. Natl. Cancer Inst., 1998, 90: 889–905. FINGAR V.H., WIEMANT J., DOAK K.W., Role of thromboxane and prostacyclin release on photodynamic therapy-induced tumor destruction. Cancer Res., 1990, 50: 2599–2603. GLISSEN M.J., VAN DE MERBEL-DE-VIT L.E., STAR W.M. et al., Effect of photodynamc therapy on the endothelium dependent relaxation of isolated rat aortas. Cancer Res., 1993, 53: 2548–2552. EL-SHARABASY M.M., EL-WASEEF A.M., HAFEZ M.M. et al., Porphyrin metabolism in some malignant diseases. Br. J. Cancer, 1992, 65: 409–412. TAUB A.F., Photodynamic therapy in dermatology: history and horizons. J. Drugs Dermatol., 2004; 3(1 suppl): S8–S25. ACKROYD R., KELTY C., BROWN N., REED M., The history of photodetection and photodynamic therapy. Photochemistry and photobiology, 2001, 74(5): 656–669. SIHVO E.L., LUOSTARINEN M.E., SALO J.A., Fate of patients with adenocarcinoma of the esophagus and the esophagogastric junction: a population-based analysis. Am. J. Gastroenterol., 2004; 99: 419–424. McCAUGHAN J.S. Jr., HICKS W., LAUFMAN L. et al., Palliation of esophageal malignancy with photoradiation therapy. Cancer, 1984; 54: 2905–2910 LIGHTDALE C.J., HEIER S.K., MARCON N.E., McCAUGHAN J.S. et al., Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd: YAG laser for palliation of esophageal cancer: a multicenter randomized trial. Gastrointest. Endosc., 1995, 42: 507–512. GROSJEAN P., SAVARY J.F., MIZERET J. et al., Photodynamic therapy for cancer of the upper aerodigestive tract using tetra(m-hydroxyphenyl)chlorin. J. Clin. Laser Med. Surg., 1996; 14: 281–287. PATRICE T., FOULTIER M.T., YACTAYO S. et al., Endoscopic photodynamic therapy with hematoporphyrin derivative for primary tretament of gastrointestinal neoplasms in inoperable patients. Digest. Dis. Sci., 1990, 35(5): 545–552. OVERHOLT B.F. et al., Photodynamic therapy for Barrett’s esophagus: follow-up in 100 patients. Gastrointest. Endosc., 1999, 49: 1–7. ORTNER M.E., CACA K., BERR F. et al., Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology, 2003; 125(5): 1355–63. HUANG Z., A review of progress in clinical photodynamic therapy. Tech. Cancer Res. Treat., 2005; 4: 283–294. WEBBER J., HERMAN M., KESSEL D., FROMM D., Current concepts in gastrointestinal photodynamic therapy. Annals of surgery, 1999, 230(1): 12–23. GOSSNER L., STROKA R., HAHN E.G., ELI C., Photodynamic therapy successful destruction of gastrointestinal cancer after oral administration of aminolevulinic acid. Gastrointest. Endosc., 1995, 41(1): 55–58. BARR H., KRASNER N., BOULOS P.B, CHATLANI P., BOWN S.G., Photodynamic therapy for colorectal cancer: a quantitative pilot study. Br. J. Surg., 1990, 77: 93–96. BRUNETAUD J.M., MAUNOURY V., COCHELARD D., Lasers in rectosigmoid tumors. Semin. Surg. Oncol., 1995; 11: 319–327. MIKVY P., MESSMANN H., DEBINSKI H. et al., Photodynamic therapy for polyps in familial adenomatous polyposis – a pilot study. Eur. J. Cancer, 1995, 31A: 1160–1165. COOPER M.P., TAN I.B., OPPELAAR H. et al., Meta-tetra(hydroxyphenyl)chlorin photodynamic therapy in early-stage squamous cell carcinoma of the head and neck. Arch. Otolaryngol. Head Neck Surg., 2003; 129:709–711. HOPPER C., Photodynamic Therapy with Foscan (Temoporfin) in Primary Squamous Cell Carcinoma of the Head and Neck. Proceedings Fifth International Congress on Head and Neck Oncology; San Francisco, USA (2000). FEYH J., Photodynamic therapy for cancers of the head and neck, J. Photochem. Photobiol. B. Biol., 1996, 36: 175–177. LOU P.J., JAGER, H.R., JONES, L. et al., Interstitial photodynamic therapy as a salvage treatment for recurrent head-and neck cancers. 2003. Br. J. Cancer, 2004; 91:441–446. SOLER A.M., WARLOE T., BERNER A., A follow-up study of recurrence and cosmesis in completely responding superficial and nodular basal cell carcinomas treated with methyl 5-aminolaevulinate-based photodynamic therapy alone and with prior curettage, Br. J. Dermatol., 2001, 145: 467–71. SVANBERG K., ANDERSSON T., KILLANDER D., Photodynamic therapy of non-melanoma malignanat tumours if the skin using topical delta-aminolevulinic acid sensitization and laser irradiation, Br. J. Dermatol., 1994, 130(6): 743–51.


Photodynamic therapy in malignant treatment


34. RHODES L.E., RIE M., ENSTROM Y. et al., Photodynamic therapy using topical methyl aminolaevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomised prospective trial. Arch. Dermatol., 2004, 140: 17–23. 35. WANG I., BENDSOE N., KLINTEBERG C.A.F., Photodynamic therapy vs. cryosurgery of carcinomas: results of a phase III clinical trial. Br. J. Dermatol., 2001, 144: 832–40. 36. MORTON C.A, BROWN S.B, COLLINS S., Guidelines for topical photodynamic therapy: report of a workshop of the EU Photodermatology Group, 2001. 37. SALIM A., LEMAN N.J., MCCOLL J.H., Randomized comparison pf photodynamic therapy with topical 5-fluouracil in Bowen's disease. Br. J. Dermatol., 2003, 148: 539–43. 38. FIJAN S., HONIGSMAN H., ORTEL B., Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine, Br. J. Dermatol., 1995, 133(2): 282–8. 39. KELLY J.F., SNELL M.E., BERENBAUM M.C., Photodynamic destruction of human bladder carcinoma. Br. J. Cancer, 1975; 31: 237–244. 40. NSEYO U.O., SHUMAKER B.E., KLEIN E.A., K. SUTHERLAND K., Photodynamic therapy using porfimer sodium as an alternative to cystectomy in patients with refractory transitional cell carcinoma in situ of the bladder. J. Urol., 1998, 160: 39–44. 41. SKYRME R.J., FRENCH A.J., DATTA S.N. et al., A phase-1 study of sequential mitomycin C and 5-aminolaevulinic acidmediated photodynamic therapy in recurrent superficial bladder carcinoma. B.J.U. Int., 2005; 95:1206–1210. 42. KRIEGMAIR M.R., BAUMGARTNER, W.L., WAIDELICH R., HOFSTETTER A., Early clinical experience with 5-aminolevulinic acid for the photodynamic therapy of superficial bladder cancer. Br. J. Urol., 1996, 77: 667–671. 43. TRASSIERRA V., VERA D., JIMENEZ C., Terapia fotodinamica en el cancer de prostata localizado. Actas Urol. Esp., 2007; 31(6): 633–41. 44. MOGHISSI K., DIXON K., STRINGER M. et al., The place of bronchoscopic photodynamic therapy in advanced unresectable lung cancer: experience of 100 cases. Eur. J. Cardiothorac. Surg., 1999; 15:1–6. 45. KATO H., Photodynamic therapy for lung cancer – a review of 19 years’experience. J. Photochem. Photobiol. B, 1998; 42: 96–99. Received September 1, 2008


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